U.S. patent application number 14/023590 was filed with the patent office on 2014-03-20 for methods for treating psoriasis.
The applicant listed for this patent is Walid M. Awni, Yanjun Bao, William T. Barchuk, Elliot K. Chartash, William G. Glass, Kenneth B. Gordon, Yihua Gu, Thomas C. Harris, Martin Kaul, Parvez M. Mulani, Peter A. Noertersheuser, Martin M. Okun, Susan K. Paulson, Joaquin Mario Valdes. Invention is credited to Walid M. Awni, Yanjun Bao, William T. Barchuk, Elliot K. Chartash, William G. Glass, Kenneth B. Gordon, Yihua Gu, Thomas C. Harris, Martin Kaul, Parvez M. Mulani, Peter A. Noertersheuser, Martin M. Okun, Susan K. Paulson, Joaquin Mario Valdes.
Application Number | 20140079714 14/023590 |
Document ID | / |
Family ID | 43732849 |
Filed Date | 2014-03-20 |
United States Patent
Application |
20140079714 |
Kind Code |
A1 |
Valdes; Joaquin Mario ; et
al. |
March 20, 2014 |
METHODS FOR TREATING PSORIASIS
Abstract
The invention provides methods of treating psoriasis in a
subject by administering to a subject an antibody capable of
binding to the p40 subunit of IL-12 and/or IL-23.
Inventors: |
Valdes; Joaquin Mario;
(Mundelein, IL) ; Chartash; Elliot K.; (Marietta,
GA) ; Barchuk; William T.; (San Diego, CA) ;
Paulson; Susan K.; (Downers Grove, IL) ; Gordon;
Kenneth B.; (Northbrook, IL) ; Awni; Walid M.;
(Green Oaks, IL) ; Bao; Yanjun; (Buffalo Grove,
IL) ; Glass; William G.; (Libertyville, IL) ;
Gu; Yihua; (Vernon Hills, IL) ; Harris; Thomas
C.; (Gurnee, IL) ; Kaul; Martin; (Neustadt,
DE) ; Mulani; Parvez M.; (Gurnee, IL) ;
Noertersheuser; Peter A.; (Grosskarlbach, DE) ; Okun;
Martin M.; (Libertyville, IL) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Valdes; Joaquin Mario
Chartash; Elliot K.
Barchuk; William T.
Paulson; Susan K.
Gordon; Kenneth B.
Awni; Walid M.
Bao; Yanjun
Glass; William G.
Gu; Yihua
Harris; Thomas C.
Kaul; Martin
Mulani; Parvez M.
Noertersheuser; Peter A.
Okun; Martin M. |
Mundelein
Marietta
San Diego
Downers Grove
Northbrook
Green Oaks
Buffalo Grove
Libertyville
Vernon Hills
Gurnee
Neustadt
Gurnee
Grosskarlbach
Libertyville |
IL
GA
CA
IL
IL
IL
IL
IL
IL
IL
IL
IL |
US
US
US
US
US
US
US
US
US
US
DE
US
DE
US |
|
|
Family ID: |
43732849 |
Appl. No.: |
14/023590 |
Filed: |
September 11, 2013 |
Related U.S. Patent Documents
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Application
Number |
Filing Date |
Patent Number |
|
|
12881902 |
Sep 14, 2010 |
8557239 |
|
|
14023590 |
|
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61242288 |
Sep 14, 2009 |
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61245967 |
Sep 25, 2009 |
|
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61297623 |
Jan 22, 2010 |
|
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61360299 |
Jun 30, 2010 |
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Current U.S.
Class: |
424/142.1 ;
424/158.1 |
Current CPC
Class: |
A61K 2039/545 20130101;
A61P 17/00 20180101; C07K 16/244 20130101; A61K 2039/505 20130101;
A61P 17/06 20180101; C07K 2317/76 20130101; C07K 2317/21
20130101 |
Class at
Publication: |
424/142.1 ;
424/158.1 |
International
Class: |
C07K 16/24 20060101
C07K016/24 |
Claims
1. A method of treating psoriasis in a subject comprising
administering to the subject a first dose amount of an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, according to a first
periodicity, and administering a second dose amount of the
antibody, or antigen-binding portion thereof, to the subject
according to a second periodicity, thereby treating psoriasis in
the subject.
2. (canceled)
3. The method of claim 1, wherein the first dose amount of the
antibody, or antigen-binding portion thereof, is at least about 100
mg to about 200 mg; wherein the first dose amount of the antibody,
or antigen-binding portion thereof, is at least about 100 mg;
wherein the first dose amount of the antibody, or antigen-binding
portion thereof, is at least about 200 mg; wherein the second dose
amount of the antibody, or antigen-binding portion thereof, is at
least about 200 mg; wherein the second dose amount of the antibody,
or antigen-binding portion thereof, is at least about 100 mg;
wherein the second dose amount of the antibody, or antigen-binding
portion thereof, is the same as the first dose amount of the
antibody, or antigen-binding portion thereof; wherein the second
dose amount of the antibody, or antigen-binding portion thereof, is
different than the first dose amount of the antibody, or
antigen-binding portion thereof; wherein the second dose amount of
the antibody, or antigen-binding portion thereof, is about 40-60%
of the first dose amount of the antibody, or antigen-binding
portion thereof; or wherein the second dose amount of the antibody,
or antigen-binding portion thereof, is about 190-210% of the first
dose amount of the antibody, or antigen-binding portion
thereof.
4.-14. (canceled)
15. The method of claim 12, wherein the first periodicity of
administration of the antibody, or antigen-binding portion thereof,
is about once a week; wherein the first periodicity of
administration of the antibody, or antigen-binding portion thereof,
is about once every other week; wherein the first periodicity of
administration of the antibody, or antigen-binding portion thereof,
is about once every four weeks; wherein the second periodicity of
administration of the antibody, or antigen-binding portion thereof,
is about once a week; wherein the second periodicity of
administration of the antibody, or antigen-binding portion thereof,
is about once every other week; wherein the second periodicity of
administration of the antibody, or antigen-binding portion thereof,
is about once every four weeks; or wherein the second periodicity
of administration of the antibody, or antigen-binding portion
thereof, is about once every 30-200 days.
16.-21. (canceled)
22. The method of claim 1, wherein the duration of the first
periodicity is about 12 weeks; wherein the duration of the first
periodicity is about 8 weeks; wherein the duration of the first
periodicity is about 4 weeks; wherein the duration of the first
periodicity is about 2 weeks; wherein the duration of the first
periodicity is about 1 week; wherein the duration of the second
periodicity is about 60 weeks; wherein the duration of the second
periodicity is about 44 weeks; wherein the duration of the second
periodicity is about 12 weeks; wherein the duration of the second
periodicity is about 4 weeks; wherein the duration of the second
periodicity is about 2 weeks; wherein the duration of the second
periodicity is about 1 week; wherein the duration of the second
periodicity is at least about 12 weeks; wherein the duration of the
second periodicity is at least about 44 weeks; or wherein the
duration of the second periodicity is at least about 60 weeks.
23.-35. (canceled)
36. The method of claim 1, wherein the second dose amount is
administered to the subject upon a flare of psoriasis; or wherein
the second dose amount is administered to the subject prior to a
flare of psoriasis; optionally, wherein the flare of psoriasis is
indicated by a loss of Psoriasis Area and Severity Index (PASI) 90
response; wherein the flare of psoriasis is loss of a Psoriasis
Area and Severity Index (PASI) 75 response; wherein the flare of
psoriasis is loss of a Psoriasis Area and Severity Index (PASI) 50
response; or wherein the flare of psoriasis is loss of a clear or
minimal Physician's Global Assessment (PGA) rating.
37.-40. (canceled)
41. The method of claim 36, wherein the loss of PASI response is
loss of PASI response of a single body region; wherein the loss of
PASI response is loss of PASI response of two body regions; wherein
the loss of PASI response is loss of PASI response of three body
regions; or wherein the loss of PASI response is loss of PASI
response of four body regions, wherein the body region is selected
from the group consisting of trunk, lower extremities, upper
extremities, and head and neck.
42.-46. (canceled)
47. The method of claim 1, wherein the psoriasis is chronic
psoriasis; wherein the psoriasis is chronic psoriasis affecting
about >20 body surface area of the subject; or wherein the
psoriasis is plaque psoriasis; optionally wherein the plaque
psoriasis is moderate to severe plaque psoriasis.
48.-50. (canceled)
51. The method of claim 1, wherein the antibody is administered
subcutaneously.
52.-54. (canceled)
55. The method of claim 1, wherein the subject achieves at least a
PGA score of 0 or 1; optionally wherein the subject maintains the
PGA score of 0 or 1 for at least 4 weeks; wherein the subject
achieves at least a PASI 75 response; optionally wherein the
subject maintains the PASI 75 response for at least 4 weeks;
wherein the subject achieves at least a PASI 90 response;
optionally wherein the subject maintains the PASI 90 response for
at least 4 weeks; or wherein the subject achieves at least a PASI
100 response.
56.-84. (canceled)
85. A method of treating psoriasis in a population of subjects,
comprising administering to each subject in the population an
antibody, or antigen-binding portion thereof, which is capable of
binding to the p40 subunit of IL-12 and/or IL-23, wherein at least
60% of the population of subjects achieve a PASI 75 response by
about week 12; wherein at least 25% of the population of subjects
achieve a PASI 90 response by about week 12; or wherein at least
10% of the population of subjects achieve a PASI 100 response by
about week 12.
86.-89. (canceled)
90. The method of claim 85, wherein the psoriasis is moderate to
severe or chronic psoriasis; wherein the psoriasis is plaque
psoriasis; wherein the antibody is administered subcutaneously;
wherein the antibody is a human antibody; or wherein the antibody
is ABT-874.
91.-94. (canceled)
95. The method of claim 1, wherein the subject or population of
subjects achieves at least a PASI 75 response by about week 24;
wherein the subject or population of subjects achieves at least a
PASI 75 response by about week 52; wherein the subject or
population of subjects achieves at least a PGA score of 0 or 1 by
about week 24; or wherein the subject or population of subjects
achieves at least a PGA score of 0 or 1 by about week 52.
96-98. (canceled)
99. A method of treating psoriasis in a population of subjects,
comprising administering to each subject in the population an
antibody, or antigen-binding portion thereof, which is capable of
binding to the p40 subunit of IL-12 and/or IL-23, wherein at least
41% of the population of subjects achieve at least a PASI 75
response by about week 24; wherein at least 35% of the population
of subjects achieve at least a PGA score of 0 or 1 by about week
24; wherein at least 25% of the population of subjects achieve at
least a PASI 75 response by about week 52; or wherein at least 21%
of the population of subjects achieve at least a PGA score of 0 or
1 by about week 52.
100.-102. (canceled)
103. The method of claim 1, wherein the subject or population of
subjects achieves an improvement in a Dermatology Life Quality
Index (DLQI) score or mean Dermatology Life Quality Index (DLQI)
score of at least about -9; wherein the subject or population of
subjects achieves an improvement in a Short Form 36 Health Survey
Physical Component Summary (PCS) score or mean Short Form 36 Health
Survey Physical Component Summary (PCS) score of at least about 2;
wherein the subject or population of subjects achieves an
improvement in a Short Form 36 Health Survey Mental Component
Summary (MCS) score or mean Short Form 36 Health Survey Mental
Component Summary (MCS) score of at least about 4; wherein the
subject or population of subjects achieves an improvement in a
visual analog scale score or mean visual analog scale score for
psoriasis-related pain (VAS-Ps) of at least about -25; or wherein
the subject or population of subjects achieves an improvement in a
visual analog scale score for psoriatic arthritis-related pain
(VAS-PsA) or mean visual analog scale score for psoriatic
arthritis-related pain (VAS-PsA) of at least about -32.
104.-107. (canceled)
108. A method of treating psoriasis in a population of subjects
comprising administering to each subject in the population an
antibody, or antigen-binding portion thereof, which is capable of
binding to the p40 subunit of IL-12 and/or IL-23, wherein the
population of subjects achieves a minimum clinically important
difference (MCID) response rate for psoriasis-related pain (VAS-Ps)
of at least about 60%; wherein the population of subjects achieves
a minimum clinically important difference (MCID) response rate for
Dermatology Life Quality Index (DLQI) of at least about 70% by
about week 12; wherein the population of subjects achieves a
minimum clinically important difference (MCID) response rate for
Dermatology Life Quality Index (DLQI) of at least about 81% by
about week 52; wherein the population of subjects achieves a
minimum clinically important difference (MCID) response rate for
Total Activity Impairment (TAI) of at least about 45% by about week
12; or wherein the population of subjects achieves a minimum
clinically important difference (MCID) response rate for Total
Activity Impairment (TAI) of at least about 57% by about week
52.
109.-112. (canceled)
113. A method of treating psoriasis in a population of subjects,
comprising administering to each subject in the population an
antibody, or antigen-binding portion thereof, which is capable of
binding to the p40 subunit of IL-12 and/or IL-23, wherein at least
65% of the population of subjects achieve at least a PGA 0/1
response by about week 12, wherein each subject was treated with a
biologic prior to administration of the antibody; wherein at least
74% of the population of subjects achieve at least a PASI 75
response by about week 12, wherein each subject was treated with a
biologic prior to administration of the antibody; wherein at least
78% of the population of subjects achieve at least a PGA 0/1
response by about week 12, wherein none of the subjects were
treated with a biologic prior to administration of the antibody;
wherein at least 82% of the population of subjects achieve at least
a PASI 75 response by about week 12, wherein none of the subjects
were treated with a biologic prior to administration of the
antibody; wherein at least 78% of the population of subjects
achieve at least a PGA 0/1 response by about week 52, wherein each
subject was treated with a biologic prior to administration of the
antibody; wherein at least 79% of the population of subjects
achieve at least a PGA 0/1 response by about week 52, wherein none
of the subjects were treated with a biologic prior to
administration of the antibody; wherein at least 71% of the
population of subjects achieve at least a PGA 0/1 response by about
week 12, wherein each subject has a prior history of psoriatic
arthritis; wherein at least 78% of the population of subjects
achieve at least a PASI 75 response by about week 12, wherein each
subject has a prior history of psoriatic arthritis; wherein at
least 77% of the population of subjects achieve at least a PGA 0/1
response by about week 12, wherein none of the subjects has a prior
history of psoriatic arthritis; wherein at least 81% of the
population of subjects achieve at least a PASI 75 response by about
week 12, wherein none of the subjects has a prior history of
psoriatic arthritis; wherein at least 77% of the population of
subjects achieve at least a PGA 0/1 response by about week 52,
wherein each subject has a prior history of psoriatic arthritis; or
wherein at least 79% of the population of subjects achieve at least
a PGA 0/1 response by about week 52, wherein none of the subjects
has a prior history of psoriatic arthritis.
114.-124. (canceled)
125. A method for decreasing the risk that a subject treated with
an antibody, or antigen binding portion thereof, which is capable
of binding to the p40 subunit of IL-12 and/or IL-23, will develop a
Major Adverse Cardiovascular Event (MACE), comprising: (a)
selecting a subject having less than 2 risk factors selected from
the group consisting of (i) a body mass index (BMI) of greater than
30, (ii) a history of diabetes mellitus, (iii) blood pressure
greater than 140/90, (iv) a history of myocardial infarction, (v) a
history of angina requiring hospitalization, (vi) a history of
coronary artery disease requiring revascularization, (vii) a
history of peripheral artery disease, (viii) a history of
congestive heart failure requiring hospitalization, (ix) a history
of stroke or transient ischemic attack; and (b) administering the
antibody, or antigen binding portion thereof to the selected
subject, thereby decreasing the risk that the subject will develop
a Major Adverse Cardiovascular Events.
126. The method of claim 125, wherein the antibody is ABT-874;
wherein the subject has 1 risk factor; wherein the subject has 0
risk factors; wherein the MACE is myocardial infarction; or wherein
the MACE is cerebrovascular stroke.
127.-135. (canceled)
136. A method of treating psoriasis in a population of subjects,
comprising administering to each subject in the population an
antibody, or antigen-binding portion thereof, which is capable of
binding to the p40 subunit of IL-12 and/or IL-23, wherein at least
69% of the population of subjects achieve at least a PGA 0/1
response by about week 12, wherein each subject had a baseline PASI
greater than 20 prior to administration of the antibody; wherein at
least 79% of the population of subjects achieve at least a PGA 0/1
response by about week 12, wherein each subject had a baseline PASI
less than or equal to 20 prior to administration of the antibody;
wherein at least 79% of the population of subjects achieve at least
a PASI 75 response by about week 12, wherein each subject had a
baseline PASI greater than 20 prior to administration of the
antibody; wherein at least 81% of the population of subjects
achieve at least a PASI 75 response by about week 12, wherein each
subject had a baseline PASI less than or equal to 20 prior to
administration of the antibody; wherein at least 67% of the
population of subjects achieve at least a PGA 0/1 response by about
week 12, wherein each subject had a baseline weight of greater than
or equal to 100 kilograms prior to administration of the antibody;
wherein at least 80% of the population of subjects achieve at least
a PGA 0/1 response by about week 12, wherein each subject had a
baseline weight of less than 100 kilograms prior to administration
of the antibody; wherein at least 72% of the population of subjects
achieve at least a PASI 75 response by about week 12, wherein each
subject had a baseline weight of greater than or equal to 100
kilograms prior to administration of the antibody; wherein at least
85% of the population of subjects achieve at least a PASI 75
response by about week 12, wherein each subject had a baseline
weight of less than 100 kilograms prior to administration of the
antibody; wherein at least 41% of the population of subjects
maintains at least a PGA 0/1 response through at least week 52 of
treatment; wherein at least 79% of the population of subjects
maintains at least a PGA 0/1 response through at least week 52 of
treatment; wherein at least 45% of the population of subjects
maintains at least a PASI 75 response through at least week 52 of
treatment; wherein at least 82% of the population of subjects
maintains at least a PASI 75 response through at least week 52 of
treatment; wherein at least 23% of the population of subjects
maintains at least a PASI 75 response through at least week 52 of
treatment; or wherein at least 63% of the population of subjects
maintains at least a PASI 75 response through at least week 52 of
treatment.
137.-156. (canceled)
157. A method of treating psoriasis in a population of subjects,
comprising administering to each subject in the population an
antibody, or antigen-binding portion thereof, which is capable of
binding to the p40 subunit of IL-12 and/or IL-23, wherein at least
10% of the population of subjects achieves a PGA score of 0 by week
24 of treatment; wherein at least 5% of the population of subjects
achieve at least a PASI 50 response by about week 2; wherein at
least 70% of the population of subjects achieve at least a PASI 50
response and maintain at least a PASI 50 response through at least
week 52 of treatment; wherein at least 5% of the population of
subjects achieve at least a PASI 75 response by about week 4;
wherein at least 40% of the population of subjects achieve at least
a PASI 75 response and maintain at least a PASI 75 response through
at least week 52 of treatment; wherein at least 10% of the
population of subjects achieve at least a PASI 90 response by about
week 8; wherein at least 25% of the population of subjects achieve
at least a PASI 90 response and maintain at least a PASI 90
response through at least week 52 of treatment; wherein at least 5%
of the population of subjects achieve at least a PASI 100 response
by about week 8; wherein at least 10% of the population of subjects
achieve at least a PASI 100 response and maintain at least a PASI
100 response through at least week 52 of treatment; wherein at
least 5% of the population of subjects achieve at least a PGA score
of 0 or 1 by about week 4; or wherein at least 35% of the
population of subjects achieve at least a PGA score of 0 or 1 and
maintain at least a PGA score of 0 or 1 through at least week 52 of
treatment.
158.-174. (canceled)
175. A method of treating psoriasis in a population of subjects
comprising administering to each subject in the population an
antibody, or antigen-binding portion thereof, which is capable of
binding to the p40 subunit of IL-12 and/or IL-23, wherein at least
35% of the population of subjects achieves a Dermatology Life
Quality Index (DLQI) score of 0 or 1 by about week 24; wherein at
least 18% of the population of subjects achieves a Dermatology Life
Quality Index (DLQI) score of 0 or 1 by about week 52; wherein at
least 50% of the population of subjects achieves a clinically
meaningful reduction in Dermatology Life Quality Index (DLQI) score
by about week 24; or wherein at least 20% of the population of
subjects achieves a clinically meaningful reduction in Dermatology
Life Quality Index (DLQI) score by about week 52.
176.-179. (canceled)
180. The method of claim 1, wherein the method comprises
administering to the subject or to each subject in the population:
a) a first dose amount of the antibody, or antigen-binding portion
thereof, according to a first periodicity of about once every 4
weeks; and b) administering a second dose amount that is about
40-60% of the first dose amount of the antibody, or antigen-binding
portion thereof, according to a second periodicity of about once
every 4 weeks; wherein the antibody, or antigen-binding portion
thereof, is ABT-874, or an antigen-binding portion thereof, and is
administered to the subject or to each subject in the population:
a) at about 200 mg once every four weeks for two doses; and b) at
about 100 mg every four weeks thereafter; or wherein the antibody,
or antigen-binding portion thereof, is ABT-874, or an
antigen-binding portion thereof, and is administered to the subject
or to each subject in the population: a) at about 200 mg at weeks 0
and 4; and b) at about 100 mg at week 8 and every 4 weeks
thereafter.
181.-182. (canceled)
183. A method of treating psoriasis in a subject comprising
administering to the subject: a) about 200 mg of an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, once every four weeks for two
doses; and b) about 100 mg of the antibody, or antigen-binding
portion thereof, every four weeks thereafter, thereby treating
psoriasis in the subject.
184. A method of treating psoriasis in a subject comprising
administering to the subject: a) about 200 mg of an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, at weeks 0 and 4; and b) about
100 mg of the antibody, or antigen-binding portion thereof, at week
8 and every 4 weeks thereafter, thereby treating psoriasis in the
subject.
185. (canceled)
186. A method of treating psoriasis in a subject comprising
administering to the subject: a) about 200 mg of ABT-874 once every
four weeks for two doses; and b) about 100 mg of ABT-874 every four
weeks thereafter, thereby treating psoriasis in the subject.
187. A method of treating psoriasis in a subject comprising
administering to the subject: a) about 200 mg of ABT-874 at weeks 0
and 4; and b) about 100 mg of ABT-874 at week 8 and every 4 weeks
thereafter, thereby treating psoriasis in the subject.
Description
RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 12/881,902, filed on Sep. 14, 2010, which, in turn, claims
priority to U.S. Application Ser. No. 61/242,288 entitled Methods
for Treating Psoriasis, filed on Sep. 14, 2009, U.S. Application
Ser. No. 61/245,967 entitled Methods for Treating Psoriasis, filed
on Sep. 25, 2009, U.S. Application Ser. No. 61/297,623, entitled
Methods for Treating Psoriasis, filed on Jan. 22, 2010, and U.S.
Application Ser. No. 61/360,299, entitled Methods for Treating
Psoriasis, filed on Jun. 30, 2010. The entire contents of each of
the foregoing applications are expressly incorporated herein by
reference.
BACKGROUND OF THE INVENTION
[0002] Psoriasis is a T cell-mediated inflammatory disease that is
considered to be one of the most common autoimmune diseases,
affecting approximately 2% to 3% of adults, though the global
prevalence varies widely (Stem R. S., et al., J Investig Dermatol
Symp Proc 2004, 9: 136-39; Davidson A and Diamond B. N Engl J Med
2001, 345: 340-50; Langley R. G. B., et al., Ann Rheum Dis 2005,
64(Suppl II): ii18-23). Psoriasis has a major impact on quality of
life (de Korte J, et al., J Investig Dermatol Symp Proc 2004, 9:
140-7; Krueger G, et al., Arch Dermatol 2001, 137: 280-4; Finlay A
Y and Coles E C, Br J Dermatol 1995, 132: 236-44) and is associated
with a number of psychological and psychosocial problems (Kimball A
B, et al., Am J Clin Dermatol 2005, 6: 383-92; Russo P A, et al.,
Australas J Dermatol 2004, 45: 155-9). Many traditional psoriasis
therapies have toxic adverse effects; therefore, their long-term
use is limited (Lebwohl M. and Ali S., J Am Acad Dermatol 2001, 45:
487-98; Lebwohl M. and Ali S., J Am Acad Dermatol 2001, 45:
649-61). In addition, many patients with psoriasis are dissatisfied
with traditional therapies (Stern R S, et al., J Investig Dermatol
Symp Proc 2004, 9: 136-39; Finlay A Y and Ortonne J P, J Cutan Med
Surg 2004, 8: 310-20); thus, there is a clear need for therapies
that are safer and easier to use and that can be prescribed on a
long-term basis.
[0003] Interleukin-12 (IL-12) and the related cytokine IL-23 are
members of the IL-12 superfamily of cytokines that share a common
p40 subunit (Anderson E J R, et al., Springer Semin Immunopathol
2006, 27: 425-42). Both cytokines contribute to the development of
the type 1T helper cell (Th1) immune response in psoriasis, but
each has a unique role (Rosmarin D and Strober B E, J Drugs
Dermatol 2005, 4: 318-25; Hong K, et al., J Immunol 1999, 162:
7480-91; Yawalkar N, et al., J Invest Dermatol 1998, 111: 1053-57).
IL-12 primarily stimulates differentiation of Th1 cells and
subsequent secretion of interferon-gamma, whereas IL-23
preferentially stimulates differentiation of naive T cells into
effector T helper cells (Th17) that secrete IL-17, a
proinflammatory mediator Rosmarin D and Strober B E, J Drugs
Dermatol 2005, 4: 318-25; Harrington Le, et al., Nature Immunol
2005, 6: 1123-32; Park H, et al. Nature Immunol 2005, 6: 1132-41).
The overexpression of IL-12 p40 and IL-23 p40 messenger RNA in
psoriatic skin lesions suggests that the inhibition of IL-12 and
IL-23 with a neutralizing antibody to the IL-12/23 p40 subunit
protein may offer an effective therapeutic approach for the
treatment of psoriasis (Yawalkar N, et al., J Invest Dermatol 1998,
111: 1053-57; Lee E, et al., J Exp Med 2004, 199: 125-30; Shaker O
G, et al., Clin Biochem 2006, 39: 119-25; Piskin G, et al., J
Immunol 2006, 176: 1908-15). Such therapeutic approaches for the
treatment of psoriasis are clearly needed in the art.
SUMMARY OF THE INVENTION
[0004] The present invention provides methods and compositions for
treating psoriasis, e.g., chronic psoriasis, using an antibody, or
antigen-binding portion thereof, that binds human IL-12 and/or
human IL-23.
[0005] In one aspect, the invention provides methods of treating
psoriasis in a subject comprising administering to the subject a
first dose amount of an antibody, or antigen-binding portion
thereof, which is capable of binding to the p40 subunit of IL-12
and/or IL-23, according to a periodicity, and administering a
second dose amount of the antibody, or antigen-binding portion
thereof, at the same periodicity, thereby treating psoriasis in the
subject.
[0006] In another aspect, the invention provides methods of
treating psoriasis in a subject comprising administering to the
subject a first dose amount of an antibody, or antigen-binding
portion thereof, which is capable of binding to the p40 subunit of
IL-12 and/or IL-23, according to a first periodicity, and
administering a second dose amount of the antibody, or
antigen-binding portion thereof, according to a second periodicity,
thereby treating psoriasis in the subject.
[0007] In various embodiments, the first dose amount of the
antibody, or antigen-binding portion thereof, is at least about 100
mg to about 200 mg, is at least about 100 mg, or is at least about
200 mg. In other embodiments, the first dose amount of the
antibody, or antigen-binding portion thereof, is about 100 mg, 110
mg, about 120 mg, about 130 mg, about 140 mg, about 150 mg, about
160 mg, about 170 mg, about 180 mg, about 190 mg, about 200 mg.
[0008] The second dose amount of the antibody, or antigen-binding
portion thereof, may be the same as the first dose amount of the
antibody, or antigen-binding portion thereof, or different than the
first dose amount of the antibody, or antigen-binding portion
thereof. In various embodiments, the second dose amount of the
antibody, or antigen-binding portion thereof, is at least about 100
mg to about 200 mg, is at least about 200 mg, or is at least about
100 mg. In other embodiment, the second dose amount of the
antibody, or antigen-binding portion thereof, is about 40-60% of
the first dose amount of the antibody, or antigen-binding portion
thereof, or about 190-210% of the first dose amount of the
antibody, or antigen-binding portion thereof. In other embodiments,
the first dose amount of the antibody, or antigen-binding portion
thereof, is about 100 mg, 110 mg, about 120 mg, about 130 mg, about
140 mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg,
about 190 mg, 200 mg.
[0009] The first and second periodicities of administration of the
antibody, or antigen-binding portion thereof, may be about once a
week, about once every other week, about once every four weeks. In
one embodiment, the second periodicity of administration of the
antibody, or antigen-binding portion thereof, is about once every
30-200 days.
[0010] The duration of the first periodicity may be about 12 weeks,
about 8 weeks, about 4 weeks, about 2 weeks, or about 1 week. The
duration of the first periodicity may be at least about 12 weeks,
at least about 8 weeks, at least about 4 weeks, at least about 2
weeks, or at least about 1 week.
[0011] The duration of the second periodicity may be about 60
weeks, about 44 weeks, about 12 weeks, about 4 weeks, about 2
weeks, or about 1 week. The duration of the second periodicity may
be at least about 60 weeks, at least about 44 weeks, at least about
12 weeks, at least about 4 weeks, at least about 2 weeks, or at
least about 1 week.
[0012] In one embodiment, the second dose amount is administered to
the subject upon a flare of psoriasis. In another embodiment, the
second dose amount is administered to the subject prior to a flare
of psoriasis.
[0013] The flare of psoriasis may be indicated by loss of a
Psoriasis Area and Severity Index (PASI) 90 response, by loss of a
Psoriasis Area and Severity Index (PASI) 75 response, by loss of a
Psoriasis Area and Severity Index (PASI) 50 response, or by loss of
a clear or minimal Physician's Global Assessment (PGA) rating.
[0014] The loss of a PASI response may be loss of PASI response of
a single body region, loss of PASI response of two body regions,
loss of PASI response of three body regions, or loss of PASI
response of four body regions.
[0015] The body region may be trunk, lower extremities, upper
extremities, or head and neck.
[0016] In another aspect, the invention provides a method of
treating psoriasis in a subject comprising administering to the
subject an antibody, or antigen-binding portion thereof, which is
capable of binding to the p40 subunit of IL-12 and/or IL-23,
according to a periodicity of about once every 4 weeks, thereby
treating psoriasis in the subject.
[0017] In yet another aspect, the invention provides a method of
treating psoriasis in a subject comprising administering to the
subject an antibody, or antigen-binding portion thereof, which is
capable of binding to the p40 subunit of IL-12 and/or IL-23,
according to a periodicity of about once every 12 weeks, thereby
treating psoriasis in the subject.
[0018] In a related aspect, the invention provides a method of
treating psoriasis in a subject comprising administering to the
subject: a) a first dose amount of an antibody, or antigen-binding
portion thereof, which is capable of binding to the p40 subunit of
IL-12 and/or IL-23; and b) a second dose amount that is about
40-60% of the first dose amount of the antibody, or antigen-binding
portion thereof, according to a periodicity of about once every 12
weeks, thereby treating psoriasis in the subject.
[0019] In one embodiment, the subject achieves at least a PGA score
of 0 or 1. In one embodiment, the subject achieves at least a PASI
75 response. In one embodiment, the subject achieves at least a
PASI 90 response. In one embodiment, the subject achieves at least
a PASI 100 response. In one embodiment, the subject maintains the
PGA score of 0 or 1 during treatment. In one embodiment, the
subject maintains the PASI 75 response during treatment. In one
embodiment, the subject maintains the PASI 90 response during
treatment.
[0020] In one embodiment, the first dose amount is at least about
200 mg.
[0021] In one embodiment, the second dose amount is at least about
100 mg.
[0022] In another aspect, the invention provides a method of
treating psoriasis in a subject comprising administering to the
subject: a) a first dose amount of an antibody, or antigen-binding
portion thereof, which is capable of binding to the p40 subunit of
IL-12 and/or IL-23, according to a first periodicity of about once
every 4 weeks; and b) administering a second dose amount that is
about 40-60% of the first dose amount of the antibody, or
antigen-binding portion thereof, according to a second periodicity
of about once every 4 weeks, thereby treating psoriasis in the
subject.
[0023] In one embodiment, the first dose amount is at least about
200 mg.
[0024] In one embodiment, the second dose amount is at least about
100 mg.
[0025] In one embodiment, the duration of the first periodicity is
at least about 8 weeks.
[0026] In one embodiment, the duration of the second periodicity is
at least about 4 weeks, at least about 16 weeks, or at least about
44 weeks.
[0027] In another aspect, the invention provides a method of
treating psoriasis in a subject comprising administering to the
subject: a) a first dose amount of an antibody, or antigen-binding
portion thereof, which is capable of binding to the p40 subunit of
IL-12 and/or IL-23, according to a first periodicity of about once
every 4 weeks; and b) a second dose amount that is about 40-60% of
the first dose amount of the antibody, or antigen-binding portion
thereof, according to a second periodicity of about once every 4
weeks; and c) the second dose amount of the antibody, or
antigen-binding portion thereof, according to a third periodicity
of about once every 12 weeks, thereby treating psoriasis in the
subject.
[0028] In one embodiment, the first dose amount is at least about
200 mg.
[0029] In one embodiment, the second dose amount is at least about
100 mg.
[0030] In one embodiment, the duration of the first periodicity is
at least about 8 weeks.
[0031] In one embodiment, the duration of the second periodicity is
at least about 4 weeks.
[0032] In one embodiment, the duration of the third periodicity is
at least about 12 weeks or at least about 36 weeks.
[0033] In one embodiment, the subject achieves a PGA score of 0 or
1, e.g., by about week 12. In one embodiment, the subject achieves
at least a PASI 75 response, e.g., by about week 12. In one
embodiment, the subject achieves at least a PASI 90 response, e.g.,
by about week 12. In one embodiment, the subject achieves at least
a PASI 100 response, e.g., by about week 12.
[0034] In one embodiment, the subject maintains the PGA score of 0
or 1 through the duration of treatment. In one embodiment, the
subject maintains the PASI 75 response through the duration of
treatment. In one embodiment, the subject maintains the PASI 90
response through the duration of treatment.
[0035] In another aspect, the invention provides a method of
treating psoriasis in a population of subjects, comprising
administering to each subject in the population an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, wherein at least 60% of the
population of subjects achieve a PASI 75 response by about week
12.
[0036] In yet another aspect, the invention provides a method of
treating psoriasis in a population of subjects comprising
administering to each subject in the population an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, wherein at least 25% of the
population of subjects achieve a PASI 90 response by about week
12.
[0037] In still another aspect, the invention provides a method of
treating psoriasis in a population of subjects comprising
administering to each subject in the population an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, wherein at least 10% of the
population of subjects achieve a PASI 100 response by about week
12.
[0038] In one embodiment, the method comprises administering to
each subject in the population: a) a first dose amount of the
antibody, or antigen-binding portion thereof, according to a first
periodicity of about once every 4 weeks; and b) administering a
second dose amount that is about 40-60% of the first dose amount of
the antibody, or antigen-binding portion thereof, according to a
second periodicity of about once every 4 weeks.
[0039] In one embodiment, the method comprises administering to
each subject in the population: a) a first dose amount of the
antibody, or antigen-binding portion thereof, according to a first
periodicity of about once every 4 weeks; and b) a second dose
amount that is about 40-60% of the first dose amount of the
antibody, or antigen-binding portion thereof, according to a second
periodicity of about once every 4 weeks; and c) the second dose
amount of the antibody, or antigen-binding portion thereof,
according to a third periodicity of about once every 12 weeks.
[0040] In one embodiment, the antibody is administered
subcutaneously.
[0041] In one embodiment, the antibody is a human antibody. In a
preferred embodiment, the antibody is ABT-874.
[0042] In one embodiment, the subject or population of subjects
achieves at least a PASI 75 response by about week 24 or at least a
PASI 75 response by about week 52. In another embodiment, the
subject or population of subjects achieves at least a PGA score of
0 or 1 by about week 24 or at least a PGA score of 0 or 1 by about
week 52.
[0043] In another aspect, the invention is directed to a method of
treating psoriasis in a population of subjects, by administering to
each subject in the population an antibody, or antigen-binding
portion thereof, which is capable of binding to the p40 subunit of
IL-12 and/or IL-23, wherein at least 41% of the population of
subjects achieve at least a PASI 75 response by about week 24.
[0044] In yet another aspect, the invention is directed to a method
of treating psoriasis in a population of subjects, by administering
to each subject in the population an antibody, or antigen-binding
portion thereof, which is capable of binding to the p40 subunit of
IL-12 and/or IL-23, wherein at least 35% of the population of
subjects achieve at least a PGA score of 0 or 1 by about week
24.
[0045] In a further aspect, the invention is directed to a method
of treating psoriasis in a population of subjects, by administering
to each subject in the population an antibody, or antigen-binding
portion thereof, which is capable of binding to the p40 subunit of
IL-12 and/or IL-23, wherein at least 25% of the population of
subjects achieve at least a PASI 75 response by about week 52.
[0046] In another aspect, the invention is directed to a method of
treating psoriasis in a population of subjects, by administering to
each subject in the population an antibody, or antigen-binding
portion thereof, which is capable of binding to the p40 subunit of
IL-12 and/or IL-23, wherein at least 21% of the population of
subjects achieve at least a PGA score of 0 or 1 by about week
52.
[0047] In certain embodiments of the foregoing aspects, the subject
or population of subjects achieves (i) an improvement in a
Dermatology Life Quality Index (DLQI) score or mean Dermatology
Life Quality Index (DLQI) score of at least about -9; (ii) an
improvement in a Short Form 36 Health Survey Physical Component
Summary (PCS) score or mean Physical Component Summary (PCS) score
of at least about 2; (iii) an improvement in a Short Form 36 Health
Survey Mental Component Summary (MCS) score or mean Short Form 36
Health Survey Mental Component Summary (MCS) score of at least
about 4; (iv) an improvement in a visual analog scale score or mean
visual analog scale score for psoriasis-related pain (VAS-Ps) of at
least about -25; (v) an improvement in a visual analog scale score
for psoriatic arthritis-related pain (VAS-PsA) or mean visual
analog scale score for psoriatic arthritis-related pain (VAS-PsA)
of at least about -32; and/or (vi) a minimum clinically important
difference (MCID) response rate for psoriasis-related pain (VAS-Ps)
of at least about 60%.
[0048] In various aspects, the invention is directed to a method of
treating psoriasis in a population of subjects comprising
administering to each subject in the population an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, wherein the population of
subjects achieves (i) a minimum clinically important difference
(MCID) response rate for Dermatology Life Quality Index (DLQI) of
at least about 70% by about week 12; (ii) a minimum clinically
important difference (MCID) response rate for Dermatology Life
Quality Index (DLQI) of at least about 81% by about week 52; (iii)
a minimum clinically important difference (MCID) response rate for
Total Activity Impairment (TAI) of at least about 45% by about week
12; and/or (iv) a minimum clinically important difference (MCID)
response rate for Total Activity Impairment (TAI) of at least about
57% by about week 52. In one embodiment, the antibody, or
antigen-binding portion thereof, is administered once every four
weeks. In another embodiment, the antibody, or antigen-binding
portion thereof, is administered once every 12 weeks.
[0049] In further aspects, the invention is directed to a method of
treating psoriasis in a population of subjects, by administering to
each subject in the population an antibody, or antigen-binding
portion thereof, which is capable of binding to the p40 subunit of
IL-12 and/or IL-23, wherein (i) at least 65% of the population of
subjects achieve at least a PGA 0/1 response by about week 12,
wherein each subject was treated with a biologic prior to
administration of the antibody; (ii) at least 74% of the population
of subjects achieve at least a PASI 75 response by about week 12,
wherein each subject was treated with a biologic prior to
administration of the antibody; (iii) at least 78% of the
population of subjects achieve at least a PGA 0/1 response by about
week 12, wherein none of the subjects were treated with a biologic
prior to administration of the antibody; (iv) at least 82% of the
population of subjects achieve at least a PASI 75 response by about
week 12, wherein none of the subjects were treated with a biologic
prior to administration of the antibody; (v) at least 78% of the
population of subjects achieve at least a PGA 0/1 response by about
week 52, wherein each subject was treated with a biologic prior to
administration of the antibody; (vi) at least 79% of the population
of subjects achieve at least a PGA 0/1 response by about week 52,
wherein none of the subjects were treated with a biologic prior to
administration of the antibody; (vii) at least 71% of the
population of subjects achieve at least a PGA 0/1 response by about
week 12, wherein each subject has a prior history of psoriatic
arthritis; (viii) at least 78% of the population of subjects
achieve at least a PASI 75 response by about week 12, wherein each
subject has a prior history of psoriatic arthritis; (ix) at least
77% of the population of subjects achieve at least a PGA 0/1
response by about week 12, wherein none of the subjects has a prior
history of psoriatic arthritis; (x) at least 81% of the population
of subjects achieve at least a PASI 75 response by about week 12,
wherein none of the subjects has a prior history of psoriatic
arthritis; (xi) at least 77% of the population of subjects achieve
at least a PGA 0/1 response by about week 52, wherein each subject
has a prior history of psoriatic arthritis; and/or (xii) at least
79% of the population of subjects achieve at least a PGA 0/1
response by about week 52, wherein none of the subjects has a prior
history of psoriatic arthritis.
[0050] In yet another aspect, the invention is directed to methods
for decreasing the risk that a subject treated with an antibody, or
antigen binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, will develop a Major Adverse
Cardiovascular Event (MACE). The methods include (a) selecting a
subject having less that 2 risk factors selected from the group
consisting of (i) a body mass index (BMI) of greater than 30, (ii)
a history of diabetes mellitus, (iii) blood pressure greater than
140/90, (iv) a history of myocardial infarction, (v) a history of
angina requiring hospitalization, (vi) a history of coronary artery
disease requiring revascularization, (vii) a history of peripheral
artery disease, (viii) a history of congestive heart failure
requiring hospitalization, (ix) a history of stroke or transient
ischemic attack; and (b) administering the antibody, or antigen
binding portion thereof to the selected subject; thereby decreasing
the risk that the subject will develop a Major Adverse
Cardiovascular Event. In a particular embodiment, the antibody is
ABT-874 or ustekinumab.
[0051] In certain embodiments, the subject has 0 or 1 risk factor.
In certain embodiments, the MACE is myocardial infarction and/or
cerebrovascular stroke.
[0052] In other embodiments, the antibody, or antigen binding
portion thereof, is administered to the selected subject in a first
dose amount of at least about 100 mg to about 200 mg. In a further
embodiment, the antibody, or antigen binding portion thereof, is
administered to the selected subject in a second dose amount of at
least about 100 mg to about 200 mg. In certain embodiments, the
risk factors are re-evaluated prior to administration of the second
dose amount to the selected subject.
[0053] In certain embodiments of the various aspects of the
invention, the subject achieves at least a 50% reduction in PASI
score. In one aspect the subject achieves at least a 50% reduction
in PASI score by about week 4.
[0054] In other embodiments of the various aspects of the
invention, the subject achieves at least an 80% reduction in PASI
score. In one aspect the subject achieves at least an 80% reduction
in PASI score by about week 12.
[0055] In further aspects, the invention is directed to a method of
treating psoriasis in a population of subjects, comprises
administering to each subject in the population an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, wherein: (i) at least 69% of the
population of subjects achieve at least a PGA 0/1 response by about
week 12, wherein each subject had a baseline PASI greater than 20
prior to administration of the antibody; (ii) at least 79% of the
populatin of subjects achieve at least a PGA 0/1 response by about
week 12, wherein each subject had a baseline PASI less than or
equal to 20 prior to administration of the antibody; (iii) at least
79% of the population of subjects achieve at least a PASI 75
response by about week 12, wherein each subject had a baseline PASI
greater than 20 prior to administration of the antibody; (iv) at
least 81% of the population of subjects achieve at least a PASI 75
response by about week 12, wherein each subject had a baseline PASI
less than or equal to 20 prior to administration of the antibody;
(v) at least 67% of the population of subjects achieve at least a
PGA 0/1 response by about week 12, wherein each subject had a
baseline weight of greater than or equal to 100 kilograms prior to
administration of the antibody; (vi) at least 80% of the population
of subjects achieve at least a PGA 0/1 response by about week 12,
wherein each subject had a baseline weight of less than 100
kilograms prior to administration of the antibody; (vii) at least
72% of the population of subjects achieve at least a PASI 75
response by about week 12, wherein each subject had a baseline
weight of greater than or equal to 100 kilograms prior to
administration of the antibody; and/or (viii) at least 85% of the
population of subjects achieve at least a PASI 75 response by about
week 12, wherein each subject had a baseline weight of less than
100 kilograms prior to administration of the antibody.
[0056] In still further aspects, the invention is directed to a
method of treating psoriasis in a population of subjects comprises
administering to each subject in the population an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, wherein: (i) at least 41% of the
population of subjects maintains at least a PGA 0/1 response
through at least week 52 of treatment; (ii) at least 79% of the
population of subjects maintains at least a PGA 0/1 response
through at least week 52 of treatment; (iii) at least 45% of the
population of subjects maintains at least a PASI 75 response
through at least week 52 of treatment; (iv) at least 82% of the
population of subjects maintains at least a PASI 75 response
through at least week 52 of treatment; (v) at least 23% of the
population of subjects maintains at least a PASI 75 response
through at least week 52 of treatment; and/or (vi) at least 63% of
the population of subjects maintains at least a PASI 75 response
through at least week 52 of treatment.
[0057] In certain embodiments of the various aspects of the
invention, the method of treating psoriasis comprises administering
to each subject in a population: a) a first dose amount of the
antibody, or antigen-binding portion thereof, according to a first
periodicity of about once every 4 weeks; and b) administering a
second dose amount that is about 40-60% of the first dose amount of
the antibody, or antigen-binding portion thereof, according to a
second periodicity of about once every 4 weeks.
[0058] In other embodiments of the various aspects of the
invention, the method of treating psoriasis comprises administering
to each subject in a population: a) a first dose amount of the
antibody, or antigen-binding portion thereof, according to a first
periodicity of about once every 4 weeks; and b) a second dose
amount that is about 40-60% of the first dose amount of the
antibody, or antigen-binding portion thereof, according to a second
periodicity of about once every 4 weeks; and c) the second dose
amount of the antibody, or antigen-binding portion thereof,
according to a third periodicity of about once every 12 weeks.
[0059] In certain embodiments of the various aspects of the
invention, a subject treated for psoriasis achieves a PGA of 0 or 1
in less than about 171 days. In some embodiments, a subject treated
for psoriasis achieves a PGA of 0 or 1 in less than about 30, 40,
50, 60, 70, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135,
140, 145, 150, 155, 160, 165, 166, 167, 168, 169 or 170 days. In
certain embodiments, a patient achieves a PGA of 0 or 1 by about 69
days.
[0060] In related embodiments of the various aspects of the
invention, the patient achieves a PASI 75 response in less than
about 140 days. In some embodiments, a subject treated for
psoriasis achieves a PASI 75 in less than about 30, 40, 50, 60, 70,
80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 136, 137,
138 or 139 days. In certain embodiments, the patient achieves a
PASI 75 by about 56 days.
[0061] In still other embodiments of the various aspects of the
invention, the subject achieves at least a 60% improvement in PASI
score and maintain at least a 60% improvement in PASI score, e.g.,
through at least week 52 of treatment.
[0062] In another aspect, the invention is directed to a method of
treating psoriasis in a population of subjects, comprising
administering to each subject in the population an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, wherein: (i) at least 10% of the
population of subjects achieves a PGA score of 0 by week 24 of
treatment; (ii) at least 5% of the population of subjects achieve
at least a PASI 50 response by about week 2; (iii) at least 70% of
the population of subjects achieve at least a PASI 50 response and
maintain at least a PASI 50 response through at least week 52 of
treatment; (iv) at least 5% of the population of subjects achieve
at least a PASI 75 response by about week 4; (v) at least 40% of
the population of subjects achieve at least a PASI 75 response and
maintain at least a PASI 75 response through at least week 52 of
treatment; (vi) at least 10% of the population of subjects achieve
at least a PASI 90 response by about week 8; (vii) at least 25% of
the population of subjects achieve at least a PASI 90 response and
maintain at least a PASI 90 response through at least week 52 of
treatment; (viii) at least 5% of the population of subjects achieve
at least a PASI 100 response by about week 8; (ix) at least 10% of
the population of subjects achieve at least a PASI 100 response and
maintain at least a PASI 100 response through at least week 52 of
treatment; (x) at least 5% of the population of subjects achieve at
least a PGA score of 0 or 1 by about week 4; and/or (xi) at least
35% of the population of subjects achieve at least a PGA score of 0
or 1 and maintain at least a PGA score of 0 or 1 through at least
week 52 of treatment.
[0063] In certain embodiments of the various aspects of the
invention, the subject achieves a Nail Psoriasis Severity Index
(NAPSI) score of about 2.1 or less. In certain embodiments, the
subject achieves a Nail Psoriasis Severity Index (NAPSI) score of
about 2.1 or less by about week 24. In related embodiments of the
various aspects of the invention, the subject achieves a Nail
Psoriasis Severity Index (NAPSI) score of about 1.2 or less. In
certain embodiments, the subject achieves a Nail Psoriasis Severity
Index (NAPSI) score of about 1.2 or less by about week 52.
[0064] In other embodiments of the various aspects of the
invention, the subject achieves a Dermatology Life Quality Index
(DLQI) score of about 0 or 1. In certain embodiments, the subject
achieves a Dermatology Life Quality Index (DLQI) score of about 0
or 1 by about week 24 or by about week 52.
[0065] In certain embodiments, the subject achieves a clinically
meaningful reduction in Dermatology Life Quality Index (DLQI)
score. A clinically meaningful reduction in Dermatology Life
Quality Index (DLQI) score may be, e.g., a decrease of greater than
5 points in DLQI score. In one embodiment, the subject achieves a
clinically meaningful reduction in DLQI score by about week 24. In
one embodiment, the subject achieves a clinically meaningful
reduction in DLQI score by about week 52.
[0066] In certain embodiments, the subject or population of
subjects achieves an improvement in Dermatology Life Quality Index
(DLQI) score of at least about -7, e.g., by week 12.
[0067] In a further aspect, the invention is directed to a method
of treating psoriasis in a population of subjects, comprising
administering to each subject in the population an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, wherein: (i) at least 35% of the
population of subjects achieves a Dermatology Life Quality Index
(DLQI) score of 0 or 1 by about week 24; (ii) at least 18% of the
population of subjects achieves a Dermatology Life Quality Index
(DLQI) score of 0 or 1 by about week 52; (iii) at least 50% of the
population of subjects achieves a clinically meaningful reduction
in Dermatology Life Quality Index (DLQI) score by about week 24;
and/or (iv) at least 20% of the population of subjects achieves a
clinically meaningful reduction in Dermatology Life Quality Index
(DLQI) score by about week 52.
[0068] In several embodiments of the various aspects of the
invention, the subject achieves a minimum clinically important
difference (MCID) in one or more health-related quality of life
outcomes selected from the group consisting of Dermatology Life
Quality Index (DLQI), Total Activity Impairment (TAI), Ps-related
(VAS-Ps) pain, psoriatic arthritis-related (VAS-PsA) pain, Short
Form 36 Health Survey Mental Component Summary score (MCS) and
Short Form 36 Health Survey Mental Component Summary score (PCS).
In various embodiments, the subject achieves a minimum clinically
important difference (MCID) in two, three, four, five or all six of
Dermatology Life Quality Index (DLQI), Total Activity Impairment
(TAI), Ps-related (VAS-Ps) pain, psoriatic arthritis-related
(VAS-PsA) pain, Short Form 36 Health Survey Mental Component
Summary score (MCS) or Short Form 36 Health Survey Physical
Component Summary score (PCS).
[0069] In related embodiments, the population of subjects achieves
a minimum clinically important difference (MCID) response rate for
one or more health-related quality of life outcomes selected from
the group consisting of Dermatology Life Quality Index (DLQI),
Total Activity Impairment (TAI), Ps-related (VAS-Ps) pain,
psoriatic arthritis-related (VAS-PsA) pain, Short Form 36 Health
Survey Mental Component Summary score (MCS) and Short Form 36
Health Survey Mental Component Summary score (PCS). In various
embodiments, the population of subjects achieves a minimum
clinically important difference (MCID) response rate for two,
three, four, five or all six of Dermatology Life Quality Index
(DLQI), Total Activity Impairment (TAI), Ps-related (VAS-Ps) pain,
psoriatic arthritis-related (VAS-PsA) pain, Short Form 36 Health
Survey Mental Component Summary score (MCS) or Short Form 36 Health
Survey Physical Component Summary score (PCS).
[0070] In one embodiment of all of the foregoing aspects of the
invention, the method comprises administering to the subject or to
each subject in the population: a) a first dose amount of the
antibody, or antigen-binding portion thereof, according to a first
periodicity of about once every 4 weeks; and b) administering a
second dose amount that is about 40-60% of the first dose amount of
the antibody, or antigen-binding portion thereof, according to a
second periodicity of about once every 4 weeks.
[0071] In another embodiment of all of the foregoing aspects of the
invention, the method comprises administering to the subject or to
each subject in the population: a) about 200 mg of ABT-874 once
every four weeks for two doses; and b) about 100 mg of ABT-874
every four weeks thereafter.
[0072] In still another embodiment of all of the foregoing aspects
of the invention, the method comprises administering to the subject
or to each subject in the population: a) about 200 mg of ABT-874 at
weeks 0 and 4; and b) about 100 mg of ABT-874 at week 8 and every 4
weeks thereafter. In one embodiment, the antibody is ABT-874 (i.e.,
Briakinumab.TM.).
[0073] In a further aspect, the invention provides a method of
treating psoriasis in a subject comprising administering to the
subject: a) about 200 mg of an antibody, or antigen-binding portion
thereof, which is capable of binding to the p40 subunit of IL-12
and/or IL-23, once every four weeks for two doses; and b) about 100
mg of the antibody, or antigen-binding portion thereof, every four
weeks thereafter, thereby treating psoriasis in the subject. In one
embodiment, the antibody is ABT-874. In one embodiment, the
psoriasis is plaque psoriasis, e.g., chronic plaque psoriasis, such
as moderate to severe chronic plaque psoriasis.
[0074] In yet a further aspect, the invention provides a method of
treating psoriasis in a subject comprising administering to the
subject: a) about 200 mg of an antibody, or antigen-binding portion
thereof, which is capable of binding to the p40 subunit of IL-12
and/or IL-23, at weeks 0 and 4; and b) about 100 mg of the
antibody, or antigen-binding portion thereof, at week 8 and every 4
weeks thereafter, thereby treating psoriasis in the subject. In one
embodiment, the antibody is ABT-874. In one embodiment, the
psoriasis is plaque psoriasis, e.g., chronic plaque psoriasis, such
as moderate to severe chronic plaque psoriasis.
[0075] In a still further aspect, the invention provides a method
of treating psoriasis in a subject comprising administering to the
subject: a) about 200 mg of ABT-874 once every four weeks for two
doses; and b) about 100 mg of ABT-874 every four weeks thereafter,
thereby treating psoriasis in the subject. In one embodiment, the
antibody is ABT-874. In one embodiment, the psoriasis is plaque
psoriasis, e.g., chronic plaque psoriasis, such as moderate to
severe chronic plaque psoriasis.
[0076] In a still further aspect, the invention provides a method
of treating psoriasis in a subject comprising administering to the
subject: a) about 200 mg of ABT-874 at weeks 0 and 4; and b) about
100 mg of ABT-874 at week 8 and every 4 weeks thereafter, thereby
treating psoriasis in the subject. In one embodiment, the antibody
is ABT-874. In one embodiment, the psoriasis is plaque psoriasis,
e.g., chronic plaque psoriasis, such as moderate to severe chronic
plaque psoriasis.
[0077] In one embodiment, the psoriasis is chronic psoriasis. In
one embodiment, the psoriasis is plaque psoriasis, e.g., chronic
plaque psoriasis. In another embodiment, the psoriasis is chronic
psoriasis, e.g., chronic plaque psoriasis. In yet another
embodiment, the psoriasis is moderate to severe psoriasis, e.g.,
moderate to severe plaque psoriasis, moderate to severe chronic
psoriasis or moderate to severe chronic plaque psoriasis. In one
embodiment, the subject has had a clinical diagnosis of psoriasis
for at least 6 months. In another embodiment, the subject has had
stable plaque psoriasis for at least 2 months.
[0078] In one embodiment, the antibody is administered via
subcutaneous injection.
[0079] In one embodiment, the antibody, or antigen-binding portion
thereof, used in the methods of the invention is capable of binding
to an epitope of the p40 subunit of IL-12 and/or IL-23.
[0080] In another embodiment, the antibody, or antigen-binding
portion thereof, is capable of binding to the epitope of the p40
subunit when the p40 subunit is bound to the p35 subunit of IL-12.
In yet another embodiment, the antibody, or antigen-binding portion
thereof, is capable of binding to the epitope of the p40 subunit
when the p40 subunit is bound to a p19 subunit, i.e., the p19
subunit of IL-23. In one embodiment, the antibody, or
antigen-binding portion thereof, is capable of binding to the
epitope of the p40 subunit when the p40 subunit is bound to the p35
subunit of IL-12 and when the p40 subunit is bound to a p19
subunit.
[0081] In one embodiment, the antibody, or antigen binding portion
thereof, binds to an epitope of the p40 subunit of IL-12 to which
an antibody selected from the group consisting of Y61 and J695
binds.
[0082] In another embodiment, the antibody is further capable of
binding to a first heterodimer and is also capable of binding to a
second heterodimer, wherein the first heterodimer comprises the p40
subunit of 11-12 and the p35 subunit of 11-12, and wherein the
second heterodimer comprises the p40 subunit of IL-12 and a p19
subunit, i.e., the p19 subunit of IL-23.
[0083] In a further embodiment, the antibody neutralizes the
activity of the first heterodimer. In another embodiment, the
antibody neutralizes the activity of the second heterodimer. In yet
another embodiment, the antibody neutralizes the activity of the
first heterodimer and the second heterodimer.
[0084] In a further embodiment, the antibody, or antigen binding
portion thereof, used in the methods of the invention inhibits
phytohemagglutinin blast proliferation in an in vitro PHA assay
with an IC.sub.50 of 1.times.10.sup.-9M or less, or which inhibits
human IFN.gamma. production with an IC.sub.50 of 1.times.10.sup.-10
M or less.
[0085] In one embodiment, the antibody, or antigen binding portion
thereof, used in the methods of the invention dissociates from the
p40 subunit of IL-12 with a K.sub.d of 1.times.10.sup.-10 M or less
or a k.sub.off rate constant of 1.times.10.sup.-3 s.sup.-1 or less,
as determined by surface plasmon resonance.
[0086] In one embodiment, the isolated antibody, or antigen binding
portion thereof, used in the methods of the invention is a chimeric
antibody, a humanized antibody or a human antibody.
[0087] In another embodiment, the antibody, or antigen binding
portion thereof, used in the methods of the invention has a heavy
chain CDR3 comprising the amino acid sequence of SEQ ID NO: 25 and
a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:
26;
[0088] In a further embodiment, the antibody, or antigen binding
portion thereof, used in the methods of the invention has a heavy
chain CDR2 comprising the amino acid sequence of SEQ ID NO: 27 and
a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:
28.
[0089] In one embodiment, the antibody, or antigen binding portion
thereof, used in the methods of the invention has a heavy chain
CDR1 comprising the amino acid sequence of SEQ ID NO: 29 and a
light chain CDR1 comprising the amino acid sequence of SEQ ID NO:
30.
[0090] In another embodiment, the antibody, or antigen-binding
portion thereof, used in the methods of the invention is capable of
binding to an interleukin comprising a p40 subunit. In one
embodiment, the interleukin comprises a p40 subunit and a p35
subunit, e.g., the interleukin is IL-12. In another embodiment, the
interleukin comprises a p40 subunit and a p19 subunit, e.g., the
interleukin is IL-23. In yet another embodiment, the antibody, or
antigen binding portion thereof, neutralizes the activity of the
interleukin.
[0091] In one embodiment, the antibody, or antigen binding portion
thereof, binds to an epitope of the p40 subunit.
[0092] In one embodiment, the antibody, or antigen-binding portion
thereof, is administered to a subject in a pharmaceutical
composition comprising the antibody, or antigen binding portion
thereof, and a pharmaceutically acceptable carrier. The
pharmaceutical composition may also comprise an additional agent,
such as a therapeutic agent, e.g., budenoside, epidermal growth
factor, corticosteroids, cyclosporin, sulfasalazine,
aminosalicylates, 6-mercaptopurine, azathioprine, metronidazole,
lipoxygenase inhibitors, mesalamine, olsalazine, balsalazide,
antioxidants, thromboxane inhibitors, IL-1 receptor antagonists,
anti-IL-113 monoclonal antibodies, anti-IL-6 monoclonal antibodies,
growth factors, elastase inhibitors, pyridinyl-imidazole compounds,
antibodies or agonists of TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8,
IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, and PDGF, antibodies of
CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or
their ligands, methotrexate, cyclosporin, FK506, rapamycin,
mycophenolate mofetil, leflunomide, NSAIDs, ibuprofen,
corticosteroids, prednisolone, phosphodiesterase inhibitors,
adenosine agonists, antithrombotic agents, complement inhibitors,
adrenergic agents, IRAK, NIK, IKK, p38, MAP kinase inhibitors,
IL-1.beta. converting enzyme inhibitors, TNF.alpha.
.quadrature.converting enzyme inhibitors, T-cell signaling
inhibitors, metalloproteinase inhibitors, sulfasalazine,
azathioprine, 6-mercaptopurines, angiotensin converting enzyme
inhibitors, soluble cytokine receptors, soluble p55 TNF receptor,
soluble p75 TNF receptor, sIL-1RI, sIL-1RII, sIL-6R,
anti-inflammatory cytokines, IL-4, IL-10, IL-11, IL-13 and
TGF.beta..
[0093] In another embodiment, the therapeutic agent in the
pharmaceutical composition administered to the subject may be
selected from the group consisting of anti-TNF antibodies and
antibody fragments thereof, TNFR-Ig constructs, TACE inhibitors,
PDE4 inhibitors, corticosteroids, budenoside, dexamethasone,
sulfasalazine, 5-aminosalicylic acid, olsalazine, IL-1.beta.
converting enzyme inhibitors, IL-1ra, tyrosine kinase inhibitors,
6-mercaptopurines and IL-11.
[0094] In another embodiment, the therapeutic agent may be selected
from the group consisting of corticosteroids, prednisolone,
methylprednisolone, azathioprine, cyclophosphamide, cyclosporine,
methotrexate, 4-aminopyridine, tizanidine, interferon-.beta.1a,
interferon-.beta.1b, Copolymer 1, hyperbaric oxygen, intravenous
immunoglobulin, clabribine, antibodies or agonists of TNF, LT,
IL-1, IL-2, IL-6, IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF,
FGF, PDGF, antibodies to CD2, CD3, CD4, CD8, CD25, CD28, CD30,
CD40, CD45, CD69, CD80, CD86, CD90 or their ligands, methotrexate,
cyclosporine, FK506, rapamycin, mycophenolate mofetil, leflunomide,
NSAIDs, ibuprofen, corticosteroids, prednisolone, phosphodiesterase
inhibitors, adenosine agonists, antithrombotic agents, complement
inhibitors, adrenergic agents, IRAK, NIK, IKK, p38 or MAP kinase
inhibitors, IL-1.beta. converting enzyme inhibitors, TACE
inhibitors, T-cell signaling inhibitors, kinase inhibitors,
metalloproteinase inhibitors, sulfasalazine, azathioprine,
6-mercaptopurines, angiotensin converting enzyme inhibitors,
soluble cytokine receptors, soluble p55 TNF receptor, soluble p75
TNF receptor, sIL-1RI, sIL-1RII, sIL-6R, sIL-13R, anti-P7s,
p-selectin glycoprotein ligand (PSGL), anti-inflammatory cytokines,
IL-4, IL-10, IL-13 and TGF.beta..
[0095] In one embodiment, the antibody, or antigen-binding portion
thereof, used in the methods of the invention binds to human IL-12
and/or human IL-23 and dissociates from human IL-12 and/or human
IL-23, respectively, with a K.sub.d of 1.times.10.sup.-10M or less
and a k.sub.off rate constant of 1.times.10.sup.-3 s.sup.-1 or
less, as determined by surface plasmon resonance. In one
embodiment, the antibody, or antigen-binding portion thereof,
dissociates from human IL-12 and/or human IL-23 with a k.sub.off
rate constant of 1.times.10.sup.-4s.sup.-1 or less. In another
embodiment, the antibody, or antigen-binding portion thereof,
dissociates from human IL-12 and/or human IL-23 with a k.sub.off
rate constant of 1.times.10.sup.-5s.sup.-1 or less.
[0096] In another embodiment, the antibody, or antigen-binding
portion thereof, binds to human IL-12 and/or human IL-23 and
dissociates from human IL-12 and/or human Il-23, respectively, with
a k.sub.off rate constant of 1.times.10.sup.-2s.sup.-1 or less, as
determined by surface plasmon resonance. In yet another embodiment,
the antibody, or antigen-binding portion thereof, dissociates from
human IL-12 and/or human IL-23 with a k.sub.off rate constant of
1.times.10.sup.-3 s.sup.-1 or less. In a still further another
embodiment, the antibody, or antigen-binding portion thereof,
dissociates from human IL-12 and/or human IL-23 with a k.sub.off
rate constant of 1.times.10.sup.-4 s.sup.-1 or less. In another
embodiment, the antibody, or antigen-binding portion thereof,
dissociates from human IL-12 and/or human IL-23 with a k.sub.off
rate constant of 1.times.10.sup.-5s.sup.-1 or less.
[0097] In still another embodiment, the antibody, or
antigen-binding portion thereof, binds to human IL-12 and/or human
IL-23 and dissociates from human IL-12 and/or human IL-23,
respectively, with a K.sub.d of 1.34.times.10.sup.-10 M or less. In
yet another embodiment, the antibody, or antigen-binding portion
thereof, binds to human IL-12 and/or human IL-23 and dissociates
from human IL-12 and/or human IL-23, respectively, with a K.sub.d
of 9.74.times.10.sup.-11M or less. In one embodiment, the antibody,
or antigen-binding portion thereof, is a recombinant antibody, or
antigen-binding portion thereof.
[0098] In one embodiment, the antibody, or antigen-binding portion
thereof, used in the methods of the invention is a neutralizing
antibody, e.g., neutralizes the activity of human IL-12 and/or
human IL-23. In one embodiment, the neutralizing antibody, or
antigen-binding portion thereof, inhibits phytohemagglutinin blast
proliferation in an in vitro PHA assay with an IC.sub.50 of
1.times.10.sup.-9M or less. In another embodiment, the neutralizing
antibody, or antigen-binding portion thereof, inhibits
phytohemagglutinin blast proliferation in an in vitro PHA assay
with an IC.sub.50 of 1.times.10.sup.-1-M or less. In still another
embodiment, the neutralizing antibody of, or antigen-binding
portion thereof, inhibits phytohemagglutinin blast proliferation in
an in vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-11-M or
less. In yet another embodiment, the neutralizing antibody, or
antigen-binding portion thereof, inhibits phytohemagglutinin blast
proliferation in an in vitro phytohemagglutinin blast proliferation
assay (PHA assay) with an IC.sub.50 of 1.times.10.sup.-7 M or less.
In still another embodiment, the neutralizing antibody, or
antigen-binding portion thereof, inhibits phytohemagglutinin blast
proliferation in an in vitro PHA assay with an IC.sub.50 of
1.times.10.sup.-8 M or less. In one embodiment, the neutralizing
antibody, or antigen-binding portion thereof, inhibits human
IFN.gamma. production with an IC.sub.50 of 1.times.10.sup.-10 M or
less. In still another embodiment, the neutralizing antibody, or
antigen-binding portion thereof, inhibits human IFN.gamma.
production with an IC.sub.50 of 1.times.10.sup.-11 M or less. In
yet a further embodiment, the neutralizing antibody, or
antigen-binding portion thereof, inhibits human IFN.gamma.
production with an IC.sub.50 of 5.times.10.sup.-12 M or less.
[0099] In one embodiment, the antibody, or an antigen-binding
portion thereof, used in the methods of the invention
[0100] a) inhibits phytohemagglutinin blast proliferation in an in
vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-9M or
less;
[0101] b) has a heavy chain CDR3 comprising the amino acid sequence
of SEQ ID NO: 25; and
[0102] c) has a light chain CDR3 comprising the amino acid sequence
of SEQ ID NO: 26. In one embodiment, the antibody further has a
heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:
27; and a light chain CDR2 comprising the amino acid sequence of
SEQ ID NO: 28. In still another embodiment, the antibody, or
antigen-binding portion thereof, further has a heavy chain CDR1
comprising the amino acid sequence of SEQ ID NO: 29; and a light
chain CDR1 comprising the amino acid sequence of SEQ ID NO: 30. In
still another embodiment, the antibody, or antigen-binding portion
thereof, further inhibits phytohemagglutinin blast proliferation in
an in vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-10 M or
less. In still another embodiment, the antibody, or antigen-binding
portion thereof, further inhibits phytohemagglutinin blast
proliferation in an in vitro PHA assay with an IC.sub.50 of
1.times.10.sup.-11 M or less.
[0103] In one embodiment, the antibody, or antigen-binding portion
thereof, used in the methods of the invention has a heavy chain
variable region comprising the amino acid sequence of SEQ ID NO:
31, and a light chain variable region comprising the amino acid
sequence of SEQ ID NO: 32.
[0104] In one embodiment, the antibody, or antigen-binding portion
thereof, used in the methods of the invention comprises a heavy
chain constant region selected from the group consisting of IgG1,
IgG2, IgG3, IgG4, IgM, IgA and IgE constant regions. In one
embodiment, the antibody heavy chain constant region is IgG1. In
another embodiment, the antibody is a Fab fragment, F(ab').sub.2
fragment, or a single chain Fv fragment.
[0105] In one embodiment, the antibody, or antigen-binding portion
thereof, used in the methods of the invention dissociates from
human IL-12 and/or human IL-23 with a K.sub.d of 1.times.10.sup.-10
M or less and binds to an epitope on the p40 subunit of human IL-12
and/or human IL-23.
[0106] In one embodiment, the antibody, or antigen-binding portion
thereof, used in the methods of the invention is a human antibody,
or antigen-binding portion thereof, which
[0107] a) dissociates from human IL-12 with a k.sub.off rate
constant of 1.times.10.sup.-3 s.sup.-1 or less, as determined by
surface plasmon resonance;
[0108] b) has a heavy chain CDR3 comprising the amino acid sequence
of SEQ ID NO: 25; and
[0109] c) has a light chain CDR3 comprising the amino acid sequence
of SEQ ID NO: 26.
[0110] In another embodiment, the antibody, or antigen-binding
portion thereof, used in the methods of the invention dissociates
from human IL-12 with a k.sub.off rate constant of
1.times.10.sup.-4 s.sup.-1 or less. In a further embodiment, the
human antibody, or antigen-binding portion thereof, dissociates
from human IL-12 with a k.sub.off rate constant of
1.times.10.sup.-5 s.sup.-1 or less.
[0111] In one embodiment, the antibody, or antigen-binding portion
thereof, used in the methods of the invention is a human antibody,
or antigen-binding portion thereof, that binds to human IL-12 and
comprises:
[0112] a light chain CDR3 domain comprising the amino acid sequence
of SEQ ID NO: 26; and
[0113] a heavy chain CDR3 domain comprising the amino acid sequence
of SEQ ID NO: 25.
[0114] In one embodiment, the antibody, or antigen-binding portion
thereof, has a light chain variable region (LCVR) having a CDR3
domain comprising the amino acid sequence of SEQ ID NO: 26, and has
a heavy chain variable region (HCVR) having a CDR3 domain
comprising the amino acid sequence of SEQ ID NO: 25. In another
embodiment, the antibody, or antigen-binding portion thereof,
comprises an LCVR further having a CDR2 domain comprising the amino
acid sequence of SEQ ID NO: 28 and an HCVR further comprising a
CDR2 domain comprising the amino acid sequence of SEQ ID NO: 27. In
yet another embodiment, the LCVR further has CDR1 domain comprising
the amino acid sequence of SEQ ID NO: 30 and the HCVR has a CDR1
domain comprising the amino acid sequence of SEQ ID NO: 29.
[0115] In one embodiment, the antibody, or antigen-binding portion
thereof, binds human IL-12 and/or human IL-23 and is the antibody
J695 (also referred to as ABT-874), or an antigen binding portion
thereof.
[0116] In one embodiment, the antibody, or antigen-binding portion
thereof, binds to human IL-12 and/or human IL-23 and dissociates
from human IL-12 and/or human IL-23 with a K.sub.d of
1.34.times.10.sup.-1.degree. M or less, and neutralizes human IL-12
and/or human IL-23.
[0117] In one embodiment, the antibody, or antigen-binding portion
thereof, dissociates from human IL-12 and/or human IL-23 with a
K.sub.d of 9.74.times.10.sup.-11M or less. In one embodiment, the
antibody, or antigen-binding portion thereof, inhibits
phytohemagglutinin blast proliferation in an in vitro PHA assay
with an IC.sub.50 of 1.times.10.sup.-7 M or less. In one
embodiment, the antibody, or antigen-binding portion thereof,
inhibits phytohemagglutinin blast proliferation in an in vitro PHA
assay with an IC.sub.50 of 1.times.10.sup.-8 M or less. In one
embodiment, the antibody, or antigen-binding portion thereof,
inhibits phytohemagglutinin blast proliferation in an in vitro PHA
assay with an IC.sub.50 of 1.times.10.sup.-9 M or less. In one
embodiment, the antibody, or antigen-binding portion thereof,
inhibits phytohemagglutinin blast proliferation in an in vitro PHA
assay with an IC.sub.50 of 1.times.10.sup.-10 M or less. In one
embodiment, the antibody, or antigen-binding portion thereof,
inhibits phytohemagglutinin blast proliferation in an in vitro PHA
assay with an IC.sub.50 of 1.times.10.sup.-11 M or less. In one
embodiment, the antibody, or antigen-binding portion thereof,
inhibits human IFN.gamma. production with an IC.sub.50 of
1.times.10.sup.-10 M or less. In one embodiment, the antibody, or
antigen-binding portion thereof, inhibits human IFN.gamma.
production with an IC.sub.50 of 1.times.10.sup.-11 M or less. In
one embodiment, the antibody, or antigen-binding portion thereof,
inhibits human IFN.gamma. production with an IC.sub.50 of
5.times.10.sup.-12 M or less.
[0118] In one embodiment, the antibody, or antigen-binding portion
thereof, used in the methods of the invention inhibits IL-12 and/or
IL-23 binding to its receptor in an IL-12 or IL-23 receptor binding
assay (RBA), respectively, with an IC.sub.50 of 1.times.10.sup.-9 M
or less. In one embodiment, the antibody, or antigen-binding
portion thereof, inhibits IL-12 and/or IL-23 binding to its
receptor in an IL-12 or IL-23 receptor binding assay (RBA),
respectively, with an IC.sub.50 of 1.times.10.sup.-10 M or less. In
one embodiment, the antibody, or antigen-binding portion thereof,
inhibits IL-12 and/or IL-23 binding to its receptor in an IL-12 or
IL-23 receptor binding assay (RBA), respectively, with an IC.sub.50
of 1.times.10.sup.-11 M or less.
BRIEF DESCRIPTION OF THE DRAWINGS
[0119] FIG. 1 shows the patient disposition of the trial. (The term
"eow" refers to every other week dosing.)
[0120] FIG. 2 shows the percentage of patients with at least a 75%
improvement in the psoriasis area and severity index (PASI 75)
during the 12-week portion of the trial By week 8, with the
exception of the 200 mg.times.1 group, the percentage of patients
who had a PASI 75 response was statistically significantly greater
(p<0.001) in each ABT-874 treatment group for each comparison
with placebo based on an analysis of variance of observed data for
the intention-to-treat population. (The term "eow" refers to every
other week dosing.)
[0121] FIG. 3 shows the mean percentage improvement in psoriasis
area and severity index (PASI) scores from baseline. The data show
that *p<0.001 for each ABT-874 treatment group compared with
placebo at all time points (except 100 mg eow at week 1, p=0.023)
based on an analysis of variance of observed data for the
intention-to-treat population. (The term "eow" refers to every
other week dosing.)
[0122] FIGS. 4A-4C show the percentage of patients who maintained a
PASI 50, PASI 75 and PASI 90 response, respectively, at week 24 of
the trial, i.e, at 12 weeks following discontinuation of
administration of the antibody.
[0123] FIG. 4D shows the percentage of patients maintaining a PASI
75 response over time during the 24 week period of the trial.
[0124] FIG. 5A displays the mean percentage improvement from
baseline in PASI scores from Week 4 to Week 12.
[0125] FIG. 5B displays the mean percentage improvement from
baseline in PASI scores from Week 4 to Week 12 post
retreatment.
[0126] FIG. 6A displays the serum concentration-time curve for IV
dosing of ABT-874.
[0127] FIG. 6B displays the serum concentration-time curve for SC
dosing of ABT-874.
[0128] FIG. 7A displays the percentage of patients re-achieving a
PASI 75 response following retreatment.
[0129] FIG. 7B displays the median time to achieve a PASI 75
response across all ABT-874 dosage groups during retreatment.
[0130] FIG. 7C displays the median time to loss of a PASI 75
response following the initial 12 weeks of treatment.
[0131] FIG. 7D displays the percentage of patients achieving a PGA
score of 0 or 1 following retreatment.
[0132] FIGS. 8A-8B show the heavy chain variable region amino acid
sequence alignments of a series of human antibodies that bind human
IL-12 compared to germline sequences Cos-3/JH3 and DpI18 Lv1042.
Kabat numbering is used to identify amino acid positions. For the
Joe 9 wild type, the full sequence is shown. For the other
antibodies, only those amino acids positions that differ from Joe 9
wild type are shown.
[0133] FIGS. 8C-8D show the light chain variable region amino acid
sequence alignments of a series of human antibodies that bind human
IL-12. Kabat numbering is used to identify amino acid positions.
For the Joe 9 wild type, the full sequence is shown. For the other
antibodies, only those amino acids positions that differ from Joe 9
wild type are shown.
[0134] FIGS. 9A, 9A1-9A4, 9B, 9B1-9B4, 9C, 9C1, 9D, 9D1-9D4, 9E and
9E1-9E2 show the CDR positions in the heavy chain of the Y61
antibody that were mutated by site-directed mutagenesis and the
respective amino acid substitutions at each position. The graphs at
the right of the figures show the off-rates for the substituted
antibodies (black bars) as compared to unmutated Y61 (open
bar).
[0135] FIGS. 9F, 9F1-9F3, 9G, 9G1-9G2, 9H, and 9H1-9H3 show the CDR
positions in the light chain of the Y61 antibody that were mutated
by site-directed mutagenesis and the respective amino acid
substitutions at each position. The graphs at the right of the
figures show the off-rates for the substituted antibodies (black
bars) as compared to unmutated Y61 (open bar).
[0136] FIG. 10 shows the mean PASI score at time of retreatment.
The mean (SD) PASI scores at retreatment for all 58 patients who
received retreatment following loss of PASI 50 response during the
observation/retreatment phase. N values represent the number of
patients receiving retreatment. EOW=every other week;
PASI=Psoriasis Area and Severity Index.
[0137] FIG. 11 shows the time to loss of PASI 75 during the
observation/retreatment phase. Time to loss of the response during
the observation/retreatment phase is depicted; this loss is
following primary achievement of a PASI 75 response at the initial
12-week endpoint. Loss of response was calculated from the time of
the last dose received during the first 12 weeks of the study. N
values represent the number of patients losing response. EOW=every
other week; PASI=Psoriasis Area and Severity Index.
[0138] FIG. 12 shows the time to achieve PASI 75 during the
observation/retreatment phase. Among patients who achieved a PASI
75 response following ABT-874 retreatment during the
observation/retreatment phase, time to achieve the response is
depicted for each ABT-874 treatment group. N values represent the
number of patients achieving response. EOW=every other week;
PASI=Psoriasis Area and Severity Index.
[0139] FIG. 13 shows the percentage of patients achieving PASI 75
and PASI 90 at week 12.
[0140] FIGS. 14A-14D show the percentage of patients achieving PASI
75 and PASI 90 at week 12 in four specific body regions: (A) head
and neck; (B) upper extremities; (C) trunk; and (D) lower
extremities.
[0141] FIG. 15 shows the percentage of patients achieving PASI 75
and PASI 90 at week 12.
[0142] FIG. 16 shows the percentage of patients achieving PASI 75
at week 12 by baseline body weight.
[0143] FIG. 17 shows the percentage of patients achieving PASI 75
at week 12 in patients with and without a history of psoriatic
arthritis.
[0144] FIG. 18 shows the percentage of patients achieving PASI 75
response at week 12 in patients with severe or very severe baseline
physician's global assessment.
[0145] FIG. 19 shows the percentage of patients achieving PASI 75
response at week 12 by baseline PASI.
[0146] FIG. 20 shows the VERO study design of Example 12.
[0147] FIG. 21 shows subject disposition throughout the VERO study
of Example 12.
[0148] FIG. 22 shows the response of PGA of "clear" or "minimal" at
week 12 of the VERO study.
[0149] FIG. 23 shows the PASI Response rates at week 12 of the VERO
study.
[0150] FIG. 24 shows the maintenance of PGA 0/1 response rates from
week 12 to week 52, analyzed using nonresponder imputation of the
VERO study.
[0151] FIG. 25 shows the percentages of patients maintaining PASI
75 and 90 responses at week 52, analyzed using nonresponder
imputation of the VERO study.
[0152] FIG. 26 shows the timing of major adverse cardiac events in
relation to study drug dosing of the VERO study.
[0153] FIG. 27 shows the study design of Example 13.
[0154] FIG. 28 shows the percentage of patients achieving PGA 0/1
("Clear" or "Minimal") at week 12*. PGA=Physician's Global
Assessment; non-responder imputation; P<0.001, ABT-874 vs.
placebo and ABT-874 vs. etanercept.
[0155] FIG. 29 shows the percentage of patients achieving a PASI 75
response at week 12*. PASI=Psoriasis Area and Severity Index;
*non-responder imputation; P<0.001, ABT-874 vs. placebo and
ABT-874 vs. etanercept.
[0156] FIG. 30 shows the percentage of patients achieving a PASI 90
response at week 12*. PASI=Psoriasis Area and Severity Index;
*non-responder imputation; P<0.001, ABT-874 vs. placebo and
ABT-874 vs. etanercept.
[0157] FIG. 31 shows the percentage of patients achieving a PASI
100 response at week 12*. PASI=Psoriasis Area and Severity Index;
*non-responder imputation; P<0.001, ABT-874 vs. placebo and
ABT-874 vs. etanercept.
[0158] FIG. 32 shows the study design in Example 14.
[0159] FIG. 33 shows the percentage of patients achieving a PGA 0/1
("Clear or "Minimal") at week 12. *P<0.001, ABT-874 vs. Placebo,
.sup..dagger.P<0.001, ABT-874 vs. ETN, NRI.
[0160] FIG. 34 shows the percentage of patients achieving a PASI 75
Response at week 12. *P<0.001, ABT-874 vs. Placebo,
.sup..dagger.P<0.001, ABT-874 vs. ETN, NRI.
[0161] FIG. 35 shows the PASI 90 response rate at week 12.
*P<0.001, ABT-874 vs. Placebo, .sup..dagger.P<0.001, ABT-874
vs. ETN, NRI.
[0162] FIG. 36 shows the PASI 100 response rate at week 12.
*P<0.001, ABT-874 vs. Placebo, .sup..dagger.P<0.001, ABT-874
vs. ETN, NRI.
[0163] FIG. 37 depicts the results of certain Phase III clinical
studies demonstrating the efficacy of ABT-874 in moderate to sever
psoriasis, as described in Example 23.
[0164] FIG. 38 depicts the interim efficacy results and
specifically, PASI 75 over time upon treatment with ABT-874, as
described in Example 23.
[0165] FIG. 39 depicts the interim efficacy results and
specifically, PASI 100 over time upon treatment with ABT-874, as
described in Example 23.
[0166] FIG. 40 depicts the frequency of MACE upon administration
with ABT-874, as described in Example 23.
[0167] FIG. 41 shows the study design as described in Example 24.
A=2:1 randomization; B*=all patients who had a physician's global
assessment score of "clear" or "minimal" at week 12 were stratified
by treatment received during induction phase and re-randomized
2:2:1.
[0168] FIG. 42 shows the study flow and patient disposition as
described in Example 24. *Lack of efficacy was defined as a PGA
score of "mild" or higher. .dagger.lack of efficacy was defined as
a PGA score of "moderate" or higher.
[0169] FIG. 43 shows the physician's global assessment scores of
"clear" or "minimal" by treatment group during the induction phase
as described in Example 24. Intention-to-treat analysis: patients
with missing physician's global assessment scores were considered
nonresponders. p<0.001 at week 12, based on
Cochran-Mantel-Haenszel test adjusted by center; p=0.186 for week
1, and p<0.001 for weeks 4 to 12 based on Chi Square test.
[0170] FIG. 44 shows the mean improvement in psoriasis area and
severity index scores by treatment group during the induction phase
as described in Example 24. Intention-to-treat analysis: missing
psoriasis area and severity scores were imputed with last
observation, excluding baseline, carried forward. p<0.001 for
all time points based on ANCOVA with treatment as a factor and
baseline value as a covariate.
[0171] FIGS. 45A-45C show the maintenance of physician's global
assessment scores of "clear" or "minimal" through week 52 (A), and
proportions achieving PASI 75 responses (B), and PASI 100 responses
(C) through week 52, as described in Example 24. *One patient in
the ABT-874 every 4 week group was re-randomized but did not
receive any study drug in the Maintenance Phase. .dagger.Represents
all patients who received ABT-874 in the Induction Phase, had a
physician's global assessment score of "clear" or "minimal" at week
12, and were re-randomized in the Maintenance Phase.
Intention-to-treat analysis: patients with missing physician's
global assessment scores were considered non-responders (A).
Intention-to-treat analysis: patients with missing PASI scores were
considered non-responders (B and C). p values based on Chi Square
test.
[0172] FIG. 46 shows the study design and dosing regimens as
described in Example 25. .sup.aAt Week 24, patients who achieved
PASI.gtoreq.75 and a PGA of 0 or 1 maintained their current weekly
MTX dosage through Week 51. The dosage was adjusted only for
laboratory abnormalities. Patients in either treatment group who
did not achieve PASI .gtoreq.75 or a PGA of 0 or 1 or who lost
response (defined as PASI<50 and PGA.gtoreq.3) after Week 24
discontinued the trial and were eligible to enrol in an open-label
extension study of Briakinumab.TM.. MTX, methotrexate; PASI,
Psoriasis Activity and Severity Index; PGA, Physician's Global
Assessment.
[0173] FIG. 47 shows the patient disposition as described in
Example 25. MTX, methotrexate.
[0174] FIGS. 48A-48D show the Psoriasis Activity and Severity Index
(PASI) responses through Week 52 as described in Example 25. The
percentages of patients achieving PASI 75 (A), PASI 50 (B), PASI 90
(C), and PASI 100 (D) were significantly greater in the
Briakinumab.TM. group than the methotrexate (MTX) group by Week 8
(or earlier) and at all time points through Week 52. *p<0.001
vs. MTX. Nonresponder imputation was used to handle missing
data.
[0175] FIG. 49 shows the mean percentage improvements in Psoriasis
Activity and Severity Index (PASI) scores from baseline as
described in Example 25. At each visit, the mean percentage
improvement from baseline was significantly greater in the
Briakinumab.TM. group than the methotrexate (MTX) group (p<0.001
at all time points). Last observation carried forward was used to
handle missing data.
[0176] FIG. 50 shows the percentages of patients achieving a
Physician's Global Assessment (PGA) of 0 or 1 ("Clear" or
"Minimal") through Week 52 as described in Example 25. *p<0.001
vs. methotrexate (MTX).
[0177] FIG. 51 shows the changes from baseline in Dermatology Life
Quality Index (DLQI) score by visit as described in Example 25.
Patients in the Briakinumab.TM. group had statistically
significantly greater decreases from baseline in DLQI scores
compared with the MTX group at all time points assessed.
*p<0.001 vs. methotrexate (MTX)
DETAILED DESCRIPTION OF THE INVENTION
[0178] In order that the present invention may be more readily
understood, certain terms are first defined.
[0179] The term "activity enhancing amino acid residue" includes an
amino acid residue which improves the activity of the antibody. It
should be understood that the activity enhancing amino acid residue
may replace an amino acid residue at a contact, hypermutation or
preferred selective mutagenesis position and, further, more than
one activity enhancing amino acid residue can be present within one
or more CDRs. An activity enhancing amino acid residue include, an
amino acid residue that improves the binding specificity/affinity
of an antibody, for example anti-human IL-12 antibody binding to
human IL-12. The activity enhancing amino acid residue is also
intended to include an amino acid residue that improves the
neutralization potency of an antibody, for example, the human IL-12
antibody which inhibits human IL-12.
[0180] The term "antibody" includes an immunoglobulin molecule
comprised of four polypeptide chains, two heavy (H) chains and two
light (L) chains inter-connected by disulfide bonds. Each heavy
chain is comprised of a heavy chain variable region (abbreviated
herein as HCVR or VH) and a heavy chain constant region. The heavy
chain constant region is comprised of three domains, CH1, CH2 and
CH3. Each light chain is comprised of a light chain variable region
(abbreviated herein as LCVR or VL) and a light chain constant
region. The light chain constant region is comprised of one domain,
CL. The VH and VL regions can be further subdivided into regions of
hypervariability, termed complementarity determining regions
(CDRs), interspersed with regions that are more conserved, termed
framework regions (FR). Each VH and VL is composed of three CDRs
and four FRs, arranged from amino-terminus to carboxy-terminus in
the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. In one
embodiment, the antibody used in the compositions and methods of
the invention is the antibody described in U.S. Pat. No. 6,914,128,
incorporated by reference herein. In another embodiment, the
antibody used in the compositions and methods of the invention is
the antibody ABT-874 (also referred to as J695; Abbott
Laboratories).
[0181] The term "antigen-binding portion" of an antibody (or
"antibody portion") includes fragments of an antibody that retain
the ability to specifically bind to an antigen (e.g., hIL-12). It
has been shown that the antigen-binding function of an antibody can
be performed by fragments of a full-length antibody. Examples of
binding fragments encompassed within the term "antigen-binding
portion" of an antibody include (i) a Fab fragment, a monovalent
fragment consisting of the VL, VH, CL and CH1 domains; (ii) a
F(ab').sub.2 fragment, a bivalent fragment comprising two Fab
fragments linked by a disulfide bridge at the hinge region; (iii) a
Fd fragment consisting of the VH and CH1 domains; (iv) a Fv
fragment consisting of the VL and VH domains of a single arm of an
antibody, (v) a dAb fragment (Ward et al., (1989) Nature
341:544-546), which consists of a VH domain; and (vi) an isolated
complementarity determining region (CDR). Furthermore, although the
two domains of the Fv fragment, VL and VH, are coded for by
separate genes, they can be joined, using recombinant methods, by a
synthetic linker that enables them to be made as a single protein
chain in which the VL and VH regions pair to form monovalent
molecules (known as single chain Fv (scFv); see e.g., Bird et al.
(1988) Science 242:423-426; and Huston et al. (1988) Proc. Natl.
Acad. Sci. USA 85:5879-5883). Such single chain antibodies are also
intended to be encompassed within the term "antigen-binding
portion" of an antibody. Other forms of single chain antibodies,
such as diabodies are also encompassed. Diabodies are bivalent,
bispecific antibodies in which VH and VL domains are expressed on a
single polypeptide chain, but using a linker that is too short to
allow for pairing between the two domains on the same chain,
thereby forcing the domains to pair with complementary domains of
another chain and creating two antigen binding sites (see e.g.,
Holliger, P., et al. (1993) Proc. Natl. Acad. Sci. USA
90:6444-6448; Poljak, R. J., et al. (1994) Structure 2:1121-1123).
Still further, an antibody or antigen-binding portion thereof may
be part of a larger immunoadhesion molecules, formed by covalent or
non-covalent association of the antibody or antibody portion with
one or more other proteins or peptides. Examples of such
immunoadhesion molecules include use of the streptavidin core
region to make a tetrameric scFv molecule (Kipriyanov, S. M., et
al. (1995) Human Antibodies and Hybridomas 6:93-101) and use of a
cysteine residue, a marker peptide and a C-terminal polyhistidine
tag to make bivalent and biotinylated scFv molecules (Kipriyanov,
S. M., et al. (1994) Mol. Immunol. 31:1047-1058). Antibody
portions, such as Fab and F(ab').sub.2 fragments, can be prepared
from whole antibodies using conventional techniques, such as papain
or pepsin digestion, respectively, of whole antibodies. Moreover,
antibodies, antibody portions and immunoadhesion molecules can be
obtained using standard recombinant DNA techniques, as described
herein. Preferred antigen binding portions are complete domains or
pairs of complete domains.
[0182] The term "backmutation" refers to a process in which some or
all of the somatically mutated amino acids of a human antibody are
replaced with the corresponding germline residues from a homologous
germline antibody sequence. The heavy and light chain sequences of
the human antibody of the invention are aligned separately with the
germline sequences in the VBASE database to identify the sequences
with the highest homology. Differences in the human antibody of the
invention are returned to the germline sequence by mutating defined
nucleotide positions encoding such different amino acid. The role
of each amino acid thus identified as candidate for backmutation
should be investigated for a direct or indirect role in antigen
binding and any amino acid found after mutation to affect any
desirable characteristic of the human antibody should not be
included in the final human antibody; as an example, activity
enhancing amino acids identified by the selective mutagenesis
approach will not be subject to backmutation. To minimize the
number of amino acids subject to backmutation those amino acid
positions found to be different from the closest germline sequence
but identical to the corresponding amino acid in a second germline
sequence can remain, provided that the second germline sequence is
identical and colinear to the sequence of the human antibody of the
invention for at least 10, preferably 12 amino acids, on both sides
of the amino acid in question. Backmutation may occur at any stage
of antibody optimization; preferably, backmutation occurs directly
before or after the selective mutagenesis approach. More
preferably, backmutation occurs directly before the selective
mutagenesis approach.
[0183] The phrase "human interleukin 12" (abbreviated herein as
hIL-12, or IL-12), as used herein, includes a human cytokine that
is secreted primarily by macrophages and dendritic cells. The term
includes a heterodimeric protein comprising a 35 kD subunit (p35)
and a 40 kD subunit (p40) which are both linked together with a
disulfide bridge. The heterodimeric protein is referred to as a
"p70 subunit". The structure of human IL-12 is described further
in, for example, Kobayashi, et al. (1989) J. Exp Med. 170:827-845;
Seder, et al. (1993) Proc. Natl. Acad. Sci. 90:10188-10192; Ling,
et al. (1995) J. Exp Med. 154:116-127; Podlaski, et al. (1992)
Arch. Biochem. Biophys. 294:230-237. The term human IL-12 is
intended to include recombinant human IL-12 (rh IL-12), which can
be prepared by standard recombinant expression methods.
[0184] The terms "Kabat numbering", "Kabat definitions and "Kabat
labeling" are used interchangeably herein. These terms, which are
recognized in the art, refer to a system of numbering amino acid
residues which are more variable (i.e. hypervariable) than other
amino acid residues in the heavy and light chain variable regions
of an antibody, or an antigen binding portion thereof (Kabat et al.
(1971) Ann. NY Acad, Sci. 190:382-391 and, Kabat, E. A., et al.
(1991) Sequences of Proteins of Immunological Interest, Fifth
Edition, U.S. Department of Health and Human Services, NIH
Publication No. 91-3242). For the heavy chain variable region, the
hypervariable region ranges from amino acid positions 31 to 35 for
CDR1, amino acid positions 50 to 65 for CDR2, and amino acid
positions 95 to 102 for CDR3. For the light chain variable region,
the hypervariable region ranges from amino acid positions 24 to 34
for CDR1, amino acid positions 50 to 56 for CDR2, and amino acid
positions 89 to 97 for CDR3.
[0185] The Kabat numbering is used herein to indicate the positions
of amino acid modifications made in antibodies of the invention.
For example, the Y61 anti-IL-12 antibody can be mutated from serine
(S) to glutamic acid (E) at position 31 of the heavy chain CDR1
(H31S.fwdarw.E), or glycine (G) can be mutated to tyrosine (Y) at
position 94 of the light chain CDR3 (L94G.fwdarw.Y).
[0186] The term "human antibody" includes antibodies having
variable and constant regions corresponding to human germline
immunoglobulin sequences as described by Kabat et al. (See Kabat,
et al. (1991) Sequences of Proteins of Immunological Interest,
Fifth Edition, U.S. Department of Health and Human Services, NIH
Publication No. 91-3242). The human antibodies of the invention may
include amino acid residues not encoded by human germline
immunoglobulin sequences (e.g., mutations introduced by random or
site-specific mutagenesis in vitro or by somatic mutation in vivo),
for example in the CDRs and in particular CDR3. The mutations
preferably are introduced using the "selective mutagenesis
approach" described herein. The human antibody can have at least
one position replaced with an amino acid residue, e.g., an activity
enhancing amino acid residue which is not encoded by the human
germline immunoglobulin sequence. The human antibody can have up to
twenty positions replaced with amino acid residues which are not
part of the human germline immunoglobulin sequence. In other
embodiments, up to ten, up to five, up to three or up to two
positions are replaced. In a preferred embodiment, these
replacements are within the CDR regions as described in detail
below. However, the term "human antibody", as used herein, is not
intended to include antibodies in which CDR sequences derived from
the germline of another mammalian species, such as a mouse, have
been grafted onto human framework sequences.
[0187] The phrase "recombinant human antibody" includes human
antibodies that are prepared, expressed, created or isolated by
recombinant means, such as antibodies expressed using a recombinant
expression vector transfected into a host cell (described further
in Section II, below), antibodies isolated from a recombinant,
combinatorial human antibody library (described further in Section
III, below), antibodies isolated from an animal (e.g., a mouse)
that is transgenic for human immunoglobulin genes (see e.g.,
Taylor, L. D., et al. (1992) Nucl. Acids Res. 20:6287-6295) or
antibodies prepared, expressed, created or isolated by any other
means that involves splicing of human immunoglobulin gene sequences
to other DNA sequences. Such recombinant human antibodies have
variable and constant regions derived from human germline
immunoglobulin sequences (See Kabat, E. A., et al. (1991) Sequences
of Proteins of Immunological Interest, Fifth Edition, U.S.
Department of Health and Human Services, NIH Publication No.
91-3242). In certain embodiments, however, such recombinant human
antibodies are subjected to in vitro mutagenesis (or, when an
animal transgenic for human Ig sequences is used, in vivo somatic
mutagenesis) and thus the amino acid sequences of the VH and VL
regions of the recombinant antibodies are sequences that, while
derived from and related to human germline VH and VL sequences, may
not naturally exist within the human antibody germline repertoire
in vivo. In certain embodiments, however, such recombinant
antibodies are the result of selective mutagenesis approach or
backmutation or both.
[0188] An "isolated antibody" includes an antibody that is
substantially free of other antibodies having different antigenic
specificities (e.g., an isolated antibody that specifically binds
hIL-12 is substantially free of antibodies that specifically bind
antigens other than hIL-12). An isolated antibody that specifically
binds hIL-12 may bind IL-12 molecules from other species (discussed
in further detail below). Moreover, an isolated antibody may be
substantially free of other cellular material and/or chemicals.
[0189] A "neutralizing antibody" (or an "antibody that neutralized
hIL-12 activity") includes an antibody whose binding to hIL-12
results in inhibition of the biological activity of hIL-12. This
inhibition of the biological activity of hIL-12 can be assessed by
measuring one or more indicators of hIL-12 biological activity,
such as inhibition of human phytohemagglutinin blast proliferation
in a phytohemagglutinin blast proliferation assay (PHA), or
inhibition of receptor binding in a human IL-12 receptor binding
assay (see Example 3-Interferon-gamma Induction Assay of U.S. Pat.
No. 6,914,128). These indicators of hIL-12 biological activity can
be assessed by one or more of several standard in vitro or in vivo
assays known in the art (see Example 3 of U.S. Pat. No.
6,914,128).
[0190] The term "activity" includes activities such as the binding
specificity/affinity of an antibody for an antigen, for example, an
anti-hIL-12 antibody that binds to an IL-12 antigen and/or the
neutralizing potency of an antibody, for example, an anti-hIL-12
antibody whose binding to hIL-12 inhibits the biological activity
of hIL-12, e.g. inhibition of PHA blast proliferation or inhibition
of receptor binding in a human IL-12 receptor binding assay (see
Example 3 of U.S. Pat. No. 6,914,128).
[0191] The phrase "surface plasmon resonance" includes an optical
phenomenon that allows for the analysis of real-time biospecific
interactions by detection of alterations in protein concentrations
within a biosensor matrix, for example using the BIAcore system
(Pharmacia Biosensor AB, Uppsala, Sweden and Piscataway, N.J.). For
further descriptions, see Example 5 of U.S. Pat. No. 6,914,128 and
Jonsson, U., et al. (1993) Ann. Biol. Clin. 51:19-26; Jonsson, U.,
et al. (1991) Biotechniques 11:620-627; Johnsson, B., et al. (1995)
J. Mol. Recognit. 8:125-131; and Johnson, B., et al. (1991) Anal.
Biochem. 198:268-277.
[0192] The term "K.sub.off", as used herein, is intended to refer
to the off rate constant for dissociation of an antibody from the
antibody/antigen complex.
[0193] The term "K.sub.d", as used herein, is intended to refer to
the dissociation constant of a particular antibody-antigen
interaction.
[0194] The phrase "nucleic acid molecule" includes DNA molecules
and RNA molecules. A nucleic acid molecule may be single-stranded
or double-stranded, but preferably is double-stranded DNA.
[0195] The phrase "isolated nucleic acid molecule", as used herein
in reference to nucleic acids encoding antibodies or antibody
portions (e.g., VH, VL, CDR3) that bind hIL-12 including "isolated
antibodies"), includes a nucleic acid molecule in which the
nucleotide sequences encoding the antibody or antibody portion are
free of other nucleotide sequences encoding antibodies or antibody
portions that bind antigens other than hIL-12, which other
sequences may naturally flank the nucleic acid in human genomic
DNA. Thus, for example, an isolated nucleic acid of the invention
encoding a VH region of an anti-IL-12 antibody contains no other
sequences encoding other VH regions that bind antigens other than
IL-12. The phrase "isolated nucleic acid molecule" is also intended
to include sequences encoding bivalent, bispecific antibodies, such
as diabodies in which VH and VL regions contain no other sequences
other than the sequences of the diabody.
[0196] The term "vector" includes a nucleic acid molecule capable
of transporting another nucleic acid to which it has been linked.
One type of vector is a "plasmid", which refers to a circular
double stranded DNA loop into which additional DNA segments may be
ligated. Another type of vector is a viral vector, wherein
additional DNA segments may be ligated into the viral genome.
Certain vectors are capable of autonomous replication in a host
cell into which they are introduced (e.g., bacterial vectors having
a bacterial origin of replication and episomal mammalian vectors).
Other vectors (e.g., non-episomal mammalian vectors) can be
integrated into the genome of a host cell upon introduction into
the host cell, and thereby are replicated along with the host
genome. Moreover, certain vectors are capable of directing the
expression of genes to which they are operatively linked. Such
vectors are referred to herein as "recombinant expression vectors"
(or simply, "expression vectors"). In general, expression vectors
of utility in recombinant DNA techniques are often in the form of
plasmids. In the present specification, "plasmid" and "vector" may
be used interchangeably as the plasmid is the most commonly used
form of vector. However, the invention is intended to include such
other forms of expression vectors, such as viral vectors (e.g.,
replication defective retroviruses, adenoviruses and
adeno-associated viruses), which serve equivalent functions.
[0197] The phrase "recombinant host cell" (or simply "host cell")
includes a cell into which a recombinant expression vector has been
introduced. It should be understood that such terms are intended to
refer not only to the particular subject cell but to the progeny of
such a cell. Because certain modifications may occur in succeeding
generations due to either mutation or environmental influences,
such progeny may not, in fact, be identical to the parent cell, but
are still included within the scope of the term "host cell" as used
herein.
[0198] The term "modifying", as used herein, is intended to refer
to changing one or more amino acids in the antibodies or
antigen-binding portions thereof. The change can be produced by
adding, substituting or deleting an amino acid at one or more
positions. The change can be produced using known techniques, such
as PCR mutagenesis.
[0199] The phrase "contact position" includes an amino acid
position of in the CDR1, CDR2 or CDR3 of the heavy chain variable
region or the light chain variable region of an antibody which is
occupied by an amino acid that contacts antigen in one of the
twenty-six known antibody-antigen structures. If a CDR amino acid
in any of the 26 known solved structures of antibody-antigen
complexes contacts the antigen, then that amino acid can be
considered to occupy a contact position. Contact positions have a
higher probability of being occupied by an amino acid which contact
antigen than non-contact positions. Preferably a contact position
is a CDR position which contains an amino acid that contacts
antigen in greater than 3 of the 26 structures (>11.5%). Most
preferably a contact position is a CDR position which contains an
amino acid that contacts antigen in greater than 8 of the 25
structures (>32%).
[0200] The term "hypermutation position" includes an amino acid
residue that occupies position in the CDR1, CDR2 or CDR3 region of
the heavy chain variable region or the light chain variable region
of an antibody that is considered to have a high frequency or
probability for somatic hypermutation during in vivo affinity
maturation of the antibody. "High frequency or probability for
somatic hypermutation" includes frequencies or probabilities of a 5
to about 40% chance that the residue will undergo somatic
hypermutation during in vivo affinity maturation of the antibody.
It should be understood that all ranges within this stated range
are also intended to be part of this invention, e.g., 5 to about
30%, e.g., 5 to about 15%, e.g., 15 to about 30%.
[0201] The term "preferred selective mutagenesis position" includes
an amino acid residue that occupies a position in the CDR1, CDR2 or
CDR3 region of the heavy chain variable region or the light chain
variable region which can be considered to be both a contact and a
hypermutation position.
[0202] The phrase "selective mutagenesis approach" includes a
method of improving the activity of an antibody by selecting and
individually mutating CDR amino acids at least one preferred
selective mutagenesis position, hypermutation, and/or contact
position. A "selectively mutated" human antibody is an antibody
which contains a mutation at a position selected using a selective
mutagenesis approach. In another embodiment, the selective
mutagenesis approach is intended to provide a method of
preferentially mutating selected individual amino acid residues in
the CDR1, CDR2 or CDR3 of the heavy chain variable region
(hereinafter H1, H2, and H3, respectively), or the CDR1, CDR2 or
CDR3 of the light chain variable region (hereinafter referred to as
L1, L2, and L3, respectively) of an antibody Amino acid residues
may be selected from preferred selective mutagenesis positions,
contact positions., or hypermutation positions. Individual amino
acids are selected based on their position in the light or heavy
chain variable region. It should be understood that a hypermutation
position can also be a contact position. In an embodiment, the
selective mutagenesis approach is a "targeted approach". The
language "targeted approach" is intended to include a method of
preferentially mutating selected individual amino acid residues in
the CDR1, CDR2 or CDR3 of the heavy chain variable region or the
CDR1, CDR2 or CDR3 of the light chain variable region of an
antibody in a targeted manner, e.g., a "Group-wise targeted
approach" or "CDR-wise targeted approach". In the "Group-wise
targeted approach", individual amino acid residues in particular
groups are targeted for selective mutations including groups I
(including L3 and H3), II (including H2 and L1) and III (including
L2 and HD, the groups being listed in order of preference for
targeting. In the "CDR-wise targeted approach", individual amino
acid residues in particular CDRs are targeted for selective
mutations with the order of preference for targeting as follows:
H3, L3, H2, L1, H1 and L2. The selected amino acid residue is
mutated, e.g., to at least two other amino acid residues, and the
effect of the mutation on the activity of the antibody is
determined. Activity is measured as a change in the binding
specificity/affinity of the antibody, and/or neutralization potency
of the antibody. It should be understood that the selective
mutagenesis approach can be used for the optimization of any
antibody derived from any source including phage display,
transgenic animals with human IgG germline genes, human antibodies
isolated from human B-cells. Preferably, the selective mutagenesis
approach is used on antibodies which can not be optimized further
using phage display technology. It should be understood that
antibodies from any source including phage display, transgenic
animals with human IgG germline genes, human antibodies isolated
from human B-cells can be subject to backmutation prior to or after
the selective mutagenesis approach.
[0203] The term "activity enhancing amino acid residue" includes an
amino acid residue which improves the activity of the antibody. It
should be understood that the activity enhancing amino acid residue
may replace an amino acid residue at a preferred selective
mutagenesis position, contact position, or a hypermutation position
and, further, more than one activity enhancing amino acid residue
can be present within one or more CDRs. An activity enhancing amino
acid residue include, an amino acid residue that improves the
binding specificity/affinity of an antibody, for example anti-human
IL-12 antibody binding to human IL-12. The activity enhancing amino
acid residue is also intended to include an amino acid residue that
improves the neutralization potency of an antibody, for example,
the human IL-12 antibody which inhibits human IL-12.
[0204] The term "C.sub.max" refers to the maximum or peak serum or
plasma concentration of an agent observed in a subject after its
administration.
[0205] The term "T.sub.max" refers to the time at which C.sub.max
occurred.
[0206] The term "bioavailability" or "F %" refers to a fraction or
percent of a dose which is absorbed and enters the systemic
circulation after administration of a given dosage form. The dose
of the agent may be administered through any route, and,
preferably, via intravenous or subcutaneous injection.
[0207] The term "combination" as in the phrase "a first agent in
combination with a second agent" includes co-administration of a
first agent and a second agent, which for example may be dissolved
or intermixed in the same pharmaceutically acceptable carrier, or
administration of a first agent, followed by the second agent, or
administration of the second agent, followed by the first agent.
The present invention, therefore, includes methods of combination
therapeutic treatment and combination pharmaceutical
compositions.
[0208] The term "concomitant" as in the phrase "concomitant
therapeutic treatment" includes administering an agent in the
presence of a second agent. A concomitant therapeutic treatment
method includes methods in which the first, second, third, or
additional agents are co-administered. A concomitant therapeutic
treatment method also includes methods in which the first or
additional agents are administered in the presence of a second or
additional agents, wherein the second or additional agents, for
example, may have been previously administered. A concomitant
therapeutic treatment method may be executed step-wise by different
actors. For example, one actor may administer to a subject a first
agent and a second actor may to administer to the subject a second
agent, and the administering steps may be executed at the same
time, or nearly the same time, or at distant times, so long as the
first agent (and additional agents) are after administration in the
presence of the second agent (and additional agents). The actor and
the subject may be the same entity (e.g., human).
[0209] The term "combination therapy", as used herein, refers to
the administration of two or more therapeutic substances, e.g., an
anti-IL-12, anti-IL-23 antibody and another drug. The other drug(s)
may be administered concomitant with, prior to, or following the
administration of an anti-IL-12, anti-IL-23 antibody.
[0210] The term "dosing", as used herein, refers to the
administration of a substance (e.g., an anti-IL-12, anti-IL-23
antibody) to achieve a therapeutic objective (e.g., treatment of
psoriasis).
[0211] As used herein, the term "dose amount" refers to the
quantity, e.g., milligrams (mg), of the substance which is
administered to the subject. In one embodiment, the dose amount is
a fixed dose, e.g., is not dependent on the weight of the subject
to which the substance is administered. In another embodiment, the
dose amount is not a fixed dose, e.g., is dependent on the weight
of the subject to which the substance is administered. Exemplary
dose amounts, e.g., fixed dose amounts, for use in the methods of
the invention include, about 100 mg, about 110 mg, about 120 mg,
about 130 mg, about 140 mg, about 150 mg, about 160 mg, about 170
mg, about 180 mg, or about 190 mg, about 200 mg, about 210 mg,
about 220 mg, about 230 mg, about 240 mg, about 250 mg, about 260
mg, about 270 mg, about 280 mg, about 290 mg, or about 300 mg. In
one embodiment, the dose amount is about 100 to about 300 mg. In
yet another embodiment, the dose amount is about 100 to about 200
mg. Ranges intermediate to the above-recited ranges are also
contemplated by the invention. For example, ranges having any one
of these values as the upper or lower limits are also intended to
be part of the invention, e.g., about 110 mg to about 170 mg, about
150 mg to about 220 mg, etc.
[0212] As used herein, the term "periodicity" as it relates to the
administration of a substance (e.g., an antibody which binds to the
p40 subunit of -IL-12 and/or -IL-23) refers to a (regular)
recurring cycle of administering the substance to a subject. In one
embodiment, the recurring cycle of administration of the substance
to the subject achieves a therapeutic objective. The periodicity of
administration of the substance may be about once a week, once
every other week, about once every three weeks, about once every 4
weeks, about once every 5 weeks, about once every 6 weeks, about
once every 7 weeks, about once every 8 weeks, about once every 9
weeks, about once every 10 weeks, about once every 11 weeks, about
once every 12 weeks, about once every 13 weeks, about once every 14
weeks, about once every 15 weeks, about once every 16 weeks, about
once every 17 weeks, about once every 18 weeks, about once every 19
weeks, about once every 20 weeks, about once every 21 weeks, about
once every 22 weeks, about once every 23 weeks, about once every 24
weeks, about once every 5-10 days, about once every 10-20 days,
about once every 10-50 days, about once every 10-100 days, about
once every 10-200 days, about once every 25-35 days, about once
every 20-50 days, about once every 20-100 days, about once every
20-200 days, about once every 30-50 days, about once every 30-90
days, about once every 30-100 days, about once every 30-200 days,
about once every 50-150 days, about once every 50-200 days, about
once every 60-180 days, or about once every 80-100 days.
Periodicities intermediate to the above-recited times are also
contemplated by the invention. Ranges intermediate to the
above-recited ranges are also contemplated by the invention. For
example, ranges having any one of these values as the upper or
lower limits are also intended to be part of the invention, e.g.,
about 110 days to about 170 days, about 160 days to about 220 days,
etc.
[0213] As used herein, the phrase "periodicity of about once every
4 weeks" as it relates to the administration of a substance (e.g.,
an antibody which binds to the p40 subunit of -IL-12 and/or IL-23),
refers to a (regular) recurring cycle of administering the
substance to a subject about once every 4 weeks, about once every
28 days, or about once every month. In one embodiment, the
recurring cycle of administration of the substance to the subject
achieves or maintains a therapeutic objective (e.g., treating
psoriasis), either alone or in conjunction with other recurring
cycles (e.g., if a first periodicity, then in conjunction with a
second and/or third periodicity; if a second periodicity, then in
conjunction with a first and/or third periodicity; and if a third
periodicity, then in conjunction with a first and second
periodicity) of administering the substance. Preferably, the
substance is administered once every 22-34 days, every 24-32 days,
even more preferably, every 26-30 days (e.g., every 26, 27, 28, 29
or 30 days), and most preferably every 28 days.
[0214] As used herein, the phrase "periodicity of about once every
12 weeks" as it relates to the administration of a substance (e.g.,
an antibody which binds to the p40 subunit of -IL-12 and/or IL-23),
refers to a (regular) recurring cycle of administering the
substance to a subject about once every 12 weeks, about once every
84 days, or about once every 3 months. In one embodiment, the
recurring cycle of administration of the substance to the subject
achieves or maintains a therapeutic objective (e.g., treating
psoriasis), either alone or in conjunction with other recurring
cycles (e.g., if a first periodicity, then in conjunction with a
second and/or third periodicity; if a second periodicity, then in
conjunction with a first and/or third periodicity; and if a third
periodicity, then in conjunction with a first and second
periodicity) of administering the substance. Preferably, the
substance is administered once every 78-90 days, every 80-88 days,
even more preferably, every 82-86 days (e.g., every 82, 83, 84, 85
or 86 days), and most preferably every 84 days.
[0215] The "duration of a periodicity" refers to a time over which
the recurring cycle of administration occurs.
[0216] For example, a duration of the periodicity of administration
of a substance may be may about 12 weeks during which the
periodicity of administration is about once every week. For
example, a duration of the periodicity may be about 6 weeks during
which the periodicity of administration is about once every 4
weeks, e.g., the substance is administered at week zero and at week
four.
[0217] The duration of periodicity may be about 1 week, about 2
weeks, about 3 weeks, about 4 weeks, about 5 weeks, about 6 weeks,
about 7 weeks, about 8 weeks, about 9 weeks, about 10 weeks, about
11 weeks, about 12 weeks, about 15 weeks, about 20 weeks, about 25
weeks, about 30 weeks, about 35 weeks, about 40 weeks, about 45
weeks, about 50 weeks, about 52 weeks, about 55 weeks, about 60
weeks, about 70 weeks, about 80 weeks, about 90 weeks, or about 100
weeks, or longer. In one embodiment, the duration of periodicity is
for a length of time necessary or required to achieve a therapeutic
objective, e.g., treatment, maintenance of treatment, etc. e.g.,
maintain a PASI 50, PASI 75, PASI 90, PASI 100 score or PGA of 0 or
1 score. Durations of a periodicity intermediate to the
above-recited times are also contemplated by the invention.
[0218] The duration of periodicity may be about 4 weeks, about 8
weeks, about 12 weeks, about 16 weeks, about 20 weeks, about 24
weeks, about 28 weeks, about 32 weeks, about 36 weeks, about 40
weeks, about 44 weeks, about 48 weeks, about 52 weeks, or longer.
The duration of periodicity may be at least about 4 weeks, at least
about 8 weeks, at least about 12 weeks, at least about 16 weeks, at
least about 20 weeks, at least about 24 weeks, at least about 28
weeks, at least about 32 weeks, at least about 36 weeks, at least
about 40 weeks, at least about 44 weeks, at least about 48 weeks,
or at least about 52 weeks.
[0219] Furthermore, the duration of periodicity may be at least
about 1 week, at least about 2 weeks, at least about 3 weeks, at
least about 4 weeks, at least about 5 weeks, at least about 6
weeks, at least about 7 weeks, at least about 8 weeks, at least
about 9 weeks, at least about 10 weeks, at least about 11 weeks, at
least about 12 weeks, at least about 15 weeks, at least about 20
weeks, at least about 25 weeks, at least about 30 weeks, at least
about 35 weeks, at least about 40 weeks, at least about 45 weeks,
at least about 50 weeks, at least about 55 weeks, at least about 60
weeks, at least about 70 weeks, at least about 80 weeks, at least
about 90 weeks, or at least about 100 weeks.
[0220] The term "treated," "treating" or "treatment" includes the
diminishment or alleviation of at least one symptom associated or
caused by the state, disorder or disease being treated. For
example, treatment can be diminishment of one or more symptoms of a
disorder or complete eradication of a disorder. "Treatment" or
"treating" (e.g., treating psoriasis) means achieving or
maintaining a therapeutic objective. "Treatment" or "treating" can
mean maintaining a response to a prior treatment (e.g., a prior
response achieved following administration of a first dose amount
according to a first periodicity; or achieved following
administration of a first dose amount according to a first
periodicity and a second dose amount according to a second
periodicity; or achieved following administration of a first dose
amount according to a first periodicity and a first or second dose
amount according to a second periodicity, and a first, second, or
third dose amount according to a third periodicity. "Treatment of"
or "treating" psoriasis may mean achieving or maintaining a PGA
score of 0/1 or a PASI 50, PASI 75, PASI 90, or PASI 100 response
score for a period of time during or following treatment (e.g., for
at least 2, 4, 6, 8, 10, 12, 14, 16, 18, 20, 22, 24, 26, 28, 30,
32, 34, 36, 38, 40, 42, 46, 48, 50, 52, 54, 56, 58 or 60 weeks or
longer). "Treatment of" or "treating" psoriasis may also mean
achieving or maintaining a health-related quality of life (HRQOL)
outcome. HRQOL outcomes include Dermatology Life Quality Index
(DLQI), visual analog scales for Ps-related (VAS-Ps) and psoriatic
arthritis-related (VAS-PsA) pain, Short Form 36 Health Survey
Mental (MCS) and Physical (PCS) Component Summary scores, and Total
Activity Impairment (TAI) scores. "Treatment of" or "treating"
psoriasis may also mean achieving or maintaining a minimum
clinically important difference (MCID) for any of the HRQOL
outcomes provided herein, e.g., any one or combination of DLQI,
VAS-Ps, VAS-PsA, MCS, PCS and TAI. "Treatment of" or "treating"
psoriasis may also mean achieving or maintaining a minimum
clinically important difference (MCID) response rate for any of the
HRQOL outcomes provided herein, e.g., any one or combination of
DLQI, VAS-Ps, VAS-PsA, MCS, PCS and TAI. "Treatment of" or
"treating" psoriasis may also mean achieving or maintaining a
clinically meaningful reduction in any of the HRQOL outcomes
provided herein, e.g., any one or combination of DLQI, VAS-Ps,
VAS-PsA, MCS, PCS and TAI. "Treatment of" or "treating" psoriasis
may also mean achieving or maintaining a Nail Psoriasis Severity
Index (NAPSI) score for a period of time during or following
treatment (e.g., for at least 2, 4, 6, 8, 10, 12, 14, 16, 18, 20,
22, 24, 26, 28, 30, 32, 34, 36, 38, 40, 42, 46, 48, 50, 52, 54, 56,
58 or 60 weeks or longer). "Treatment of" or "treating" psoriasis
may also mean achieving or maintaining any of the outcomes provided
herein in a certain percentage of a population of subjects (e.g.,
in at least about 10%, 15%, 20%, 25%, 30%, 35%, 40%, 45%, 50%, 55%,
60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or 100% of a
population of subjects).
[0221] The term "kit" as used herein refers to a packaged product
comprising components with which to administer the anti-IL-12,
anti-IL-23 antibody of the invention for treatment of a IL-12
related disorder. The kit preferably comprises a box or container
that holds the components of the kit. The box or container is
affixed with a label or a Food and Drug Administration approved
protocol. The box or container holds components of the invention
which are preferably contained within plastic, polyethylene,
polypropylene, ethylene, or propylene vessels. The vessels can be
capped-tubes or bottles. The kit can also include instructions for
administering an anti-IL-12, anti-IL-23 antibody.
[0222] Various aspects of the invention are described in further
detail in the following subsections.
I. Human Antibodies that Bind to the p40 Subunit of Human
IL-12/Human IL-23
[0223] This invention provides methods and compositions for using
human antibodies, or antigen-binding portions thereof, that bind to
human IL-12 for the treatment of psoriasis. The invention also
includes methods and compositions for using an antibody which binds
both IL-12 and IL-23. Preferably, the human antibodies used in the
invention are recombinant, neutralizing human anti-hIL-12/IL-23
antibodies.
[0224] In one embodiment, the antibody used in the invention is the
antibody ABT-874 (see U.S. Pat. No. 6,914,128). ABT-874 is a fully
human antibody against interleukin 12 (IL-12) and IL-23. It binds
with great affinity to the p40 subunit common to both IL-12 and
IL-23, validated targets in the treatment of psoriasis (Ps).
[0225] Antibodies that bind to the p40 subunit of human IL-12/IL-23
can be selected, for example, by screening one or more human
V.sub.L and V.sub.H cDNA libraries with hIL-12, such as by phage
display techniques as described in Example 1 of U.S. Pat. No.
6,914,128. Screening of human V.sub.L and V.sub.H cDNA libraries
initially identified a series of anti-IL-12 antibodies of which one
antibody, referred to herein as "Joe 9" (or "Joe 9 wild type"), was
selected for further development. Joe 9 is a relatively low
affinity human IL-12 antibody (e.g., a K.sub.off of about 0.1
sec.sup.-1), yet is useful for specifically binding and detecting
hIL-12. The affinity of the Joe 9 antibody was improved by
conducting mutagenesis of the heavy and light chain CDRs, producing
a panel of light and heavy chain variable regions that were "mixed
and matched" and further mutated, leading to numerous additional
anti-hIL-12 antibodies with increased affinity for hIL-12 (see
Example 1, table 2 of U.S. Pat. No. 6,914,128 (see table 2 of
Appendix A attached hereto)) and the sequence alignments of FIGS.
1A-D of U.S. Pat. No. 6,914,128 (see FIG. 8A-D herein).
[0226] Of these antibodies, the human anti-hIL-12 antibody referred
to herein as Y61 demonstrated a significant improvement in binding
affinity (e.g., a K.sub.off of about 2.times.10.sup.-4 sec.sup.-1).
The Y61 anti-hIL-12 antibody was selected for further affinity
maturation by individually mutating specific amino acids residues
within the heavy and light chain CDRs Amino acids residues of Y61
were selected for site-specific mutation (selective mutagenesis
approach) based on the amino acid residue occupying a preferred
selective mutagenesis position, contact and/or a hypermutation
position. A summary of the substitutions at selected positions in
the heavy and light chain CDRs is shown in FIGS. 2A-2H of U.S. Pat.
No. 6,914,128 (FIGS. 9A-H herein). A preferred recombinant
neutralizing antibody of the invention, referred to herein as J695
(also referred to as ABT-874 (Abbott Laboratories), resulted from a
Gly to Tyr substitution at position 50 of the light chain CDR2 of
Y61, and a Gly to Tyr substitution at position 94 of the light
chain CDR3 of Y61.
[0227] Amino acid sequence alignments of the heavy and light chain
variable regions of a panel of anti-IL-12 antibodies used in the
invention, on the lineage from Joe 9 wild type to J695, are shown
in FIGS. 1A-1D of U.S. Pat. No. 6,914,128 (FIGS. 8A-D herein).
These sequence alignments allowed for the identification of
consensus sequences for preferred heavy and light chain variable
regions of antibodies of the invention that bind hIL-12, as well as
consensus sequences for the CDR3, CDR2, and CDR1, on the lineage
from Joe 9 to J695. Moreover, the Y61 mutagenesis analysis
summarized in FIGS. 2A-2H of U.S. Pat. No. 6,914,128 (FIGS. 9A-H
herein) allowed for the identification of consensus sequences for
heavy and light chain variable regions that bind hIL-12, as well as
consensus sequences for the CDR3, CDR2, and CDR1 that bind hIL-12
on the lineage from Y61 to J695 that encompasses sequences with
modifications from Y61 yet that retain good hIL-12 binding
characteristics. Preferred CDR, VH and VL sequences of the
invention (including consensus sequences) as identified by sequence
identifiers in the attached Sequence Listing, are summarized
below.
TABLE-US-00001 SEQ ID ANTIBODY NO: CHAIN REGION SEQUENCE 1
Consensus CDR H3 (H/S)-G-S-(H/Y)-D- Joe 9 to (N/T/Y) J695 2
Consensus CDR L3 Q-(S/T)-Y-(D/E)-(S/R/K)- Joe 9 to
(S/G/Y)-(L/F/T/S)- J695 (R/S/T/W/H)-(G/P)- (S/T/A/L)-(R/S/M/T/L)-
(V/I/T/M/L) 3 Consensus CDR H2 F-I-R-Y-D-G-S-N-K-Y-Y-A- Joe 9 to
D-S-V-K-G J695 4 Consensus CDR L2 (G/Y)-N-(D/S)-(Q/N)-R-P- Joe 9 to
S J695 5 Consensus CDR H1 F-T-F-S-(S/E)-Y-G-M-H Joe 9 to J695 6
Consensus CDR L1 (S/T)-G-(G/S)-(R/S)-S-N- Joe 9 to
I-(G/V)-(S/A)-(N/G/Y)- J695 (T/D)-V-(K/H) 7 Consensus VH (full VH
sequence; see Joe 9 to sequence listing) J695 8 Consensus VL (full
VL sequence; see Joe 9 to sequence listing) J695 9 Consensus CDR H3
H-(G/V/C/H)-(S/T)- Y61 to J695 (H/T/V/R/I)-(D/S)- (N/K/A/T/S/F/W/H)
10 Consensus CDR L3 Q-S-Y-(D/S)-(Xaa)- Y61 to J695
(G/D/Q/L/F/R/H/N/Y)-T-H- P-A-L-L 11 Consensus CDR H2
(F/T/Y)-I-(R/A)-Y- Y61 to J695 (D/S/E/A)-(G/R)-S-(Xaa)-
K-(Y/E)-Y-A-D-S-V-K-G 12 Consensus CDR L2 (G/Y/S/T/N/Q)-N-D-Q-R-P-
Y61 to J695 S 13 Consensus CDR H1 F-T-F-(Xaa)-(Xaa)-(Y/H)- Y61 to
J695 (G/M/A/N/S)-M-H 14 Consensus CDR L1 S-G-G-R-S-N-I-G- Y61 to
J695 (S/C/R/N/D/T)-(N/M/I)- (T/Y/D/H/K/P)-V-K 15 Consensus VH (full
VH sequence; see Y61 to J695 sequence listing) 16 Consensus VL
(full VL sequence; see Y61 to J695 sequence listing) 17 Y61 CDR H3
H-G-S-H-D-N 18 Y61 CDR L3 Q-S-Y-D-R-G-T-H-P-A-L-L 19 Y61 CDR H2
F-I-R-Y-D-G-S-N-K-Y-Y-A- D-S-V-K-G 20 Y61 CDR L2 G-N-D-Q-R-P-S 21
Y61 CDR H1 F-T-F-S-S-Y-G-M-H 22 Y61 CDR L1 S-G-G-R-S-N-I-G-S-N-T-V-
K 23 Y61 VH (full VH sequence; see sequence listing) 24 Y61 VL
(full VL sequence; see sequence listing) 25 J695 CDR H3 H-G-S-H-D-N
26 J695 CDR L3 Q-S-Y-D-R-Y-T-H-P-A-L-L 27 J695 CDR H2
F-I-R-Y-D-G-S-N-K-Y-Y-A- D-S-V-K-G 28 J695 CDR L2 Y-N-D-Q-R-P-S 29
J695 CDR H1 F-T-F-S-S-Y-G-M-H 30 J695 CDR L1
S-G-S-R-S-N-I-G-S-N-T-V- K 31 J695 VH (full VH sequence; see
sequence listing) 32 J695 VL (full VL sequence; see sequence
listing)
[0228] Antibodies produced from affinity maturation of Joe 9 wild
type were functionally characterized by surface plasmon resonance
analysis to determine the K.sub.d and K.sub.off rate. A series of
antibodies were produced having a K.sub.off rate within the range
of about 0.1 s.sup.-1 to about 1.times.10.sup.-5 s.sup.-1, and more
preferably a K.sub.off of about 1.times.10.sup.-4 s.sup.-1 to
1.times.10.sup.-5 s.sup.-1 or less. Antibodies were also
characterized in vitro for their ability to inhibit
phytohemagglutinin (PHA) blast proliferation, as described in
Example 3 of U.S. Pat. No. 6,914,128. A series of antibodies were
produced having an IC.sub.50 value in the range of about
1.times.10.sup.-6 M to about 1.times.10.sup.-11 M, more preferably
about 1.times.10.sup.-10 M to 1.times.10.sup.-11 M or less.
[0229] Accordingly, in one aspect, the invention provides methods
and compositions for using an isolated human antibody, or
antigen-binding portion thereof, that binds to human IL-12 and
dissociates from human IL-12 with a K.sub.off rate constant of 0.1
s.sup.-1 or less, as determined by surface plasmon resonance, or
which inhibits phytohemagglutinin blast proliferation in an in
vitro phytohemagglutinin blast proliferation assay (PHA assay) with
an IC.sub.50 of 1.times.10.sup.-6 M or less. In preferred
embodiments, the isolated human IL-12 antibody, or an
antigen-binding portion thereof, dissociates from human IL-12 with
a K.sub.off rate constant of 1.times.10.sup.-2 s.sup.-1 or less, or
inhibits phytohemagglutinin blast proliferation in an in vitro PHA
assay with an IC.sub.50 of 1.times.10.sup.-7 M or less. In more
preferred embodiments, the isolated human IL-12 antibody, or an
antigen-binding portion thereof, dissociates from human IL-12 with
a K.sub.off rate constant of 1.times.10.sup.-3 s.sup.-1 or less, or
inhibits phytohemagglutinin blast proliferation in an in vitro PHA
assay with an IC.sub.50 of 1.times.10.sup.-8 M or less. In more
preferred embodiments, the isolated human IL-12 antibody, or an
antigen-binding portion thereof, dissociates from human IL-12 with
a K.sub.off rate constant of 1.times.10.sup.-4 s.sup.-1 or less, or
inhibits phytohemagglutinin blast proliferation in an in vitro PHA
assay with an IC.sub.50 of 1.times.10.sup.-9 M or less. In more
preferred embodiments, the isolated human IL-12 antibody, or an
antigen-binding portion thereof, dissociates from human IL-12 with
a K.sub.off rate constant of 1.times.10.sup.-5 s.sup.-1 or less, or
inhibits phytohemagglutinin blast proliferation in an in vitro PHA
assay with an IC.sub.50 of 1.times.10.sup.-10 M or less. In even
more preferred embodiments, the isolated human IL-12 antibody, or
an antigen-binding portion thereof, dissociates from human IL-12
with a K.sub.off rate constant of 1.times.10.sup.-5 s.sup.-1 or
less, or inhibits phytohemagglutinin blast proliferation in an in
vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-11 M or
less.
[0230] The dissociation rate constant (K.sub.off) of an IL-12
antibody can be determined by surface plasmon resonance (see
Example 5 of U.S. Pat. No. 6,914,128). Generally, surface plasmon
resonance analysis measures real-time binding interactions between
ligand (recombinant human IL-12 immobilized on a biosensor matrix)
and analyte (antibodies in solution) by surface plasmon resonance
(SPR) using the BIAcore system (Pharmacia Biosensor, Piscataway,
N.J.). Surface plasmon analysis can also be performed by
immobilizing the analyte (antibodies on a biosensor matrix) and
presenting the ligand (recombinant IL-12 in solution).
Neutralization activity of IL-12 antibodies, or antigen binding
portions thereof, can be assessed using one or more of several
suitable in vitro assays (see Example 3 of U.S. Pat. No.
6,914,128).
[0231] It is well known in the art that antibody heavy and light
chain CDRs play an important role in the binding
specificity/affinity of an antibody for an antigen. Accordingly,
the invention encompasses human antibodies having light and heavy
chain CDRs of Joe 9, as well as other antibodies having CDRs that
have been modified to improve the binding specificity/affinity of
the antibody. As demonstrated in Example 1 of U.S. Pat. No.
6,914,128, a series of modifications to the light and heavy chain
CDRs results in affinity maturation of human anti-hIL-12
antibodies. The heavy and light chain variable region amino acid
sequence alignments of a series of human antibodies ranging from
Joe 9 wild type to J695 that bind human IL-12 is shown in FIGS.
1A-1D of U.S. Pat. No. 6,914,128 (FIGS. 8A-D herein). Consensus
sequence motifs for the CDRs of antibodies can be determined from
the sequence alignment. For example, a consensus motif for the VH
CDR3 of the lineage from Joe 9 to J695 comprises the amino acid
sequence: (H/S)-G-S-(H/Y)-D-(N/T/Y) (SEQ ID NO: 1), which
encompasses amino acids from position 95 to 102 of the consensus
HCVR shown in SEQ ID NO: 7. A consensus motif for the VL CDR3
comprises the amino acid sequence:
Q-(S/T)-Y-(D/E)-(S/R/K)-(S/G/Y)-(L/F/T/S)-(R/S/T/W/H)-(G/P)-(S/T/A/L)-(R/-
S/M/T/L-V/I/T/M/L) (SEQ ID NO: 2), which encompasses amino acids
from position 89 to 97 of the consensus LCVR shown in SEQ ID NO:
8.
[0232] Accordingly, in another aspect, the invention provides
methods and compositions comprising an isolated human antibody, or
an antigen-binding portion thereof, which has the following
characteristics:
[0233] a) inhibits phytohemagglutinin blast proliferation in an in
vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-6 M or
less;
[0234] b) has a heavy chain CDR3 comprising the amino acid sequence
of SEQ ID NO: 1; and
[0235] c) has a light chain CDR3 comprising the amino acid sequence
of SEQ ID NO: 2.
[0236] In a preferred embodiment, the antibody further comprises a
VH CDR2 comprising the amino acid sequence:
F-I-R-Y-D-G-S-N-K-Y-Y-A-D-S-V-K-G (SEQ ID NO: 3) (which encompasses
amino acids from position 50 to 65 of the consensus HCVR comprising
the amino acid sequence SEQ ID NO: 7) and further comprises a VL
CDR2 comprising the amino acid sequence: (G/Y)-N-(D/S)-(Q/N)-R-P-S
(SEQ ID NO: 4) (which encompasses amino acids from position 50 to
56 of the consensus LCVR comprising the amino acid sequence SEQ ID
NO: 8).
[0237] In another preferred embodiment, the antibody further
comprises a VH CDR1 comprising the amino acid sequence:
F-T-F-S-(S/E)-Y-G-M-H (SEQ ID NO: 5) (which encompasses amino acids
from position 27 to 35 of the consensus HCVR comprising the amino
acid sequence SEQ ID NO: 7) and further comprises a VL CDR1
comprising the amino acid sequence:
(S/T)-G-(G/S)-(R/S)-S-N-I-(G/V)-(S/A)-(N/G/Y)-(T/D)-V--(K/H) (SEQ
ID NO: 6) (which encompasses amino acids from position 24 to 34 of
the consensus LCVR comprising the amino acid sequence SEQ ID NO:
8).
[0238] In yet another preferred embodiment, the antibody used in
the invention comprises a HCVR comprising the amino acid sequence
of SEQ ID NO: 7 and a LCVR comprising the amino acid sequence of
SEQ ID NO: 8.
[0239] Additional consensus motifs can be determined based on the
mutational analysis performed on Y61 that led to the J695 antibody
(summarized in FIGS. 2A-2H of U.S. Pat. No. 6,914,128; FIGS. 9A-H
herein). As demonstrated by the graphs shown in FIGS. 2A-2H of U.S.
Pat. No. 6,914,128 (FIGS. 9A-H herein), certain residues of the
heavy and light chain CDRs of Y61 were amenable to substitution
without significantly impairing the hIL-12 binding properties of
the antibody. For example, individual substitutions at position 30
in CDR H1 with twelve different amino acid residues did not
significantly reduce the K.sub.off rate of the antibody, indicating
that is position is amenable to substitution with a variety of
different amino acid residues. Thus, based on the mutational
analysis (i.e., positions within Y61 that were amenable to
substitution by other amino acid residues) consensus motifs were
determined. The consensus motifs for the heavy and light chain
CDR3s are shown in SEQ ID NOs: 9 and 10, respectively, consensus
motifs for the heavy and light chain CDR2s are shown in SEQ ID NOs:
11 and 12, respectively, and consensus motifs for the heavy and
light chain CDR1s are shown in SEQ ID NOs: 13 and 14, respectively.
Consensus motifs for the VH and VL regions are shown in SEQ ID NOs:
15 and 16, respectively.
[0240] Accordingly, in one aspect, the invention includes an
isolated human antibody, or an antigen-binding portion thereof,
which has the following characteristics:
[0241] a) inhibits phytohemagglutinin blast proliferation in an in
vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-9 M or
less;
[0242] b) has a heavy chain CDR3 comprising the amino acid sequence
of SEQ ID NO: 9; and
[0243] c) has a light chain CDR3 comprising the amino acid sequence
of SEQ ID NO: 10.
[0244] In a preferred embodiment, the antibody further comprises a
VH CDR2 comprising the amino acid sequence of SEQ ID NO: 11 and
further comprises a VL CDR2 comprising the amino acid sequence of
SEQ ID NO: 12.
[0245] In another preferred embodiment, the antibody further
comprises a VH CDR1 comprising the amino acid sequence of SEQ ID
NO: 13 and further comprises a VL CDR1 comprising the amino acid
sequence of SEQ ID NO: 14.
[0246] In yet another preferred embodiment, the antibody used in
the invention comprises a HCVR comprising the amino acid sequence
of SEQ ID NO: 15 and a LCVR comprising the amino acid sequence of
SEQ ID NO: 16.
[0247] A preferred antibody used in the invention, the human
anti-hIL-12 antibody Y61, can be produced by affinity maturation of
Joe 9 wild type by PCR mutagenesis of the CDR3 (as described in
Example 1 of U.S. Pat. No. 6,914,128). Y61 had an improved
specificity/binding affinity determined by surface plasmon
resonance and by in vitro neutralization assays. The heavy and
light chain CDR3s of Y61 are shown in SEQ ID NOs: 17 and 18,
respectively, the heavy and light chain CDR2s of Y61 are shown in
SEQ ID NOs: 19 and 20, respectively, and the heavy and light chain
CDR1s of Y61 are shown in SEQ ID NOs: 21 and 22, respectively. The
VH of Y61 has the amino acid sequence of SEQ ID NO: 23 and the VL
of Y61 has the amino acid sequence of SEQ ID NO: 24 (these
sequences are also shown in FIGS. 1A-1D of U.S. Pat. No. 6,914,128
(FIGS. 8A-D herein) aligned with Joe9).
[0248] Accordingly, in another aspect, the invention features use
of an isolated human antibody, or an antigen-binding portion
thereof, which
[0249] a) inhibits phytohemagglutinin blast proliferation in an in
vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-9 M or
less;
[0250] b) has a heavy chain CDR3 comprising the amino acid sequence
of SEQ ID NO: 17; and
[0251] c) has a light chain CDR3 comprising the amino acid sequence
of SEQ ID NO: 18.
[0252] In a preferred embodiment, the isolated human antibody, or
an antigen-binding portion thereof, used in the methods and
compositions of the invention has a heavy chain CDR2 comprising the
amino acid sequence of SEQ ID NO: 19 and a light chain CDR2
comprising the amino acid sequence of SEQ ID NO: 20.
[0253] In another preferred embodiment, the isolated human
antibody, or an antigen-binding portion thereof, used in the
methods and compositions of the invention, has a heavy chain CDR1
comprising the amino acid sequence of SEQ ID NO: 21 and a light
chain CDR1 comprising the amino acid sequence of SEQ ID NO: 22.
[0254] In yet another preferred embodiment, the isolated human
antibody, or an antigen-binding portion thereof, used in the
methods and compositions of the invention comprising a the heavy
chain variable region comprising the amino acid sequence of SEQ ID
NO: 23, and a light chain variable region comprising the amino acid
sequence of SEQ ID NO: 24.
[0255] In certain embodiments, the full length antibody comprises a
heavy chain constant region, such as IgG1, IgG2, IgG3, IgG4, IgM,
IgA and IgE constant regions, and any allotypic variant therein as
described in Kabat (Kabat, E. A., et al. (1991) Sequences of
Proteins of Immunological Interest, Fifth Edition, U.S. Department
of Health and Human Services, NIH Publication No. 91-3242).
Preferably, the antibody heavy chain constant region is an IgG1
heavy chain constant region. Alternatively, the antibody portion
can be an Fab fragment, an F(ab'.sub.2) fragment or a single chain
Fv fragment.
[0256] Modifications of individual residues of Y61 led to the
production of a panel of antibodies shown in FIGS. 2A-2H of U.S.
Pat. No. 6,914,128 (FIGS. 9A-H herein). The specificity/binding
affinity of each antibody was determined by surface plasmon
resonance and/or by in vitro neutralization assays.
[0257] Accordingly, in another aspect, the invention features an
isolated human antibody, or an antigen-binding portion thereof,
which
[0258] a) inhibits phytohemagglutinin blast proliferation in an in
vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-9 M or
less;
[0259] b) has a heavy chain CDR3 comprising the amino acid sequence
selected from the group consisting of SEQ ID NO: 404-SEQ ID NO:
469; and
[0260] c) has a light chain CDR3 comprising the amino acid sequence
selected from the group consisting of SEQ ID NO: 534-SEQ ID NO:
579.
[0261] In preferred embodiment, the isolated human antibody, or an
antigen-binding portion thereof, used in the methods and
compositions of the invention has a heavy chain CDR2 comprising the
amino acid sequence selected from the group consisting of SEQ ID
NO:335-SEQ ID NO: 403; and a light chain CDR2 comprising the amino
acid sequence selected from the group consisting of SEQ ID NO:
506-SEQ ID NO: 533.
[0262] In another preferred embodiment, the isolated human
antibody, or an antigen-binding portion thereof, has a heavy chain
CDR1 comprising the amino acid sequence selected from the group
consisting of SEQ ID NO: 288-SEQ ID NO: 334; and a light chain CDR1
comprising the amino acid sequence selected from the group
consisting of SEQ ID NO: 470-SEQ ID NO: 505.
[0263] In yet another preferred embodiment, the isolated human
antibody, or an antigen-binding portion thereof, comprising a the
heavy chain variable region comprising the amino acid sequence of
SEQ ID NO: 23, and a light chain variable region comprising the
amino acid sequence of SEQ ID NO: 24.
[0264] In certain embodiments, the full length antibody comprising
a heavy chain constant region such as IgG1, IgG2, IgG3, IgG4, IgM,
IgA and IgE constant regions and any allotypic variant therein as
described in Kabat (, Kabat, E. A., et al. (1991) Sequences of
Proteins of Immunological Interest, Fifth Edition, U.S. Department
of Health and Human Services, NIH Publication No. 91-3242).
Preferably, the antibody heavy chain constant region is an IgG1
heavy chain constant region. Alternatively, the antibody portion
can be a Fab fragment, an F(ab'.sub.2) fragment or a single chain
Fv fragment.
[0265] A particularly preferred recombinant, neutralizing antibody,
J695, which may be used in the invention was produced by
site-directed mutagenesis of contact and hypermutation amino acids
residues of antibody Y61 (see Example 2 of U.S. Pat. No. 6,914,128
and section III below). J695 differs from Y61 by a Gly to Tyr
substitution in Y61 at position 50 of the light chain CDR2 and by a
Gly to Tyr substitution at position 94 of the light chain CDR3. The
heavy and light chain CDR3s of J695 are shown in SEQ ID NOs: 25 and
26, respectively, the heavy and light chain CDR2s of J695 are shown
in SEQ ID NOs: 27 and 28, respectively, and the heavy and light
chain CDR1s of J695 are shown in SEQ ID NOs: 29 and 30,
respectively. The VH of J695 has the amino acid sequence of SEQ ID
NO: 31 and the VL of J695 has the amino acid sequence of SEQ ID NO:
32 (these sequences are also shown in FIGS. 1A-1D of U.S. Pat. No.
6,914,128 (FIGS. 8A-D herein), aligned with Joe9).
[0266] Accordingly, in another aspect, the invention features an
isolated human antibody, or an antigen-binding portion thereof,
which a) inhibits phytohemagglutinin blast proliferation in an in
vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-9 M or less;
b) has a heavy chain CDR3 comprising the amino acid sequence of SEQ
ID NO: 25; and c) has a light chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 26.
[0267] In preferred embodiment, the isolated human antibody, or an
antigen-binding portion thereof, used in the invention has a heavy
chain CDR2 comprising the amino acid sequence of SEQ ID NO: 27, and
a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:
28.
[0268] In another preferred embodiment, the isolated human
antibody, or an antigen-binding portion thereof, used in the
invention has a heavy chain CDR1 comprising the amino acid sequence
of SEQ ID NO: 29, and a light chain CDR1 comprising the amino acid
sequence of SEQ ID NO: 30.
[0269] In yet another preferred embodiment, the isolated human
antibody, or an antigen-binding portion thereof, used in the
invention has a heavy chain variable region comprising the amino
acid sequence of SEQ ID NO: 31, and a light chain variable region
comprising the amino acid sequence of SEQ ID NO: 32.
[0270] In certain embodiments, the full length antibody comprises a
heavy chain constant region, such as IgG1, IgG2, IgG3, IgG4, IgM,
IgA and IgE constant regions and any allotypic variant therein as
described in Kabat (, Kabat, E. A., et al. (1991) Sequences of
Proteins of Immunological Interest, Fifth Edition, U.S. Department
of Health and Human Services, NIH Publication No. 91-3242).
Preferably, the antibody heavy chain constant region is an IgG1
heavy chain constant region. Alternatively, the antibody portion
can be an Fab fragment, an F(ab'.sub.2) fragment or a single chain
Fv fragment.
[0271] Additional mutations in the preferred consensus sequences
for CDR3, CDR2, and CDR1 of antibodies on the lineage from Joe 9 to
J695, or from the lineage Y61 to J695, can be made to provide
additional anti-IL-12 antibodies of the invention. Such methods of
modification can be performed using standard molecular biology
techniques, such as by PCR mutagenesis, targeting individual
contact or hypermutation amino acid residues in the light chain
and/or heavy chain CDRs-, followed by kinetic and functional
analysis of the modified antibodies as described herein (e.g.,
neutralization assays described in Example 3 of U.S. Pat. No.
6,914,128, and by BIAcore analysis, as described in Example 5 of
U.S. Pat. No. 6,914,128).
[0272] Accordingly, in another aspect the invention features use of
an isolated human antibody, or an antigen-binding portion thereof,
which
[0273] a) inhibits phytohemagglutinin blast proliferation in an in
vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-6 M or
less;
[0274] b) comprises a heavy chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino
acid sequence of SEQ ID NO: 3 and a heavy chain CDR1 comprising the
amino acid sequence of SEQ ID NO: 5, or a mutant thereof having one
or more amino acid substitutions at a preferred selective
mutagenesis position or a hypermutation position, wherein said
mutant has a k.sub.off rate no more than 10-fold higher than the
antibody comprising a heavy chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 1, a heavy chain CDR2 comprising the amino
acid sequence of SEQ ID NO: 3, and a heavy chain CDR1 comprising
the amino acid sequence of SEQ ID NO: 5; and
[0275] c) comprises a light chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 2, a light chain CDR2 comprising the amino
acid sequence of SEQ ID NO: 4, and a light chain CDR1 comprising
the amino acid sequence of SEQ ID NO: 6, or a mutant thereof having
one or more amino acid substitutions at a preferred selective
mutagenesis position or a hypermutation position, wherein said
mutant has a k.sub.off rate no more than 10-fold higher than the
antibody comprising a light chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 2, a light chain CDR2 comprising the amino
acid sequence of SEQ ID NO: 4, and a light chain CDR1 comprising
the amino acid sequence of SEQ ID NO: 6.
[0276] In another aspect the invention features use of an isolated
human antibody, or an antigen-binding portion thereof, which
[0277] a) inhibits phytohemagglutinin blast proliferation in an in
vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-9 M or
less;
[0278] b) comprises a heavy chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 9, a heavy chain CDR2 comprising the amino
acid sequence of SEQ ID NO: 11 and a heavy chain CDR1 comprising
the amino acid sequence of SEQ ID NO: 13, or a mutant thereof
having one or more amino acid substitutions at a preferred
selective mutagenesis position, contact position or a hypermutation
position, wherein said mutant has a k.sub.off rate no more than
10-fold higher than the antibody comprising a heavy chain CDR3
comprising the amino acid sequence of SEQ ID NO: 9, a heavy chain
CDR2 comprising the amino acid sequence of SEQ ID NO: 11, and a
heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:
13; and
[0279] c) comprises a light chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 10, a light chain CDR2 comprising the amino
acid sequence of SEQ ID NO: 12, and a light chain CDR1 comprising
the amino acid sequence of SEQ ID NO: 14, or a mutant thereof
having one or more amino acid substitutions at a preferred
selective mutagenesis position, contact position or a hypermutation
position, wherein said mutant has a k.sub.off rate no more than
10-fold higher than the antibody comprising a light chain CDR3
comprising the amino acid sequence of SEQ ID NO: 10, a light chain
CDR2 comprising the amino acid sequence of SEQ ID NO: 12, and a
light chain CDR1 comprising the amino acid sequence of SEQ ID NO:
14.
[0280] An ordinarily skilled artisan will also appreciate that
additional mutations to the CDR regions of an antibody, for example
in Y61 or in J695, can be made to provide additional anti-IL-12
antibodies of the invention. Such methods of modification can be
performed using standard molecular biology techniques, as described
above. The functional and kinetic analysis of the modified
antibodies can be performed as described in Example 3 of U.S. Pat.
No. 6,914,128 and Example 5 of U.S. Pat. No. 6,914,128,
respectively. Modifications of individual residues of Y61 that led
to the identification of J695 are shown in FIGS. 2A-2H of U.S. Pat.
No. 6,914,128 (FIGS. 9A-H herein) and are described in Example 2 of
U.S. Pat. No. 6,914,128.
[0281] Accordingly, in another aspect the invention features use of
an isolated human antibody, or an antigen-binding portion thereof,
which
[0282] a) inhibits phytohemagglutinin blast proliferation in an in
vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-9 M or
less;
[0283] b) comprises a heavy chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 17, a heavy chain CDR2 comprising the amino
acid sequence of SEQ ID NO: 19 and a heavy chain CDR1 comprising
the amino acid sequence of SEQ ID NO: 21, or a mutant thereof
having one or more amino acid substitutions at a preferred
selective mutagenesis position or a hypermutation position, wherein
said mutant has a k.sub.off rate no more than 10-fold higher than
the antibody comprising a heavy chain CDR3 comprising the amino
acid sequence of SEQ ID NO: 17, a heavy chain CDR2 comprising the
amino acid sequence of SEQ ID NO: 19, and a heavy chain CDR1
comprising the amino acid sequence of SEQ ID NO: 21; and
[0284] c) comprises a light chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 18, a light chain CDR2 comprising the amino
acid sequence of SEQ ID NO: 20, and a light chain CDR1 comprising
the amino acid sequence of SEQ ID NO: 22, or a mutant thereof
having one or more amino acid substitutions at a preferred
selective mutagenesis position or a hypermutation position, wherein
said mutant has a k.sub.off rate no more than 10-fold higher than
the antibody comprising a light chain CDR3 comprising the amino
acid sequence of SEQ ID NO: 18, a light chain CDR2 comprising the
amino acid sequence of SEQ ID NO: 20, and a light chain CDR1
comprising the amino acid sequence of SEQ ID NO: 22.
[0285] In another aspect the invention features use of an isolated
human antibody, or an antigen-binding portion thereof, which
[0286] a) inhibits phytohemagglutinin blast proliferation in an in
vitro PHA assay with an IC.sub.50 of 1.times.10.sup.-9 M or
less;
[0287] b) comprises a heavy chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 25, a heavy chain CDR2 comprising the amino
acid sequence of SEQ ID NO: 27 and a heavy chain CDR1 comprising
the amino acid sequence of SEQ ID NO: 29, or a mutant thereof
having one or more amino acid substitutions at a preferred
selective mutagenesis position or a hypermutation position, wherein
said mutant has a k.sub.off rate no more than 10-fold higher than
the antibody comprising a heavy chain CDR3 comprising the amino
acid sequence of SEQ ID NO: 25, a heavy chain CDR2 comprising the
amino acid sequence of SEQ ID NO: 27, and a heavy chain CDR1
comprising the amino acid sequence of SEQ ID NO: 29; and
[0288] c) comprises a light chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 26, a light chain CDR2 comprising the amino
acid sequence of SEQ ID NO: 28, and a light chain CDR1 comprising
the amino acid sequence of SEQ ID NO: 30, or a mutant thereof
having one or more amino acid substitutions at a preferred
selective mutagenesis position or a hypermutation position, wherein
said mutant has a k.sub.off rate no more than 10-fold higher than
the antibody comprising a light chain CDR3 comprising the amino
acid sequence of SEQ ID NO: 26, a light chain CDR2 comprising the
amino acid sequence of SEQ ID NO: 28, and a light chain CDR1
comprising the amino acid sequence of SEQ ID NO: 30.
[0289] In yet another embodiment, the invention provides use of an
isolated human antibodies, or antigen-binding portions thereof,
that neutralize the activity of human IL-12, and at least one
additional primate IL-12 selected from the group consisting of
baboon IL-12, marmoset IL-12, chimpanzee IL-12, cynomolgus IL-12
and rhesus IL-12, but which do not neutralize the activity of the
mouse IL-12.
II Selection of Recombinant Human Antibodies
[0290] Recombinant human antibodies which may be used in the
invention can be isolated by screening of a recombinant
combinatorial antibody library, preferably a scFv phage display
library, prepared using human VL and VH cDNAs prepared from mRNA
derived from human lymphocytes. Methods for identifying antibodies
which may be used in the methods and compositions of the invention
are described in U.S. Pat. No. 6,914,128, incorporated by reference
herein. Methodologies for preparing and screening such libraries
are known in the art. In addition to commercially available kits
for generating phage display libraries (e.g., the Pharmacia
Recombinant Phage Antibody System, catalog no. 27-9400-01; and the
Stratagene SurfZAP.TM. phage display kit, catalog no. 240612),
examples of methods and reagents particularly amenable for use in
generating and screening antibody display libraries can be found
in, for example, Kang et al. PCT Publication No. WO 92/18619;
Winter et al. PCT Publication No. WO 92/20791; Breitling et al. PCT
Publication No. WO 93/01288; McCafferty et al. PCT Publication No.
WO 92/01047; Garrard et al. PCT Publication No. WO 92/09690; Fuchs
et al. (1991) Bio/Technology 9:1370-1372; Hay et al. (1992) Hum
Antibod Hybridomas 3:81-85; Huse et al. (1989) Science
246:1275-1281; McCafferty et al., Nature (1990) 348:552-554;
Griffiths et al. (1993) EMBO J. 12:725-734; Hawkins et al. (1992) J
Mol Biol 226:889-896; Clackson et al. (1991) Nature 352:624-628;
Gram et al. (1992) PNAS 89:3576-3580; Garrad et al. (1991)
Bio/Technology 9:1373-1377; Hoogenboom et al. (1991) Nuc Acid Res
19:4133-4137; and Barbas et al. (1991) PNAS 88:7978-7982.
[0291] The antibody libraries used in this method are preferably
scFv libraries prepared from human VL and VH cDNAs. The scFv
antibody libraries are preferably screened using recombinant human
IL-12 as the antigen to select human heavy and light chain
sequences having a binding activity toward IL-12. To select for
antibodies specific for the p35 subunit of IL-12 or the p70
heterodimer, screening assays were performed in the presence of
excess free p40 subunit. Subunit preferences can be determined, for
example by, micro-Friguet titration, as described in Example 1 of
U.S. Pat. No. 6,914,128.
[0292] Once initial human VL and VH segments are selected, "mix and
match" experiments, in which different pairs of the selected VL and
VH segments are screened for IL-12 binding, are performed to select
preferred VL/VH pair combinations (see Example 1 of U.S. Pat. No.
6,914,128). Additionally, to further improve the affinity and/or
lower the off rate constant for hIL-12 binding, the VL and VH
segments of the preferred VL/VH pair(s) can be randomly mutated,
preferably within the CDR3 region of VH and/or VL, in a process
analogous to the in vivo somatic mutation process responsible for
affinity maturation of antibodies during a natural immune response.
This in vitro affinity maturation can be accomplished by amplifying
VH and VL regions using PCR primers complimentary to the VH CDR3 or
VL CDR3, respectively, which primers have been "spiked" with a
random mixture of the four nucleotide bases at certain positions
such that the resultant PCR products encode VH and VL segments into
which random mutations have been introduced into the VH and/or VL
CDR3 regions. These randomly mutated VH and VL segments can be
reselected and rescreened for binding to hIL-12 and sequences that
exhibit high affinity and a low off rate for IL-12 binding can be
selected. Table 2 of Appendix A of U.S. Pat. No. 6,914,128 (see
table 2 of Appendix A attached hereto) shows antibodies that
displayed altered binding specificity/affinity produced as a result
of in vitro affinity maturation.
[0293] Following selection, isolation and screening of an
anti-hIL-12 antibody of the invention from a recombinant
immunoglobulin display library, nucleic acid encoding the selected
antibody can be recovered from the phage particle(s) (e.g., from
the phage genome) and subcloned into other expression vectors by
standard recombinant DNA techniques. If desired, the nucleic acid
can be further manipulated to create other antibody forms of the
invention (e.g., linked to nucleic acid encoding additional
immunoglobulin domains, such as additional constant regions). To
express a recombinant human antibody isolated by screening of a
combinatorial library, the DNA encoding the antibody is cloned into
a recombinant expression vector and introduced into a mammalian
host cells, as described in further detail in Section IV below.
[0294] Methods for selecting human IL-12 binding antibodies by
phage display technology, and affinity maturation of selected
antibodies by random or site-directed mutagenesis of CDR regions
are described in further detail in Example 1 of U.S. Pat. No.
6,914,128.
[0295] As described in Example 1 of U.S. Pat. No. 6,914,128,
screening of human VL and VH cDNA libraries identified a series of
anti-IL-12 antibodies, of which the Joe 9 antibody was selected for
further development. A comparison of the heavy chain variable
region of Joe 9 with the heavy chain germline sequences selected
from the VBASE database, revealed that Joe 9 was similar to the
COS-3 germline sequence. COS-3 belongs to the V.sub.H3 family of
germline sequences.
[0296] The V.sub.H3 family is part of the human VH germline
repertoire which is grouped into seven families, V.sub.H1-V.sub.H7,
based on nucleotide sequence homology (Tomlinson et al. (1992) J.
Mol. Biol., 227, 776-798 and Cook et al. (1995) Immunology Today,
16, 237-242). The V.sub.H3 family contains the highest number of
members and makes the largest contribution to the germline
repertoire. For any given human V.sub.H3-germline antibody
sequence, the amino acid sequence identity within the entire
V.sub.H3 family is high (See e.g., Tomlinson et al. (1992) J. Mol.
Biol., 227, 776-798 and Cook et al. (1995) Immunology Today, 16,
237-242). The range of amino acid sequence identity between any two
germline VH sequences of the V.sub.H3 family varies from 69-98
residues out of approximately 100 VH residues, (i.e., 69-98% amino
acid sequence homology between any two germline VH sequences). For
most pairs of germline sequences there is at least 80 or more
identical amino acid residues, (i.e., at least 80% amino acid
sequence homology). The high degree of amino acid sequence homology
between the V.sub.H3 family members results in certain amino acid
residues being present at key sites in the CDR and framework
regions of the VH chain. These amino acid residues confer
structural features upon the CDRs.
[0297] Studies of antibody structures have shown that CDR
conformations can be grouped into families of canonical CDR
structures based on the key amino acid residues that occupy certain
positions in the CDR and framework regions. Consequently, there are
similar local CDR conformations in different antibodies that have
canonical structures with identical key amino acid residues
(Chothia et al. (1987) J. Mol. Biol., 196, 901-917 and Chothia et
al. (1989) Nature, 342, 877-883). Within the V.sub.H3 family there
is a conservation of amino acid residue identity at the key sites
for the CDR1 and CDR2 canonical structures (Chothia et al. (1992)
J. Mol. Biol., 227, 799-817).
[0298] The COS-3 germline VH gene, is a member of the V.sub.H3
family and is a variant of the 3-30 (DP-49) germline VH allele.
COS-3, differs from Joe9 VH amino acid sequences at only 5
positions. The high degree of amino acid sequence homology between
Joe9 VH and COS-3, and between Joe9 VH and the other V.sub.H3
family members also confers a high degree of CDR structural
homology (Chothia et al. (1992) J. Mol. Biol., 227, 799-817;
Chothia et al. (1987) J. Mol. Biol., 196, 901-917 and Chothia et
al. (1989) Nature, 342, 877-883).
[0299] The skilled artisan will appreciate that based on the high
amino acid sequence and canonical structural similarity to Joe 9,
other V.sub.H3 family members could also be used to generate
antibodies that bind to human IL-12. This can be performed, for
example, by selecting an appropriate VL by chain-shuffling
techniques (Winter et al. (1994) Annual Rev. Immunol., 12, 433-55),
or by the grafting of CDRs from a rodent or other human antibody
including CDRs from antibodies of this invention onto a V.sub.H3
family framework.
[0300] The human V lambda germline repertoire is grouped into 10
families based on nucleotide sequence homology (Williams et al.
(1996) J. Mol. Biol., 264, 220-232). A comparison of the light
chain variable region of Joe 9 with the light chain germline
sequences selected from the VBASE database, revealed that Joe 9 was
similar to the DPL8 lambda germline. The Joe9 VL differs from DPL8
sequence at only four framework positions, and is highly homologous
to the framework sequences of the other V.sub..lamda.1 family
members. Based on the high amino acid sequence homology and
canonical structural similarity to Joe 9, other V.sub..lamda.1
family members may also be used to generate antibodies that bind to
human IL-12. This can be performed, for example, by selecting an
appropriate VH by chain-shuffling techniques (Winter et al. Supra,
or by the grafting of CDRs from a rodent or other human antibody
including CDRs from antibodies of this invention onto a
V.sub..lamda.1 family framework.
[0301] The methods of the invention are intended to include
recombinant antibodies that bind to hIL-12, comprising a heavy
chain variable region derived from a member of the V.sub.H3 family
of germline sequences, and a light chain variable region derived
from a member of the V.sub..lamda.1 family of germline sequences.
Moreover, the skilled artisan will appreciate that any member of
the V.sub.H3 family heavy chain sequence can be combined with any
member of the V.sub..lamda.1 family light chain sequence.
[0302] Those skilled in the art will also appreciate that DNA
sequence polymorphisms that lead to changes in the amino acid
sequences of the germline may exist within a population (e.g., the
human population). Such genetic polymorphism in the germline
sequences may exist among individuals within a population due to
natural allelic variation. Such natural allelic variations can
typically result in 1-5% variance in the nucleotide sequence of the
a gene. Any and all such nucleotide variations and resulting amino
acid polymorphisms in germline sequences that are the result of
natural allelic variation are intended to be within the scope of
the invention.
[0303] Accordingly, in one aspect, the invention features an
isolated human antibody, or an antigen-binding portion thereof,
which has the following characteristics: [0304] a) that binds to
human IL-12 and dissociates from human IL-12 with a k.sub.off rate
constant of 0.1 s.sup.-1 or less, as determined by surface plasmon
resonance, or which inhibits phytohemagglutinin blast proliferation
in an in vitro phytohemagglutinin blast proliferation assay (PHA
assay) with an IC.sub.50 of 1.times.10.sup.-6M or less. [0305] b)
has a heavy chain variable region comprising an amino acid sequence
selected from a member of the V.sub.H3 germline family, wherein the
heavy chain variable region has a mutation at a contact or
hypermutation position with an activity enhancing amino acid
residue. [0306] c) has a light chain variable region comprising an
amino acid sequence selected from a member of the V.sub..lamda.1
germline family, wherein the light chain variable region has a
mutation at a preferred selective mutagenesis position, contact or
hypermutation position with an activity enhancing amino acid
residue.
[0307] In a preferred embodiment, the isolated human antibody, or
antigen binding has mutation in the heavy chain CDR3. In another
preferred embodiment, the isolated human antibody, or antigen
binding has mutation in the light chain CDR3. In another preferred
embodiment, the isolated human antibody, or antigen binding has
mutation in the heavy chain CDR2. In another preferred embodiment,
the isolated human antibody, or antigen binding has mutation in the
light chain CDR2. In another preferred embodiment, the isolated
human antibody, or antigen binding has mutation in the heavy chain
CDR1. In another preferred embodiment, the isolated human antibody,
or antigen binding has mutation in the light chain CDR1.
[0308] An ordinarily skilled artisan will appreciate that based on
the high amino acid sequence similarity between members of the
V.sub.H3 germline family, or between members of the light chain
V.sub..lamda.1 germline family, that mutations to the germlines
sequences can provide additional antibodies that bind to human
IL-12. Table 1 of U.S. Pat. No. 6,914,128 (see Table 1 of Appendix
A attached hereto) shows the germline sequences of the V.sub.H3
family members and demonstrates the significant sequence homology
within the family members. Also shown in table 1 of U.S. Pat. No.
6,914,128 (see table 1 of Appendix A, attached hereto) are the
germline sequences for V.sub..lamda.1 family members. The heavy and
light chain sequences of Joe 9 are provided as a comparison.
Mutations to the germline sequences of V.sub.H3 or V.sub..lamda.1
family members may be made, for example, at the same amino acid
positions as those made in the antibodies of the invention (e.g.
mutations in Joe 9). The modifications can be performed using
standard molecular biology techniques, such as by PCR mutagenesis,
targeting individual amino acid residues in the germline sequences,
followed by kinetic and functional analysis of the modified
antibodies as described herein (e.g., neutralization assays
described in Example 3 of U.S. Pat. No. 6,914,128, and by BIAcore
analysis, as described in Example 5 of U.S. Pat. No.
6,914,128).
[0309] Accordingly, in one aspect, the invention features use of an
isolated human antibody, or an antigen-binding portion thereof,
which has the following characteristics: [0310] a) has a heavy
chain variable region comprising an amino acid sequence selected
from the group consisting of SEQ ID NOs: 595-667, wherein the heavy
chain variable region has a mutation at a preferred selective
mutagenesis position, contact or hypermutation position with an
activity enhancing amino acid residue. [0311] b) has a light chain
variable region comprising an amino acid sequence selected from the
group consisting of SEQ ID NOs: 669-675, wherein the light chain
variable region has a mutation at a preferred selective mutagenesis
position, contact or hypermutation position with an activity
enhancing amino acid residue.
[0312] An ordinarily skilled artisan will appreciate that based on
the high amino acid sequence similarity between Joe 9 and COS-3
heavy chain germline sequence, and between Joe 9 and DPL8 lambda
germline sequence, that other mutations to the CDR regions of these
germlines sequences can provide additional antibodies that bind to
human IL-12. Such methods of modification can be performed using
standard molecular biology techniques as described above.
[0313] Accordingly, in one aspect, the invention features use of an
isolated human antibody, or an antigen-binding portion thereof,
which has the following characteristics: [0314] a) that binds to
human IL-12 and dissociates from human IL-12 with a k.sub.off rate
constant of 0.1s.sup.-1 or less, as determined by surface plasmon
resonance, or which inhibits phytohemagglutinin blast proliferation
in an in vitro phytohemagglutinin blast proliferation assay (PHA
assay) with an IC.sub.50 of 1.times.10.sup.-6M or less. [0315] b)
has a heavy chain variable region comprising the COS-3 germline
amino acid sequence, wherein the heavy chain variable region has a
mutation at a preferred selective mutagenesis position, contact or
hypermutation position with an activity enhancing amino acid
residue. [0316] c) has a light chain variable region comprising the
DPL8 germline amino acid sequence, wherein the light chain variable
region has a mutation at a preferred selective mutagenesis
position, contact or hypermutation position with an activity
enhancing amino acid residue.
[0317] Due to certain amino acid residues occupying key sites in
the CDR and framework regions in the light and heavy chain variable
region, structural features are conferred at these regions. In
particular, the CDR2 and CDR1 regions are subject to canonical
structural classifications. Since there is a high degree of amino
acids sequence homology between family members, these canonical
features are present between family members. The skilled artisan
will appreciate that modifications at the amino acid residues that
confer these canonical structures would produce additional
antibodies that bind to IL-12. The modifications can be performed
using standard molecular biology techniques as described above.
[0318] Accordingly, in another aspect, the invention features use
of an isolated human antibody, or an antigen-binding portion
thereof, which has the following characteristics: [0319] a) that
binds to human IL-12 and dissociates from human IL-12 with a
k.sub.off rate constant of 0.1 s.sup.-1 or less, as determined by
surface plasmon resonance, or which inhibits phytohemagglutinin
blast proliferation in an in vitro phytohemagglutinin blast
proliferation assay (PHA assay) with an IC.sub.50 of
1.times.10.sup.-6M or less. [0320] b) has a heavy chain variable
region comprising an amino acid sequence selected from a member of
the V.sub.H3 germline family, wherein the heavy chain variable
region comprises a CDR2 that is structurally similar to CDR2s from
other V.sub.H3 germline family members, and a CDR1 that is
structurally similar to CDR1s from other V.sub.H3 germline family
members, and wherein the heavy chain variable region has a mutation
at a preferred selective mutagenesis position, contact or
hypermutation position with an activity enhancing amino acid
residue; [0321] c) has a light chain variable region comprising an
amino acid sequence selected from a member of the V.sub..lamda.1
germline family, wherein the light chain variable region comprises
a CDR2 that is structurally similar to CDR2s from other
V.sub..lamda.1 germline family members, and a CDR1 that is
structurally similar to CDR1s from other V.sub..lamda.1 germline
family members, and wherein the light chain variable region has a
mutation at a preferred selective mutagenesis position, contact or
hypermutation position with an activity enhancing amino acid
residue.
[0322] Recombinant human antibodies used in the invention have
variable and constant regions which are homologous to human
germline immunoglobulin sequences selected from the VBASE database.
Mutations to the recombinant human antibodies (e.g., by random
mutagenesis or PCR mutagenesis) result in amino acids that are not
encoded by human germline immunoglobulin sequences. Also, libraries
of recombinant antibodies which were derived from human donors will
contain antibody sequences that differ from their corresponding
germline sequences due to the normal process of somatic mutation
that occurs during B-cell development. It should be noted that if
the "germline" sequences obtained by PCR amplification encode amino
acid differences in the framework regions from the true germline
configuration (i.e., differences in the amplified sequence as
compared to the true germline sequence), it may be desirable to
change these amino acid differences back to the true germline
sequences (i.e., "backmutation" of framework residues to the
germline configuration). Thus, the present invention can optionally
include a backmutation step. To do this, the amino acid sequences
of heavy and light chain encoded by the germline (as found as
example in VBASE database) are first compared to the mutated
immunoglobulin heavy and light chain framework amino acid sequences
to identify amino acid residues in the mutated immunoglobulin
framework sequence that differ from the closest germline sequences.
Then, the appropriate nucleotides of the mutated immunoglobulin
sequence are mutated back to correspond to the germline sequence,
using the genetic code to determine which nucleotide changes should
be made. Mutagenesis of the mutated immunoglobulin framework
sequence is carried out by standard methods, such as PCR-mediated
mutagenesis (in which the mutated nucleotides are incorporated into
the PCR primers such that the PCR product contains the mutations)
or site-directed mutagenesis. The role of each amino acid
identified as candidate for backmutation should be investigated for
a direct or indirect role in antigen binding and any amino acid
found after mutation to affect any desirable characteristic of the
human antibody should not be included in the final human antibody;
as an example, activity enhancing amino acids identified by the
selective mutagenesis approach will not be subject to backmutation.
Assays to determine the characteristics of the antibody resulting
from mutagenesis can include ELISA, competitive ELISA, in vitro and
in vivo neutralization assays and/or (see e.g. Example 3 of U.S.
Pat. No. 6,914,128) immunohistochemistry with tissue sections from
various sources (including human, primate and/or other
species).
[0323] To minimize the number of amino acids subject to
backmutation those amino acid positions found to be different from
the closest germline sequence but identical to the corresponding
amino acid in a second germline sequence can remain, provided that
the second germline sequence is identical and colinear to the
sequence of the human antibody of the invention for at least 10,
preferably 12 amino acids, on both sides of the amino acid in
question. This would assure that any peptide epitope presented to
the immune system by professional antigen presenting cells in a
subject treated with the human antibody of the invention would not
be foreign but identical to a self-antigen, i.e. the immunoglobulin
encoded by that second germline sequence. Backmutation may occur at
any stage of antibody optimization; preferably, backmutation occurs
directly before or after the selective mutagenesis approach. More
preferably, backmutation occurs directly before the selective
mutagenesis approach.
III. Modifications to Preferred Selective Mutagenesis Positions,
Contact and/or Hypermutation Positions
[0324] Typically, selection of antibodies with improved affinities
can be carried out using phage display methods, as described in
section II above and in U.S. Pat. No. 6,914,128, incorporated by
reference herein. This can be accomplished by randomly mutating
combinations of CDR residues and generating large libraries
containing antibodies of different sequences. However, for these
selection methods to work, the antibody-antigen reaction must tend
to equilibrium to allow, over time, preferential binding of higher
affinity antibodies to the antigen. Selection conditions that would
allow equilibrium to be established could not be determined
(presumably due to additional non-specific interactions between the
antigen and phage particle) when phage display methods were used to
improve the affinity of selected anti-IL-12 antibodies, upon
attaining a certain level of affinity achieved (i.e., that of
antibody Y61). Accordingly, antibodies with even higher affinities
could not be selected by phage display methods. Thus, for at least
certain antibodies or antigens, phage display methods are limiting
in their ability to select antibodies with a highly improved
binding specificity/affinity. Accordingly, a method termed
Selective Mutagenesis Approach which does not require phage display
affinity maturation of antibodies, was established to overcome this
limitation and is provided by the invention. Although this
Selective Mutagenesis Approach was developed to overcome
limitations using the phage display system, it should be noted that
this method can also be used with the phage display system.
Moreover, the selective mutagenesis approach can be used to improve
the activity of any antibody.
[0325] To improve the activity (e.g., affinity or neutralizing
activity) of an antibody, ideally one would like to mutate every
CDR position in both the heavy and light chains to every other
possible amino acid residue. However, since there are, on average,
70 CDR positions within an antibody, such an approach would be very
time consuming and labor intensive. Accordingly, the method of the
invention allows one to improve the activity of the antibody by
mutating only certain selected residues within the heavy and/or
light chain CDRs. Furthermore, the method of the invention allows
improvement in activity of the antibody without affecting other
desirable properties of the antibody.
[0326] Determining which amino acid residues of an antibody
variable region are in contact with an antigen cannot be accurately
predicted based on primary sequence or their positions within the
variable region. Nevertheless, alignments of sequences from
antibodies with different specificities conducted by Kabat et al.
have identified the CDRs as local regions within the variable
regions which differ significantly among antibodies (Kabat et al.
(1971) Ann. NY Acad, Sci. 190:382-393, Kabat, E. A., et al. (1991)
Sequences of Proteins of Immunological Interest, Fifth Edition,
U.S. Department of Health and Human Services, NIH Publication No.
91-3242). Structural studies have shown that the antigen binding
surface is formed by amino acid residues present in the CDRs. Other
amino acid residues outside the CDR are also known to play
structural roles or be directly involved in antigen binding.
Therefore, for each antigen-antibody pair, amino acid residues
within and outside of the CDRs may be important.
[0327] The sequence alignment studies by Tomlison et al identified
a number of positions in the heavy and light chain CDR1 and CDR2,
and in a portion of the kappa chain CDR3 which are frequent sites
of somatic mutation. (Tomlison et al (1996) J. Mol. Biol. 256:
813-817). In particular, positions H31, H31B, H33, H33B, H52B, H56,
H58, L30, L31, L31A, L50, L53, L91, L92, L93 and L94 were
identified as frequent sites for somatic mutation. However, this
analysis excludes the important heavy chain CDR3 regions, and
sections of the light chain CDR3 which are known to lie in the
center of an antibody binding site, and potentially provide
important interactions with an antigen. Furthermore, Tomlison et
al. propose that somatic diversity alone does not necessarily
predict a role of a specific amino acid in antigen binding, and
suggest conserved amino acid residues that contact the antigen, and
diverse amino acid residues which do not contact the antigen. This
conclusion is further supported by mutational studies on the role
of somatic mutations to antibody affinity (Sharon, (1990), PNAS,
87:4814-7). Nineteen somatic mutations in a high-affinity
anti-p-azophenylarsonate (Ars) antibody were simultaneously
replaced with their corresponding germline residues, generating a
germline version of the anti-Ars antibody which had a two-hundred
fold loss in activity. The full affinity of the anti-Ars antibody
could be recovered by restoring only three of the nineteen somatic
mutations, demonstrating that many somatic mutations may be
permitted that do not contribute to antigen binding activity.
[0328] The result can be explained in part by the nature of
antibody diversity itself. Immature B-cells may produce initially
low affinity antibodies that recognize a number of self or non-self
antigens. Moreover, antibodies may undergo in the course of
affinity maturation sequence variations that may cause
self-reactivity. Hypermutation of such low affinity antibodies may
serve to abolish self-reactivity ("negative selection") and
increase affinity for the foreign antigen. Therefore, the analysis
of primary and structural data of a large number of antibodies does
not provide a method of predicting either (1) the role of somatic
hyper-mutation sites in the affinity maturation process versus the
process of decreasing affinity towards unwanted antigens, or (2)
how a given amino acid contributes to the properties of a specific
antigen-antibody pair.
[0329] Other attempts to address the role of specific amino acid
residues in antigen recognition were made by analyzing a number of
crystal structures of antigen-antibody complexes (MacCallum et al.
(1996) J. Mol. Biol. 262: 732-745). The potential role of positions
located within and outside the CDRs was indicated. Positions in
CDRs involved in antigen binding in more than 10 of 26 analyzed
structures included H31, H33, H50, H52, H53, H54, H56, H58, H95,
H96, H97, H98 and H100 in the heavy chain and L30A, L32, L91, L92,
L93, L94, L96 in the light chain. However, the authors noted that
prediction of antigen contacts using these and other structural
data may over and under predict contact positions, leading to the
speculation that a different strategy may have to be applied to
different antigens.
[0330] Pini et al. describe randomizing multiple residues in
antibody CDR sequences in a large phage display library to rapidly
increase antibody affinity (Pini et al. (1998) J. Biol. Chem. 273:
21769-21776). However, the high affinity antibodies discussed by
Pini et al. had mutations in a total of eight positions, and a
reductionary analysis of which changes are absolutely required to
improve affinity of the antibody becomes impractical because of the
large number of possible combinations to be tested for the smallest
number of amino acids required.
[0331] Furthermore, randomizing multiple residues may not
necessarily preserve other desired properties of the antibody.
Desirable properties or characteristics of an antibody are
art-recognized and include for example, preservation of non-cross
reactivity, e.g., with other proteins or human tissues and
preservation of antibody sequences that are close to human germline
immunoglobulin sequences improvement of neutralization potency.
Other desirable properties or characteristics include ability to
preserve species cross reactivity, ability to preserve epitope
specificity and ability to preserve high expression levels of
protein in mammalian cells. The desirable properties or
characteristics can be observed or measured using art-recognized
techniques including but not limited to ELISA, competitive ELISA,
in vitro and in vivo neutralization assays (see e.g. Example 3 of
U.S. Pat. No. 6,914,128), immunohistochemistry with tissue sections
from different sources including human, primate or other sources as
the need may be, and studies to expression in mammalian cells using
transient expression or stable expression.
[0332] In addition, the method of Pini et al may introduce more
changes than the minimal number actually required to improve
affinity and may lead to the antibodies triggering
anti-human-antibody (HAMA) formation in human subjects.
[0333] Further, as discussed elsewhere, the phage display as
demonstrated here, or other related method including ribosome
display may not work appropriately upon reaching certain affinities
between antibody and antigen and the conditions required to reach
equilibrium may not be established in a reasonable time frame
because of additional interactions including interactions with
other phage or ribosome components and the antigen.
[0334] The ordinarily skilled artisan may glean interesting
scientific information on the origin of antibody diversity from the
teachings of the references discussed above. The present invention,
however, provides a method for increasing antibody affinity of a
specific antigen-antibody pair while preserving other relevant
features or desirable characteristics of the antibody. This is
especially important when considering the desirability of imparting
a multitude of different characteristics on a specific antibody
including antigen binding.
[0335] If the starting antibody has desirable properties or
characteristics which need to be retained, a selective mutagenesis
approach can be the best strategy for preserving these desirable
properties while improving the activity of the antibody. For
example, in the mutagenesis of Y61, the aim was to increase
affinity for hIL-12, and to improve the neutralization potency of
the antibody while preserving desired properties. Desired
properties of Y61 included (1) preservation of non-cross reactivity
with other proteins or human tissues, (2) preservation of fine
epitope specificity, i.e. recognizing a p40 epitope preferably in
the context of the p70 (p40/p35) heterodimer, thereby preventing
binding interference from free soluble p40; and (3) generation of
an antibody with heavy and light chain amino acid sequences that
were as close as possible to their respective germline
immunoglobulin sequences.
[0336] In one embodiment, the method of the invention provides a
selective mutagenesis approach as a strategy for preserving the
desirable properties or characteristics of the antibody while
improving the affinity and/or neutralization potency. The term
"selective mutagenesis approach" is as defined above and includes a
method of individually mutating selected amino acid residues. The
amino acid residues to be mutated may first be selected from
preferred selective mutagenesis positions, then from contact
positions, and then from hypermutation positions. The individual
selected position can be mutated to at least two other amino acid
residue and the effect of the mutation both on the desired
properties of the antibody, and improvement in antibody activity is
determined.
[0337] The Selective Mutagenesis approach comprises the steps
of:
[0338] selecting candidate positions in the order 1) preferred
selective mutagenesis positions; 2) contact positions; 3)
hypermutation positions and ranking the positions based on the
location of the position within the heavy and light chain variable
regions of an antibody (CDR3 preferred over CDR2 preferred over
CDR1);
[0339] individually mutating candidate preferred selective
mutagenesis positions, hypermutation and/or contact positions in
the order of ranking, to all possible other amino acid residues and
analyzing the effect of the individual mutations on the activity of
the antibody in order to determine activity enhancing amino acid
residues;
[0340] if necessary, making stepwise combinations of the individual
activity enhancing amino acid residues and analyzing the effect of
the various combinations on the activity of the antibodies;
selecting mutant antibodies with activity enhancing amino acid
residues and ranking the mutant antibodies based on the location
and identity of the amino acid substitutions with regard to their
immunogenic potential. Highest ranking is given to mutant
antibodies that comprise an amino acid sequence which nearly
identical to a variable region sequence that is described in a
germline database, or has an amino acid sequence that is comparable
to other human antibodies. Lower ranking is given to mutant
antibodies containing an amino acid substitution that is rarely
encountered in either germline sequences or the sequences of other
human antibodies. The lowest ranking is given to mutant antibodies
with an amino acid substitution that has not been encountered in a
germline sequence or the sequence of another human antibody. As set
forth above, mutant antibodies comprising at least one activity
enhancing amino acid residue located in CDR3 is preferred over CDR2
which is preferred over CDR1. The CDRs of the heavy chain variable
regions are preferred over those of the light chain variable
region.
[0341] The mutant antibodies can also be studied for improvement in
activity, e.g. when compared to their corresponding parental
antibody. The improvement in activity of the mutant antibody can be
determined for example, by neutralization assays, or binding
specificity/affinity by surface plasmon resonance analysis (see
Example 3 of U.S. Pat. No. 6,914,128). Preferably, the improvement
in activity can be at least 2-20 fold higher than the parental
antibody. The improvement in activity can be at least "x.sub.1" to
"x.sub.2" fold higher than the parental antibody wherein "x.sub.1"
and "x.sub.2" are integers between and including 2 to 20, including
ranges within the state range, e.g. 2-15, e.g. 5-10.
[0342] The mutant antibodies with the activity enhancing amino acid
residue also can be studied to determine whether at least one other
desirable property has been retained after mutation. For example,
with anti-hIL-12 antibodies testing for, (1) preservation of
non-cross reactivity with other proteins or human tissues, (2)
preservation of epitope recognition, i.e. recognizing a p40 epitope
preferably in the context of the p70 (p40/p35) heterodimer, thereby
preventing binding interference from free soluble p40; and (3)
generation of antibodies with heavy and light chain amino acid
sequences that were as close as possible to their respective
germline immunoglobulin sequences, and determining which would be
least likely to elicit a human immune response based on the number
of differences from the germline sequence. The same observations
can be made on an antibody having more than one activity enhancing
amino acid residues, e.g. at least two or at least three activity
enhancing amino acid residues, to determine whether retention of
the desirable property or characteristic has occurred.
[0343] An example of the use of a "selective mutagenesis approach",
in the mutagenesis of Y61 is described below. The individual
mutations H31S.fwdarw.E, L50.fwdarw.Y, or L94G.fwdarw.Y each
improved neutralization activity of the antibody. However, when
combination clones were tested, the activity of the combined clone
H31S.fwdarw.E+L50.fwdarw.Y+L94G.fwdarw.Y was no better than
L50.fwdarw.Y+L94G.fwdarw.Y (J695). Therefore, changing the germline
amino acid residue Ser to Glu at position 31 of CDR1 was
unnecessary for the improved activity of J695 over Y61. The
selective mutagenesis approach therefore, identified the minimal
number of changes that contributed to the final activity, thereby
reducing the immunogenic potential of the final antibody and
preserving other desired properties of the antibody.
[0344] Isolated DNA encoding the VH and VL produced by the selected
mutagenesis approach can be converted into full length antibody
chain genes, to Fab fragment genes as to a scFV gene, as described
in section IV. For expression of VH and VL regions produced by the
selected mutagenesis approach, expression vectors encoding the
heavy and light chain can be transfected into variety host cells as
described in detail in section IV. Preferred host cells include
either prokaryotic host cells, for example, E coli, or eukaryotic
host cells, for example, yeast cells, e.g., S. cerevisae. Most
preferred eukaryotic host cells are mammalian host cells, described
in detail in section IV.
[0345] The selective mutagenesis approach provides a method of
producing antibodies with improved activities without prior
affinity maturation of the antibody by other means. The selective
mutagenesis approach provides a method of producing antibodies with
improved affinities which have been subject to back mutations. The
selective mutagenesis approach also provides a method of improving
the activity of affinity matured antibodies.
[0346] The skilled artisan will recognize that the selective
mutagenesis approach can be used in standard antibody manipulation
techniques known in the art. Examples include, but are not limited
to, CDR grafted antibodies, chimeric antibodies, scFV fragments,
Fab fragments of a full length antibodies and human antibodies from
other sources, e.g., transgenic mice.
[0347] Rapid large scale mutational analysis of antibodies include
in vitro transcription and translation using ribosome display
technology (see e.g., Hanes et al., (1997) Proc. Natl. Acad. Sci.
94: 4937-4942; Dall Acqua et al., (1998) Curr. Opin. Struc. Biol.
8: 443-450; He et al., (1997) Nucleic Acid Res. 25: 5132-5134), and
U.S. Pat. Nos. 5,643,768 and 5,658,754 issued to Kawasaki. The
selective mutagenesis approach also provides a method of producing
antibodies with improved activities that can be selected using
ribosomal display techniques.
[0348] In the methods of the invention, antibodies or antigen
binding portions thereof are further modified by altering
individual positions in the CDRs of the HCVR and/or LCVR. Although
these modifications can be made in phage-displayed antibodies, the
method is advantageous in that it can be performed with antibodies
that are expressed in other types of host systems, such as
bacterial, yeast or mammalian cell expression systems. The
individual positions within the CDRs selected for modification are
based on the positions being a contact and/or hypermutation
position.
[0349] Preferred contact positions and hypermutation positions as
defined herein are shown in Table 3 of U.S. Pat. No. 6,914,128 (see
Appendix A of U.S. Pat. No. 6,914,128 and Table 3 of Appendix A
attached hereto) and their modification in accordance with the
method of the invention is described in detail in Example 2 of U.S.
Pat. No. 6,914,128. Preferred contact positions are selected from
the group consisting of H30, H31, H31B, H32, H33, H35, H50, H52,
H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32,
L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96. Preferred
hypermutation positions are selected from the group consisting of
H30, H31, H31B, H32, H52, H56, H58, L30, L31, L32, L53 and L93.
More preferred amino acid residues (referred to as "preferred
selective mutagenesis positions") are both contact and
hypermutation positions and are selected from the group consisting
of H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31, L32, L50,
L91, L92, L93, L94. Particularly preferred contact positions are
selected from the group consisting of L50 and L94.
[0350] Preferred activity enhancing amino acid residues replace
amino acid residues located at positions selected from the group
consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53,
H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50,
L52, L53, L55, L91, L92, L93, L94, and L96. More preferred activity
enhancing amino acid residues replace amino acid residues located
at positions H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31,
L32, L50, L91, L92, L93, L94. Particularly, preferred activity
enhancing amino acid residues replace amino acid residues located
at positions selected from the group consisting of L50 and L94.
[0351] In general, the method of the invention involves selecting a
particular preferred selective mutagenesis position, contact and/or
hypermutation position within a CDR of the heavy or light chain of
a parent antibody of interest, or antigen binding portion thereof,
randomly mutagenizing that individual position (e.g., by genetic
means using a mutagenic oligonucleotide to generate a
"mini-library" of modified antibodies), or mutating a position to
specific desired amino acids, to identify activity enhancing amino
acid residues expressing, and purifying the modified antibodies
(e.g., in a non-phage display host system), measuring the activity
of the modified antibodies for antigen (e.g., by measuring
k.sub.off rates by BIAcore analysis), repeating these steps for
other CDR positions, as necessary, and combining individual
mutations shown to have improved activity and testing whether the
combination(s) generate an antibody with even greater activity
(e.g., affinity or neutralizing potency) than the parent antibody,
or antigen-binding portion thereof.
[0352] Accordingly, in one embodiment, the invention provides a
method for improving the activity of an antibody, or
antigen-binding portion thereof, comprising:
[0353] a) providing a parent antibody or antigen-binding portion
thereof;
[0354] b) selecting in order a 1) preferred selective mutagenesis
position, 2) contact position, or 3) hypermutation position within
a complementarity determining region (CDR) for mutation, thereby
identifying a selected preferred selective mutagenesis position,
contact or hypermutation position;
[0355] c) individually mutating said selected preferred selective
mutagenesis position, contact or hypermutation position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof;
[0356] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof;
[0357] e) optionally, repeating steps a) through d) for at least
one other preferred selective mutagenesis position, contact or
hypermutation position;
[0358] f) combining, in the parent antibody, or antigen-binding
portion thereof, individual mutations shown to have improved
activity, to form combination antibodies, or antigen-binding
portions thereof; and
[0359] g) evaluating the activity of the combination antibodies, or
antigen-binding portions thereof, relative to the parent antibody
or antigen-binding portion thereof; until an antibody, or
antigen-binding portion thereof, with an improved activity,
relative to the parent antibody, or antigen-binding portion
thereof, is obtained. Preferably, the selected antibody or
antibodies have an improved activity without loss or with retention
of at least one desirable characteristic or property of the
parental antibody as described above. The desirable characteristic
or property can be measured or observed by the ordinarily skilled
artisan using art-recognized techniques.
[0360] Preferred contact positions are selected from the group
consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53,
H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50,
L52, L53, L55, L91, L92, L93, L94 and L96. Preferred hypermutation
positions are selected from the group consisting of H30, H31, H31B,
H32, H52, H56, H58, L30, L31, L32, L53 and L93. More preferred
selective mutagenesis positions are selected from the group
consisting of H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31,
L32, L50, L91, L92, L93 and L94. Particularly preferred contact
positions are selected from the group consisting of L50 and
L94.
[0361] In another embodiment, the invention provides a method for
improving the activity of an antibody, or antigen-binding portion
thereof, comprising:
[0362] a) providing a parent antibody or antigen-binding portion
thereof;
[0363] b) selecting a preferred selective mutagenesis position,
contact or hypermutation position within a complementarity
determining region (CDR) for mutation;
[0364] c) individually mutating said selected preferred selective
mutagenesis position, contact or hypermutation position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof;
[0365] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof, thereby
identifying an activity enhancing amino acid residue;
[0366] e) optionally, repeating steps a) through d) for at least
one other preferred selective mutagenesis position, contact or
hypermutation position;
[0367] f) combining, in the parent antibody, or antigen-binding
portion thereof, two individual activity enhancing amino acid
residues shown to have improved activity, to form combination
antibodies, or antigen-binding portions thereof; and
[0368] g) evaluating the activity of the combination antibodies, or
antigen-binding portions thereof with two activity enhancing amino
acid residues, relative to the parent antibody or antigen-binding
portion thereof;
until an antibody, or antigen-binding portion thereof, with an
improved activity, relative to the parent antibody, or
antigen-binding portion thereof, is obtained.
[0369] Preferred contact positions are selected from the group
consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53,
H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50,
L52, L53, L55, L91, L92, L93, L94 and L96. Preferred hypermutation
positions are selected from the group consisting of H30, H31, H31B,
H32, H52, H56, H58, L30, L31, L32, L53 and L93. More preferred
selective mutagenesis positions are selected from the group
consisting of H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31,
L32, L50, L91, L92, L93 and L94. Particularly preferred contact
positions are selected from the group consisting of L50 and
L94.
[0370] In another embodiment, the invention provides a method for
improving the activity of an antibody, or antigen-binding portion
thereof, comprising:
[0371] a) providing a parent antibody or antigen-binding portion
thereof;
[0372] b) selecting a preferred selective mutagenesis position,
contact or hypermutation position within a complementarity
determining region (CDR) for mutation;
[0373] c) individually mutating said selected preferred selective
mutagenesis position, contact or hypermutation position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof;
[0374] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof, thereby
identifying an activity enhancing amino acid residue;
[0375] e) optionally, repeating steps a) through d) for at least
one other preferred selective mutagenesis position, contact or
hypermutation position;
[0376] f) combining, in the parent antibody, or antigen-binding
portion thereof, three individual activity enhancing amino acid
residues shown to have improved activity, to form combination
antibodies, or antigen-binding portions thereof; and
[0377] g) evaluating the activity of the combination antibodies, or
antigen-binding portions thereof with two activity enhancing amino
acid residues, relative to the parent antibody or antigen-binding
portion thereof; until an antibody, or antigen-binding portion
thereof, with an improved activity, relative to the parent
antibody, or antigen-binding portion thereof, is obtained.
[0378] Preferably, the activity enhancing amino acid residue
replaces amino acid residues located at positions selected from the
group consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A,
H53, H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34,
L50, L52, L53, L55, L91, L92, L93, L94 and L96.
[0379] Following mutagenesis of individual selected positions,
mutated clones can be sequenced to identify which amino acid
residues have been introduced into the selected position in each
clone. A small number of clones (e.g., about 24) can be selected
for sequencing, which statistically should yield 10-15 unique
antibodies, whereas larger numbers of clones (e.g., greater than
60) can be sequenced to ensure that antibodies with every possible
substitution at the selected position are identified.
[0380] In one embodiment, contact and/or hypermutation positions
within the CDR3 regions of the heavy and/or light chains are first
selected for mutagenesis. However, for antibodies that have already
been affinity matured in vitro by random mutagenesis of the CDR3
regions via phage display selection, it may be preferably to first
select contact and/or hypermutation positions within CDR1 or CDR2
of the heavy and/or light chain.
[0381] In a more preferred embodiment, preferred selective
mutagenesis positions within the CDR3 regions of the heavy and/or
light chains are first selected for mutagenesis. However, for
antibodies that have already been affinity matured in vitro by
random mutagenesis of the CDR3 regions via phage display selection,
it may be preferably to first select preferred selective
mutagenesis positions within CDR1 or CDR2 of the heavy and/or light
chain.
[0382] In another preferred embodiment, the optimization of a
selected antibody by the selective mutagenesis approach is done
sequentially as follows: preferred selective mutagenesis positions
selected from the group consisting of H30, H31, H31B, H32, H33,
H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94 are mutated
first to at least 2 other amino acids each (preferably 5-14 other
amino acids) and the resulting antibodies are characterized for
increased affinity, neutralization potency (and possibly also for
at least one other retained characteristic or property discussed
elsewhere). If a mutation of a single preferred selective
mutagenesis position does not increase the affinity or
neutralization potency at all or sufficiently and if even the
combination of multiple activity enhancing amino acids replacing
amino acids in preferred selective mutagenesis positions does not
result in an combination antibody which meets the target activity
(including affinity and/or neutralization potency), additional
amino acid residues will be selected for selective mutagenesis from
the group consisting of H35, H50, H53, H54, H95, H96, H97, H98,
L30A and L96 are mutated to at least 2 other amino acids each
(preferably 5-14 other amino acids) and the resulting antibodies
are characterized for increased affinity, neutralization potency
(and possibly also for at least one other retained characteristic
or property discussed elsewhere).
[0383] If a mutation of a single amino acid residue selected from
the group consisting of H35, H50, H53, H54, H95, H96, H97, H98,
L30A and L96 does not increase the activity (including affinity
and/or neutralization potency) at all or not sufficiently and if
even the combination of multiple activity enhancing amino acids
replacing amino acids in those positions does not result in an
combination antibody which meets the targeted activity (including
affinity and/or target neutralization potency), additional amino
acid residues will be selected for selective mutagenesis from the
group consisting of H33B, H52B, L31 A and are mutated to at least 2
other amino acids each (preferably 5-14 other amino acids) and the
resulting antibodies are characterized for increased affinity,
neutralization potency (and possibly also for at least one other
retained characteristic or property discussed elsewhere).
[0384] It should be understood that the sequential selective
mutagenesis approach may end at any of the steps outline above as
soon as an antibody with the desired activity (including affinity
and neutralization potency) has been identified. If mutagenesis of
the preselected positions has identified activity enhancing amino
acids residues but the combination antibody still do not meet the
targets set for activity (including affinity and neutralization
potency) and/or if the identified activity enhancing amino acids
also affect other desired characteristics and are therefore not
acceptable, the remaining CDR residues may be subjected to
mutagenesis (see section IV).
[0385] The method of the invention can be used to improve activity
of an antibody, or antigen binding portion thereof, to reach a
predetermined target activity (e.g. a predetermined affinity and/or
neutralization potency, and/or a desired property or
characteristic).
[0386] Accordingly, the invention provides a method of improving
the activity of an antibody, or antigen-binding portion thereof, to
attain a predetermined target activity, comprising: [0387] a)
providing a parent antibody a antigen-binding portion thereof;
[0388] b) selecting a preferred selective mutagenesis position
selected from group consisting of H30, H31, H31B, H32, H33, H52,
H56, H58, L30, L31, L32, L50, L91, L92, L93, L94. [0389] c)
individually mutating the selected preferred selective mutagenesis
position to at least two other amino acid residues to hereby create
a first panel of mutated antibodies, or antigen binding portions
thereof; [0390] d) evaluating the activity of the first panel of
mutated antibodies, or antigen binding portions thereof to
determined if mutation of a single selective mutagenesis position
produces an antibody or antigen binding portion thereof with the
predetermined target activity or a partial target activity; [0391]
e) combining in a stepwise fashion, in the parent antibody, or
antigen binding portion thereof, individual mutations shown to have
an improved activity, to form combination antibodies, or antigen
binding portions thereof. [0392] f) evaluating the activity of the
combination antibodies, or antigen binding portions thereof to
determined if the combination antibodies, or antigen binding
portions thereof have the predetermined target activity or a
partial target activity. [0393] g) if steps d) or f) do not result
in an antibody or antigen binding portion thereof having the
predetermined target activity, or result an antibody with only a
partial activity, additional amino acid residues selected from the
group consisting of H35, H50, H53, H54, H95, H96, H97, H98, L30A
and L96 are mutated to at least two other amino acid residues to
thereby create a second panel of mutated antibodies or
antigen-binding portions thereof; [0394] h) evaluating the activity
of the second panel of mutated antibodies or antigen binding
portions thereof, to determined if mutation of a single amino acid
residue selected from the group consisting of H35, H50, H53, H54,
H95, H96, H97, H98, L30A and L96 results an antibody or antigen
binding portion thereof, having the predetermined target activity
or a partial activity; [0395] i) combining in stepwise fashion in
the parent antibody, or antigen-binding portion thereof, individual
mutations of step g) shown to have an improved activity, to form
combination antibodies, or antigen binding portions thereof; [0396]
j) evaluating the activity of the combination antibodies or antigen
binding portions thereof, to determined if the combination
antibodies, or antigen binding portions thereof have the
predetermined target activity or a partial target activity; [0397]
k) if steps h) or j) do not result in an antibody or antigen
binding portion thereof having the predetermined target activity,
or result in an antibody with only a partial activity, additional
amino acid residues selected from the group consisting of H33B,
H52B and L31 A are mutated to at least two other amino acid
residues to thereby create a third panel of mutated antibodies or
antigen binding portions thereof; [0398] l) evaluating the activity
of the third panel of mutated antibodies or antigen binding
portions thereof, to determine if a mutation of a single amino acid
residue selected from the group consisting of H33B, H52B and L31A
resulted in an antibody or antigen binding portion thereof, having
the predetermined target activity or a partial activity; [0399] m)
combining in a stepwise fashion in the parent antibody, or antigen
binding portion thereof, individual mutation of step k) shown to
have an improved activity, to form combination antibodies, or
antigen binding portions, thereof; [0400] n) evaluating the
activity of the combination antibodies or antigen-binding portions
thereof, to determine if the combination antibodies, or antigen
binding portions thereof have the predetermined target activity to
thereby produce an antibody or antigen binding portion thereof with
a predetermined target activity.
[0401] A number of mutagenesis methods can be used, including PCR
assembly, Kunkel (dut-ung-) and thiophosphate (Amersham Sculptor
kit) oligonucleotide-directed mutagenesis.
[0402] A wide variety of host expression systems can be used to
express the mutated antibodies, including bacterial, yeast,
baculoviral and mammalian expression systems (as well as phage
display expression systems). An example of a suitable bacterial
expression vector is pUC119(Sfi). Other antibody expression systems
are known in the art and/or are described below in section V.
[0403] The modified antibodies, or antigen binding portions
thereof, produced by the method of the invention can be identified
without the reliance on phage display methods for selection.
Accordingly, the method of the invention is particularly
advantageous for improving the activity of a recombinant parent
antibody or antigen-binding portion thereof, that was obtained by
selection in a phage-display system but whose activity cannot be
further improved by mutagenesis in the phage-display system.
[0404] Accordingly, in another embodiment, the invention provides a
method for improving the affinity of an antibody, or
antigen-binding portion thereof, comprising:
[0405] a) providing a recombinant parent antibody or
antigen-binding portion thereof; that was obtained by selection in
a phage-display system but whose activity cannot be further
improved by mutagenesis in said phage-display system;
[0406] b) selecting a preferred selective mutagenesis position,
contact or hypermutation position within a complementarity
determining region (CDR) for mutation, thereby identifying a
selected contact or hypermutation position;
[0407] c) individually mutating said selected preferred selective
mutagenesis position, contact or hypermutation position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof, and expressing
said panel in a non-phage display system;
[0408] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof;
[0409] e) optionally repeating steps b) through d) for at least one
other preferred selective mutagenesis position, contact or
hypermutation position;
[0410] f) combining, in the parent antibody, or antigen-binding
portion thereof, individual mutations shown to have improved
activity, to form combination antibodies, or antigen-binding
portions thereof; and
[0411] g) evaluating the activity of the combination antibodies, or
antigen-binding portions thereof, relative to the parent antibody
or antigen-binding portion thereof; until an antibody, or
antigen-binding portion thereof, with an improved activity,
relative to the parent antibody, or antigen-binding portion
thereof, is obtained.
[0412] Preferred contact positions are selected from the group
consisting of H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53,
H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50,
L52, L53, L55, L91, L92, L93, L94 and L96. Preferred hypermutation
positions are selected from the group consisting of H30, H31, H31B,
H32, H52, H56, H58, L30, L31, L32, L53 and L93. More preferred
selective mutagenesis positions are selected from the group
consisting of H30, H31, H31B, H32, H33, H52, H56, H58, L30, L31,
L32, L50, L91, L92, L93 and L94. Particularly preferred contact
positions are selected from the group consisting of L50 and
L94.
[0413] With available methods it is not possible or it is extremely
laborious to derive an antibody with increased binding affinity and
neutralization potency while retaining other properties or
characteristics of the antibodies as discussed above. The method of
this invention, however, can readily identify such antibodies. The
antibodies subjected to the method of this invention can come from
any source.
[0414] Therefore, in another embodiment, the invention provides a
method for improving the activity of an antibody, or
antigen-binding portion thereof, comprising:
[0415] a) providing a recombinant parent antibody or
antigen-binding portion thereof;
[0416] b) selecting a preferred selective mutagenesis position,
contact or hypermutation position within a complementarity
determining region (CDR) for mutation, thereby identifying a
selected preferred selective mutagenesis position, contact or
hypermutation position;
[0417] c) individually mutating said selected preferred selective
mutagenesis position, contact or hypermutation position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof and expressing said
panel in an appropriate expression system;
[0418] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof, thereby
identifying an activity enhancing amino acid residue;
[0419] e) evaluating the panel of mutated antibodies, or
antigen-binding portions thereof, relative to the parent antibody
or antigen-binding portion thereof for at least one other property
or characteristics, wherein the property or characteristic is one
that needs to be retained in the antibody;
until an antibody, or antigen-binding portion thereof, with an
improved activity and at least one retained property or
characteristic, relative to the parent antibody, or antigen-binding
portion thereof, is obtained.
[0420] In a preferred embodiment, the contact positions are
selected from the group consisting of H30, H31, H31B, H32, H33,
H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101,
L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96
and the other characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
[0421] In another preferred embodiment, the hypermutation positions
are selected from the group consisting of H30, H31, H31B, H32, H52,
H56, H58, L30, L31, L32, L53 and L93 and the other characteristic
is selected from 1) preservation of non-crossreactivity with other
proteins or human tissues, 2) preservation of epitope recognition,
i.e. recognizing p40 epitope preferably in the context of the p70
p40/p35 heterodimer preventing binding interference from free,
soluble p40 and/or 3) to produce an antibody with a close to
germline immunoglobulin sequence.
[0422] In a more preferred embodiment the residues for selective
mutagenesis are selected from the preferred selective mutagenesis
positions from the group consisting of H30, H31, H31B, H32, H33,
H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94 and the other
characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
[0423] In a more preferred embodiment, the contact positions are
selected from the group consisting of L50 and L94 and the other
characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
[0424] If therefore, the affinity of an antibody for a specific
antigen should be improved, but where the phage display (or related
system including ribosome display) method is no longer applicable,
and other desirable properties or characteristics should be
retained, the method of the invention can be used. Accordingly, in
another embodiment, the invention provides a method for improving
the activity of an antibody, or antigen-binding portion thereof,
comprising:
[0425] a) providing a recombinant parent antibody or
antigen-binding portion thereof; that was obtained by selection in
a phage-display system but whose activity cannot be further
improved by mutagenesis in said phage-display system;
[0426] b) selecting a preferred selective mutagenesis position,
contact or hypermutation position within a complementarity
determining region (CDR) for mutation, thereby identifying a
selected preferred selective mutagenesis position, contact or
hypermutation position;
[0427] c) individually mutating said selected preferred selective
mutagenesis position, contact or hypermutation position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof, and expressing
said panel in a non-phage display system;
[0428] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof thereby
identifying an activity enhancing amino acid residue;
[0429] e) evaluating the panel of mutated antibodies, or
antigen-binding portions thereof, relative to the parent antibody
or antigen-binding portion thereof for at least one other property
or characteristic, wherein the property or characteristic is one
that needs to be retained, until an antibody, or antigen-binding
portion thereof, with an improved activity and at least one
retained property or characteristic, relative to the parent
antibody, or antigen-binding portion thereof, is obtained.
[0430] f) optionally, repeating steps a) through e) for at least
one other preferred selective mutagenesis position, contact or
hypermutation position;
[0431] g) combining, in the parent antibody, or antigen-binding
portion thereof, at least two individual activity enhancing amino
acid residues shown to have improved activity and at least one
retained property or characteristic, to form combination
antibodies, or antigen-binding portions thereof; and
[0432] h) evaluating the activity of the combination antibodies, or
antigen-binding portions thereof, relative to the parent antibody
or antigen-binding portion thereof;
until an antibody, or antigen-binding portion thereof, with an
improved activity and at least one retained other property or
characteristic, relative to the parent antibody, or antigen-binding
portion thereof, is obtained.
[0433] In a preferred embodiment, the contact positions are
selected from the group consisting of H30, H31, H31B, H32, H33,
H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101,
L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96
and the other characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
[0434] In another preferred embodiment, the hypermutation positions
are selected from the group consisting of H30, H31, H31B, H32, H52,
H56, H58, L30, L31, L32, L53 and L93 and the other characteristic
is selected from 1) preservation of non-crossreactivity with other
proteins or human tissues, 2) preservation of epitope recognition,
i.e. recognizing p40 epitope preferably in the context of the p70
p40/p35 heterodimer preventing binding interference from free,
soluble p40 and/or 3) to produce an antibody with a close to
germline immunoglobulin sequence.
[0435] In a more preferred embodiment the residues for selective
mutagenesis are selected from the preferred selective mutagenesis
positions from the group consisting of H30, H31, H31B, H32, H33,
H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94 and the other
characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
[0436] In a more preferred embodiment, the contact positions are
selected from the group consisting of L50 and L94 and the other
characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
[0437] In another embodiment, the invention provides a method for
improving the activity of an antibody, or antigen-binding portion
thereof, comprising:
[0438] a) providing a recombinant parent antibody or
antigen-binding portion thereof; that was obtained by selection in
a phage-display system but whose activity cannot be further
improved by mutagenesis in said phage-display system;
[0439] b) selecting a preferred selective mutagenesis position,
contact or hypermutation position within a complementarity
determining region (CDR) for mutation, thereby identifying a
selected contact or hypermutation position;
[0440] c) individually mutating said selected preferred selective
mutagenesis position, contact or hypermutation position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof, and expressing
said panel in a non-phage display system;
[0441] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof thereby
identifying an activity enhancing amino acid residue;
[0442] e) evaluating the panel of mutated antibodies, or
antigen-binding portions thereof, relative to the parent antibody
or antigen-binding portion thereof for at least one other property
or characteristic, wherein the property or characteristic is one
that needs to be retained, until an antibody, or antigen-binding
portion thereof, with an improved activity and at least one
retained property or characteristic, relative to the parent
antibody, or antigen-binding portion thereof, is obtained.
[0443] In a preferred embodiment, the contact positions are
selected from the group consisting of H30, H31, H31B, H32, H33,
H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101,
L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96
and the other characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
[0444] In another preferred embodiment, the hypermutation positions
are selected from the group consisting of H30, H31, H31B, H32, H52,
H56, H58, L30, L31, L32, L53 and L93 and the other characteristic
is selected from 1) preservation of non-crossreactivity with other
proteins or human tissues, 2) preservation of epitope recognition,
i.e. recognizing p40 epitope preferably in the context of the p70
p40/p35 heterodimer preventing binding interference from free,
soluble p40 and/or 3) to produce an antibody with a close to
germline immunoglobulin sequence.
[0445] In a more preferred embodiment the residues for selective
mutagenesis are selected from the preferred selective mutagenesis
positions from the group consisting of H30, H31, H31B, H32, H33,
H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94 and the other
characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
[0446] In a more preferred embodiment, the contact positions are
selected from the group consisting of L50 and L94 and the other
characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
[0447] In another embodiment, the invention provides a method for
improving the activity of an antibody, or antigen-binding portion
thereof, comprising:
[0448] a) providing a recombinant parent antibody or
antigen-binding portion thereof; that was obtained by selection in
a phage-display system but whose activity cannot be further
improved by mutagenesis in said phage-display system;
[0449] b) selecting a preferred selective mutagenesis position,
contact or hypermutation position within a complementarity
determining region (CDR) for mutation, thereby identifying a
selected contact or hypermutation position;
[0450] c) individually mutating said selected preferred selective
mutagenesis positions, contact or hypermutation position to at
least two other amino acid residues to thereby create a panel of
mutated antibodies, or antigen-binding portions thereof, and
expressing said panel in a non-phage display system;
[0451] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof thereby
identifying an activity enhancing amino acid residue;
[0452] e) evaluating the panel of mutated antibodies, or
antigen-binding portions thereof, relative to the parent antibody
or antigen-binding portion thereof for at least one other property
or characteristic, wherein the property or characteristic is one
that needs to be retained, until an antibody, or antigen-binding
portion thereof, with an improved activity and at least one
retained characteristic, relative to the parent antibody, or
antigen-binding portion thereof, is obtained.
[0453] f) optionally, repeating steps a) through e) for at least
one other preferred selective mutagenesis position, contact or
hypermutation position;
[0454] g) combining, in the parent antibody, or antigen-binding
portion thereof, at least two individual activity enhancing amino
acid residues shown to have improved activity and at least on
retained other characteristic, to form combination antibodies, or
antigen-binding portions thereof; and
[0455] h) evaluating the activity of the combination antibodies, or
antigen-binding portions thereof, relative to the parent antibody
or antigen-binding portion thereof;
until an antibody, or antigen-binding portion thereof, with an
improved activity and at least one retained property or
characteristic, relative to the parent antibody, or antigen-binding
portion thereof, is obtained.
[0456] In a preferred embodiment, the contact positions are
selected from the group consisting of H30, H31, H31B, H32, H33,
H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97, H98, H101,
L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93, L94 and L96
and the other characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
[0457] In another preferred embodiment, the hypermutation positions
are selected from the group consisting of H30, H31, H31B, H32, H52,
H56, H58, L30, L31, L32, L53 and L93 and the other characteristic
is selected from 1) preservation of non-crossreactivity with other
proteins or human tissues, 2) preservation of epitope recognition,
i.e. recognizing p40 epitope preferably in the context of the p70
p40/p35 heterodimer preventing binding interference from free,
soluble p40 and/or 3) to produce an antibody with a close to
germline immunoglobulin sequence.
[0458] In a more preferred embodiment the residues for selective
mutagenesis are selected from the preferred selective mutagenesis
positions from the group consisting of H30, H31, H31B, H32, H33,
H52, H56, H58, L30, L31, L32, L50, L91, L92, L93, L94 and the other
characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
[0459] In a more preferred embodiment, the contact positions are
selected from the group consisting of L50 and L94 and the other
characteristic is selected from 1) preservation of
non-crossreactivity with other proteins or human tissues, 2)
preservation of epitope recognition, i.e. recognizing p40 epitope
preferably in the context of the p70 p40/p35 heterodimer preventing
binding interference from free, soluble p40 and/or 3) to produce an
antibody with a close to germline immunoglobulin sequence.
IV. Modifications of Other CDR Residues
[0460] Ultimately, all CDR residues in a given antibody-antigen
pair identified by any means to be required as activity enhancing
amino acid residues and/or required directly or indirectly for
binding to the antigen and/or for retaining other desirable
properties or characteristics of the antibody. Such CDR residues
are referred to as "preferred selective mutagenesis positions". It
should be noted that in specific circumstances that preferred
selective mutagenesis residues can be identified also by other
means including co-crystallization of antibody and antigen and
molecular modeling.
[0461] If the preferred attempts to identify activity enhancing
amino acids focusing on the preferred selective mutagenesis
positions, contact or hypermutation positions described above are
exhausted, or if additional improvements are required, the
remaining CDR residues may be modified as described below. It
should be understood that the antibody could already be modified in
any one or more contact or hypermutation positions according to the
embodiments discussed above but may require further improvements.
Therefore, in another embodiment, the invention provides a method
for improving the activity of an antibody, or antigen-binding
portion thereof, comprising:
[0462] a) providing a parent antibody or antigen-binding portion
thereof;
[0463] b) selecting an amino acid residue within a complementarity
determining region (CDR) for mutation other than H30, H31, H31B,
H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97,
H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93,
L94 and L96;
[0464] c) individually mutating said selected position e.g., to at
least two other amino acid residues to thereby create a mutated
antibody or a panel of mutated antibodies, or antigen-binding
portions thereof;
[0465] d) evaluating the activity of the mutated antibody or the
panel of mutated antibodies, or antigen-binding portions thereof,
relative to the parent antibody or antigen-binding portion thereof
thereby identifying an activity enhancing amino acid residue;
[0466] e) evaluating the mutated antibody or the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof, for changes in
at least one other property or characteristic until an antibody, or
antigen-binding portion thereof, with an improved activity,
relative to the parent antibody, or antigen-binding portion
thereof, is obtained.
[0467] Preferably, the other characteristic or property is selected
from 1) preservation of non-crossreactivity with other proteins or
human tissues, 2) preservation of epitope recognition, i.e.
recognizing p40 epitope preferably in the context of the p70
p40/p35 heterodimer preventing binding interference from free,
soluble p40 and/or 3) to produce an antibody with a close to
germline immunoglobulin sequence
[0468] If mutagenesis of a single residue is not sufficient other
residues can be included; therefore, in another embodiment, the
invention provides a method for improving the activity of an
antibody, or antigen-binding portion thereof, comprising:
[0469] a) providing a parent antibody or antigen-binding portion
thereof;
[0470] b) selecting an amino acid residue within a complementarity
determining region (CDR) for mutation other than H30, H31, H31B,
H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97,
H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93,
L94 and L96;
[0471] c) individually mutating said selected position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof;
[0472] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof, thereby
identifying an activity enhancing amino acid residue;
[0473] e) repeating steps b) through d) for at least one other CDR
position which is neither the position selected under b) nor a
position at H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53,
H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50,
L52, L53, L55, L91, L92, L93, L94 and L96;
[0474] f) combining, in the parent antibody, or antigen-binding
portion thereof, at least two individual activity enhancing amino
acid residues shown to have improved activity, to form combination
antibodies, or antigen-binding portions thereof; and
[0475] g) evaluating the activity of the combination antibodies, or
antigen-binding portions thereof with two activity enhancing amino
acid residues, relative to the parent antibody or antigen-binding
portion thereof until an antibody, or antigen-binding portion
thereof, with an improved activity, relative to the parent
antibody, or antigen-binding portion thereof, is obtained.
[0476] If the preferred attempts to identify activity enhancing
amino acids focusing on the contact or hypermutation positions
described above are exhausted, or if additional improvements are
required, and the antibody in question can not further be optimized
by mutagenesis and phage display (or related ribosome display)
methods the remaining CDR residues may be modified as described
below. It should be understood that the antibody could already be
modified in any one or more preferred selective mutagenesis
position, contact or hypermutation positions according to the
embodiments discussed above but may require further
improvements.
[0477] Therefore, in another embodiment, the invention provides a
method for improving the activity of an antibody, or
antigen-binding portion thereof, comprising:
[0478] a) providing a recombinant parent antibody or
antigen-binding portion thereof; that was obtained by selection in
a phage-display system but whose activity cannot be further
improved by mutagenesis in said phage-display system;
[0479] b) selecting a selecting an amino acid residue within a
complementarity determining region (CDR) for mutation other than
H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58,
H95, H96, H97, H98, H101, L30, L31, L32, L34, L50, L52, L53, L55,
L91, L92, L93, L94 and;
[0480] c) individually mutating said selected contact or
hypermutation position to at least two other amino acid residues to
thereby create a panel of mutated antibodies, or antigen-binding
portions thereof, and expressing said panel in a non-phage display
system;
[0481] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof thereby
identifying an activity enhancing amino acid residue;
[0482] e) evaluating the panel of mutated antibodies, or
antigen-binding portions thereof, relative to the parent antibody
or antigen-binding portion thereof, for changes in at least one
other property or characteristic, until an antibody, or
antigen-binding portion thereof, with an improved activity,
relative to the parent antibody, or antigen-binding portion
thereof, is obtained.
[0483] Preferably, the other characteristic or property is selected
from 1) preservation of non-crossreactivity with other proteins or
human tissues, 2) preservation of epitope recognition, i.e.
recognizing p40 epitope preferably in the context of the p70
p40/p35 heterodimer preventing binding interference from free,
soluble p40 and/or 3) to produce an antibody with a close to
germline immunoglobulin sequence.
[0484] If a single mutagenesis is not sufficient to increase the
affinity of the antibody other residues may be included in the
mutagenesis. Therefore, in another embodiment, the invention
provides a method for improving the activity of an antibody, or
antigen-binding portion thereof, comprising:
[0485] a) providing a parent antibody or antigen-binding portion
thereof that was obtained by selection in a phage-display system
but whose activity cannot be further improved by mutagenesis in
said phage-display system;
[0486] b) selecting an amino acid residue within a complementarity
determining region (CDR) for mutation other than H30, H31, H31B,
H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97,
H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93,
L94 and L96;
[0487] c) individually mutating said selected position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof and expression in a
non-phage display system;
[0488] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof thereby
identifying an activity enhancing amino acid residue;
[0489] e) repeating steps b) through d) for at least one other
position which is neither the position selected under b) nor a
position at H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53,
H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50,
L52, L53, L55, L91, L92, L93, L94;
[0490] g) combining, in the parent antibody, or antigen-binding
portion thereof, at least two individual activity enhancing amino
acid residues shown to have improved activity, to form combination
antibodies, or antigen-binding portions thereof; and
[0491] h) evaluating the activity and other property or
characteristic of the combination antibodies, or antigen-binding
portions thereof with two activity enhancing amino acid residues,
relative to the parent antibody or antigen-binding portion thereof;
until an antibody, or antigen-binding portion thereof, with an
improved activity, relative to the parent antibody, or
antigen-binding portion thereof, is obtained.
[0492] Preferably, the other characteristic or property is selected
from 1) preservation of non-crossreactivity with other proteins or
human tissues, 2) preservation of epitope recognition, i.e.
recognizing p40 epitope preferably in the context of the p70
p40/p35 heterodimer preventing binding interference from free,
soluble p40 and/or 3) to produce an antibody with a close to
germline immunoglobulin sequence
[0493] The preferred attempts to identify activity enhancing amino
acids focusing on the preferred selective mutagenesis positions,
contact or hypermutation positions described may be exhausted, or
additional improvements may be required, and it is important to
retain other properties or characteristics of the antibody.
[0494] Therefore, in another embodiment, the invention provides a
method for improving the activity of an antibody, or
antigen-binding portion thereof, without affecting other
characteristics, comprising:
[0495] a) providing a parent antibody or antigen-binding portion
thereof;
[0496] b) selecting an amino acid residue within a complementarity
determining region (CDR) for mutation other than H30, H31, H31B,
H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97,
H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93,
L94 and L96;
[0497] c) individually mutating said selected position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof;
[0498] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof thereby
identifying an activity enhancing amino acid residue;
[0499] e) evaluating the panel of mutated antibodies, or
antigen-binding portions thereof, relative to the parent antibody
or antigen-binding portion thereof, for changes in at least one
other property or characteristic until an antibody, or
antigen-binding portion thereof, with an improved activity and
retained other property or characteristic, relative to the parent
antibody, or antigen-binding portion thereof, is obtained.
[0500] Preferably, the other characteristic or property is selected
from 1) preservation of non-crossreactivity with other proteins or
human tissues, 2) preservation of epitope recognition, i.e.
recognizing p40 epitope preferably in the context of the p70
p40/p35 heterodimer preventing binding interference from free,
soluble p40 and/or 3) to produce an antibody with a close to
germline immunoglobulin sequence
[0501] If mutagenesis of a single residue is not sufficient other
residues can be included; therefore, in another embodiment, the
invention provides a method for improving the activity of an
antibody, or antigen-binding portion thereof, comprising:
[0502] a) providing a parent antibody or antigen-binding portion
thereof;
[0503] b) selecting an amino acid residue within a complementarity
determining region (CDR) for mutation other than H30, H31, H31B,
H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97,
H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93,
L94 and L96;
[0504] c) individually mutating said selected position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof;
[0505] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof, thereby
identifying an activity enhancing amino acid residue;
[0506] e.) evaluating the panel of mutated antibodies or
antigen-binding portions thereof, relative to the parent antibody
or antigen-portion thereof, for changes in at least one other
characteristic or property;
[0507] e) repeating steps b) through e) for at least one other CDR
position which is neither the position selected under b) nor a
position at H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53,
H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50,
L52, L53, L55, L91, L92, L93, L94 and L96;
[0508] f) combining, in the parent antibody, or antigen-binding
portion thereof, at least two individual activity enhancing amino
acid residues shown to have improved activity and not affecting at
least one other property or characteristic, to form combination
antibodies, or antigen-binding portions thereof; and
[0509] g) evaluating the activity and the retention of at least one
other property or characteristic of the combination antibodies, or
antigen-binding portions thereof with two activity enhancing amino
acid residues, relative to the parent antibody or antigen-binding
portion thereof until an antibody, or antigen-binding portion
thereof, with an improved activity and at least one retained other
property or characteristic, relative to the parent antibody, or
antigen-binding portion thereof, is obtained.
[0510] Mutagenesis of the preferred selective mutagenesis position,
contact and hypermutation residues may not have increased the
affinity of the antibody sufficiently, and mutagenesis and the
phage display method (or related ribosome display method) may no
longer be useful and at least one other characteristic or property
of the antibody should be retained.
[0511] Therefore, in another embodiment the invention provides a
method to improve the affinity of an antibody or antigen-binding
portion thereof, comprising:
[0512] a) providing a parent antibody or antigen-binding portion
thereof that was obtained by selection in a phage-display system
but whose activity cannot be further improved by mutagenesis in
said phage-display system;
[0513] b) selecting an amino acid residue within a complementarity
determining region (CDR) for mutation other than H30, H31, H31B,
H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97,
H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93,
L94 and L96;
[0514] c) individually mutating said selected position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof and expression in a
non-phage display system;
[0515] d) evaluating the activity of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof thereby
identifying an activity enhancing amino acid residue;
[0516] e) evaluating the panel of mutated antibodies, or
antigen-binding portions thereof, relative to the parent antibody
or antigen-binding portion thereof, for changes in at least one
other property or characteristic until an antibody, or
antigen-binding portion thereof, with an improved activity,
relative to the parent antibody, or antigen-binding portion
thereof, is obtained.
[0517] Preferably, the other characteristic or property is selected
from 1) preservation of non-crossreactivity with other proteins or
human tissues, 2) preservation of epitope recognition, i.e.
recognizing p40 epitope preferably in the context of the p70
p40/p35 heterodimer preventing binding interference from free,
soluble p40 and/or 3) to produce an antibody with a close to
germline immunoglobulin sequence
[0518] If mutagenesis of a single residue is not sufficient other
residues can be included; therefore, in another embodiment, the
invention provides a method for improving the activity of an
antibody, or antigen-binding portion thereof, comprising:
[0519] a) providing a parent antibody or antigen-binding portion
thereof that was obtained by selection in a phage-display system
but whose activity cannot be further improved by mutagenesis in
said phage-display system;
[0520] b) selecting an amino acid residue within a complementarity
determining region (CDR) for mutation other than H30, H31, H31B,
H32, H33, H35, H50, H52, H52A, H53, H54, H56, H58, H95, H96, H97,
H98, H101, L30, L31, L32, L34, L50, L52, L53, L55, L91, L92, L93,
L94 and L96;
[0521] c) individually mutating said selected position to at least
two other amino acid residues to thereby create a panel of mutated
antibodies, or antigen-binding portions thereof and expression in a
non-phage display system;
[0522] d) evaluating the activity and retention of at least one
other property or characteristic of the panel of mutated
antibodies, or antigen-binding portions thereof, relative to the
parent antibody or antigen-binding portion thereof, thereby
identifying an activity enhancing amino acid residue;
[0523] e) repeating steps b) through d) for at least one other CDR
position which is neither the position selected under b) nor a
position at H30, H31, H31B, H32, H33, H35, H50, H52, H52A, H53,
H54, H56, H58, H95, H96, H97, H98, H101, L30, L31, L32, L34, L50,
L52, L53, L55, L91, L92, L93, L94 and L96;
[0524] f) combining, in the parent antibody, or antigen-binding
portion thereof, at least two individual activity enhancing amino
acid residues shown to have improved activity and not to affect at
least one other property or characteristic, to form combination
antibodies, or antigen-binding portions thereof; and
[0525] g) evaluating the activity and retention of at least one
property or characteristic of the combination antibodies, or
antigen-binding portions thereof with two activity enhancing amino
acid residues, relative to the parent antibody or antigen-binding
portion thereof until an antibody, or antigen-binding portion
thereof, with an improved activity and at least one other retained
characteristic or property, relative to the parent antibody, or
antigen-binding portion thereof, is obtained.
V. Expression of Antibodies
[0526] An antibody, or antibody portion, of the invention can be
prepared by recombinant expression of immunoglobulin light and
heavy chain genes in a host cell. To express an antibody
recombinantly, a host cell is transfected with one or more
recombinant expression vectors carrying DNA fragments encoding the
immunoglobulin light and heavy chains of the antibody such that the
light and heavy chains are expressed in the host cell and,
preferably, secreted into the medium in which the host cells are
cultured, from which medium the antibodies can be recovered.
Standard recombinant DNA methodologies are used to obtain antibody
heavy and light chain genes, incorporate these genes into
recombinant expression vectors and introduce the vectors into host
cells, such as those described in Sambrook, Fritsch and Maniatis
(eds), Molecular Cloning; A Laboratory Manual, Second Edition, Cold
Spring Harbor, N.Y., (1989), Ausubel, F. M. et al. (eds.) Current
Protocols in Molecular Biology, Greene Publishing Associates,
(1989) and in U.S. Pat. No. 4,816,397 by Boss et al.
[0527] To obtain a DNA fragment encoding the heavy chain variable
region of Joe 9 wt or a Joe 9 wt-related antibody, antibodies
specific for human IL-12 were screened from human libraries and
mutated, as described in section II. Once DNA fragments encoding
Joe 9 wt or Joe 9 wt-related VH and VL segments are obtained,
mutagenesis of these sequences is carried out by standard methods,
such as PCR site directed mutagenesis (PCR-mediated mutagenesis in
which the mutated nucleotides are incorporated into the PCR primers
such that the PCR product contains the mutations) or other
site-directed mutagenesis methods. Human IL-12 antibodies that
displayed a level of activity and binding specificity/affinity that
was desirable, for example J695, were further manipulated by
standard recombinant DNA techniques, for example to convert the
variable region genes to full-length antibody chain genes, to Fab
fragment genes or to a scFv gene. In these manipulations, a VL- or
VH-encoding DNA fragment is operatively linked to another DNA
fragment encoding another protein, such as an antibody constant
region or a flexible linker. The term "operatively linked", as used
in this context, is intended to mean that the two DNA fragments are
joined such that the amino acid sequences encoded by the two DNA
fragments remain in-frame.
[0528] The isolated DNA encoding the VH region can be converted to
a full-length heavy chain gene by operatively linking the
VH-encoding DNA to another DNA molecule encoding heavy chain
constant regions (CH1, CH2 and CH3). The sequences of human heavy
chain constant region genes are known in the art (see e.g., Kabat,
E. A., et al. (1991) Sequences of Proteins of Immunological
Interest, Fifth Edition, U.S. Department of Health and Human
Services, NIH Publication No. 91-3242) and DNA fragments
encompassing these regions can be obtained by standard PCR
amplification. The heavy chain constant region can be an IgG1,
IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region and any
allotypic variant therein as described in Kabat (, Kabat, E. A., et
al. (1991) Sequences of Proteins of Immunological Interest, Fifth
Edition, U.S. Department of Health and Human Services, NIH
Publication No. 91-3242), but most preferably is an IgG1 or IgG4
constant region. For a Fab fragment heavy chain gene, the
VH-encoding DNA can be operatively linked to another DNA molecule
encoding only the heavy chain CH1 constant region.
[0529] The isolated DNA encoding the VL region can be converted to
a full-length light chain gene (as well as a Fab light chain gene)
by operatively linking the VL-encoding DNA to another DNA molecule
encoding the light chain constant region, CL. The sequences of
human light chain constant region genes are known in the art (see
e.g., Kabat, E. A., et al. (1991) Sequences of Proteins of
Immunological Interest, Fifth Edition, U.S. Department of Health
and Human Services, NIH Publication No. 91-3242) and DNA fragments
encompassing these regions can be obtained by standard PCR
amplification. The light chain constant region can be a kappa or
lambda constant region, but most preferably is a lambda constant
region.
[0530] To create a scFv gene, the VH- and VL-encoding DNA fragments
are operatively linked to another fragment encoding a flexible
linker, e.g., encoding the amino acid sequence
(Gly.sub.4-Ser).sub.3, such that the VH and VL sequences can be
expressed as a contiguous single-chain protein, with the VL and VH
regions joined by the flexible linker (see e.g., Bird et al. (1988)
Science 242:423-426; Huston et al. (1988) Proc. Natl. Acad. Sci.
USA 85:5879-5883; McCafferty et al., Nature (1990)
348:552-554).
[0531] To express the antibodies, or antibody portions of the
invention, DNAs encoding partial or full-length light and heavy
chains, obtained as described above, are inserted into expression
vectors such that the genes are operatively linked to
transcriptional and translational control sequences. In this
context, the term "operatively linked" is intended to mean that an
antibody gene is ligated into a vector such that transcriptional
and translational control sequences within the vector serve their
intended function of regulating the transcription and translation
of the antibody gene. The expression vector and expression control
sequences are chosen to be compatible with the expression host cell
used. The antibody light chain gene and the antibody heavy chain
gene can be inserted into separate vector or, more typically, both
genes are inserted into the same expression vector. The antibody
genes are inserted into the expression vector by standard methods
(e.g., ligation of complementary restriction sites on the antibody
gene fragment and vector, or blunt end ligation if no restriction
sites are present). Prior to insertion of the J695 or J695-related
light or heavy chain sequences, the expression vector may already
carry antibody constant region sequences. For example, one approach
to converting the J695 or J695-related VH and VL sequences to
full-length antibody genes is to insert them into expression
vectors already encoding heavy chain constant and light chain
constant regions, respectively, such that the VH segment is
operatively linked to the CH segment(s) within the vector and the
VL segment is operatively linked to the CL segment within the
vector. Additionally or alternatively, the recombinant expression
vector can encode a signal peptide that facilitates secretion of
the antibody chain from a host cell. The antibody chain gene can be
cloned into the vector such that the signal peptide is linked
in-frame to the amino terminus of the antibody chain gene. The
signal peptide can be an immunoglobulin signal peptide or a
heterologous signal peptide (i.e., a signal peptide from a
non-immunoglobulin protein).
[0532] In addition to the antibody chain genes, the recombinant
expression vectors of the invention carry regulatory sequences that
control the expression of the antibody chain genes in a host cell.
The term "regulatory sequence" is intended to include promoters,
enhancers and other expression control elements (e.g.,
polyadenylation signals) that control the transcription or
translation of the antibody chain genes. Such regulatory sequences
are described, for example, in Goeddel; Gene Expression Technology:
Methods in Enzymology 185, Academic Press, San Diego, Calif.
(1990). It will be appreciated by those skilled in the art that the
design of the expression vector, including the selection of
regulatory sequences may depend on such factors as the choice of
the host cell to be transformed, the level of expression of protein
desired, etc. Preferred regulatory sequences for mammalian host
cell expression include viral elements that direct high levels of
protein expression in mammalian cells, such as promoters and/or
enhancers derived from cytomegalovirus (CMV) (such as the CMV
promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40
promoter/enhancer), adenovirus, (e.g., the adenovirus major late
promoter (AdMLP)) and polyoma. For further description of viral
regulatory elements, and sequences thereof, see e.g., U.S. Pat. No.
5,168,062 by Stinski, U.S. Pat. No. 4,510,245 by Bell et al. and
U.S. Pat. No. 4,968,615 by Schaffner et al., U.S. Pat. No.
5,464,758 by Bujard et al. and U.S. Pat. No. 5,654,168 by Bujard et
al.
[0533] In addition to the antibody chain genes and regulatory
sequences, the recombinant expression vectors of the invention may
carry additional sequences, such as sequences that regulate
replication of the vector in host cells (e.g., origins of
replication) and selectable marker genes. The selectable marker
gene facilitates selection of host cells into which the vector has
been introduced (see e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and
5,179,017, all by Axel et al.). For example, typically the
selectable marker gene confers resistance to drugs, such as G418,
hygromycin or methotrexate, on a host cell into which the vector
has been introduced. Preferred selectable marker genes include the
dihydrofolate reductase (DHFR) gene (for use in dhfr.sup.- host
cells with methotrexate selection/amplification) and the neo gene
(for G418 selection).
[0534] For expression of the light and heavy chains, the expression
vector(s) encoding the heavy and light chains is transfected into a
host cell by standard techniques. The various forms of the term
"transfection" are intended to encompass a wide variety of
techniques commonly used for the introduction of exogenous DNA into
a prokaryotic or eukaryotic host cell, e.g., electroporation,
calcium-phosphate precipitation, DEAE-dextran transfection and the
like. Although it is theoretically possible to express the
antibodies of the invention in either prokaryotic or eukaryotic
host cells, expression of antibodies in eukaryotic cells, and most
preferably mammalian host cells, is the most preferred because such
eukaryotic cells, and in particular mammalian cells, are more
likely than prokaryotic cells to assemble and secrete a properly
folded and immunologically active antibody. Preferred mammalian
host cells for expressing the recombinant antibodies of the
invention include Chinese Hamster Ovary (CHO cells) (including
dhfr- CHO cells, described in Urlaub and Chasin, (1980) Proc. Natl.
Acad. Sci. USA 77:4216-4220, used with a DHFR selectable marker,
e.g., as described in R. J. Kaufman and P.A. Sharp (1982) Mol.
Biol. 159:601-621), NS0 myeloma cells, COS cells and SP2 cells.
When recombinant expression vectors encoding antibody genes are
introduced into mammalian host cells, the antibodies are produced
by culturing the host cells for a period of time sufficient to
allow for expression of the antibody in the host cells or, more
preferably, secretion of the antibody into the culture medium in
which the host cells are grown. Antibodies can be recovered from
the culture medium using standard protein purification methods.
[0535] Host cells can also be used to produce portions of intact
antibodies, such as Fab fragments or scFv molecules. It will be
understood that variations on the above procedure are within the
scope of the present invention. For example, it may be desirable to
transfect a host cell with DNA encoding either the light chain or
the heavy chain (but not both) of an antibody of this invention.
Recombinant DNA technology may also be used to remove some or all
of the DNA encoding either or both of the light and heavy chains
that is not necessary for binding to hIL-12 The molecules expressed
from such truncated DNA molecules are also encompassed by the
antibodies of the invention. In addition, bifunctional antibodies
may be produced in which one heavy and one light chain are an
antibody of the invention and the other heavy and light chain are
specific for an antigen other than hIL-12 by crosslinking an
antibody of the invention to a second antibody by standard chemical
crosslinking methods.
[0536] In a preferred system for recombinant expression of an
antibody, or antigen-binding portion thereof, of the invention, a
recombinant expression vector encoding both the antibody heavy
chain and the antibody light chain is introduced into dhfr- CHO
cells by calcium phosphate-mediated transfection. Within the
recombinant expression vector, the antibody heavy and light chain
genes are each operatively linked to enhancer/promoter regulatory
elements (e.g., derived from SV40, CMV, adenovirus and the like,
such as a CMV enhancer/AdMLP promoter regulatory element or an SV40
enhancer/AdMLP promoter regulatory element) to drive high levels of
transcription of the genes. The recombinant expression vector also
carries a DHFR gene, which allows for selection of CHO cells that
have been transfected with the vector using methotrexate
selection/amplification. The selected transformant host cells are
culture to allow for expression of the antibody heavy and light
chains and intact antibody is recovered from the culture medium.
Standard molecular biology techniques are used to prepare the
recombinant expression vector, transfect the host cells, select for
transformants, culture the host cells and recover the antibody from
the culture medium. Antibodies or antigen-binding portions thereof
of the invention can be expressed in an animal (e.g., a mouse) that
is transgenic for human immunoglobulin genes (see e.g., Taylor, L.
D. et al. (1992) Nucl. Acids Res. 20: 6287-6295). Plant cells can
also be modified to create transgenic plants that express the
antibody or antigen binding portion thereof, of the invention.
[0537] In view of the foregoing, another aspect of the invention
pertains to nucleic acid, vector and host cell compositions that
can be used for recombinant expression of the antibodies and
antibody portions of the invention. Preferably, the invention
features isolated nucleic acids that encode CDRs of J695, or the
full heavy and/or light chain variable region of J695. Accordingly,
in one embodiment, the invention features an isolated nucleic acid
encoding an antibody heavy chain variable region that encodes the
J695 heavy chain CDR3 comprising the amino acid sequence of SEQ ID
NO: 25. Preferably, the nucleic acid encoding the antibody heavy
chain variable region further encodes a J695 heavy chain CDR2 which
comprises the amino acid sequence of SEQ ID NO: 27. More
preferably, the nucleic acid encoding the antibody heavy chain
variable region further encodes a J695 heavy chain CDR1 which
comprises the amino acid sequence of SEQ ID NO: 29. Even more
preferably, the isolated nucleic acid encodes an antibody heavy
chain variable region comprising the amino acid sequence of SEQ ID
NO: 31 (the full VH region of J695).
[0538] In other embodiments, the invention features an isolated
nucleic acid encoding an antibody light chain variable region that
encodes the J695 light chain CDR3 comprising the amino acid
sequence of SEQ ID NO: 26. Preferably, the nucleic acid encoding
the antibody light chain variable region further encodes a J695
light chain CDR2 which comprises the amino acid sequence of SEQ ID
NO: 28. More preferably, the nucleic acid encoding the antibody
light chain variable region further encodes a J695 light chain CDR1
which comprises the amino acid sequence of SEQ ID NO: 30. Even more
preferably, the isolated nucleic acid encodes an antibody light
chain variable region comprising the amino acid sequence of SEQ ID
NO: 32 (the full VL region of J695).
[0539] The invention also provides recombinant expression vectors
encoding both an antibody heavy chain and an antibody light chain.
For example, in one embodiment, the invention provides a
recombinant expression vector encoding:
[0540] a) an antibody heavy chain having a variable region
comprising the amino acid sequence of SEQ ID NO: 31; and
[0541] b) an antibody light chain having a variable region
comprising the amino acid sequence of SEQ ID NO: 32.
[0542] The invention also provides host cells into which one or
more of the recombinant expression vectors of the invention have
been introduced. Preferably, the host cell is a mammalian host
cell, more preferably the host cell is a CHO cell, an NS0 cell or a
COS cell. Still further the invention provides a method of
synthesizing a recombinant human antibody of the invention by
culturing a host cell of the invention in a suitable culture medium
until a recombinant human antibody of the invention is synthesized.
The method can further comprise isolating the recombinant human
antibody from the culture medium.
VI. Pharmaceutical Compositions and Pharmaceutical
Administration
[0543] The antibodies and antibody-portions of the invention can be
incorporated into pharmaceutical compositions suitable for
administration to a subject. Typically, the pharmaceutical
composition comprises an antibody or antibody portion of the
invention and a pharmaceutically acceptable carrier. As used
herein, "pharmaceutically acceptable carrier" includes any and all
solvents, dispersion media, coatings, antibacterial and antifungal
agents, isotonic and absorption delaying agents, and the like that
are physiologically compatible. Examples of pharmaceutically
acceptable carriers include one or more of water, saline, phosphate
buffered saline, dextrose, glycerol, ethanol and the like, as well
as combinations thereof. In many cases, it will be preferable to
include isotonic agents, for example, sugars, polyalcohols such as
mannitol, sorbitol, or sodium chloride in the composition.
Pharmaceutically acceptable carriers may further comprise minor
amounts of auxiliary substances such as wetting or emulsifying
agents, preservatives or buffers, which enhance the shelf life or
effectiveness of the antibody or antibody portion.
[0544] The antibodies and antibody-portions of the invention can be
incorporated into a pharmaceutical composition suitable for
parenteral administration. Preferably, the antibody or
antibody-portions will be prepared as an injectable solution
containing 0.1-250 mg/ml antibody. The injectable solution can be
composed of either a liquid or lyophilized dosage form in a flint
or amber vial, ampule or pre-filled syringe. The buffer can be
L-histidine (1-50 mM), optimally 5-10 mM, at pH 5.0 to 7.0
(optimally pH 6.0). Other suitable buffers include but are not
limited to, sodium succinate, sodium citrate, sodium phosphate or
potassium phosphate. Sodium chloride can be used to modify the
toxicity of the solution at a concentration of 0-300 mM (optimally
150 mM for a liquid dosage form). Cryoprotectants can be included
for a lyophilized dosage form, principally 0-10% sucrose (optimally
0.5-1.0%). Other suitable cryoprotectants include trehalose and
lactose. Bulking agents can be included for a lyophilized dosage
form, principally 1-10% mannitol (optimally 2-4%). Stabilizers can
be used in both liquid and lyophilized dosage forms, principally
1-50 mM L-Methionine (optimally 5-10 mM). Other suitable bulking
agents include glycine, arginine, can be included as 0-0.05%
polysorbate-80 (optimally 0.005-0.01%). Additional surfactants
include but are not limited to polysorbate 20 and BRIJ
surfactants.
[0545] In one embodiment, the invention provides a formulation
comprising the antibody in combination with a polyol, a surfactant,
a stabilizer, and a buffer system with a pH of about 5 to 5. In one
embodiment said formulation is free of metal. In a preferred
embodiment, the formulation comprises the antibody and mannitol,
histidine, methionine, polysorbate 80, hydrochloric acid, and
water.
[0546] In one embodiment, an aqueous formulation is prepared
comprising the antibody in a pH-buffered solution. The buffer of
this invention has a pH ranging from about 4 to about 8, preferably
from about 4.5 to about 7.5, more preferably from about 5 to about
7, more preferably from about 5.5 to about 6.5, and most preferably
has a pH of about 6.0 to about 6.2. In a particularly preferred
embodiment, the buffer has a pH of about 6. Ranges intermediate to
the above recited pH's are also intended to be part of this
invention. For example, ranges of values using a combination of any
of the above recited values as upper and/or lower limits are
intended to be included. Examples of buffers that will control the
pH within this range include acetate (e.g. sodium acetate),
succinate (such as sodium succinate), gluconate, histidine,
citrate, phosphate and other organic acid buffers. In a preferred
embodiment of the invention, the formulation contains a buffer
system comprising histidine. In a preferred embodiment of the
invention, the buffer is histidine, e.g., L-histidine. In preferred
embodiments, the formulation of the invention comprises a buffer
system comprising about 1-100 mM histidine, preferably about 5-50
mM histidine, and most preferably 10 mM histidine. One of skill in
the art will recognize that sodium chloride can be used to modify
the toxicity of the solution, e.g., at a concentration of 1-300 mM,
and optimally 150 mM for a liquid dosage form.
[0547] A polyol, which acts as a tonicifier and may stabilize the
antibody, is also included in the formulation. The polyol is added
to the formulation in an amount that may vary with respect to the
desired isotonicity of the formulation. Preferably the aqueous
formulation is isotonic. The amount of polyol added may also vary
with respect to the molecular weight of the polyol. For example, a
lower amount of a monosaccharide (e.g., mannitol) may be added,
compared to a disaccharide (such as trehalose). In a preferred
embodiment of the invention, the polyol that is used in the
formulation as a tonicity agent is mannitol. In a preferred
embodiment, the composition comprises about 10 to about 100 mg/ml,
or about 20 to about 80, about 20 to about 70, about 30 to about
60, about 30 to about 50 mg/ml of mannitol, for example, about 10,
about 20, about 30, about 40, about 50, about 60, about 70, about
80, about 90, and about 100 mg/ml of mannitol In a preferred
embodiment, the formulation comprises about 40 mg/ml of mannitol
(corresponding to about 4% mannitol). In a preferred embodiment,
the composition comprises between about 1% to about 10% mannitol,
more preferably between about 2% to about 6% mannitol, and most
preferably about 4% mannitol. In another embodiment of the
invention, the polyol sorbitol is included in the formulation.
[0548] A stabilizer or antioxidant is also added to the antibody
formulation. A stabilizer can be used in both liquid and
lyophilized dosage forms. Formulations of the invention preferably
comprise the stabilizer methionine, e.g., L-Methionine. Other
stabilizers useful in formulations of the invention are known to
those of skill in the art and include, but are not limited to,
glycine and arginine. Cryoprotectants can be included for a
lyophilized dosage form, principally sucrose (e.g., 1-10% sucrose,
and optimally 0.5-1.0% sucrose). Other suitable cyroprotectants
include trehalose and lactose.
[0549] A detergent or surfactant is also added to the antibody
formulation. Exemplary detergents include nonionic detergents such
as polysorbates (e.g., polysorbates 20, 80 etc.) or poloxamers
(e.g., poloxamer 188). The amount of detergent added is such that
it reduces aggregation of the formulated antibody and/or minimizes
the formation of particulates in the formulation and/or reduces
adsorption. In a preferred embodiment of the invention, the
formulation includes a surfactant that is a polysorbate. In another
preferred embodiment of the invention, the formulation contains the
detergent polysorbate 80 or Tween 80. Tween 80 is a term used to
describe polyoxyethylene (20) sorbitanmonooleate (see Fiedler,
Lexikon der Hifsstoffe, Editio Cantor Verlag Aulendorf, 4th ed.,
1996). In one preferred embodiment, the formulation contains
between 0.001 to about 0.1% polysorbate 80, or between about 0.005
and 0.05% polysorbate 80, for example, about 0.001, about 0.005,
about 0.01, about 0.05, or about 0.1% polysorbate 80. In a
preferred embodiment, about 0.01% polysorbate 80 is found in the
formulation of the invention.
[0550] In a preferred embodiment of the invention, the formulation
is a 1.0 mL solution in a container containing the ingredients
shown below in Table 1. In another embodiment, the formulation is a
0.8 mL solution in a container.
TABLE-US-00002 TABLE 1 A 1.0 mL Solution.sup.1) of J695 Formulation
for Injection Name of Ingredient Quantity Function Active
substance: Antibody (J695).sup.2) 50.0 or 100.0 mg Active substance
Excipients: Mannitol 40 mg Tonicity agent Polysorbate 80 0.10 mg
Detergent/Surfactant Histidine 1.55 mg Buffer Methionine 1.49 mg
Stabilizer Water for injection To one 1 ml Solvent Hydrochloric
Acid q.s. pH adjustment to 6.0 .sup.1)Density of the solution:
1.0398 g/mL .sup.2)Is used as concentrate
[0551] In one embodiment, the formulation is a formulation
described in U.S. application Ser. No. 12/625,057, which published
as U.S. 2010/0172862 A1, the entire contents of which are hereby
expressly incorporated by reference.
[0552] In one embodiment, the formulation contains the
above-identified agents (i.e., antibody, polyol, surfactant,
stabilizer and buffer) and is essentially free of one or more
preservatives, such as benzyl alcohol, phenol, m-cresol,
chlorobutanol and benzethonium Cl. In another embodiment, a
preservative may be included in the formulation, particularly where
the formulation is a multidose formulation. One or more other
pharmaceutically acceptable carriers, excipients or stabilizers
such as those described in Remington's Pharmaceutical Sciences 16th
edition, Osol, A. Ed. (1980) may be included in the formulation
provided that they do not significantly adversely affect the
desired characteristics of the formulation. Acceptable carriers,
excipients or stabilizers are nontoxic to recipients at the dosages
and concentrations employed and include; additional buffering
agents; co-solvents; antioxidants such as ascorbic acid; chelating
agents such as EDTA; metal complexes (e.g. Zn-protein complexes);
biodegradable polymers such as polyesters; and/or salt-forming
counterions such as sodium.
[0553] In one embodiment, the formulations of the invention have
improved properties as compared to art-recognized formulations. For
example, the formulations of the invention have an improved shelf
life and/or stability as compared to art recognized formulations.
In one embodiment, the formulations of the invention have a shelf
life of at least 18 months, e.g., in a liquid state or in a solid
state. In another embodiment, the formulations of the invention
have a shelf life of at least 24 months, e.g., in a liquid state or
in a solid state. In a preferred embodiment, the formulations of
the invention have a shelf life of at least 24 months at a
temperature of 2-8.degree. C. In a preferred embodiment, the
formulations of the invention have a shelf life of at least 18
months or of at least 24 months at a temperature of between about
-20 and -80.degree. C. In another embodiment, the formulations of
the invention maintain stability following at least 5 freeze/thaw
cycles of the formulation. In a preferred aspect, the formulations
of the invention comprise, e.g., an antibody, comprising at least a
portion of a lambda light chain, e.g., J695, wherein the
formulation provides enhanced resistance to fragmentation of the
lambda light chain, e.g., reduced cleavage of the lambda light
chain, as compared to art recognized formulations.
[0554] In one embodiment, the formulations of the invention are
substantially free of metal. In one embodiment, the formulations of
the invention are substantially free of a metal selected from the
group consisting of Fe2+, Fe3+, Ca2+and Cu1+. In one embodiment,
the formulations of the invention comprise an amount of metal that
is sufficiently low to reduce or prevent cleavage of the lambda
chain in the presence of histidine, e.g., the metal is present at a
concentration of less than about 5,060 ppb, less than about 1,060
ppb, less than about 560 ppb, less than about 500 ppb, less than
about 450 ppb, less than about 400 ppb, less than about 350 ppb,
less than about 310 ppb, less than about 300 ppb, less than about
250 ppb, less than about 200 ppb, less than about 160 ppb, less
than about 150 ppb, less than about 140 ppb, less than about 130
ppb, less than about 120 ppb, less than about 110 ppb, less than
about 100 ppb, less than about 90 ppb, less than about 80 ppb, less
than about 70 ppb, less than about 60 ppb, less than about 50 ppb,
less than about 40 ppb, less than about 30 ppb, less than about 20
ppb, less than about 10 ppb, or less than about 1 ppb. In one
embodiment, the metal is present at a concentration of less than
about 160 ppb. In one embodiment, the metal is present at a
concentration of less than about 110 ppb. In one embodiment, the
metal is present at a concentration of less than about 70 ppb,
e.g., a concentration of about 60 ppb. Maximum concentrations
intermediate to the above recited concentrations, e.g., less than
about 65 ppb, are also intended to be part of this invention.
Further, ranges of values using a combination of any of the above
recited values as upper and/or lower limits, e.g., concentrations
between about 50 ppb and about 70 ppb, are also intended to be
included.
[0555] In one embodiment, the formulations of the invention are
substantially free of metal following subjection to at least one
procedure that removes metal, such as filtration, buffer exchange,
chromatography or resin exchange. Procedures useful to remove metal
from formulations of the invention are known to one of skill in the
art and are further described herein. In one embodiment, the
formulations of the invention comprise a metal chelator, e.g., such
that the molecule is not cleaved within the hinge region or is
cleaved within the hinge region at a level which is less than the
level of cleavage observed in the absence of the metal chelator. In
the formulations of the invention, the metal chelator may be, for
example, a siderophore, calixerenes, an aminopolycarboxylic acid, a
hydroxyaminocarboxylic acid, an N-substituted glycine, a
2-(2-amino-2-oxoethyl)aminoethane sulfonic acid (BES), a bidentate,
tridentate or hexadentate iron chelator, a copper chelator, and
derivatives, analogues, and combinations thereof. Metal chelators
useful in formulations of the invention are known to one of skill
in the art, and are further described below.
[0556] Particular siderophores useful in formulations of the
invention include, but are not limited to, aerobactin, agrobactin,
azotobactin, bacillibactin, N-(5-C3-L (5
aminopentyl)hydroxycarbamoyl)-propionamido)pentyl)-3(5-(N-hydroxyacetoami-
do)-pentyl)carbamoyl)-proprionhydroxamic acid (deferoxamine,
desferrioxamine or DFO or DEF), desferrithiocin, enterobactin,
erythrobactin, ferrichrome, ferrioxamine B, ferrioxamine E,
fluviabactin, fusarinine C, mycobactin, parabactin, pseudobactin,
vibriobactin, vulnibactin, yersiniabactin, ornibactin, and
derivatives, analogues, and combinations thereof.
[0557] Aminopolycarboxylic acids useful in formulations of the
invention include, but are not limited to,
ethylenediaminetetraacetic acid (EDTA), nitriloacetic acid (NTA),
trans-diaminocyclohexane tetraacetic acid (DCTA),
diethylenetriamine pentaacetic acid (DTPA),
N-2-acetamido-2-iminodiacetic acid (ADA), aspartic acid,
bis(aminoethyl)glycolether N,N,N'N'-tetraacetic acid (EGTA),
glutamic acid, and
N,N'-bis(2-hydroxybenzyl)ethylenediamine-N,N'-diacetic acid (HBED),
and derivatives, analogues, and combinations thereof.
[0558] Hydroxyaminocarboxylic acids useful in formulations of the
invention include, but are not limited to,
N-hydroxyethyliminodiacetic acid (HIMDA),
N,N-bishydroxyethylglycine (bicine), and
N-(trishydroxymethylmethyl) glycine (tricine), and derivatives,
analogues, and combinations thereof. N-substituted glycines, e.g.,
glycylglycine, as well as derivatives, analogues, or combinations
thereof, are also useful as metal chelators in formulations of the
invention. The metal chelator 2-(2-amino-2-oxoethyl)aminoethane
sulfonic acid (BES), and derivatives, analogues, and combinations
thereof, can also be used.
[0559] Particular calixarenes useful in formulations of the
invention include, but are not limited to, a macrocycle or cyclic
oligomer based on a hydroxyalkylation product of a phenol and an
aldehyde, and derivatives, analogues, and combinations thereof.
Particular copper chelators useful in the invention include
triethylenetetramine (trientine), etraethylenepentamine,
D-penicillamine, ethylenediamine, bispyridine, phenantroline,
bathophenanthroline, neocuproine, bathocuproine sulphonate,
cuprizone, cis,cis-1,3,5,-triaminocyclohexane (TACH), tachpyr, and
derivatives, analogues, and combinations thereof.
[0560] Additional metal chelators that can be employed in
formulations of the invention include a hydroxypyridine-derivate, a
hydrazone-derivate, and hydroxyphenyl-derivate, or a
nicotinyl-derivate, such as 1,2-dimethyl-3-hydroxypyridin-4-one
(Deferiprone, DFP or Ferriprox);
2-deoxy-2-(N-carbamoylmethyl-[N'-2'-methyl-3'-hydroxypyridin-4'-one])-D-g-
lucopyranose (Feralex-G), pyridoxal isonicotinyl hydrazone (P1H);
4,5-dihydro-2-(2,4-dihydroxyphenyl)-4-methylthiazole-4-carboxylic
acid (GT56-252),
4-[3,5-bis(2-hydroxyphenyl)-[1,2,4]-triazol-1-yl]benzoic acid
(ICL-670); N,N'-bis(o-hydroxybenzyl)ethylenediamine-N,N'-diacetic
acid (HBED), 5-chloro-7-iodo-quinolin-8-ol (clioquinol), and
derivatives, analogues, and combinations thereof.
[0561] It will be recognized that combinations of two or more of
any of the foregoing metal chelators can be used in combination in
the formulations of the invention. For example, in a particular
embodiment of the invention, the formulation comprises a
combination of DTPA and DEF. In another embodiment, the formulation
comprises a combination of EDTA, EGTA and DEF.
[0562] The amount of antibody present in the formulation is
determined, for example, by taking into account the desired dose
volumes and mode(s) of administration. In one embodiment of the
invention, the concentration of the antibody in the formulation is
between about 0.1 to about 250 mg of antibody per ml of liquid
formulation. In one embodiment of the invention, the concentration
of the antibody in the formulation is between about 1 to about 200
mg of antibody per ml of liquid formulation. In various
embodiments, the concentration of the antibody in the formulation
is between about 30 to about 140 mg per ml, between about 40 to
about 120 mg/ml, between about 50 to about 110 mg/ml, or between
about 60 to about 100 mg/ml. The formulation is especially suitable
for large antibody dosages of more than 15 mg/ml. In various
embodiments, the concentration of the antibody in the formulation
is about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110, 120, 130,
140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or 250 mg/ml.
In a preferred embodiment, the concentration of the antibody is 50
mg/ml. In another preferred embodiment, the concentration of the
antibody is 100 mg/ml. In a preferred embodiment, the concentration
of the antibody is at least about 100 mg/ml, at least about 110
mg/ml or at least about 120 mg/ml.
[0563] In various embodiments of the invention, the concentration
of the antibody in the formulation is about 0.1-250 mg/ml, 0.5-220
mg/ml, 1-210 mg/ml, about 5-200 mg/ml, about 10-195 mg/ml, about
15-190 mg/ml, about 20-185 mg/ml, about 25-180 mg/ml, about 30-175
mg/ml, about 35-170 mg/ml, about 40-165 mg/ml, about 45-160 mg/ml,
about 50-155 mg/ml, about 55-150 mg/ml, about 60-145 mg/ml, about
65-140 mg/ml, about 70-135 mg/ml, about 75-130 mg/ml, about 80-125
mg/ml, about 85-120 mg/ml, about 90-115 mg/ml, about 95-110 mg/ml,
about 95-105 mg/ml, or about 100 mg/ml. Ranges intermediate to the
above recited concentrations, e.g., about 31-174 mg/ml, are also
intended to be part of this invention. For example, ranges of
values using a combination of any of the above recited values as
upper and/or lower limits are intended to be included.
[0564] In one, the formulation provides an effective dose of 40 mg,
50 mg, 80 mg, 100 mg, or 200 mg per injection of the active
ingredient, the antibody. In another embodiment, the formulation
provides an effective dose which ranges from about 0.1 to 250 mg of
antibody. If desired, the effective daily dose of the
pharmaceutical formulation may be administered as two, three, four,
five, six or more sub-doses administered separately at appropriate
intervals throughout the day, optionally, in unit dosage forms. In
an embodiment of the invention, the dosage of the antibody in the
formulation is between about 1 to about 200 mg. In an embodiment,
the dosage of the antibody in the formulation is between about 30
and about 140 mg, between about 40 and about 120 mg, between about
50 and about 110 mg, between about 60 and about 100 mg, or between
about 70 and about 90 mg. In one embodiment, the pharmaceutical
composition includes the antibody at a dose of about 100 to about
200 mg. In a further embodiment, the composition includes the
antibody at about 1, 10, 20, 30, 40, 50, 60, 70, 80, 90, 100, 110,
120, 130, 140, 150, 160, 170, 180, 190, 200, 210, 220, 230, 240 or
250 mg.
[0565] Ranges intermediate to the above recited dosages, e.g.,
about 2-139 mg, are also intended to be part of this invention. For
example, ranges of values using a combination of any of the above
recited values as upper and/or lower limits are intended to be
included.
[0566] The compositions of this invention may be in a variety of
forms. These include, for example, liquid, semi-solid and solid
dosage forms, such as liquid solutions (e.g., injectable and
infusible solutions), dispersions or suspensions, tablets, pills,
powders, liposomes and suppositories. The preferred form depends on
the intended mode of administration and therapeutic application.
Typical preferred compositions are in the form of injectable or
infusible solutions, such as compositions similar to those used for
passive immunization of humans with other antibodies. The preferred
mode of administration is parenteral (e.g., intravenous,
subcutaneous, intraperitoneal, intramuscular). In a preferred
embodiment, the antibody, or antigen-binding fragment thereof, is
administered by subcutaneous injection.
[0567] Therapeutic compositions typically must be sterile and
stable under the conditions of manufacture and storage. The
composition can be formulated as a solution, microemulsion,
dispersion, liposome, or other ordered structure suitable to high
drug concentration. Sterile injectable solutions can be prepared by
incorporating the active compound (i.e., antibody or antibody
portion) in the required amount in an appropriate solvent with one
or a combination of ingredients enumerated above, as required,
followed by filtered sterilization. Generally, dispersions are
prepared by incorporating the active compound into a sterile
vehicle that contains a basic dispersion medium and the required
other ingredients from those enumerated above. In the case of
sterile, lyophilized powders for the preparation of sterile
injectable solutions, the preferred methods of preparation are
vacuum drying and spray-drying that yields a powder of the active
ingredient plus any additional desired ingredient from a previously
sterile-filtered solution thereof. The proper fluidity of a
solution can be maintained, for example, by the use of a coating
such as lecithin, by the maintenance of the required particle size
in the case of dispersion and by the use of surfactants. Prolonged
absorption of injectable compositions can be brought about by
including in the composition an agent that delays absorption, for
example, monostearate salts and gelatin.
[0568] The antibodies and antibody-portions of the present
invention can be administered by a variety of methods known in the
art, although for many therapeutic applications, the preferred
route/mode of administration is subcutaneous injection, intravenous
injection or infusion. As will be appreciated by the skilled
artisan, the route and/or mode of administration will vary
depending upon the desired results. In certain embodiments, the
active compound may be prepared with a carrier that will protect
the compound against rapid release, such as a controlled release
formulation, including implants, transdermal patches, and
microencapsulated delivery systems. Biodegradable, biocompatible
polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Many methods for the preparation of such
formulations are patented or generally known to those skilled in
the art. See, e.g., Sustained and Controlled Release Drug Delivery
Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York,
1978.
[0569] In certain embodiments, an antibody or antibody portion of
the invention may be orally administered, for example, with an
inert diluent or an assimilable edible carrier. The compound (and
other ingredients, if desired) may also be enclosed in a hard or
soft shell gelatin capsule, compressed into tablets, or
incorporated directly into the subject's diet. For oral therapeutic
administration, the compounds may be incorporated with excipients
and used in the form of ingestible tablets, buccal tablets,
troches, capsules, elixirs, suspensions, syrups, wafers, and the
like. To administer a compound of the invention by other than
parenteral administration, it may be necessary to coat the compound
with, or co-administer the compound with, a material to prevent its
inactivation.
[0570] Supplementary active compounds can also be incorporated into
the compositions. In certain embodiments, an antibody or antibody
portion of the invention is coformulated with and/or coadministered
with one or more additional therapeutic agents that are useful for
treating disorders in which IL-12 activity is detrimental. For
example, an anti-hIL-12 antibody or antibody portion of the
invention may be coformulated and/or coadministered with one or
more additional antibodies that bind other targets (e.g.,
antibodies that bind other cytokines or that bind cell surface
molecules). Furthermore, one or more antibodies of the invention
may be used in combination with two or more of the foregoing
therapeutic agents. Such combination therapies may advantageously
utilize lower dosages of the administered therapeutic agents, thus
avoiding possible toxicities or complications associated with the
various monotherapies. It will be appreciated by the skilled
practitioner that when the antibodies of the invention are used as
part of a combination therapy, a lower dosage of antibody may be
desirable than when the antibody alone is administered to a subject
(e.g., a synergistic therapeutic effect may be achieved through the
use of combination therapy which, in turn, permits use of a lower
dose of the antibody to achieve the desired therapuetic
effect).
[0571] Interleukin 12 plays a critical role in the pathology
associated with a variety of diseases involving immune and
inflammatory elements. These diseases include, but are not limited
to, rheumatoid arthritis, osteoarthritis, juvenile chronic
arthritis, Lyme arthritis, psoriatic arthritis, reactive arthritis,
spondyloarthropathy, systemic lupus erythematosus, Crohn's disease,
ulcerative colitis, inflammatory bowel disease, insulin dependent
diabetes mellitus, thyroiditis, asthma, allergic diseases,
psoriasis, dermatitis scleroderma, atopic dermatitis, graft versus
host disease, organ transplant rejection, acute or chronic immune
disease associated with organ transplantation, sarcoidosis,
atherosclerosis, disseminated intravascular coagulation, Kawasaki's
disease, Grave's disease, nephrotic syndrome, chronic fatigue
syndrome, Wegener's granulomatosis, Henoch-Schoenlein purpurea,
microscopic vasculitis of the kidneys, chronic active hepatitis,
uveitis, septic shock, toxic shock syndrome, sepsis syndrome,
cachexia, infectious diseases, parasitic diseases, acquired
immunodeficiency syndrome, acute transverse myelitis, Huntington's
chorea, Parkinson's disease, Alzheimer's disease, stroke, primary
biliary cirrhosis, hemolytic anemia, malignancies, heart failure,
myocardial infarction, Addison's disease, sporadic, polyglandular
deficiency type I and polyglandular deficiency type II, Schmidt's
syndrome, adult (acute) respiratory distress syndrome, alopecia,
alopecia greata, seronegative arthopathy, arthropathy, Reiter's
disease, psoriatic arthropathy, ulcerative colitic arthropathy,
enteropathic synovitis, chlamydia, yersinia and salmonella
associated arthropathy, spondyloarthopathy, atheromatous
disease/arteriosclerosis, atopic allergy, autoimmune bullous
disease, pemphigus vulgaris, pemphigus foliaceus, pemphigoid,
linear IgA disease, autoimmune haemolytic anaemia, Coombs positive
haemolytic anaemia, acquired pernicious anaemia, juvenile
pernicious anaemia, myalgic encephalitis/Royal Free Disease,
chronic mucocutaneous candidiasis, giant cell arteritis, primary
sclerosing hepatitis, cryptogenic autoimmune hepatitis, Acquired
Immunodeficiency Disease Syndrome, Acquired Immunodeficiency
Related Diseases, Hepatitis C, common varied immunodeficiency
(common variable hypogammaglobulinaemia), dilated cardiomyopathy,
female infertility, ovarian failure, premature ovarian failure,
fibrotic lung disease, cryptogenic fibrosing alveolitis,
post-inflammatory interstitial lung disease, interstitial
pneumonitis, connective tissue disease associated interstitial lung
disease, mixed connective tissue disease associated lung disease,
systemic sclerosis associated interstitial lung disease, rheumatoid
arthritis associated interstitial lung disease, systemic lupus
erythematosus associated lung disease, dermatomyositis/polymyositis
associated lung disease, Sjogren's disease associated lung disease,
ankylosing spondylitis associated lung disease, vasculitic diffuse
lung disease, haemosiderosis associated lung disease, drug-induced
interstitial lung disease, radiation fibrosis, bronchiolitis
obliterans, chronic eosinophilic pneumonia, lymphocytic
infiltrative lung disease, postinfectious interstitial lung
disease, gouty arthritis, autoimmune hepatitis, type-1 autoimmune
hepatitis (classical autoimmune or lupoid hepatitis), type-2
autoimmune hepatitis (anti-LKM antibody hepatitis), autoimmune
mediated hypoglycemia, type B insulin resistance with acanthosis
nigricans, hypoparathyroidism, acute immune disease associated with
organ transplantation, chronic immune disease associated with organ
transplantation, osteoarthrosis, primary sclerosing cholangitis,
idiopathic leucopenia, autoimmune neutropenia, renal disease NOS,
glomerulonephritides, microscopic vasulitis of the kidneys, lyme
disease, discoid lupus erythematosus, male infertility idiopathic
or NOS, sperm autoimmunity, multiple sclerosis (all subtypes),
insulin-dependent diabetes mellitus, sympathetic ophthalmia,
pulmonary hypertension secondary to connective tissue disease,
Goodpasture's syndrome, pulmonary manifestation of polyarteritis
nodosa, acute rheumatic fever, rheumatoid spondylitis, Still's
disease, systemic sclerosis, Takayasu's disease/arteritis,
autoimmune thrombocytopenia, idiopathic thrombocytopenia,
autoimmune thyroid disease, hyperthyroidism, goitrous autoimmune
hypothyroidism (Hashimoto's disease), atrophic autoimmune
hypothyroidism, primary myxoedema, phacogenic uveitis, primary
vasculitis and vitiligo. The human antibodies, and antibody
portions of the invention can be used to treat autoimmune diseases,
in particular those associated with inflammation, including,
rheumatoid spondylitis, allergy, autoimmune diabetes, autoimmune
uveitis.
[0572] Preferably, the antibodies of the invention or
antigen-binding portions thereof, are used to treat rheumatoid
arthritis, Crohn's disease, multiple sclerosis, insulin dependent
diabetes mellitus and psoriasis, as described in more detail in
section VII.
[0573] A human antibody, or antibody portion, of the invention also
can be administered with one or more additional therapeutic agents
useful in the treatment of autoimmune and inflammatory
diseases.
[0574] Antibodies of the invention, or antigen binding portions
thereof can be used alone or in combination to treat such diseases.
It should be understood that the IL-12 antibodies of the invention
or antigen binding portion thereof can be used alone or in
combination with an additional agent, e.g., a therapeutic agent,
said additional agent being selected by the skilled artisan for its
intended purpose. For example, the additional agent can be a
therapeutic agent art-recognized as being useful to treat the
disease or condition being treated by the antibody of the present
invention. The additional agent also can be an agent which imparts
a beneficial attribute to the therapeutic composition e.g., an
agent which effects the viscosity of the composition.
[0575] It should further be understood that the combinations which
are to be included within this invention are those combinations
useful for their intended purpose. The agents set forth below are
illustrative for purposes and not intended to be limited. The
combinations which are part of this invention can be the antibodies
of the present invention and at least one additional agent selected
from the lists below. The combination can also include more than
one additional agent, e.g., two or three additional agents if the
combination is such that the formed composition can perform its
intended function. Furthermore, additional agents described herein
used in combination with an IL-12 antibody, are not limited to the
disorder to which they are attributed for treatment.
[0576] Preferred combinations are non-steroidal anti-inflammatory
drug(s) also referred to as NSAIDS which include drugs like
ibuprofen. Other preferred combinations are corticosteroids
including prednisolone; the well known side-effects of steroid use
can be reduced or even eliminated by tapering the steroid dose
required when treating patients in combination with the anti-IL-12
antibodies of this invention. Non-limiting examples of therapeutic
agents for rheumatoid arthritis with which an antibody, or antibody
portion, of the invention can be combined include the following:
cytokine suppressive anti-inflammatory drug(s) (CSAIDs); antibodies
to or antagonists of other human cytokines or growth factors, for
example, TNF (including adalimumab/HUMIRA), LT, IL-1, IL-2, IL-6,
IL-7, IL-8, IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, and PDGF.
Antibodies of the invention, or antigen binding portions thereof,
can be combined with antibodies to cell surface molecules such as
CD2, CD3, CD4, CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80
(B7.1), CD86 (B7.2), CD90, or their ligands including CD154 (gp39
or CD40L).
[0577] Preferred combinations of therapeutic agents may interfere
at different points in the autoimmune and subsequent inflammatory
cascade; preferred examples include TNF antagonists like chimeric,
humanized or human TNF antibodies, D2E7, (U.S. application Ser. No.
08/599,226 filed Feb. 9, 1996), cA2 (Remicade.TM.), CDP 571,
anti-TNF antibody fragments (e.g., CDP870), and soluble p55 or p75
TNF receptors, derivatives thereof, (p75TNFR1gG (Enbrel.TM.) or
p55TNFR1gG (Lenercept), soluble IL-13 receptor (sIL-13), and also
TNF.alpha. converting enzyme (TACE) inhibitors; similarly IL-1
inhibitors (e.g., Interleukin-1-converting enzyme inhibitors, such
as Vx740, or IL-1RA etc.) may be effective for the same reason.
Other preferred combinations include Interleukin 11, anti-P7s and
p-selectin glycoprotein ligand (PSGL). Yet another preferred
combination are other key players of the autoimmune response which
may act parallel to, dependent on or in concert with IL-12
function; especially preferred are IL-18 antagonists including
IL-18 antibodies or soluble IL-18 receptors, or IL-18 binding
proteins. It has been shown that IL-12 and IL-18 have overlapping
but distinct functions and a combination of antagonists to both may
be most effective. Yet another preferred combination are
non-depleting anti-CD4 inhibitors. Yet other preferred combinations
include antagonists of the co-stimulatory pathway CD80 (B7.1) or
CD86 (B7.2) including antibodies, soluble receptors or antagonistic
ligands.
[0578] Anti-IL12 antibodies, or antigen binding portions thereof,
may also be combined with agents, such as methotrexate, 6-MP,
azathioprine sulphasalazine, mesalazine, olsalazine
chloroquinine/hydroxychloroquine, pencillamine, aurothiomalate
(intramuscular and oral), azathioprine, cochicine, corticosteroids
(oral, inhaled and local injection), beta-2 adrenoreceptor agonists
(salbutamol, terbutaline, salmeteral), xanthines (theophylline,
aminophylline), cromoglycate, nedocromil, ketotifen, ipratropium
and oxitropium, cyclosporin, FK506, rapamycin, mycophenolate
mofetil, leflunomide, NSAIDs, for example, ibuprofen,
corticosteroids such as prednisolone, phosphodiesterase inhibitors,
adensosine agonists, antithrombotic agents, complement inhibitors,
adrenergic agents, agents which interfere with signaling by
proinflammatory cytokines such as TNF.alpha. or IL-1 (e.g. IRAK,
NIK, IKK, p38 or MAP kinase inhibitors), IL-1.beta. converting
enzyme inhibitors (e.g., Vx740), anti-P7s, p-selectin glycoprotein
ligand (PSGL), TNF.alpha. converting enzyme (TACE) inhibitors,
T-cell signaling inhibitors such as kinase inhibitors,
metalloproteinase inhibitors, sulfasalazine, azathioprine,
6-mercaptopurines, angiotensin converting enzyme inhibitors,
soluble cytokine receptors and derivatives thereof (e.g. soluble
p55 or p75 TNF receptors and the derivatives p75TNFRIgG
(Enbrel.TM.) and p55TNFRIgG (Lenercept), sIL-1R1, sIL-1R11, sIL-6R,
soluble IL-13 receptor (sIL-13)) and anti-inflammatory cytokines
(e.g. IL-4, IL-10, IL-11, IL-13 and TGF.beta.). Preferred
combinations include methotrexate or leflunomide and in moderate or
severe rheumatoid arthritis cases, cyclosporine.
[0579] Non-limiting examples of therapeutic agents for inflammatory
bowel disease with which an anti-IL-12 antibody, or antibody
portion, can be combined include the following: budenoside;
epidermal growth factor; corticosteroids; cyclosporin,
sulfasalazine; aminosalicylates; 6-mercaptopurine; azathioprine;
metronidazole; lipoxygenase inhibitors; mesalamine; olsalazine;
balsalazide; antioxidants; thromboxane inhibitors; IL-1 receptor
antagonists; anti-IL-1.beta. monoclonal antibodies; anti-IL-6
monoclonal antibodies; growth factors; elastase inhibitors;
pyridinyl-imidazole compounds; antibodies to or antagonists of
other human cytokines or growth factors, for example, TNF
(including adalimumab/HUMIRA), LT, IL-1, IL-2, IL-6, IL-7, IL-8,
IL-15, IL-16, IL-18, EMAP-II, GM-CSF, FGF, and PDGF. Antibodies of
the invention, or antigen binding portions thereof, can be combined
with antibodies to cell surface molecules such as CD2, CD3, CD4,
CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD90 or their ligands. The
antibodies of the invention, or antigen binding portions thereof,
may also be combined with agents, such as methotrexate,
cyclosporin, FK506, rapamycin, mycophenolate mofetil, leflunomide,
NSAIDs, for example, ibuprofen, corticosteroids such as
prednisolone, phosphodiesterase inhibitors, adenosine agonists,
antithrombotic agents, complement inhibitors, adrenergic agents,
agents which interfere with signaling by proinflammatory cytokines
such as TNF.alpha. or IL-1 (e.g. IRAK, NIK, IKK, p38 or MAP kinase
inhibitors), IL-1.beta. converting enzyme inhibitors (e.g., Vx740),
anti-P7s, p-selectin glycoprotein ligand (PSGL), TNF.alpha.
converting enzyme inhibitors, T-cell signaling inhibitors such as
kinase inhibitors, metalloproteinase inhibitors, sulfasalazine,
azathioprine, 6-mercaptopurines, angiotensin converting enzyme
inhibitors, soluble cytokine receptors and derivatives thereof
(e.g. soluble p55 or p75 TNF receptors, sIL-1R1, sIL-1R11, sIL-6R,
soluble IL-13 receptor (sIL-13)) and anti-inflammatory cytokines
(e.g. IL-4, IL-10, IL-11, IL-13 and TGF.beta.).
[0580] Preferred examples of therapeutic agents for Crohn's disease
in which an antibody or an antigen binding portion can be combined
include the following: TNF antagonists, for example, anti-TNF
antibodies, D2E7 (adalimumab/HUMIRA), cA2 (Remicade.TM.), CDP 571,
anti-TNF antibody fragments (e.g., CDP870), TNFR-Ig constructs
(p75TNFRIgG (Enbref.TM.) and p55TNFRIgG (Lenercept)), anti-P7s,
p-selectin glycoprotein ligand (PSGL), soluble IL-13 receptor
(sIL-13), and PDE4 inhibitors. Antibodies of the invention or
antigen binding portions thereof, can be combined with
corticosteroids, for example, budenoside and dexamethasone.
Antibodies may also be combined with agents such as sulfasalazine,
5-aminosalicylic acid and olsalazine, and agents which interfere
with synthesis or action of proinflammatory cytokines such as IL-1,
for example, IL-1.beta. converting enzyme inhibitors (e.g., Vx740)
and IL-1ra. Antibodies or antigen binding portion thereof may also
be used with T cell signaling inhibitors, for example, tyrosine
kinase inhibitors 6-mercaptopurines. Antibodies or antigen binding
portions thereof, can be combined with IL-11.
[0581] Non-limiting examples of therapeutic agents for multiple
sclerosis with which an antibody, or antibody portion, can be
combined include the following: corticosteroids; prednisolone;
methylprednisolone; azathioprine; cyclophosphamide; cyclosporine;
methotrexate; 4-aminopyridine; tizanidine; interferon-.beta.1a
(Avonex; Biogen); interferon-.beta.1b (Betaseron; Chiron/Berlex);
Copolymer 1 (Cop-1; Copaxone; Teva Pharmaceutical Industries,
Inc.); hyperbaric oxygen; intravenous immunoglobulin; clabribine;
antibodies to or antagonists of other human cytokines or growth
factors, for example, TNF, LT, IL-1, IL-2, IL-6, IL-7, IL-8, IL-15,
IL-16, IL-18, EMAP-II, GM-CSF, FGF, and PDGF. Antibodies of the
invention, or antigen binding portions thereof, can be combined
with antibodies to cell surface molecules such as CD2, CD3, CD4,
CD8, CD25, CD28, CD30, CD40, CD45, CD69, CD80, CD86, CD90 or their
ligands. The antibodies of the invention, or antigen binding
portions thereof, may also be combined with agents, such as
methotrexate, cyclosporine, FK506, rapamycin, mycophenolate
mofetil, leflunomide, NSAIDs, for example, ibuprofen,
corticosteroids such as prednisolone, phosphodiesterase inhibitors,
adensosine agonists, antithrombotic agents, complement inhibitors,
adrenergic agents, agents which interfere with signaling by
proinflammatory cytokines such as TNF.alpha. or IL-1 (e.g. IRAK,
NIK, IKK, p38 or MAP kinase inhibitors), IL-1.beta. converting
enzyme inhibitors (e.g., Vx740), anti-P7s, p-selectin glycoprotein
ligand (PSGL), TACE inhibitors, T-cell signaling inhibitors such as
kinase inhibitors, metalloproteinase inhibitors, sulfasalazine,
azathioprine, 6-mercaptopurines, angiotensin converting enzyme
inhibitors, soluble cytokine receptors and derivatives thereof
(e.g. soluble p55 or p75 TNF receptors, sIL-1R1, sIL-1R11, sIL-6R,
soluble IL-13 receptor (sIL-13)) and anti-inflammatory cytokines
(e.g. IL-4, IL-10, IL-13 and TGF.beta.).
[0582] Preferred examples of therapeutic agents for multiple
sclerosis in which the antibody or antigen binding portion thereof
can be combined to include interferon-.beta., for example,
IFN.beta.1a and IFN.beta.1b; copaxone, corticosteroids, IL-1
inhibitors, TNF inhibitors, and antibodies to CD40 ligand and
CD80.
[0583] An antibody, antibody portion, may be used in combination
with other agents to treat skin conditions. For example, an
antibody, antibody portion, or other IL-12 inhibitor of the
invention is combined with PUVA therapy. PUVA is a combination of
psoralen (P) and long-wave ultraviolet radiation (UVA) that is used
to treat many different skin conditions. The antibodies, antibody
portions, or other IL-12 inhibitors of the invention can also be
combined with pimecrolimus. In another embodiment, the antibodies
of the invention are used to treat psoriasis, wherein the
antibodies are administered in combination with tacrolimus. In a
further embodiment, tacrolimus and IL-12 inhibitors are
administered in combination with methotrexate and/or cyclosporine.
In still another embodiment, the IL-12 inhibitor of the invention
is administered with excimer laser treatment for treating
psoriasis.
[0584] The pharmaceutical compositions of the invention may include
a "therapeutically effective amount" or a "prophylactically
effective amount" of an antibody or antibody portion of the
invention. A "therapeutically effective amount" refers to an amount
effective, at dosages and for periods of time necessary, to achieve
the desired therapeutic result. A therapeutically effective amount
of the antibody or antibody portion may vary according to factors
such as the disease state, age, sex, and weight of the individual,
and the ability of the antibody or antibody portion to elicit a
desired response in the individual. A therapeutically effective
amount is also one in which any toxic or detrimental effects of the
antibody or antibody portion are outweighed by the therapeutically
beneficial effects. A "prophylactically effective amount" refers to
an amount effective, at dosages and for periods of time necessary,
to achieve the desired prophylactic result. Typically, since a
prophylactic dose is used in subjects prior to or at an earlier
stage of disease, the prophylactically effective amount will be
less than the therapeutically effective amount.
[0585] Dosage regimens may be adjusted to provide the optimum
desired response (e.g., a therapeutic or prophylactic response).
For example, a single bolus may be administered, several divided
doses may be administered over time or the dose may be
proportionally reduced or increased as indicated by the exigencies
of the therapeutic situation.
[0586] It is especially advantageous to formulate parenteral
compositions in dosage unit form for ease of administration and
uniformity of dosage. Dosage unit form as used herein refers to
physically discrete units suited as unitary dosages for the
mammalian subjects to be treated; each unit containing a
predetermined quantity of active compound calculated to produce the
desired therapeutic effect in association with the required
pharmaceutical carrier. The specification for the dosage unit forms
of the invention are dictated by and directly dependent on (a) the
unique characteristics of the active compound and the particular
therapeutic or prophylactic effect to be achieved, and (b) the
limitations inherent in the art of compounding such an active
compound for the treatment of sensitivity in individuals.
[0587] Treatment of psoriasis may be achieved by administration of
a single dose amount (or more than one sub-doses totaling the dose
amount) of a substance according to a single periodicity.
[0588] In one embodiment, a method of treating psoriasis in a
subject comprises administering to the subject an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, according to a periodicity of
about once every 4 weeks, thereby treating psoriasis in the
subject.
[0589] In another embodiment, a method of treating psoriasis in a
subject comprises administering to the subject an antibody, or
antigen-binding portion thereof, which is capable of binding to the
p40 subunit of IL-12 and/or IL-23, according to a periodicity of
about once every 12 weeks, thereby treating psoriasis in the
subject.
[0590] Thus, a single periodicity may be employed in a single
treatment regimen. Alternatively, multiple periodicities may be
employed in a single treatment regimen. For example, a first dose
amount may be administered according to a first periodicity, and
then the first dose amount or a second dose amount may be
administered according to a second periodicity. Furthermore, the
first dose amount or second dose amount administered according to a
second periodicity may optionally be followed by a first, second,
or third dose amount administered according to a third
periodicity.
[0591] In one embodiment, an antibody, or antigen-binding portion
thereof, which is capable of binding to the p40 subunit of IL-12
and/or IL-23 is administered to a subject as a first dose amount
according to a periodicity, and is further administered to the
subject as a second dose amount at the same periodicity.
[0592] In another embodiment, an antibody, or antigen-binding
portion thereof, which is capable of binding to the p40 subunit of
IL-12 and/or IL-23 is administered to a subject as a first dose
amount according to a periodicity, and is further administered to
the subject as a second dose amount according to a second
periodicity.
[0593] In one embodiment, an antibody, or antigen-binding portion
thereof, which is capable of binding to the p40 subunit of IL-12
and/or IL-23 is administered to a subject as a first dose amount
according to a periodicity, and is further administered to the
subject as a second dose amount according to a second periodicity,
and is further administered to the subject as a first, second, or
third dose amount according to a third periodicity.
[0594] The first dose amount of the antibody, or antigen-binding
portion thereof, may be at least about 100 mg to about 200 mg, is
at least about 100 mg, or is at least about 200 mg. The first dose
amount of the antibody, or antigen-binding portion thereof, may be
about 100 mg, about 110 mg, about 120 mg, about 130 mg, about 140
mg, about 150 mg, about 160 mg, about 170 mg, about 180 mg, about
190 mg, or about 200 mg. In one embodiment, the first dose amount
is about 180-220 mg, 185-215 mg, 190-210 mg, or 195-205 mg. In one
embodiment, the first dose amount is 200 mg. In one embodiment, the
first dose amount is about 80-120 mg, 85-115 mg, 90-110 mg or
95-105 mg. In one embodiment, the first dose amount is 100 mg. It
should be noted that doses intermediate to the above specified
doses are also included herein, e.g., 105 mg, 127 mg, etc.
[0595] The second dose amount of the antibody, or antigen-binding
portion thereof, may be the same as the first dose amount of the
antibody, or antigen-binding portion thereof, or different than the
first dose amount of the antibody, or antigen-binding portion
thereof. The second dose amount of the antibody, or antigen-binding
portion thereof, may be at least about 100 mg to about 200 mg, is
at least about 200 mg, or is at least about 100 mg. Alternatively,
the second dose amount of the antibody, or antigen-binding portion
thereof, is about 40-60% (e.g., 40, 41, 42, 43, 44, 45, 46, 47, 48,
49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59 or 60%), e.g., about
50%, of the first dose amount of the antibody, or antigen-binding
portion thereof, or antigen-binding portion thereof, or about
190-210% (e.g., 190, 191, 192, 193, 194, 195, 196, 197, 198, 199,
200, 201, 202, 203, 204, 205, 206, 207, 208, 209, 210%), e.g.,
about 200%, of the first dose amount of the antibody, or
antigen-binding portion thereof. The second dose amount of the
antibody, or antigen-binding portion thereof, may be about 100 mg,
about 110 mg, about 120 mg, about 130 mg, about 140 mg, about 150
mg, about 160 mg, about 170 mg, about 180 mg, about 190 mg, or
about 200 mg. In one embodiment, the second dose amount is about
80-120 mg, 85-115 mg, 90-110 mg or 95-105 mg. In one embodiment,
the second dose amount is 100 mg. In another embodiment, the second
dose amount is about 180-220 mg, 185-215 mg, 190-210 mg, or 195-205
mg. In one embodiment, the second dose amount is 200 mg. It should
be noted that doses intermediate to the above specified doses are
also included herein, e.g., 105 mg, 127 mg, etc.
[0596] The first and second periodicities of administration of the
antibody, or antigen-binding portion thereof, may be about once a
week, about once every other week, about once every four weeks. The
second periodicity of administration of the antibody, or
antigen-binding portion thereof, may be about once every 30-200
days.
[0597] The duration of the first periodicity may be about 12 weeks,
about 8 weeks, about 4 weeks, about 2 weeks, or about 1 week.
[0598] The duration of the second periodicity may be about 60
weeks, about 44 weeks, about 12 weeks, about 4 weeks, about 2
weeks, or about 1 week.
[0599] The duration of a third periodicity may be, for example,
about 4 weeks, about 12 weeks, about 24 weeks, about 36 weeks,
about 48 weeks or about 60 weeks.
[0600] Thus, in one aspect, a method of treating psoriasis in a
subject comprises administering to the subject a first dose amount
of an antibody, or antigen-binding portion thereof, which is
capable of binding to the p40 subunit of IL-12 and/or IL-23; and a
second dose amount that is about 40-60% of the first dose amount of
the antibody, or antigen-binding portion thereof, according to a
periodicity of about once every 12 weeks, thereby treating
psoriasis in the subject.
[0601] In another aspect, a method of treating psoriasis in a
subject comprises administering to the subject a first dose amount
of an antibody, or antigen-binding portion thereof, which is
capable of binding to the p40 subunit of IL-12 and/or IL-23,
according to a first periodicity of about once every 4 weeks; and
administering a second dose amount that is about 40-60% of the
first dose amount of the antibody, or antigen-binding portion
thereof, according to a second periodicity of about once every 4
weeks, thereby treating psoriasis in the subject.
[0602] In another aspect, a method of treating psoriasis in a
subject comprises administering to the subject a first dose amount
of an antibody, or antigen-binding portion thereof, which is
capable of binding to the p40 subunit of IL-12 and/or IL-23,
according to a first periodicity of about once every 4 weeks; and a
second dose amount that is about 40-60% of the first dose amount of
the antibody, or antigen-binding portion thereof, according to a
second periodicity of about once every 4 weeks; and the second dose
amount of the antibody, or antigen-binding portion thereof,
according to a third periodicity of about once every 12 weeks,
thereby treating psoriasis in the subject.
[0603] In one embodiment, the second dose amount is administered to
the subject upon a flare of psoriasis. In another embodiment, the
second dose amount is administered to the subject prior to a flare
of psoriasis.
[0604] The flare of psoriasis may be monitored by determining a
subject's Psoriasis Area and Severity Index (PASI), e.g., PASI 100
response, PASI 90 response, PASI 75 response, PASI 50 response, the
PASI response of a single body region, two body regions, three body
regions, or four body regions, e.g., trunk, lower extremities,
upper extremities, or head and neck. Alternatively, the flare of
psoriasis may be monitored by determining a subject's Physician's
Global Assessment (PGA) rating.
[0605] In one embodiment, the subject achieves or maintains a
specific response to treatment. In one embodiment, the subject
achieves or maintains at least a PASI 50 response. In one
embodiment, the subject achieves or maintains at least a PASI 75
response. In one embodiment, the subject achieves or maintains at
least a PASI 90 response. In one embodiment, the subject achieves
or maintains at least a PASI 100 response. In one embodiment the
PASI 50, 75, 90, or 100 response is achieved by about (e.g., at
least about) week 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17,
18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34,
35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51,
or 52 following treatment (e.g., following initial treatment, e.g.,
at week 0). In one embodiment, the PASI 50, 75, 90, or 100 response
is maintained for about (e.g., at least about) 4, 5, 6, 7, 8, 9,
10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26,
27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43,
44, 45, 46, 47, 48, 49, 50, 51, 52 weeks, e.g., following
administration of a first dose amount at a first periodicity, or
following administration of a first or second dose amount at a
second periodicity, or following administration of a first, second
or third dose amount according to a third periodicity. In one
embodiment, the PASI 50, 75, 90 or 100 response is maintained, once
achieved, throughout the duration of treatment.
[0606] In one embodiment, the subject achieves a PGA score of 0 or
1. In one embodiment the PGA score of 0 or 1 is achieved by about
(e.g., at least about) week 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14,
15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31,
32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48,
49, 50, 51, or 52 following treatment (e.g., following initial
treatment, e.g., at week 0). In one embodiment, the PGA score of 0
or 1 is maintained for about (e.g., at least about) 4, 5, 6, 7, 8,
9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25,
26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42,
43, 44, 45, 46, 47, 48, 49, 50, 51, 52 weeks, e.g., following
administration of a first dose amount at a first periodicity, or
following administration of a first or second dose amount at a
second periodicity, or following administration of a first, second
or third dose amount according to a third periodicity. In one
embodiment, the PGA score of 0 or 1 is maintained, once achieved,
throughout the duration of treatment.
[0607] In one embodiment, the subject achieves a PGA score of 0,
i.e., total clearance. In one embodiment the PGA score of 0 is
achieved by about (e.g., at least about) week 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27,
28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44,
45, 46, 47, 48, 49, 50, 51, or 52 following treatment (e.g.,
following initial treatment, e.g., at week 0). In one embodiment,
the PGA score of 0 is maintained for about (e.g., at least about)
4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21,
22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38,
39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52 weeks, e.g.,
following administration of a first dose amount at a first
periodicity, or following administration of a first or second dose
amount at a second periodicity, or following administration of a
first, second or third dose amount according to a third
periodicity. In one embodiment, the PGA score of 0 is maintained,
once achieved, throughout the duration of treatment.
[0608] A method of treating psoriasis in a population of subjects
may comprise administering to each subject in the population an
antibody, or antigen-binding portion thereof, which is capable of
binding to the p40 subunit of IL-12 and/or IL-23, wherein at least
60% of the population of subjects achieve a PASI 75 response, e.g.,
by about week 12.
[0609] A method of treating psoriasis in a population of subjects
may comprise administering to each subject in the population an
antibody, or antigen-binding portion thereof, which is capable of
binding to the p40 subunit of IL-12 and/or IL-23, wherein at least
25% of the population of subjects achieve a PASI 90 response, e.g.,
by about week 12.
[0610] A method of treating psoriasis in a population of subjects
may comprise administering to each subject in the population an
antibody, or antigen-binding portion thereof, which is capable of
binding to the p40 subunit of IL-12 and/or IL-23, wherein at least
10% of the population of subjects achieve a PASI 100 response,
e.g., by about week 12.
[0611] A method of treating psoriasis in a subject or a population
of subjects may comprise administering to the subject or each
subject in the population an antibody, or antigen-binding portion
thereof, which is capable of binding to the p40 subunit of IL-12
and/or IL-23, wherein the subject or a percentage of the population
of subjects (e.g., at least about 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or
100% of a population of subjects) achieves at least a PASI 50
response by about week 12, 24, 36, 48, 52, or 60.
[0612] A method of treating psoriasis in a subject or a population
of subjects may comprise administering to the subject or each
subject in the population an antibody, or antigen-binding portion
thereof, which is capable of binding to the p40 subunit of IL-12
and/or IL-23, wherein the subject or a percentage of the population
of subjects (e.g., at least about 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or
100% of a population of subjects) achieves at least a PASI 75
response by about week 12, 24, 36, 48, 52, or 60.
[0613] A method of treating psoriasis in a subject or a population
of subjects may comprise administering to the subject or each
subject in the population an antibody, or antigen-binding portion
thereof, which is capable of binding to the p40 subunit of IL-12
and/or IL-23, wherein the subject or a percentage of the population
of subjects (e.g., at least about 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or
100% of a population of subjects) achieves at least a PASI 90
response by about week 12, 24, 36, 48, 52, or 60.
[0614] A method of treating psoriasis in a subject or a population
of subjects may comprise administering to the subject or each
subject in the population an antibody, or antigen-binding portion
thereof, which is capable of binding to the p40 subunit of IL-12
and/or IL-23, wherein the subject or a percentage of the population
of subjects (e.g., at least about 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or
100% of a population of subjects) achieves at least a PASI 100
response by about week 12, 24, 36, 48, 52, or 60.
[0615] A method of treating psoriasis in a subject or a population
of subjects may comprise administering to the subject or each
subject in the population an antibody, or antigen-binding portion
thereof, which is capable of binding to the p40 subunit of IL-12
and/or IL-23, wherein the subject or a percentage of the population
of subjects (e.g., at least about 10%, 15%, 20%, 25%, 30%, 35%,
40%, 45%, 50%, 55%, 60%, 65%, 70%, 75%, 80%, 85%, 90%, 95%, 99%, or
100% of a population of subjects) achieves at least a PGA score of
0 or 1 by about week 12, 24, 36, 48, 52, or 60.
[0616] In one aspect, the subject or population of subjects treated
achieves an improvement in a Dermatology Life Quality Index (DLQI)
score or mean Dermatology Life Quality Index (DLQI) score of at
least about -6.8, -6.9, -7.0, -8.0, -8.5, -9, -10, -10.5, -11, -12,
-13, -14, -15, -16, -17, -18, -19, -20 or lower. An improvement in
DLQI is a reduction in DLQI score, e.g., a reduction by at least
about 6.8, 6.9, 7.0, 8.0, 8.5, 9, 10, 10.5, 11, 12, 13, 14, 15, 16,
17, 18, 19, 20 or more. Dermatology Life Quality Index (DLQI) is a
patient-reported measure of the extent to which psoriasis impacts
health-related quality of life. The DLQI yields a score ranging
from 0 to 30, with a lower score indicating lower impact.
[0617] In certain embodiments, the subject achieves a clinically
meaningful reduction in Dermatology Life Quality Index (DLQI)
score. A clinically meaningful reduction in Dermatology Life
Quality Index (DLQI) score may be, e.g., a decrease of greater than
5 points in DLQI score.
[0618] In another aspect, the subject or population of subjects
treated achieves an improvement in a Short Form 36 Health Survey
Physical Component Summary (PCS) score or mean Physical Component
Summary (PCS) score of at least about 2, 3, 4, 5, 6, or more. An
improvement in PCS is an increase in PCS score, e.g., an increase
by at least about 2, 3, 4, 5, 6, or more.
[0619] In another aspect, the subject or population of subjects
treated achieves an improvement in a Short Form 36 Health Survey
Mental Component Summary (MCS) score or mean Mental Component
Summary (MCS) score of at least about 3.5, 4, 4.5, 6, 6.5, 7, or
more. An improvement in PCS is an increase in MCS score, e.g., an
increase by at least about 3.5, 4, 4.5, 6, 6.5, 7, or more.
[0620] In another aspect, the subject or population of subjects
treated achieves an improvement in a visual analog scale score or a
mean visual analog scale score for psoriasis-related pain (VAS-Ps)
of at least about -25, -26, -27, -28, -29, -30, -31, -32, -33, -34,
-35, -40, -45, -50, or less. An improvement in VAS-Ps is a
reduction in VAS-Ps score, e.g., a reduction by at least about 25,
26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 40, 45, 50, or more.
[0621] In another aspect, the subject or population of subjects
treated achieves an improvement in a visual analog scale score for
psoriatic arthritis-related pain (VAS-PsA) or a mean visual analog
scale score for psoriatic arthritis-related pain (VAS-PsA) of at
least about -25, -26, -27, -28, -29, -30, -31, -32, -33, -34, -35,
-40, -45, -50, or less. An improvement in VAS-PsA is a reduction in
VAS-Ps score, e.g., a reduction by at least about 25, 26, 27, 28,
29, 30, 31, 32, 33, 34, 35, 40, 45, 50, or more.
[0622] In another aspect, the population of subjects treated
achieves a minimum clinically important difference (MCID) response
rate in any one or more HRQOL outcomes including, e.g., DLQI, TAI,
VAS-Ps, Vas-PsA, MCS and PCS of at least about 60%, 65%, 70%, 75%,
80%, 85%, 90%.
[0623] In another aspect, the population of subjects treated
achieves a minimum clinically important difference (MCID) response
rate for psoriasis-related pain (VAS-Ps) of at least about 60%,
65%, 70%, 75%, or more, e.g., by about week 12 or by about week
52.
[0624] In another aspect, the population of subjects treated
achieves a minimum clinically important difference (MCID) response
rate for Dermatology Life Quality Index (DLQI) of at least about
70%, 75%, 80% or more by about week 12.
[0625] In another aspect, the population of subjects treated
achieves a minimum clinically important difference (MCID) response
rate for Dermatology Life Quality Index (DLQI) of at least about
75%, 80%, 85%, 90%, or more by about week 52.
[0626] In another aspect, the population of subjects treated
achieves a minimum clinically important difference (MCID) response
rate for Total Activity Impairment (TAI) of at least about 45%,
50%, 55%, 60%, 70%, or more by about week 12.
[0627] In another aspect, the population of subjects treated
achieves a minimum clinically important difference (MCID) response
rate for Total Activity Impairment (TAI) of at least about 50%,
55%, 57%, 60%, 65% or more by about week 52.
[0628] In another aspect, efficacy may be assessed by Nail
Psoriasis Severity Index (NAPSI) scores, which range from 0 (no
nail psoriasis) to 80 (psoriasis in all 10 fingernails). In certain
embodiments, the subject achieves a Nail Psoriasis Severity Index
(NAPSI) score of about 40, 35, 30, 25, 20, 15, 10, 9, 8, 7, 6, 5,
4, 3, 2, 1 or less. In certain embodiments, the subject achieves a
Nail Psoriasis Severity Index (NAPSI) score of about 2.1 or less.
In certain embodiments, the subject achieves a Nail Psoriasis
Severity Index (NAPSI) score of about 2.1 or less by about week 24.
In certain embodiments, the subject achieves a Nail Psoriasis
Severity Index (NAPSI) score of about 1.2 or less. In certain
embodiments, the subject achieves a Nail Psoriasis Severity Index
(NAPSI) score of about 1.2 or less by about week 52.
[0629] In another aspect at least 40%, 45%, 50%, 55%, 60%, 65%, or
more of the population of subjects treated achieve at least a PGA
0/1 response by about week 12, wherein each subject was treated
with a biologic prior to administration of the antibody.
[0630] In another aspect, at least 50%, 55%, 60%, 65%, 70%, 75% of
the population of subjects treated achieve at least a PASI 75
response by about week 12, wherein each subject was treated with a
biologic prior to administration of the antibody.
[0631] In another aspect, at least 60%, 65%, 70%, 75%, 78%, or more
of the population of subjects treated achieve at least a PGA 0/1
response by about week 12, wherein none of the subjects were
treated with a biologic prior to administration of the
antibody.
[0632] In another aspect, at least 60%, 65%, 70%, 75%, 80%, 82% or
more of the population of subjects achieve at least a PASI 75
response by about week 12, wherein none of the subjects were
treated with a biologic prior to administration of the
antibody.
[0633] In another aspect, at least 60%, 65%, 70%, 75%, 78%, or more
of the population of subjects treated achieve at least a PGA 0/1
response by about week 52, wherein each subject was treated with a
biologic prior to administration of the antibody.
[0634] In another aspect at least 60%, 65%, 70%, 75%, 79%, 80%, 82%
or more of the population of subjects treated achieve at least a
PGA 0/1 response by about week 52, wherein none of the subjects
were treated with a biologic prior to administration of the
antibody.
[0635] In another aspect, at least 50%, 55%, 60%, 65%, 70%, 71%, or
more of the population of subjects treated achieve at least a PGA
0/1 response by about week 12, wherein each subject treated has a
prior history of psoriatic arthritis.
[0636] In another aspect, at least 60%, 65%, 70%, 75%, 78%, or more
of the population of subjects treated achieve at least a PASI 75
response by about week 12, wherein each subject treated has a prior
history of psoriatic arthritis.
[0637] In another aspect, at least 60%, 65%, 70%, 75%, 77%, or more
of the population of subjects treated achieve at least a PGA 0/1
response by about week 12, wherein none of the subjects treated has
a prior history of psoriatic arthritis.
[0638] In another aspect, at least 60%, 65%, 70%, 75%, 81%, or more
of the population of subjects treated achieve at least a PASI 75
response by about week 12, wherein none of the subjects treated has
a prior history of psoriatic arthritis.
[0639] In another aspect, at least 60%, 65%, 70%, 75%, 77%, or more
of the population of subjects treated achieve at least a PGA 0/1
response by about week 52, wherein each subject treated has a prior
history of psoriatic arthritis.
[0640] In another aspect, at least 60%, 65%, 70%, 75%, 79%, or more
of the population of subjects treated achieve at least a PGA 0/1
response by about week 52, wherein none of the subjects treated has
a prior history of psoriatic arthritis.
[0641] In another aspect, at least 50%, 55%, 60%, 65%, 69%, or more
of the population of subjects achieve at least a PGA 0/1 response
by about week 12, wherein each subject had a baseline PASI greater
than 20 prior to administration of the antibody.
[0642] In another aspect, at least 60%, 65%, 70%, 75%, 79%, or more
of the population of subjects achieve at least a PGA 0/1 response
by about week 12, wherein each subject had a baseline PASI less
than or equal to 20 prior to administration of the antibody.
[0643] In another aspect, at least 60%, 65%, 70%, 75%, 79%, or more
of the population of subjects achieve at least a PASI 75 response
by about week 12, wherein each subject had a baseline PASI greater
than 20 prior to administration of the antibody.
[0644] In another aspect, at least 60%, 65%, 70%, 75%, 80%, 81%, or
more of the population of subjects achieve at least a PASI 75
response by about week 12, wherein each subject had a baseline PASI
less than or equal to 20 prior to administration of the
antibody.
[0645] In another aspect, at least 50%, 55%, 60%, 65%, 67%, or more
of the population of subjects achieve at least a PGA 0/1 response
by about week 12, wherein each subject had a baseline weight of
greater than or equal to 100 kilograms prior to administration of
the antibody.
[0646] In another aspect, at least 60%, 65%, 70%, 75%, 80%, or more
of the population of subjects achieve at least a PGA 0/1 response
by about week 12, wherein each subject had a baseline weight of
less than 100 kilograms prior to administration of the
antibody.
[0647] In another aspect, at least 50%, 55%, 60%, 65%, 70%, 72% or
more of the population of subjects achieve at least a PASI 75
response by about week 12, wherein each subject had a baseline
weight of greater than or equal to 100 kilograms prior to
administration of the antibody.
[0648] In another aspect, at least 60%, 65%, 70%, 75%, 80%, 85%, or
more of the population of subjects achieve at least a PASI 75
response by about week 12, wherein each subject had a baseline
weight of less than 100 kilograms prior to administration of the
antibody.
[0649] It is to be noted that dosage values may vary with the type
and severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions, and that dosage
ranges set forth herein are exemplary only and are not intended to
limit the scope or practice of the claimed composition.
VII. Uses of the Invention
[0650] The invention provides methods for inhibiting IL-12 activity
in a subject suffering from a disorder in which IL-12 activity is
detrimental.
[0651] IL-12 has been implicated in the pathophysiology of a wide
variety of disorders (Windhagen et al., (1995) J. Exp. Med. 182:
1985-1996; Morita et al. (1998) Arthritis and Rheumatism. 41:
306-314; Bucht et al., (1996) Clin. Exp. Immunol. 103: 347-367;
Fais et al. (1994) J. Interferon Res. 14:235-238; Parronchi et al.,
(1997) Am. J. Path. 150:823-832; Monteleone et al., (1997)
Gastroenterology. 112:1169-1178, and Berrebi et al., (1998) Am. J.
Path 152:667-672; Parronchi et al (1997) Am. J. Path. 150:823-832).
The invention provides methods for inhibiting IL-12 activity in a
subject suffering from such a disorder, which method comprises
administering to the subject an antibody or antibody portion of the
invention such that IL-12 activity in the subject is inhibited.
Preferably, the IL-12 is human IL-12 and the subject is a human
subject. Alternatively, the subject can be a mammal expressing a
IL-12 with which an antibody of the invention cross-reacts. Still
further the subject can be a mammal into which has been introduced
hIL-12 (e.g., by administration of hIL-12 or by expression of an
hIL-12 transgene). An antibody of the invention can be administered
to a human subject for therapeutic purposes (discussed further
below). Moreover, an antibody of the invention can be administered
to a non-human mammal expressing a IL-12 with which the antibody
cross-reacts for veterinary purposes or as an animal model of human
disease. Regarding the latter, such animal models may be useful for
evaluating the therapeutic efficacy of antibodies of the invention
(e.g., testing of dosages and time courses of administration).
[0652] As used herein, the phrase "a disorder in which IL-12
activity is detrimental" is intended to include diseases and other
disorders in which the presence of IL-12 in a subject suffering
from the disorder has been shown to be or is suspected of being
either responsible for the pathophysiology of the disorder or a
factor that contributes to a worsening of the disorder.
Accordingly, a disorder in which IL-12 activity is detrimental is a
disorder in which inhibition of IL-12 activity is expected to
alleviate the symptoms and/or progression of the disorder. Such
disorders may be evidenced, for example, by an increase in the
concentration of IL-12 in a biological fluid of a subject suffering
from the disorder (e.g., an increase in the concentration of IL-12
in serum, plasma, synovial fluid, etc. of the subject), which can
be detected, for example, using an anti-IL-12 antibody as described
above. There are numerous examples of disorders in which IL-12
activity is detrimental. In one embodiment, the antibodies or
antigen binding portions thereof, can be used in therapy to treat
the diseases or disorders described herein. In another embodiment,
the antibodies or antigen binding portions thereof, can be used for
the manufacture of a medicine for treating the diseases or
disorders described herein. The use of the antibodies and antibody
portions of the invention in the treatment of a few non-limiting
specific disorders is discussed further below:
A. Rheumatoid Arthritis:
[0653] Interleukin-12 has been implicated in playing a role in
inflammatory diseases such as rheumatoid arthritis. Inducible
IL-12p40 message has been detected in synovia from rheumatoid
arthritis patients and IL-12 has been shown to be present in the
synovial fluids from patients with rheumatoid arthritis (see e.g.,
Morita et al., (1998) Arthritis and Rheumatism 41: 306-314). IL-12
positive cells have been found to be present in the sublining layer
of the rheumatoid arthritis synovium. The human antibodies, and
antibody portions of the invention can be used to treat, for
example, rheumatoid arthritis, juvenile rheumatoid arthritis, Lyme
arthritis, rheumatoid spondylitis, osteoarthritis and gouty
arthritis. Typically, the antibody, or antibody portion, is
administered systemically, although for certain disorders, local
administration of the antibody or antibody portion may be
beneficial. An antibody, or antibody portion, of the invention also
can be administered with one or more additional therapeutic agents
useful in the treatment of autoimmune diseases.
[0654] In the collagen induced arthritis (CIA) murine model for
rheumatoid arthritis, treatment of mice with an anti-IL-12 mAb (rat
anti-mouse IL-12 monoclonal antibody, C17.15) prior to arthritis
profoundly suppressed the onset, and reduced the incidence and
severity of disease. Treatment with the anti-IL-12 mAb early after
onset of arthritis reduced severity, but later treatment of the
mice with the anti-IL-12 mAb after the onset of disease had minimal
effect on disease severity.
B. Crohn's Disease
[0655] Interleukin-12 also plays a role in the inflammatory bowel
disease, Crohn's disease. Increased expression of IFN-.gamma. and
IL-12 occurs in the intestinal mucosa of patients with Crohn's
disease (see e.g., Fais et al., (1994) J. Interferon Res. 14:
235-238; Parronchi et al., (1997) Amer. J. Pathol. 150: 823-832;
Monteleone et al., (1997) Gastroenterology 112: 1169-1178; Berrebi
et al., (1998) Amer. J. Pathol. 152: 667-672). Anti-IL-12
antibodies have been shown to suppress disease in mouse models of
colitis, e.g., TNBS induced colitis IL-2 knockout mice, and
recently in IL-10 knock-out mice. Accordingly, the antibodies, and
antibody portions, of the invention, can be used in the treatment
of inflammatory bowel diseases.
C. Multiple Sclerosis
[0656] Interleukin-12 has been implicated as a key mediator of
multiple sclerosis. Expression of the inducible IL-12 p40 message
or IL-12 itself can be demonstrated in lesions of patients with
multiple sclerosis (Windhagen et al., (1995) J. Exp. Med. 182:
1985-1996, Drulovic et al., (1997) J. Neurol. Sci. 147: 145-150).
Chronic progressive patients with multiple sclerosis have elevated
circulating levels of IL-12. Investigations with T-cells and
antigen presenting cells (APCs) from patients with multiple
sclerosis revealed a self-perpetuating series of immune
interactions as the basis of progressive multiple sclerosis leading
to a Th1-type immune response. Increased secretion of IFN-.gamma.
from the T cells led to increased IL-12 production by APCs, which
perpetuated the cycle leading to a chronic state of a Th1-type
immune activation and disease (Balashov et al., (1997) Proc. Natl.
Acad. Sci. 94: 599-603). The role of IL-12 in multiple sclerosis
has been investigated using mouse and rat experimental allergic
encephalomyelitis (EAE) models of multiple sclerosis. In a
relapsing-remitting EAE model of multiple sclerosis in mice,
pretreatment with anti-IL-12 mAb delayed paralysis and reduced
clinical scores. Treatment with anti-IL-12 mAb at the peak of
paralysis or during the subsequent remission period reduced
clinical scores. Accordingly, the antibodies or antigen binding
portions thereof of the invention may serve to alleviate symptoms
associated with multiple sclerosis in humans.
D. Insulin-Dependent Diabetes Mellitus
[0657] Interleukin-12 has been implicated as an important mediator
of insulin-dependent diabetes mellitus (IDDM). IDDM was induced in
NOD mice by administration of IL-12, and anti-IL-12 antibodies were
protective in an adoptive transfer model of IDDM. Early onset IDDM
patients often experience a so-called "honeymoon period" during
which some residual islet cell function is maintained. These
residual islet cells produce insulin and regulate blood glucose
levels better than administered insulin. Treatment of these early
onset patients with an anti-IL-12 antibody may prevent further
destruction of islet cells, thereby maintaining an endogenous
source of insulin.
E. Psoriasis
[0658] Interleukin-12 (IL-12) and the related cytokine IL-23 have
been implicated as key mediators in psoriasis. Psoriasis involves
acute and chronic skin lesions that are associated with a TH1-type
cytokine expression profile (Hamid et al. (1996) J. Allergy Clin.
Immunol. 1:225-231; Turka et al. (1995) Mol. Med. 1:690-699). Both
IL-12 and IL-23 contribute to the development of the type 1T helper
cell (Th1) immune response in psoriasis. Moreover, the IL-12 p40
and IL-23 p40 messenger RNA is overexpressed in psoriatic skin
lesions. Accordingly, the antibodies or antigen binding portions
thereof of the invention may serve to alleviate chronic skin
disorders such psoriasis.
[0659] In one embodiment, the invention provides a method for
treating psoriasis. Treatment for psoriasis often includes a
topical corticosteroids, vitamin D analogs, and topical or oral
retinoids, or combinations thereof. In one embodiment, an IL-12
and/or IL-23 antibody is administered in combination with or the
presence of one of these common treatments. Additional therapeutic
agents which can be combined with the IL-12 and/or IL-23 antibody
for treatment of psoriasis are described in more detail below.
[0660] The diagnosis of psoriasis is usually based on the
appearance of the skin. Additionally a skin biopsy, or scraping and
culture of skin patches may be needed to rule out other skin
disorders. An x-ray may be used to check for psoriatic arthritis if
joint pain is present and persistent.
[0661] Improvements in psoriasis in a subject can be monitored by
the subject's Psoriasis Area and Severity Index Score (PASI). The
method for determining the PASI has been described in Fredriksson
and Pettersson (1978) Dermatologica 157:238 and Marks et al. (1989)
Arch Dermatol 125:235. Briefly, the index is based on evaluation of
four anatomic sites, including the head, upper extremities, trunk,
and lower extremities, for erythema, induration, and desquamation
using a 5 point scale (0=no symptoms; 1=slight; 2=moderate;
3=marked; 4=very marked). Based on the extent of lesions in a given
anatomic site, the area affected is assigned a numerical value
(0=0; 1=<10%; 2=10-29%; 3=30-49%; 4=50-69%; 5=70=89%;
6=90-100%). The PASI score is then calculated, wherein the possible
range of PASI score is 0.0 to 72.0 with the highest score
representing complete erythroderma of the severest degree.
[0662] In one embodiment of the invention, an IL-12 and/or IL-23
antibody is used for the treatment of psoriasis, including plaque
psoriasis, e.g., chronic plaque psoriasis, moderate plaque
psoriasis, and severe plaque psoriasis, guttate psoriasis, inverse
psoriasis, pustular psoriasis, pemphigus vulgaris, erythrodermic
psoriasis, psoriasis associated with inflammatory bowel disease
(IBD), and psoriasis associated with rheumatoid arthritis (RA). In
another embodiment, an IL-12 and/or IL-23 antibody, such as
J695/ABT-874, is used to treat subjects who have psoriasis in
combination with PsA. In one embodiment of the invention, an IL-12
and/or IL-23 antibody is used for the treatment of nail
psoriasis.
[0663] In one aspect, the invention provides methods for treating
psoriasis in difficult to treat subjects by administering
antibodies, and antigen binding portions thereof, of the invention,
for example, ABT-874. Difficult to treat subjects may include, for
example, subjects who have been previously administered biologics
for the treatment of psoriasis, subjects who have had a history of
psoriatic arthritis, subjects who have psoriasis and weigh greater
than 100 kg, and subjects who have a baseline PASI greater than 20.
Accordingly, in one aspect, the invention provides methods for
treating subjects who have been previously administered biologics
for the treatment of psoriasis by administering antibodies, and
antigen binding portions thereof, of the invention, for example,
ABT-874. Specifically, the methods involve selecting subjects who
have received prior biologic treatment and administering antibodies
of the invention. As set forth in Example 19, the data demonstrates
efficacy of ABT-874 in the treatment of psoriasis in this subgroup
of subjects. In another aspect, the invention provides methods for
treating subjects who have had a history of psoriatic arthritis by
administering antibodies, and antigen binding portions thereof, of
the invention, for example, ABT-874. Specifically, the methods
involve selecting subjects who have had a history of psoriatic
arthritis and administering antibodies of the invention. In another
aspect, the invention provides methods for treating subjects who
weigh greater than 100 kg by administering antibodies, and antigen
binding portions thereof, of the invention, for example, ABT-874.
Specifically, the methods involve selecting subjects who weigh
greater than 100 kg and administering antibodies of the invention.
In yet another aspect, the invention provides methods for treating
subjects who had a baseline PASI greater than 20 by administering
antibodies, and antigen binding portions thereof, of the invention,
for example, ABT-874. Specifically, the methods involve selecting
subjects who have a baseline PASI greater than 20 prior to
administration of the antibody and administering antibodies of the
invention.
[0664] Specific types of psoriasis included in the treatment
methods of the invention are described in detail below:
[0665] a. Chronic Plaque Psoriasis
[0666] Chronic plaque psoriasis (also referred to as psoriasis
vulgaris) is the most common form of psoriasis. Chronic plaque
psoriasis is characterized by raised reddened patches of skin,
ranging from coin-sized to much larger. In chronic plaque
psoriasis, the plaques may be single or multiple, they may vary in
size from a few millimeters to several centimeters. The plaques are
usually red with a scaly surface, and reflect light when gently
scratched, creating a "silvery" effect. Lesions (which are often
symmetrical) from chronic plaque psoriasis occur all over body, but
with predilection for extensor surfaces, including the knees,
elbows, lumbosacral regions, scalp, and nails. Occasionally chronic
plaque psoriasis can occur on the penis, vulva and flexures, but
scaling is usually absent. Diagnosis of patients with chronic
plaque psoriasis is usually based on the clinical features
described above. In particular, the distribution, color and typical
silvery scaling of the lesion in chronic plaque psoriasis are
characteristic of chronic plaque psoriasis.
[0667] b. Guttate Psoriasis
[0668] Guttate psoriasis refers to a form of psoriasis with
characteristic water drop shaped scaly plaques. Flares of guttate
psoriasis generally follow an infection, most notably a
streptococcal throat infection. Diagnosis of guttate psoriasis is
usually based on the appearance of the skin, and the fact that
there is often a history of recent sore throat.
[0669] c. Inverse Psoriasis
[0670] Inverse psoriasis is a form of psoriasis in which the
patient has smooth, usually moist areas of skin that are red and
inflammed, which is unlike the scaling associated with plaque
psoriasis. Inverse psoriasis is also referred to as intertiginous
psoriasis or flexural psoriasis. Inverse psoriasis occurs mostly in
the armpits, groin, under the breasts and in other skin folds
around the genitals and buttocks, and, as a result of the locations
of presentation, rubbing and sweating can irritate the affected
areas.
[0671] d. Pustular Psoriasis
[0672] Pustular psoriasis, also referred to as palmar plantar
psoriasis, is a form of psoriasis that causes pus-filled blisters
that vary in size and location, but often occur on the hands and
feet. The blisters may be localized, or spread over large areas of
the body. Pustular psoriasis can be both tender and painful, can
cause fevers.
[0673] e. Other Psoriasis Disorders
[0674] Other examples of psoriatic disorders which can be treated
with the IL-12 and/or IL-23 antibody include erythrodermic
psoriasis, vulgaris, psoriasis associated with IBD, and psoriasis
associated with arthritis, including rheumatoid arthritis.
[0675] The present invention is further illustrated by the
following examples which should not be construed as limiting in any
way. The contents of all cited references, including literature
references, issued patents, and published patent applications, as
cited throughout this application are hereby expressly incorporated
herein by reference. It should further be understood that the
contents of all the tables attached hereto (see Appendix A attached
hereto and Appendix A of U.S. Pat. No. 6,914,128) as well as the
entire contents of U.S. Pat. No. 6,914,128 are incorporated herein
by reference.
Appendix A
TABLE-US-00003 [0676] TABLE 1 VH3 Family Germline Amino Acid
Sequences Numbering according to Kabat (Joe9 VH included for
comparison) SEQ germ- ID line CDR H1 NO: VH 1 2 3 4 5 6 7 8 9 10 11
12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 594 dp-29
E V Q L V E S G G G L V Q P G G S L R L S C A A S G F T F S 595
DP-30 E V Q L V E S G G G L V Q P G G S L R L S C A A S G F T F S
596 HC15-7 E V Q L V E S G G G L V Q P G G S L R L S C A A S G F T
F S 597 VHD26 E V Q L L E S G G G L V Q P G G S L R L S C A A S G F
T F S 598 DP-31 E V Q L V E S G G G L V Q P G R S L R L S C A A S G
F T F D 599 DP-32 E V Q L V E S G G G V V R P G G S L R L S C A A S
G F T F D 600 DP-33 E V Q L V E S G G V V V Q P G G S L R L S C A A
S G F T F D 601 dp-35 Q V Q L V E S G G G L V K P G G S L R L S C A
A S G F T F S 602 VH3-8 V Q V L L E S G G G L V K P G G S L R L S C
A A S G F T F S 603 yac-9 E V Q L V E S G G G L V Q P G G S L K L S
C A A S G F T F S 604 dp-38 E V Q L V E S G G G L V K P G G S L R L
S C A A S G F T F S 605 LSG2 E V Q L V E S G G G L V K P G G S L R
L S C A A S G F T F S 606 LSG3 E V Q L V E S G G G L V K P G G S L
R L S C A A S G F T F S 607 LSG4 E V Q L V E S G G G L V K P G G S
L R L S C A A S G F T F S 608 LSG6 E V Q L V E S G G G L V K P G G
S L R L S C A A S G F T F S 609 v3-15 E V Q L V E S G G A L V K P G
G S L R L S C A A S G F T F S 610 dp-39 E V Q L V E S G G G L V Q P
G G S L R L S C P A S G F T F S 611 dp-40 E V Q L V E S G G G L V Q
P G G S L R L S C A A S G F T F S 612 dp-59 E V Q L V E S G G G L V
Q P G G S L R L S C A A S G F T F S 613 v3-15p E V Q L V E S G G G
L V Q P G G S L R L S C A A S G F T F S 614 v3-19p T V Q L V E S G
G G L V E P G G S L R L S C A A S G F T F S 615 v3-13 E V H L V E S
G G G L V Q P G G A L R L S C A A S G F T F S 616 DP-42 E V Q L V E
T G G G L I Q P G G S L R L S C A A S G F T V S 617 dp-44 E V Q L V
Q S G G G L V H P G G S L R L S C A G S G F T F S 618 DP-45 E V Q L
V Q S G G G L V Q P G G S L R L S C A G S G F T F S 619 dp-47 E V Q
L L E S G G G L V Q P G G S L R L S C A A S G F T F S 620 flm E V Q
L V E S G G G L V Q P G G S L R L S C S A S G F T F S 621 P1 E V Q
L V E S G G G L V Q P G G S L R L S C S A S G F T F S 622 v3-64 E V
Q L V E S G G G L V Q P G G S L R L S C A A S G F T F S 623 vh26 E
V Q L L E S G G G L V Q P G G S L R L S C A A S G F T F S 624 B25 Q
V Q L V E S G G G V V Q P G R S L R L S C A A S G F T F S 625 b32e
Q V Q L V E S G G G V V Q P G R S L R L S C A A S G F T F S 626 B37
Q V Q L V E S G G G V V Q P G R S L R L S C A A S G F T F S 627 B43
Q V Q L V E S G G G V V Q P G R S L R L S C A A S G F T F S 628 B48
Q V Q L V E S G G G V V Q P G R S L R L S C A A S G F T F S 629 B52
Q V Q L V E S G G G V V Q P G R S L R L S C A A S G F T F S 630 B54
Q V Q L V E S G G G V V Q P G R S L R L S C A A S G F T F S 631
cos-8 Q V Q L V E S G G G V V Q P G R S L R L S C A A S G F T F S
632 dp-46 Q V Q L V E S G G G V V Q P G R S L R L S C A A S G F T F
S 633 F2M Q V Q L V E S G G G L V Q P G G S L R L S C S A S G F T F
S 634 F3 Q V Q L V E S G G G L V Q P G G S L R L S C S A S G F T F
S 635 F7 Q V Q L V E S G G G V V Q P G R S L R L S C A A S G F T F
S 636 hv3005 Q V Q L V E S G G G V V Q P G R S L R L S C A A S G F
T F S 637 P2 Q V Q L V E S G G G V V Q P G R S L R L S C A A S G F
T F S 638 dp-48 E V Q L V E S G G G L V Q P G G S L R L S C A A S G
F T F S 639 dp-58 E V Q L V E S G G G L V Q P G G S L R L S C A A S
G F T F S 640 B1 Q V Q L V E S G G G V V Q P G R S L R L S C A A S
G F T F S 651 B13 Q V Q L V E S G G G V V Q P G R S L R L S C A A S
G F T F S 642 B18 Q V Q L V E S G G G V V Q P G R S L R L S C A A S
G F T F S 643 B26 Q V Q L V E S G G G V V Q P G R S L R L S C A A S
G F T F S 644 B28E Q V Q L V E S G G G V V Q P G R S L R L S C A A
S G F T F S 645 B29E Q V Q L V E S G G G V V Q P G R S L R L S C A
A S G F T F S 646 B29M Q V Q L V E S G G G V V Q P G R S L R L S C
A A S G F T F S 647 B30 Q V Q L V E S G G G V V Q P G R S L R L S C
A A S G F T F S 648 B32M Q V Q L V E S G G G V V Q P G R S L R L S
C A A S G F T F S 649 cos-3 Q V Q L V E S G G G V V Q P G G S L R L
S C A A S G F T F S 650 dp-49 Q V Q L V E S G G G V V Q P G R S L R
L S C A A S G F T F S 651 dp-50 Q V Q L V E S G G G V V Q P G R S L
R L S C A A S G F T F S 652 P6 Q V Q L V E S G G G V V Q P G R S L
R L S C A A S G F T F S 653 P9E Q V Q L V E S G G G V V Q P G R S L
R L S C A A S G F T F S 654 v3-30 Q V Q L V E S G G G V V Q P G R S
L R L S C A A S G F T F S 655 v3-33 Q V Q L V E S G G G V V Q P G R
S L R L S C A A S G F T F S 656 dp-51 E V Q L V E S G G G L V Q P G
G S L R L S C A A S G F T F S 657 dp-77 E V Q L V E S G G G L V K P
G G S L R L S C A A S G F T F S 658 HHG4 E V Q L V E S G G G L V K
P G G S L R L S C A A S G F T F S 659 v3-21 E V Q L V E S G G G L V
K P G G S L R L S C A A S G F T F S 660 v3-48 E V Q L V E S G G G L
V Q P G G S L R L S C A A S G F T F S 661 DP-52 E D Q L V E S G G G
L V Q P G G S L R P S C A A S G F A F S 662 cos-6 E V Q L V E S G G
G L V Q P G G S L R L S C A A S G F T F S 663 dp-53 E V Q L V E S G
G G L V Q P G G S L R L S C A A S G F T F S 664 dp-54 E V Q L V E S
G G G L V Q P G G S L R L S C A A S G F T F S 665 dp-87 E V Q L V E
S G G G L V Q P G G S L R L S C A A S G F T F S 666 VH3-11 E V Q L
V E S G G G L V Q P G G S L R L S C A A S G F T F S 667 JOE9 VH Q V
Q L V Q S G G G V V Q P G R S L R L S C A A S G F T F S SEQ ID CDR
H1 CDR H2 NO: 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48
49 50 51 52 52A 52B 52C 53 54 55 56 594 D H Y M D W V R Q A Q G K G
L E L V G R T R N K A N S Y T 595 D H Y M S W V R Q A Q G K G L E L
V G L T R N K A N S Y T 596 D H Y M S W V R Q A Q G K G L E L V G L
T R N K A N S Y T 597 D H Y M S W V R Q A Q G K G L E L V G L T R N
K A N S Y T 598 D Y A M H W V R Q A P G K G L E W V S G I S W . . N
S G S 599 D Y G M S W V R Q A P G K G L E W V S G I N W . . N G G S
600 D Y T M H W V R Q A P G K G L E W V S L I S W . . D G G S 601 D
Y Y M S W I R Q A P G K G L E W V S Y I . . S S S G S T 602 D Y Y M
S W I R Q A P G K G L E W V S Y I . . S S S S S Y 603 G S A M H W V
R Q A S G K G L E W V G R I R S K A N S Y A 604 N A W M S W V R Q A
P G K G L E W V G R I K S K T D G G T 605 N A W M S W V R Q A P G K
G L E W V G R I E S K T D G G T 606 N A W M S W V R Q A P G K G L E
W V G R I K S K T D G G T 607 N A W M S W V R Q A P G K G L E W V G
R I K S K T D G G T 608 N A W M N W V R Q A P G K G L E W V G R I K
S K T D G G T 609 N A W M S W V R Q A P G K G L E W V G R I K S K T
D G G T 610 N H Y M S W V R Q A P G K G L E W V S Y I I . . S D G G
Y 611 N H Y T S W V R Q A P G K G L E W V S Y S I . . S D G G Y 612
N S D M N W V H Q A P G K G L E W V S G V . . S W N G S R 613 N S D
M N W A R K A P G K G L E W V S G V . . S W N G S R 614 N S D M N W
V R Q A P G K G L E W V S G V . . S W N G S R 615 N Y D M H W V R Q
A T G K G L E W V S A N . . G T A G . D 616 S N Y M S W V R Q A P G
K G L E W V S V I . Y . . S G G S 617 S Y A M H W V R Q A P G K G L
E W V S A I . . . G T G G G 618 S Y A M H W V R Q A P G K G L E W V
S A I . . . G T G G G 619 S Y A M S W V R Q A P G K G L E W V S A I
. . S G S G G S 620 S Y A M H W V R Q A P G K G L E Y V S A I . . S
S N G G S 621 S Y A M H W V R Q A P G K G L E Y V S A I . . S S N G
G S 622 S Y A M H W V R Q A P G K G L E Y V S A I . . S S N G G S
623 S Y A M S W V R Q A P G K G L E W V S A I . . S G S G G S 624 S
Y A M H W V R Q A P G K G L E W V A V I . . S Y D G S K 625 S Y A M
H W V R Q A P G K G L E W V A V I . . S Y D G S N 626 S Y A M H W V
R Q A P G K G L E W V A V I . . S Y D G S N 627 S Y A M H W V R Q A
P G K G L E W V A V I . . S Y D G S N 628 S Y A M H W V R Q A P G K
G L E W V A V I . . S Y D G S N 629 S Y A M H W V R Q A P G K G L E
W V A V I . . S Y D G S N 630 S Y A M H W V R Q A P G K G L E W V A
V I . . S Y D G S N 631 S Y A M H W V R Q A P G K G L E W V A V I .
. S Y D G S N 632 S Y A M H W V R Q A P G K G L E W V A V I . . S Y
D G S N 633 S Y A M H W V R Q A P G K G L E Y V S A I . . S S N G G
S 634 S Y A M H W V R Q A P G K G L E Y V S A I . . S S N G G S 635
S Y A M H W V R Q A P G K G L E W V A V I . . S Y D G S N 636 S Y A
M H W V R Q A P G K G L E W V A V I . . S
S N G G S 637 S Y A M H W V R Q A P G K G L E W V A V I . . S Y D G
S N 638 S Y D M H W V R Q A T G K G L E W V S A I . . G T A G . D
639 S Y E M N W V R Q A P G K G L E W V S Y I . . S S S G S T 640 S
Y G M H W V R Q A P G K G L E W V A V I . . S Y D G S N 641 S Y G M
H W V R Q A P G K G L E W V A V I . . S Y D G S N 642 S Y G M H W V
R Q A P G K G L E W V A V I . . S Y D G S N 643 S Y G M H W V R Q A
P G K G L E W V A V I . . S Y D G S N 644 S Y G M H W V R Q A P G K
G L E W V A V I . . S Y D G S N 645 S Y G M H W V R Q A P G K G L E
W V A V I . . S Y D G S N 646 S Y G M H W V R Q A P G K G L E W V A
V I . . W Y D G S N 647 S Y G M H W V R Q A P G K G L E W V A V I .
. S Y D G S N 648 S Y G M H W V R Q A P G K G L E W V A F I . . R Y
D G S N 649 S Y G M H W V R Q A P G K G L E W V A V I . . S Y D G S
N 650 S Y G M H W V R Q A P G K G L E W V A V I . . W Y D G S N 651
S Y G M H W V R Q A P G K G L E W V A V I . . W Y D G S N 652 S Y G
M H W V R Q A P G K G L E W V A V I . . S Y D G S N 653 S Y G M H W
V R Q A P G K G L E W V A V I . . S Y D G S N 654 S Y G M H W V R Q
A P G K G L E W V A V I . . W Y D G S N 655 S Y G M H W V R Q A P G
K G L E W V A Y I . . S S S S S T 656 S Y S M N W V R Q A P G K G L
E W V S S I . . S S S S S Y 657 S Y S M N W V R Q A P G K G L E W V
S S I . . . S S S S Y 658 S Y S M N W V R Q A P G K G L E W V S S I
. . S S S S S Y 659 S Y S M N W V R Q A P G K G L E W V S S I . . S
S S S S T 660 S Y S M N W V R Q A P G K G L E W V S Y I . . S S S S
S T 661 S Y V L H W V R R A P G K G P E W V S A I G . . . T G G D
662 S Y W M H W V R Q A P G K G L V W V S R I . . N S D G S S 663 S
Y W M H W V R Q A P G K G L V W V S N I . . N S D G S S 664 S Y W M
S W V R Q A P G K G L E W V A R I . . K Q D G S E 665 S Y W M H W V
R Q A P G K G L V W V S N I . . N S D G S S 666 S Y W M S W V R Q A
P G K G L E W V A R I . . K Q D G S E 667 S Y G M H W V R Q P A G K
G L E W V A F I . . R Y D G S N SEQ ID CDR H2 NO: 57 58 59 60 61 62
63 64 65 66 67 68 69 70 71 71 72 73 74 75 76 77 78 79 594 T E Y A A
S V K G R F T I S R D D S K N S L Y L 595 T E Y A A S V K G R L T I
S R E D S K N S L Y L 596 T E Y A A S V K G R L T I S R E D S K N S
M Y L 597 T E Y A A S V K G R L T I S R E D S K N S L Y L 598 I G Y
A D S V K G R F T I S R D N A K N S L Y L 599 T G Y A D S V K G R F
T I S R D N A K N S L Y L 600 T Y Y A D S V K G R F T I S R D N S K
N S L Y L 601 I Y Y A D S V K G R F T I S R D N A K N S L Y L 602 T
N Y A D S V K G R F T I S R D N A K N S L Y L 603 T A Y A A S V K G
R F T I S R D D S K N T A Y L 604 T D Y A A P V K G R F T I S R D D
S K N T L Y L 605 T D Y A A P V K G R F T I S R D D S K N T L Y L
606 T D Y A A P V K G R F T I S R D D S K N T L Y L 607 T N Y A A P
V K G R F T I S R D D S K N T L Y L 608 T D Y A A P V K G R F T I S
R D D S K N T L Y L 609 T D Y A A P V K G R F T I S R D D S K N T L
Y L 610 T H Y A D S V K G R F T I S R D N A N N S L Y L 611 T H Y A
D S V K G R F T I S R D N A K N S L Y L 612 T H Y A D S V K G R F T
I S R D N S R N S L Y L 613 T H Y V D S V K R R F T I S R D N S R N
T L Y L 614 T H Y A D S V K G R F T I S R D N S N N S L Y L 615 T Y
Y P G S V K G R F T I S R D N S N N F L Y L 616 T Y Y A D S V K G R
F T I S R E N A N N S L Y L 617 T Y Y A D S V K G R F T I S R D N S
K N T L Y L 618 T Y Y A D S V K G R F T I S R D N A K N S L Y L 619
T Y Y A D S V K G R F T I S R D N A K N S L Y L 620 T Y Y A D S V K
G R F T I S R D N S K N T L Y L 621 T Y Y A D S V K G R F T I S R D
N S K N T L Y L 622 T Y Y A N S V K G R F T I S R D N A N N S L Y L
623 T Y Y G D S V K G R F T I S R D N S K N T L Y L 624 K Y Y T D S
V K G R F T I S R D N S K T S L Y L 625 K Y Y A D S V K G R F T I S
R D N S K N T L Y L 626 K Y Y A D S V K G R F T I S R D N S K N T L
Y L 627 K Y Y A D S V K G R F T I S R D N S K N T L Y L 628 K Y Y A
D S V K G R F T I S R D N S N N T L Y L 629 K Y Y A D S V K G R F T
I S R D N S N N T L Y L 630 K Y Y A D S V K G R F T I S R D N S K N
T L Y L 631 K Y Y A D S V K G R F T I S R D N S K N T L Y L 632 K Y
Y A D S V K G R F T I S R D N S K N T L Y L 633 T Y Y A D S V K G R
F T I S R D N S N N T L Y L 634 T Y Y A D S V K G R F T I S R D N S
K N T L Y L 635 K Y Y A D S V K G R F T I S R D N S K N T L Y L 636
K Y Y A D S V K G R F T I S R D N S K N T L Y L 637 K Y Y A D S V K
G R F T I S R D N S K N T L Y L 638 T Y Y P G S V K G R F T I S R E
N A K N S L Y L 639 I Y Y A D S V K G R F T I S R D N A K N S L Y L
640 K Y Y A D S V K G R F T I S R D N S K N T L Y L 651 K Y Y A D S
V K G R F T I S R D N S K N T L Y L 642 K Y Y A D S V K G R F T I S
R D N S K N T L Y L 643 K Y Y A D S V K G R F T I S R D N S K N T L
Y L 644 K Y Y A D S V K G R F T I S R D N S K N T L Y L 645 K Y Y A
D S V K G R F T I S R D N S K N R L Y L 646 K Y Y A D S V K G R F T
I S R D N S K N T L Y L 647 K Y Y A D S V K G R F T I S R D N S K N
T L Y L 648 K Y Y A D S V K G R F T I S R D N S K N T L Y L 649 K Y
Y A D S V K G R F T I S R D N S K N T L Y L 650 K Y Y A D S V K G R
F T I S R D N S K N T L Y L 651 K Y Y A D S V K G R F T I S R D N S
K N T L Y L 652 K Y Y A D S V K G R F T I S R D N S K N T L Y L 653
K Y Y A D S V K G R F T I S R D N S K N T L Y L 654 K Y Y A D S V K
G R F T I S R D N S K N T L Y L 655 K Y Y A D S A K G R F T I S R D
N S K N T L F L 656 I Y Y A D S V K G R F T I S R D N A K N S L Y L
657 I Y Y A D S V K G R F T I S R D N S K N S L Y L 658 I Y Y A D S
V K G R F T I S R D N S K N S L Y L 659 I Y Y A D S V K G R F T I S
R D N A K N S L Y L 660 I Y Y A D S V K G R F T I S R D N A K N S L
Y L 661 T Y Y A D S V M G R F T I S R D N A K K S L Y L 662 T S Y A
D S V K G R F T I S R D N A K N T L Y L 663 T S Y A D S V K G R F T
I S R D N A K N T L Y L 664 K Y Y V D S V K G R F T I S R D N A K N
S L Y L 665 T S Y A D S M K G R F T I S R D N A K N T L Y L 666 K Y
Y V D S V K G R F T I S R D N A K N S L Y L 667 K Y Y A D S V K G R
F T I S R D N A K N T L Y L CDR H2 SEQ ID NO: 80 81 82 83 83A 83B
83C 84 85 86 87 88 89 90 91 92 93 94 594 L Q M N S L K T E D T A V
Y Y C A R 595 L Q M S S L K T E D L A V Y Y C A R 596 L Q M S N L K
T E D L A V Y Y C A R 597 L Q M S S L K T E D L A V Y Y C A R 598 L
Q M N S L R A E D T A L Y Y C A K 599 L Q M N S L R A E D T A L Y H
C A R 600 L Q M N S L R T E D T A L Y Y C A K 601 L Q M N S L R A E
D T A V Y Y C A R 602 L Q M N S L R A E D T A V Y Y C A R 603 L Q M
N S L K T E D T A V Y Y C T R 604 L Q M N S L K T E D T A V Y Y C T
T 605 L Q M N S L K T E D T A V Y Y C T T 606 L Q M N S L K T E D T
A V Y Y C T T 607 L Q M N S L K T E D T A V Y Y C T T 608 L Q M N S
L K T E D T A V Y Y C T T 609 L Q M N S L K T E D T A V Y Y C T T
610 L Q M N S L R A E D T A V Y Y C V K 611 L Q M N S L R A E D T A
V Y Y C V K 612 L Q T N S L R A E D T A V Y Y C V R 613 L Q K N R R
R A E D M A V Y Y C V R 614 Q Q M N S L R P E D M A V Y Y C V R 615
L Q M N S L R A G D T A V Y Y C A R 616 L Q M N S L R A E D T A V Y
Y C A R 617 L Q M N S L R A E D M A V Y Y C A R 618 L Q M N S L R A
E D M A V Y Y C A R 619 L Q M N S L R A E D T A V Y Y C A K 620 V Q
M S S L R A E D T A V Y Y C V K 621 V Q M S S L R A E D T A V Y Y C
V K 622 L Q M G S L R A E D M A V Y Y C A R 623 L Q M N S L R A E D
T A V Y Y C A K 624 L Q M N S L R A E D T A V Y Y C A R
625 L Q M N S L R A E D T A V Y Y C A R 626 L Q M S S L R A E D T A
V Y Y C A R 627 L Q M N S L R A E D T A V Y Y C A R 628 L Q M N S L
R A E D T A V Y Y C A R 629 L Q M N S L R A E D T A V Y Y C A R 630
L Q M N S L R A E D T A V Y Y C A R 631 L Q M N S L R A E D T A V Y
Y C A R 632 L Q M N S L R A E D T A V Y Y C A R 633 V Q M S S L R A
E D T A V Y Y C V K 634 L Q M N S L R A E D T A V Y Y C A R 635 L Q
M N S L R A E D T A V Y Y C A R 636 L Q M N S L R A E D T A V Y Y C
A R 637 L Q M N S L R A E D T A V Y Y C A K 638 L Q M N S L R A G D
T A V Y Y C A R 639 L Q M N S L R A E D T A V Y Y C A R 640 L Q M N
S L R L R A R L C I T V R E 651 L W M N S L R A E D T A V Y Y C A R
642 L Q M N S L R A E D T A V Y Y C A R 643 L Q M N S L R A E D T A
V Y Y C A R 644 L Q M N S L R A E D T A V Y Y C A R 645 L Q M N S L
R A E D T A V Y Y C A R 646 L Q M N S L R A E D T A V Y Y C A R 647
L Q M N S L R A E D T A V Y Y C A R 648 L Q M N S L R A E D T A V Y
Y C A R 649 L Q M N S L R A E D T A V Y Y C A K 650 L Q M N S L R A
E D T A V Y Y C A K 651 L Q M N S L R A E D T A V Y Y C A R 652 L Q
M N S L R A E D T A V Y Y C A K 653 L Q M N S L R A E D T A V R K -
- - 654 L Q M N S L R A E D T A V Y Y C A R 655 L Q M N S L R A E D
T A V Y Y C A R 656 L Q M N S L R D E D T A V Y Y C A R 657 L Q M N
S L R A E D T A V Y Y C A R 658 L Q M N S L R A E D T A V Y Y C A R
659 L Q M N S L R A E D T A V Y Y C A R 660 L Q M N S L R A E D T A
V Y Y C A R 661 L Q M N S L I A E D M A V Y Y C A R 662 L Q M N S L
R A E D T A V Y Y C A R 663 L Q M N S L R A E D T A V Y Y C A R 664
L Q M N S L R A E D T A V Y Y C A R 665 L Q M N S L R A E D M A V Y
Y C T R 666 L Q M N S L R A E D T A V Y Y C A R 667
LQMKSLRAEDTAVYYCTT V.lamda.1 Family Germline Amino Acid Sequences
Numbering according to Kabat. (Joe9 VL included for comparison) SEQ
ID CDR L1 NO: gene* VL 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18
19 20 21 22 24 25 26 27 668 1b DPL5 Q S V L T Q P P S V S A A P G Q
K V T I S C S G S S 669 1d DPL4 Q S V L T Q P P S V S A A P G Q K V
T I S C S G S S 670 1c DPL2 Q S V L T Q P P S A S G T P G Q R V T I
S C S G S S 671 1g DPL3 Q S V L T Q P P S A S G T P G Q R V T I S C
S G S S 672 1a DPL1 Q S V L T Q P P S V S E A P R Q R V T I S C S G
S S 637 1f DPL9 Q S V L T Q P P S V S G A P G Q R V T I S C T G S S
674 1e DPL8 Q S V V T Q P P S V S G A P G Q R V T I S C T G S S 675
JOE9 VL S I V L T Q P P S V S G T P G Q R V T I S C S G G R SEQ ID
CDR L1 NO: 27A 27B 27C 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42
43 44 45 46 47 668 S N I G N N Y . V S W Y Q Q L P G T A P K L L
669 S D M G N Y A . V S W Y Q Q L P G T A P K L L 670 S N I G S N T
. V N W Y Q Q L P G T A P K L L 671 S N I G S N Y . V Y W Y Q Q L P
G T A P K L L 672 S N I G N N . A V N W Y Q Q L P G K A P K L L 637
S N I G A G Y V V H W Y Q Q L P G T A P K L L 674 S N I G A G Y D V
H W Y Q Q L P G T A P K L L 675 S N I G S H T . V K W Y Q Q L P G T
A P K L L CDR L1 SEQ ID NO: 48 49 50 51 52 53 54 55 56 668 I Y D N
N K R P S 669 I Y E N N K R P S 670 I Y S N N Q R P S 671 I Y R N N
Q R P S 672 I Y Y D D L L P S 637 I Y G N S N R P S 674 I Y G N S N
R P S 675 I Y G N D Q R P S SEQ ID CDR L2 NO: 57 58 59 60 61 62 63
64 65 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85
86 668 G I P D R F S G S K S G T S A T L G I T G L Q T G D E A D Y
669 G I P D R F S G S K S G T S A T L G I T G L W P E D E A D Y 670
G V P D R F S G S K S G T S A S L A I S G L Q S E D E A D Y 671 G V
P D R F S G S K S G T S A S L A I S G L R S E D E A D Y 672 G V S D
R F S G S K S G T S A S L A I S G L Q S E D E A D Y 637 G V P D Q F
S G S K S G T S A S L A I T G L Q S E D E A D Y 674 G V P D R F S G
S K S G T S A S L A I T G L Q A E D E A D Y 675 G V P D R F S G S K
S G T S A S L A I T G V Q A E D E A D Y SEQ ID CDRL3 NO: 87 88 89
90 91 92 93 94 95 95A 95B 668 Y C G T N D S S L S A 669 Y C L A W D
T S P R A 670 Y C A A W D D S L N G 671 Y C A A W D D S L S G 672 Y
C A A W D D S L N G 637 Y C K A W D N S L N A 674 Y C Q S Y D S S L
S G 675 Y C Q S Y D S S L R G *Williams, J M B, 1996, 264,
220-232
TABLE-US-00004 TABLE 2 H3 SEQ L3 SEQ RB assay PHA assay IFN gamma
Clone ID NO: H3 ID NO: L3 koff IC50 (M) IC50 (M) IC50 (M) Joe9 wt
77 SGSYDY 110 QSYDSSLRGSRV 1.00E-01 1.50E-06 1.00E-06 Joe9 wt IgG1
77 SGSYDY 110 QSYDSSLRGSRV 5.00E-07 70-1 78 HGSHDN 110 Joe9 wt 1.34
e-2 2.00E-07 701- IgG1 78 HGSHDN 110 Joe9 wt 2.00E-07 70-2 79
HGSYDY 110 Joe9 wt 3.30E-02 3-5.0E-7 70-7 80 RRRSNY 110 Joe9 wt
1.29E-01 3-5.0E-7 70-13 81 SGSIDY 110 Joe9 wt 7.20E-02 3-5.0E-7
78-34 77 wt 111 QSYDRGFTGSRV 1.64 e-2 2.00E-07 6.00E-07 78-25 77 wt
112 QSYDSSLRGSRV 5.00E-02 78-28 77 wt 112 QSYDSSLRGSRV 4.66E-02
78-35 77 wt 113 QSYDSSLTGSRV 4.99E-02 4.00E-07 79-1 77 wt 114
QSYDSSLWGSRV 2.00E-07 6.00E-07 101-14 79 70-2 111 78-34 7.52E-03
101-9 79 70-2 113 78-35 8.54E-03 101-19 81 70-13 111 78-34 4.56E-02
101-8 81 70-13 111 78-34 1.01E-02 101-4 81 70-13 113 78-35 9.76E-03
101-5 81 70-13 113 78-35 4.45E-02 101-11 (12) 78 70-1 111 78-34 4.5
e-3 3.00E-08 101-11 IgG1 78 70-1 111 78-34 1.60E-09 26-1 (2, 3) 78
70-1 114 79-1 7.4 e-3 6.00E-08 136-9 82 HGSHDD 115 QTYDISESGSRV
3.20E-03 136-10 82 HGSHDD 116 QSYDRGFTGSRV 1.40E-03 2.00E-09 136-14
83 HGSHDN 117 QTYDRGFTGSRV 1.10E-03 3.00E-10 1.00E-07 136-15 83
HGSHDS 118 QTYDKGFTGSSV 7.4 e-4 1.00E-10 2.00E-09 136-15 germline
83 HGSHDN 118 QTYDKGFTGSSV 4.60E-04 6.00E-09 136-16 83 HGSHDN 119
QSYDRRFTGSRV 6.10E-04 3.00E-10 5.00E-09 136-17 83 HGSHDN 120
QSYDWNFTGSRV 2.90E-05 2.00E-09 7.00E-09 136-18 83 HGSHDN 121
QSYDRGFTGSRV 1.10E-03 8.00E-10 136-21 83 HGSHDN 122 QSYDNGFTGSRV
4.20E-04 2.00E-09 136-24 83 HGSHDN 123 QSYDNAVTASKV 8.90E-04
1.00E-09 101-11 84 TT HGSHDN WGQG 124 QSYDRGFTGSKV 4.5 .times. 10-3
2 .times. 10-5 2.00E-08 136-15M1 85 AK ...... .... 124 QSYDRGFTGSRV
4.00E-10 149-4 86 .. ...... .S.. 124 ............ 1.37 .times. 10-3
8 .times. 10-11 3.00E-09 149-5 87 .. .....T .... 125 QSYDSSLWGTRV
1.02 .times. 10-3 1.2 .times. 10-10 3.00E-09 149-6 84 .. ......
.... 124 ............ 2.73 .times. 10-3 6 .times.10-10 2.00E-09
149-7 84 .. ...... .... 126 .....D...... 1.13 .times. 10-3 9
.times. 10-10 3.00E-09 149-8 88 K. ...... .... 2.33 .times. 10-3 3
.times. 10-9 149-9 89 K. ...... ..H. 127 ...E......M. 3.54 .times.
10-3 1.8 .times. 10-10 149-11 90 .. ...... .S.. 128 ....N....A..
1.43 .times. 10-2 2 .times. 10-10 4.00E-09 149-12 84 .. ...... ....
3.73 .times. 10-3 neutralising 149-13 84 .. ...... .... 2.22
.times. 10-3 5 .times. 10-10 149-14 91 .. .R..N. .... 1.5 .times.
10-10 6.00E-09 92 TT HGSHDN 124 QSYDRGFTGSRV 156-1 93 .. .....T 126
.....D...... 5.00E-03 156-2 93 .. .....T 129 .....R...... 156-3 93
.. .....T 128 ....N....A.. 9.00E-03 156-4 93 .. .....T ...E.....SM.
156-5 93 .. .....T .T..K.....S. 156-6 92 .. ...... 126 .....D......
3.00E-03 156-7 92 .. ...... 129 .....R...... 156-8 92 .. ...... 128
...N....A.. 159-9 92 .. ...... 127 ...E.....SM. 156-10 92 .. ......
130 .T..K.....S. 156-11 94 .K ...... 126 .....D...... 156-12 94 .K
...... 129 .....K...... 156-13 94 .K ...... 128 ....N....A.. 156-14
94 .K ...... 127 ...E.....SM. 156-15 94 .K ...... 130 .T..K.....S.
156-16 93 .. .....T 124 ............ 156-17 92 .. ...... 125
....SSLW.T.. 6.00E-03 156-18 93 .. .....T 125 ....SSLW.T.. 92 TT
HGSHDN 124 QSYDRGFTGSEV 103-1 95 .. Q.R... 124 ............ 2.9
.times. 10-3 103-2 96 K. R.R... 130 .T..K.....S. 7.3 .times. 10-4
7.00E-11 1.00E-09 103-3 97 .. .....K 124 ............ 2.5 .times.
10-3 103-6 131 .....D...T.. 4.5 .times. 10-4 103-7 98 .. .....D 131
.....D...T.. 3.7 .times. 10-4 1.40E-10 1.00E-09 103-8 99 K. ......
130 .T..K.....S. 3.3 .times. 10-4 6.00E-11 1.50E-09 103-14 & 9
100 KT HGSHDN 132 QSYDRGFTGSMV 6.7 e-4 4.00E-11 1.20E-98 103-8
& 2 100 KT HGSHDN 133 QTYDKGFTGSSV 5.3 e-4 1.50E-09 103-4 101
TT HGSHDN 134 QSYDRGFTGARV 1.6 e-4 8.60E-11 9.00E-10 103-152 101 TT
HGSHDN 135 QSYERGFTGARV 8.60E-11 102 TT SGSYDY 136 QSYDRGFTGSRVF
170-1 102 .. ...... 137 .........FK.. 2.35E-03 170-2 102 .. ......
138 .......VSAY.. 8.80E-04 170-3 102 .. ...... 139 ......L.VTK..
1.11E-03 170-4 102 .. ...... 140 ......Y.A.... 8.11E-04 170-7 102
.. ...... 141 ..........K.. 5.30E-04 170-11 102 .. ...... 142
......L..F... 4.40E-04 170-13 102 .. ...... 143 ..........YK..
1.59E-03 170-15 102 .. ...... 144 ......L..Y.L. 4.43E-03 170-19 103
.. H..H.N 145 ........DYK.. 1.00E-03 170-21 104 .. H..Q.N 146
.........P.L. 3.89E-03 170-22 102 .. ...... 147 ......L......
5.60E-04 170-23 103 .. H..H.N 148 .........A..W 1.00E-03 2.00E-10
170-24 104 .. H..Q.N 149 .........Y... 2.80E-04 5.00E-10 170-35 105
A. H..Q.N 136 ............. 1.00E-05 170-38 150 .........P...
2.10E-04 170-39 151 ......M.S.... 2.79E-03 170-36 83 HGSHDN 152
QSYDRDSTGSRVF 4.00E-04 2.00E-10 170-25 106 HGSQDT 153 QSYDSSLRGSRVF
5.00E-04 5.00E-11 106 SGSYDY 136 QSYDRGFTGSRVF 73-B1 107 SGSYDY 154
H...SD....... 3.25E-03 >1E-8 73-B2 107 SGSYDY 155 H.SES........
2.07E-03 73-B6 107 SGSYDY 156 H...NR....... 2.51E-03 >1E-8 73-C1
107 SGSYDY 157 H...SR....... 2.71E-03 >1E-8 73-C2 107 SGSYDY 158
...SE....... 3.79E-03 73-C6 107 SGSYDY 159 ...T........ 3.96E-03
73-D1 107 SGSYDY 160 H...S........ 3.99E-03 73-D2 107 SGSYDY 161
....T........ 3.56E-03 73-D4 107 SGSYDY 162 H...TK....... 5.36E-03
73-D5 107 SGSYDY 163 H.S.S........ 3.57E-03 73-E3 107 SGSYDY 164
....SD....... 4.98E-03 73-E6 107 SGSYDY 165 H..ES........ 4.17E-03
73-F3 107 SGSYDY 166 ....SPWS..... 7.08E-03 73-F5 107 SGSYDY 167
...DSD....K.. 3.74E-03 73-G2 107 SGSYDY 158 HTN.S........ 3.98E-03
73-G3 107 SGSYDY 169 H..TR....... 3.50E-03 73-G4 107 SGSYDY 170
....MR....... 6.58E-03 73-G5 107 SGSYDY 171 H.S.SDS...... 6.01E-03
73-G6 107 SGSYDY 172 ...NTD....... 6.30E-03 73-H2 107 SGSYDY 173
....S........ 5.93E-03 73-F6 107 SGSYDY 174 H...M........ 5.87E-03
73-H3 107 SGSYDY 175 H...N........ 6.85E-03 73-C5 107 SGSYDY 176
H.H..D....... 4.84E-03 73-B7 108 HGSQDN 177 QSYDSSLRGSRV 2.50E-03
7.00E-09 136 QSYDRGFTGSRVF M2 A2 83 HGSHDN 178 ......IH.....
4.00E-02
M2 A4 83 HGSHDN 179 ....S..P..... 8.49E-03 M2 A5 83 HGSHDN 180
....I.S...... 4.01E-02 M2 B1 83 HGSHDN 181 ....S.L...... 7.97E-03
M2 B3 83 HGSHDN 182 ....I.M...... 4.60E-02 M2 B4 83 HGSHDN 183
....I.L...... 4.42E-02 M2 B5 83 HGSHDN 184 ....S.V...... 8.38E-03
M2 B6 82 HGSHDN 185 ......L.A.... 2.81E-02 M2 C2 83 HGSHDN 181
....S.L...... 4.85E-02 M2 C3 83 HGSHDN 186 ....T.L...... 4.62E-02
M2 C4 83 HGSHDN 181 ....S.L...... 8.16E-03 M2 C5 83 HGSHDN 187
....TAL...... 4.71E-02 M2 D1 83 HGSHDN 188 ....IR....... 3.71E-02
M2 D2 83 HGSHDN 189 ....IRS...... 3.85E-02 M2 D3 83 HGSHDN 190
....NRL...... 3.33E-02 M2 D4 83 HGSHDN 191 ...ETS....... 5.81E-02
M2 D5 83 HGSHDN 192 ....SSS...... 5.18E-02 M2 D6 83 HGSHDN 193
....S...A.... 5.01E-02 M2 E1 83 HGSHDN 194 .T..K.....S.. 5.32E-02
M2 E2 82 HGSHDN 195 ....N........ 4.77E-02 M2 E6 83 HGSHDN 196
....T...K.... 9.77E-03 M2 F1 83 HGSHDN 197 ....SDV...... 6.16E-02
M2 H5 83 HGSHDN 198 ....A........ 9.90E-03 124 QSYDRGFTGSRV A5 83
HGSHDN 199 ......THPSML 1.12E-03 A12 83 HGSHDN 200 ......TTPRPM
1.43E-03 A4 83 HGSHDN 201 ......RNPALT 1.47E-03 A6 83 HGSHDN 202
......THPWLH 1.87E-03 A10 83 HGSHDN 203 ......NSPATV 1.87E-03 A11
83 HGSHDN 204 ......TFPSPQ 2.07E-03 C2 83 HGSHDN 205 ......LNPSAT
2.23E-03 A8 83 HGSHDN 206 ......KSNKML 2.37E-03 B8 83 HGSHDN 207
......HTAHLY 2.40E-03 C6 83 HGSHDN 208 ......QTPSIT 2.42E-03 A3 83
HGSHDN 209 ......YPRNIL 2.51E-03 B11 83 HGSHDN 210 ......ITPGLA
2.95E-03 B5 83 HGSHDN 211 ......QPHAVL 3.04E-03 C10 83 HGSHDN 212
......NSPIPT 3.10E-03 C4 83 HGSHDN 213 ......TPNNSF 3.23E-03 C3 83
HGSHDN 214 ....S.VDPGPY 3.34E-03 B2 83 HGSHDN 215 ......RPRHAL
3.61E-03 A2 83 HGSHDN 216 ......PYHPIR 3.80E-03 C5 83 HGSHDN 217
......PHTQPT 3.91E-03 A7 83 HGSHDN 218 ......HNNFSP 3.95E-03 C9 83
HGSHDN 219 ......PTHLPH 3.97E-03 B3 83 HGSHDN 220 ......TPSYPT
2.12E-03 C8 83 HGSHDN 221 ....S.TSNLLP 5.36E-03 B7 83 HGSHDN 222
......DSNHDL 5.45E-03 A1 83 HGSHDN 223 ......LPRLTH 5.66E-03 C7 83
HGSHDN 224 ......IPTSY L 5.83E-03 C12 83 HGSHDN 225 ......LRVQAP
5.85E-03 B10 83 HGSHDN 226 ......LSDSPL 6.04E-03 B6 83 HGSHDN 227
....S.SLRRIL 7.58E-03 A9 83 HGSHDN 228 ......PARTSP 7.98E-03 B9 83
HGSHDN 229 ......RAAHPQ 8.66E-03 124 QSYDRGFTGSRV 177-D7 83 HGSHDN
230 ......TQPABI 4.07E-04 177-G6 83 HGSHDN 231 ......THPTMI
5.50E-04 177-D9 83 HGSHDN 232 ......RIPABT 6.32E-04 177-C6 83
HGSHDN 233 ......THPVPA 7.94E-04 177-H5 83 HGSHDN 234 ......SBPIPA
1.32E-03 177-H9 83 HGSHDN 235 ......THPVPA 1.58E-03 177-H10 83
HGSHDN 236 ......THPTMY 3.44E-03 144-F1 83 HGSHDN 237 ......HHYTTF
5.80E-04 43-E3 83 HGSHDN 238 ......SHPAAE 8.00E-04 43-E9 83 HGSHDN
239 ......TIPSIE 8.00E-04 43-G2 83 HGSHDN 240 ......SSPAIM 7.00E-04
43-G3 83 HGSHDN 241 ......IQPNLN 9.00E-04 31-A6 83 HGSHDN 242
......THPNLN 5.00E-04 31-B5 83 HGSHDN 243 ......THPSIS 5.00E-04 124
QSYDRGFTGSRV Y17 83 HGSHDN 244 QSYDRGSAPMIN 8.90E-05 4.50E-10
>1E-8 Y19 83 HGSHDN 245 QSYDRGHHPAMS 2.26E-04 3.00E-11 >1E-8
Y38 83 HGSHDN 246 ......THPSIT 5.08E-04 5.50E-11 2.60E-09 Y45 83
HGSHDN 247 ......TDPAIV 6.17E-04 4.00E-11 4.30E-09 Y61 83 HGSHDN
248 ......THPALL 2.75 e-4 4E-11 1.40E-10 Y61 IgG 83 HGSHDN 248
......THPALL 1.50E-04 1.60E-11 1.30E-10 Y61 IgG 83 HGSHDN 248
......THPALL 1.50E-04 1.60E-11 1.30E-10 1.60E-10 germline Y139 83
HGSHDN 249 ......SHPALT 5.92E-04 3E-11 4.50E-10 Y139 IgG1 83 HGSHDN
249 ......SHPALT 1.00E-09 Y174 83 HGSHDN 250 ......TTPAPE 7.55E-04
6E-11 2.00E-09 Y177 83 HGSHDN 251 ......SHPTLI 6.61E-04 5E-11
1.00E-09 A5 83 HGSHDN 252 ......THPSML 4.50E-04 6.60E-11 A12 83
HGSHDN 253 ......TTPRPM 5.57E-04 2.50E-10 D9 83 HGSHDN 254
......RLPAQT 8.21E-04 3.5E-9 >> G6 83 HGSHDN 255 ......THPLTI
5.08E-04 1E-10 1.00E-09 G6 IgG1 83 HGSHDN 255 ......THPLTI 1.00E-09
C6 83 HGSHDN 256 QSYDRGQTPSIT 1.07E-03 3.5E-10 1.00E-08 Y55 83
HGSHDN 257 QSYDRGTHFQMY 1.06E-03 1.40E-10 >1E-8 A4 83 HGSHDN 258
QSYDRGRNPALT 6.30E-04 2.50E-10 AO3 83 HGSHDN 259 QSYDRGTHPLTM
3.04E-04 3.00E-11 4.00E-10 AO3 IgG1 83 HGSHDN 260 QSYDRGTHPLTM 3.04
e-04 2.90E-11 3.80E-10 AO3 IgG 83 HGSHDN 260 QSYDRGTHPLTM 2.50E-04
3.50E-11 1.75E-10 germline 99-B11 83 HGSHDN 261 QSYDSGYTGSRV
5.40E-03 99-C11 83 HGSHDN 262 QSYDSGFTGSRV 5.70E-03 99-H4 83 HGSHDN
263 QSYDSRFTGSRV 4.80E-03 99-E9 83 HGSHDN 262 QSYDSGFTGSRV 5.40E-03
99-H7 83 HGSHDN 264 QSYPDGTPASRV 3.30E-03 99-H11 83 HGSHDN 265
QSYSTHMPISRV 4.90E-03 99-F6 83 HGSHDN 266 QSYDSGSTGSRV 4.90E-03
99-F7 83 HGSHDN 267 QSYPNSYPISRV 4.80E-03 99-F8 83 HGSHDN 268
QSYIRAPQQV 3.70E-03 99-F11 83 HGSHDN 262 QSYDSGFTGSRV 5.40E-03
99-G7 83 HGSHDN 269 QSY LKSRAFSRV 4.80E-03 99-G11 83 HGSHDN 270
QSYDSRFTGSRV 4.30E-03 124 QSYDRGFTGSRV L3.3R3M-B1 83 HGSHDN 271
......FTGSMV 5.46E+00 L3.3R3M-B3 83 HGSHDN 272 ......FTGSMV
5.51E+00 L3-3R3M-C6 83 HGSHDN 273 ......FTGFDG 6.17E+00 L3.3R3M-F9
83 HGSHDN 274 ......TAPALS 4.99E+00 L3.3R3M-G8 83 HGSHDN 275
......SYPALR 5.55E+00 L3.3R3M-H6 83 HGSHDN 276 ......NQPNSN
5.69E+00 L3.3R3M-H10 83 HGSHDN 277 ......TAPSLL 5.35E+00 L3.3R3M-A3
83 HGSHDN 278 ......FTGSMV 5.37E+00 L3.3R3M-F8 83 HGSHDN 279
......TTPRIR 4.99E+00 L3.3R3M-G1 83 HGSHDN 280 ......FTGSMV
4.21E+00 L3.3R3M-G7 83 HGSHDN 281 ......FTGSMV 4.24E+00 L3-3R3M-H11
83 HGSHDN 282 ......MIPALT 3.95E+00 Y61-L94N 109 CKT HGSHDN 283
QSYDRNTHPALL 8.00E-11 Y61-L94F 109 CKT HGSHDN 284 QSYDRFTHPALL
6.00E-11 Y61-L94Y 109 CKT HGSHDN 285 QSYDRYTHPALL 2.00E-11 Y61-L94Y
IgG 109 CKT HGSHDN 285 QSYDRYTHPALL 1.27E-04 6.00E-11 5.00E-11
4.00E-11 Y61-L50Y 109 CKT HGSHDN 286 QSYDRGTHPALL 2.00E-11 2.00E-11
Y61-L50Y* IgG 109 CKT HGSHDN 286 QSYDRGTHPALL 6.98E-05 2.00E-11
3.00E-11
Y-61-L50Y- 109 CKT HGSHDN 286 QSYDRGTHPALL 2.99E-05 6.00E-11
2.00E-11 H31E**gG Y61-L50Y-H31E- 109 CKT HGSHDN 287 QSYDRYTHPALL
4.64E-05 1.00E-11 1.00E-11 L94Y ** IgG J695 (Y61-L94Y- 109 CKT
HGSHDN 287 QSYDRYTHPALL 5.14E-05 5.00E-11 1.00E-11 5.00E-12 L50Y
IgG*) *CDR L2: L50G to Y **CDRL2: L50G to Y; CDR H1: H31S to E
TABLE-US-00005 TABLE 3 CDR H1 CDR H2 Kabat Number 27 28 29 30 31 32
33 34 35 50 51 52 52A 53 54 55 56 57 58 59 60 61 62 63 64 65 Y61 VH
F T F S S Y G M H F I R Y D G S N K Y Y A D S V K G Contact x x x x
x x x x x x x x Positions Hypermutation x x x x x x Positions CDR
L1 CDR L2 Kabat Number 24 25 26 27 27A 27B 28 29 30 31 32 33 34 50
51 52 53 54 55 56 Y61 VH S G G R S N I G S N T V K G N D Q R P S
Contact x x x x x x x x Positions Hypermutation x x x x Positions
CDR H3 CDR L3 Kabat number 95 96 97 98 101 102 89 90 91 92 93 94 95
95A 95B 95C 96 97 Y61 VL H G S H D N Q S Y D R G T H P A L L
Contact x x x x x x x x x x Positions Hypermutation x Positions x
contact and/or hypermutation position x contact and/or
hypermutation position mutated in Y61
TABLE-US-00006 TABLE 4 Neutralization Activity in the Presence of
Excess Free IL-12 p40 PHA assay PHA assay PHA assay SEQ ID IC50 (M)
IC50 (M) IC50 (M) NO: Clone p70:p40 1:0 p70:p40 1:20 p70:p40 1:50
VH: 47 136-15 2.00E-09 5.00E-09 4.00E-09 VL: 48 VH: 51 149-5
6.50E-09 7.00E-09 4.00E-09 VL: 52 VH: 53 149-6 9.00E-10 1.00E-09
1.00E-09 VL: 54 VH: 84 149-7 3.50E-09 2.50E-09 4.00E-09 VL: 126 VH:
23 Y61 IgG 1.80E-10 1.80E-10 VL: 24 VH: 65 AO3 IgG1 2.50E-10
2.20E-10 VL: 66 VH: 31 J695 1.00E-11 3.50E-11 VL: 32
EXAMPLES
Example 1
Efficacy of the Fully Human IL-12/IL-23 Monoclonal Antibody,
ABT-874, In the Treatment of Moderate to Severe Plaque
Psoriasis
[0677] ABT-874 is a fully human antibody against interleukin-12
(IL-12) and IL-23. It binds with great affinity to the p40 subunit
common to both IL-12 and IL-23, both validated targets in the
treatment of psoriasis (Ps).
[0678] The objective of the following study was to evaluate the
efficacy of subcutaneous injections of ABT-874 in the treatment of
patients with moderate to severe plaque Ps.
[0679] Adult patients with Ps affecting .gtoreq.10% body surface
area (BSA) and a Psoriasis Area and Severity Index (PASI) score
.gtoreq.12 at baseline were eligible for this 12-week,
double-blind, placebo-controlled study. Patients were randomized to
1 of 6 arms: 1) 100-mg ABT-874 every other week (eow) for 12 weeks;
2) one 200-mg ABT-874 dose at Week 0; 3) 200-mg ABT-874 every week
for 4 weeks; 4) 200-mg ABT-874 eow for 12 weeks; 5) 200-mg ABT-874
every week for 12 weeks; or 6) placebo. Primary endpoint was a
.gtoreq.PASI75 response at Week 12. Other efficacy assessments
included the PASI50 and Physician's Global Assessment (PGA).
Patients who met the primary endpoint entered a 36-week
blinded/retreatment phase and were monitored for time to loss of
response.
[0680] A total of 180 patients enrolled in the study, 30 in each
arm. Baseline characteristics were similar between arms and
indicative of moderate to severe Ps (all mean values except %
male): age, 46 yrs, 74% male; 21 yrs duration of Ps; PASI 19; and
25% BSA affected. At Week 12, the percentages of patients achieving
.gtoreq.PASI75 were statistically significantly greater for
patients in each of the 5 ABT-874 arms vs. placebo (93%, 63%, 90%,
93%, 90%, vs. 3%, respectively, p<0.001, ITT). In addition, the
percentages of patients achieving .gtoreq.PASI50 were statistically
significantly greater for patients in each of the 5 ABT-874 arms
vs. placebo (100%, 77%, 97%, 97%, and 100%, vs. 17%, p<0.001).
The mean percentage decreases (improvements) in PASI at Week 12
were 90%, 70%, 92%, 92%, and 90%, respectively, in the ABT-874
arms, and 26% for placebo. Similarly, the percentages of patients
with a PGA of Clear/Minimal were 83%, 50%, 73%, 87% and 87%,
respectively, in the ABT-874 arms, and 3% for placebo.
[0681] In conclusion, ABT-874 was significantly more efficacious
than placebo in the treatment of moderate to severe plaque
psoriasis.
Example 2
Safety and Efficacy of the Fully Human IL-12/-23 Monoclonal
Antibody, ABT-874, in the Treatment of Moderate to Severe Plaque
Psoriasis
[0682] ABT-874 is a fully human antibody against interleukin 12
(IL-12) and IL-23. It binds with great affinity to the p40 subunit
common to both IL-12 and IL-23, validated targets in the treatment
of psoriasis (Ps). The objective of this Phase II study was to
investigate the efficacy and safety of subcutaneous injections of
ABT-874 in the treatment of moderate to severe plaque Ps.
[0683] Adults with Ps affecting .gtoreq.10% body surface area (BSA)
and a PASI score .gtoreq.12 were eligible for this 12-wk,
double-blind, placebo-controlled study. Patients were randomized to
1 of 6 arms: 1) 100-mg ABT-874 every other week (eow) for 12 wks;
2) one 200-mg ABT-874 dose at Wk 0; 3) 200-mg ABT-874 every wk for
4 wks; 4) 200-mg ABT-874 eow for 12 wks; 5) 200-mg ABT-874 every wk
for 12 wks; or 6) placebo. The primary endpoint was a
.gtoreq.PASI75 response at Wk 12. Patients who met the primary
endpoint entered a 36-wk blinded/retreatment phase and were
monitored for time to loss of response. All patients were evaluated
for safety through Wk 54.
[0684] 180 patients enrolled, 30 in each arm. Baseline
characteristics were similar between arms (mean values presented
except % male): age, 46 yrs, 74% male; 21 yrs duration of Ps;
PASI=19; and 25% BSA affected. At Wk 12, the % s of patients with
.gtoreq.PASI75 were statistically significantly greater in each of
the 5 ABT-874 arms vs. placebo (93%, 63%, 90%, 93%, 90%, vs. 3%,
respectively, p<0.001, ITT). During the 12-wk, DB phase,
infectious AEs for the ABT-874 groups ranged from 23-43% and for
the placebo group was 23%, with the most common being
nasopharyngitis (7-17% for ABT-874; 3% for placebo). There were no
statistically significant differences between arms. No serious
infectious AEs were reported, and no deaths occurred.
[0685] In conclusion, ABT-874 was significantly more efficacious
than placebo in the treatment of moderate to severe plaque Ps, and
appears to have a favorable safety profile.
Example 3
Maintenance of Response with the Fully Human IL-12/-23 Monoclonal
Antibody, ABT-874, in the Treatment of Moderate to Severe Plaque
Psoriasis
[0686] The efficacy and safety of ABT-874 was evaluated in a
12-week, Phase II, randomized controlled trial and 36-week
follow-up phase. The objective of the following example was to
analyze maintenance of response following discontinuation of
therapy during the second 12 weeks of this Phase II study of
subcutaneous injections of ABT-874 in the treatment of moderate to
severe plaque Ps.
[0687] Adults with Ps affecting .gtoreq.10% body surface area (BSA)
and a PASI score .gtoreq.12 were eligible for this 12-week,
double-blind, placebo-controlled study. Patients were randomized to
1 of 6 arms:
[0688] 1) 100-mg ABT-874 every other week (eow) for 12 wks;
[0689] 2) one 200-mg ABT-874 dose at Wk 0;
[0690] 3) 200-mg ABT-874 every wk for 4 wks;
[0691] 4) 200-mg ABT-874 eow for 12 wks;
[0692] 5) 200-mg ABT-874 every wk for 12 wks; or
[0693] 6) placebo.
[0694] The primary endpoint was a .gtoreq.PASI75 response at Week
12. Patients who met the primary endpoint entered a 36-week
blinded/retreatment phase. Treatment with study drug was
discontinued, and patients were monitored for time to loss of
response (a decrease in PASI score, any time during the 36-week
follow-up period, to <PASI 50). Maintenance of PASI response was
evaluated through Week 24.
[0695] A total of 180 patients enrolled, 30 in each arm. Baseline
characteristics were similar between arms (mean values presented
except % male): age, 46 years, 74% male; 21 years duration of Ps;
PASI=19; and 25% BSA affected.
[0696] At Week 12, the percentages of patients with .gtoreq.PASI75
were statistically significantly greater in each of the 5 ABT-874
arms vs. placebo (Table 1). At Week 24, substantial percentages of
PASI 75 responders in the active treatments arms had maintained at
least a PASI 50 response.
TABLE-US-00007 TABLE 1 24-Week Efficacy of ABT-874 Maintenance of
PASI Response: .gtoreq.PASI75 at Wk 12 Wk 24 vs. Wk 12 100 mg eow
for 28/30 (93%)* 24/28 (86%) 12 wks 200 mg, one dose 19/30 (63%)*
15/19 (79%) 200-mg every wk for 27/30 (90%)* 23/27 (85%) 4 wks
200-mg eow for 28/30 (93%)* 26/28 (93%) 12 wks 200-mg every wk for
27/30 (90%)* 26/27 (96%) 12 wks Placebo 1/30 (3%) -- *p < 0.001
vs. placebo, NRI.
[0697] In conclusion, ABT-874 was significantly more efficacious
than placebo in the treatment of moderate to severe plaque Ps.
Substantial percentages of PASI 75 responders maintained these
responses at Week 24, following discontinuation of active
therapy.
Example 4
Safety and Efficacy of ABT-874, a Fully Human IL-12/-23 Monoclonal
Antibody, in the Treatment of Moderate to Severe Chronic Plaque
Psoriasis
[0698] The objective of the following example was to demonstrate
the efficacy and safety of a range of doses of a human IL-12/23
monoclonal antibody (ABT-874) compared with placebo in the
treatment of patients with clinically stable moderate to severe
chronic plaque psoriasis.
I. Materials and Methods
[0699] A. Study Design:
[0700] The following study was a 12-week, multicentre, randomised,
double-blind, phase II, placebo-controlled trial that was conducted
at 24 centres in the United States (16 sites) and Canada (8 sites).
ABT-874 (Abbott Laboratories, Abbott Park, Ill.) is a human
monoclonal antibody with genetically engineered
complementarity-determining regions that have high affinity for the
IL-12/23 p40 subunit protein. Patients were randomised in a
1:1:1:1:1:1 ratio to receive 1 of 6 treatments: 200 mg of ABT-874,
1 dose at week 0 (200 mg.times.1); 100 mg of ABT-874 every other
week (eow) for 12 weeks (100 mg eow); 200 mg of ABT-874 weekly for
the first 4 weeks (200 mg.times.4); 200 mg of ABT-874 eow for 12
weeks (200 mg eow); 200 mg of ABT-874 weekly for 12 weeks (200 mg
weekly); or placebo. After week 12, all patients who achieved at
least a 75% reduction in psoriasis area and severity index (PASI
75) response continued into a 36-week blinded
observation/retreatment phase.
[0701] B. Patients:
[0702] Patients were .gtoreq.18 years of age and had a clinical
diagnosis of psoriasis for at least 6 months (determined by patient
interview and confirmation of diagnosis through physical
examination by the investigator), stable plaque psoriasis for at
least 2 months before screening and at baseline visits as
determined by subject interview, moderate to severe plaque
psoriasis defined by .gtoreq.10% body surface area (BSA)
involvement at the baseline visit, a PASI score of .gtoreq.12 at
the baseline visit, and a physician's global assessment (PGA) of at
least moderate disease at the baseline visit.
[0703] Patients were ineligible if they had previous exposure to
systemic or biologic anti-IL-12 therapy; nonplaque psoriasis;
inability to discontinue the following therapies before the
baseline visit: topical psoriasis therapies at least 2 weeks
before, ultraviolet B light phototherapy at least 2 weeks before,
psoralen-ultraviolet-light phototherapy at least 4 weeks before,
systemic therapies at least 4 weeks before, and biologic therapies
at least 12 weeks before; required intake of oral or injectable
corticosteroids during the study (inhaled corticosteroids for
stable medical conditions were allowed); an exacerbation of asthma
requiring hospitalization in the 10 years prior to screening; an
infection or risk factors for severe infection; a history of
malignancies other than successfully treated basal cell carcinoma
(patients with a history of squamous cell carcinoma were excluded)
or cervical carcinoma in situ; or a history of major immunologic
reaction (e.g., serum sickness or anaphylactoid reaction) to an
immunoglobulin G-containing agent (e.g., intravenous gamma
globulin, a fusion protein, or monoclonal antibody).
[0704] Patients were allowed to continue treatment with medicated
shampoos that did not contain corticosteroids, bland (without beta-
or alpha-hydroxy acids) emollients, or Class VI or VII low-potency
topical corticosteroids on their palms, soles, face, inframammary
area, and groin area during the course of the study. Application of
these topical psoriasis therapies was not to occur within 24 hours
of a study visit. Vaccination with a live viral agent was not
allowed within 1 month prior to dosing with ABT-874, during the
study, or for 1 month after the last dose of study drug was
administered.
[0705] Occurrence of any of the following clinically significant
abnormal laboratory results led to immediate withdrawal of a
patient from the study: aspartate transaminase or alanine
transaminase >5 times the upper limit of normal; serum total
bilirubin >3 times the upper limit of normal; serum creatinine
>3 times the upper limit of normal; creatine phosphokinase >5
times the upper limit of normal; hemoglobin <8 g/dL; white blood
cell count <2.times.10.sup.9/L; or platelet count
<75.times.10.sup.9/L.
[0706] C. Efficacy Assessments:
[0707] The primary efficacy assessment was the percentage of
patients achieving a PASI 75 response at week 12, defined as at
least a 75% reduction in PASI score relative to the baseline score.
PASI is a measure of the severity of psoriatic lesions (in terms of
erythema, induration, and desquamation) and the extent of BSA
involvement. The PASI score ranges from 0 (no psoriasis) to 72
(severe disease) (Fredriksson T, Pettersson U. Dermatologica 1978;
157: 238-44). Other efficacy measures included the percentage of
patients who achieved at least PASI 75 at weeks 1, 2, 4, and 8; the
percentage of patients who achieved at least PASI 50 or PASI 90 at
weeks 1, 2, 4, 8, and 12; and the percentage of patients who
attained a PGA of clear or minimal at week 12 and at weeks 1, 2, 4,
and 8. The PGA measures the severity of disease on a 6-point scale,
which ranges from 0 (no disease, or clear) to 5 (very severe) (Ko
H-S. Clinical trial design in psoriasis. Presented at: 49th Meeting
of the Dermatologic and Ophthalmologic Advisory Committee; Mar. 20,
1998; Bethesda, Md.).
[0708] D. Safety Assessments:
[0709] Adverse events, laboratory data, and vital signs were
assessed throughout the study. Patients were closely monitored for
signs of infection, malignancy, and immunologic reaction.
Treatment-emergent AEs were defined as those events that occurred
between week 0 and the earlier of 45 days after the last nonmissing
study drug dose or 1 day prior to the first retreatment dose (for
those patients continuing on to the 36-week trial).
[0710] E. Statistical Analysis:
[0711] The sample size was calculated using nQuery Advisor.degree.
4.0 (Statistical Solutions, Saugus, Mass.). With the assumption
that 15% of the patients in the placebo group would achieve a PASI
75 response at week 12, the study designers determined that a
sample size of 26 in each dosage group would be adequate to detect
at least a 45% difference from a treated group using the Fisher
exact test with 90% power at a 0.05 2-sided significance level. The
study was designed to enroll approximately 180 patients, with 30
patients in each group.
[0712] The intention-to-treat population included all patients who
were randomised at week 0 and received at least 1 injection of
study drug; this population was used for the efficacy analyses. All
tests were performed at .alpha.=0.05. Nonresponder imputation was
used for all efficacy analyses; any patient with a missing PASI or
PGA score at any visit was considered a nonresponder at that visit.
To assess the impact of the missing data, sensitivity analyses of
week-12 data were completed using the
last-observation-carried-forward method. The primary analysis of
PASI 75 response at week 12 was performed using the following
sequential order to adjust for multiplicity: 200 mg weekly versus
placebo, 200 mg eow versus placebo, 100 mg eow versus placebo, 200
mg.times.4 versus placebo, and 200 mg.times.1 versus placebo. The
treatment difference between each ABT-874 treatment group and the
placebo group for mean percentage change in PASI score was assessed
using analysis of variance, with baseline PASI score and treatment
group as factors. The safety analyses were conducted using the
safety population, which included all patients who received at
least 1 injection of study drug.
II. Results
[0713] A. Patients:
[0714] A total of 180 patients were enrolled and randomised to 1 of
the 6 treatment groups (FIG. 1). The majority of patients (76.7% of
placebo-treated patients and 98% of all ABT-874 treatment group
patients) completed the 12-week portion of the study.
[0715] Patients were well balanced across treatment groups with
respect to demographic characteristics and disease activity (table
1). Patients were predominantly male (74.4%) and white (92.2%).
Mean BSA involvement was 25% and mean PASI score was 18.8.
[0716] B. Efficacy:
[0717] The percentage of patients achieving the primary endpoint of
PASI 75 response at week 12 was statistically significantly greater
(p<0.001) in all of the ABT-874 treatment groups (200
mg.times.1: 63.3%, 19 of 30; 100 mg eow: 93.3%, 28 of 30; 200
mg.times.4: 90.0%, 27 of 30; 200 mg eow: 93.3%, 28 of 30; 200 mg
weekly: 90.0%, 27 of 30) compared with placebo (3.3%, 1 of 30). For
the relatively short duration of this trial, PASI 75 responses in
all ABT-874 treatment groups were similar with the exception of the
200 mg.times.1 treatment group (FIG. 2).
[0718] A subgroup analysis by demographics (gender, age, race, and
weight), baseline disease characteristics (history of psoriatic
arthritis, BSA, and PASI score), and baseline therapy for psoriasis
within 12 months of receiving study treatment (systemic biologic
and nonbiologic, topical, and phototherapy) demonstrated that
ABT-874-treated patients within the various subgroups consistently
achieved high levels of PASI 75 response at week 12.
[0719] Nearly 100% of the higher ABT-874 dosage groups attained at
least a PASI 50 response by week 12 (200 mg.times.1: 76.7%, 23 of
30; 100 mg eow: 100.0%, 30 of 30; 200 mg.times.4: 96.7%, 29 of 30;
200 mg eow: 96.7%, 29 of 30; 200 mg weekly: 100.0%, 30 of 30;
placebo: 16.7%, 5 of 30; p<0.001 for each comparison with
placebo). The percentage of patients achieving at least a PASI 90
response at week 12 was statistically significantly greater
(p<0.001) in all but 1 (200 mg.times.1) of the ABT-874 treatment
groups when compared with placebo, as follows: 200 mg.times.1:
16.7%, 5 of 30; 100 mg eow: 53.3%, 16 of 30; 200 mg.times.4: 63.3%,
19 of 30; 200 mg eow: 76.6%, 23 of 30; 200 mg weekly: 53.3%, 16 of
30; and placebo: 0%, 0 of 30. In addition, by week 12,
significantly more (p<0.001) patients in all ABT-874 treatment
groups had attained a clear or minimal PGA rating compared with
patients in the placebo group, as follows: 200 mg.times.1: 50.0%,
15 of 30; 100 mg eow: 83.3%, 25 of 30; 200 mg.times.4: 73.3%, 22 of
30; 200 mg eow: 86.7%, 26 of 30; 200 mg weekly: 86.7%, 26 of 30;
versus placebo: 3.3%, 1 of 30.
[0720] The percentage of patients achieving the primary endpoint of
PASI 100 response at week 12 was statistically significantly
greater (p<0.001) in the following ABT-874 treatment groups (200
mg eow: 46.7%, 14 of 30; 200 mg weekly: 36.7%, 11 of 30) compared
with placebo (0%, 0 of 30).
[0721] Response to ABT-874 was rapid. The mean percentage
improvement in PASI scores from baseline increased over time for
all ABT-874 treatment groups (FIG. 3) and were statistically
significantly greater for each ABT-874 treatment group compared
with placebo at each time point (p<0.001, except for the 100 mg
eow group at week 1, p=0.023).
[0722] C. Safety:
[0723] ABT-874 therapy was generally well tolerated (table 2). One
(0.7%) patient treated with ABT-874 discontinued the study owing to
a localised skin discoloration; 2 (6.7%) patients treated with
placebo discontinued the study, 1 for psoriatic arthropathy and 1
for ovarian cancer. Two (1.1%) patients experienced serious adverse
effects (AEs); 1 placebo-treated patient was diagnosed with ovarian
cancer on day 37, and 1 ABT-874-treated patient (200 mg.times.1)
was diagnosed with costochondritis on day 10. No patients
experienced myocardial or cerebral infarctions, and there were no
deaths.
[0724] Patients receiving any dose of ABT-874 were significantly
(p=0.033) more likely than patients receiving placebo to experience
an AE at least possibly related to study drug (ABT-874: 36.0%, 54
of 150; placebo: 10.0%, 3 of 30; table 2); most of these AEs were
related to the injection site (injection-site reaction, erythema,
pruritus, or irritation).
[0725] Most AEs were mild (mild AEs occurred in 46.0% [69 of 150]
of ABT-874-treated patients and 30.0% [9 of 30] placebo-treated
patients). The most common AE was injection-site reaction,
occurring in 16.7% (25 of 150) of patients treated with any dose of
ABT-874 (no reported injection-site reactions for placebo-treated
patients; p=0.028; table 3). There were no statistically
significant differences between the incidences of other AEs in the
ABT-874-treated patients compared with placebo-treated patients.
The next most frequently reported AEs were nasopharyngitis and
upper respiratory tract infection.
[0726] Infectious AEs were reported by 32.8% (59 of 180) of all
patients (placebo: 23.3%, 7 of 30; all ABT-874-treated patients:
34.7%, 52 of 150). The most common infectious AEs reported for any
ABT-874 treatment group were nasopharyngitis (12.0%, 18 of 150),
upper respiratory tract infection (10.7%, 16 of 150), and
bronchitis and viral infection (both 2.7%, 4 of 150). No serious
infectious AEs were reported.
[0727] Two patients reported malignancies during the study. One
placebo-treated patient was diagnosed with ovarian cancer, which
was ongoing as of day 129. One ABT-874-treated patient (200
mg.times.4) was diagnosed with a non-melanoma skin cancer (squamous
cell carcinoma) that was removed on day 133. The medical history
for this patient included removal of a benign skin growth in March
2005.
[0728] There were no clinically significant hematology, chemistry
(including blood glucose concentrations), or vital sign changes
compared with placebo.
TABLE-US-00008 TABLE 1 Baseline demographics and clinical
characteristics Treatment Group 100 mg 200 mg 200 mg All Placebo
200 mg .times. 1 eow 200 mg .times. 4 eow weekly ABT-874
Characteristic N = 30 N = 30 N = 30 N = 30 N = 30 N = 30 N = 150
Age, y 49 .+-. 14.4 52 .+-. 12.0 45 .+-. 13.8 43 .+-. 13.8 44 .+-.
16.0 46 .+-. 14.0 46 .+-. 14.1 Male, No. (%) 22 (73.3) 23 (76.7) 22
(73.3) 21 (70.0) 23 (76.7) 23 (76.7) 112 (74.7) White, No. (%) 28
(93.3) 25 (83.3) 28 (93.3) 27 (90.0) 30 (100.0) 28 (93.3) 138
(92.0) Weight, kg 89 .+-. 17.6 94 .+-. 21.2 94 .+-. 17.9 92 .+-.
27.8 93 .+-. 24.1 95 .+-. 18.0 94 .+-. 21.9 Duration of psoriasis,
y 21 .+-. 12.4 20 .+-. 13.2 24 .+-. 14.6 22 .+-. 14.2 18 .+-. 11.5
18 .+-. 10.9 21 .+-. 13.0 PASI score 16 .+-. 2.9 18 .+-. 6.7 20
.+-. 6.3 20 .+-. 7.6 20 .+-. 6.2 19 .+-. 6.3 19 .+-. 6.6 BSA
affected, % 21 .+-. 9.2 24 .+-. 13.6 28 .+-. 15.7 24 .+-. 13.0 29
.+-. 16.8 23 .+-. 12.6 26 .+-. 14.5 PGA, No. (%) Mild 1 (3.3) 0 0 0
0 0 0 Moderate 20 (66.7) 19 (63.3) 17 (56.7) 13 (43.3) 15 (50.0) 17
(56.7) 81 (54.0) Severe 9 (30.0) 11 (36.7) 12 (40.0) 14 (46.7) 13
(43.3) 11 (36.7) 61 (40.7) History of PsA, No. (%) 9 (30.0) 7
(23.3) 12 (40.0) 9 (30.0) 6 (20.0) 9 (30.0) 43 (28.7) Previous
psoriasis treatment,* No. (%) Topical therapy 19 (63.3) 21 (70.0)
26 (86.7) 15 (50.0) 21 (70.0) 23 (76.7) 106 (70.7) Phototherapy 1
(3.3) 6 (20.0) 4 (13.3) 4 (13.3) 3 (10.0) 5 (16.7) 22 (14.7)
Systemic nonbiologic 6 (20.0) 4 (13.3) 7 (23.3) 5 (16.7) 6 (20.0) 8
(26.7) 30 (20.0) Systemic biologic 3 (10.0) 3 (10.0) 7 (23.3) 6
(20.0) 4 (13.3) 7 (23.3) 27 (18.0) Values are mean .+-. SD unless
otherwise noted. *Within past 12 months prior to study treatment.
BSA = body surface area; eow = every other week; PASI = psoriasis
area and severity index; PGA = physician's global assessment; PsA =
psoriatic arthritis
TABLE-US-00009 TABLE 2 Clinical treatment-emergent adverse events
summary Treatment Group 100 mg 200 mg 200 mg All Placebo 200 mg
.times. 1 eow 200 mg .times. 4 eow weekly ABT-874 N = 30 N = 30 N =
30 N = 30 N = 30 N = 30 N = 150 Event No. (%) Any AE 18 (60.0) 18
(60.0) 22 (73.3) 21 (70.0) 21 (70.0) 19 (63.3) 101 (67.3) Any AE at
least possibly drug- 3 (10.0) 9 (30.0) 12 (40.0) 14 (46.7) 11
(36.7) 8 (26.7) 54 (36.0) related* Any severe AE 3 (10.0) 1 (3.3) 0
0 0 1 (3.3) 2 (1.3) Any serious AE.sup..dagger. 1 (3.3) 1 (3.3) 0 0
0 0 1 (0.7) Any AE leading to 2 (6.7) 1 (3.3) 0 0 0 0 1 (0.7)
discontinuation of study drug Any AE at least possibly drug- 0 0 0
0 0 0 0 related* and serious Any infectious AE 7 (23.3) 7 (23.3) 9
(30.0) 13 (43.3) 13 (43.3) 10 (33.3) 52 (34.7) Any serious
infectious AE 0 0 0 0 0 0 0 Any malignant neoplasms 1 (3.3) 0 0 1
(3.3) 0 0 1 (0.7) Deaths 0 0 0 0 0 0 0 *As assessed by the
investigator. .sup..dagger.Serious adverse events included the
following: any event that resulted in death; any event that was
life-threatening; any event that resulted in admission to the
hospital for any length of time; any event that occurred while the
patient was hospitalized and resulted in prolongation of hospital
stay; any event that resulted in persistent or significant
disability/incapacity; or any important medical event that required
medical or surgical intervention to prevent serious outcome. AE =
adverse event; eow = every other week.
TABLE-US-00010 TABLE 3 Treatment-emergent adverse events with an
incidence .gtoreq.5% in any treatment group by descending frequency
of patients treated with any dosage of ABT-874 Treatment Group 100
mg 200 mg 200 mg All Placebo 200 mg .times. 1 eow 200 mg .times. 4
eow weekly ABT-874 N = 30 N = 30 N = 30 N = 30 N = 30 N = 30 N =
150 Event No. (%) Injection-site reaction 0 2 (6.7) 7 (23.3) 5
(16.7) 7 (23.3) 4 (13.3) 25 (16.7) Nasopharyngitis 1 (3.3) 4 (13.3)
4 (13.3) 3 (10.0) 2 (6.7) 5 (16.7) 18 (12.0) Upper respiratory
tract infection 2 (6.7) 2 (6.7) 4 (13.3) 3 (10.0) 5 (16.7) 2 (6.7)
16 (10.7) Headache 2 (6.7) 5 (16.7) 0 1 (3.3) 3 (10.0) 2 (6.7) 11
(7.3) Injection site pruritus 0 0 1 (3.3) 2 (6.7) 2 (6.7) 2 (6.7) 7
(4.7) Injection site erythema 0 0 0 4 (13.3) 2 (6.7) 1 (3.3) 7
(4.7) Injection site irritation 0 1 (3.3) 3 (10.0) 2 (6.7) 0 0 6
(4.0) Fatigue 0 2 (6.7) 2 (6.7) 0 0 1 (3.3) 5 (3.3) Pain in
extremity 0 1 (3.3) 0 0 1 (3.3) 2 (6.7) 4 (2.7) Arthralgia 0 2
(6.7) 0 0 0 2 (6.7) 4 (2.7) Viral infection 0 0 0 2 (6.7) 1 (3.3) 1
(3.3) 4 (2.7) Bronchitis 0 1 (3.3) 0 1 (3.3) 2 (6.7) 0 4 (2.7)
Nausea 1 (3.3) 0 3 (10.0) 0 0 0 3 (2.0) Otitis externa 0 0 0 0 2
(6.7) 0 2 (1.3) Vomiting 1 (3.3) 0 0 2 (6.7) 0 0 2 (1.3) Urinary
tract infection 2 (6.7) 1 (3.3) 0 1 (3.3) 0 0 2 (1.3) Herpes
simplex 0 0 2 (6.7) 0 0 0 2 (1.3) Limb injury 0 2 (6.7) 0 0 0 0 2
(1.3) Pruritus 2 (6.7) 0 0 0 0 0 0 *As assessed by the
investigator.
III. Conclusion
[0729] The phase II, multicentre, randomised, double-blind,
placebo-controlled trial described in this Example demonstrated
statistically and clinically significant efficacy of ABT-874 in the
treatment of moderate to severe chronic plaque psoriasis. With the
exception of the ABT-874 200 mg.times.1 treatment group, 90% or
more of patients in all ABT-874 treatment groups achieved PASI 75
or greater by week 12, compared with 3.3% of placebo-treated
patients. Even in the group that received only 1 dose of study drug
(200 mg.times.1), a majority (63.3%) of patients had achieved at
least PASI 75 by week 12. In addition, almost 100% of patients
treated with ABT-874 reached PASI 50 or greater, which is
considered to be a clinically significant improvement (Carlin C S,
Feldman S R, Krueger J G, Menter A, Krueger G G. J Am Acad Dermatol
2004; 50: 859-66) by week 12. The results for other secondary
endpoints, such as PASI 90 and PGA of clear or minimal, were
consistent with and supported the primary efficacy analysis.
[0730] Response to ABT-874 was rapid. Statistically significant
separation between placebo- and ABT-874-treated patients occurred
as early as week 1 for the mean percentage improvement in PASI
scores. Improvement was sustained for the 12-week duration of the
trial, even for patients in the ABT-874 200 mg.times.1 and 200
mg.times.4 dosage groups.
[0731] ABT-874 was well tolerated, and most AEs were mild. Although
ABT-874-treated patients were significantly more likely to
experience an AE at least possibly related to study drug, most of
these were injection site-related AEs (injection-site reaction,
erythema, pruritus, or irritation). There was no apparent
association between an increased dose of ABT-874 and an increased
incidence of AEs. Of note, there were no myocardial or cerebral
infarctions.
[0732] Immunologic-related events are of particular interest for
patients receiving anti-IL-12/23 antibodies. The most frequently
reported infectious AEs were nasopharyngitis, upper respiratory
tract infection, bronchitis, and viral infection. There were no
serious infectious AEs reported for the duration of this trial. Of
the 2 malignancies diagnosed during the study, ovarian cancer was
diagnosed in a placebo-treated patient, and non-melanoma skin
cancer was diagnosed in an ABT-874-treated patient who had a
history of a benign skin growth.
[0733] In summary, ABT-874 demonstrated statistically and
clinically significant benefit for the treatment of patients with
moderate to severe chronic plaque psoriasis, and was well
tolerated.
Example 5
Maintenance of Response with the Fully Human IL-12/-23 Monoclonal
Antibody, ABT-874, in the Treatment of Moderate to Severe Plaque
Psoriasis
[0734] The efficacy and safety of ABT-874 was evaluated in a
12-week, Phase II, randomized controlled trial and 36-week
follow-up phase. The objective of the following example was to
analyze maintenance of response following discontinuation of
therapy during the second 12 weeks of this Phase II study of
subcutaneous injections of ABT-874 in the treatment of moderate to
severe plaque Ps.
[0735] Adults with Ps affecting .gtoreq.10% body surface area (BSA)
and a PASI score .gtoreq.12 were eligible for this 12-week,
double-blind, placebo-controlled study. Patients were randomized to
1 of 6 arms:
[0736] 1) 100-mg ABT-874 every other week (eow) for 12 wks;
[0737] 2) one 200-mg ABT-874 dose at Wk 0;
[0738] 3) 200-mg ABT-874 every wk for 4 wks;
[0739] 4) 200-mg ABT-874 eow for 12 wks;
[0740] 5) 200-mg ABT-874 every wk for 12 wks; or
[0741] 6) placebo.
[0742] The primary endpoint was a .gtoreq.PASI 75 response at Week
12. Patients who met the primary endpoint entered a 36-week
blinded/retreatment phase. Treatment with study drug was
discontinued, and patients were monitored for PASI score at various
times during the 36-week follow-up period, including PASI 50, PASI
75 and PASI 90 responses. Maintenance of PASI response was
evaluated through Week 24.
[0743] A total of 180 patients enrolled, 30 in each arm. Baseline
characteristics were similar between arms (mean values presented
except % male): age, 46 years, 74% male; 21 years duration of Ps;
PASI=19; and 25% BSA affected.
[0744] At Week 12, the percentages of patients with .gtoreq.PASI 75
were statistically significantly greater in each of the 5 ABT-874
arms vs. placebo (Table 4). At Week 24, substantial percentages of
PASI 75 responders in the active treatments arms had maintained at
least a PASI score of .gtoreq.PASI 50. Further, substantial
percentages of PASI 75 responders in the active treatments arms had
also maintained at least a PASI score of .gtoreq.PASI 75, as well
as a PASI score of .gtoreq.PASI 90 (Table 4 and FIGS. 4A-C). The
percentage of patients maintaining a PASI 75 response over time
during the 24 week period is depicted in FIG. 4D.
TABLE-US-00011 TABLE 4 24-Week Efficacy of ABT-874 Maintenance
Maintenance Maintenance of .gtoreq.PASI 50 of .gtoreq.PASI 75 of
.gtoreq.PASI 90 Response: Response: Response: .gtoreq.PASI 75 at Wk
24 vs. Wk 24 vs. Wk 24 vs. Wk 12 Wk 12 Wk 12 Wk 12 100 mg eow 93%*
71% 60% 33% for 12 wks 200 mg, one 63%* 68% 23% 7% dose 200-mg
every 90%* 82% 60% 23% wk for 4 wks 200-mg eow 93%* 89% 73% 53% for
12 wks 200-mg every 90%* 85% 83% 57% wk for 12 wks Placebo 3% -- 7%
7% *p < 0.001 vs. placebo, NRI.
[0745] In conclusion, ABT-874 was significantly more efficacious
than placebo in the treatment of moderate to severe plaque Ps.
Substantial percentages of PASI 75 responders maintained a response
of .gtoreq.PASI 50, .gtoreq.PASI 75, and .gtoreq.PASI 90 at Week
24, following discontinuation of active therapy.
Example 6
Maintenance of Re-treatment Response with the Fully Human IL-12/-23
Monoclonal Antibody, ABT-874, in the Treatment of Moderate to
Severe Plaque Psoriasis
[0746] The efficacy and safety of ABT-874 was evaluated in a
48-week, Phase II, randomized controlled trial that included a
12-week initial treatment phase and a 36-week re-treatment phase of
patients responding to initial treatment. The initial 12-week
efficacy results and maintenance of response results are described
in the above examples. The objective of the following example was
to examine the re-treatment response during the 36-week
re-treatment/follow-up phase in patients who lost their initial
responses of this Phase II study of subcutaneous injections of
ABT-874 in the treatment of moderate to severe plaque Ps. The
further objective of the following example was to examine safety of
subcutaneous injections of ABT-874 in the treatment of moderate to
severe plaque Ps through 48 weeks.
[0747] At baseline, demographics and clinical characteristics were
similar across treatment groups (summarized in Table 5 below).
TABLE-US-00012 TABLE 5 Baseline Demographics and Clinical
Characteristics Treatment Group* Placebo 200 mg .times. 1 100 mg
eow 200 mg .times. 4 200 mg eow 200 mg Weekly All Characteristic (n
= 30) (n = 30) (n = 30) (n = 30) (n = 30) (n = 30) (N = 150) Age,
yrs .sup. 49 (14.4) .sup. 52 (12.0) .sup. 45 (13.8) .sup. 43 (13.8)
44 (16.0) .sup. 46 (14.0) .sup. 46 (14.1) Sex, n (%) male 22 (73)
23 (77) 22 (73) 21 (70) 23 (77) 23 (77) 112 (75) Race, n (%) white
28 (93) 25 (83) 28 (93) 27 (90) 30 (100) 28 (93) 138 (92) Weight,
kg .sup. 89 (17.6) .sup. 94 (21.2) .sup. 94 (17.9) .sup. 92 (27.8)
93 (24.1) .sup. 95 (18.0) .sup. 94 (21.9) Duration of psoriasis,
yrs .sup. 21 (12.4) .sup. 20 (13.2) .sup. 24 (14.6) .sup. 22 (14.2)
18 (11.5) .sup. 18 (10.9) .sup. 21 (13.0) PASI score Mean (SD) 16
(2.9) 18 (6.7) 20 (6.3) 20 (7.6) 20 (6.2) 19 (6.3) 19 (6.6) Median,
IQ 16.1, 3.8 15.0, 7.5 18.7, 7.4 17.0, 10.2 18.0, 10.0 16.8, 5.8
17.3, 8.0 BSA affected, % Mean (SD) 21 (9.2) .sup. 24 (13.6) .sup.
28 (15.7) .sup. 24 (13.0) 29 (16.8) .sup. 23 (12.6) .sup. 26 (14.5)
Median, IQ 17.5, 13.0 17.5, 16.0 22.5, 19.5 20.3, 17.0 22.0, 24.5
19.5, 17.0 20.0, 21.0 PGA, n (%).sup..dagger. Mild 1 (3) 0 0 0 0 0
0 Moderate 20 (67) 19 (63) 17 (57) 13 (43) 15 (50) 17 (57) 81 (54)
Severe 9 (30) 11 (37) 12 (40) 14 (47) 13 (43) 11 (37) 61 (41)
History of PsA, n (%) 9 (30) 7 (23) 12 (40) 9 (30) 6 (20) 9 (30) 43
(29) Previous psoriasis treatment,.sup..dagger-dbl. n (%) Topical
therapy 19 (63) 21 (70) 26 (87) 15 (50) 21 (70) 23 (77) 106 (71)
Phototherapy 1 (3) 6 (20) 4 (13) 4 (13) 3 (10) 5 (17) 22 (15)
Systemic nonbiologic 6 (20) 4 (13) 7 (23) 5 (17) 6 (20) 8 (27) 30
(20) Systemic biologic 3 (10) 3 (10) 7 (23) 6 (20) 4 (13) 7 (23) 27
(18) BSA, body surface area; PsA, psoriatic arthritis. *Values are
mean (SD) unless otherwise noted. .sup..dagger.Data are presented
for only 3 of 5 possible categories and therefore do not sum up to
30 for each group. .sup..dagger-dbl.Within the 12 months before
study treatment. indicates data missing or illegible when filed
[0748] Adults with psoriasis affecting .gtoreq.10% body surface
area and a Psoriasis Area and Severity Index (PASI) score
.gtoreq.12 were randomized to 1 of 6 arms: 1) one 200-mg dose
ABT-874 at Week 0; 2) 100 mg of ABT-874 every other wk (eow) for 12
weeks; 3) 200 mg of ABT-874 weekly for 4 weeks; 4) 200 mg of
ABT-874 eow for 12 weeks; 5) 200 mg of ABT-874 weekly for 12 weeks;
or 6) placebo. The primary endpoint was a .gtoreq.PASI 75 response
at Week 12. Patients who met the primary endpoint entered a 36-week
re-treatment phase. Treatment with study drug was discontinued, and
patients who lost response (.ltoreq.PASI 50) during weeks 12-36
received re-treatment with the same dosing regimen assigned during
the initial 12-week period. Re-treatment lasted for 12 weeks.
Regardless of disposition, all patients were monitored for the
entire duration of the study, or until discontinuation.
[0749] Of the 180 patients initially enrolled, 130 (1 placebo)
entered the retreatment phase and 58 (all ABT-874) were re-treated.
The percentages of patients who achieved .gtoreq.PASI 75 at week 12
and then again at 12 weeks after re-treatment were as follows for
each group: one 200-mg dose, 63% vs. 55%; 100 mg eow, 93% vs 94%;
200 mg weekly 4 wks, 90% vs. 69%; 200 mg eow, 93% vs. 75%; and 200
mg weekly, 90% vs. 83%, respectively. Of the total 58 patients who
were retreated, 76% achieved .gtoreq.PASI 75 at 12 weeks after
re-treatment.
[0750] The improvement in PASI scores over time for the re-treated
patients is depicted in FIGS. 5A-B. Specifically, FIG. 5A displays
the mean percentage improvement from baseline in PASI scores from
weeks 4 to week 12 in PASI responders, and FIG. 5B displays the
mean percentage improvement from baseline in PASI scores from weeks
4 to week 12 post retreatment in PASI 75 responders.
[0751] The percentages of patients who achieved .gtoreq.PASI 50 at
12 weeks after re-treatment were as follows for each group: one
200-mg dose, 82%; 100 mg eow, 100%; 200 mg weekly 4 wks, 77%; 200
mg eow, 83%; and 200 mg weekly, 100%. Of the total 58 patients who
were retreated, 88% achieved .gtoreq.PASI 50 at 12 weeks after
re-treatment.
[0752] The percentages of patients who achieved a PGA of "clear" or
"minimal" at 12 weeks after re-treatment were as follows for each
group: one 200-mg dose, 36%; 100 mg eow, 75%; 200 mg weekly 4 wks,
62%; 200 mg eow, 67%; and 200 mg weekly, 83%. Of the total 58
patients who were retreated, 64% achieved a PGA of "clear" or
"minimal" at 12 weeks after re-treatment.
[0753] Adverse events (AEs) occurring .gtoreq.5% in at least 1
treatment group in descending order through week 48 were:
nasopharyngitis, injection-site reaction, upper respiratory tract
infection, headache, hypertension, and arthralgia. An overview of
treatment-emergent adverse events through Week 48 is displayed in
Table 6 below. An overview of treatment-emergent adverse events
with an incidence .gtoreq.5% in any treatment group is displayed in
Table 7 below.
TABLE-US-00013 TABLE 6 Overview of Treatment-Emergent Adverse
Events Through Week 48* Placebo* 200 mg .times. 1 100 mg eow 200 mg
.times. 4 200 mg eow 200 mg Weekly All ABT n = 30 n = 30 n = 30 n =
30 n = 30 n = 30 N = 150 Event n (%) n (%) n (%) n (%) n (%) n (%)
n (%) Any AE 18 (60.0) 20 (66.7) 25 (83.3) 25 (83.3) 25 (83.3) 21
(70.0) 116 (77.3) Any AE at least possibly drug- 4 (13.3) 9 (30.0)
16 (53.3) 16 (53.3) 13 (43.3) 10 (33.3) 64 (42.7)
related.sup..dagger. Any severe AE 4 (13.3) 1 (3.3) 0 2 (6.7) 1
(3.3) 1 (3.3) 5 (3.3) Any serious AE 1 (3.3) 1 (3.3) 0 1 (3.3) 2
(6.7) 0 4 (2.7) Any AE leading to 2 (6.7) 1 (3.3) 0 0 0 0 1 (0.7)
discontinuation of study drug Any AE at least possibly drug- 0 0 0
1 (3.3) 0 1 (0.7) related and serious.sup..dagger. Any infectious
AE 7 (23.3) 10 (33.3) 12 (40.0) 14 (46.7) 16 (53.3) 10 (33.3) 62
(41.3) Any serious infectious AE 0 0 0 0 1 (3.3) 0 1 (0.7) Any
malignant AE 1 (3.3) 0 0 1 (3.3) 0 0 1 (0.7) Any lymphomas 0 0 0 0
0 0 0 Any nonmelanoma skin cancer 0 0 0 1 (3.3) 0 0 1 (0.7) Any
injection-site reaction- 0 4 (13.3) 11 (36.7) 12 (40.0) 11 (36.7) 6
(20.0) 44 (29.3) related AE Deaths 0 0 0 0 0 0 0 *Placebo data are
only for the first 12 weeks of the study; all 12-week data
previously reported. .sup..dagger.As assessed by investigator. AE,
adverse event. indicates data missing or illegible when filed
TABLE-US-00014 TABLE 7 Treatment-Emergent Adverse Events With an
Incidence of 5% or More in any Treatment Group Through Week 48*
Placebo* 200 mg .times. 1 100 mg eow 200 mg .times. 4 200 mg eow
200 mg Weekly All ABT n = 30 n = 30 n = 30 n = 30 n = 30 n = 30 N =
150 Event n (%) n (%) n (%) n (%) n (%) n (%) n (%) Injection-site
reaction 0 2 (6.7) 7 (23.3) 8 (26.7) 8 (26.7) 4 (13.3) 29 (19.3)
Nasopharyngitis 1 (3.3) 5 (16.7) 6 (20.0) 3 (10.0) 4 (13.3) 5
(16.7) 23 (15.3) Upper respiratory tract infection 2 (6.7) 2 (6.7)
5 (16.7) 3 (10.0) 5 (16.7) 2 (6.7) 17 (11.3) Headache 2 (6.7) 5
(16.7) 1 (3.3) 1 (3.3) 3 (10.0) 2 (6.7) 12 (8.0) Injection-site
erythema 0 0 1 (3.3) 14 (13.3) 2 (6.7) 1 (3.3) 8 (5.3)
Injection-site pruritus 0 0 1 (3.3) 2 (6.7) 2 (6.7) 2 (6.7) 7 (4.7)
Injection-site irritation 0 1 (3.3) 3 (10.0) 2 (6.7) 0 0 6 (4.0)
Arthralgia 1 (3.3) 2 (6.7) 1 (3.3) 0 0 2 (6.7) 5 (3.3) Viral
infection 0 0 0 2 (6.7) 2 (6.7) 1 (3.3) 5 (3.3) Gastroenteritis
viral 0 1 (3.3) 0 2 (6.7) 1 (3.3) 1 (3.3) 5 (3.3) Fatigue 0 2 (6.7)
2 (6.7) 0 0 1 (3.3) 5 (3.3) Hypertriglyceridemia 0 1 (3.3) 2 (6.7)
2 (6.7) 0 0 5 (3.3) Pain in extremity 0 1 (3.3) 0 0 1 (3.3) 2 (6.7)
4 (2.7) Bronchitis 0 1 (3.3) 0 1 (3.3) 2 (6.7) 0 4 (2.7)
Pharyngolaryngeal pain 0 2 (6.7) 0 0 0 1 (3.3) 3 (2.0) Influenza 1
(3.3) 0 1 (3.3) 0 2 (6.7) 0 3 (2.0) Back pain 0 0 1 (3.3) 0 2 (6.7)
0 3 (2.0) Blood triglycerides increased 1 (3.3) 0 0 2 (6.7) 1 (3.3)
0 3 (2.0) Urinary tract infection 2 (6.7) 1 (3.3) 0 1 (3.3) 1 (3.3)
0 3 (2.0) Insomnia 1 (3.3) 2 (6.7) 0 1 (3.3) 1 (3.3) 0 3 (2.0)
Nausea 2 (6.7) 0 3 (10.0) 0 0 0 3 (2.0) Cyst 0 1 (3.3) 2 (6.7) 0 0
0 3 (2.0) Gastroenteritis 0 0 0 0 0 2 (6.7) 2 (1.3) Rhinorrhea 0 0
0 0 0 2 (6.7) 2 (1.3) Otitis extema 0 0 0 0 2 (6.7) 0 2 (1.3)
Vomiting 1 (3.3) 0 0 2 (6.7) 0 0 2 (1.3) Hypercholesterolemia 0 0 0
2 (6.7) 0 0 2 (1.3) Blood pressure increased 0 0 2 (6.7) 0 0 0 2
(1.3) Procedural pain 0 0 2 (6.7) 0 0 0 2 (1.3) Limb injury 0 2
(6.7) 0 0 0 0 2 (1.3) Pruritis 2 (6.7) 0 0 0 0 1 (3.3) 1 (0.7)
Psoriatic arthropathy 2 (6.7) 1 (3.3) 0 0 0 0 1 (0.7) *Placebo data
are only for the first 12 weeks of the study; all 12-week data
previously reported.
[0754] The foregoing data demonstrate that ABT-874 was highly
efficacious in the treatment of moderate to severe psoriasis. Upon
loss of response and re-treatment, a majority of patients were able
to re-achieve a PASI 75 response. Moreover, ABT-874 appears to have
a favorable safety profile in the long term.
Example 7
Pharmacokinetics of a Fully Human IL-12/-23 Monoclonal Antibody,
ABT-874, in Normal Healthy Volunteers
[0755] The tolerability, safety, and pharmacokinetics (PK) of a
range of doses of ABT-874 were evaluated in a randomized,
double-blind, placebo-controlled dose-ranging study. The objective
of the following example was to investigate the pharmacokinetics of
intravenous (IV) and subcutaneous (SC) injections of ABT-874 in
healthy volunteers.
[0756] The main inclusion criteria were: (i) healthy male
volunteers between 18 and 45 years of age; (ii) no clinically
relevant abnormalities in any of the investigations of the
screening examination (physical exam, vital signs,
electrocardiogram, biochemistry, hematology, urinalysis, serology);
and (iii) chest x-rays normal within 12 months prior to entering
the study. The main exclusion criteria were: (i) smoking more than
10 cigarettes per day; (ii) drinking more than 30 g of alcohol per
day; (iii) positive urine drug screen; (iv) chronic infections,
especially by intracellular bacterial pathogens such as
Mycobacterium tuberculosis; and (v) major infections requiring
hospitalization or IV antibiotics within the previous 2 years.
[0757] Young (18-45 years of age), healthy male volunteers received
2 equal doses (1 IV and 1 SC administered 8 weeks apart) of 0.1,
0.3, 1.0, or 5.0 mg/kg ABT-874 in a 2-period crossover (2.times.2
Latin square) design. Blood samples for the determination of
ABT-874 concentrations were collected before the first dose (0) and
at 0.5, 1, 1.5, 2, 4, 8, 12, 24, 48, 72, 120, 168, 336, 504 and 672
hours after dosing. Serum concentrations of ABT-874 were measured
by an enzyme-linked immunosorbent assay.
[0758] ABT-874 serum concentrations were tabulated individually,
described by statistical characteristics (including geometric mean
and geometric standard deviation) and displayed as individual as
well as mean, median, and geometric mean concentration vs. time
curves for IV and SC treatment and each treatment group. The
following PK parameters were estimated using noncompartmental
methods: [0759] Cmax maximum serum concentration (.mu.g/mL) [0760]
Tmax time to reach Cmax (hr) [0761] AUC area under the serum
concentration-time curve (.mu.g.times.hr/mL) [0762] t1/2 half-life
(hr) [0763] CL clearance (mL/hr) (for IV administration) [0764] Vz
volume of distribution (mL) (for IV administration) [0765] CL/F
apparent CL (mL/hr) (for SC administration) [0766] V/F apparent Vz
(mL) (for SC administration)
[0767] A total of 64 patients were randomized; 12 received ABT-874
and 4 received placebo for each dose group. ABT-874 appeared to
follow bi-exponential kinetics following IV administration,
entering the terminal phase approximately 7 days after
administration. The mean+SD terminal half-lives for the 0.1-, 0.3-,
1.0-, and 3.0-mg IV doses were 81.2.+-.55.6, 147.+-.73.2,
208.+-.79.2, and 196.+-.55.4 hours, respectively. The mean.+-.SD
terminal half-lives for the 0.1-, 0.3-, 1.0-, and 3.0-mg SC doses
were 221.+-.103, 161.+-.92.6, 210.+-.90.9, and 208.+-.79.2 hours,
respectively. The mean terminal half-life for IV administration
ranged from 81.2.+-.55.6 hours to 208.+-.79.2 hours. The mean
terminal half-life for SC administration ranged from 161.+-.92.6
hours to 221.+-.103 hours. The overall mean terminal half-life was
8-9 days.
[0768] The pharmacokinetics of ABT-874 (maximum concentration of
drug [C.sub.max] or area under the curve [AUC]) increased
proportionally to dose after both IV and SC administrations. The
serum concentration-time curve for IV and SC dosing is displayed in
FIGS. 6A and 6B, respectively. The volume of distribution ranged
from approximately 8-10 L after IV administration to 24-67 L after
SC administration. After SC administration, the time to reach
C.sub.max was approximately 3-4 days. Bioavailability after SC
administration ranged between 42% and 62% for the doses evaluated.
The pharmacokinetic parameters following IV or SC administration at
each dose, including C.sub.max (the maximum serum concentration in
.mu.g/mL), AUC (area under the serum concentration-time curve in
.mu.g.times.hr/mL), t.sub.max (time to reach Cmax in hrs),
t.sub.1/2 (half-life in hrs), CL (clearance in mL/hr) and Vz
(volume of distribution (mL)), are displayed in Table 8 below.
TABLE-US-00015 TABLE 8 PK Parameters (Mean .+-. SD) in Healthy
Human Volunteers Following IV or SC Administration of ABT-874
C.sub.max t.sub.max AUC.sub.0-z t.sub.1/2 CL* Vz.sup..dagger.
Cohort Route (.mu.g/mL) (hr) (.mu.g .times. hr/mL) (hr) (mL/hr)
(mL) 0.1 mg/kg IV 1.99 .+-. 0.931 -- 146 .+-. 78.8 81.2 .+-. 55.6
596 .+-. 1,850 8,010 .+-. 7,600 SC 0.245 .+-. 0.100 66.7 .+-. 10.6
84.4 .+-. 40.6 221 .+-. 103 183 .+-. 248 66,500 .+-. 135,000 0.3
mg/kg IV 7.99 .+-. 3.08 -- 562 .+-. 202 147 .+-. 73.2 50.4 .+-.
32.7 8,512 .+-. 3,746 SC 1.09 .+-. 1.12 90.0 .+-. 43.6 244 .+-. 150
161 .+-. 92.6 183 .+-. 196 24,800 .+-. 7,430 1.0 mg/kg IV 27.7 .+-.
8.33 -- 2,410 .+-. 717 208 .+-. 79.2 36.2 .+-. 9.80 10,400 .+-.
3,840 SC 2.83 .+-. 0.633 82.0 .+-. 23.9 1,000 .+-. 318 210 .+-.
90.9 91.1 .+-. 41.2 23,900 .+-. 8,590 5.0 mg/kg IV 150 .+-. 50.6 --
12,700 .+-. 3,390 196 .+-. 55.4 33.6 .+-. 9.26 9,360 .+-. 3,360 SC
13.4 .+-. 5.34 82.0 .+-. 36.1 4,840 .+-. 2,420 208 .+-. 79.2 229
.+-. 480 31,800 .+-. 19,500 *For SC administration, CL/F
.sup..dagger.For SC administration, V/F
[0769] The foregoing data demonstrate that ABT-874 administered IV
and SC in single doses between 0.1 and 5.0 mg/kg was well-tolerated
by young healthy male individuals. The pharmacokinetic properties
of ABT-874, with its half-life of 8-9 days, are as would be
expected for an IgG.sub.1 antibody.
Example 8
Maintenance of Re-treatment Response with the Fully Human IL-12/-23
Monoclonal Antibody, ABT-874, in the Treatment of Moderate to
Severe Plaque Psoriasis
[0770] The efficacy and safety of ABT-874 was evaluated in a
48-week, Phase II, randomized controlled trial that included a
12-week initial treatment phase and a 36-week re-treatment phase of
patients responding to initial treatment. The initial 12-week
efficacy results and maintenance of response results are described
in examples 1-5 above. The objective of the following example was
to examine the re-treatment response during the 36-week
re-treatment/follow-up phase in patients who lost their initial
responses of this Phase II study of subcutaneous injections of
ABT-874 in the treatment of moderate to severe plaque Ps. The
further objective of the following example was to examine safety of
subcutaneous injections of ABT-874 in the treatment of moderate to
severe plaque Ps through 48 weeks.
[0771] The main inclusion criteria for the trial were: (i) adults
with clinical diagnosis of psoriasis for at least 6 months and
stable plaque psoriasis for at least 2 months prior to screening;
and (ii) moderate to severe plaque psoriasis (.gtoreq.10% body
surface area involvement, Psoriasis Area and Severity Index [PASI]
score .gtoreq.12 and a Physician's Global Assessment [PGA] of at
least moderate disease) at the baseline visit.
[0772] A first exclusion criteria for the trial was previous
exposure to systemic or biologic anti-IL-12 therapy. A second
exclusion criteria was inability to discontinue the following
therapies before the baseline visit: topical psoriasis therapies
.gtoreq.2 weeks prior; ultraviolet (UV)-B light phototherapy
.gtoreq.2 weeks prior; psoralen-UV light phototherapy .gtoreq.4
weeks prior; systemic therapies .gtoreq.4 weeks prior; and biologic
therapies .gtoreq.12 weeks prior.
[0773] At baseline, demographics and clinical characteristics were
similar across treatment groups (summarized in Table 5 of Example
6, above).
[0774] Adults with psoriasis affecting .gtoreq.10% body surface
area and a Psoriasis Area and Severity Index (PASI) score
.gtoreq.12 were randomized to 1 of 6 arms: 1) one 200-mg dose
ABT-874 at Week 0; 2) 100 mg of ABT-874 every other wk (eow) for 12
weeks; 3) 200 mg of ABT-874 weekly for 4 weeks; 4) 200 mg of
ABT-874 eow for 12 weeks; 5) 200 mg of ABT-874 weekly for 12 weeks;
or 6) placebo. The primary endpoint was a .gtoreq.PASI 75 response
at Week 12. Patients who met the primary endpoint entered a 36-week
re-treatment phase. Treatment with study drug was discontinued, and
patients who lost response (.ltoreq.PASI 50) during weeks 12-36
received re-treatment with the same dosing regimen assigned during
the initial 12-week period. Re-treatment lasted for 12 weeks.
Regardless of disposition, all patients were monitored for the
entire duration of the study, or until discontinuation.
[0775] Outcome measurements included the following: (i) percentage
of patients achieving PASI 75; (i) median time to achieve PASI 75
response after retreatment; (iii) median time to lose PASI 75
response (iii) percentage of patients with a PGA score of "Clear"
or "Minimal" after retreatment.
[0776] Statistical analysis was carried out as follows.
Intention-to-treat (ITT) analyses were performed by randomized
treatment group. For PASI assessments obtained after retreatment
with ABT-874, the assessments were assigned to study visits
according to the number of days after the first dose of the
retreatment. The proportion of patients achieving PASI response
(yes/no) are presented according to the derived study visit. All
statistical tests were 2-tailed with a significance value of
0.05
[0777] Of the 180 patients initially enrolled (30 patients per
treatment group), 130 (1 placebo) entered the retreatment phase and
58 (all ABT-874) were re-treated. The percentages of patients who
achieved .gtoreq.PASI 75 at week 12 and then again at 12 weeks
after re-treatment were as follows for each group: one 200-mg dose,
63% vs. 55%; 100 mg eow, 93% vs 94%; 200 mg weekly 4 wks, 90% vs.
69%; 200 mg eow, 93% vs. 75%; and 200 mg weekly, 90% vs. 83%,
respectively. Of the total 58 patients who were retreated, 76%
achieved .gtoreq.PASI 75 at 12 weeks after re-treatment. A majority
of patients were able to re-achieve a PASI 75 response (FIG.
7A).
[0778] The median time (in days) to achieve PASI 75 during the
retreatment phase across all ABT-874 dosage groups is depicted in
FIG. 7B. The median time to achieve .gtoreq.PASI 75 during
retreatment were as follows for each group: one 200-mg dose,
between 60 and 65 days; 100 mg eow, between 55 and 60 days; 200 mg
weekly 4 wks, between 55 and 60 days; 200 mg eow, between 25 and 35
days; and 200 mg weekly, between 55 and 60 days, respectively.
[0779] The median time (in days) to lose PASI 75 following the
initial 12 weeks of treatment is depicted in FIG. 7C. The median
time to lose PASI 75 following the initial 12 weeks of treatment
were as follows for each group: one 200-mg dose, between 55 and 60
days; 100 mg eow, between 110 and 120 days; 200 mg weekly 4 wks,
between 110 and 120 days; 200 mg eow, between 160 and 180 days; and
200 mg weekly, between 180 and 190 days, respectively.
[0780] The percentages of patients who achieved a PGA of "clear" or
"minimal" (e.g., PGA of 0 or 1) at 12 weeks after re-treatment are
depicted in FIG. 7D. The percentages of patients who achieved a PGA
of 0 or 1 during re-treatment were as follows for each group: one
200-mg dose, between 35% and 40%; 100 mg eow, between 70% and 80%;
200 mg weekly 4 wks, between 60% and 65%; 200 mg eow, between 60%
and 70%; and 200 mg weekly, between 80% and 90%, respectively. Of
the total patients who were retreated, between 60 and 65% achieved
a PGA of 0 or 1 after re-treatment.
[0781] Adverse events (AEs) occurring .gtoreq.5% in at least 1
treatment group in descending order through week 48 were:
nasopharyngitis, injection-site reaction, upper respiratory tract
infection, headache, hypertension, and arthralgia. An overview of
treatment-emergent adverse events through Week 48 is displayed in
Table 6 of Example 6, above. An overview of treatment-emergent
adverse events with an incidence .gtoreq.5% in any treatment group
is displayed in Table 7 of Example 6, above.
[0782] The foregoing data demonstrate that ABT-874 was highly
efficacious in the treatment of moderate to severe psoriasis. Upon
loss of response and re-treatment, a majority of patients were able
to re-achieve a PASI 75 response. Moreover, ABT-874 appears to have
a favorable safety profile in the long term.
Example 9
Efficacy and Safety of a Fully Human Interleukin 12/23 Monoclonal
Antibody for the Treatment of Chronic Plaque Psoriasis: 36-Week
Observation/Retreatment and 60-Week Open-Label Extension Phases
I. Materials and Methods
[0783] A. Study Design
[0784] The following was a phase 2, multicenter study that
consisted of 3 phases: a 12-week, double-blind, placebo-controlled
phase; a 36-week observation/retreatment phase; and a 60-week,
open-label extension phase. Data from the initial 12-week phase of
the current study is described above in Examples 1, 2, 4, and 7.
Data from the 36-week observation/retreatment phase of the current
study is described above in Examples 3, 5, 6, and 8. The study
methods for the previous studies are briefly reviewed in this
Example with an emphasis on the 36-week observation/retreatment
phase and the 60-week, open-label, extension phase.
[0785] 1. Treatment During Initial 12-Week and
Retreatment/Observation Phases
[0786] Patients were randomized equally to 1 of 6 groups: one
ABT-874 200-mg dose at week 0 (200 mg.times.1); ABT-874 100 mg
every other week for 12 weeks (100 mg EOW); ABT-874 200 mg weekly
for 4 weeks (200 mg.times.4); ABT-874 200 mg EOW for 12 weeks (200
mg EOW); ABT-874 200 mg weekly for 12 weeks (200 mg weekly); or
placebo. Responding patients (i.e., patients who achieved a PASI 75
response at week 12 entered the 36-week single-blinded
observation/retreatment phase in which they were only eligible for
ABT-874 retreatment if they lost response; nonresponders at 12
weeks were monitored, but ineligible for retreatment. During the
36-week observation/retreatment phase, patients who lost PASI 50
response compared with baseline were eligible for 12 weeks of
ABT-874 retreatment if the loss of response occurred after week 12
and through week 36. Retreated patients received the same regimen
of ABT-874 assigned during the 12-week double-blind phase, with the
exception of patients assigned to placebo who received ABT-874 200
mg every other week (EOW). Regardless of which study arm they
entered, all patients were monitored until week 54 or study
discontinuation.
[0787] 2. Treatment During Open-Label Extension Phase
[0788] Patients who achieved at least a PASI 75 response at week 12
of initial treatment and were actively participating in the
observation/retreatment phase were allowed to enter the open-label
extension phase. During this phase of the study, patients who lost
PASI 50 response compared with baseline were retreated with either
200 mg ABT-874.times.1 dose or .times.2 doses (1 dose/wk for 2 wk)
based on their dosing regimen during the initial 12-week phase of
the study. Patients receiving 200 mg ABT-874.times.1 dose included
those who were initially randomized to receive 200 mg.times.1, 100
mg EOW, or 200 mg.times.4. Patients receiving ABT-874.times.2 doses
included those who were initially randomized to receive 200 mg EOW,
200 mg weekly, or placebo. Patients who experienced subsequent loss
of PASI 50 response that occurred within less than 12 weeks of the
previous retreatment were retreated again with the same dosing
regimen (1 or 2 doses of ABT-874); retreatment could be repeated
until week 56 of the open-label extension phase.
[0789] 3. Participants
[0790] Key inclusion criteria were: .gtoreq.18 years of age;
clinical diagnosis of psoriasis for .gtoreq.6 months; stable plaque
psoriasis for .gtoreq.2 months before screening and at baseline;
moderate to severe plaque psoriasis (i.e., psoriasis on .gtoreq.10%
body surface area at baseline); a PASI score .gtoreq.12 at
baseline; and a PGA score of moderate or higher at baseline.
[0791] Key exclusion criteria included the following: previous
anti-IL-12 therapy; diagnosis of nonplaque psoriasis; inability to
discontinue various treatments for psoriasis within predefined time
frames, including topical therapies, ultraviolet light
phototherapy, and systemic therapies; select comorbid disease or
risk factors; and abnormal laboratory values.
[0792] 4. Efficacy and Safety Assessments
[0793] The primary study outcome of PASI 75 response at week 12
relative to baseline was described above in Example 3-8. Adverse
events, vital signs, and laboratory parameters were monitored
throughout all phases of the study. Secondary endpoints examined
during the 36-week observation/retreatment phase, and evaluated in
the current analysis, include the proportion of retreated patients
who achieved PASI 50, 75, and 90 scores after 12 weeks of
retreatment; median time to loss of PASI 75 response; median time
to regain PASI 75 response among retreated patients; PGA scores;
and safety. Secondary endpoints assessed during the 60-week
open-label extension phase, and evaluated in the current analysis,
include the proportion of patients who achieved PASI 50, 75, and 90
scores 12 weeks after retreatment; PGA scores; and safety. A
further assessment of the 12-week data examined the impact of
baseline covariates (e.g., weight, PASI or PGA score, psoriatic
arthritis history, or prior therapy) on subsequent achievement of
PASI 75 and is presented here.
[0794] PASI scores ranged from 0="no psoriasis" to 72="severe
disease" and were calculated as previously described. Severity of
disease was measured using PGA scores, which ranged from 0="clear"
to 5="very severe" as previously described.
[0795] 5. Statistical Analyses
[0796] Efficacy analyses were conducted using the intent-to-treat
population (N=180), which included all patients who were randomly
assigned at week 0 and received at least 1 study drug injection
during the first 12-week, double-blind phase of the study. Efficacy
analyses were conducted for the observation/retreatment period on
those patients who were randomized to ABT-874 at week 0 and who
achieved PASI 75 response at week 12, n=130. For the open-label
extension phase, only data for patients who continued in this phase
were analyzed. The efficacy variables in the
observation/retreatment period and open-label retreatment period
were summarized. Patients with missing PASI or PGA scores were
counted as nonresponders. Categorical variables were summarized
using patient count and percentage. Continuous variables were
summarized using descriptive statistics (m, mean, and standard
derivation). Safety analyses were conducted using the safety
population, which included all patients who received at least 1
study drug injection.
II. Results
[0797] A. Patient Demographics
[0798] Demographic data for these patients were described above in
Examples 3-8 and are summarized below. In the ABT-874 treatment
arms, patients, on average, were similar in terms of age (mean, 46
years), were predominantly male (75%) and primarily of white race
(92%), and averaged 94 kg in weight. Average duration of psoriasis
was 21 years, with mean PASI scores of 19. Patients receiving
ABT-874 were divided between moderate (54%) and severe (41%)
psoriasis, as determined by PGA scores, with a mean 25.6% of their
body surface area affected. Prior therapies consisted of topical
therapy (71%), followed by systemic nonbiologic (20%) or biologic
(18%) treatment or phototherapy (15%).
[0799] B. Baseline Covariates in Responders
[0800] At the 12-week evaluation, a majority of all ABT-874 treated
patients achieved a PASI 75 score regardless of differences in
baseline clinical and demographic covariate characteristics (e.g.,
weight, PASI or PGA score, psoriatic arthritis history, or prior
therapy, Table 9).
TABLE-US-00016 TABLE 9 Twelve-Week PASI 75 Responders Stratified by
Baseline Covariates (Double-Blind Period; Intention-to-Treat Set)
PASI 75 Responder, n/N (%) ABT-874 Treatment Group 100 mg 200 mg
200 mg Covariate, n (%) Placebo 200 mg .times. 1 EOW 200 mg .times.
4 EOW weekly All ABT-874 Weight, kg .ltoreq.100 0/23 (0) 11/18
(61.1) 18/18 (100) 18/20 (90.0) 19/20 (95.0) 20/21 (95.2) 86/97
(88.7) >100 1/7 (14.3) 8/12 (66.7) 10/12 (83.3) 9/10 (90.0) 9/10
(90.0) 7/9 (77.8) 43/53 (81.1) PGA score severe/very severe 1/9
(11.1) 8/11 (72.7) 12/13 (92.3) 15/17 (88.2) 13/15 (86.7) 11/13
(84.6) 59/69 (85.5) Psoriatic arthritis history Yes 0/9 (0) 6/7
(85.7) 11/12 (91.7) 8/9 (88.9) 5/6 (83.3) 6/9 (66.7) 36/43 (83.7)
No 1/21 (4.8) 13/23 (56.5) 17/18 (94.4) 19/21 (90.5) 23/24 (95.8)
21/21 (100) 93/107 (86.9) Age <40 0/7 (0) 2/4 (50.0) 9/10 (90.0)
11/12 (91.7) 14/15 (93.3) 10/10 (100) 46/51 (90.2) .gtoreq.40 1/23
(4.3) 17/26 (65.4) 19/20 (95.0) 16/18 (88.9) 14/15 (93.3) 17/20
(85.0) 83/99 (83.8) Sex Male 1/22 (4.5) 15/23 (65.2) 21/22 (95.5)
19/21 (90.5) 22/23 (95.7) 20/23 (87.0) 97/112 (86.6) Female 0/8 (0)
4/7 (57.1) 7/8 (87.5) 8/9 (88.9) 6/7 (85.7) 7/7 (100) 32/38 (84.2)
BSA, % .ltoreq.20 1/19 (5.3) 12/18 (66.7) 13/15 (86.7) 13/15 (86.7)
14/14 (100) 16/16 (100) 68/78 (87.2) >20 0/11 (0) 7/12 (58.3)
15/15 (100) 14/15 (93.3) 14/16 (87.5) 11/14 (78.6) 61/72 (84.7)
PASI .ltoreq.20 1/28 (3.6) 14/22 (63.6) 16/18 (88.9) 19/21 (90.5)
17/18 (94.4) 21/21 (100) 87/100 (87.0) >20 0/2 (0) 5/8 (62.5)
12/12 (100) 8/9 (88.9) 11/12 (91.7) 6/9 (66.7) 42/50 (84.0) BSA, %
and PASI .ltoreq.20 1/19 (5.3) 11/17 (64.7) 10/12 (83.3) 13/15
(86.7) 14/14 (100) 15/15 (100) 63/73 (86.3) >20 0/2 (0) 4/7
(57.1) 9/9 (100) 8/9 (88.9) 11/12 (91.7) 5/8 (62.5) 37/45 (82.2)
Systemic biologic treatment within last 12 mo Yes 0/3 (0) 2/3
(66.7) 6/7 (85.7) 5/6 (83.3) 4/4 (100) 6/7 (85.7) 23/27 (85.2) No
1/27 (3.7) 17/27 (63.0) 22/23 (95.7) 22/24 (91.7) 24/26 (92.3)
21/23 (91.3) 106/123 (86.2) Systemic nonbiologic treatment within
last 12 mo Yes 0/6 (0) 1/4 (25.0) 7/7 (100) 5/5 (100) 6/6 (100) 8/8
(100) 27/30 (90.0) No 1/24 (4.2) 18/26 (69.2) 21/23 (91.3) 22/25
(88.0) 22/24 (91.7) 19/22 (86.4) 102/120 (85.0) Topical treatment
within last 12 mo Yes 0/19 (100) 14/21 (66.7) 25/26 (96.2) 15/15
(100) 20/21 (95.2) 20/23 (87.0) 94/106 (88.7) No 1/11 (9.1) 5/9
(55.6) 3/4 (75.0) 12/15 (80.0) 8/9 (88.9) 7/7 (100) 35/44 (79.5)
Phototherapy within last 12 mo Yes 0/1 (0) 4/6 (66.7) 4/4 (100) 4/4
(100) 3/3 (100) 5/5 (100) 20/22 (90.9) No 1/29 (3.4) 15/24 (62.5)
24/26 (92.3) 23/26 (88.5) 25/27 (92.6) 22/25 (88.0) 109/128 (85.2)
BSA = body surface area; EOW = every other week; PASI = Psoriasis
Area and Severity Index; PGA = physician's global assessment.
[0801] C. Observation/Retreatment Phase (36 Weeks)
[0802] Patients who responded with a PASI 75 score at the end of
the initial 12-week study were eligible for retreatment during the
36-week observation/retreatment phase (n=130); nonresponders (n=40)
were monitored, but not eligible for retreatment.
[0803] Of the 130 patients who were eligible for and entered the
retreatment phase at week 12, 72 patients maintained a response,
whereas 58 patients lost their PASI 50 response and were retreated
with ABT-874 in the subsequent 12 weeks. The mean PASI score for
all 58 retreated patients at the time of retreatment was 13.85,
with a range of 13.2 to 14.9 across treatment groups (FIG. 10). In
patients who lost their PASI 75 response during the entire
observation/retreatment phase (n=120/130), the median time to loss
of the response (calculated from the last dose received during the
initial 12 weeks of the study) ranged from 57 to 184 days (FIG.
11). Among retreated patients, the percentage of patients who
achieved PASI 75 scores 12 weeks after reinitiation of ABT-874
therapy was 54.5% for the 200 mg.times.1 treatment group, 93.8% for
100 mg EOW, 69.2% for 200 mg.times.4, 75.0% for 200 mg EOW, and
83.3% for 200 mg weekly. PASI 50 response 12 weeks after
reinitiation of therapy ranged from 76.9% to 100%; PASI 90 response
ranged from 9.1% to 83.3% (Table 10). The single-dose treatment
group (ABT-874 200 mg.times.1) generally had the lowest proportion
of patients achieving a given level of response. Patients who
achieved a PASI 75 response during 12 weeks of retreatment showed
median times to achieve a response ranging from 30 to 62 days (FIG.
12).
TABLE-US-00017 TABLE 10 PASI Responses After 12 Weeks of
Retreatment ABT-874 Treatment Group PASI 50, n (%) PASI 75, n (%)
PASI 90, n (%) 200 mg .times. 1 (n = 11) 9 (81.8) 6 (54.5) 1 (9.1)
100 mg EOW (n = 16) 16 (100) 15 (93.8) 12 (75.0) 200 mg .times. 4
(n = 13) 10 (76.9) 9 (69.2) 6 (46.2) 200 mg EOW (n = 12) 10 (83.3)
9 (75.0) 6 (50.0) 200 mg weekly (n = 6) 6 (100) 5 (83.3) 5 (83.3)
EOW = every other week; PASI = Psoriasis Area and Severity
Index.
[0804] The majority of retreated patients in each treatment group
achieved a PGA score of "clear" or "minimal" after 12 weeks of
retreatment (100 mg EOW, 75.0%; 200 mg.times.4, 61.5%; 200 mg EOW,
66.7%; 200 mg weekly, 83.3%), with the exception of the ABT-874 200
mg.times.1 group (200 mg.times.1, 36.4%). Median time to achieve a
PGA score of "clear" or "minimal" after commencing retreatment
ranged from 45 to 85 days (200 mg.times.1, 85 d; 100 mg EOW, 58 d;
200 mg.times.4, 58 d; 200 mg EOW, 57 d; 200 mg weekly, 45 d).
[0805] Among patients who received ABT-874 during the first 48
weeks of the study (initial 12-week and 36-week
observation/retreatment phases), there were no deaths and 4
patients with serious adverse events; 1 patient discontinued
ABT-874 treatment due to an adverse event (Table 11). Among all
patients who received ABT-874, injection site reactions,
nasopharyngitis, and upper respiratory tract infections were the
only adverse events that occurred with an incidence >10% (Table
12).
TABLE-US-00018 TABLE 11 Treatment-Emergent AEs Summary Among All
Patients Through Week 48 ABT-874 Treatment Group Placebo.sup.a 200
mg .times. 1 100 mg EOW 200 mg .times. 4 200 mg EOW 200 mg weekly
All ABT-874 Adverse Event, n (%) (n = 30) (n = 30) (n = 30) (n =
30) (n = 30) (n = 30) (n = 150) Any AE 18 (60.0) 20 (66.7) 25
(83.3) 25 (83.3) 25 (83.3) 21 (70.0) 116 (77.3) Any AE at least 4
(13.3) 9 (30.0) 16 (53.3) 16 (53.3) 13 (43.3) 10 (33.3) 64 (42.7)
possibly drug-related Any severe AE 4 (13.3) 1 (3.3) 0 2 (6.7) 1
(3.3) 1 (3.3) 5 (3.3) Any serious AE.sup.b 1 (3.3) 1 (3.3) 0 1
(3.3) 2 (6.7) 0 4 (2.7) Any AE leading to DC 2 (6.7) 1 (3.3) 0 0 0
0 1 (0.7) of study drug Any AE at least 0 0 0 0 1 (3.3) 0 1 (0.7)
possibly drug-related and serious Any infectious AE 7 (23.3) 10
(33.3) 12 (40.0) 14 (46.7) 16 (53.3) 10 (33.3) 62 (41.3) Any
serious infectious 0 0 0 0 1 (3.3) 0 1 (0.7) AE Any malignant AE 1
(3.3) 0 0 1 (3.3) 0 0 1 (0.7) Any nonmelanoma 0 0 0 1 (3.3) 0 0 1
(0.7) skin cancer Death 0 0 0 0 0 0 0 AE = adverse event; DC =
discontinuation; EOW = every other week. .sup.aPlacebo data are
only for the first 12 weeks of the study; all 12-week study data
previously reported. (Kimball 2008) .sup.bPatients experiencing
more than 1 serious adverse event are counted only once in the
serious adverse event total. A total of 4 patients reported 8
serious AE: one patient in the 200 mg EOW group reported abscess
rupture, diverticular perforation, sepsis, and peritonitis; one
patient in the 200 mg EOW group reported facial injury; one patient
in the 200 mg .times. 4 group reported injury; one patient in the
200 mg .times. 1 group reported costochondritis; one patient
receiving placebo reported ovarian cancer.
TABLE-US-00019 TABLE 12 Treatment-Emergent AEs With an Incidence
.gtoreq.2% in All ABT-874 Treatment Group Through Week 48 ABT-874
Treatment Group Placebo.sup.a 200 mg .times. 1 100 mg EOW 200 mg
.times. 4 200 mg EOW 200 mg weekly All ABT-874 Adverse Event, n (%)
(n = 30) (n = 30) (n = 30) (n = 30) (n = 30) (n = 30) (n = 150)
Injection-site reaction 0 2 (6.7) 7 (23.3) 8 (26.7) 8 (26.7) 4
(13.3) 29 (19.3) Nasopharyngitis 1 (3.3) 5 (16.7) 6 (20.0) 3 (10.0)
4 (13.3) 5 (16.7) 23 (15.3) Upper respiratory tract 2 (6.7) 2 (6.7)
5 (16.7) 3 (10.0) 5 (16.7) 2 (6.7) 17 (11.3) infection Headache 2
(6.7) 5 (16.7) 1 (3.3) 1 (3.3) 3 (10.0) 2 (6.7) 12 (8.0)
Injection-site erythema 0 0 1 (3.3) 4 (13.3) 2 (6.7) 1 (3.3) 8
(5.3) Injection-site pruritus 0 0 1 (3.3) 2 (6.7) 2 (6.7) 2 (6.7) 7
(4.7) Injection-site irritation 0 1 (3.3) 3 (10.0) 2 (6.7) 0 0 6
(4.0) Arthralgia 1 (3.3) 2 (6.7) 1 (3.3) 0 0 2 (6.7) 5 (3.3) Viral
infection 0 0 2 (6.7) 2 (6.7) 1 (3.3) 5 (3.3) Gastroenteritis viral
0 1 (3.3) 0 2 (6.7) 1 (3.3) 1 (3.3) 5 (3.3) Fatigue 0 2 (6.7) 2
(6.7) 0 0 1 (3.3) 5 (3.3) Hypertriglyceridemia 0 1 (3.3) 2 (6.7) 2
(6.7) 0 0 5 (3.3) Pain in extremity 0 1 (3.3) 0 0 1 (3.3) 2 (6.7) 4
(2.7) Bronchitis 0 1 (3.3) 0 1 (3.3) 2 (6.7) 0 4 (2.7)
Pharyngolaryngeal pain 0 2 (6.7) 0 0 0 1 (3.3) 3 (2.0) Influenza 1
(3.3) 0 1 (3.3) 0 2 (6.7) 0 3 (2.0) Back pain 0 0 1 (3.3) 0 2 (6.7)
0 3 (2.0) Blood TGs increased 1 (3.3) 0 0 2 (6.7) 1 (3.3) 0 3 (2.0)
Urinary tract infection 2 (6.7) 1 (3.3) 0 1 (3.3) 1 (3.3) 0 3 (2.0)
Insomnia 1 (3.3) 2 (6.7) 0 1 (3.3) 1 (3.3) 0 3 (2.0) Nausea 2 (6.7)
0 3 (10.0) 0 0 0 3 (2.0) Cyst 0 1 (3.3) 2 (6.7) 0 0 0 3 (2.0) AE =
adverse event; BP = blood pressure; EOW = every other week; TGs =
triglycerides. .sup.aPlacebo data are only for the first 12 weeks
of the study; all 12-week study data previously reported. (Kimball
2008)
[0806] D. Open-Label Extension Phase (60 Weeks)
[0807] Patients who achieved a PASI 75 at week 12 and were actively
participating in the study (i.e., eligible for retreatment) during
the 36-week observation/retreatment phase were allowed to enter the
open-label extension phase (n=105). There were no appreciable
shifts in overall demographic characteristics in the open-label
phase, although there was a statistically significant difference
between the ABT-874 200 mg.times.1 and .times.2 dose groups in the
distribution of subjects in each age category (P=0.010).
[0808] After week 48, patients received retreatment upon loss of
response (<PASI 50) with 200 mg ABT-874.times.1 or .times.2
based on their initial randomized dosing group. Of the 105 subjects
who entered the open-label extension phase at week 48, 96 (n=52 and
n=44 for ABT-874 200 mg.times.1 and .times.2 dose groups,
respectively) were retreated at least once. Patients were retreated
up to 5 times, with the majority of retreated patients being
retreated 3 times. Nine patients were not retreated with ABT-874 in
the open-label extension phase because they never lost PASI 50
response, but were monitored through the end of the study.
[0809] With each cycle of retreatment, the proportion of patients
who achieved PASI 50, 75, and 90 responses generally decreased, and
response rates after retreatment were lower than those seen after
initial treatment (Table 13). However, the proportion of patients
who achieved a PASI 50 response was similar in the ABT-874 200
mg.times.2 dose group for the first 3 retreatments, and the overall
PASI 75 response rates were similar for the first and second
retreatments. The majority of all retreated patients achieved a
PASI 50 response with the first 3 retreatments.
TABLE-US-00020 TABLE 13 PASI Responses 12 Weeks After ABT-874
Retreatment in Open-Label Extension Phase.sup.a ABT-874 200 ABT-874
200 mg .times. 1 mg .times. 2 All ABT-874 PASI Response n (%) n (%)
n (%) First Retreatment N = 52 N = 44 N = 96 PASI 50 38 (77.6) 37
(92.5) 75 (84.3) PASI 75 23 (46.9) 23 (57.5) 46 (51.7) PASI 90 13
(26.5) 16 (40.0) 29 (32.6) Second Retreatment N = 42 N = 36 N = 78
PASI 50 25 (67.6) 30 (90.9) 55 (78.6) PASI 75 16 (43.2) 21 (63.6)
37 (52.9) PASI 90 5 (13.5) 10 (30.3) 15 (21.4) Third Retreatment N
= 31 N = 20 N = 51 PASI 50 10 (47.6) 13 (92.9) 23 (65.7) PASI 75 4
(19.0) 5 (35.7) 9 (25.7) PASI 90 0 0 0
[0810] PGA scores also declined with each cycle of open-label
retreatment and were lower than observed during the initial phase
of the study. During the first cycle of retreatment, 30.6% of
patients receiving ABT-874 200 mg.times.1 dose and 41.5% of
patients receiving ABT-874 200 mg.times.2 doses achieved a PGA
score of "clear" or "minimal" 12 weeks after retreatment. The
proportion of patients achieving PGA scores of "clear" or "minimal"
declined somewhat after the second cycle of open-label retreatment
(200 mg.times.1, 23.7%; 200 mg.times.2, 39.4% after 12 weeks) but
was substantially lower following the third retreatment (200
mg.times.1, 4.8%; 200 mg.times.2, 7.1% after 12 weeks).
[0811] Sixteen patients (16.7%) in the open-label extension phase
experienced a treatment-emergent adverse event (occurring on or
after each open-label ABT-874 dose up until 45 days after the date
of stopping each dose) deemed possibly study drug-related (Table
14). While no deaths or serious infections were reported during the
open-label extension phase, 3 patients experienced serious adverse
events. The only adverse events that occurred with a prevalence
>5%, but less than 10%, during the open-label extension phase
were nasopharyngitis, upper respiratory tract infection, injection
site reactions, and hypertension (Table 14).
TABLE-US-00021 TABLE 14 Overview of Treatment-Emergent AEs During
Open-Label Extension Phase.sup.a ABT-874 Treatment Group 200 mg
.times. 1 200 mg .times. 2 All ABT-874 Adverse Event, n (%) (n =
52) (n = 44) (n = 96) Any AE 32 (61.5) 22 (50.0) 54 (56.3) Any AE
at least 11 (21.2) 5 (11.4) 16 (16.7) possibly drug-related Any
severe AE 2 (3.8) 1 (2.3) 3 (3.1) Any serious AE.sup.b 3 (5.8) 0 3
(3.1) Any AE leading to DC 2 (3.8) 0 2 (2.1) of study drug Any AE
at least possibly 0 0 0 drug-related and serious Any infectious AE
15 (28.8) 13 (29.5) 28 (29.2) Any serious infectious AE 0 0 0 Any
malignant or non- 0 0 0 melanoma skin cancer AE Death 0 0 0
Treatment-emergent AE with an incidence .gtoreq.5% in any treatment
group Nasopharyngitis 5 (9.6) 3 (6.8) 8 (8.3) Upper respiratory
tract 4 (7.7) 4 (9.1) 8 (8.3) infection Injection site reaction 5
(9.6) 1 (2.3) 6 (6.3) Hypertension 2 (3.8) 3 (6.8) 5 (5.2) Headache
1 (1.9) 3 (6.8) 4 (4.2) Influenza 0 3 (6.8) 3 (3.1) AE = adverse
event; DC = discontinuation. .sup.aAdverse events are reported for
patients who received ABT-874 during open-label extension phase; 96
of 105 patients who entered this phase received retreatment.
.sup.bPatients experiencing more than 1 serious adverse event are
counted only once in the serious adverse event total. In the 200 mg
.times. 1 group, one patient experienced chest discomfort, chest
pain, and dyspnea, one patient experienced obesity, and one patient
experienced meningioma.
III. Conclusion
[0812] The preliminary efficacy and safety profile of ABT-874 in
patients being retreated for moderate to severe chronic plaque
psoriasis was assessed. Current study data show that anti-IL-12/23
therapy has significant promise for treatment and retreatment of
patients with moderate to severe plaque psoriasis.
[0813] Among all patients who received any ABT-874 therapy, a large
majority of patients achieved PASI 75 responses following 12 weeks
of treatment, regardless of baseline weight, PGA and PASI scores,
psoriatic arthritis history, or prior psoriasis treatment.
[0814] After achieving a PASI 75 response following 12 weeks of
treatment in the initial double-blind period and discontinuing
treatment in the observation/retreatment period, many patients were
able to maintain a PASI 75 response for some time without
retreatment. The median time until loss of response was greater in
patients receiving higher doses of ABT-874, with the median time to
loss of PASI 75 response ranging up to 184 days in the weekly
dosing arm.
[0815] Of particular note, the time required to regain PASI 75
responsiveness among the ABT-874 retreated patients was relatively
short, ranging from 30 to 62 days. This is likely dose related, as
was time to relapse. In the initial 12-week study phase, a PASI 75
response was achieved by the majority of patients in each ABT-874
treatment group after 8 to 12 weeks, with a median of 57 to 85
days. Results from the open-label extension phase show a
diminishing response to subsequent rounds of ABT-874 retreatment.
Possible explanations for this reduced response include the
abbreviated dosing regimen used during the open-label extension
(ABT-874 200 mg.times.1 or .times.2), as well as the amount of drug
received and corresponding pharmacokinetic factors such as ABT-874
concentration.
[0816] In conclusion, these data show that ABT-874 is an
efficacious and safe treatment option for treatment and retreatment
of moderate to severe chronic plaque psoriasis.
Example 10
Efficacy of Treatment With ABT-874, an Interleukin-12/23 Monoclonal
Antibody, Across Body Regions of Patients with Moderate to Severe
Psoriasis
I. Materials and Methods
[0817] A. Study Design
[0818] The following was a twelve-week, randomized, double-blind,
placebo-controlled, multi-center study. One hundred and eighty
adult patients with psoriasis affecting .gtoreq.10% body surface
area and a Psoriasis Area and Severity Index (PASI) score
.gtoreq.12 were randomized to: one 200-mg dose ABT-874 at Week 0,
100 mg ABT-874 every other week (eow) for 12 weeks, 200 mg ABT-874
weekly for 4 weeks, 200 mg ABT-874 eow for 12 weeks, 200 mg ABT-874
weekly for 12 weeks, or placebo. The primary endpoint was
.gtoreq.PASI 75 response by week 12. Individual PASI scores in the
four body regions utilized for PASI evaluation were also
assessed.
[0819] B. Main Inclusion and Exclusion Criteria
[0820] The main inclusion criteria for the study were:
[0821] Adult patients with chronic moderate to severe plaque
psoriasis for at least 6 months;
[0822] Stable for at least 2 months;
[0823] .gtoreq.10% BSA;
[0824] PASI.gtoreq.12; and
[0825] Moderate or severe Physician's Global Assessment (PGA)
[0826] The main exclusion criteria for the study were:
[0827] Previous exposure to any systemic anti-IL-12 therapy,
including ABT-874;
[0828] Diagnosis of erythrodermic psoriasis, pustular psoriasis,
medication-induced or medication-exacerbated psoriasis, or new
onset guttate psoriasis;
[0829] Diagnosis of other active skin diseases or skin infections
that might interfere with evaluation of psoriasis;
[0830] Inability to discontinue prior medication;
[0831] Topicals and phototherapy for 2 weeks;
[0832] Nonbiologic systemic therapies for 4 weeks; and
[0833] Biologics for 12 weeks
[0834] C. Efficacy Measures
[0835] The following efficacy measures were used in the present
study:
[0836] The percentage of patients in each group achieving
.gtoreq.PASI 75 and .gtoreq.PASI 90 response at Week 12; and
[0837] The percentage of patients in each group achieving
.gtoreq.PASI 75 and .gtoreq.PASI 90 response at week 12 in specific
regions: [0838] Head and neck; [0839] Upper extremities; [0840]
Trunk; and [0841] Lower extremities
[0842] D. Safety Measures
[0843] Laboratory results, vital signs, and adverse events (AEs)
were used to determine the safety of the treatment.
[0844] E. Statistical Methods
[0845] The following statistical methods were used to determine
efficacy of the treatment:
[0846] Comparison of the proportion of subjects achieving
.gtoreq.PASI 75 at Week 12 between ABT-874 dose group and placebo
group using Fisher's exact test, with 2-sided 95% confidence
interval for the difference in proportion;
[0847] Patients for whom data were missing were assumed to be
non-responders (non-responder imputation); and
[0848] P<0.05 indicated statistical significance
II. Results
[0849] A. Baseline Demographics
[0850] Baseline demographic and clinical characteristics were
similar across treatment groups. See Table 15.
TABLE-US-00022 TABLE 15 Baseline Demographics and Disease
Characteristics Treatment Group 200 mg All Placebo 100 mg eow 4
Dose 200 mg eow 200 mg ew ABT-874 Total Parameter N = 30 200 mg 1
Dose N = 30 N = 30 N = 30 N = 30 N = 30 N = 150 N = 180 Age (years)
Mean .+-. SD 49.2 .+-. 14.36 51.5 .+-. 12.00 44.5 .+-. 13.76 43.4
.+-. 13.77 43.5 .+-. 15.95 46.3 .+-. 14.00 45.9 .+-. 14.09 46.4
.+-. 14.15 Median (range) 49.5 (18-80) 52.5 (24-69) 45.0 (18-65)
43.0 (20-73) 39.0 (25-79) 47.0 (19-76) 46.0 (18-79) 47.0 (18-80)
Sex, n (%) Female 8 (26.7) 7 (23.3) 8 (26.7) 9 (30.0) 7 (23.3) 7
(23.3) 38 (25.3) 46 (25.6) Male 22 (73.3) 23 (76.7) 22 (73.3) 21
(70.0) 23 (76.7) 23 (76.7) 112 (74.7) 134 (74.4) Weight (kg) Mean
.+-. SD 89.3 .+-. 17.57 93.5 .+-. 21.21 93.9 .+-. 17.88 92.1 .+-.
27.85 93.4 .+-. 24.06 94.6 .+-. 18.03 93.5 .+-. 21.85 92.8 .+-.
21.21 Median 90.0 (43.0-140.0) 89.5 (61.0-145.0) 91.1 (60.0-125.0)
89.0 (54.0-169.0) 89.0 (62.0-161.0) 93.2 (68.0-153.0) 90.0
(54.0-169.0) 90.0 (43.0-169.0) (range) Family History of 9 (30.0)
17 (56.7) 21 (70.0) 23 (76.7) 15 (50.0) 12 (40.0) 88 (58.7) 97
(53.9) Psoriasis, n (%) Duration of Chronic Plaque Psoriasis
(years) Mean .+-. SD 21.43 .+-. 12.40 19.78 .+-. 13.18 23.95 .+-.
14.60 22.09 .+-. 14.24 18.5 .+-. 11.52 17.93 .+-. 10.89 20.45 .+-.
12.99 20.61 .+-. 12.87 Median (range) 20.55 (1.0-48.1) 17.55
(1.6-43.0) 22.05 (3.2-59.1) 21.0 (1.3-53.0) 18.09 (0.8-55.1) 15.68
(4.1-47.1) 19.11 (0.8-59.1) 19.58 (0.8-59.1) PASI .ltoreq.20 28
(93.3) 22 (73.3) 18 (60.0) 21 (70.0) 18 (60.0) 21 (70.0) 100 (66.7)
128 (71.1) >20 2 (6.7) 8 (26.7) 12 (40.0) 9 (30.0) 12 (40.0) 9
(30.0) 50 (33.3) 52 (28.9) Mean .+-. SD 15.83 .+-. 2.86 17.96 .+-.
6.72 19.93 .+-. 6.29 19.94 .+-. 7.57 19.86 .+-. 6.20 18.96 .+-.
6.33 19.33 .+-. 6.60 18.75 .+-. 6.27 Median (range) 16.10
(10.2-22.6) 14.95 (12.1-35.4) 18.65 (12.4-34.4) 16.95 (12.3-41.4)
18.0 (11.9-33.4) 16.75 (12.2-37.2) 17.25 (11.9-41.4) 16.85
(10.2-41.4) BSA (%) .ltoreq.20% 19 (63.3) 18 (60.0) 15 (50.0) 15
(50.0) 14 (46.7) 16 (53.3) 78 (52.0) 97 (53.9) >20% 11 (36.7) 12
(40.0) 15 (50.0) 15 (50.0) 16 (53.3) 14 (46.7) 72 (48.0) 83 (46.1)
Mean .+-. SD 20.88 .+-. 9.18 24.06 .+-. 13.58 27.88 .+-. 15.68
24.15 .+-. 13.05 29.06 .+-. 16.84 22.92 .+-. 12.61 25.61 .+-. 14.45
24.83 .+-. 13.81 Median (range) 17.5 (11.0-45.0) 17.5 (10.0-57.5)
22.5 (11.0-74.0) 20.3 (10.0-59.0) 22.0 (11.0-82.0) 19.5 (10.0-53.0)
20.0 (10.0-82.0) 20.0 (10.0-82.0) PGA Minimal 0 0 0 0 0 0 0 0 Mild
1 (3.3) 0 0 0 0 0 0 1 (0.6) Moderate 20 (66.7) 19 (63.3) 17 (56.7)
13 (43.3) 15 (50.0) 17 (56.7) 81 (54.0) 101 (56.1) Severe 9 (30.0)
11 (36.7) 12 (40.0) 14 (46.7) 13 (43.3) 11 (36.7) 61 (40.7) 70
(38.9) Very Severe 0 0 1 (3.3) 3 (10.0) 2 (6.7) 2 (6.7) 8 (5.3) 8
(4.4) History of Psoriatic 9 (30.0) 7 (23.3) 12 (40.0) 9 (30.0) 6
(20.0) 9 (30.0) 43 (28.7) 52 (28.9) Arthritis, n (%) Duration of
Psoriatic Arthritis (years) Mean .+-. SD 10.69 .+-. 11.70 13.51
.+-. 10.67 11.25 .+-. 12.00 13.0 .+-. 12.60 8.6 .+-. 8.31 14.18
.+-. 11.78 12.23 .+-. 11.06 11.96 .+-. 11.07 Median (range) 5.82
(0.1-30.0) 16.05 (2.2-31.0) 8.03 (1.1-45.1) 10.91 (0.1-37.2) 4.33
(2.6 .+-. 22.9) 11.1 (0.2-36.0) 8.13 (0.1-45.1) 7.02 (0.1-45.1)
Swollen, Tender, or Stiff 8 (26.7) 11 (36.7) 10 (33.3) 10 (33.3) 9
(30.0) 15 (50.0) 55 (36.7) 63 (35.0) Joints, n (%) eow: every other
week ew: every week
[0851] B. Efficacy
[0852] A greater percentage of patients treated with any dose of
ABT-874 achieved .gtoreq.PASI 75 or .gtoreq.PASI 90 at week 12
compared with placebo (FIG. 13).
[0853] In the specific body regions examined, a greater percentage
of patients treated with ABT-874 achieved .gtoreq.PASI 75 and
.gtoreq.PASI 90 at week 12 compared with placebo (FIGS.
14A-14D).
[0854] The percentage of patients achieving .gtoreq.PASI 75 or
.gtoreq.PASI 90 at Week 12 was greater for all ABT-874 dosage
groups combined vs. the placebo group (86.0% vs. 3.3% and 52.7% vs.
0.0%, respectively). For all ABT-874 dosage groups combined, a
greater percentage of patients achieved .gtoreq.75% and .gtoreq.90%
improvements in PASI scores as compared to placebo patients for all
body regions examined: head and neck (PASI 75, 83.3% vs. 13.3%;
PASI 90, 72.0% vs. 13.3%), upper extremities (PASI 75, 81.3% vs.
3.3%; PASI 90, 57.3% vs. 3.3%), trunk (PASI 75, 82.0% vs. 3.3%;
PASI 90, 68.0% vs. 3.3%), lower extremities (PASI 75, 78.0% vs.
3.3%; PASI 90, 48.0% vs. 0.0%).
[0855] C. Safety
[0856] An overview of the number and percentage of subjects with
treatment-emergent adverse events is presented in Table 16. Most
reported AEs were mild or moderate in severity. The percentage of
patients experiencing serious AEs was low. The most frequently
reported treatment-emergent adverse events occurring in .gtoreq.5%
of patients are listed in Table 17.
TABLE-US-00023 TABLE 16 Overview of Treatment-Emergent Adverse
Events ABT-874 200 mg 100 mg 200 mg 200 mg 200 mg All ABT- Placebo
1 Dose eow 4 Dose eow ew 874 N = 30 N = 30 N = 30 N = 30 N = 30 N =
30 N = 150 n (%) Any adverse event (AE) 18 (60.0) 18 (60.0) 24
(80.0) 22 (73.3) 23 (76.7) 21 (70.0) 108 (72.0) Any AE at least
possibly drug-related.sup.a 4 (13.3) 9 (30.0) 14 (46.7) 14 (46.7)
12 (40.0) 9 (30.0) .sup. 58 (38.7).sup.b Any severe AE 4 (13.3) 1
(3.3) 0 0 1 (3.3) 1 (3.3) 3 (2.0) Any serious AE 1 (3.3) 1 (3.3) 0
0 1 (3.3) 0 2 (1.3) Any AE leading to discontinuation of study drug
2 (6.7) 1 (3.3) 0 0 0 0 1 (0.7) Any at least possibly drug-related
serious AE.sup.a 0 0 0 0 1 (3.3) 0 1 (0.7) Any infectious AE 7
(23.3) 8 (26.7) 11 (36.7) 14 (46.7) 15 (50.0) 10 (33.3) 58 (38.7)
Any serious infectious AE 0 0 0 0 1 (3.3) 0 1 (0.7) Any malignant
AE 1 (3.3) 0 0 1 (3.3) 0 0 1 (0.7) Any lymphomas AE 0 0 0 0 0 0 0
Any non-melanoma skin cancer (NMSC) AE 0 0 0 1 (3.3) 0 0 1 (0.7)
Any AE of malignancy (excluding NMSC 1 (3.3) 0 0 0 0 0 0 and
lymphomas) Any AE of malignancy (including lymphomas, 1 (3.3) 0 0 0
0 0 0 excluding NMSC) Any injection site reaction related AE 0 4
(13.3) 9 (30.0) 10 (33.3) 10 (33.3) 6 (20.0) .sup. 39 (26.0).sup.c
Deaths.sup.d 0 0 0 0 0 0 0 eow = every other week; ew = every week
.sup.aAs assessed by Investigator. .sup.bP value = 0.045 vs.
placebo. .sup.cP value = 0.002 vs. placebo. .sup.dIncludes
non-treatment emergent deaths. Note: Treatment-emergent adverse
event is defined as any adverse event with an onset date on or
after the first double-blind dose and up to 45 days after the last
double-blind dose. An event with unknown severity is being counted
as severe. P values from Fisher's exact test to compare six
treatment groups.
TABLE-US-00024 TABLE 17 Treatment-Emergent Adverse Events Occurring
In .gtoreq.5% Of Patients ABT-874 200 mg 100 mg 200 mg 200 mg 200
mg All ABT- Placebo 1 Dose eow 4 Dose eow ew 874 N = 30 N = 30 N =
30 N = 30 N = 30 N = 30 N = 150 MedDRA Preferred Term n (%)
Injection site reaction 0 2 (6.7) 7 (23.3) 5 (16.7) 7 (23.3) 4
(13.3) 25 (16.7).sup.a Nasopharyngitis 1 (3.3) 5 (16.7) 6 (20.0) 3
(10.0) 3 (10.0) 5 (16.7) 22 (14.7) Upper respiratory tract
infection 2 (6.7) 2 (6.7) 4 (13.3) 3 (10.0) 5 (16.7) 2 (6.7) 16
(10.7) Headache 2 (6.7) 5 (16.7) 0 1 (3.3) 3 (10.0) 2 (6.7) 11
(7.3) Injection site pruritus 0 0 1 (3.3) 2 (6.7) 2 (6.7) 2 (6.7) 7
(4.7) Injection site erythema 0 0 0 4 (13.3) 2 (6.7) 1 (3.3) 7
(4.7).sup.b Injection site irritation 0 1 (3.3) 3 (10.0) 2 (6.7) 0
0 6 (4.0) Fatigue 0 2 (6.7) 2 (6.7) 0 0 1 (3.3) 5 (3.3) Pain in
extremity 0 1 (3.3) 0 0 1 (3.3) 2 (6.7) 4 (2.7) Arthralgia 1 (3.3)
2 (6.7) 0 0 0 2 (6.7) 4 (2.7) Viral infection 0 0 0 2 (6.7) 1 (3.3)
1 (3.3) 4 (2.7) Bronchitis 0 1 (3.3) 0 1 (3.3) 2 (6.7) 0 4 (2.7)
Hypertriglyceridaemia 0 1 (3.3) 1 (3.3) 2 (6.7) 0 0 4 (2.7)
Influenza 1 (3.3) 0 1 (3.3) 0 2 (6.7) 0 3 (2.0) Nausea 2 (6.7) 0 3
(10.0)) 0 0 0 3 (2.0).sup.c Cyst 0 1 (3.3) 2 (6.7) 0 0 0 3 (2.0)
Gastroenteritis 0 0 0 0 0 2 (6.7) 2 (1.3) Back pain 0 0 0 0 2 (6.7)
0 2 (1.3) Otitis externa 0 0 0 0 2 (6.7) 0 2 (1.3) Vomiting 1 (3.3)
0 0 2 (6.7) 0 0 2 (1.3) Hypercholesterolaemia 0 0 0 2 (6.7) 0 0 2
(1.3) Urinary tract infection 2 (6.7) 1 (3.3) 0 1 (3.3) 0 0 2 (1.3)
Blood pressured increased 0 0 2 (6.7) 0 0 0 2 (1.3) Limb injury 0 2
(6.7) 0 0 0 0 2 (1.3) Pruritus 2 (6.7) 0 0 0 0 1 (3.3) 1 (0.7)
Psoriatic arthropathy 2 (6.7) 0 0 0 0 0 0 eow = every other week;
ew = every week .sup.aP value = 0.028 .sup.bP value = 0.052 .sup.cP
value = 0.053 Note: Treatment-emergent adverse event is defined as
any adverse event with an onset date on or after the first
double-blind dose and up to 45 days after the last double-blind
dose. An event with unknown severity is being counted as severe. P
values from Fisher's exact test to compare six treatment
groups.
III. Conclusion
[0857] In this study, treatment with ABT-874 resulted in clinically
meaningful improvements in all four body regions comprising the
PASI score, including traditionally resistant areas such as the
head and neck and the lower extremities, in patients with moderate
to severe psoriasis
[0858] Regional as well as overall benefits were demonstrated with
all doses of ABT-874 compared with placebo
[0859] The results of this study support the utility of IL-12/23 as
a therapeutic target in chronic plaque psoriasis.
Example 11
Effect of Baseline Characteristics on the Efficacy of ABT-874 for
the Treatment of Moderate to Severe Psoriasis
I. Methods
[0860] A. Study Design
[0861] The following was a twelve-week, randomized, double-blind,
placebo-controlled, multi-center study. One hundred and eighty
adult patients with psoriasis affecting .gtoreq.10% body surface
area and a Psoriasis Area and Severity Index (PASI) score
.gtoreq.12 were randomized to: one 200-mg dose ABT-874 at Week 0,
100 mg ABT-874 every other week (eow) for 12 weeks, 200 mg ABT-874
weekly for 4 weeks, 200 mg ABT-874 eow for 12 weeks, 200 mg ABT-874
weekly for 12 weeks, or placebo. The effects of the following
baseline characteristics on week 12 PASI 75 response rates were
examined: weight, PsA history, PASI score, previous psoriasis
treatments and PGA score (severe/very severe). PGA score was a
post-hoc analysis. Results are presented for all ABT-874 dosage
groups combined following 12 weeks of treatment.
[0862] B. Main Inclusion and Exclusion Criteria
[0863] The main inclusion criteria for the study were:
[0864] Adult patients with chronic moderate to severe plaque
psoriasis for at least 6 months;
[0865] Stable for at least 2 months;
[0866] .gtoreq.10% BSA;
[0867] PASI.gtoreq.12; and
[0868] Moderate or severe Physician's Global Assessment (PGA)
[0869] The main exclusion criteria for the study were:
[0870] Previous exposure to any systemic anti-IL-12 therapy,
including ABT-874;
[0871] Diagnosis of erythrodermic psoriasis, pustular psoriasis,
medication-induced or medication-exacerbated psoriasis, or new
onset guttate psoriasis;
[0872] Diagnosis of other active skin diseases or skin infections
that might interfere with evaluation of psoriasis;
[0873] Inability to discontinue prior medication;
[0874] Topicals and phototherapy for 2 weeks;
[0875] Nonbiologic systemic therapies for 4 weeks; and
[0876] Biologics for 12 weeks
[0877] C. Efficacy Measures
[0878] The following efficacy measures were used in the present
study:
[0879] The percentage of patients in each group achieving
.gtoreq.PASI 75 and .gtoreq.PASI 90 response at Week 12; and
[0880] Efficacy Analysis Subgroups (Baseline): [0881] Weight
(.ltoreq.100 kg or >100 kg) [0882] Psoriatic arthritis (PsA)
history [0883] Previous psoriasis treatments [0884] PGA score
[0885] D. Safety Measures
[0886] Laboratory results, vital signs, and adverse events (AEs)
were used to determine the safety of the treatment.
[0887] E. Statistical Methods
[0888] The following statistical methods were used to determine
efficacy of the treatment:
[0889] Comparison of the proportion of subjects achieving
.gtoreq.PASI 75 at Week 12 between ABT-874 dose group and placebo
group using Fisher's exact test, with 2-sided 95% confidence
interval for the difference in proportion;
[0890] Patients for whom data were missing were assumed to be
non-responders (non-responder imputation); and
[0891] P<0.05 indicated statistical significance
II. Results
[0892] A. Baseline Demographics
[0893] Baseline demographic and clinical characteristics were
similar across treatment groups. See Table 18.
TABLE-US-00025 TABLE 18 Baseline Demographic Baseline Demographics
and Disease Characteristics Treatment Group 200 mg 200 mg All
Placebo 1 Dose 100 mg eow 4 Dose 200 mg eow 200 mg ew ABT-874 Total
Parameter N = 30 N = 30 N = 30 N = 30 N = 30 N = 30 N = 150 N = 180
Age (years) Mean .+-. SD 49.2 .+-. 14.36 51.5 .+-. 12.00 44.5 .+-.
13.76 43.4 .+-. 13.77 43.5 .+-. 15.95 46.3 .+-. 14.00 45.9 .+-.
14.09 46.4 .+-. 14.15 Median (range) 49.5 (18-80) 52.5 (24-69) 45.0
(18-65) 43.0 (20-73) 39.0 (25-79) 47.0 (19-76) 46.0 (18-79) 47.0
(18-80) Sex, n (%) Female 8 (26.7) 7 (23.3) 8 (26.7) 9 (30.0) 7
(23.3) 7 (23.3) 38 (25.3) 46 (25.6) Male 22 (73.3) 23 (76.7) 22
(73.3) 21 (70.0) 23 (76.7) 23 (76.7) 112 (74.7) 134 (74.4) Weight
(kg) Mean .+-. SD 89.3 .+-. 17.57 93.5 .+-. 21.21 93.9 .+-. 17.88
92.1 .+-. 27.85 93.4 .+-. 24.06 94.6 .+-. 18.03 93.5 .+-. 21.85
92.8 .+-. 21.21 Median 90.0 (43.0-140.0) 89.5 (61.0-145.0) 91.1
(60.0-125.0) 89.0 (54.0-169.0) 89.0 (62.0-161.0) 93.2 (68.0-153.0)
90.0 (54.0-169.0) 90.0 (43.0-169.0) (range) Weight group, n (%)
.ltoreq.100 kg 23 (76.7) 18 (60.0) 18 (60.0) 20 (66.7) 20 (66.7) 21
(70.0) 97 (64.7) 120 (66.7) >100 kg 7 (23.3) 12 (40.0) 12 (40.0)
10 (33.3) 10 (33.3) 9 (30.0) 53 (35.3) 60 (33.3) Family History of
9 (30.0) 17 (56.7) 21 (70.0) 23 (76.7) 15 (50.0) 12 (40.0) 88
(58.7) 97 (53.9) Psoriasis (n, %) Duration of Chronic Plaque
Psoriasis (years) Mean .+-. SD 21.43 .+-. 12.40 19.78 .+-. 13.18
23.95 .+-. 14.60 22.09 .+-. 14.24 18.5 .+-. 11.52 17.93 .+-. 10.89
20.45 .+-. 12.99 20.61 .+-. 12.87 Median (range) 20.55 (1.0-48.1)
17.55 (1.6-43.0) 22.05 (3.2-59.1) 21.0 (1.3-53.0) 18.09 (0.8-55.1)
15.68 (4.1-47.1) 19.11 (0.8-59.1) 19.58 (0.8-59.1) PASI .ltoreq.20
28 (93.3) 22 (73.3) 18 (60.0) 21 (70.0) 18 (60.0) 21 (70.0) 100
(66.7) 128 (71.1) >20 2 (6.7) 8 (26.7) 12 (40.0) 9 (30.0) 12
(40.0) 9 (30.0) 50 (33.3) 52 (28.9) Mean .+-. SD 15.83 .+-. 2.86
17.96 .+-. 6.72 19.93 .+-. 6.29 19.94 .+-. 7.57 19.86 .+-. 6.20
18.96 .+-. 6.33 19.33 .+-. 6.60 18.75 .+-. 6.27 Median (range)
16.10 (10.2-22.6) 14.95 (12.1-35.4) 18.65 (12.4-34.4) 16.95
(12.3-41.4) 18.0 (11.9-33.4) 16.75 (12.2-37.2) 17.25 (11.9-41.4)
16.85 (10.2-41.4) BSA (%) .ltoreq.20% 19 (63.3) 18 (60.0) 15 (50.0)
15 (50.0) 14 (46.7) 16 (53.3) 78 (52.0) 97 (53.9) >20% 11 (36.7)
12 (40.0) 15 (50.0) 15 (50.0) 16 (53.3) 14 (46.7) 72 (48.0) 83
(46.1) Mean .+-. SD 20.88 .+-. 9.18 24.06 .+-. 13.58 27.88 .+-.
15.68 24.15 .+-. 13.05 29.06 .+-. 16.84 22.92 .+-. 12.61 25.61 .+-.
14.45 24.83 .+-. 13.81 Median (range) 17.5 (11.0-45.0) 17.5
(10.0-57.5) 22.5 (11.0-74.0) 20.3 (10.0-59.0) 22.0 (11.0-82.0) 19.5
(10.0-53.0) 20.0 (10.0-82.0) 20.0 (10.0-82.0) PGA Minimal 0 0 0 0 0
0 0 0 Mild 1 (3.3) 0 0 0 0 0 0 1 (0.6) Moderate 20 (66.7) 19 (63.3)
17 (56.7) 13 (43.3) 15 (50.0) 17 (56.7) 81 (54.0) 101 (56.1) Severe
9 (30.0) 11 (36.7) 12 (40.0) 14 (46.7) 13 (43.3) 11 (36.7) 61
(40.7) 70 (38.9) Very Severe 0 0 1 (3.3) 3 (10.0) 2 (6.7) 2 (6.7) 8
(5.3) 8 (4.4) History of Psoriatic 9 (30.0) 7 (23.3) 12 (40.0) 9
(30.0) 6 (20.0) 9 (30.0) 43 (28.7) 52 (28.9) Arthritis, n (%)
Duration of Psoriatic Arthritis (years) Mean .+-. SD 10.69 .+-.
11.70 13.51 .+-. 10.67 11.25 .+-. 12.00 13.0 .+-. 12.60 8.6 .+-.
8.31 14.18 .+-. 11.78 12.23 .+-. 11.06 11.96 .+-. 11.07 Median
(range) 5.82 (0.1-30.0) 16.05 (2.2-31.0) 8.03 (1.1-45.1) 10.91
(0.1-37.2) 4.33 (2.6 .+-. 22.9) 11.1 (0.2-36.0) 8.13 (0.1-45.1)
7.02 (0.1-45.1) Swollen, Tender, or 8 (26.7) 11 (36.7) 10 (33.3) 10
(33.3) 9 (30.0) 15 (50.0) 55 (36.7) 63 (35.0) Stiff Joints, n (%)
eow: every other week ew: every week
[0894] B. Efficacy
[0895] A greater percentage of patients treated with any dose of
ABT-874 achieved .gtoreq.PASI 75 or .gtoreq.PASI 90 at week 12
compared with placebo (FIG. 15).
[0896] The effect of baseline characteristics on efficacy was
examined. Similar percentages of patients in two weight categories
(.ltoreq.100 kg or >100 kg) treated with any dose of ABT-874
achieved PASI 75 at Week 12 (FIG. 16). In particular, at week 12,
the percentage of patients achieving PASI 75 in the .ltoreq.100 kg
or >100 kg groups was 88.7% vs. 81.1% respectively. Similar
percentages of patients with or without a history of PsA achieved
PASI 75 at Week 12 (FIG. 17). In particular, PASI 75 responses for
patients with and without previous PsA were 83.7% vs. 86.9%
respectively. A majority of patients (85.5%) with severe or very
severe baseline PGA score achieved PASI 75 at Week 12 (FIG. 18).
Similar percentages of patients in two baseline PASI categories
(.ltoreq.20 or >20) achieved PASI 75 at Week 12 (FIG. 19). For
patients with baseline PASI scores of .ltoreq.20 or >20, 87.0%
vs. 84.0% achieved PASI 75 responses at week 12, respectively.
Finally, prior psoriasis treatments such as systemic or biologic
agents, topicals or phototherapy did not appear to effect PASI 75
response rates, and thus had minimal effect on the efficacy of
ABT-874 (Table 19).
TABLE-US-00026 TABLE 19 PASI 75 Response at Week 12 by Prior
Psoriasis Treatment. Systemic Biologic Topical Phototherapy + - + -
+ - + - ABT- n 30 120 30 123 106 44 22 128 874 % achieving PASI 75
90% 85% 85.2% 86.2% 88.7% 79.5% 90.9% 85.2% Placebo n 6 24 3 27 19
11 1 29 % achieving PASI 75 0.0% 4.2% 0.0% 3.7% 0.0% 9.1% 0.0%
3.4%
[0897] C. Safety
[0898] An overview of the number and percentage of subjects with
treatment-emergent adverse events is presented in Table 20. Most
reported AEs were mild or moderate in severity. The percentage of
patients experiencing serious AEs was low. The most frequently
reported treatment-emergent adverse events occurring in .gtoreq.5%
of patients are listed in Table 21.
TABLE-US-00027 TABLE 20 Overview of Treatment-Emergent Adverse
Events ABT-874 200 mg 100 mg 200 mg 200 mg 200 mg All ABT- Placebo
1 Dose eow 4 Dose eow ew 874 N = 30 N = 30 N = 30 N = 30 N = 30 N =
30 N = 150 n (%) Any adverse event (AE) 18 (60.0) 18 (60.0) 24
(80.0) 22 (73.3) 23 (76.7) 21 (70.0) 108 (72.0) Any AE at least
possibly drug-related.sup.a 4 (13.3) 9 (30.0) 14 (46.7) 14 (46.7)
12 (40.0) 9 (30.0) 58 (38.7).sup.b Any severe AE 4 (13.3) 1 (3.3) 0
0 1 (3.3) 1 (3.3) 3 (2.0) Any serious AE 1 (3.3) 1 (3.3) 0 0 1
(3.3) 0 2 (1.3) Any AE leading to discontinuation of study 2 (6.7)
1 (3.3) 0 0 0 0 1 (0.7) drug Any at least possibly drug-related
serious AE.sup.a 0 0 0 0 1 (3.3) 0 1 (0.7) Any infectious AE 7
(23.3) 8 (26.7) 11 (36.7) 14 (46.7) 15 (50.0) 10 (33.3) 58 (38.7)
Any serious infectious AE 0 0 0 0 1 (3.3) 0 1 (0.7) Any malignant
AE 1 (3.3) 0 0 1 (3.3) 0 0 1 (0.7) Any lymphomas AE 0 0 0 0 0 0 0
Any non-melanoma skin cancer (NMSC) AE 0 0 0 1 (3.3) 0 0 1 (0.7)
Any AE of malignancy (excluding NMSC and 1 (3.3) 0 0 0 0 0 0
lymphomas) Any AE of malignancy (including lymphomas, 1 (3.3) 0 0 0
0 0 0 excluding NMSC) Any injection site reaction related AE 0 4
(13.3) 9 (30.0) 10 (33.3) 10 (33.3) 6 (20.0) 39 (26.0).sup.c Any
fatal AE 0 0 0 0 0 0 0 Deaths.sup.d 0 0 0 0 0 0 0 eow = every other
week; ew = every week .sup.aAs assessed by Investigator. .sup.bP
value = 0.045 vs. placebo. .sup.cP value = 0.002 vs. placebo.
.sup.dIncludes non-treatment emergent deaths. Note:
Treatment-emergent adverse event is defined as any adverse event
with an onset date on or after the first double-blind dose and up
to 45 days after the last double-blind dose. An event with unknown
severity is being counted as severe. P values from Fisher's exact
test to compare six treatment groups.
TABLE-US-00028 TABLE 21 Treatment-Emergent Adverse Events Occurring
In .gtoreq.5% Of Patients ABT-874 200 mg 100 mg 200 mg 200 mg 200
mg All ABT- Placebo 1 Dose eow 4 Dose eow ew 874 N = 30 N = 30 N =
30 N = 30 N = 30 N = 30 N = 150 MedDRA Preferred Term n (%)
Injection site reaction 0 2 (6.7) 7 (23.3) 5 (16.7) 7 (23.3) 4
(13.3) 25 (16.7).sup.a Nasopharyngitis 1 (3.3) 5 (16.7) 6 (20.0) 3
(10.0) 3 (10.0) 5 (16.7) 22 (14.7) Upper respiratory tract
infection 2 (6.7) 2 (6.7) 4 (13.3) 3 (10.0) 5 (16.7) 2 (6.7) 16
(10.7) Headache 2 (6.7) 5 (16.7) 0 1 (3.3) 3 (10.0) 2 (6.7) 11
(7.3) Injection site pruritus 0 0 1 (3.3) 2 (6.7) 2 (6.7) 2 (6.7) 7
(4.7) Injection site erythema 0 0 0 4 (13.3) 2 (6.7) 1 (3.3) 7
(4.7).sup.b Injection site irritation 0 1 (3.3) 3 (10.0) 2 (6.7) 0
0 6 (4.0) Fatigue 0 2 (6.7) 2 (6.7) 0 0 1 (3.3) 5 (3.3) Pain in
extremity 0 1 (3.3) 0 0 1 (3.3) 2 (6.7) 4 (2.7) Arthralgia 1 (3.3)
2 (6.7) 0 0 0 2 (6.7) 4 (2.7) Viral infection 0 0 0 2 (6.7) 1 (3.3)
1 (3.3) 4 (2.7) Bronchitis 0 1 (3.3) 0 1 (3.3) 2 (6.7) 0 4 (2.7)
Hypertriglyceridaemia 0 1 (3.3) 1 (3.3) 2 (6.7) 0 0 4 (2.7)
Influenza 1 (3.3) 0 1 (3.3) 0 2 (6.7) 0 3 (2.0) Nausea 2 (6.7) 0 3
(10.0)) 0 0 0 3 (2.0).sup.c Cyst 0 1 (3.3) 2 (6.7) 0 0 0 3 (2.0)
Gastroenteritis 0 0 0 0 0 2 (6.7) 2 (1.3) Back pain 0 0 0 0 2 (6.7)
0 2 (1.3) Otitis externa 0 0 0 0 2 (6.7) 0 2 (1.3) Vomiting 1 (3.3)
0 0 2 (6.7) 0 0 2 (1.3) Hypercholesterolaemia 0 0 0 2 (6.7) 0 0 2
(1.3) Urinary tract infection 2 (6.7) 1 (3.3) 0 1 (3.3) 0 0 2 (1.3)
Blood pressured increased 0 0 2 (6.7) 0 0 0 2 (1.3) Limb injury 0 2
(6.7) 0 0 0 0 2 (1.3) Pruritus 2 (6.7) 0 0 0 0 1 (3.3) 1 (0.7)
Psoriatic arthropathy 2 (6.7) 0 0 0 0 0 0 eow = every other week;
ew = every week .sup.aP value = 0.028 .sup.bP value = 0.052 .sup.cP
value = 0.053 Note: Treatment-emergent adverse event is defined as
any adverse event with an onset date on or after the first
double-blind dose and up to 45 days after the last double-blind
dose. An event with unknown severity is being counted as severe. P
value from Fisher's exact test to compare 6 treatment groups. Only
P values .ltoreq.0.100 are presented.
III. Conclusion
[0899] In this study, a majority of patients with moderate to
severe psoriasis treated with ABT-874 achieved a PASI 75 response
at Week 12. The percentage of patients achieving PASI 75 at Week 12
was similar, regardless of baseline characteristics, including
weight, physician's global assessment, PASI scores, history of
psoriatic arthritis, or prior psoriasis treatments.
Example 12
Efficacy and Safety Results from a Phase III, Randomized Controlled
Trial Comparing Two Dosing Regimens of ABT-874 to Placebo in
Patients with Moderate to Severe Psoriasis: The Vero Study
I. Methods
Design
[0900] Phase III, 52-week, double-blind, placebo-controlled,
multi-center clinical trial with two-phases: Induction and
Maintenance (FIG. 20) (NCT00570986) [0901] Induction Phase: [0902]
Patients were randomized 2:1 and received 1 of 2 treatments: [0903]
ABT-874, 200 mg at Weeks 0 and 4, followed by 100 mg at Week 8
[0904] Placebo [0905] Maintenance Phase: [0906] Patients who
achieved a Physicians Global Assessment score of "clear" or
"minimal" (PGA 0/1) at Week 12 in the Induction Phase were
re-randomized 2:2:1 (stratified by treatment received in Induction
Phase) to 1 of 3 treatment arms: [0907] ABT-874, 100 mg every 4
weeks (q 4 wk) [0908] ABT-874, 100 mg every 12 weeks (q 12 wk)
[0909] Placebo q 4 wk
Efficacy and Safety Measures
[0909] [0910] Efficacy was measured using a 6-point Physician's
Global Assessment (PGA) scale and Psoriasis Area and Severity Index
at Weeks 0, 1, 4, and 8 in the Induction Phase, and every month
during the Maintenance Phase (Weeks 12 to 52) [0911] Patients were
assessed for adverse events throughout the study, and up to 45 days
following the last dose of study medication
Patients
[0911] [0912] Key inclusion criteria: [0913] Adult patients with
chronic plaque psoriasis for at least 6 months (and stable for at
least 2 months) prior to baseline [0914] Moderate to severe
psoriasis defined by the following at baseline: [0915] Affected
body surface area (BSA).gtoreq.10% [0916] PGA at least "moderate"
(defined as .gtoreq.3) [0917] PASI.gtoreq.12 [0918] Key exclusion
criteria: [0919] Previous exposure to anti-interleukin 12 therapy,
including ABT-874 [0920] Other forms of psoriasis (other than
plaque psoriasis) [0921] Treatment with any of the following:
[0922] Topical treatments (i.e., corticosteroids, vitamin D
analogs, or retinoids) or UVB phototherapy within 2 weeks of
baseline [0923] PUVA phototherapy or systemic treatments for
psoriasis within 4 weeks of baseline [0924] Biologic treatments
within 12 weeks of baseline
Statistical Methods
[0924] [0925] Proportions of patients who achieved the following 3
primary endpoints were compared between treatment groups: [0926]
PGA 0/1 at Week 12 [0927] 75% improvement from baseline in PASI
(PASI 75) at Week 12 [0928] Maintenance of PGA 0/1 at Week 52
[0929] Efficacy analyses were conducted in the intent-to-treat
population, and missing values were dealt with using non-responder
imputation (NRI) [0930] All statistical tests were two-tailed. The
primary analysis at week 12 was conducted using the
Cochran-Mantel-Haenszel test.* In all other cases, one-way ANOVA
and Chi Square test/Fisher's Exact test were used for continuous
and discrete variables, respectively. [0931] Statistical
significance level was set at P<0.05 *Adjusted for pooled
centers, where the smallest center was pooled with the next
smallest center to achieve at least 100 patients per pooled
center.
Results
Efficacy
[0931] [0932] 1465 patients were enrolled into the Vero study (FIG.
21) [0933] Induction Phase: [0934] ABT-874, N=981 [0935] Placebo,
N=484 [0936] Maintenance Phase: (for patients receiving ABT-874
during Induction) [0937] ABT-874 q4 wk, N=298 [0938] ABT-874 q12
wk, N=298 [0939] Placebo, N=149 [0940] Baseline demographics and
clinical characteristics were similar between treatment groups
(Table 22)
TABLE-US-00029 [0940] TABLE 22 Baseline Demographics and Clinical
Characteristics Induction Phase Maintenance Phase ABT-874 Placebo
ABT-874 q4 ABT-874 q12 Placebo Total Baseline Characteristics (N =
981) (N = 484) (N = 298).sup.a (N = 298) (N = 149) (N = 1465) Mean
age, yrs.sup.b 45.7 .+-. 13.2 45.1 .+-. 13.5 44.6 .+-. 13.3 45.5
.+-. 12.6 45.0 .+-. 13.4 45.5 .+-. 13.3 Gender (l/m), n (%) 315/666
141/343 92/206 97/201 49/100 456/1009 (32.1/67.9) (29.1/70.9)
(30.9/69.1) (32.6/67.4) (32.9/67.1) (31.1/68.9) Caucasian, n (%)
888 (90.5) 432 (89.3) 275 (92.3) 278 (93.3) 127 (85.2) 1320 (90.1)
Weight, kg.sup.b 93.8 .+-. 23.6 93.1 .+-. 23.0 91.3 .+-. 21.3 93.7
.+-. 23.4 89.3 .+-. 24.6 93.5 .+-. 23.4 BSA, % .+-. SD 24.8 .+-.
16.3 25.7 .+-. 16.9 23.7 .+-. 14.8 22.3 .+-. 13.5 25.2 .+-. 17.1
25.1 .+-. 16.5 PASI Score.sup.b 19.1 .+-. 7.5 19.3 .+-. 7.3 18.4
.+-. 6.5 18.3 .+-. 6.2 18.9 .+-. 8.2 19.2 .+-. 7.4 Psoriasis
duration, yrs.sup.b 18.9 .+-. 12.3 19.2 .+-. 11.9 19.1 .+-. 12.1
18.5 .+-. 12.1 18.9 .+-. 12.4 19.0 .+-. 12.2 PGA, n (%) Moderate
514 (52.4) 242 (50.0) 170 (57.0) 164 (55.0) 85 (57.0) 756 (51.6)
Severe 408 (41.6) 218 (45.0) 113 (37.9) 124 (41.6) 53 (35.6) 626
(42.7) Very Severe 59 (6.0) 24 (5.0) 15 (5.0) 10 (3.4) 11 (7.4) 83
(5.7) Previous Medical History, n (%) Any CVD 395 (40.3) 178 (36.8)
108 (36.2) 117 (39.3) 51 (34.2) 573 (39.1) Hyperlipidemia 145
(14.8) 57 (11.8) 34 (11.4) 51 (17.1) 24 (16.1) 202 (13.8) DM 98
(10.0) 40 (8.3) 15 (5.0) 29 (9.7) 18 (12.1) 138 (9.4) q4 = every 4
weeks; q12 = every 12 weeks; BSA = Affected body surface area; PASI
= Psoriasis Area and Severity Index; PGA = Physician's Global
Assessment; CVD = cardiovascular disease; DM = diabetes mellitus.
.sup.aOne patient in the ABT-874 q4 group was re-randomized but did
not receive any study drug in the Maintenance Phase. .sup.bMean
value .+-. SD.
[0941] Significantly greater percentages of patients treated with
ABT-874 vs. placebo achieved the endpoints of PGA 0/1 and PASI 75
at Week 12 (P<0.001, NRI for each analysis) (FIGS. 22 and 23)
[0942] Continued dosing with ABT-874 in subjects who achieved a PGA
0/1 response at week 12 resulted in better maintenance of a PGA 0/1
response at week 52 compared with treatment withdrawal (FIG. 24)
[0943] Dosing ABT-874 every 4 weeks resulted in better maintenance
of PASI 75 and PASI 90 responses than dosing every 12 weeks (FIG.
25)
Safety
[0943] [0944] The most common adverse events reported among
patients randomized to ABT-874 in the Induction Phase and receiving
any ABT-874 through 52 weeks were: nasopharyngitis, headache, and
upper respiratory tract infection (Table 23) [0945] 16 patients in
the ABT-874 q4 wk treatment group experienced back pain as compared
to 6 patients in the q12 wk group, and 3 patients in the placebo
group, suggesting a possible dose response relationship for this
event. The reason for any potential association is unknown.
TABLE-US-00030 [0945] TABLE 23 Treatment-Emergent Adverse Events
Occurring in .gtoreq.5% of Patients Induction Phase Maintenance
Phase ABT-874 Placebo ABT-874 q4 ABT-874 q12 Placebo All ABT-874 (N
= 981) (N = 484) (N = 297) (N = 298) (N = 149) (N = 998).sup.a n
(%) Nasopharyngitis 63 (6.4) 20 (4.1) 39 (13.1) 35 (11.7) 9 (6.0)
106 (10.6) Headache 53 (5.4) 9 (1.9) 0 0 0 66 (6.6) Upper
Respiratory Tract Infection 49 (5.0) 20 (5.0) 48 (16.2) 24 (8.1) 8
(5.4) 104 (10.4) Back Pain 0 0 16 (5.4) 6 (2.0) 3 (2.0) <5%
.sup.aAll patients randomized to ABT-874 in the Induction Phase and
re-randomized to ABT-874 in the Maintenance Phase.
[0946] Serious adverse events occurred in 20 (2.0%) ABT-874 and 6
(1.2%) placebo treated patients during the Induction Phase (Table
24) [0947] Of the serious adverse events, 5 (0.5%) in the ABT-874
group and 1 (0.2%) in the placebo group involved an event of
infection (Table 24) [0948] During the placebo-controlled Induction
Phase, 6 events of malignancy were reported in the ABT-874 group,
while none were reported in the placebo group [0949] Of the
malignant events observed in patients treated with ABT-874, most
were either squamous cell or basal cell skin carcinomas (Table 24)
[0950] A total of 7 major adverse cardiac events (MACE) defined as
myocardial infarction, stroke or cardiovascular death, occurred in
patients receiving ABT-874. There were no MACE events observed in
patients receiving placebo. (Table 24)
TABLE-US-00031 [0950] TABLE 24 Summary of Treatment-Emergent
Adverse Events and Adverse Events of Interest Induction Phase
Maintenance Phase ABT-874 Placebo ABT-874 q4 ABT-874 q12 Placebo (N
= 981) (N = 484) (N = 297) (N = 298) (N = 149) n (%) Any AE 517
(52.7) 229 (47.3) 215 (72.4) 183 (61.4) 86 (57.7) Any AE leading to
17 (1.7) 4 (0.8) 3 (1.0) 6 (2.0) 1 (0.7) discontinuation of study
drug Any serious AE 20 (2.0) 6 (1.2) 4 (1.3) 9 (3.0) 2 (1.3) Deaths
.sup. 1.sup.a 0 0 0.sup.b 0 AEs of special interest: Any Infection
219 (22.3) 96 (19.8) 132 (44.4) 107 (35.9) 41 (27.5) Serious
Infections 5 (0.5) 1 (0.2) 0 2 (0.7) 1 (0.7) Malignancies 6 (0.6) 0
3 (1.0) 5 (1.7) 0 SCC 4 (0.4) na 0 2 (0.7) na BCC 0 na 2 (0.7) 2
(0.7) na Other 2 (0.2).sup.c na 1 (0.3).sup.d 1 (0.3).sup.e na
Cardiovascular 5 (0.5).sup.f 0 1 (0.3).sup.g 1 (0.3).sup.h 0 AE =
adverse event; SCC = squamous cell carcinoma; BCC = basal cell
carcinoma; na = not applicable. .sup.aOne patient experienced
cardiac arrest resulting in death (event also listed in AEs of
special interest, cardiovascular). .sup.bOne event of death
occurred >45 days after study discontinuation in a patient who
had a cardiovascular event listed in AEs of special interest.
.sup.cOne patient diagnosed with lung cancer on study day 43, and 1
with nasopharyngeal cancer on study day 15. .sup.dOne patient
diagnosed with colon cancer on study day 285. .sup.eOne patient
diagnosed with tonsil cancer on study day 266. .sup.fOne patient
had cardiac arrest, 3 had myocardial infarction, and 1 had stroke.
.sup.gOne patient had an event of acute coronary syndrome.
.sup.hOne patient had myocardial infarction.
[0951] Five of 7 MACE events occurred within the first 2 months of
study treatment (FIG. 26) [0952] All MACE events occurred in
patients who had underlying risk factors for coronary heart disease
(CHD).sup.2
Conclusions
[0952] [0953] ABT-874 induced rapid and significantly higher
efficacy responses in patients with moderate to severe psoriasis
compared to placebo [0954] Dosing ABT-874 every 4 weeks resulted in
better maintenance of response than every 12 weeks [0955] A higher
incidence of infection and malignancy adverse events were observed
in ABT-874 vs. placebo treated patients. Considering the
immunomodulating mechanism of ABT-874, these findings are not
unexpected and support the need for monitoring and surveillance for
these events. [0956] A numerical imbalance was observed for MACE
events, with 7 cases reported in the ABT-874 group compared with no
events in the placebo group. While cardiovascular events are not
unexpected in the psoriasis patient population, further evaluation
will determine if an increase in the number of MACE events is a
reproducible phenomenon in patients treated with ABT-874.
Example 13
Efficacy and Safety Results from a Phase III, Randomized Controlled
Trial Comparing the Safety and Efficacy of ABT-874 to Etanercept
(ETN) and Placebo in Patients with Moderate to Severe Chronic
Plaque Psoriasis
Objective
[0957] The primary objective of study M10-315 was to compare, in a
Phase III trial, the efficacy and safety of ABT-874 to etanercept
and placebo in subjects with moderate to severe chronic plaque
psoriasis over 12 weeks
Methods
[0958] Main Inclusion Criteria [0959] Males and females .gtoreq.18
years with a clinical diagnosis of chronic plaque psoriasis for at
least 6 months [0960] Stable plaque Ps for at least 2 months before
Screening and at Baseline (Week 0) visits [0961] Affected body
surface area (BSA).gtoreq.10% [0962] Physician's Global Assessment
(PGA) of at least moderate (.gtoreq.3) and PASI score of .gtoreq.12
at the Baseline (Week 0) visit
Main Exclusion Criteria
[0962] [0963] Previous exposure to systemic anti-IL-12/23p40
therapy, including ABT-874 [0964] Previous exposure to ETN or known
hypersensitivity to ETN [0965] Inability to discontinue topical
therapies, phototherapies, or systemic therapies
Study Design (FIG. 27)
[0965] [0966] 12-week double-blind, double dummy, multicenter,
randomized study [0967] Patients were randomized to 1 of the 3
following treatment arms (2:2:1); "a" indicates the second dose of
the week when doses were administered twice weekly: [0968] 200 mg
ABT-874 SC at Weeks 0 and 4 followed by 100 mg ABT-874 SC at Week 8
[0969] 50 mg of ETN SC twice weekly 3-4 days apart at Weeks 0, 0a,
1, 1a, 2, 2a, 3, 3a, 4, 4a, 5, 5a, 6, 6a, 7, 7a, 8, 8a, 9, 9a, 10,
10a, 11, and 11a [0970] Placebo SC at Week 0 and 4 followed by
placebo SC at Week 8 to match ABT-874 dosing, or placebo SC twice
weekly 3-4 days apart at Weeks 0, 0a, 1, 1a, 2, 2a, 3, 3a, 4, 4a,
5, 5a, 6, 6a, 7, 7a, 8, 8a, 9, 9a, 10, 10a, 11, and 11a to match
ETN dosing
Efficacy Measures
[0970] [0971] Proportion of patients achieving a PGA score of
"Clear" or "Minimal" (0/1) at Week 12 [0972] Proportion of patients
achieving a PASI 75/90/100 response at Week 12
Safety Measures
[0972] [0973] Adverse events and serious adverse events were
assessed throughout the study
Statistical Methods
[0973] [0974] The efficacy analyses were conducted in the
intent-to-treat (ITT) population; non-responder imputation was used
to handle missing data [0975] Cochran-Mantel-Haenszel tests
stratified by pooled center were used to compare the proportion of
patients in each treatment group achieving PGA 0/1 or PASI 75 at
Week 12 in the primary analysis [0976] A Chi-Square test, or
Fisher's exact test as appropriate, was used to compare proportions
of patients in each treatment group achieving PASI 90 or 100 at
Week 12 [0977] All statistical tests were two-sided with the
significance level of 0.05 [0978] The safety analyses were
conducted in the safety population; safety variables were
summarized by treatment group
Results
[0978] [0979] 350 patients were enrolled and analyzed [0980]
ABT-874, N=139 [0981] Etanercept, N=139 [0982] Placebo, N=72 [0983]
Baseline demographics and clinical characteristics were similar
across treatment groups (Table 25)
TABLE-US-00032 [0983] TABLE 25 Baseline Demographics and Clinical
Characteristics Placebo Etanercept ABT-874 Total (N = 72) (N = 139)
(N = 139) (N = 350) Age (yrs).sup.a 45.0 (13.6) 45.2 (14.8) 44.9
(12.9) 45.1 (13.8) Male, n (%) 46 (63.9) 85 (61.2) 93 (66.9) 224
(64.0) Caucasian, n (%) 67 (93.1) 127 (91.4) 122 (87.8) 316 (90.3)
Duration of psoriasis.sup.a 15.5 (11.7) 15.2 (12.1) 16.3 (12.0)
15.7 (11.9) Body weight (kg).sup.a 92.9 (25.2) 96.9 (24.9) 96.1
(24.5) 95.8 (24.8) % BSA.sup.a 22.1 (13.4) 24.7 (13.9) 24.9 (17.8)
24.2 (15.5) PGA, n (%) Moderate 34 (47.2) 69 (49.6) 63 (45.3) 166
(47.4) Severe 35 (48.6) 63 (45.3) 67 (48.2) 165 (47.1) Very Severe
3 (4.2) 7 (5.0) 9 (6.5) 19 (5.4) PASI score.sup.a 18.3 (6.4) 18.5
(6.0) 19.4 (7.9) 18.8 (6.9) Previous medical history, n (%) Any CVD
26 (36.1) 56 (40.3) 52 (37.4) 134 (38.3) Hyperlipidemia 6 (8.3) 8
(5.8) 15 (10.8) 29 (8.3) Diabetes mellitus 7 (9.7) 13 (9.4) 9 (6.5)
29 (8.3) PGA = Physician's Global Assessment PASI = Psoriasis Area
and Severity Index BSA = Body Surface Area .sup.aMean (SD)
.sup.bAny patient who reported 2 or more diagnoses in the same body
system were only counted once in body system total
Efficacy
[0984] A statistically significant greater percentage of patients
in the ABT-874 treatment group (72.7%) achieved a PGA of 0/1 at
Week 12 as compared with patients receiving placebo (4.2%) or
etanercept (29.5%), P<0.001 (FIG. 28) [0985] A statistically
significantly greater percentage of patients in the ABT-874
treatment group (80.6%) achieved a PASI 75 response at Week 12 as
compared with patients receiving placebo (6.9%) or etanercept
(39.6%) [P<0.001] [FIG. 29] [0986] At Week 12, PASI 90 and PASI
100 responses were achieved by a statistically significantly
greater percentage of patients in the ABT-874 treatment group
(55.4% and 28.8%, respectively) as compared with patients receiving
placebo (4.2% and 0, respectively) or etanercept (13.7% and 5.8%,
respectively) [FIGS. 30 and 31]
Safety
[0986] [0987] A higher percentage of patients in the ABT-874 and
etanercept treatment groups experienced adverse events than
patients in the placebo treatment group, respectively (50.4%, 49.6%
and 44.4%, respectively) [Table 26] [0988] Treatment
discontinuation was low in both etanercept and ABT-874 treatment
groups with 2.9% (4/139) discontinuing in each group (Table 26)
[0989] Serious adverse events were reported in 2 (2.8%) patients
receiving placebo (coronary artery disease, psoriasis), 1 (0.7%)
patient receiving etanercept (breast cancer), and 2 (1.4%) patients
receiving ABT-874 (colon cancer, convulsion) (Table 26) [0990] No
deaths occurred during the study (Table 26)
TABLE-US-00033 [0990] TABLE 26 Overview of Treatment-Emergent
Adverse Events (AEs) Treatment Group, n (%) Placebo Etanercept
ABT-874 N = 72 N = 139 N = 139 Any AE 32 (44.4) 69 (49.6) 70 (50.4)
Any severe AE 2 (2.8) 1 (0.7) 2 (1.4) Any serious AE 2 (2.8) 1
(0.7) 2 (1.4) Any AE leading to discontinuation 2 (2.8) 4 (2.9) 4
(2.9) of study drug Deaths 0 0 0
[0991] The incidence of adverse events of infection including
serious adverse events of infection was comparable between the
ABT-874 treatment group and the etanercept treatment group (Table
27) [0992] Eight patients experienced malignancies: three in the
ABT-874 treatment group (colon, basal cell skin, squamous cell
skin), four in the etanercept treatment group (2 basal cell skin, 1
squamous cell skin, breast) and 1 melanoma in the placebo treatment
group (Table 27) [0993] Eight patients reported ischaemic heart
disease related events. Seven of these events were increased
creatine phosphokinase and one event of coronary heart disease in a
placebo patient [0994] No major adverse cardiac events (MACE),
defined as myocardial infarction, stroke, or cardiovascular death,
were reported in any of the treatment groups (Table 27)
TABLE-US-00034 [0994] TABLE 27 Treatment-Emergent Adverse Events of
Interest Treatment Group Placebo Etanercept ABT-874 N = 72 N = 139
N = 139 n (%) n (%) n (%) Any infection 10 (13.9) 39 (28.1) 34
(24.5) Any serious infection 0 0 0 Any opportunistic infection 0 0
0 Any malignancy 1 (1.4) 4 (2.9) 3 (2.2) Squamous cell carcinoma 0
1 (0.7) 1 (0.7).sup.a Basal cell carcinoma 0 2 1 (0.7) Other 1
(1.4).sup.b 1 (0.7).sup.c 1 (0.7).sup.d Any injection site reaction
3 (4.2) 12 (8.6) 5 (3.6) Any nervous system disorder 0 0 1
(0.7).sup.e Any MACE.sup.f 0 0 0 .sup.aOne patient diagnosed with
lip neoplasm, malignant stage unspecified, on study day 92
.sup.bOne patient diagnosed with melanoma on study day 30 .sup.cOne
patient diagnosed with breast cancer in situ on study day 110
.sup.dOne patient diagnosed with colon cancer on study day 66
.sup.eOne patient diagnosed with convulsion on study day 73
.sup.fMajor Adverse Cardiac Event, defined as myocardial
infarction, stroke, or cardiovascular death
[0995] The most frequently reported treatment-emergent adverse
events occurring in at least 5% of patients in both the ABT-874 and
etanercept treatment groups were upper respiratory tract infection
(7.2% and 11.5%, respectively) and nasopharyngitis (7.2% and 7.9%,
respectively) (Table 28)
TABLE-US-00035 [0995] TABLE 28 Treatment-Emergent Adverse Events
Occurring in .gtoreq.5% of Patients in Any Treatment Group
Treatment Group Placebo Etanercept ABT-874 N = 72 N = 139 N = 139 n
(%) n (%) n (%) Upper respiratory tract infection 0 16 (11.5) 10
(7.2) .sup..dagger. Nasopharyngitis 6 (8.3) 11 (7.9) 10 (7.2).sup.
.sup..dagger. P = 0.017, ABT-874 vs. placebo
Conclusions
[0996] ABT-874 was superior to both placebo and etanercept as
demonstrated by the statistically significant result of the two
co-primary endpoints: PGA 0/1 (P<0.001) and PASI 75 (P<0.001)
at 12 weeks [0997] In this study population, no deaths, no MACE,
and a comparably low incidence of serious infections and
malignancies were reported across treatment groups
Example 14
Efficacy and Safety of ABT-874 Versus Etanercept and Placebo in
Patients With Moderate to Severe Psoriasis: The VERTO Study
Objective
[0998] The aim of the VERTO study was to assess the efficacy,
safety, and tolerability of ABT-874 compared with etanercept and
placebo for the treatment of moderate to severe chronic plaque
psoriasis over 12 weeks
Methods
Main Inclusion Criteria
[0999] Males and females .gtoreq.18 years with a clinical diagnosis
of chronic plaque psoriasis for at least 6 months [1000] Stable
plaque Ps for at least 2 months before Screening and at Baseline
(Week 0) visits [1001] Affected body surface area (BSA).gtoreq.10%
[1002] Physician's Global Assessment (PGA) of at least moderate
(.gtoreq.3) and Psoriasis Area and Severity Index (PASI) score of
.gtoreq.12 at the Baseline (Week 0) visit
Main Exclusion Criteria
[1002] [1003] Previous exposure to systemic anti-IL-12/23p40
therapy, including ABT-874 [1004] Previous exposure to ETN or known
hypersensitivity to ETN [1005] Inability to discontinue topical
therapies, phototherapies, or systemic therapies
Study Design (FIG. 32)
[1005] [1006] 12-week double-blind, double dummy, multicenter,
randomized study [1007] Patients were randomized to 1 of the 3
following treatment arms (2:2:1); "a" indicates the second dose of
the week when doses were administered twice weekly: [1008] 200 mg
ABT-874 SC at Weeks 0 and 4 followed by 100 mg ABT-874 SC at Week 8
[1009] 50 mg of ETN SC twice weekly 3-4 days apart at Weeks 0, 0a,
1, 1a, 2, 2a, 3, 3a, 4, 4a, 5, 5a, 6, 6a, 7, 7a, 8, 8a, 9, 9a, 10,
10a, 11, and 11a [1010] Placebo SC at Week 0 and 4 followed by
placebo SC at Week 8 to match ABT-874 dosing, or placebo SC twice
weekly 3-4 days apart at Weeks 0, 0a, 1, 1a, 2, 2a, 3, 3a, 4, 4a,
5, 5a, 6, 6a, 7, 7a, 8, 8a, 9, 9a, 10, 10a, 11, and 11a to match
ETN dosing
Efficacy Measures
[1010] [1011] Proportion of patients achieving a PGA score of
"Clear" or "Minimal" (0/1) at Week 12 [1012] Proportion of patients
achieving a PASI 75/90/100 response at Week 12
Safety Measures
[1012] [1013] Adverse events and serious adverse events (SAE) were
assessed throughout the study
Statistical Methods
[1013] [1014] The efficacy analyses were conducted in the
intent-to-treat (ITT) population; non-responder imputation (NRI)
was used to handle missing data [1015] Cochran-Mantel-Haenszel
tests stratified by pooled center were used to compare the
proportion of patients in each treatment group achieving PGA 0/1 or
PASI 75 at Week 12 [1016] A Chi-Square test, or Fisher's exact test
as appropriate, was used to compare proportions of patients in each
treatment group achieving PASI 90 or 100 at Week 12 [1017] All
statistical tests were two-sided with the significance level of
0.05 [1018] The safety analyses were conducted in the safety
population; safety variables were summarized by treatment group
[1019] Results
[1020] A total of 347 patients were enrolled in VERTO. Baseline
demographic and clinical characteristics were similar across
treatment groups (Table 29).
TABLE-US-00036 Treatment Group Placebo ETN ABT-874 Total
Characteristic (N = 68) (N = 141) (N = 138) (N = 347) Age
(yrs).sup.a 44.0 (13.6) 43.1 (12.5) 43.6 (14.3) 43.4 (13.4) Male, n
(%) 47 (69.1) 98 (69.5) 89 (64.5) 234 (67.4) Race, n (%) Caucasian
65 (95.6) 127 (90.1) 126 (91.3) 318 (91.6) Black 1 (1.5) 7 (5.0) 4
(2.9) 12 (3.5) Asian 2 (2.9) 6 (4.3) 4 (2.9) 12 (3.5) Other 0 (0.0)
1 (0.7) 1 (0.7) 2 (0.6) Duration of psoriasis.sup.a 19.1 (13.2)
17.0 (12.7) 16.1 (12.5) 17.03 (12.7) Body weight (kg).sup.a 96.5
(27.2) 94.5 (20.4) 93.2 (22.9) 94.3 (22.8) % BSA.sup.a 23.8 (15.5)
24.1 (15.0) 23.6 (16.6) 23.8 (15.7) PGA, n(%) Moderate 42 (61.8) 72
(51.1) 77 (55.8) 191 (55.0) Severe 24 (35.3) 60 (42.6) 57 (41.3)
141 (40.6) Very severe 2 (2.9) 9 (6.4) 4 (2.9) 15 (4.3) PASI
score.sup.a 18.5 (6.9) 19.4 (8.0) 18.4 (7.2) 18.8 (7.5) Previous
medical history, n (%) Any CVD.sup.b 28 (41.2) 37 (26.2) 49 (35.5)
114 (32.9) Hyperlipidemia 5 (7.4) 11 (7.8) 15 (10.9) 31 (8.9)
Diabetes mellitus 4 (5.9) 6 (4.3) 6 (4.3) 16 (4.6) .sup.aMean (SD).
.sup.bA patient who reported 2 or more diagnoses in the same body
system were only counted once in body system total.
Efficacy
[1021] A statistically significantly greater percentage of patients
in the ABT-874 treatment group (71.0%) achieved a PGA of 0/1 at
Week 12 as compared with patients receiving placebo (2.9%) or ETN
(39.7%; FIG. 33) [1022] A statistically significantly greater
percentage of patients in the ABT-874 treatment group (81.9%)
achieved a PASI 75 response at Week 12 as compared with patients
receiving placebo (7.4%) or ETN (56.0%; FIG. 34) [1023] At Week 12,
PASI 90 and PASI 100 responses were achieved by a statistically
significantly greater percentage of patients in the ABT-874
treatment group (59.4% and 37.0%. respectively) as compared with
patients receiving placebo (1.5% and 0%, respectively) or ETN
(23.4% and 7.1%, respectively; FIGS. 35 and 36)
Safety
[1023] [1024] A slightly higher percentage of patients receiving
ETN or ABT-874 experienced adverse events (AE) as compared with
patients receiving placebo; however, the safety profile for the two
active treatments was similar (Table 30) [1025] Serious adverse
events were reported in 4 (2.9%) patients receiving ABT-874 (viral
infection, melanoma in situ, anxiety/pain, lumbar vertebral
fracture), 1 (0.7%) patient receiving ETN (skin infection), and 1
(1.5%) placebo patient (hip fracture; Table 30) [1026] No deaths
occurred during the study (Table 30)
TABLE-US-00037 [1026] TABLE 30 Overview of Treatment-Emergent
Adverse Events Treatment Group, n (%) Placebo ETN ABT-874 (N = 68)
(N = 141) (N = 138) Any AE 31 (45.6) 76 (53.9) 68 (49.3) Any severe
AE 1 (1.5) 3 (2.1) 6 (4.3) Any serious AE 1 (1.5) 1 (0.7) 4 (2.9)
Any AE leading to discontinuation 0 4 (2.8) 4 (2.9) of study drug
Deaths 0 0 0
[1027] The percentage of patients with adverse events of infection
including serious adverse events of infection was comparable across
treatment groups (Table 31) [1028] One malignancy each was reported
in the ETN and ABT-874 groups; one patient receiving ETN was
diagnosed with a basal cell carcinoma on study day 84, and one
ABT-874 treated patient was diagnosed with malignant melanoma in
situ on study day 29 (Table 31) [1029] Three incidences of ischemic
heart disease AE were reported in the ETN group; 4 incidences were
reported for ABT-874 treated patients [1030] No major adverse
cardiac events (MACE), defined as myocardial infarction, stroke, or
cardiovascular death, were reported in any of the treatment groups
(Table 31)
TABLE-US-00038 [1030] TABLE 31 Treatment-Emergent Adverse Events of
Interest Treatment Group, n (%) Placebo ETN ABT-874 (N = 68) (N =
141) (N = 138) Any infection 13 (19.1) 34 (24.1) 31 (22.5) Any
serious infection 0 1 (0.7).sup.a 1 (0.7).sup.b Any opportunistic
infection 0 0 0 Tuberculosis 0 0 0 Any malignancy 0 1 (0.7).sup.c 1
(0.7).sup.d Non-melanoma skin cancer 0 1 (0.7) 0 MACE 0 0 0
.sup.aSkin infection. .sup.bViral infection. .sup.cPatient was
diagnosed with basal cell carcinoma on study day 84. .sup.dPatient
was diagnosed with malignant melanoma in situ on study day 29.
[1031] The most common adverse events occurring in patients
receiving ABT-874 or ETN were nasopharyngitis, upper respiratory
tract infection, injection site reaction, and headache; the most
frequently reported adverse event for placebo patients was upper
respiratory tract infection (Table 32)
TABLE-US-00039 [1031] TABLE 32 Treatment-Emergent Adverse Events
Occurring in .gtoreq.5% of Patients in Any Treatment Group
Treatment Group, n (%) Placebo ETN ABT-874 (N = 68) (N = 141) (N =
138) Nasopharyngitis 2 (2.9) 11 (7.8) 10 (7.2) Upper respiratory
tract infection 6 (8.8) 8 (5.7) 9 (6.5) Injection site reaction 3
(4.4) 13 (9.2) 8 (5.8) Headache 2 (2.9) 7 (5.0) 2 (1.4)
Conclusions
[1032] In patients with moderate to severe psoriasis, ABT-874 was
superior to both placebo and etanercept as demonstrated by the
statistically significant result of the 2 co-primary endpoints: PGA
0/1 (P<0.001) and PASI 75 (P<0.001) following 12 weeks of
treatment [1033] No deaths or MACE events occurred during this
study. In addition, no differences were seen across treatment
groups for percentage of patients experiencing serious infections
or malignancies.
Example 15
Efficacy and Safety of ABT-874 Versus Methotrexate in Patients with
Moderate to Severe Psoriasis
[1034] Aims:
[1035] To compare the efficacy and safety of ABT-874 with that of
methotrexate for treatment of moderate to severe psoriasis.
[1036] Methods:
[1037] Phase III, 52-week, double-blind, active-controlled trial
(NCT00679731). Patients were randomized 1:1 to:ABT-874 (200 mg at
Weeks 0 and 4, followed by 100 mg ABT-874 every 4 weeks for Weeks
8-48) or methotrexate (5-25 mg weekly). Non-responding patients
(patients with psoriasis area and severity index (PASI)<75 and
Physician's Global Assessment (PGA)>0/1 at Week 24 or PASI
<50 and PGA >3 after Week 24) were discontinued from the
study. The four primary endpoints were percentage of patients with:
PASI 75 at Week 24, PGA of 0 or 1 at Week 24, PASI 75 at Week 52,
and PGA score of 0 or 1 at Week 52. Safety assessments were made
throughout the study. Non-responder imputation (NRI) was used to
handle missing data.
[1038] Results:
[1039] 317 patients were enrolled in the study; 68.8% of
ABT-874-treated patients completed the study compared with 27.6% of
methotrexate-treated patients. At Week 24, PASI 75 was achieved by
81.8% of ABT-874-treated patients vs. 39.9% of methotrexate-treated
patients (P<0.001) and a PGA of 0 or 1 was achieved by 80.5% of
ABT-874 patients vs. 34.4% of methotrexate patients (P<0.001).
At Week 52, 66.2% of ABT-874 patients achieved PASI 75 vs. 23.9% of
methotrexate patients (P<0.001), and 63.0% of ABT-874 patients
vs. 20.2% of methotrexate patients achieved a PGA of 0 or 1
(P<0.001). Numbers of patients with serious adverse events or
discontinuing due to adverse events were similar for both treatment
groups.
[1040] Conclusions:
[1041] At 24 and 52 weeks, ABT-874 was superior to methotrexate
with respect to the primary endpoints of PASI 75 and PGA 0/1 in
patients with moderate to severe psoriasis.
Example 16
ABT-874 Versus Etanercept or Placebo Treatment for Moderate to
Severe Psoriasis Health-Related Quality of Life Outcomes
[1042] Aims:
[1043] Assess effects of treatment with ABT-874 vs. etanercept or
placebo on health-related quality of life (HRQOL) in patients with
psoriasis.
[1044] Methods:
[1045] In this 12-week double-blind comparative study, patients
were randomized to treatment with ABT-874 (200 mg at Weeks 0 and 4,
100 mg at Week 8), etanercept (50 mg twice weekly), or placebo.
HRQOL outcomes included the Dermatology Life Quality Index (DLQI),
visual analog scales for Ps-related (VAS-Ps) and psoriatic
arthritis-related (VAS-PsA) pain, and Short Form 36 Health Survey
Mental (MCS) and Physical (PCS) Component Summary scores. Lower
DLQI and VAS scores and higher MCS and PCS scores indicated better
outcomes. The last-observation-carried-forward method was used for
missing values. Treatments were compared using analyses of
covariance for mean changes from baseline to Week 12. Percentages
of patients with improvement at or above the minimum clinically
important difference (MCID response) were compared with chi-squared
tests.
[1046] Results:
[1047] Treatment with ABT-874 (N=138) was associated with
significantly (p<0.05) greater mean improvements than etanercept
(N=141) or placebo (N=68) in DLQI (-10.3 vs. -8.1 or -3.0), VAS-Ps
(-29.1 vs. -24.0 or -6.1) and MCS (5.4 vs. 3.2 or 1.0), and vs.
placebo only in PCS (4.6 vs. -0.3) and VAS-PsA (-23.5 vs. -7.2).
Significantly greater MCID response rates were observed with
ABT-874 vs. etanercept or placebo for MCS (43.4 vs. 30.6 or 20.6%)
and vs. placebo only for DLQI (81.5 vs. 38.1%), PCS (45.0 vs.
28.6%), VAS-PsA (69.2 vs. 28.6%), and VAS-Ps (56.6 vs. 25.8%).
[1048] Conclusions:
[1049] ABT-874 demonstrated significantly greater improvements in
all Health-Related Quality of Life outcome measurements vs. placebo
and in DLQI, VAS-Ps and MCS vs. etanercept. Significantly more
patients achieved clinically meaningful improvement with ABT-874 in
all outcome measurements vs. placebo and in MCS vs. etanercept.
Example 17
Effects of ABT-874 Versus Etanercept or Placebo on Health-Related
Quality of Life in Patients With Moderate to Severe Psoriasis
[1050] Aims:
[1051] Assess effects of ABT-874 vs. etanercept or placebo on
health-related quality of life (HRQOL) in psoriasis patients.
[1052] Methods:
[1053] Patients were randomized to 12-week double-blind treatment
with ABT-874 (200 mg at Weeks 0 and 4, 100 mg at Week 8),
etanercept (50 mg twice weekly) or placebo. Assessments included
the Dermatology Life Quality Index (DLQI), visual analog scales for
psoriasis-related (VAS-Ps) and psoriatic arthritis-related
(VAS-PsA) pain, and the Short Form 36 Health Survey Mental (MCS)
and Physical (PCS) Component Summary scores. The
last-observation-carried-forward method was used for missing
values. Analyses of covariance compared treatments in mean changes
at Week 12 from baseline. Chi-square tests compared treatments in
percentages of patients with improvement at or above the minimum
clinically important difference (MCID response).
[1054] Results:
[1055] ABT-874 treatment (N=139) had significantly (p<0.05)
greater improvement than placebo (N=72) for all outcomes (DLQI,
11.1 vs. 3.0; PCS, 4.6 vs. 1.1; MCS, 6.3 vs. 2.1; VAS-Ps, 36.0 vs.
7.5; VAS-PsA, 38.6 vs. 3.2). ABT-874 was associated with
significantly greater improvement than etanercept (N=139) for DLQI
(11.1 vs. 9.0), VAS-Ps (36.0 vs. 29.4), and MCS (6.3 vs. 3.9). MCID
response rates for VAS-Ps were significantly greater for ABT-874
than etanercept or placebo (73.9% vs. 58.0% vs. 29.6%). MCID
response rates for DLQI, MCS, PCS, and VAS-PsA were greater with
ABT-874 vs. etanercept or placebo, but the differences were
significant only vs. placebo (DLQI, 81.8% vs. 32.9%; MCS, 45.6% vs.
30.4%; PCS, 55.9% vs. 34.8%; VAS-PsA, 83.9% vs. 20.0%).
[1056] Conclusions:
[1057] Compared with placebo, ABT-874 was associated with
significantly greater mean improvements and MCID response rates in
all HRQOL measurements. Compared with etanercept, ABT-874 had
significantly greater improvement in DLQI, VAS-Ps, and MCS and
greater MCID response rates for VAS-Ps.
Example 18
Psoriasis Treatment With ABT-874: Effects on Health-Related Quality
of Life and Work Productivity and Activity Impairment
[1058] Aims:
[1059] Evaluate effects of ABT-874 on health-related quality of
life (HRQOL), work productivity and activity impairment (WPAI) in
psoriasis patients.
[1060] Methods:
[1061] Patients were randomized to receive induction-phase ABT-874
(200 mg at Weeks 0 and 4, 100 mg at Week 8) or placebo. Patients
achieving a Week-12 Physician's Global Assessment of
"clear/minimal" were re-randomized to maintenance-phase ABT-874
(100 mg every 4 [q4] or 12 [q12] weeks) or placebo up to Week 52.
HRQOL outcomes included the Dermatology Life Quality Index (DLQI),
visual analog scales for plaque psoriasis- and psoriatic
arthritis-related pain, and Short Form 36 Health Survey Mental and
Physical Component Summary scores. Total activity impairment (TAI)
was assessed by WPAI-SHP: PSO questionnaire.
Last-observation-carried-forward method was used for missing
values. Analysis of covariance compared mean improvements from
baseline to Weeks 12 and 52 between treatments. Chi-squared tests
compared percentages of patients with improvement at or above the
minimum clinically important difference (MCID response).
[1062] Results:
[1063] ABT-874 treatment (N=981) had significantly (p<0.05)
greater Week-12 MCID response rates than placebo (N=484) for all
outcomes (e.g., DLQI, 78.1% vs. 19.4%; TAI, 51.4% vs. 15.3%). After
re-randomization, Week-52 MCID response rates were significantly
greater for ABT-874 q4 (N=297) than for q12 (N=298) in all outcomes
except for psoriatic arthritis-related pain. Both ABT-874 groups
had significantly greater MCID response rates than placebo (N=149)
for all outcomes (e.g., DLQI, 81.1% vs. 71.1% vs. 49.3%; TAI, 56.9%
vs. 45.1% vs. 31.0%). Mean improvements in all outcomes were
significantly greater for ABT-874 than placebo at Week 12 and for
ABT-874 q4 than ABT-874 q12 or placebo at Week 52.
[1064] Conclusion:
[1065] ABT-874 treatment for psoriasis versus placebo was
associated with significantly greater improvements in HRQOL and
reduced TAI in both induction and maintenance phases.
Example 19
Responses to ABT-874 Across Subgroups of Patients with Moderate to
Severe Psoriasis
[1066] Aims:
[1067] To evaluate the efficacy of ABT-874 in subgroups of patients
with moderate to severe psoriasis.
[1068] Methods:
[1069] In a 52-week, double-blind study patients were randomized to
ABT-874 (200 mg, weeks-0 and 4; 100 mg, week-8) or placebo (PCB);
then, if PGA "clear/minimal" (PGA 0/1) was achieved at week 12,
re-randomized to ABT-874 100 mg every 4 weeks (q4wk), 100 mg every
12 weeks (q12wk), or PCB q4wk (NCT00570986). Primary endpoints were
PGA 0/1 (weeks-12 and 52) and PASI 75 (week-12). NRI analysis of
endpoints was conducted by baseline characteristics. Safety was
assessed throughout the study.
[1070] Results:
[1071] 1,465 patients were randomized at baseline (mean PASI:
19.2.+-.7.4; ABT-874, N=981; PCB, N=484). Responses at week-12 in
patients with/without prior biologics, for ABT-874 (n=173/808) vs
PCB (n=76/408) were, PGA 0/1: 65.9%/78.2% vs 1.3%/4.9%; and PASI
75: 74.6%/82.1% vs 1.3/5.1%; responses at week-52 for ABT-874-q4wk
(n=46/252) vs -q12wk (n=49/249) were, PGA 0/1: 78.3%/79.4% vs
34.7%/43.0%. For patients with/without a history of PsA, week-12
responses for ABT-874 (n=290/691) vs PCB (n=150/334) were, PGA 0/1:
71.7%/77.9% vs 0.7%/6.0%; and PASI 75: 78.6%/81.6% vs 1.3%/6.0%;
responses at week-52 for ABT-874-q4wk (n=86/212) vs -q12wk
(n=79/219) were, PGA 0/1: 77.9%/79.7% vs 30.4%/45.7%. More
infections and malignancies occurred in patients receiving ABT-874
vs PCB up to week-12 (22.3% vs. 19.8% and 0.6% vs. 0,
respectively). Major adverse cardiac events (MACE) occurred in 7
ABT-874-treated patients (none had prior biologics; 1 had PsA; mean
baseline PASI: 15.8.+-.3.2). No MACE occurred in PCB-treated
patients.
[1072] Conclusions:
[1073] High percentages of ABT-874-treated patients achieved PGA
0/1 (weeks-12 and 52) and PASI 75 (week-12), regardless of prior
biologic treatment or history of PsA. More infections, malignancies
and MACE occurred in ABT-874 vs PCB-treated patients, indicating
the importance of close surveillance for these events.
Example 20
Long-term Safety of ABT-874 for the Treatment of Moderate to Severe
Psoriasis-Interim Analysis from an Open-Label Extension Study
[1074] Introduction:
[1075] Interim results from an ongoing, open-label extension study
(OLE) of the anti-IL-12/23 agent, ABT-874, provide preliminary,
long-term safety data.
[1076] Methods:
[1077] Patients randomized to ABT-874 in a prior phase 2 or 3
psoriasis trial are eligible for this 160-week, multi-center OLE
upon completion or loss of response in the respective prior study.
Patients receive 100 mg ABT-874 every 4 weeks, starting at OLE
baseline. This analysis includes all patients with .gtoreq.1 dose
of ABT-874 during the OLE (safety set). Adverse events (AEs) from
the first dose of ABT-874, whether from OLE or preceding study, and
.ltoreq.45 days following the last dose of study drug are recorded.
This interim analysis provides data available through Nov. 26,
2009.
[1078] Results:
[1079] As of the cutoff date, the safety set consisted of 2,298
patients (2904.0 PY drug exposure, 421.7.+-.186.8 mean days on
treatment; 68.8% male; mean age, 45.2.+-.13.2 years). 2.7% have
withdrawn due to AEs; 89.1% are still enrolled. AEs occurring in
.gtoreq.5% of patients were: URI (13.6%), nasopharyngitis (13.4%),
headache (6.7%), arthralgia (5.8%), and hypertension (5.2%).
Infectious AEs occurred in 45.5%; serious infections in 1.0% (most
common: cellulitis, n=8; pneumonia, n=5; sepsis, n=4; and
diverticulitis, n=3); and opportunistic infections in 0.3%
(candidiasis, n=3; oral candidiasis, n=1; esophageal candidiasis,
n=1; and coccidiomycosis, n=1). 1.6% of patients had malignancies;
1.2% had NMSCs (BCC, n=15; SCC, n=16); 1 melanoma in-situ occurred.
No lymphomas were observed. 18 major adverse cardiovascular events
(MACE) occurred (7 during preceding study, 11 during OLE;
myocardial infarction, n=11; stroke, n=3; and cardiovascular death,
n=4; 72.2% male; 88.9% age .gtoreq.45 years; all had .gtoreq.2 CAD
risks; mean time to OLE events 31.5 weeks).
[1080] Conclusions:
[1081] An OLE interim analysis supports the need to closely monitor
AEs of infection, NMSC, and MACE in patients receiving ABT-874 for
the treatment of moderate to severe psoriasis.
Example 21
A Pooled Analysis of Phase III, Randomized, Placebo-Controlled
Clinical Trials of the Anti-Interleukin 12/23 Monoclonal Antibody,
ABT-874
[1082] Objective:
[1083] To determine the efficacy and safety experience in moderate
to severe psoriasis across ABT-874 phase III clinical trials.
[1084] Methods:
[1085] Data from 3 randomized, placebo-controlled studies were
pooled through 12 weeks. In all studies, patients with moderate to
severe psoriasis were randomized 2:1 to ABT-874 (200 mg at weeks 0
and 4, followed by 100 mg at week 8) or matching placebo. The 3
trials measured common primary endpoints of physician's global
assessment "clear" or "minimal" scores (PGA 0/1), and 75%
improvement from baseline psoriasis area and severity index (PASI
75) at week 12 (each analyzed using nonresponder imputation).
Secondary endpoints included PASI 90/100, and DLQI. Adverse events
were collected during each study and up to 45 days from the last
dose of study drug.
[1086] Results:
[1087] Data were pooled for 1882 patients (ABT-874, N=1258 [67.4%
male, 90.3% white, mean [SD] age 45.3 [13.3] yrs; placebo, N=624,
with similar demographics). Baseline PASI was similar between
groups (19.0 [7.5] and 19.1 [7.2] for ABT-874 and placebo,
respectively). 75.1% (945/1258) and 80.8% (1017/1258) of
ABT-874-treated patients achieved a PGA 0/1 and PASI 75,
respectively, at week 12, compared with 4.2% (26/624) and 5.1%
(32/624) of those receiving placebo (p<0.001 for both
endpoints). PASI 90 responses at week 12 were 60.7% (763/1258) vs.
1.8% (11/624) in the ABT-874 vs. placebo groups, respectively; PASI
100 response was 32.4% (407/1258) with ABT-874, and was not
achieved in the placebo group (p<0.001 for both endpoints).
Baseline DLQI scores were 12.9 [7.0] and 12.8 [6.9] for ABT-874-
and placebo-treated patients; at week 12, mean percent change in
DLQI for each group was -79.1 [28.9] vs. 1.4 [69.8], respectively.
Serious adverse event (AE) rates were 2.1% and 1.4% for ABT-874 vs.
placebo. Incidence rates for infectious and serious infectious AEs
were 22.6% and 0.5% for ABT-874, and 19.1% and 0.2% for placebo.
NMSCs were observed in 6 patients receiving ABT-874; none were
observed with placebo. 5 ABT-874-treated patients had major adverse
cardiovascular events (MACE); no MACE were observed with
placebo.
[1088] Conclusions:
[1089] Efficacy results pooled from 3 phase III, placebo-controlled
trials in moderate to severe psoriasis demonstrated superior PGA
and PASI responses with ABT-874 vs. placebo. Higher rates of
infection, NMSC, and MACE occurred with ABT-874 vs. placebo,
highlighting the need to monitor for these events in a larger
psoriasis population.
Example 22
Pooled Safety and Efficacy Results from Two Phase III Trials
Comparing Briakinumab.TM. With Etanercept and Placebo for the
Treatment of Moderate to Severe Psoriasis
[1090] Aims:
[1091] To provide an integrated analysis of efficacy and safety
results from two independent trials comparing Briakinumab.TM.
versus etanercept (ETN) and placebo (pbo) for moderate to severe
psoriasis treatment.
[1092] Methods:
[1093] Efficacy and safety data were pooled from two 12-week, phase
III, double-dummy, randomized trials (NCT00710580, NCT00691964).
Patients were randomized 2:2:1 to receive Briakinumab.TM. (200 mg
at Weeks 0 and 4, followed by 100 mg at Week 8), ETN (50 mg twice
weekly), or matching pbo. At Week 12, primary efficacy endpoints
were percentage of patients achieving a PGA score of "Clear" or
"Minimal" (0/1) and percentage of patients achieving a PASI 75
response. Secondary endpoints included Week 12 PASI 90 and PASI 100
response rates. Adverse events (AE) were assessed throughout the
study. Non-responder imputation (NRI) was used to handle missing
data.
[1094] Results:
[1095] Individual trial results demonstrated superior efficacy of
Briakinumab.TM. vs. ETN and pbo (P<0.001, Briakinumab.TM. vs.
ETN or pbo, both primary endpoints for both studies). For this
pooled analysis, data from 697 patients were analyzed:
Briakinumab.TM. N=277; ETN, N=280; pbo, N=140. At Week 12, 71.8%,
34.6%, and 3.6% of Briakinumab.TM., ETN-, and pbo-treated patients,
respectively, achieved a PGA 0/1 (P<0.001, Briakinumab.TM. vs.
ETN or pbo). Week 12 PASI 75 response rates for Briakinumab.TM.-,
ETN-, and pbo-treated patients were 81.2%, 47.9%, and 7.1%,
respectively (P<0.001, Briakinumab.TM. vs. ETN or pbo). Week 12
PASI 90 and PASI 100 response rates were 57.4%/18.6%/2.9% and
32.9%/6.4%/0.0% for patients treated with Briakinumab.TM./ETN/pbo,
respectively (P<0.001, Briakinumab.TM. vs. ETN or pbo for both
PASI 90 and 100). Serious AE rates were: 2.2%/0.7%/2.1% for
Briakinumab.TM./ETN/pbo patients. Serious infection rates were:
0.4%/0.4%/0% for Briakinumab.TM./ETN/pbo patients. There were no
deaths or major adverse cardiovascular events (MACE) in any
treatment group.
[1096] Conclusions:
[1097] Pooled efficacy results from two independent trials
demonstrate that Briakinumab.TM. was superior to ETN and pbo for
moderate to severe psoriasis treatment. Serious adverse events were
low across all groups and no MACE were observed.
Example 23
Long term Safety and Efficacy of ABT-874 for the Treatment of
Moderate to Severe Psoriasis--Interim Analysis from an Open Label
Extension Study
[1098] The safety and efficacy of ABT-874 in the treatment of
psoriasis were assessed on an interim basis in view of results
obtained as of Nov. 26, 2009. Patients were eligible for enrollment
following completion or loss of response in a preceding ABT-874
psoriasis phase II or phase III trial. The duration of the study
was planned for 160 weeks with treatment comprising 100 mg ABT
every 4 weeks beginning at week 0.
[1099] Preceding phase II or phase III clinical trials include the
studies set forth in Table 33:
TABLE-US-00040 TABLE 33 Phase II and III studies Study Design Study
N OLE N M05-736 Phase II, 3-period, 180 84 dose-ranging study;
12-wk DB, 36-wk obs./re- treatment, followed by 60-wk OL
re-treatment M06-890 Phase III, 2-period 1465 1346 study; 12-wk
Induction Phase, 40-wk Maintenance Phase M10-114 Phase III, 12-wk,
347 308 DB, placebo and active comparator (ETN) M10-315 Phase III,
12-wk, 350 314 DB, placebo and active comparator (ETN) M10-255
Phase III, 52-wk, 317 246 DB, active- comparator (MTX)
[1100] The efficacy of ABT-874 in treatment of moderate to serious
psoriasis was demonstrated in these previous studies, as depicted
in FIG. 37.
[1101] The data presented in this example represents an interim
analysis of results.
[1102] Maintenance of Efficacy
[1103] Patients evaluated included those (i) with at least one dose
of ABT-874 during the preceding phase II or III study and in the
current Open Lable Extension (OLE) study and (ii) with a
physician's global assessment score of "clear" or "minimal" (PGA
0/1) at the last evaluation on or before the first dose in OLE. PGA
scores and psoriasis area and severity index (PASI) responses were
determined every 12 weeks during the OLE. (Note that patients
enrolled from study M06-890 must have received at least 1 dose of
ABT-874 during the Induction Phase).
[1104] 2298 patients had received at least 1 dose of ABT-874 in the
OLE as of this interim analysis. Specifically, 251 (10.9%) patients
had discontinued from the OLE and 61 (2.7%) withdrew due to adverse
events. Ultimately, 625 patients met the criteria for the
Maintenance of Efficacy population (i.e., patients who had received
loading dose in the initial study (200-200-100 mg) and had a
PGA-Score of "clear" or "minimal" at entry in the OLE study). The
demographics and clinical characteristics of the population were as
follows:
TABLE-US-00041 TABLE 34 Demographics and Clinical Characteristics
of Population at Preceding Study Baseline All briakinumab .TM. (N =
2298) Male, n (%) 1581 (68.8) White, n (%) 2101 (91.4) Age, yrs,
mean (SD) 45.2 (13.2) Weight, kg, mean (SD) 93.1 (23.0) Duration of
psoriasis, yrs, mean (SD) 18.6 (12.3) PASI* prior 1st dose, mean
(SD) 16.6 (8.8) BSA* prior 1st dose, %, mean (SD) 24.8 (16.1) *From
baseline prior to 1.sup.st dose of ABT-874 (whether in preceding
study or OLE).
[1105] Results of the Maintenance of Efficacy interim analysis are
depicted in FIGS. 38 and 39. Specifically, FIG. 38 depicts the
percentage of patients who have maintained PASI 75 over time while
FIG. 39 depicts the percentage of patients who have maintained PASI
100 over time. These results suggest that high levels of PASI and
PGA response as achieved in the preceding phase II and III studies
were generally maintained upon further treatment with 100 mg every
four weeks.
[1106] Safety Analysis:
[1107] Patients evaluated included those (i) with at least one dose
of ABT-874 in the current Open Lable Extension (OLE) study and (ii)
with adverse effects from the first dose of ABT-874 received either
in the preceding studies or the OLE. Safety was assessed throughout
the studies and up to 45 days from the last dose study drug.
[1108] The following table summarizes the occurrences of particular
adverse effects:
TABLE-US-00042 TABLE 35 Interim Safety Results Briakinumab .TM.
Patients with events (%) Events (E/100 PYs) (N = 2298) (PYs = 2904)
Any AE 1673 (72.8) 7177 (247.1) Most common AEs* Upper resp. tract
313 (13.6) 426 (14.7) infections Nasopharyngitis 309 (13.4) 456
(15.7) Headache 154 (6.7) 220 (7.6) Arthralgia 133 (5.8) 146 (5.0)
Hypertension 120 (5.2) 126 (4.3) Any infection 1045 (45.5) 2002
(68.9) Any serious infection 24 (1.0) 30 (1.0) Opportunistic
infections 6 (0.3) 6 (0.2) Malignancy 37 (1.6) 42 (1.4) NMSC 28
(1.2) 33 (1.1) Lymphoma 0 0
[1109] Accordingly, patients receiving ABT-874 for treatment of
moderate to severe psoriasis should be monitored for certain
adverse events, in particular, infection, non-melanoma skin cancer
(NMSC) and cardiovascular events.
[1110] MACE Analysis:
[1111] Patients evaluated included those with at least one dose of
ABT-874 in the preceding clinical studies or in the current Open
Lable Extension (OLE) study (N=2520; 3010.6 Patient Years). A total
of 18 MACE (Major Adverse Cardiovascular Events) were identified. 7
MACE were identified in one randomized controlled preliminary
clinical trial including 5 during the initial 12 week placebo
controlled treatment period and 2 between week 12 and week 52. In
addition 11 MACE were identified in the OLE study.
[1112] Of the 18 MACE cases, 11 were non-fatal myocardial
infarction, 3 were non-fatal cerebrovascular strokes and 4 were
cardiovascular deaths.
[1113] The MACE rates were as depicted in Table 36:
TABLE-US-00043 TABLE 36 MACE Rates Patient MACE Years MACE/ MACE
Rates: (n) (PYs) 100 PYs 95% CI 12-week Pl.-contr. period 5 376.7
1.33 (0.43, 3.10) All briakinumab .TM. 18 3010.6 0.60 (0.35, 0.94)
treatment periods* *Cut-Off: Nov. 26, 2009
[1114] The frequency of MACE appeared to be equally distributed
over time as depicted in FIG. 40. Accordingly, no association with
the duration of exposure to ABT-874 was noted.
[1115] A further risk analysis was performed whereby the standard
cardiovascular risk factors were analyzed by univariate analyses in
patients with at least one dose of ABT-874 in a prior phase III or
phase II study or in the OLE. The standard cardiovascular risk
factors include body mass index (BMI), HDL-cholesterol,
LDL-cholesterol, triglycerides, systolic/diastolic blood pressure,
history of hypertension, history of diabetes, history of
cardiovascular disease (CVD), current cigarette smoking and
age.
[1116] As set forth in Table 37, the 18 subjects experiencing MACE
had the following risk factors:
TABLE-US-00044 TABLE 37 Percentages of Patients with MACE Having
Cardiovascular Risk Factors Cardiovascular Risk n (%) BMI
.gtoreq.30 kg/m.sup.2 16 (88.9) BL HDL <40 mg/dL 8 (44.4) BL LDL
>100 mg/dL 8 (44.4) BL TG >200 mg/dL 7 (38.9) BL Glc
.gtoreq.126 mg/dL 8 (44.4) Current Smoker 4 (22.2) Male Sex 13
(72.2) M .gtoreq.45 yrs/F .gtoreq.55 yrs 16 (88.9) Hypertension 12
(66.7) Diabetes Mellitus 4 (22.2)
[1117] Four specific cardiovascular risk factors were identified to
be predictive for MACE including (1) history of diabetes; (2) a
body mass index of at least 30 or higher; (3) inadequate blood
pressure control (blood pressure of at least 140/90 or higher; and
(4) a history of cardiovascular disease defined as at least one of
(i) myocardial infarction; (ii) angina requiring hospitalization;
(iii) coronary artery disease requiring revascularization; (iv)
peripheral artery disease; (v) congestive heart failure requiring
hospitalization; (vi) stroke or (vii) transient ischemic
attack.
[1118] In conclusion, as set forth in Table 38, the analysis showed
that the rate of MACE was higher in patients with at least 2
cardiovascular risk factors as compared to patients having only 0
or 1 cardiovascular risk factors.
TABLE-US-00045 TABLE 38 Risk of MACE by Number of Risk Factors
Number of Risk MACE MACE Factors* (points) N Proportion (Event) PY
E/100PY 0 or 1 3 1937 0.15% 3 2314.5 0.13 2 to 4 15 583 2.57% 15
696.1 2.15 Overall 18 2520 0.71% 18 3010.6 0.60 *Hx Diabetes, Hx
CVD, Uncontrolled BP (.gtoreq.140/90) at Baseline, BMI .gtoreq.
30
[1119] The data confirms that, in patients with one or no
cardiovascular risk factors, the rate of MACE may be significantly
reduced upon administration of ABT-874.
Example 24
A Phase III, Randomized, Placebo-Controlled Trial Evaluating the
Efficacy and Safety of Two Dosing Regimens of the Fully Human
Interleukin-12/23 Monoclonal Antibody, Briakinumab.TM., for the
Treatment of Moderate to Severe Psoriasis
Introduction
[1120] A previous phase II study demonstrated that Briakinumab.TM.,
a fully human anti-IL12/23 monoclonal antibody, was efficacious for
the treatment of moderate to severe psoriasis (see, e.g., Examples
1-11 above) (Kimball A B, et al., Arch Dermatol 2008; 144: 200-7.
The current study further evaluated the efficacy and safety of
Briakinumab.TM., and compared two maintenance therapy dosing
regimens against placebo. Findings from this study offer expanded
insights on the benefit-risk profile for anti-IL-12/23 treatment in
moderate to severe psoriasis.
Methods
Study Design, Ethics, and Participants
[1121] A 52-week, randomized, double-blind, placebo-controlled
trial was conducted in two phases: a 12-week induction phase and a
maintenance phase, during which treatment continued through 52
weeks (FIG. 41). At baseline, patients were randomized 2:1 to
receive Briakinumab.TM. or placebo. Treatment began at week 0 with
a 200 mg subcutaneous dose of Briakinumab.TM., followed by 200 mg
at week 4, and 100 mg at week 8; or matched placebo at weeks 0, 4
and 8. At week 12, patients achieving a physician's global
assessment (PGA) score of "clear" or "minimal" were re-randomized
2:2:1 to receive one of three maintenance regimens: Briakinumab.TM.
100 mg every 4 weeks, 100 mg Briakinumab.TM. every 12 weeks, or
placebo every 4 weeks.
[1122] The study protocol and patient informed consent were
approved by an Independent Ethics Committee or Institutional Review
Board at each participating study site, and informed consent was
signed by all patients prior to initiating any study-related
procedures. Patients were recruited from 116 clinical sites within
the United States and Canada. Adults, aged 18 and over, were
eligible to participate if they had moderate to severe plaque-type
psoriasis (defined as .gtoreq.10% affected body surface area, PGA
score of at least "moderate", and Psoriasis Area and Severity Index
(PASI) of .gtoreq.12) for at least six months, and were candidates
for systemic therapy or phototherapy.
[1123] Women of childbearing potential were required to use at
least two methods of contraception throughout the study and for 60
days following the last dose of study drug; women who were pregnant
or breastfeeding were excluded from participation. Other reasons
for exclusion included previous exposure to an IL-12 inhibitor, or
any active skin condition that would interfere with the evaluation
of psoriasis. Patients were not enrolled if they had any poorly
controlled medical condition, or any hepatic, renal, or hematologic
disease. Patients with infections, or risk for severe infections,
were also excluded from the study. Tuberculosis (TB) screening was
conducted on all patients prior to enrollment. Those with a
purified protein derivative test result of .gtoreq.5 mm induration
(regardless of prior BCG vaccination), and/or chest x-ray findings
suggestive of latent TB were not enrolled, unless prophylactic
treatment as recommended by local guidelines was instituted prior
to initiating study treatment. Patients with a history of
malignancy, other than a successfully treated basal cell or
non-metastatic squamous cell skin cancer, or cervical carcinoma in
situ, were not enrolled.
[1124] Use of the following therapies was not permitted during the
study, and must have been discontinued within the respective
timeframes prior to baseline: topical treatments, including
corticosteroids, vitamin D analogs, or retinoids within 2 weeks
(other than low potency topical corticosteroids on the palms,
soles, face, inframammary area, or groin); UVB phototherapy within
2 weeks; psoralen and UVA phototherapy within 4 weeks; systemic
nonbiologic therapies within 4 weeks; or biologic therapies within
12 weeks. Any use of oral or injectable corticosteroids was not
permitted; however, inhaled corticosteroids could be continued for
stable medical conditions.
Study Objectives and Outcomes
[1125] The study was conducted to evaluate the efficacy and safety
of Briakinumab.TM. for the treatment of moderate to severe
psoriasis, and to compare two maintenance dosing regimens against
placebo. Three primary endpoints were measured: PGA score of
"clear" or "minimal" at weeks 12 and 52, and at least 75%
improvement from baseline PASI (.gtoreq.PASI 75) at week 12.
Statistical comparisons were ranked in the following order: 1) week
12 PGA "clear" or "minimal" response rates for Briakinumab.TM. vs
placebo; followed by 2) comparison of week 12 PASI 75 response
rates between the two treatment groups; and then 3) week 52 PGA
"clear" or "minimal" maintenance rates for the Briakinumab.TM.
every 4 week group vs placebo; followed by 4) week 52 PGA "clear"
or "minimal" maintenance rates for the Briakinumab.TM. every 12
week group vs placebo.
[1126] Secondary efficacy analyses compared the proportions of
patients achieving PASI 75, and 90% and 100% improvement from
baseline PASI (PASI 90 and PASI 100) over time, change in PASI
relative to baseline, and Dermatology Life Quality Index (DLQI)
scores over time. PASI 100, PASI 90, and change from baseline DLQI
at week 12 were ranked secondary endpoints; while mean PASI scores
and PASI response rates over time were non-ranked. Efficacy
outcomes were compared between each Briakinumab.TM. dosing group vs
placebo, and between the two Briakinumab.TM. dosing groups.
[1127] An additional analysis evaluated PGA "clear" or "minimal"
scores, and PASI 75 responses by the following subgroups: with or
without prior biologic treatment; with or without psoriatic
arthritis (PsA); baseline PASI score of >20 or .ltoreq.20; and
baseline weight .gtoreq.100 kg or <100 kg. The prevalence of any
cardiovascular medical history or underlying cardiovascular risk
factors was determined post hoc, by treatment group.
[1128] Patients were assessed for adverse events throughout the
study and for 45 days following the last dose of study
treatment.
Statistical Analyses
[1129] It was estimated a priori that a sample size of 1350
subjects (900 receiving Briakinumab.TM., and 450 receiving placebo)
would provide >90% power to demonstrate the superiority of
Briakinumab.TM. over placebo (with superiority defined as a PGA
score of "clear" or "minimal" in 70% vs. 4% of Briakinumab.TM. vs.
placebo treated patients at week 12, respectively). The sample
sizes needed in each treatment group after week 12 were determined
assuming that approximately 630 patients would be re-randomized,
and that 40% of patients receiving placebo would maintain a PGA
score of "clear" or "minimal" up to week 52. It was established
that re-randomization would occur at week 12 in a 2:2:1 fashion,
and that 250 patients allocated to each Briakinumab.TM. arm and 125
allocated to placebo would provide 90% power to detect an 18%
difference in PGA response rates.
[1130] A randomization schedule was prepared and maintained by the
study sponsor's department of statistics, and administered via an
interactive voice response system. Randomization at week 0 was
performed by center; and re-randomization at week 12 was stratified
by the treatment assigned at week 0. All doses of study drug were
provided in a blinded fashion, and assigned treatment groups were
concealed from study investigators and site personnel, subjects,
and the sponsor's clinical team responsible for conduct of the
study.
[1131] All statistical tests were two-tailed with alpha level set
at 0.05. Primary and ranked secondary variables were analyzed in a
hierarchical fashion, where each successive comparison was made
only if statistical significance was observed with the next highest
ranking variable. Efficacy analyses were conducted in the
intention-to-treat population, with missing values imputed using
nonresponder imputation for categorical variables and last
observation carried forward for continuous variables. The primary
analyses were conducted using a Cochran-Mantel-Haenszel test,
adjusted by center. Chi-square test was used for pair-wise
comparisons. Treatment differences for mean change scores were
analyzed using ANCOVA, with treatment as a factor and baseline
value as a covariate.
[1132] One subject randomized at week 12 to the every 4 week
Briakinumab.TM. arm did not receive study drug during the
Maintenance Phase and was therefore not included in the safety
analysis.
Results
Induction Phase
[1133] 1465 patients were randomized (Briakinumab.TM., n=981;
placebo, n=484; FIG. 42). Baseline demographics and clinical
characteristics were comparable between the two treatment groups
(Table 39), and similar to those observed in other phase III
clinical trials for moderate to severe psoriasis (Reich K, et al.
Lancet 2005; 366: 1367-74; Menter A, et al. J Am Acad Dermatol
2008; 58: 106-15; Saurat J H, et al. Br J Dermatol 2008; 158:
558-66; Papp K A, et al. Lancet 2008; 371: 1675-84). The
percentages of patients with a cardiovascular-related medical
history, or risk factors for coronary heart disease (CHD)
(Executive Summary of The Third Report of The National Cholesterol
Education Program (NCEP) Expert Panel on Detection, Evaluation, And
Treatment of High Blood Cholesterol In Adults (Adult Treatment
Panel III). Jama 2001; 285: 2486-97) were generally similar between
groups (Table 40).
[1134] Compared with placebo, the percentage of patients achieving
a PGA score of "clear" or "minimal" at week 12 was significantly
higher with Briakinumab.TM. (76.0% in the Briakinumab.TM. group vs
4.3% in the placebo group, p<0.001; FIG. 43). PASI 75 responses
were observed in 792 (80.7%) patients receiving Briakinumab.TM.
compared to 22 (4.5%) placebo-treated patients (p<0.001; table
41). 61.6% of patients treated with Briakinumab.TM. achieved PASI
90, and 32.2% achieved PASI 100. The response was rapid: a 51.7%
reduction in PASI was observed with Briakinumab.TM. by week 4, and
improvement continued through week 12, when the mean reduction in
PASI was 85.4% (FIG. 44).
[1135] A large reduction in mean DLQI score was also observed in
Briakinumab.TM.-treated patients, indicating significant benefits
in quality of life within 12 weeks. Mean DLQI score for the
Briakinumab.TM. group declined from 12.8 (SD 7.02) at baseline to
2.7 (SD 4.12) at week 12, while DLQI scores in the placebo group
remained relatively stable over this period (Table 41).
[1136] A subgroup analysis demonstrated that greater than 65% to
70% of patients receiving Briakinumab.TM. achieved a PGA score of
"clear" or "minimal" and PASI 75 response at week 12, regardless of
prior biologic treatment, baseline PASI score, history of psoriatic
arthritis, or baseline weight (Table 41).
Maintenance Phase
[1137] After 12 weeks of treatment, 766 patients had attained a PGA
of "clear" or "minimal" and entered the Maintenance Phase, a
majority of whom were from the Briakinumab.TM. group (n=745; FIG.
42). For these patients, 596 were re-randomized to continue
receiving Briakinumab.TM. at either 4 week (n=298) or 12 week
(n=298) intervals, while 149 patients were allocated to placebo and
were thus withdrawn from Briakinumab.TM. treatment (withdrawal
group). Demographic and clinical characteristics at baseline for
these 3 treatment groups were generally similar, and comparable to
those observed in the Induction Phase treatment groups (Table 42).
This report excludes efficacy results for patients who initially
received placebo and were re-randomized in the Maintenance Phase,
as the number in this group was very small (n=21).
[1138] The percentages of patients maintaining a PGA score of
"clear" or "minimal" through week 52 were greater for the two
Briakinumab.TM. treatment groups than for the treatment withdrawal
group, and highest in the every 4 week dosing arm (FIG. 45 [A]). Of
149 patients in the withdrawal group, 6.0% had a PGA score of
"clear" or "minimal" at week 52 compared with 41.6% and 79.2% of
298 patients each in the every 12 week and every 4 week treatment
groups, respectively (p<0.001). However, it is notable that high
response levels achieved during induction lingered over a prolonged
period in the withdrawal group: at week 24, during the Maintenance
Phase and 12 weeks following treatment withdrawal, 45.6% of
patients had maintained a PGA score of "clear" or "minimal".
[1139] PASI 75 response rates during the Maintenance Phase were
highest among patients who continued Briakinumab.TM. treatment;
82.6% and 45.6% of patients in the every 4 week and every 12 week
dosing groups, respectively, vs 8.7% in the withdrawal group
maintained this efficacy response at week 52 (FIG. 45B). PASI 100
responses, achieved by a large proportion of patients who had a PGA
score of "clear" or "minimal" at re-randomization, generally
continued to increase with ongoing treatment through week 32 and,
in the high dose arm, did not deteriorate for the remainder of the
maintenance phase (FIG. 45C). 63.4% and 23.5% in the every 4 week
and every 12 week Briakinumab.TM. groups, respectively, had a PASI
100 response at week 52, compared with 4.0% of patients withdrawn
from treatment (p<0.001). PASI response rates in patients
withdrawn from therapy mirrored PGA results, with a protracted
return toward baseline levels of disease.
Safety Results
[1140] The most commonly observed adverse events in patients
receiving Briakinumab.TM. were nasopharyngitis, headache, upper
respiratory tract infection (URI), and back pain (table 43). While
back pain was observed in all treatment groups, it was reported
more frequently in patients receiving Briakinumab.TM. every 4 weeks
vs every 12 weeks, or placebo (5.4% vs 2.0% and 2.0%, respectively;
Table 41).
[1141] Serious adverse events (SAE) were observed in 3.3% of all
patients who received Briakinumab.TM. during the Induction and/or
Maintenance Phases. SAE rates during the Induction Phase were
similar for Briakinumab.TM. vs placebo (2.0% vs 1.2%,
respectively). During maintenance treatment, the SAE rate was
higher for the every 12 week dosing arm compared with the every 4
week or placebo arms (3.0% vs 1.3% and 1.3%, respectively).
[1142] The overall rate of infections in patients exposed to
Briakinumab.TM. was higher than the infection rate for placebo
during the Induction Phase (39.8% of 998 vs 19.8% of 484). Rates of
infection during maintenance treatment were higher than those
observed during the placebo-controlled period, and highest in the
every 4 week dosing group (table 43). The total number of
infections per 100 patient-years of Briakinumab.TM. treatment was
100.1 (663 events, and 662.2 patient-years of Briakinumab.TM.
exposure). Serious infections were relatively infrequent for all
treatment groups, however were observed more often in
Briakinumab.TM.-vs placebo-treated patients during the first 12
weeks (0.5% vs 0.2%, respectively). Cellulitis, which was observed
in 0.4% of Briakinumab.TM.-treated patients, was the most
frequently reported serious infection. There were no serious
infections observed beyond week 12 in patients who received every 4
week dosing, and low rates were observed in the every 12 week and
treatment withdrawal arms (0.7% and 0.7%, respectively).
Opportunistic infections were limited to two nonserious events of
oral candidiasis (one patient each in the Induction Phase placebo
arm, and the Maintenance Phase every 4 week arm); and one serious
event of worsening cytomegalovirus, localized bilaterally in the
eyes, in a patient receiving placebo during the Induction Phase. 69
patients initiated treatment for latent TB (Briakinumab.TM., n=52;
placebo, n=17) prior to beginning study drug. No events of TB
infection were observed during the study.
[1143] Combining the placebo-controlled and maintenance treatment
periods, nonmelanoma skin cancers were observed in a total of 10
patients treated with Briakinumab.TM. (six patients with squamous
cell carcinoma, and four with basal cell carcinoma; table 43), none
were reported in the placebo arm. Four of the events of squamous
cell carcinoma were diagnosed within the first 12 weeks of
treatment.
[1144] Major adverse cardiovascular events (MACE), defined as
cardiac arrest, myocardial infarction, stroke, or acute coronary
syndrome, were observed in seven patients treated with
Briakinumab.TM.. No MACE were observed in placebo-treated patients.
Five of the seven events occurred during the induction phase, with
onset ranging from 21 to 55 days following initiation of study
treatment. The two remaining events occurred on days 131 and 225,
during maintenance treatment. Of the five events observed during
the Induction Phase, one was a cardiac arrest resulting in death,
which occurred on day 38 in a 50 year old male patient with several
underlying risk factors for CHD (including body mass index of
.gtoreq.30 kg/m.sup.2, baseline triglyceride level >200 mg/dL,
and blood glucose of .gtoreq.126 mg/dL). All other events also
occurred in patients with 3 or more pre-existing risk factors for
CHD.
Discussion
[1145] This large, randomized, placebo-controlled trial in patients
with moderate to severe psoriasis demonstrated robust efficacy
responses to a treatment modality targeting the IL-12/23 pathways,
further validating previous work which has linked these cytokines
to the psoriasis disease process. Following 12 weeks of treatment,
the primary endpoints of PGA "clear" or "minimal" and PASI 75 were
achieved by 76% and 81% of Briakinumab.TM.-treated patients,
respectively. Moreover, a 52% mean improvement in PASI was observed
by week 4 suggesting a rapid onset of efficacy. The percentage of
patients achieving a PASI 100 response continued to rise through 20
weeks of treatment, and this degree of improvement was sustained
remarkably well through 52 weeks. For each endpoint, response was
maintained best with the every 4 week dosing regimen.
[1146] The high degree of clinical response which was observed in
various subgroups of patients is notable. Because patients who have
failed to respond to prior biologic therapy and/or have severe
psoriasis are generally more difficult to treat, the fact that most
patients meeting these criteria in this study achieved a PGA score
of "clear" or "minimal" and PASI 75 response highlights the
considerable efficacy benefits observed with Briakinumab.TM..
Likewise, equally high response levels were seen in patients having
arthritic involvement, and in those with higher weight, further
underscoring the particularly robust effects of this anti-IL-12/23
agent.
[1147] Safety findings in this phase III study were generally
consistent with preliminary results in an earlier, dose-ranging
study (Kimball A B, et al. Arch Dermatol 2008; 144: 200-7),
particularly with regard to the observed rates of infection, which
were comparable to those reported for ustekinumab, another
anti-IL-12/23 agent (Papp K A, et al. Lancet 2008; 371: 1675-84;
Leonardi C L, et al. Lancet 2008; 371: 1665-74). In this study,
infection rates appeared higher during maintenance treatment;
however, this may have been related to the large numbers of
patients lost at week 12 as a result of not meeting the efficacy
criteria of PGA "clear" or "minimal". Still, it is important to
note that a potential increased risk for infection with an
immunomodulating treatment is not unexpected, and monitoring for
these events during treatment with an anti-IL-12/23 agent is
warranted.
[1148] Rates of serious infection were low, with the most commonly
observed event being cellulitis. It is noteworthy that no TB or
serious opportunistic fungal infections occurred in this large
study; only a single case of candidiasis, in a patient receiving
Briakinumab.TM. every 4 weeks during maintenance treatment was
observed. Among more common adverse events reported, there appeared
to be a potential dose-response relationship for back pain, as the
percentage of patients reporting this event was higher for the
every 4 week dosing group vs the every 12 week or placebo groups,
although an explanation for this is unclear.
[1149] Seven major adverse cardiovascular events occurred in this
study, all in patients receiving Briakinumab.TM.. Recent evidence
suggests that patients with psoriasis may be more likely to have
major risk factors for cardiac events (Ludwig R J, et al. Br J
Dermatol 2007; 156: 271-6; Gisondi P, et al. Br J Dermatol 2007;
157: 68-73) and may be at higher risk for myocardial infarction
(Gelfand J M, et al. Jama 2006; 296: 1735-41). Compelling evidence
from a large, prospective, population-based study in a broadly
representative cohort of patients with psoriasis, identified from
the UK's General Practice Research Database, found that younger age
and severe disease independently raised the relative risk of
myocardial infarction by 3 times. Cytokines within atherosclerotic
lesions have been reported to promote a Th1 response leading to
production of interferon .gamma., and a cascade of other cytokines
(including tumor necrosis factor, IL-1, and IL-6), creating an
inflammatory milieu that promotes atherosclerosis (Hansson GK.
Inflammation, atherosclerosis, and coronary artery disease. N Engl
J Med 2005; 352: 1685-95). Considering the role of Th1-related
cytokines in psoriasis, current evidence suggests an association
between the inflammatory processes involved in psoriasis and those
inherent in coronary artery disease. However, there is a lack of
data distinguishing whether other variables potentially associated
with psoriasis, such as poor management of lifestyle risk factors
or stress, may be contributing to the risk of heart disease.
[1150] No major adverse cardiovascular events were observed among
the placebo-treated patients in this study. This finding is
consistent with studies in psoriasis patients treated with the
IL-12/23 blocker, ustekinumab. Four of 252 patients receiving
ustekinumab in a phase II, placebo-controlled trial, experienced
cardiac events that required hospitalization, including two
myocardial infarctions and one event of cardiac failure; while no
events occurred in the placebo group (Krueger G G, et al. N Engl J
Med 2007; 356: 580-92). In a larger, phase III study of
ustekinumab, major adverse cardiovascular events were observed in 4
of 753 ustekinumab-treated patients, while a single event was
observed in a placebo-treated patient after crossing over to
receive ustekinumab (Leonardi C L, et al. Lancet 2008; 371:
1665-74). In a comparator trial of ustekinumab and etanercept in
patients with moderate to severe psoriasis, 3 major adverse
cardiovascular events were observed with ustekinumab, while none
occurred with etanercept (Griffiths C E, et al. N Engl J Med; 362:
118-28). Conversely, no major adverse cardiovascular events were
observed in a phase II investigation of Briakinumab.TM. (Kimball A
B, et al. Arch Dermatol 2008; 144: 200-7), or in a second phase III
trial of ustekinumab (Papp K A, et al. Lancet 2008; 371: 1675-84).
Our post hoc analysis of underlying cardiac risk factors revealed a
slight imbalance between groups; however, these marginal
differences may not account for the disproportion in observed
cardiac events. Because the MACE observed in the current study and
those observed in previous studies of ustekinumab have been mostly
isolated to anti-IL-12/23 treatment exposed patients, more evidence
will be crucial to determine whether treatment with this new
therapy, the potential risk posed by psoriasis itself, or a
combination of the two, is contributing to their occurrence. In
light of the weight of evidence thus far, identification of cardiac
risk factors prior to commencing anti IL 12/23 treatment in
patients with psoriasis, and close monitoring during therapy, will
be important precautionary measures.
[1151] In summary, efficacy results from this 52-week, multicentre,
randomized, placebo-controlled trial demonstrate that
Briakinumab.TM. rapidly induces and maintains high efficacy
responses in patients with moderate to severe psoriasis, even among
those generally considered to have more complicated treatment
issues, such as prior failure of biologic therapy, arthritic
involvement or higher weight. Efficacy responses were optimally
maintained with a monthly dosing regimen. Safety results were
mostly consistent with those observed in phase II testing of
Briakinumab.TM., however the number of infections, nonmelanoma skin
cancers, and MACE warrant further investigation in a larger patient
population, and highlight the need to monitor for these events with
the use of anti-IL-12/23 agents.
TABLE-US-00046 TABLE 39 Demographic and clinical characteristics at
baseline by induction phase treatment group ABT-874 Placebo Total
(N = 981) (N = 484) (N = 1465) Demographic characteristics Age
(years) 45.7 (13.2) 45.1 (13.5) 45.5 (13.3) Sex, male 666 (67.9%)
343 (70.9%) 1009 (68.9%) Weight (kg) 93.8 (23.6) 93.1 (23.0) 93.5
(23.4) Race Asian 44 (4.5%) 18 (3.7%) 62 (4.2%) Black 31 (3.2%) 15
(3.1%) 46 (3.1%) White 888 (90.5%) 432 (89.3%) 1320 (90.1%) Other
18 (1.8%) 19 (3.9%) 37 (2.5%) Clinical characteristics Body surface
area 24.8 (16.3) 25.7 (16.9) 25.1 (16.5) affected (%) Psoriasis
area and 19.1 (7.5) 19.3 (7.3) 19.2 (7.4) severity index
Dermatology life 12.8 (7.0) 12.7 (6.9) 12.8 (7.0) quality index
Duration of psoriasis 18.9 (12.3) 19.2 (11.9) 19.0 (12.2) (years)
Patients with 290 (29.6%) 150 (31.0%) 440 (30.0%) psoriatic
arthritis Physician's global assessment Moderate 514 (52.4%) 242
(50.0%) 756 (51.6%) Severe 408 (41.6%) 218 (45.0%) 626 (42.7%) Very
Severe 59 (6.0%) 24 (5.0%) 83 (5.7%) Data are mean (SD) or n
(%).
TABLE-US-00047 TABLE 40 Risk factors for cardiovascular disease at
baseline by induction phase treatment group ABT-874 Placebo Total
(N = 981) (N = 484) (N = 1465) Cardiovascular disease medical
history Any cardiovascular disease 395 (40.3%) 178 (36.8%) 573
(39.1%) Angina 6 (0.6%) 2 (0.4%) 8 (0.5%) Cardiac arrhythmia 8
(0.8%) 5 (1.0%) 13 (0.9%) Congestive heart failure 4 (0.4%) 1
(0.2%) 5 (0.3%) Coronary artery disease 16 (1.6%) 5 (1.0%) 21
(1.4%) Hypertension 302 (30.8%) 139 (28.7%) 441 (30.1%) Myocardial
Infarction 19 (1.9%) 6 (1.2%) 25 (1.7%) Syncope 2 (0.2%) 0 2 (0.1%)
Other 171 (17.4%) 80 (16.5%) 251 (17.1%) Cardiovascular and
metabolic syndrome risk factors.sup.(ATP III 2001) Hypertension
(blood pressure .gtoreq.140/90 426 (43.4%) 199 (41.1%) 625 (42.7%)
mm/Hg, or taking antihypertensive drug) Cigarette smoking 304
(31.0%) 148 (30.6%) 452 (30.9%) Diabetes mellitus 98 (10.0%) 40
(8.3) 138 (9.4%) Obesity (BMI .gtoreq.30 kg/m.sup.2) 508 (51.8%)
245 (50.6%) 753 (51.4%) Male .gtoreq.45 years 374 (38.1%) 175
(36.2%) 549 (37.5%) Female .gtoreq.55 years 78 (8.0%) 40 (8.3%) 118
(8.1%) LDL cholesterol >100 mg/dL 542 (58.1%) 253 (55.0%) 795
(57.1%) Triglycerides >200 mg/dL 289 (29.6%) 132 (27.4%) 421
(28.9%) HDL cholesterol <40 mg/dL 294 (30.1%) 145 (30.1%) 439
(30.1%) Multiple cardiovascular risk factors .gtoreq.1 risk factor
928 (94.6%) 456 (94.2%) 1384 (94.5%) .gtoreq.2 risk factors 804
(82.0%) 386 (79.8%) 1190 (81.2%) .gtoreq.3 risk factors 600 (61.2%)
268 (55.4% 868 (59.2%) .gtoreq.4 risk factors 361 (36.8%) 166
(34.3%) 527 (36.0%) Data are mean (SD) or n (%)
TABLE-US-00048 TABLE 41 Overall results on the psoriasis area and
severity index (PASI) and dermatoloy life quality index (DLQI), and
clinical response across subgroups of patients at week 12 by
nonresponder imputation, unless otherwise noted ABT-874 Placebo (N
= 981) (N = 484) p value PASI 75 792 (80.7%) 22 (4.5%) <0.001
PASI 90 604 (61.6%) 7 (1.4%) <0.001 PASI 100 316 (32.2%) 0
<0.001 DLQI.sup.a Mean (SD) baseline score 12.8 (7.02) 12.7
(6.93) Mean (SD) week 12 score 2.69 (4.12) 12.2 (7.58) PGA "clear"
or "minimal" PASI 75 ABT-874 Placebo ABT-874 Placebo Prior
treatment Biologics 114/173 (65.9%) 1/76 (1.3%) 129/173 (74.6%)
1/76 (1.3%) No biologics 632/808 (78.2%) 20/408 (4.9%) 663/808
(82.1%) 21/408 (5.1%) Disease Severity Baseline PASI >20 207/299
(69.2%) 4/166 (2.4%) 237/299 (79.3%) 7/166 (4.2%) Baseline PASI
.ltoreq.20 539/682 (79.0%) 17/318 (5.3%) 555/682 (81.4%) 15/318
(4.7%) History of psoriatic arthritis Yes 208/290 (71.7%) 1/150
(0.7%) 228/290 (78.6%) 2/150 (1.3%) No 538/691 (77.9%) 20/334
(6.0%) 564/691 (81.6%) 20/334 (6.0%) Weight .gtoreq.100 kg 233/346
(67.3%) 4/172 (2.3%) 252/346 (72.8%) 4/172 (2.3%) <100 kg
513/635 (80.8%) 17/312 (5.4%) 540/635 (85.0%) 18/312 (5.8%) Values
are n (%), unless otherwise noted. Missing DLQI scores were imputed
with last observation, other than baseline, carried forward
(ABT-874, n = 954; placebo, n = 468)
TABLE-US-00049 TABLE 42 Demographic and clinical characteristics at
baseline by maintenance phase treatment group, for patients
randomized to ABT-874 during the induction phase Withdrawal ABT-874
every ABT-874 every from ABT-874 4 weeks 12 weeks (placebo) (N =
298) (N = 298) (N = 149) Demographic characteristics Age (years)
44.6 (13.3) 45.5 (12.6) 45.0 (13.4) Sex, male 206 (69.1%) 201
(67.4%) 100 (67.1%) Weight (kg) 91.3 (21.3) 93.7 (23.4) 89.3 (24.6)
Race Asian 13 (4.4%) 7 (2.3%) 14 (9.4%) Black 7 (2.3%) 7 (2.3%) 5
(3.4%) White 275 (92.3%) 278 (93.3%) 127 (85.2%) Other 3 (1.0%) 6
(2.0%) 3 (2.0%) Clinical characteristics Body surface area 23.7
(14.8) 22.3 (13.5) 25.2 (17.1) affected (%) Psoriasis area and 18.4
(6.5) 18.3 (6.2) 18.9 (8.2) severity index Dermatology life 12.7
(7.1) 12.6 (6.8) 11.9 (7.0) quality index Duration of psoriasis
19.1 (12.1) 18.5 (12.1) 18.9 (12.4) (years) Patients with 86
(28.9%) 79 (26.5%) 42 (28.2%) psoriatic arthritis Physician's
global assessment Moderate 170 (57.0%) 164 (55.0%) 85 (57.0%)
Severe 113 (37.9%) 124 (41.6%) 53 (35.6%) Very Severe 15 (5.0%) 10
(3.4%) 11 (7.4%) Data are mean (SD) or n (%).
TABLE-US-00050 TABLE 43 Adverse events observed during the
induction phase, during the maintenance phase for patients
allocated to ABT-874 in the induction phase, and for all patients
exposed to ABT-874 from baseline to week 52. Induction Phase
Maintenance Phase* ABT-874 Placebo ABT-874 q4 ABT-874 q12 Placebo
All ABT-874 (N = 981) (N = 484) (N = 297) (N = 298) (N = 149) (N =
998).sup..dagger. Any AE 517 (52.7%) 229 (47.3%) 215 (72.4%) 183
(61.4%) 86 (57.7%) 688 (68.9%) Most frequently
observed.sup..dagger-dbl. Nasopharyngitis 63 (6.4%) 20 (4.1%) 39
(13.1%) 35 (11.7%) 9 (6.0%) 117 (11.7%) Headache 53 (5.4%) 9 (1.9%)
14 (4.7%) 10 (3.4%) 4 (2.7%) 67 (6.7%) Upper Respiratory Tract
Infection 49 (5.0%) 20 (4.1%) 48 (16.2%) 24 (8.1%) 8 (5.4%) 113
(11.3%) Back Pain 15 (1.5%) 9 (1.9%) 16 (5.4%) 6 (2.0%) 3 (2.0%) 36
(3.6%) Any AE leading to discontinuation of 17 (1.7%) 4 (0.8%) 3
(1.0%) 6 (2.0%) 1 (0.7%) 27 (2.7%) study drug Any serious AE 20
(2.0%) 6 (1.2%) 4 (1.3%) 9 (3.0%) 2 (1.3%) 33 (3.3%) Deaths 1
(0.1%).sup..sctn. 0 0 0.sup..parallel. 0 1 (0.1%) AEs of special
interest Any Infection 219 (22.3%) 96 (19.8%) 132 (44.4%) 107
(35.9%) 41 (27.5%) 397 (39.8%) Any serious infection 5 (0.5%) 1
(0.2%) 0 2 (0.7%) 1 (0.7%) 8 (0.8%) Appendicitis 1 (0.1%) 0 0 0 0 1
(0.1%) Cellulitis 1 (0.1%) 0 0 2 (0.7%) 1 (0.7%) 4 (0.4%)
Cytomegalovirus infection 0 1 (0.2%) 0 0 0 0 Pneumonia 2 (0.2%) 0 0
0 0 2 (0.2%) Pyelonephritis 1 (0.1%) 0 0 0 0 1 (0.1%) Sepsis 0 0 0
1 (0.3%) 0 1 (0.1%) Any opportunitistic infection 0 2 (0.4%) 1
(0.3%) 0 0 1 (0.1%) Candidiasis 0 1 (0.2%) 1 (0.3%) 0 0 1 (0.1%)
Cytomegalovirus 0 1 (0.2%) 0 0 0 0 Any malignancy 6 (0.6%) 0 3
(1.0%) 5 (1.7%) 0 14 (1.4%) Squamous cell carcinoma 4 (0.4%) 0 0 2
(0.7%) 0 6 (0.6%) Basal cell carcinoma 0 0 2 (0.7%) 2 (0.7%) 0 4
(0.4%) Other 2 (0.2%).sup. 0 1 (0.3%)** 1
(0.3%).sup..dagger..dagger. 0 4 (0.4%) Any major adverse cardiac
event 5 (0.5%) 0 1 (0.3%) 1 (0.3%) 0 7 (0.7%) Cardiac arrest 1
(0.1%) 0 0 0 0 1 (0.1%) Myocardial infarction 3 (0.3%) 0 0 1 (0.3%)
0 4 (0.4%) Stroke 1 (0.1%) 0 0 0 0 1 (0.1%) Acute coronary syndrome
0 0 1 (0.3%) 0 0 1 (0.1%) Data are number of patients (%) [patients
may have had .gtoreq.1 adverse event]. *Patients who were
randomized to ABT-874 during the induction phase. .sup..dagger.All
patients who received at least one dose of ABT-874 during the
induction of maintenance phases. .sup..dagger-dbl.Adverse events
reported at an incidence rate of .gtoreq.5% in any of the treatment
groups shown. .sup..sctn.One patient experienced cardiac arrest
resulting in death (event also listed in AEs of special interest,
cardiovascular). .sup..parallel.One event of death occurred >45
days after study discontinuation in a patient who had a
cardiovascular event listed in AEs of special interest. .sup. One
patient diagnosed with lung cancer on study day 43, and 1 with
nasopharyngeal cancer on study day 15. **One patient diagnosed with
colon cancer on study day 285. .sup..dagger..dagger.One patient
diagnosed with tonsil cancer on study day 266.
Example 25
Efficacy and Safety of Briakinumab.TM., a Fully Human
Interleukin-12/23 Monoclonal Antibody, Versus Methotrexate in
Patients With Moderate to Severe Chronic Plaque Psoriasis: 52-Week
Results From a Phase III, Randomised, Double-Blind Trial
[1152] Although there is strong evidence supporting the use of
biologic therapy for the treatment of psoriasis (Schmitt J, et al.
Efficacy and tolerability of biologic and nonbiologic systemic
treatments for moderate-to-severe psoriasis: meta-analysis of
randomized controlled trials. Br J Dermatol 2008; 159: 513-26),
there is a need to establish the optimal use of biologics,
particularly as alternatives to traditional systemic therapies such
as methotrexate (MTX). MTX is the most commonly prescribed systemic
therapy for psoriasis worldwide (Menter A, et al. Guidelines of
care for the management of psoriasis and psoriatic arthritis:
section 4. Guidelines of care for the management and treatment of
psoriasis with traditional systemic agents. J Am Acad Dermatol
2009; 61: 451-85). Common adverse effects associated with MTX
include nausea, anorexia, stomatitis, and fatigue, and cumulative
or idiosyncratic toxicities of concern include hepatotoxicity,
myelosuppression, and pulmonary fibrosis (Menter A, et al., ibid).
Although clinical experience with MTX is abundant, large comparator
trials of biologic therapy vs. MTX are sparse. Superior efficacy
with adalimumab vs. MTX was reported in a 16-week, Phase III
randomised trial (Saurat J H, et al, Efficacy and safety results
from the randomized controlled comparative study of adalimumab vs.
methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br
J Dermatol 2008; 158: 558-66.), and preliminary results of a
26-week trial demonstrated superior efficacy with infliximab vs.
MTX (Reich K, et al., Infliximab is associated with greater
improvement in health-related quality of life versus methotrexate
for moderate-to-severe plaque-type psoriasis--the RESTORE 1 trial.
Abstract P1187), but data are limited on the long-term use of MTX.
In this Example the results of the first trial to evaluate the
efficacy and safety of 1 year of treatment with MTX in comparison
with Briakinumab.TM. in patients with moderate to severe plaque
psoriasis are reported.
Methods
Patients
[1153] This Phase III, multicentre, randomised, double-blind trial
was conducted at 43 sites in Europe and Canada. Patients aged
.gtoreq.18 years were eligible to participate if they had a
clinical diagnosis of psoriasis for .gtoreq.6 months; had stable
plaque psoriasis for .gtoreq.2 months; were candidates for systemic
therapy or phototherapy; and had .gtoreq.10% body surface area
involvement, a Physician's Global Assessment (PGA) score .gtoreq.3,
and a Psoriasis Activity and Severity Index (PASI) score .gtoreq.12
at baseline.
[1154] Patients were ineligible if they had nonplaque forms of
psoriasis or if they had previously received IL-12/-23
p40-targeting therapy or MTX. Patients also were ineligible if they
had received treatment with biologics or investigational agents
within the previous 12 weeks or 5 drug half-lives, conventional
systemic psoriasis treatment or phototherapy within the previous 4
weeks, or topical therapy within 2 weeks of the study baseline.
Patients were excluded if they had severe infections; a history of
clinically significant hematologic, renal, or liver disease; a
history of malignancy (except successfully treated basal cell
carcinoma, nonmetastatic cutaneous squamous cell carcinoma, or
cervical carcinoma in situ); or a history of active tuberculosis or
evidence of latent tuberculosis (unless prophylactic treatment was
received previously or initiated prior to administration of study
drug).
[1155] The study protocol was approved by an independent ethics
committee or institutional review board at each study site, and
each patient provided written informed consent.
Procedures
[1156] At baseline (Week 0), patients were randomised 1:1 to
receive Briakinumab.TM. (200 mg subcutaneously at Weeks 0 and 4 and
100 mg every 4 weeks from Weeks 8 to 48) or oral MTX (5 to 25 mg
weekly from Weeks 0 to 51) plus oral folate (5 mg weekly from Weeks
0 to 51) (FIG. 46). Patients in the MTX group received MTX 5 mg at
Week 0, 10 mg at Week 1, and 15 mg/wk from Weeks 2 to 9. At Weeks
10 and 16, MTX dosage was increased by 5 mg (to 20 mg/wk at Week 10
and 25 mg/wk at Week 16) for patients who did not achieve
PASI.gtoreq.75 or a PGA of 0 or 1. To maintain the blind, patients
in the Briakinumab.TM. group also received placebo capsules to
match MTX and placebo tablets to match folate, and patients in the
MTX group also received subcutaneous injections of placebo to match
Briakinumab.TM.
[1157] Treatment success was defined as having achieved both
PASI.gtoreq.75 and a PGA of 0 or 1 at Week 24. Patients in the MTX
group who achieved treatment success maintained their current
weekly MTX dose for the remainder of the study duration. At any
time during the study, the safety assessor could reduce or withhold
the MTX dose as a result of patient-reported symptoms, physical
examination, adverse events, or laboratory abnormalities (aspartate
aminotransferase or alanine aminotransferase
.gtoreq.1.5.times.upper limit of normal, platelet count
<100,000/mm.sup.3, total white blood cell count
<3,000/mm.sup.3, creatinine >2.times.upper limit of normal).
Patients in either treatment group who did not achieve treatment
success or who lost response (defined as PASI <50 and PGA
.gtoreq.3) after Week 24 discontinued the trial and were eligible
to enroll in an open-label extension study of Briakinumab.TM.. The
largest decrease in the percentage of patients remaining in the
study occurred between Weeks 24 and 28, with more patients
remaining in the MTX group than in the Briakinumab.TM. group
discontinuing owing to lack of efficacy. PASI and PGA responses
were calculated in a conservative fashion by imputing discontinued
patients as non-responders.
[1158] The primary efficacy endpoints were the percentages of
patients achieving PASI 75 at Week 24, a PGA of 0 or 1 at Week 24,
PASI 75 at Week 52, and a PGA of 0 or 1 at Week 52. The PASI is a
measure of the severity of skin symptoms of psoriasis, with scores
ranging from 0 to 72 (Fredriksson and Pettersson, 1978). A PASI
greater than 10 is considered to represent moderate to severe skin
symptoms of psoriasis (Pathirana et al, European S3-guidelines on
the systemic treatment of psoriasis vulgaris. J Eur Acad Dermatol
Venereol 2009; 23(Suppl 2): 1-70; Smith et al, British Association
of Dermatologists' guidelines for biologic interventions for
psoriasis 2009. Br J Dermatol 2009; 161: 987-1019). The PGA used
was a 6-point ordinal scale with 0 equaling "Clear"; 1, "Minimal";
2, "Mild"; 3, "Moderate"; 4, "Severe"; and 5, "Very Severe" (Ko,
1998).
[1159] Secondary efficacy variables included median time to achieve
PASI 75 response, PASI 50/75/90/100 response rates through Week 52,
proportion of patients with a PGA 0 or 1 by visit over 52 weeks,
and mean percentage improvements in PASI scores from baseline.
Efficacy assessments also included the change from baseline in Nail
Psoriasis Severity Index (NAPSI) scores, which range from 0 (no
nail psoriasis) to 80 (psoriasis in all 10 fingernails) (Rich and
Scher, 2003). Patients with nonzero baseline NAPSI scores had NAPSI
assessments at subsequent visits, using a single target fingernail
(the nail most affected by psoriasis at baseline), with a NAPSI
score range from 0 to 8.
[1160] An additional secondary efficacy parameter was the
Dermatology Life Quality Index (DLQI), a patient-reported measure
of the extent to which psoriasis impacts health-related quality of
life. The DLQI yields a score ranging from 0 to 30, with a lower
score indicating lower impact (Finlay and Khan, 1994). Assessments
included the percentages of patients with a DLQI score of 0 or 1
(no effect of psoriasis) (Hongbo et al, Translating the science of
quality of life into practice: What do dermatology life quality
index scores mean? J Invest Dermatol 2005; 125: 659-64),
percentages of patients with a decrease of .gtoreq.5 points (a
clinically meaningful reduction) (Khilji et al, Clinical meaning of
change in Dermatology Life Quality Index scores. Br J Dermatol
2002; 147(Suppl 62): 50), and change from baseline DLQI scores.
[1161] Adverse events, laboratory data, and vital signs were
assessed throughout the study. Patients were closely monitored for
signs of infection, malignancy, and immunologic reaction.
Treatment-emergent adverse events were defined as those occurring
on or after the first dose of study drug and up to 45 days after
the last dose of study drug.
Statistical Analysis
[1162] According to the original study plan, approximately 250
patients were to be randomised. Assuming that the PASI 75 response
rates at Week 24 were 70% in the Briakinumab.TM. group and 50% in
the MTX group, this sample size would provide 90% power to
demonstrate the superiority of Briakinumab.TM. over MTX (2-sided
chi-square test at level of significance 5%). However, owing to
difficulties in obtaining accurate enrolment numbers in a timely
manner, more than 250 patients were enrolled. Given an actual
enrolment number of 317 patients, the power increased from 90% to
95%. This change in power had little impact because of the large
differences in endpoints between treatment groups observed in the
study.
[1163] The intention-to-treat population included all patients who
were randomised at Week 0. The intention-to-treat population was
used for the efficacy analyses. For the primary efficacy
assessments, all comparisons were performed using a 2-sided
Cochran-Mantel-Haenszel test adjusted for country at an alpha level
of 0.05. The type I error rate was controlled at 0.05 by adhering
to the a priori defined order of statistical hypotheses.
Nonresponder imputation was used to handle missing data. Any
patient with a missing PASI or PGA score at a visit was considered
a nonresponder at that visit. Last observation carried forward
(LOCF) was used as a sensitivity analysis.
[1164] For categorical variables, the chi-square test or Fisher's
exact test (if the expected cell size was <5) was used to
evaluate the superiority of Briakinumab.TM. vs. MTX. Nonresponder
imputation was used to handle missing data. LOCF was used as a
sensitivity analysis. The median times to achieve PASI 75 response
and PGA score of 0 or 1 were calculated using the Kaplan-Meier
method. The treatment group difference was tested using the
log-rank test. Patients who did not achieve a response on or before
Week 52 were censored at the date of the last PASI/PGA
evaluation.
[1165] Differences between treatment groups in the change in PASI,
DLQI, and other continuous variables were analysed using analysis
of covariance with baseline value and treatment group in the model.
LOCF was used to handle missing data. Analysis as observed was done
as sensitivity analysis. To calculate the percentage change in
NAPSI score, only patients with nonzero baseline NAPSI scores were
included in the analysis. Wilcoxon 2-sample tests were used to
compare the treatment difference in the change. LOCF was used to
handle missing data. Analysis as observed was done as sensitivity
analysis.
[1166] The safety analyses were conducted using the safety
population, which included all patients who received at least 1
injection of study drug.
Results
[1167] A total of 317 patients met the inclusion criteria and were
randomised to Briakinumab.TM. (N=154) or MTX (N=163) (FIG. 47). No
randomised patients were excluded from the efficacy analysis
(intention-to-treat population). A total of 106 (68.8%) patients in
the Briakinumab.TM. group and 45 (27.6%) patients in the MTX group
completed the study through Week 52. Reasons for discontinuing the
study are shown in FIG. 47.
[1168] Baseline demographics, clinical characteristics, and disease
severity were similar between treatment groups (Table 44). Mean
duration of psoriasis was 18.9 years, mean PASI score was 18.1, and
mean body surface area involvement was 26.1%. Approximately 52% of
patients had previously received systemic nonbiologic treatment
(other than MTX) and 18% had previously received biologic
therapy.
[1169] Significantly more patients in the Briakinumab.TM. group
than the MTX group achieved the primary endpoints of PASI 75
response at Week 24 (81.8% vs. 39.9%; p<0.001) and at Week 52
(66.2% vs. 23.9%; p<0.001). Median time to achieve PASI 75
response was 56 days for the Briakinumab.TM. group vs. 140 days for
the MTX group (p<0.001). The percentage of patients who achieved
a PASI 75 response was significantly greater in the Briakinumab.TM.
group by Week 4 and at all time points through Week 52 (FIG. 48A).
Similarly, significant differences between treatment groups were
apparent beginning at Week 2 for PASI 50 and at Week 8 for PASI 90
and PASI 100; greater response rates in the Briakinumab.TM. group
were maintained through Week 52 (FIGS. 3B-3D). The mean percentage
improvement in PASI scores from baseline increased over time in
both treatment groups but was significant greater in the
Briakinumab.TM. group at all time points (FIG. 49). PASI 75/90/100
response rates at Week 16 for MTX-treated patients were similar to
those seen at Week 16 of CHAMPION. (Saurat J H, Stingl G, Dubertret
L, et al; CHAMPION Study Investigators. Efficacy and safety results
from the randomized controlled comparative study of adalimumab vs.
methotrexate vs. placebo in patients with psoriasis (CHAMPION). Br
J Dermatol 2008; 158: 558-66.)
[1170] Significantly more patients in the Briakinumab.TM. group
than the MTX group achieved the primary endpoints of PGA of 0 or 1
at Week 24 (80.5% vs. 34.4%; p<0.001) and at Week 52 (63.0% vs.
20.2%; p<0.001). In addition, cleared disease as assessed by a
PGA of 0 was evident in significantly more patients in the
Briakinumab.TM. group than the MTX group at Week 24 (46.1% vs.
9.2%; p<0.001) and at Week 52 (45.5% vs. 9.8%; p<0.001).
Median time to achieve a PGA of 0 or 1 was 69 days for the
Briakinumab.TM.group vs. 171 days for the MTX group (p<0.001).
Significantly greater percentages of patients in the
Briakinumab.TM. group attained a PGA of 0 or 1 at each time point
from Week 4 to Week 52 (FIG. 50).
[1171] Baseline NAPSI scores were similar between treatment groups
(Table 44). In the Briakinumab.TM. group, the mean NAPSI score for
the target fingernail decreased from 4.8 at baseline to 2.1 at Week
24 and 1.2 at Week 52. In the MTX group, the mean NAPSI score for
the target fingernail decreased from 4.8 at baseline to 3.0 at Week
24 and was also 3.0 at Week 52. The change from baseline in mean
NAPSI score for the target fingernail was significantly greater in
the Briakinumab.TM. group than in the MTX group at Week 24 and Week
52 (p<0.001 for both comparisons).
[1172] Significantly more patients in the Briakinumab.TM. group
than the MTX group had a DLQI score of 0 or 1 at Week 24 (70.8% vs.
34.4%; p<0.001) and at Week 52 (61.7% vs. 17.8%; p<0.001).
Similarly, significantly more patients in the Briakinumab.TM. group
than the MTX group achieved a clinically meaningful reduction in
DLQI score (decrease of .gtoreq.5 points) at Week 24 (66.2% vs.
47.9%; p<0.001) and at Week 52 (56.5% vs. 18.4%; p<0.001).
Patients in the Briakinumab.TM. group had significantly greater
decreases from baseline in DLQI scores compared with the MTX group
at all time points assessed (FIG. 51). At Week 24, the mean DLQI
score had decreased from 11.0 at baseline to 1.6 in the
Briakinumab.TM. group, vs. a decrease from 11.2 at baseline to 4.6
in the MTX group (difference between groups in change from
baseline: -3.0; 95% confidence interval [CI]: -3.9, -2.1;
p<0.001). DLQI scores at Week 52 (1.5 in the Briakinumab.TM.
group vs. 4.6 in the MTX group) reflected a similarly greater
change from baseline with Briakinumab.TM. vs. MTX (-3.1; 95% CI:
-4.0, -2.2; p<0.001).
[1173] For all efficacy variables, sensitivity analyses performed
for missing data yielded similar results.
[1174] Adverse event profiles were similar between Briakinumab.TM.
and MTX (Table 45). The most common treatment-emergent adverse
events were nasopharyngitis, headache, diarrhoea, arthralgia, and
upper respiratory tract infection. Diarrhoea (9.7% vs. 3.7%,
p=0.04) and injection-site-related adverse events (8.4% vs. 1.8%;
p=0.009) were more frequent in the Briakinumab.TM. group than the
MTX group.
[1175] Of the 317 patients randomised, 22 patients discontinued the
study owing to 1 or more adverse events. Twelve (7.8%) patients in
the Briakinumab.TM. group discontinued; adverse events for 5
patients were serious (gastrointestinal hypomotility and legionella
infection, breast cancer, breast neoplasm, prostate cancer, and
herpes zoster). Ten (6.1%) patients in the MTX group discontinued;
adverse events for 5 patients were serious (hepatic enzyme
increases and hepatitis, sacroiliitis, diverticulitis,
erythrodermic psoriasis, angioedema and urticaria).
[1176] Fourteen (9.1%) patients in the Briakinumab.TM. group and 10
(6.1%) patients in the MTX group reported treatment-emergent
serious adverse events. Seven patients experienced serious
infections, including 4 patients in the Briakinumab.TM. group (1
case of legionella infection with candidaemia, and septic shock, 1
case of osteomyelitis, 1 case of herpes zoster, and 1 case of
tonsillitis) and 3 patients in the MTX group (2 cases of
diverticulitis and 1 case of hepatitis). The incidence rates of
serious infectious adverse events were 4.1 and 2.7 per
100-patient-years in the Briakinumab.TM. and MTX groups,
respectively.
[1177] Fourteen patients in each treatment group had positive
purified protein derivative tests at baseline; however, no patient
had active tuberculosis at screening or reported
tuberculosis-related adverse events during the study. Three
patients in the Briakinumab.TM. group experienced malignancies (1
patient had breast cancer, 1 patient had breast neoplasm, and 1
patient had prostate cancer). One death was reported (oesophageal
rupture in a patient in the MTX group).
[1178] There were no reports of major cardiovascular events such as
sudden cardiac death, myocardial infarction, or stroke. Six
patients in the Briakinumab.TM. group and 4 patients in the MTX
group had ischemic heart disease adverse events (2 patients in the
Briakinumab.TM. group experienced angina pectoris and all other
patients experienced increased creatinine phosphokinase), none of
which were serious.
Discussion
[1179] In this 52-week, Phase III, multicentre, randomised,
double-blind study, Briakinumab.TM. was superior to MTX in reducing
the signs and symptoms of moderate to severe plaque psoriasis,
improving nail psoriasis, and favourably influencing
patient-reported health-related quality of life. Treatment with
Briakinumab.TM. produced a rapid clinical response that was
maintained through 52 weeks when compared to MTX. No clinically
important safety concerns were identified in the study.
[1180] The present study is the first comparator trial to evaluate
the efficacy and safety of MTX versus an IL-12/-23 p40-neutralizing
antibody. Compared with MTX, Briakinumab.TM. demonstrated faster
onset of action and superior efficacy through Week 52, with a
generally similar safety profile. In the Briakinumab.TM. group, a
PASI 75 response was achieved by 81.8% of patients at Week 24 and
by 66.2% of patients at Week 52. It is difficult to compare
maintenance of clinical response over 1 year with Briakinumab.TM.
in this trial vs. ustekinumab in previous trials because the
present study of Briakinumab.TM. was a straightforward
intention-to-treat analysis, whereas ustekinumab trials included
dose escalation (Papp K A, et al., Efficacy and safety of
ustekinumab, a human interleukin-12/23 monoclonal antibody, in
patients with psoriasis: 52-week results from a randomised,
double-blind, placebo-controlled trial (PHOENIX 2). Lancet 2008;
371: 1675-84) and several selection steps of responding patients
(Leonardi C L, et al., Efficacy and safety of ustekinumab, a human
interleukin-12/23 monoclonal antibody, in patients with psoriasis:
76-week results from a randomised, double-blind, placebo-controlled
trial (PHOENIX 1). Lancet 2008; 371: 1665-74.).
[1181] This first-ever 1-year study of MTX provides insight into
the maintenance of response with MTX. After Week 24, there was a
relatively sharp drop in the percentage of MTX-treated patients
with a PASI 75 response (39.9% at Week 24 compared with 30.7% at
Week 28) and a smaller drop in the percentage of patients with a
PGA of 0 or 1 (34.4% at Week 24 compared with 28.8% at Week 28). It
should be noted that at Week 24, patients who did not achieve both
PASI .gtoreq.75 and a PGA of 0 or 1 were discontinued per protocol.
Previous MTX comparator trials have been short term. In a 16-week
study of MTX vs. cyclosporine, no differences in clinical responses
were observed between groups (Heydendael V M, et al., Methotrexate
versus cyclosporine in moderate-to-severe chronic plaque psoriasis.
N Engl J Med 2003; 349: 658-65). More recent trials have
demonstrated better efficacy with biologic therapy vs. MTX. In a
16-week trial of MTX vs. adalimumab, significantly more patients
treated with adalimumab achieved PASI 75 response at Week 16 (80%
vs. 36%; p<0.001) (Saurat J H, et al., Efficacy and safety
results from the randomized controlled comparative study of
adalimumab vs. methotrexate vs. placebo in patients with psoriasis
(CHAMPION). Br J Dermatol 2008; 158: 558-66). Moreover, similar to
the findings of the present study, clinical response occurred more
rapidly with biologic therapy than with MTX. Preliminary results of
a 26-week trial of MTX vs. infliximab demonstrated that
significantly more patients treated with infliximab achieved PASI
75 at Week 26 (77% vs. 31%; p<0.001) (Reich K, et al.,
Infliximab is associated with greater improvement in health-related
quality of life versus methotrexate for moderate-to-severe
plaque-type psoriasis--the RESTORE 1 trial. Abstract P1187). In
addition, greater improvement in DLQI scores from baseline to Week
26 was evident with infliximab than with MTX (-11.3 vs. -9.1;
p<0.004) (Reich K, et al. Infliximab is associated with greater
improvement in health-related quality of life versus methotrexate
for moderate-to-severe plaque-type psoriasis--the RESTORE 1 trial.
Abstract P1187).
[1182] With respect to the long-term safety of MTX, previous
16-week trials reported hepatic-related adverse events leading to
discontinuation in 12 (28%) of 43 patients who received 15 mg
weekly (Heydendael V M, et al. Methotrexate versus cyclosporine in
moderate-to-severe chronic plaque psoriasis. N Engl J Med 2003;
349: 658-65) and in 4 (4%) of 110 patients who received a starting
MTX dosage of 7.5 mg weekly that was increased as needed and
tolerated to 25 mg weekly (Saurat J H, et al. Efficacy and safety
results from the randomized controlled comparative study of
adalimumab vs. methotrexate vs. placebo in patients with psoriasis
(CHAMPION). Br J Dermatol 2008; 158: 558-66). In the present study
of 52 weeks of MTX treatment (5 to 25 mg weekly, per titration
schedule), 16 (10%) patients in the MTX group experienced
hepatic-related adverse events, but only 2 (1%) patients
discontinued the study. These results suggest that initiating MTX
with a low dosage that is titrated up as indicated and tolerated
may be a safe strategy for long-term use of MTX.
[1183] With respect to safety of Briakinumab.TM., 52 weeks of
treatment was associated with a low incidence of serious adverse
events. The incidence of serious infectious adverse events was 4.1
events per 100-patient-years with Briakinumab.TM. and 2.7 events
per 100-patient-years with MTX. Previous studies have reported a
rate of 1.3 serious infectious events per 100-patient-years with
adalimumab or infliximab (Menter A, et al. Adalimumab therapy for
moderate to severe psoriasis: A randomized, controlled phase III
trial. J Am Acad Dermatol 2008; 58: 106-15; Burmester G R, et al.
Adalimumab safety and mortality rates from global clinical trials
of six immune-mediated inflammatory diseases. Ann Rheum Dis 2009;
68: 1863-69). In the present study of Briakinumab.TM., no serious
cardiovascular events (eg, myocardial infarction, stroke) were
reported, in contrast with low frequencies of such events in
another trial of Briakinumab.TM. (M06-890 reference) and in trials
of ustekinumab (Krueger G G, et al. A human interleukin-12/23
monoclonal antibody for the treatment of psoriasis. N Engl J Med
2007; 356: 580-92; Leonardi C L, et al. Efficacy and safety of
ustekinumab, a human interleukin-12/23 monoclonal antibody, in
patients with psoriasis: 76-week results from a randomised,
double-blind, placebo-controlled trial (PHOENIX 1). Lancet 2008;
371: 1665-74; Papp K A, et al. Efficacy and safety of ustekinumab,
a human interleukin-12/23 monoclonal antibody, in patients with
psoriasis: 52-week results from a randomised, double-blind,
placebo-controlled trial (PHOENIX 2). Lancet 2008; 371:
1675-84).
Conclusions
[1184] In this head-to-head trial of Briakinumab.TM. vs. MTX in
patients with moderate to severe plaque psoriasis, Briakinumab.TM.
demonstrated superior efficacy compared with MTX on all primary and
secondary endpoints, including clinical response measures and
patient-reported health-related quality of life, through 52 weeks
of treatment. Based on the superior efficacy and a safety profile
without clinically significant findings compared with MTX, these
results demonstrate a favourable benefit-risk ratio for
Briakinumab.TM. vs. MTX as a therapeutic option for the treatment
of psoriasis.
TABLE-US-00051 TABLE 44 Baseline Demographic and Clinical
Characteristics Briakinumab .TM. MTX Characteristic (N = 154) (N =
163) Age (years), mean (SD) 45.0 (13.1) 43.1 (12.9) Male 111 (72.1)
111 (68.1) White 149 (96.8) 158 (96.9) Weight (kg), mean (SD) 85.1
(17.5) 82.0 (18.6) Duration of psoriasis (years), 18.6 (11.9) 19.1
(11.3) mean (SD) BSA affected by psoriasis (%), 26.1 (16.7) 26 1
(16.3) mean (SD) History of psoriatic arthritis 25 (16.2) 28 (17.2)
PASI score, mean (SD) 18.4 (6.7) 17 8 (6.1) NAPSI score,* mean (SD)
27.7 (16.4) 27 9 (19.1) NAPSI score for target fingernail,* 4.8
(2.0) 4.8 (2.1) mean (SD) PGA "Clear," "Minimal," or "Mild" 0 0
"Moderate" 75 (48.7) 87 (53.4) "Severe" 65 (42.2) 72 (44.2) "Very
Severe" 14 (9.1) 4 (2.5) DLQI score,.sup..dagger. mean (SD) 11.1
(6.6) 11.3 (7.5) Previous psoriasis treatment Topical therapy 141
(91.6) 148 (90.8) Phototherapy 100 (64.9) 105 (64.4) Systemic
nonbiologic treatment 77 (50.0) 89 (54.6) Systemic biologic
treatment 24 (15.6) 34 (20.9) Etanercept 14 (9.1) 12 (7.4)
Infliximab 9 (5.8) 11 (6.7) Adalimumab 5 (3.2) 7 (4.3) Alefacept 2
(1.3) 2 (1.2) Efalizumab 6 (3.9) 3 (1.8) Other 3 (1.9) 7 (4.3)
Values are n (%) unless otherwise noted. *N = 115 (briakinumab
.TM.), N = 108 (MTX). .sup..dagger.N = 154 (briakinumab .TM., N =
162 (MTX). BSA, body surface area; DLQI, Dermatology Life Quality
Index; MTX, methotrexate; NAPSI, Nail Psoriasis Severity Index;
PASI, Psoriasis Area and Severity Index; PGA, Physician's Global
Assessment.
TABLE-US-00052 TABLE 45 Adverse Events by Treatment Group
Briakinumab .TM. MTX Event* (N = 154) (N = 163) Any adverse event
131 (85.1) 145 (89.0) Serious adverse events 14 (9.1) 10 (6.1)
Adverse events leading to 12 (7.8) 10 (6.1) discontinuation Common
adverse events.sup..dagger. Nasopharyngitis 44 (28.6) 45 (27.6)
Headache 18 (11.7) 22 (13.5) Diarrhoea 15 (9.7).sup..dagger-dbl. 6
(3.7) Arthralgia 12 (7.8) 11 (6.7) Upper respiratory tract 11 (7.1)
12 (7.4) infection Back pain 10 (6.5) 9 (5.5) Fatigue 10 (6.5) 10
(6.1) Gastroenteritis 10 (6.5) 11 (6.7) Cough 9 (5.8) 12 (7.4)
Nausea 9 (5.8) 19 (11.7) Influenza 8 (5.2) 9 (5.5) Rhinitis 8 (5.2)
6 (3.7) Adverse events of special interest Infections 89 (57.8) 102
(62.6) Serious infections 4 (2.6) 3 (1.8) Opportunistic infections
1 (0.6) 0 Malignancies 3 (1.9) 0 Cardiovascular events.sup..sctn. 0
0 Ischemic heart disease 6 (3.9) 4 (2.5) Deaths.sup..parallel. 0 1
(0.6) Values are n (%). *Occurred on or after the first dose of
study drug and up to 45 days after the last dose of study drug.
.sup..dagger.Occurred in .gtoreq.5% of patients in either treatment
group. .sup..dagger-dbl.p = 0 04 vs. MTX group. .sup..sctn.Any
serious adverse event of sudden cardiac death, myocardial
infarction, or stroke. .sup..parallel.Includes
non-treatment-emergent deaths. MTX, methotrexate.
EQUIVALENTS
[1185] Those skilled in the art will recognize, or be able to
ascertain using no more than routine experimentation, many
equivalents to the specific embodiments of the invention described
herein. Such equivalents are intended to be encompassed by the
following claims.
Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID
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<223> OTHER INFORMATION: Xaa at position 1 could be either
His or Ser <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Xaa
at position 4 could be either Tyr or His <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Xaa at position 6 could be either
Tyr, Asn or Thr <400> SEQUENCE: 1 Xaa Gly Ser Xaa Asp Xaa 1 5
<210> SEQ ID NO 2 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (2)..(2)
<223> OTHER INFORMATION: Xaa at position 2 could be either
Ser or Thr <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (4)..(4) <223> OTHER INFORMATION: Xaa
at position 4 could be either Asp or Glu <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (5)..(5)
<223> OTHER INFORMATION: Xaa at position 5 could be either
Ser, Arg or Lys <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (6)..(6) <223> OTHER
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<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa at position 7
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<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8)
<223> OTHER INFORMATION: Xaa at position 8 could be either
Arg, Ser, Thr, Trp or His <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (9)..(9) <223>
OTHER INFORMATION: Xaa at position 9 could be either Gly or Pro
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
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<223> OTHER INFORMATION: Xaa at position 11 could be either
Arg, Ser, Met, Thr or Leu <220> FEATURE: <221>
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Xaa Xaa Xaa Xaa Xaa 1 5 10 <210> SEQ ID NO 3 <211>
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<400> SEQUENCE: 3 Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr
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<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Xaa at position 1 could be either Gly or Tyr
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa at position 3
could be either Asp or Ser <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (4)..(4) <223>
OTHER INFORMATION: Xaa at position 4 could be either Gln or Asn
<400> SEQUENCE: 4 Xaa Asn Xaa Xaa Arg Pro Ser 1 5 <210>
SEQ ID NO 5 <211> LENGTH: 9 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:
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5 Phe Thr Phe Ser Xaa Tyr Gly Met His 1 5 <210> SEQ ID NO 6
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Xaa at position 1 could be either Ser or Thr
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa at position 3
could be either Ser or Gly <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (4)..(4) <223>
OTHER INFORMATION: Xaa at position 4 could be either Arg or Ser
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa at position 8
could be either Gly or Val <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (9)..(9) <223>
OTHER INFORMATION: Xaa at position 9 could be either Ser or Ala
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa at position
10 could be either Asn, Gly or Tyr <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223>
OTHER INFORMATION: Xaa at position 11 could be either Thr or Asp
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa at position
13 could be either Lys or His <400> SEQUENCE: 6 Xaa Gly Xaa
Xaa Ser Asn Ile Xaa Xaa Xaa Xaa Val Xaa 1 5 10 <210> SEQ ID
NO 7 <211> LENGTH: 115 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:
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INFORMATION: Xaa at position 6 could be either Gln or Glu
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa at position
16 could be either Arg or Gly <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (31)..(31) <223>
OTHER INFORMATION: Xaa at position 31 could be either Ser or Glu
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (84)..(84) <223> OTHER INFORMATION: Xaa at position
84 could be either Lys or Asn <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (97)..(97) <223>
OTHER INFORMATION: Xaa at position 97 could be either Thr, Ala or
Lys <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (98)..(98) <223> OTHER INFORMATION: Xaa
at position 98 could be either Thr or Lys <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (99)..(99)
<223> OTHER INFORMATION: Xaa at position 99 could be either
Ser or His <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (102)..(102) <223> OTHER INFORMATION:
Xaa at position 102 could be either Tyr or His <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(104)..(104) <223> OTHER INFORMATION: Xaa at position 104
could be either Tyr, Asn or Thr <400> SEQUENCE: 7 Gln Val Gln
Leu Val Xaa Ser Gly Gly Gly Val Val Gln Pro Gly Xaa 1 5 10 15 Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Xaa Tyr 20 25
30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val
35 40 45 Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp
Ser Asx 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys
Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Xaa Ser Leu Arg Ala Glu Asp
Thr Ala Val Tyr Tyr Cys 85 90 95 Xaa Xaa Xaa Gly Ser Xaa Asp Xaa
Trp Gly Gln Gly Thr Met Val Thr 100 105 110 Val Ser Ser 115
<210> SEQ ID NO 8 <211> LENGTH: 112 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Xaa at position 1 could be either
Ser or Gln <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa
at position 2 could be either Tyr or Ser <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (13)..(13)
<223> OTHER INFORMATION: Xaa at position 13 could be either
Thr or Ala <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (23)..(23) <223> OTHER INFORMATION: Xaa
at position 23 could be either Ser or Thr <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (25)..(25)
<223> OTHER INFORMATION: Xaa at position 25 could be either
Gly or Ser <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (26)..(26) <223> OTHER INFORMATION: Xaa
at position 26 could be either Arg or Ser <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (30)..(30)
<223> OTHER INFORMATION: Xaa at position 30 could be either
Gly or Val <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (31)..(31) <223> OTHER INFORMATION: Xaa
at position 31 could be either Ser or Ala <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (32)..(32)
<223> OTHER INFORMATION: Xaa at position 32 could be either
Asn, Gly or Tyr <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (33)..(33) <223> OTHER
INFORMATION: Xaa at position 33 could be either Thr or Asp
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (35)..(35) <223> OTHER INFORMATION: Xaa at position
35 could be either Lys or His <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (51)..(51) <223>
OTHER INFORMATION: Xaa at position 51 could be either Gly or Lys
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (53)..(53) <223> OTHER INFORMATION: Xaa at position
53 could be either Asp or Ser <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (54)..(54) <223>
OTHER INFORMATION: Xaa at position 54 could be either Gln or Asn
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (79)..(79) <223> OTHER INFORMATION: Xaa at position
79 could be either Val or Leu <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (91)..(91) <223>
OTHER INFORMATION: Xaa at 91 could be either Ser or Thr <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(93)..(93) <223> OTHER INFORMATION: Xaa at position 93 could
be either Asp or Glu <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (94)..(94) <223> OTHER
INFORMATION: Xaa at position 94 could be either Ser, Arg or Lys
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (95)..(95) <223> OTHER INFORMATION: Xaa at position
95 could be either Ser, Gly or Tyr <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (96)..(96) <223>
OTHER INFORMATION: Xaa at position 96 could be either Leu, Phe, Thr
or Ser <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (97)..(97) <223> OTHER INFORMATION: Xaa
at position 97 could be either Arg, Ser, Thr, Trp or His
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (98)..(98) <223> OTHER INFORMATION: Xaa at position
98 could be either Gly or Pro <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (99)..(99) <223>
OTHER INFORMATION: Xaa at position 99 could be either Ser, Thr, Ala
or Leu <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (100)..(100) <223> OTHER INFORMATION:
Xaa at position 100 could be either Arg, Ser, Met, Thr or Leu
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (101)..(101) <223> OTHER INFORMATION: Xaa at
position 101 could be either Val, Ile, Thr, Met or Leu <400>
SEQUENCE: 8 Xaa Xaa Val Leu Thr Gln Pro Pro Ser Val Ser Gly Xaa Pro
Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Xaa Gly Xaa Xaa Ser Asn
Ile Xaa Xaa Xaa 20 25 30 Xaa Val Xaa Trp Tyr Gln Gln Leu Pro Gly
Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Xaa Asn Xaa Xaa Arg Pro
Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr
Ser Ala Ser Leu Ala Ile Thr Gly Xaa Gln 65 70 75 80 Ala Glu Asp Glu
Ala Asp Tyr Tyr Cys Gln Xaa Tyr Xaa Xaa Xaa Xaa 85 90 95 Xaa Xaa
Xaa Xaa Xaa Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly 100 105 110
<210> SEQ ID NO 9 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (2)..(2) <223>
OTHER INFORMATION: Xaa at position 2 could be either Gly, Val, Cys
or His <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa
at position 3 could be either Ser or Thr <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Xaa at position 4 could be either
His, Thr, Val, Arg, or Ile <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (5)..(5) <223>
OTHER INFORMATION: Xaa at position 5 could be either Asp or Ser
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (6)..(6) <223> OTHER INFORMATION: Xaa at position 6
could be either Asn, Lys, Ala, Thr, Ser, Phe, Trp, or His
<400> SEQUENCE: 9 His Xaa Xaa Xaa Xaa Xaa 1 5 <210> SEQ
ID NO 10 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Xaa at position 4 could be either Asp or Ser
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (5)..(5) <223> OTHER INFORMATION: Xaa at position 5
represents any amino acid <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (6)..(6) <223>
OTHER INFORMATION: Xaa at position 6 could be either Gly, Asp, Gln,
Leu, Phe, Arg, His, Asn or Tyr <400> SEQUENCE: 10 Gln Ser Tyr
Xaa Xaa Xaa Thr His Pro Ala Leu Leu 1 5 10 <210> SEQ ID NO 11
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Xaa at position 1 could be either Phe, Thr or Tyr
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa at position 3
could be either Arg or Ala <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (5)..(5) <223>
OTHER INFORMATION: Xaa at position 5 could be either Asp, Ser, Glu
or Ala <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Xaa
at position 6 could be either Gly or Arg <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (8)..(8)
<223> OTHER INFORMATION: Xaa at position 8 represents any
amino acid <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa
at position 10 could be either Tyr or Glu <400> SEQUENCE: 11
Xaa Ile Xaa Tyr Xaa Xaa Ser Xaa Lys Xaa Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 12 <211> LENGTH: 7
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa at position 1
could be either Gly, Tyr, Ser, Thr, Asn or Gln <400>
SEQUENCE: 12 Xaa Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO
13 <211> LENGTH: 9 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (4)..(5) <223> OTHER
INFORMATION: Xaa at position 4 and 5 represents any amino acid
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (6)..(6) <223> OTHER INFORMATION: Xaa at position 6
could be either Tyr or His <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7) <223>
OTHER INFORMATION: Xaa at position 7 could be either Gly, Met, Ala,
Asn or Ser <400> SEQUENCE: 13 Phe Thr Phe Xaa Xaa Xaa Xaa Met
His 1 5 <210> SEQ ID NO 14 <211> LENGTH: 13 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (9)..(9)
<223> OTHER INFORMATION: Xaa at position 9 could be either
Ser, Cys, Arg, Asn, Asp or Thr <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10) <223>
OTHER INFORMATION: Xaa at position 10 could be either Asn, Met or
Ile <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (11)..(11) <223> OTHER INFORMATION: Xaa
at position 11 could be either Thr, Tyr, Asp, His, Lys or Pro
<400> SEQUENCE: 14 Ser Gly Gly Arg Ser Asn Ile Gly Xaa Xaa
Xaa Val Lys 1 5 10 <210> SEQ ID NO 15 <211> LENGTH: 114
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (5)..(5) <223> OTHER INFORMATION: Xaa at position 5
could be either Gln or Glu <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (30)..(30) <223>
OTHER INFORMATION: Xaa at position 30 could be Ser or Glu
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (83)..(83) <223> OTHER INFORMATION: Xaa at position
83 could be Lys or Asn <400> SEQUENCE: 15 Gln Val Gln Val Xaa
Ser Gly Gly Gly Val Val Gln Pro Gly Arg Ser 1 5 10 15 Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Xaa Tyr Gly 20 25 30 Met
His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val Ala 35 40
45 Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
50 55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
Tyr Leu 65 70 75 80 Gln Met Xaa Ser Leu Arg Ala Glu Asp Thr Ala Val
Tyr Tyr Cys Lys 85 90 95 Thr His Gly Ser His Asp Asn Trp Gly Gln
Gly Thr Met Val Thr Val 100 105 110 Ser Ser <210> SEQ ID NO
16 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Xaa at position 1 could be either Ser or Gln
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (2)..(2) <223> OTHER INFORMATION: Xaa at position 2
could be Tyr or Ser <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (13)..(13) <223> OTHER
INFORMATION: Xaa at position 13 could be either Thr or Ala
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (25)..(25) <223> OTHER INFORMATION: Xaa at position
25 could be either Gly or Ser <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (51)..(51) <223>
OTHER INFORMATION: Xaa at position 51 could be either Gly or Tyr
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (79)..(79) <223> OTHER INFORMATION: Xaa at position
79 could be either Val or Leu <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (95)..(95) <223>
OTHER INFORMATION: Xaa at position 95 could be either Gly or Tyr
<400> SEQUENCE: 16 Xaa Xaa Val Leu Thr Gln Pro Pro Ser Val
Ser Gly Xaa Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly
Xaa Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Lys Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Xaa Asn
Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Xaa Gln 65 70 75 80
Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Arg Xaa Thr 85
90 95 His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys Val Thr Val Leu
Gly 100 105 110 <210> SEQ ID NO 17 <211> LENGTH: 6
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 17 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 18 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 Gln Ser
Tyr Asp Arg Gly Thr His Pro Ala Leu Leu 1 5 10 <210> SEQ ID
NO 19 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 19 Phe Ile Arg Tyr Asp
Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 20 <211> LENGTH: 7 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 Gly
Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 21 <211>
LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 21 Phe Thr Phe Ser Ser Tyr Gly Met His 1 5
<210> SEQ ID NO 22 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 22 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 23 <211> LENGTH: 115 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 23 Gln Val
Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20
25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp
Asn Trp Gly Gln Gly Thr Met Val Thr 100 105 110 Val Ser Ser 115
<210> SEQ ID NO 24 <211> LENGTH: 112 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 24 Ser
Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10
15 Arg Val Thr Ile Ser Cys Ser Gly Gly Arg Ser Trp Ile Gly Ser Asn
20 25 30 Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
Leu Leu 35 40 45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro
Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu
Ala Ile Thr Gly Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr
Cys Gln Ser Tyr Asp Arg Gly Thr 85 90 95 His Pro Ala Leu Leu Phe
Gly Thr Gly Thr Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ
ID NO 25 <211> LENGTH: 6 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 25 His Gly Ser His Asp
Asn 1 5 <210> SEQ ID NO 26 <211> LENGTH: 12 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
26 Gln Ser Tyr Asp Arg Tyr Thr His Pro Ala Leu Leu 1 5 10
<210> SEQ ID NO 27 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 27 Phe
Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10
15 Gly <210> SEQ ID NO 28 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
28 Tyr Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 29
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 29 Phe Thr Phe Ser Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 30 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 30 Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn
Thr Val Lys 1 5 10 <210> SEQ ID NO 31 <211> LENGTH: 115
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 31 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val
Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO 32
<211> LENGTH: 112 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 32 Gln Ser Val Leu Thr Gln Pro
Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser
Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Lys
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile
Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln
65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Arg
Tyr Thr 85 90 95 His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys Val
Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 33 <211>
LENGTH: 115 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 33 Gln Val Gln Leu Val Gln Ser Gly
Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe
Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65
70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr Ser Gly Ser Tyr Asp Tyr Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
34 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 34 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Ser Ser Leu 85 90 95 Arg Gly Ser Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 35
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 35 Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Lys Ser Gly Ser Tyr Asp Tyr Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
36 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (32)..(32) <223> OTHER
INFORMATION: Xaa at position 32 represents either Gly or Tyr
<400> SEQUENCE: 36 Gln Ser Val Leu Thr Gln Pro Pro Ser Val
Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly
Ser Ser Ser Asn Ile Gly Ala Xaa 20 25 30 Asp Val His Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Asn
Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln 65 70 75 80
Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85
90 95 Ser Gly Ser Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
Gly 100 105 110 <210> SEQ ID NO 37 <211> LENGTH: 115
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 37 Gln Val Gln Leu Val Gln Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Thr Thr His Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val
Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO 38
<211> LENGTH: 112 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 38 Ser Tyr Val Leu Thr Gln Pro
Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser
Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Lys
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile
Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Val Gln
65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
Ser Leu 85 90 95 Arg Gly Ser Arg Val Phe Gly Thr Gly Thr Lys Val
Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 39 <211>
LENGTH: 115 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 39 Gln Val Gln Leu Val Gln Ser Gly
Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe
Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65
70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr Ser Gly Ser Tyr Asp Tyr Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
40 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 40 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Phe 85 90 95 Thr Gly Ser Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 41
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 41 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr Ser Gly Ser Tyr Asp Tyr Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
42 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 42 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Ser Ser Leu 85 90 95 Trp Gly Ser Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 43
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 43 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
44 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 44 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Phe 85 90 95 Thr Gly Ser Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 45
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 45 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
46 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 46 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Ser Ser Leu 85 90 95 Trp Gly Ser Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 47
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 47 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
48 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 48 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Tyr
Asp Lys Gly Phe 85 90 95 Thr Gly Ser Ser Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 49
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 49 Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
50 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 50 Gln Ser Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Tyr
Asp Lys Gly Phe 85 90 95 Thr Gly Ser Ser Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 51
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 51 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr His Gly Ser His Asp Thr Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
52 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 52 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Ser Ser Leu 85 90 95 Trp Gly Thr Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 53
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 53 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
54 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 54 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Val Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Phe 85 90 95 Thr Gly Ser Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 55
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 55 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
56 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 56 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Val Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Phe 85 90 95 Thr Gly Ala Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 57
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 57 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
58 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 58 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Tyr
Asp Lys Gly Phe 85 90 95 Thr Gly Ser Ser Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 59
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 59 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
60 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 60 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Glu Arg Gly Phe 85 90 95 Thr Gly Ser Met Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 61
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 61 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
62 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 62 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Thr 85 90 95 His Pro Leu Thr Ile Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 63
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 63 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
64 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 64 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Ser 85 90 95 His Pro Ala Leu Thr Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 65
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 65 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
66 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 66 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Thr 85 90 95 His Pro Leu Thr Met Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 67
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 67 Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
68 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 68 Gln Ser Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Thr 85 90 95 His Pro Leu Thr Met Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 69
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 69 Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
70 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 70 Gln Ser Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Thr 85 90 95 His Pro Ala Leu Leu Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 71
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 71 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Glu Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
72 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 72 Gln Ser Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Thr 85 90 95 His Pro Ala Leu Leu Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 73
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 73 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
74 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 74 Gln Ser Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Thr 85 90 95 His Pro Ala Leu Leu Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 75
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 75 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
76 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 76 Gln Ser Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Tyr Thr 85 90 95 His Pro Ala Leu Leu Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 77
<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 77 Ser Gly Ser Tyr Asp Tyr 1 5
<210> SEQ ID NO 78 <211> LENGTH: 6 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 78 His
Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 79 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 79 His Gly Ser Tyr Asp Tyr 1 5 <210>
SEQ ID NO 80 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 80 Arg Arg
Arg Ser Asn Tyr 1 5 <210> SEQ ID NO 81 <211> LENGTH: 6
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 81 Ser Gly Ser Ile Asp Tyr 1 5 <210>
SEQ ID NO 82 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 82 His Gly
Ser His Asp Asp 1 5 <210> SEQ ID NO 83 <211> LENGTH: 6
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 83 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 84 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 84 Thr Thr
His Gly Ser His Asp Asn Trp Gly Gln Gly 1 5 10 <210> SEQ ID
NO 85 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 85 Ala Lys His Gly Ser
His Asp Asn Trp Gly Gln Gly 1 5 10 <210> SEQ ID NO 86
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 86 Thr Thr His Gly Ser His Asp
Asn Trp Ser Gln Gly 1 5 10 <210> SEQ ID NO 87 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 87 Thr Thr His Gly Ser His Asp Thr Trp Gly
Gln Gly 1 5 10 <210> SEQ ID NO 88 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 88 Lys Thr His Gly Ser His Asp Asn Trp Gly
Gln Gly 1 5 10 <210> SEQ ID NO 89 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 89 Lys Thr His Gly Ser His Asp Asn Trp Gly
His Gly 1 5 10 <210> SEQ ID NO 90 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 90 Thr Thr His Gly Ser His Asp Asn Trp Ser
Gln Gly 1 5 10 <210> SEQ ID NO 91 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 91 Thr Thr His Arg Ser His Asn Asn Trp Gly
Gln Gly 1 5 10 <210> SEQ ID NO 92 <211> LENGTH: 8
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 92 Thr Thr His Gly Ser His Asp Asn 1 5
<210> SEQ ID NO 93 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 93 Thr
Thr His Gly Ser His Asp Thr 1 5 <210> SEQ ID NO 94
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 94 Thr Lys His Gly Ser His Asp
Asn 1 5 <210> SEQ ID NO 95 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
95 Thr Thr Gln Gly Arg His Asp Asn 1 5 <210> SEQ ID NO 96
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 96 Lys Thr Arg Gly Arg His Asp
Asn 1 5 <210> SEQ ID NO 97 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
97 Thr Thr His Gly Ser His Asp Lys 1 5 <210> SEQ ID NO 98
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 98 Thr Thr His Gly Ser His Asp
Asp 1 5 <210> SEQ ID NO 99 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
99 Lys Thr His Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 100
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 100 Lys Thr His Gly Ser His Asp
Asn 1 5 <210> SEQ ID NO 101 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
101 Thr Thr His Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 102
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 102 Thr Thr Ser Gly Ser Tyr Asp
Tyr 1 5 <210> SEQ ID NO 103 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
103 Thr Thr His Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 104
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 104 Thr Thr His Gly Ser Gln Asp
Asn 1 5 <210> SEQ ID NO 105 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
105 Ala Thr His Gly Ser Gln Asp Asn 1 5 <210> SEQ ID NO 106
<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 106 His Gly Ser Gln Asp Thr 1 5
<210> SEQ ID NO 107 <211> LENGTH: 6 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 107
Ser Gly Ser Tyr Asp Tyr 1 5 <210> SEQ ID NO 108 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 108 His Gly Ser Gln Asp Asn 1 5 <210>
SEQ ID NO 109 <211> LENGTH: 9 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 109 Cys
Lys Thr His Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 110
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 110 Gln Ser Tyr Asp Ser Ser Leu
Arg Gly Ser Arg Val 1 5 10 <210> SEQ ID NO 111 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 111 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 112 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 112 Gln Ser Tyr Asp Ser Ser Leu Arg Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 113 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 113 Gln Ser Tyr Asp Ser Ser Leu Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 114 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 114 Gln Ser Tyr Asp Ser Ser Leu Trp Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 115 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 115 Gln Thr Tyr Asp Ile Ser Glu Ser Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 116 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 116 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 117 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 117 Gln Thr Tyr Asp Arg Gly Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 118 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 118 Gln Thr Tyr Asp Lys Gly Phe Thr Gly Ser
Ser Val 1 5 10 <210> SEQ ID NO 119 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 119 Gln Ser Tyr Asp Arg Arg Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 120 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 120 Gln Ser Tyr Asp Trp Asn Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 121 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 121 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 122 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 122 Gln Ser Tyr Asp Asn Gly Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 123 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 123 Gln Ser Tyr Asp Asn Ala Val Thr Ala Ser
Lys Val 1 5 10 <210> SEQ ID NO 124 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 124 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 125 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 125 Gln Ser Tyr Asp Ser Ser Leu Trp Gly Thr
Arg Val 1 5 10 <210> SEQ ID NO 126 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 126 Gln Ser Tyr Asp Arg Asp Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 127 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 127 Gln Ser Tyr Glu Arg Gly Phe Thr Gly Ser
Met Val 1 5 10 <210> SEQ ID NO 128 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 128 Gln Ser Tyr Asp Asn Gly Phe Thr Gly Ala
Arg Val 1 5 10 <210> SEQ ID NO 129 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 129 Gln Ser Tyr Asp Arg Arg Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 130 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 130 Gln Thr Tyr Asp Lys Gly Phe Thr Gly Ser
Ser Val 1 5 10 <210> SEQ ID NO 131 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 131 Gln Ser Tyr Asp Arg Asp Phe Thr Gly Thr
Arg Val 1 5 10 <210> SEQ ID NO 132 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 132 Gln Ser Tyr Asp Arg Gly Phe Tyr Gly Ser
Met Val 1 5 10 <210> SEQ ID NO 133 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 133 Gln Thr Tyr Asp Lys Gly Phe Thr Gly Ser
Ser Val 1 5 10 <210> SEQ ID NO 134 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 134 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ala
Arg Val 1 5 10 <210> SEQ ID NO 135 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 135 Gln Ser Tyr Glu Arg Gly Phe Thr Gly Ala
Arg Val 1 5 10 <210> SEQ ID NO 136 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 136 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 137 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 137 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Phe
Lys Val Phe 1 5 10 <210> SEQ ID NO 138 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 138 Gln Ser Tyr Asp Arg Gly Phe Val Ser Ala
Tyr Val Phe 1 5 10 <210> SEQ ID NO 139 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 139 Gln Ser Tyr Asp Arg Gly Leu Thr Val Thr
Lys Val Phe 1 5 10 <210> SEQ ID NO 140 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 140 Gln Ser Tyr Asp Arg Gly Tyr Thr Ala Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 141 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 141 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Lys Val Phe 1 5 10 <210> SEQ ID NO 142 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 142 Gln Ser Tyr Asp Arg Gly Leu Thr Gly Phe
Arg Val Phe 1 5 10 <210> SEQ ID NO 143 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 143 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Tyr
Lys Val Phe 1 5 10 <210> SEQ ID NO 144 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 144 Gln Ser Tyr Asp Arg Gly Leu Thr Gly Tyr
Arg Leu Phe 1 5 10 <210> SEQ ID NO 145 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 145 Gln Ser Tyr Asp Arg Gly Phe Thr Asp Tyr
Lys Val Phe 1 5 10 <210> SEQ ID NO 146 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 146 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Pro
Arg Leu Phe 1 5 10 <210> SEQ ID NO 147 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 147 Gln Ser Tyr Asp Arg Gly Leu Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 148 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 148 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ala
Arg Val Trp 1 5 10 <210> SEQ ID NO 149 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 149 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Tyr
Arg Val Phe 1 5 10 <210> SEQ ID NO 150 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 150 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Pro
Arg Val Phe 1 5 10 <210> SEQ ID NO 151 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 151 Gln Ser Tyr Asp Arg Gly Met Thr Ser Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 152 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 152 Gln Ser Tyr Asp Arg Asp Ser Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 153 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 153 Gln Ser Tyr Asp Ser Ser Leu Arg Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 154 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 154 His Ser Tyr Asp Ser Asp Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 155 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 155 His Ser Ser Glu Ser Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 156 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 156 His Ser Tyr Asp Asn Arg Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 157 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 157 His Ser Tyr Asp Ser Arg Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 158 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 158 Gln Ser Tyr Asp Ser Glu Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 159 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 159 Gln Ser Tyr Asp Thr Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 160 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 160 His Ser Tyr Asp Ser Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 161 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 161 Gln Ser Tyr Asp Thr Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 162 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 162 His Ser Tyr Asp Thr Lys Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 163 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 163 His Ser Ser Asp Ser Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 164 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 164 Gln Ser Tyr Asp Ser Asp Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 165 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 165 His Ser Tyr Glu Ser Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 166 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 166 Gln Ser Tyr Asp Ala Pro Trp Ser Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 167 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 167 Gln Ser Tyr Asp Ser Asp Phe Thr Gly Ser
Lys Val Phe 1 5 10 <210> SEQ ID NO 168 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 168 His Thr Asn Asp Ser Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 169 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 169 His Ser Tyr Asp Thr Arg Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 170 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 170 Gln Ser Tyr Asp Met Arg Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 171 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 171 His Ser Ser Asp Ser Asp Ser Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 172 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 172 Gln Ser Tyr Asn Thr Asp Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 173 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 173 Gln Ser Tyr Asp Ser Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 174 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 174 His Ser Tyr Asp Met Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 175 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 175 His Ser Tyr Asp Asn Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 176 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 176 His Ser His Asp Arg Asp Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 177 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 177 Gln Ser Tyr Asp Ser Ser Leu Arg Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 178 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 178 Gln Ser Tyr Asp Arg Gly Ile His Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 179 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 179 Gln Ser Tyr Asp Ser Gly Phe Pro Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 180 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 180 Gln Ser Tyr Asp Ile Gly Ser Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 181 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 181 Gln Ser Tyr Asp Ser Gly Leu Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 182 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 182 Gln Ser Tyr Asp Ile Gly Met Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 183 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 183 Gln Ser Tyr Asp Ile Gly Leu Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 184 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 184 Gln Ser Tyr Asp Ser Gly Val Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 185 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 185 Gln Ser Tyr Asp Arg Gly Leu Thr Ala Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 186 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 186 Gln Ser Tyr Asp Thr Gly Leu Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 187 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 187 Gln Ser Tyr Asp Thr Ala Leu Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 188 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 188 Gln Ser Tyr Asp Ile Arg Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 189 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 189 Gln Ser Tyr Asp Ile Arg Ser Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 190 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 190 Gln Ser Tyr Asp Asn Arg Leu Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 191 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 191 Gln Ser Tyr Glu Thr Ser Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 192 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 192 Gln Ser Tyr Asp Ser Ser Ser Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 193 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 193 Gln Ser Tyr Asp Ser Gly Phe Thr Ala Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 194 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 194 Gln Thr Tyr Asp Lys Gly Phe Thr Gly Ser
Ser Val Phe 1 5 10 <210> SEQ ID NO 195 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 195 Gln Ser Tyr Asp Asn Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 196 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 196 Gln Ser Tyr Asp Thr Gly Phe Thr Lys Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 197 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 197 Gln Ser Tyr Asp Ser Asp Val Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 198 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 198 Gln Ser Tyr Asp Ala Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 199 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 199 Gln Ser Tyr Asp Arg Gly Thr His Pro Ser
Met Leu 1 5 10 <210> SEQ ID NO 200 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 200 Gln Ser Tyr Asp Arg Gly Thr Thr Pro Arg
Pro Met 1 5 10 <210> SEQ ID NO 201 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 201 Gln Ser Tyr Asp Arg Gly Arg Asn Pro Ala
Leu Thr 1 5 10 <210> SEQ ID NO 202 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 202 Gln Ser Tyr Asp Arg Gly Thr His Pro Trp
Leu His 1 5 10 <210> SEQ ID NO 203 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 203 Gln Ser Tyr Asp Arg Gly Asn Ser Pro Ala
Thr Val 1 5 10 <210> SEQ ID NO 204 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 204 Gln Ser Tyr Asp Arg Gly Thr Phe Pro Ser
Pro Gln 1 5 10 <210> SEQ ID NO 205 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 205 Gln Ser Tyr Asp Arg Gly Leu Asn Pro Ser
Ala Thr 1 5 10 <210> SEQ ID NO 206 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 206 Gln Ser Tyr Asp Arg Gly Lys Ser Asn Lys
Met Leu 1 5 10 <210> SEQ ID NO 207 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 207 Gln Ser Tyr Asp Arg Gly His Thr Ala His
Leu Tyr 1 5 10 <210> SEQ ID NO 208 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 208 Gln Ser Tyr Asp Arg Gly Gln Thr Pro Ser
Ile Thr 1 5 10 <210> SEQ ID NO 209 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 209 Gln Ser Tyr Asp Arg Gly Tyr Pro Arg Asn
Ile Leu 1 5 10 <210> SEQ ID NO 210 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 210 Gln Ser Tyr Asp Arg Gly Ile Thr Pro Gly
Leu Ala 1 5 10 <210> SEQ ID NO 211 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 211 Gln Ser Tyr Asp Arg Gly Gln Pro His Ala
Val Leu 1 5 10 <210> SEQ ID NO 212 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 212 Gln Ser Tyr Asp Arg Gly Asn Ser Pro Ile
Pro Thr 1 5 10 <210> SEQ ID NO 213 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 213 Gln Ser Tyr Asp Arg Gly Thr Pro Asn Asn
Ser Phe 1 5 10 <210> SEQ ID NO 214 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 214 Gln Ser Tyr Asp Ser Gly Val Asp Pro Gly
Pro Tyr 1 5 10 <210> SEQ ID NO 215 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 215 Gln Ser Tyr Asp Arg Gly Arg Pro Arg His
Ala Leu 1 5 10 <210> SEQ ID NO 216 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 216 Gln Ser Tyr Asp Arg Gly Pro Tyr His Pro
Ile Arg 1 5 10 <210> SEQ ID NO 217 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 217 Gln Ser Tyr Asp Arg Gly Pro His Thr Gln
Pro Thr 1 5 10 <210> SEQ ID NO 218 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 218 Gln Ser Tyr Asp Arg Gly His Asn Asn Phe
Ser Pro 1 5 10 <210> SEQ ID NO 219 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 219 Gln Ser Tyr Asp Arg Gly Pro Thr His Leu
Pro His 1 5 10 <210> SEQ ID NO 220 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 220 Gln Ser Tyr Asp Arg Gly Thr Pro Ser Tyr
Pro Thr 1 5 10 <210> SEQ ID NO 221 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 221 Gln Ser Tyr Asp Ser Gly Thr Ser Asn Leu
Leu Pro 1 5 10 <210> SEQ ID NO 222 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 222 Gln Ser Tyr Asp Arg Gly Asp Ser Asn His
Asp Leu 1 5 10 <210> SEQ ID NO 223 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 223 Gln Ser Tyr Asp Arg Gly Leu Pro Arg Leu
Thr His 1 5 10 <210> SEQ ID NO 224 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 224 Gln Ser Tyr Asp Arg Gly Ile Pro Thr Ser
Tyr Leu 1 5 10 <210> SEQ ID NO 225 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 225 Gln Ser Tyr Asp Arg Gly Leu Arg Val Gln
Ala Pro 1 5 10 <210> SEQ ID NO 226 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 226 Gln Ser Tyr Asp Arg Gly Leu Ser Asp Ser
Pro Leu 1 5 10 <210> SEQ ID NO 227 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 227 Gln Ser Tyr Asp Ser Gly Ser Leu Arg Arg
Ile Leu 1 5 10 <210> SEQ ID NO 228 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 228 Gln Ser Tyr Asp Arg Gly Pro Ala Arg Thr
Ser Pro 1 5 10 <210> SEQ ID NO 229 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 229 Gln Ser Tyr Asp Arg Gly Arg Ala Ala His
Pro Gln 1 5 10 <210> SEQ ID NO 230 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 230 Gln Ser Tyr Asp Arg Gly Thr Gln Pro Ala
Asx Ile 1 5 10 <210> SEQ ID NO 231 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 231 Gln Ser Tyr Asp Arg Gly Thr His Pro Thr
Met Ile 1 5 10 <210> SEQ ID NO 232 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 232 Gln Ser Tyr Asp Arg Gly Arg Ile Pro Ala
Asx Thr 1 5 10 <210> SEQ ID NO 233 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 233 Gln Ser Tyr Asp Arg Gly Thr His Pro Val
Pro Ala 1 5 10 <210> SEQ ID NO 234 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 234 Gln Ser Tyr Asp Arg Gly Ser Asx Pro Ile
Pro Ala 1 5 10 <210> SEQ ID NO 235 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 235 Gln Ser Tyr Asp Arg Gly Thr His Pro Val
Pro Ala 1 5 10 <210> SEQ ID NO 236 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 236 Gln Ser Tyr Asp Arg Gly Thr His Pro Thr
Met Tyr 1 5 10 <210> SEQ ID NO 237 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 237 Gln Ser Tyr Asp Arg Gly His His Tyr Thr
Thr Phe 1 5 10 <210> SEQ ID NO 238 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 238 Gln Ser Tyr Asp Arg Gly Ser His Pro Ala
Ala Glu 1 5 10 <210> SEQ ID NO 239 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 239 Gln Ser Tyr Asp Arg Gly Thr Ile Pro Ser
Ile Glu 1 5 10 <210> SEQ ID NO 240 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 240 Gln Ser Tyr Asp Arg Gly Ser Ser Pro Ala
Ile Met 1 5 10 <210> SEQ ID NO 241 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 241 Gln Ser Tyr Asp Arg Gly Ile Trp Pro Asn
Leu Asn 1 5 10 <210> SEQ ID NO 242 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 242 Gln Ser Tyr Asp Arg Gly Thr His Pro Asn
Leu Asn 1 5 10 <210> SEQ ID NO 243 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 243 Gln Ser Tyr Asp Arg Gly Thr His Pro Ser
Ile Ser 1 5 10 <210> SEQ ID NO 244 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 244 Gln Ser Tyr Asp Arg Gly Ser Ala Pro Met
Ile Asn 1 5 10 <210> SEQ ID NO 245 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 245 Gln Ser Tyr Asp Arg Gly His His Pro Ala
Met Ser 1 5 10 <210> SEQ ID NO 246 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 246 Gln Ser Tyr Asp Arg Gly Thr His Pro Ser
Ile Thr 1 5 10 <210> SEQ ID NO 247 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 247 Gln Ser Tyr Asp Arg Gly Thr Asp Pro Ala
Ile Val 1 5 10 <210> SEQ ID NO 248 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 248 Gln Ser Tyr Asp Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 249 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 249 Gln Ser Tyr Asp Arg Gly Ser His Pro Ala
Leu Thr 1 5 10 <210> SEQ ID NO 250 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 250 Gln Ser Tyr Asp Arg Gly Thr Thr Pro Ala
Pro Glu 1 5 10 <210> SEQ ID NO 251 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 251 Gln Ser Tyr Asp Arg Gly Ser His Pro Thr
Leu Ile 1 5 10 <210> SEQ ID NO 252 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 252 Gln Ser Tyr Asp Arg Gly Thr His Pro Ser
Met Leu 1 5 10 <210> SEQ ID NO 253 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 253 Gln Ser Tyr Asp Arg Gly Thr Thr Pro Arg
Pro Met 1 5 10 <210> SEQ ID NO 254 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 254 Gln Ser Tyr Asp Arg Gly Arg Leu Pro Ala
Gln Thr 1 5 10 <210> SEQ ID NO 255 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 255 Gln Ser Tyr Asp Arg Gly Thr His Pro Leu
Thr Ile 1 5 10 <210> SEQ ID NO 256 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 256 Gln Ser Tyr Asp Arg Gly Gln Thr Pro Ser
Ile Thr 1 5 10 <210> SEQ ID NO 257 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 257 Gln Ser Tyr Asp Arg Gly Thr His Phe Gln
Met Tyr 1 5 10 <210> SEQ ID NO 258 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 258 Gln Ser Tyr Asp Arg Gly Arg Asn Pro Ala
Leu Thr 1 5 10 <210> SEQ ID NO 259 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 259 Gln Ser Tyr Asp Arg Gly Thr His Pro Leu
Thr Met 1 5 10 <210> SEQ ID NO 260 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 260 Gln Ser Tyr Asp Arg Gly Thr His Pro Leu
Thr Met 1 5 10 <210> SEQ ID NO 261 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 261 Gln Ser Tyr Asp Ser Gly Tyr Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 262 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 262 Gln Ser Tyr Asp Ser Gly Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 263 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 263 Gln Ser Tyr Asp Ser Arg Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 264 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 264 Gln Ser Tyr Pro Asp Gly Thr Pro Ala Ser
Arg Val 1 5 10 <210> SEQ ID NO 265 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 265 Gln Ser Tyr Ser Thr His Met Pro Ile Ser
Arg Val 1 5 10 <210> SEQ ID NO 266 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 266 Gln Ser Tyr Asp Ser Gly Ser Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 267 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 267 Gln Ser Tyr Pro Asn Ser Tyr Pro Ile Ser
Arg Val 1 5 10 <210> SEQ ID NO 268 <211> LENGTH: 10
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 268 Gln Ser Tyr Ile Arg Ala Pro Gln Gln Val 1
5 10 <210> SEQ ID NO 269 <211> LENGTH: 12 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
269 Gln Ser Tyr Leu Lys Ser Arg Ala Phe Ser Arg Val 1 5 10
<210> SEQ ID NO 270 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 270
Gln Ser Tyr Asp Ser Arg Phe Thr Gly Ser Arg Val 1 5 10 <210>
SEQ ID NO 271 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 271 Gln
Ser Tyr Asp Arg Gly Phe Thr Gly Ser Met Val 1 5 10 <210> SEQ
ID NO 272 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 272 Gln Ser Tyr Asp
Arg Gly Phe Thr Gly Ser Met Val 1 5 10 <210> SEQ ID NO 273
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 273 Gln Ser Tyr Asp Arg Gly Phe
Thr Gly Phe Asp Gly 1 5 10 <210> SEQ ID NO 274 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 274 Gln Ser Tyr Asp Arg Gly Thr Ala Pro Ala
Leu Ser 1 5 10 <210> SEQ ID NO 275 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 275 Gln Ser Tyr Asp Arg Gly Ser Tyr Pro Ala
Leu Arg 1 5 10 <210> SEQ ID NO 276 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 276 Gln Ser Tyr Asp Arg Gly Asn Trp Pro Asn
Ser Asn 1 5 10 <210> SEQ ID NO 277 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 277 Gln Ser Tyr Asp Arg Gly Thr Ala Pro Ser
Leu Leu 1 5 10 <210> SEQ ID NO 278 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 278 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Met Val 1 5 10 <210> SEQ ID NO 279 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 279 Gln Ser Tyr Asp Arg Gly Thr Thr Pro Arg
Ile Arg 1 5 10 <210> SEQ ID NO 280 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 280 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Met Val 1 5 10 <210> SEQ ID NO 281 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 281 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Met Val 1 5 10 <210> SEQ ID NO 282 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 282 Gln Ser Tyr Asp Arg Gly Met Ile Pro Ala
Leu Thr 1 5 10 <210> SEQ ID NO 283 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 283 Gln Ser Tyr Asp Arg Asn Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 284 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 284 Gln Ser Tyr Asp Arg Phe Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 285 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 285 Gln Ser Tyr Asp Arg Tyr Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 286 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 286 Gln Ser Tyr Asp Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 287 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 287 Gln Ser Tyr Asp Arg Tyr Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 288 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 288 Phe Thr Phe Glu Ser Tyr Gly Met His 1 5
<210> SEQ ID NO 289 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 289
Phe Thr Phe Ser Ser Tyr Gly Met His 1 5 <210> SEQ ID NO 290
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 290 Phe Thr Phe Tyr Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 291 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 291 Phe Thr Phe His Ser Tyr Gly Met His 1 5
<210> SEQ ID NO 292 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 292
Phe Thr Phe Lys Ser Tyr Gly Met His 1 5 <210> SEQ ID NO 293
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 293 Phe Thr Phe Arg Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 294 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 294 Phe Thr Phe Asn Ser Tyr Gly Met His 1 5
<210> SEQ ID NO 295 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 295
Phe Thr Phe Thr Ser Tyr Gly Met His 1 5 <210> SEQ ID NO 296
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 296 Phe Thr Phe Gly Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 297 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 297 Phe Thr Phe Val Ser Tyr Gly Met His 1 5
<210> SEQ ID NO 298 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 298
Phe Thr Phe Ile Ser Tyr Gly Met His 1 5 <210> SEQ ID NO 299
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 299 Phe Thr Phe Trp Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 300 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 300 Phe Thr Phe Ser Glu Tyr Gly Met His 1 5
<210> SEQ ID NO 301 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 301
Phe Thr Phe Ser Cys Tyr Gly Met His 1 5 <210> SEQ ID NO 302
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 302 Phe Thr Phe Ser Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 303 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 303 Phe Thr Phe Ser Tyr Tyr Gly Met His 1 5
<210> SEQ ID NO 304 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 304
Phe Thr Phe Ser His Tyr Gly Met His 1 5 <210> SEQ ID NO 305
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 305 Phe Thr Phe Ser Arg Tyr Gly
Met His 1 5 <210> SEQ ID NO 306 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 306 Phe Thr Phe Ser Asn Tyr Gly Met His 1 5
<210> SEQ ID NO 307 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 307
Phe Thr Phe Ser Gln Tyr Gly Met His 1 5 <210> SEQ ID NO 308
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 308 Phe Thr Phe Ser Thr Tyr Gly
Met His 1 5 <210> SEQ ID NO 309 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 309 Phe Thr Phe Ser Ala Tyr Gly Met His 1 5
<210> SEQ ID NO 310 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 310
Phe Thr Phe Ser Ile Tyr Gly Met His 1 5 <210> SEQ ID NO 311
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 311 Phe Thr Phe Ser Ser Glu Gly
Met His 1 5 <210> SEQ ID NO 312 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 312 Phe Thr Phe Ser Ser Cys Gly Met His 1 5
<210> SEQ ID NO 313 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 313
Phe Thr Phe Ser Ser Ser Gly Met His 1 5 <210> SEQ ID NO 314
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 314 Phe Thr Phe Ser Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 315 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 315 Phe Thr Phe Ser Ser His Gly Met His 1 5
<210> SEQ ID NO 316 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 316
Phe Thr Phe Ser Ser Arg Gly Met His 1 5 <210> SEQ ID NO 317
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 317 Phe Thr Phe Ser Ser Asn Gly
Met His 1 5 <210> SEQ ID NO 318 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 318 Phe Thr Phe Ser Ser Thr Gly Met His 1 5
<210> SEQ ID NO 319 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 319
Phe Thr Phe Ser Ser Ala Gly Met His 1 5 <210> SEQ ID NO 320
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 320 Phe Thr Phe Ser Ser Val Gly
Met His 1 5 <210> SEQ ID NO 321 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 321 Phe Thr Phe Ser Ser Leu Gly Met His 1 5
<210> SEQ ID NO 322 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 322
Phe Thr Phe Ser Ser Ile Gly Met His 1 5 <210> SEQ ID NO 323
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 323 Phe Thr Phe Ser Ser Tyr Asp
Met His 1 5 <210> SEQ ID NO 324 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 324 Phe Thr Phe Ser Ser Tyr Glu Met His 1 5
<210> SEQ ID NO 325 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 325
Phe Thr Phe Ser Ser Tyr Cys Met His 1 5 <210> SEQ ID NO 326
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 326 Phe Thr Phe Ser Ser Tyr Ser
Met His 1 5 <210> SEQ ID NO 327 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 327 Phe Thr Phe Ser Ser Tyr Tyr Met His 1 5
<210> SEQ ID NO 328 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 328
Phe Thr Phe Ser Ser Tyr Asn Met His 1 5 <210> SEQ ID NO 329
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 329 Phe Thr Phe Ser Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 330 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 330 Phe Thr Phe Ser Ser Tyr Ala Met His 1 5
<210> SEQ ID NO 331 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 331
Phe Thr Phe Ser Ser Tyr Val Met His 1 5 <210> SEQ ID NO 332
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 332 Phe Thr Phe Ser Ser Tyr Met
Met His 1 5 <210> SEQ ID NO 333 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 333 Phe Thr Phe Ser Ser Tyr Ile Met His 1 5
<210> SEQ ID NO 334 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 334
Phe Thr Phe Ser Ser Tyr Pro Met His 1 5 <210> SEQ ID NO 335
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 335 Glu Ile Arg Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 336 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 336 Cys Ile Arg Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 337 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 337
Tyr Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 338 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 338 His Ile Arg Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 339
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 339 Lys Ile Arg Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 340 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 340 Asn Ile Arg Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 341 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 341
Gln Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 342 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 342 Thr Ile Arg Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 343
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 343 Leu Ile Arg Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 344 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 344 Phe Ile Arg Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 345 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 345
Phe Ile Glu Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 346 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 346 Phe Ile Ser Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 347
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 347 Phe Ile Tyr Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 348 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 348 Phe Ile His Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 349 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 349
Phe Ile Lys Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 350 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 350 Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 351
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 351 Phe Ile Gln Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 352 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 352 Phe Ile Thr Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 353 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 353
Phe Ile Gly Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 354 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 354 Phe Ile Ala Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 355
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 355 Phe Ile Val Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 356 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 356 Phe Ile Leu Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 357 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 357
Phe Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 358 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 358 Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 359
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 359 Phe Ile Arg Tyr Glu Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 360 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 360 Phe Ile Arg Tyr
Ser Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 361 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 361
Phe Ile Arg Tyr Tyr Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 362 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 362 Phe Ile Arg Tyr Lys Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 363
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 363 Phe Ile Arg Tyr Arg Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 364 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 364 Phe Ile Arg Tyr
Asn Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 365 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 365
Phe Ile Arg Tyr Gln Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 366 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 366 Phe Ile Arg Tyr Thr Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 367
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 367 Phe Ile Arg Tyr Ala Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 368 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 368 Phe Ile Arg Tyr
Val Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 369 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 369
Phe Ile Arg Tyr Leu Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 370 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 370 Phe Ile Arg Tyr Ile Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 371
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 371 Phe Ile Arg Tyr Phe Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 372 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 372 Phe Ile Arg Tyr
Asp Asp Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 373 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 373
Phe Ile Arg Tyr Asp Glu Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 374 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 374 Phe Ile Arg Tyr Asp Ser Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 375
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 375 Phe Ile Arg Tyr Asp Tyr Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 376 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 376 Phe Ile Arg Tyr
Asp Lys Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 377 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 377
Phe Ile Arg Tyr Asp Arg Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 378 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 378 Phe Ile Arg Tyr Asp Asn Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 379
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 379 Phe Ile Arg Tyr Asp Gln Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 380 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 380 Phe Ile Arg Tyr
Asp Thr Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 381 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 381
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 382 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 382 Phe Ile Arg Tyr Asp Val Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 383
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 383 Phe Ile Arg Tyr Asp Phe Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 384 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 384 Phe Ile Arg Tyr
Asp Gly Ser Ser Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 385 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 385
Phe Ile Arg Tyr Asp Gly Ser Tyr Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 386 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 386 Phe Ile Arg Tyr Asp Gly Ser His Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 387
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 387 Phe Ile Arg Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 388 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 388 Phe Ile Arg Tyr
Asp Gly Ser Thr Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 389 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 389
Phe Ile Arg Tyr Asp Gly Ser Gly Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 390 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 390 Phe Ile Arg Tyr Asp Gly Ser Met Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 391
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 391 Phe Ile Arg Tyr Asp Gly Ser
Leu Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 392 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 392 Phe Ile Arg Tyr
Asp Gly Ser Ile Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 393 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 393
Phe Ile Arg Tyr Asp Gly Ser Pro Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 394 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 394 Phe Ile Arg Tyr Asp Gly Ser Phe Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 395
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 395 Phe Ile Arg Tyr Asp Gly Ser
Asn Lys Glu Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 396 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 396 Phe Ile Arg Tyr
Asp Gly Ser Asn Lys Ser Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 397 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 397
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 398 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 398 Phe Ile Arg Tyr Asp Gly Ser Asn Lys Asn
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 399
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 399 Phe Ile Arg Tyr Asp Gly Ser
Asn Lys Val Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 400 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 400 Phe Ile Arg Tyr
Asp Gly Ser Asn Lys Leu Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 401 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 401
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Ile Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 402 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 402 Phe Ile Arg Tyr Asp Gly Ser Asn Lys Pro
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 403
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 403 Phe Ile Arg Tyr Asp Gly Ser
Asn Lys Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 404 <211> LENGTH: 6 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 404 Glu Gly Ser His
Asp Asn 1 5 <210> SEQ ID NO 405 <211> LENGTH: 6
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 405 Ser Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 406 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 406 His
Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 407 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 407 Lys Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 408 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 408 Gln
Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 409 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 409 Thr Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 410 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 410 Ala
Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 411 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 411 Leu Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 412 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 412 Pro
Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 413 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 413 Phe Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 414 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 414 His
Asp Ser His Asp Asn 1 5 <210> SEQ ID NO 415 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 415 His Cys Ser His Asp Asn 1 5 <210>
SEQ ID NO 416 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 416 His
His Ser His Asp Asn 1 5 <210> SEQ ID NO 417 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 417 His Arg Ser His Asp Asn 1 5 <210>
SEQ ID NO 418 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 418 His
Thr Ser His Asp Asn 1 5 <210> SEQ ID NO 419 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 419 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 420 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 420 His
Val Ser His Asp Asn 1 5 <210> SEQ ID NO 421 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 421 His Met Ser His Asp Asn 1 5 <210>
SEQ ID NO 422 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 422 His
Leu Ser His Asp Asn 1 5 <210> SEQ ID NO 423 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 423 His Ile Ser His Asp Asn 1 5 <210>
SEQ ID NO 424 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 424 His
Pro Ser His Asp Asn 1 5 <210> SEQ ID NO 425 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 425 His Trp Ser His Asp Asn 1 5 <210>
SEQ ID NO 426 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 426 His
Gly Asp His Asp Asn 1 5 <210> SEQ ID NO 427 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 427 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 428 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 428 His
Gly Tyr His Asp Asn 1 5 <210> SEQ ID NO 429 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 429 His Gly His His Asp Asn 1 5 <210>
SEQ ID NO 430 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 430 His
Gly Arg His Asp Asn 1 5 <210> SEQ ID NO 431 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 431 His Gly Asn His Asp Asn 1 5 <210>
SEQ ID NO 432 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 432 His
Gly Thr His Asp Asn 1 5 <210> SEQ ID NO 433 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 433 His Gly Gly His Asp Asn 1 5 <210>
SEQ ID NO 434 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 434 His
Gly Ala His Asp Asn 1 5 <210> SEQ ID NO 435 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 435 His Gly Ile His Asp Asn 1 5 <210>
SEQ ID NO 436 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 436 His
Gly Pro His Asp Asn 1 5 <210> SEQ ID NO 437 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 437 His Gly Trp His Asp Asn 1 5 <210>
SEQ ID NO 438 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 438 His
Gly Phe His Asp Asn 1 5 <210> SEQ ID NO 439 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 439 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 440 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 440 His
Gly Ser Arg Asp Asn 1 5 <210> SEQ ID NO 441 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 441 His Gly Ser Thr Asp Asn 1 5 <210>
SEQ ID NO 442 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 442 His
Gly Ser Ala Asp Asn 1 5 <210> SEQ ID NO 443 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 443 His Gly Ser Val Asp Asn 1 5 <210>
SEQ ID NO 444 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 444 His
Gly Ser Leu Asp Asn 1 5 <210> SEQ ID NO 445 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 445 His Gly Ser Ile Asp Asn 1 5 <210>
SEQ ID NO 446 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 446 His
Gly Ser Phe Asp Asn 1 5 <210> SEQ ID NO 447 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 447 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 448 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 448 His
Gly Ser His Ser Asn 1 5 <210> SEQ ID NO 449 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 449 His Gly Ser His Tyr Asn 1 5 <210>
SEQ ID NO 450 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 450 His
Gly Ser His His Asn 1 5 <210> SEQ ID NO 451 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 451 His Gly Ser His Arg Asn 1 5 <210>
SEQ ID NO 452 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 452 His
Gly Ser His Asn Asn 1 5 <210> SEQ ID NO 453 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 453 His Gly Ser His Gly Asn 1 5 <210>
SEQ ID NO 454 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 454 His
Gly Ser His Ala Asn 1 5 <210> SEQ ID NO 455 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 455 His Gly Ser His Val Asn 1 5 <210>
SEQ ID NO 456 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 456 His
Gly Ser His Ile Asn 1 5 <210> SEQ ID NO 457 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 457 His Gly Ser His Asp Ser 1 5 <210>
SEQ ID NO 458 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 458 His
Gly Ser His Asp His 1 5 <210> SEQ ID NO 459 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 459 His Gly Ser His Asp Lys 1 5 <210>
SEQ ID NO 460 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 460 His
Gly Ser His Asp Arg 1 5 <210> SEQ ID NO 461 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 461 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 462 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 462 His
Gly Ser His Asp Thr 1 5 <210> SEQ ID NO 463 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 463 His Gly Ser His Asp Gly 1 5 <210>
SEQ ID NO 464 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 464 His
Gly Ser His Asp Ala 1 5 <210> SEQ ID NO 465 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 465 His Gly Ser His Asp Leu 1 5 <210>
SEQ ID NO 466 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 466 His
Gly Ser His Asp Ile 1 5 <210> SEQ ID NO 467 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 467 His Gly Ser His Asp Pro 1 5 <210>
SEQ ID NO 468 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 468 His
Gly Ser His Asp Trp 1 5 <210> SEQ ID NO 469 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 469 His Gly Ser His Asp Phe 1 5 <210>
SEQ ID NO 470 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 470 Ser
Gly Gly Arg Ser Asn Ile Gly Asp Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 471 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 471 Ser
Gly Gly Arg Ser Asn Ile Gly Cys Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 472 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 472 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 473 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 473 Ser
Gly Gly Arg Ser Asn Ile Gly Tyr Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 474 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 474 Ser
Gly Gly Arg Ser Asn Ile Gly Lys Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 475 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 475 Ser
Gly Gly Arg Ser Asn Ile Gly Arg Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 476 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 476 Ser
Gly Gly Arg Ser Asn Ile Gly Asn Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 477 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 477 Ser
Gly Gly Arg Ser Asn Ile Gly Thr Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 478 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 478 Ser
Gly Gly Arg Ser Asn Ile Gly Pro Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 479 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 479 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asp Thr Val Lys 1 5 10 <210>
SEQ ID NO 480 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 480 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Glu Thr Val Lys 1 5 10 <210>
SEQ ID NO 481 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 481 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Ser Thr Val Lys 1 5 10 <210>
SEQ ID NO 482 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 482 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Tyr Thr Val Lys 1 5 10 <210>
SEQ ID NO 483 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 483 Ser
Gly Gly Arg Ser Asn Ile Gly Ser His Thr Val Lys 1 5 10 <210>
SEQ ID NO 484 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 484 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Lys Thr Val Lys 1 5 10 <210>
SEQ ID NO 485 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 485 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 486 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 486 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Gln Thr Val Lys 1 5 10 <210>
SEQ ID NO 487 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 487 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Thr Thr Val Lys 1 5 10 <210>
SEQ ID NO 488 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 488 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Gly Thr Val Lys 1 5 10 <210>
SEQ ID NO 489 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 489 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Met Thr Val Lys 1 5 10 <210>
SEQ ID NO 490 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 490 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Ile Thr Val Lys 1 5 10 <210>
SEQ ID NO 491 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 491 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Asp Val Lys 1 5 10 <210>
SEQ ID NO 492 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 492 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Cys Val Lys 1 5 10 <210>
SEQ ID NO 493 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 493 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Ser Val Lys 1 5 10 <210>
SEQ ID NO 494 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 494 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Tyr Val Lys 1 5 10 <210>
SEQ ID NO 495 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 495 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn His Val Lys 1 5 10 <210>
SEQ ID NO 496 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 496 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Lys Val Lys 1 5 10 <210>
SEQ ID NO 497 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 497 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Arg Val Lys 1 5 10 <210>
SEQ ID NO 498 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 498 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Asn Val Lys 1 5 10 <210>
SEQ ID NO 499 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 499 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Gln Val Lys 1 5 10 <210>
SEQ ID NO 500 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 500 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 501 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 501 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Ala Val Lys 1 5 10 <210>
SEQ ID NO 502 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 502 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Val Val Lys 1 5 10 <210>
SEQ ID NO 503 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 503 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Leu Val Lys 1 5 10 <210>
SEQ ID NO 504 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 504 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Ile Val Lys 1 5 10 <210>
SEQ ID NO 505 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 505 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Pro Val Lys 1 5 10 <210>
SEQ ID NO 506 <211> LENGTH: 7 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 506 Asp
Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 507 <211>
LENGTH: 7 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 507 Glu Asn Asp Gln Arg Pro Ser 1 5
<210> SEQ ID NO 508 <211> LENGTH: 7 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 508
Cys Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 509
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 509 Ser Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 510 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
510 Tyr Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 511
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 511 His Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 512 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
512 Lys Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 513
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 513 Arg Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 514 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
514 Asn Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 515
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 515 Gln Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 516 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
516 Thr Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 517
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 517 Gly Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 518 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
518 Ala Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 519
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 519 Val Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 520 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
520 Met Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 521
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 521 Leu Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 522 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
522 Ile Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 523
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 523 Pro Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 524 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
524 Trp Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 525
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 525 Phe Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 526 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
526 Gly Asn Asp Ser Arg Pro Ser 1 5 <210> SEQ ID NO 527
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 527 Gly Asn Asp Tyr Arg Pro Ser
1 5 <210> SEQ ID NO 528 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
528 Gly Asn Asp Arg Arg Pro Ser 1 5 <210> SEQ ID NO 529
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 529 Gly Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 530 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
530 Gly Asn Asp Thr Arg Pro Ser 1 5 <210> SEQ ID NO 531
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 531 Gly Asn Asp Ala Arg Pro Ser
1 5 <210> SEQ ID NO 532 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
532 Gly Asn Asp Ile Arg Pro Ser 1 5 <210> SEQ ID NO 533
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 533 Gly Asn Asp Pro Arg Pro Ser
1 5 <210> SEQ ID NO 534 <211> LENGTH: 12 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
534 Gln Ser Tyr Asp Arg Gly Thr His Pro Ala Leu Leu 1 5 10
<210> SEQ ID NO 535 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 535
Gln Ser Tyr Cys Arg Gly Thr His Pro Ala Leu Leu 1 5 10 <210>
SEQ ID NO 536 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 536 Gln
Ser Tyr Ser Arg Gly Thr His Pro Ala Leu Leu 1 5 10 <210> SEQ
ID NO 537 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 537 Gln Ser Tyr Tyr
Arg Gly Thr His Pro Ala Leu Leu 1 5 10 <210> SEQ ID NO 538
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 538 Gln Ser Tyr Asn Arg Gly Thr
His Pro Ala Leu Leu 1 5 10 <210> SEQ ID NO 539 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 539 Gln Ser Tyr Gln Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 540 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 540 Gln Ser Tyr Thr Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 541 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 541 Gln Ser Tyr Gly Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 542 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 542 Gln Ser Tyr Ala Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 543 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 543 Gln Ser Tyr Leu Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 544 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 544 Gln Ser Tyr Ile Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 545 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 545 Gln Ser Tyr Trp Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 546 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 546 Gln Ser Tyr Phe Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 547 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 547 Gln Ser Tyr Asp Asp Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 548 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 548 Gln Ser Tyr Asp Cys Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 549 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 549 Gln Ser Tyr Asp Ser Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 550 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 550 Gln Ser Tyr Asp Tyr Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 551 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 551 Gln Ser Tyr Asp Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 552 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 552 Gln Ser Tyr Asp Asn Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 553 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 553 Gln Ser Tyr Asp Gln Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 554 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 554 Gln Ser Tyr Asp Thr Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 555 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 555 Gln Ser Tyr Asp Gly Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 556 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 556 Gln Ser Tyr Asp Ala Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 557 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 557 Gln Ser Tyr Asp Val Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 558 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 558 Gln Ser Tyr Asp Met Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 559 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 559 Gln Ser Tyr Asp Leu Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 560 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 560 Gln Ser Tyr Asp Ile Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 561 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 561 Gln Ser Tyr Asp Pro Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 562 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 562 Gln Ser Tyr Asp Trp Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 563 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 563 Gln Ser Tyr Asp Arg Asp Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 564 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 564 Gln Ser Tyr Asp Arg Cys Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 565 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 565 Gln Ser Tyr Asp Arg Ser Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 566 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 566 Gln Ser Tyr Asp Arg Tyr Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 567 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 567 Gln Ser Tyr Asp Arg His Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 568 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 568 Gln Ser Tyr Asp Arg Arg Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 569 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 569 Gln Ser Tyr Asp Arg Asn Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 570 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 570 Gln Ser Tyr Asp Arg Gln Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 571 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 571 Gln Ser Tyr Asp Arg Thr Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 572 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 572 Gln Ser Tyr Asp Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 573 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 573 Gln Ser Tyr Asp Arg Ala Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 574 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 574 Gln Ser Tyr Asp Arg Val Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 575 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 575 Gln Ser Tyr Asp Arg Leu Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 576 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 576 Gln Ser Tyr Asp Arg Ile Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 577 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 577 Gln Ser Tyr Asp Arg Pro Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 578 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 578 Gln Ser Tyr Asp Arg Trp Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 579 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 579 Gln Ser Tyr Asp Arg Phe Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 580 <400> SEQUENCE: 580
000 <210> SEQ ID NO 581 <400> SEQUENCE: 581 000
<210> SEQ ID NO 582 <400> SEQUENCE: 582 000 <210>
SEQ ID NO 583 <400> SEQUENCE: 583 000 <210> SEQ ID NO
584 <400> SEQUENCE: 584 000 <210> SEQ ID NO 585
<400> SEQUENCE: 585 000 <210> SEQ ID NO 586 <400>
SEQUENCE: 586 000 <210> SEQ ID NO 587 <400> SEQUENCE:
587 000 <210> SEQ ID NO 588 <400> SEQUENCE: 588 000
<210> SEQ ID NO 589 <400> SEQUENCE: 589 000 <210>
SEQ ID NO 590 <400> SEQUENCE: 590 000 <210> SEQ ID NO
591 <400> SEQUENCE: 591 000 <210> SEQ ID NO 592
<400> SEQUENCE: 592 000 <210> SEQ ID NO 593 <400>
SEQUENCE: 593 000 <210> SEQ ID NO 594 <211> LENGTH: 100
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 594 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Tyr Met Asp Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Thr Arg
Asn Lys Ala Asn Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60 Ser Val
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Ser 65 70 75 80
Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85
90 95 Tyr Cys Ala Arg 100 <210> SEQ ID NO 595 <211>
LENGTH: 100 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 595 Glu Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Tyr Met Ser Trp
Val Arg Gln Ala Gln Gly Lys Gly Leu Glu Leu Val 35 40 45 Gly Leu
Ile Arg Asn Lys Ala Asn Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55 60
Ser Val Lys Gly Arg Leu Thr Ile Ser Arg Glu Asp Ser Lys Asn Thr 65
70 75 80 Leu Tyr Leu Gln Met Ser Ser Leu Lys Thr Glu Asp Leu Ala
Val Tyr 85 90 95 Tyr Cys Ala Arg 100 <210> SEQ ID NO 596
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 596 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Tyr Met Ser
Trp Val Arg Gln Ala Gln Gly Lys Gly Leu Glu Leu Val 35 40 45 Gly
Leu Ile Arg Asn Lys Ala Asn Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55
60 Ser Val Lys Gly Arg Leu Thr Ile Ser Arg Glu Asp Ser Lys Asn Thr
65 70 75 80 Met Tyr Leu Gln Met Ser Asn Leu Lys Thr Glu Asp Leu Ala
Val Tyr 85 90 95 Tyr Cys Ala Arg 100 <210> SEQ ID NO 597
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 597 Glu Val Gln Leu Leu Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His 20 25 30 Tyr Met Ser
Trp Val Arg Gln Ala Gln Gly Lys Gly Leu Glu Leu Val 35 40 45 Gly
Leu Ile Arg Asn Lys Ala Asn Ser Tyr Thr Thr Glu Tyr Ala Ala 50 55
60 Ser Val Lys Gly Arg Leu Thr Ile Ser Arg Glu Asp Ser Lys Asn Thr
65 70 75 80 Leu Tyr Leu Gln Met Ser Ser Leu Lys Thr Glu Asp Leu Ala
Val Tyr 85 90 95 Tyr Cys Ala Arg 100 <210> SEQ ID NO 598
<211> LENGTH: 98 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 598 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Ala Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr
Tyr Cys 85 90 95 Ala Lys <210> SEQ ID NO 599 <211>
LENGTH: 98 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 599 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Arg Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Gly Met Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Ile Asn
Trp Asn Gly Gly Ser Thr Gly Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Leu Tyr His Cys 85
90 95 Ala Arg <210> SEQ ID NO 600 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 600 Glu Val Gln Leu Val Glu Ser Gly Gly Val
Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Ser
Trp Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 601 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 601 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser
Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 602 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 602 Gln Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser
Ser Ser Ser Ser Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 603 <211> LENGTH: 100
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 603 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Gly Ser 20 25 30 Ala Met His Trp Val Arg
Gln Ala Ser Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg
Ser Lys Ala Asn Ser Tyr Ala Thr Ala Tyr Ala Ala 50 55 60 Ser Val
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85
90 95 Tyr Cys Thr Arg 100 <210> SEQ ID NO 604 <211>
LENGTH: 100 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 604 Glu Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg
Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65
70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 605
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 605 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly
Arg Ile Glu Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55
60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 606
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 606 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly
Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55
60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 607
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 607 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly
Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asn Tyr Ala Ala 50 55
60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 608
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 608 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Asn
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly
Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55
60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 609
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 609 Glu Val Gln Leu Val Glu Ser
Gly Gly Ala Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly
Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55
60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 610
<211> LENGTH: 98 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 610 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Pro Ala Ser Gly Phe Thr Phe Ser Asn His 20 25 30 Tyr Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Tyr Ile Ser Gly Asp Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Asn Asn Ser Pro Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Val Lys <210> SEQ ID NO 611 <211>
LENGTH: 98 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 611 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asn His 20 25 30 Tyr Thr Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ser Ser
Gly Asn Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Val Lys <210> SEQ ID NO 612 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 612 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asn Ser 20 25 30 Asp Met Asn Trp Val His
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Val Ser
Trp Asn Gly Ser Arg Thr His Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Ile Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr 65 70 75 80
Leu Gln Thr Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Val Arg <210> SEQ ID NO 613 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 613 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asn Ser 20 25 30 Asp Met Asn Trp Ala Arg
Lys Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Val Ser
Trp Asn Gly Ser Arg Thr His Tyr Val Asp Ser Val 50 55 60 Lys Arg
Arg Phe Ile Ile Ser Arg Asp Asn Ser Arg Asn Ser Leu Tyr 65 70 75 80
Leu Gln Lys Asn Arg Arg Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85
90 95 Val Arg <210> SEQ ID NO 614 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 614 Thr Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Glu Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asn Ser 20 25 30 Asp Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Val Ser
Trp Asn Gly Ser Arg Thr His Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Ile Ile Ser Arg Asp Asn Ser Arg Asn Phe Leu Tyr 65 70 75 80
Gln Gln Met Asn Ser Leu Arg Pro Glu Asp Met Ala Val Tyr Tyr Cys 85
90 95 Val Arg <210> SEQ ID NO 615 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 615 Glu Val His Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ala Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Asp Met His Trp Val Arg
Gln Ala Thr Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Asn Gly
Thr Ala Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 616 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 616 Glu Val Gln Leu Val Glu Thr Gly Gly Gly
Leu Ile Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Val Ser Ser Asn 20 25 30 Tyr Met Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr
Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 617 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 617 Glu Val Gln Leu Val Gln Ser Gly Gly Gly
Leu Val His Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly
Thr Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 618 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 618 Glu Val Gln Leu Val Gln Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly
Thr Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 619 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 619 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser
Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 620 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 620 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Ala Ile Ser
Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Val Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Val Lys <210> SEQ ID NO 621 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 621 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Ala Ile Ser
Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Val Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Val Lys <210> SEQ ID NO 622 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 622 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Ala Ile Ser
Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 623 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 623 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser
Gly Ser Gly Gly Ser Thr Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 624 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 624 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 625 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 625 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 626 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 626 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 627 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 627 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 628 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 628 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 629 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 629 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 630 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 630 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 631 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 631 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 632 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 632 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 633 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 633 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Ala Ile Ser
Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Val Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Val Lys <210> SEQ ID NO 634 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 634 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Ala Ile Ser
Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 635 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 635 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Ala Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 636 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 636 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 637 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 637 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 638 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 638 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Asp Met His Trp Val Arg
Gln Ala Thr Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly
Thr Ala Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 639 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 639 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Glu Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser
Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 640 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 640 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Leu Arg Ala Arg Leu Cys Ile Thr Val 85
90 95 Arg Glu <210> SEQ ID NO 641 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 641 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 642 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 642 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 643 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 643 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 644 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 644 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 645 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 645 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Arg Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 646 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 646 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 647 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 647 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 648 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 648 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Gly Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 649 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 649 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 650 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 650 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 651 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 651 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 652 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 652 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 653 <211> LENGTH: 95
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 653 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Arg Lys 85 90
95 <210> SEQ ID NO 654 <211> LENGTH: 98 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
654 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly
Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys
Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg
Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg
<210> SEQ ID NO 655 <211> LENGTH: 98 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 655
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ala Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Ala 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Thr Asn Thr Leu Phe 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg <210>
SEQ ID NO 656 <211> LENGTH: 98 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 656 Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Asp
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg <210> SEQ ID
NO 657 <211> LENGTH: 98 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 657 Glu Val Gln Leu
Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ser Ser Ile Ser Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser
Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
Ala Val Tyr Tyr Cys 85 90 95 Ala Arg <210> SEQ ID NO 658
<211> LENGTH: 97 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 658 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Ser Ile Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys 50 55
60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu
65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys Ala 85 90 95 Arg <210> SEQ ID NO 659 <211> LENGTH:
98 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 659 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser
Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 660 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 660 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser
Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 661 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 661 Glu Asp Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Pro Ser Cys Ala Ala
Ser Gly Phe Ala Phe Ser Ser Tyr 20 25 30 Val Leu His Trp Val Arg
Arg Ala Pro Gly Lys Gly Pro Glu Trp Val 35 40 45 Ser Ala Ile Gly
Thr Gly Gly Asp Thr Tyr Tyr Ala Asp Ser Val Met 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Ile Ala Glu Asp Met Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 662 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 662 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Val Trp Val 35 40 45 Ser Arg Ile Asn
Ser Asp Gly Ser Ser Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 663 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 663 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Val Trp Val 35 40 45 Ser Arg Ile Asn
Ser Asp Gly Ser Ser Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 664 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 664 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys
Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 665 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 665 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Val Trp Val 35 40 45 Ser Arg Ile Asn
Ser Asp Gly Ser Ser Thr Ser Tyr Ala Asp Ser Met 50 55 60 Lys Gly
Gln Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85
90 95 Thr Arg <210> SEQ ID NO 666 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 666 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn Ile Lys
Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 667 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 667 Gln Val Gln Leu Val Gln Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Thr Thr <210> SEQ ID NO 668 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 668 Gln Ser Val Leu Thr Gln Pro Pro Ser Val
Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly
Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn
Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85
90 95 Ser Ala <210> SEQ ID NO 669 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 669 Gln Ser Val Leu Thr Gln Pro Pro Ser Val
Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly
Ser Ser Ser Asp Met Gly Asn Tyr 20 25 30 Ala Val Ser Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Glu Asn
Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Trp 65 70 75 80
Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Leu Ala Trp Asp Thr Ser Pro 85
90 95 Arg Ala <210> SEQ ID NO 670 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 670 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala
Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly
Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ser Asn
Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85
90 95 Asn Gly <210> SEQ ID NO 671 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 671 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala
Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly
Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn
Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85
90 95 Ser Gly <210> SEQ ID NO 672 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 672 Gln Ser Val Leu Thr Gln Pro Pro Ser Val
Ser Glu Ala Pro Arg Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly
Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Ala Val Asn Trp Tyr Gln
Gln Leu Pro Gly Lys Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp
Asp Leu Leu Pro Ser Gly Val Ser Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85
90 95 Asn Gly <210> SEQ ID NO 673 <211> LENGTH: 99
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 673 Gln Ser Val Leu Thr Gln Pro Pro Ser Val
Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly
Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Val Val His Trp Tyr
Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly
Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Gln Phe 50 55 60 Ser Gly
Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80
Gln Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Lys Ala Trp Asp Asn Ser 85
90 95 Leu Asn Ala <210> SEQ ID NO 674 <211> LENGTH: 99
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 674 Gln Ser Val Val Thr Gln Pro Pro Ser Val
Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly
Ser Ser Ser Asn Ile Gly Ala Gly 20 25 30 Tyr Asp Val His Trp Tyr
Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly
Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe 50 55 60 Ser Gly
Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80
Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85
90 95 Leu Ser Gly <210> SEQ ID NO 675 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 675 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val
Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly
Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Lys Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Asn
Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Val Gln 65 70 75 80
Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85
90 95 Arg Gly
1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 675
<210> SEQ ID NO 1 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1) <223>
OTHER INFORMATION: Xaa at position 1 could be either His or Ser
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (4)..(4) <223> OTHER INFORMATION: Xaa at position 4
could be either Tyr or His <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (6)..(6) <223>
OTHER INFORMATION: Xaa at position 6 could be either Tyr, Asn or
Thr <400> SEQUENCE: 1 Xaa Gly Ser Xaa Asp Xaa 1 5 <210>
SEQ ID NO 2 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (2)..(2) <223>
OTHER INFORMATION: Xaa at position 2 could be either Ser or Thr
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (4)..(4) <223> OTHER INFORMATION: Xaa at position 4
could be either Asp or Glu <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (5)..(5) <223>
OTHER INFORMATION: Xaa at position 5 could be either Ser, Arg or
Lys <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (6)..(6) <223> OTHER INFORMATION: Xaa
at position 6 could be either Ser, Gly or Tyr <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (7)..(7)
<223> OTHER INFORMATION: Xaa at position 7 could be either
Leu, Phe, Thr or Ser <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (8)..(8) <223> OTHER
INFORMATION: Xaa at position 8 could be either Arg, Ser, Thr, Trp
or His <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (9)..(9) <223> OTHER INFORMATION: Xaa
at position 9 could be either Gly or Pro <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Xaa at position 10 could be either
Ser, Thr, Ala or Leu <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (11)..(11) <223> OTHER
INFORMATION: Xaa at position 11 could be either Arg, Ser, Met, Thr
or Leu <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (12)..(12) <223> OTHER INFORMATION: Xaa
at position 12 could be either Val, Ile, Thr, Met or Leu
<400> SEQUENCE: 2 Gln Xaa Tyr Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa
Xaa 1 5 10 <210> SEQ ID NO 3 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 3 Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr
Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 4
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Xaa at position 1 could be either Gly or Tyr
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa at position 3
could be either Asp or Ser <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (4)..(4) <223>
OTHER INFORMATION: Xaa at position 4 could be either Gln or Asn
<400> SEQUENCE: 4 Xaa Asn Xaa Xaa Arg Pro Ser 1 5 <210>
SEQ ID NO 5 <211> LENGTH: 9 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Xaa represents either Ser or Glu <400> SEQUENCE:
5 Phe Thr Phe Ser Xaa Tyr Gly Met His 1 5 <210> SEQ ID NO 6
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Xaa at position 1 could be either Ser or Thr
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa at position 3
could be either Ser or Gly <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (4)..(4) <223>
OTHER INFORMATION: Xaa at position 4 could be either Arg or Ser
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa at position 8
could be either Gly or Val <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (9)..(9) <223>
OTHER INFORMATION: Xaa at position 9 could be either Ser or Ala
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa at position
10 could be either Asn, Gly or Tyr <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11) <223>
OTHER INFORMATION: Xaa at position 11 could be either Thr or Asp
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa at position
13 could be either Lys or His <400> SEQUENCE: 6 Xaa Gly Xaa
Xaa Ser Asn Ile Xaa Xaa Xaa Xaa Val Xaa 1 5 10 <210> SEQ ID
NO 7 <211> LENGTH: 115 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Xaa at position 6 could be either Gln or Glu
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (16)..(16) <223> OTHER INFORMATION: Xaa at position
16 could be either Arg or Gly <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (31)..(31) <223>
OTHER INFORMATION: Xaa at position 31 could be either Ser or Glu
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (84)..(84) <223> OTHER INFORMATION: Xaa at position
84 could be either Lys or Asn <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (97)..(97) <223>
OTHER INFORMATION: Xaa at position 97 could be either Thr, Ala or
Lys <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (98)..(98) <223> OTHER INFORMATION: Xaa
at position 98 could be either Thr or Lys <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (99)..(99)
<223> OTHER INFORMATION: Xaa at position 99 could be either
Ser or His <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (102)..(102)
<223> OTHER INFORMATION: Xaa at position 102 could be either
Tyr or His <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (104)..(104) <223> OTHER INFORMATION:
Xaa at position 104 could be either Tyr, Asn or Thr <400>
SEQUENCE: 7 Gln Val Gln Leu Val Xaa Ser Gly Gly Gly Val Val Gln Pro
Gly Xaa 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
Phe Ser Xaa Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly
Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Asx 50 55 60 Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Xaa
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Xaa Xaa
Xaa Gly Ser Xaa Asp Xaa Trp Gly Gln Gly Thr Met Val Thr 100 105 110
Val Ser Ser 115 <210> SEQ ID NO 8 <211> LENGTH: 112
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa at position 1
could be either Ser or Gln <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (2)..(2) <223>
OTHER INFORMATION: Xaa at position 2 could be either Tyr or Ser
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa at position
13 could be either Thr or Ala <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (23)..(23) <223>
OTHER INFORMATION: Xaa at position 23 could be either Ser or Thr
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (25)..(25) <223> OTHER INFORMATION: Xaa at position
25 could be either Gly or Ser <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (26)..(26) <223>
OTHER INFORMATION: Xaa at position 26 could be either Arg or Ser
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (30)..(30) <223> OTHER INFORMATION: Xaa at position
30 could be either Gly or Val <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (31)..(31) <223>
OTHER INFORMATION: Xaa at position 31 could be either Ser or Ala
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (32)..(32) <223> OTHER INFORMATION: Xaa at position
32 could be either Asn, Gly or Tyr <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (33)..(33) <223>
OTHER INFORMATION: Xaa at position 33 could be either Thr or Asp
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (35)..(35) <223> OTHER INFORMATION: Xaa at position
35 could be either Lys or His <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (51)..(51) <223>
OTHER INFORMATION: Xaa at position 51 could be either Gly or Lys
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (53)..(53) <223> OTHER INFORMATION: Xaa at position
53 could be either Asp or Ser <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (54)..(54) <223>
OTHER INFORMATION: Xaa at position 54 could be either Gln or Asn
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (79)..(79) <223> OTHER INFORMATION: Xaa at position
79 could be either Val or Leu <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (91)..(91) <223>
OTHER INFORMATION: Xaa at 91 could be either Ser or Thr <220>
FEATURE: <221> NAME/KEY: MISC_FEATURE <222> LOCATION:
(93)..(93) <223> OTHER INFORMATION: Xaa at position 93 could
be either Asp or Glu <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (94)..(94) <223> OTHER
INFORMATION: Xaa at position 94 could be either Ser, Arg or Lys
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (95)..(95) <223> OTHER INFORMATION: Xaa at position
95 could be either Ser, Gly or Tyr <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (96)..(96) <223>
OTHER INFORMATION: Xaa at position 96 could be either Leu, Phe, Thr
or Ser <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (97)..(97) <223> OTHER INFORMATION: Xaa
at position 97 could be either Arg, Ser, Thr, Trp or His
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (98)..(98) <223> OTHER INFORMATION: Xaa at position
98 could be either Gly or Pro <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (99)..(99) <223>
OTHER INFORMATION: Xaa at position 99 could be either Ser, Thr, Ala
or Leu <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (100)..(100) <223> OTHER INFORMATION:
Xaa at position 100 could be either Arg, Ser, Met, Thr or Leu
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (101)..(101) <223> OTHER INFORMATION: Xaa at
position 101 could be either Val, Ile, Thr, Met or Leu <400>
SEQUENCE: 8 Xaa Xaa Val Leu Thr Gln Pro Pro Ser Val Ser Gly Xaa Pro
Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Xaa Gly Xaa Xaa Ser Asn
Ile Xaa Xaa Xaa 20 25 30 Xaa Val Xaa Trp Tyr Gln Gln Leu Pro Gly
Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Xaa Asn Xaa Xaa Arg Pro
Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr
Ser Ala Ser Leu Ala Ile Thr Gly Xaa Gln 65 70 75 80 Ala Glu Asp Glu
Ala Asp Tyr Tyr Cys Gln Xaa Tyr Xaa Xaa Xaa Xaa 85 90 95 Xaa Xaa
Xaa Xaa Xaa Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly 100 105 110
<210> SEQ ID NO 9 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (2)..(2) <223>
OTHER INFORMATION: Xaa at position 2 could be either Gly, Val, Cys
or His <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (3)..(3) <223> OTHER INFORMATION: Xaa
at position 3 could be either Ser or Thr <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (4)..(4)
<223> OTHER INFORMATION: Xaa at position 4 could be either
His, Thr, Val, Arg, or Ile <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (5)..(5) <223>
OTHER INFORMATION: Xaa at position 5 could be either Asp or Ser
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (6)..(6) <223> OTHER INFORMATION: Xaa at position 6
could be either Asn, Lys, Ala, Thr, Ser, Phe, Trp, or His
<400> SEQUENCE: 9 His Xaa Xaa Xaa Xaa Xaa 1 5 <210> SEQ
ID NO 10 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (4)..(4) <223> OTHER
INFORMATION: Xaa at position 4 could be either Asp or Ser
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (5)..(5) <223> OTHER INFORMATION: Xaa at position 5
represents any amino acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Xaa at position 6 could be either
Gly, Asp, Gln, Leu, Phe, Arg, His, Asn or Tyr <400> SEQUENCE:
10 Gln Ser Tyr Xaa Xaa Xaa Thr His Pro Ala Leu Leu 1 5 10
<210> SEQ ID NO 11 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (1)..(1)
<223> OTHER INFORMATION: Xaa at position 1 could be either
Phe, Thr or Tyr <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (3)..(3) <223> OTHER
INFORMATION: Xaa at position 3 could be either Arg or Ala
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (5)..(5) <223> OTHER INFORMATION: Xaa at position 5
could be either Asp, Ser, Glu or Ala <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (6)..(6)
<223> OTHER INFORMATION: Xaa at position 6 could be either
Gly or Arg <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (8)..(8) <223> OTHER INFORMATION: Xaa
at position 8 represents any amino acid <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (10)..(10)
<223> OTHER INFORMATION: Xaa at position 10 could be either
Tyr or Glu <400> SEQUENCE: 11 Xaa Ile Xaa Tyr Xaa Xaa Ser Xaa
Lys Xaa Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO
12 <211> LENGTH: 7 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (1)..(1) <223> OTHER
INFORMATION: Xaa at position 1 could be either Gly, Tyr, Ser, Thr,
Asn or Gln <400> SEQUENCE: 12 Xaa Asn Asp Gln Arg Pro Ser 1 5
<210> SEQ ID NO 13 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (4)..(5)
<223> OTHER INFORMATION: Xaa at position 4 and 5 represents
any amino acid <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (6)..(6) <223> OTHER
INFORMATION: Xaa at position 6 could be either Tyr or His
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (7)..(7) <223> OTHER INFORMATION: Xaa at position 7
could be either Gly, Met, Ala, Asn or Ser <400> SEQUENCE: 13
Phe Thr Phe Xaa Xaa Xaa Xaa Met His 1 5 <210> SEQ ID NO 14
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (9)..(9) <223> OTHER
INFORMATION: Xaa at position 9 could be either Ser, Cys, Arg, Asn,
Asp or Thr <220> FEATURE: <221> NAME/KEY: MISC_FEATURE
<222> LOCATION: (10)..(10) <223> OTHER INFORMATION: Xaa
at position 10 could be either Asn, Met or Ile <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (11)..(11)
<223> OTHER INFORMATION: Xaa at position 11 could be either
Thr, Tyr, Asp, His, Lys or Pro <400> SEQUENCE: 14 Ser Gly Gly
Arg Ser Asn Ile Gly Xaa Xaa Xaa Val Lys 1 5 10 <210> SEQ ID
NO 15 <211> LENGTH: 114 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (5)..(5) <223> OTHER
INFORMATION: Xaa at position 5 could be either Gln or Glu
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (30)..(30) <223> OTHER INFORMATION: Xaa at position
30 could be Ser or Glu <220> FEATURE: <221> NAME/KEY:
MISC_FEATURE <222> LOCATION: (83)..(83) <223> OTHER
INFORMATION: Xaa at position 83 could be Lys or Asn <400>
SEQUENCE: 15 Gln Val Gln Val Xaa Ser Gly Gly Gly Val Val Gln Pro
Gly Arg Ser 1 5 10 15 Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
Phe Ser Xaa Tyr Gly 20 25 30 Met His Trp Val Arg Gln Ala Pro Gly
Lys Gly Leu Glu Trp Val Ala 35 40 45 Phe Ile Arg Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80 Gln Met Xaa
Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Lys 85 90 95 Thr
His Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val Thr Val 100 105
110 Ser Ser <210> SEQ ID NO 16 <211> LENGTH: 112
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (1)..(1) <223> OTHER INFORMATION: Xaa at position 1
could be either Ser or Gln <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (2)..(2) <223>
OTHER INFORMATION: Xaa at position 2 could be Tyr or Ser
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (13)..(13) <223> OTHER INFORMATION: Xaa at position
13 could be either Thr or Ala <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (25)..(25) <223>
OTHER INFORMATION: Xaa at position 25 could be either Gly or Ser
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (51)..(51) <223> OTHER INFORMATION: Xaa at position
51 could be either Gly or Tyr <220> FEATURE: <221>
NAME/KEY: MISC_FEATURE <222> LOCATION: (79)..(79) <223>
OTHER INFORMATION: Xaa at position 79 could be either Val or Leu
<220> FEATURE: <221> NAME/KEY: MISC_FEATURE <222>
LOCATION: (95)..(95) <223> OTHER INFORMATION: Xaa at position
95 could be either Gly or Tyr <400> SEQUENCE: 16 Xaa Xaa Val
Leu Thr Gln Pro Pro Ser Val Ser Gly Xaa Pro Gly Gln 1 5 10 15 Arg
Val Thr Ile Ser Cys Ser Gly Xaa Arg Ser Asn Ile Gly Ser Asn 20 25
30 Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu
35 40 45 Ile Tyr Xaa Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg
Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile
Thr Gly Xaa Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln
Ser Tyr Asp Arg Xaa Thr 85 90 95 His Pro Ala Leu Leu Phe Gly Thr
Gly Thr Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO
17 <211> LENGTH: 6 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 17 His Gly Ser His Asp
Asn 1 5 <210> SEQ ID NO 18 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 18 Gln Ser Tyr Asp Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 19 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 19 Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 20
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 20 Gly Asn Asp Gln Arg Pro Ser 1
5 <210> SEQ ID NO 21 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 21 Phe
Thr Phe Ser Ser Tyr Gly Met His 1 5 <210> SEQ ID NO 22
<211> LENGTH: 13 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 22 Ser Gly Gly Arg Ser Asn Ile
Gly Ser Asn Thr Val Lys 1 5 10 <210> SEQ ID NO 23 <211>
LENGTH: 115 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 23 Gln Val Gln Leu Val Gln Ser Gly
Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe
Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65
70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
24 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 24 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Trp Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Thr 85 90 95 His Pro Ala Leu Leu Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 25
<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 25 His Gly Ser His Asp Asn 1 5
<210> SEQ ID NO 26 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 26 Gln
Ser Tyr Asp Arg Tyr Thr His Pro Ala Leu Leu 1 5 10 <210> SEQ
ID NO 27 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 27 Phe Ile Arg Tyr Asp
Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 28 <211> LENGTH: 7 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 28 Tyr
Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 29 <211>
LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 29 Phe Thr Phe Ser Ser Tyr Gly Met His 1 5
<210> SEQ ID NO 30 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 30 Ser
Gly Ser Arg Ser Asn Ile Gly Ser Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 31 <211> LENGTH: 115 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 31 Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20
25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp
Asn Trp Gly Gln Gly Thr Met Val Thr 100 105 110 Val Ser Ser 115
<210> SEQ ID NO 32 <211> LENGTH: 112 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 32 Gln
Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10
15 Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn
20 25 30 Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
Leu Leu 35 40 45 Ile Tyr Tyr Asn Asp Gln Arg Pro Ser Gly Val Pro
Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu
Ala Ile Thr Gly Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr
Cys Gln Ser Tyr Asp Arg Tyr Thr 85 90 95 His Pro Ala Leu Leu Phe
Gly Thr Gly Thr Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ
ID NO 33 <211> LENGTH: 115 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 33
Gln Val Gln Leu Val Gln Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Lys Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Ser Gly Ser
Tyr Asp Tyr Trp Gly Gln Gly Thr Met Val Thr 100 105 110 Val Ser Ser
115 <210> SEQ ID NO 34 <211> LENGTH: 112 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
34 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln
1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly
Ser Asn 20 25 30 Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala
Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly
Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala
Ser Leu Ala Ile Thr Gly Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp
Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Arg Gly Ser Arg
Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly 100 105 110
<210> SEQ ID NO 35 <211> LENGTH: 115 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 35 Gln
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Ser Gly Ser Tyr
Asp Tyr Trp Gly Gln Gly Thr Met Val Thr 100 105 110 Val Ser Ser 115
<210> SEQ ID NO 36 <211> LENGTH: 112 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <220> FEATURE:
<221> NAME/KEY: MISC_FEATURE <222> LOCATION: (32)..(32)
<223> OTHER INFORMATION: Xaa at position 32 represents either
Gly or Tyr <400> SEQUENCE: 36 Gln Ser Val Leu Thr Gln Pro Pro
Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys
Thr Gly Ser Ser Ser Asn Ile Gly Ala Xaa 20 25 30 Asp Val His Trp
Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr
Gly Asn Ser Asn Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60
Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln 65
70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser
Ser Leu 85 90 95 Ser Gly Ser Arg Val Phe Gly Thr Gly Thr Lys Val
Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 37 <211>
LENGTH: 115 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 37 Gln Val Gln Leu Val Gln Ser Gly
Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe
Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65
70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
38 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 38 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Ser Ser Leu 85 90 95 Arg Gly Ser Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 39
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 39 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr Ser Gly Ser Tyr Asp Tyr Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
40 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 40 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Phe 85 90 95 Thr Gly Ser Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 41
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 41 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly
Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys
Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg
Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Lys Ser Leu
Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Thr Thr Ser Gly
Ser Tyr Asp Tyr Trp Gly Gln Gly Thr Met Val Thr 100 105 110 Val Ser
Ser 115 <210> SEQ ID NO 42 <211> LENGTH: 112
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 42 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val
Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly
Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Lys Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Asn
Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Val Gln 65 70 75 80
Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85
90 95 Trp Gly Ser Arg Val Phe Gly Thr Gly Thr Lys Val Thr Val Leu
Gly 100 105 110 <210> SEQ ID NO 43 <211> LENGTH: 115
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 43 Gln Val Gln Leu Val Gln Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Thr Thr His Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val
Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO 44
<211> LENGTH: 112 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 44 Ser Tyr Val Leu Thr Gln Pro
Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser
Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Lys
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile
Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Val Gln
65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Arg
Gly Phe 85 90 95 Thr Gly Ser Arg Val Phe Gly Thr Gly Thr Lys Val
Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 45 <211>
LENGTH: 115 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 45 Gln Val Gln Leu Val Gln Ser Gly
Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe
Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65
70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
46 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 46 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Ser Ser Leu 85 90 95 Trp Gly Ser Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 47
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 47 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
48 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 48 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Tyr
Asp Lys Gly Phe 85 90 95 Thr Gly Ser Ser Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 49
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 49 Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50
55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu
Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
Tyr Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln
Gly Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID
NO 50 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 50 Gln Ser Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Tyr
Asp Lys Gly Phe 85 90 95 Thr Gly Ser Ser Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 51
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 51 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr His Gly Ser His Asp Thr Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
52 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 52 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Ser Ser Leu 85 90 95 Trp Gly Thr Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 53
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 53 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
54 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 54 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Val Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Phe 85 90 95 Thr Gly Ser Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 55
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 55 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
56 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 56 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Val Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Phe 85 90 95 Thr Gly Ala Arg Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 57
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 57 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80
Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val
Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO 58
<211> LENGTH: 112 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 58 Ser Tyr Val Leu Thr Gln Pro
Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser
Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Lys
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile
Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Val Gln
65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Thr Tyr Asp Lys
Gly Phe 85 90 95 Thr Gly Ser Ser Val Phe Gly Thr Gly Thr Lys Val
Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 59 <211>
LENGTH: 115 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 59 Gln Val Gln Leu Val Gln Ser Gly
Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe
Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65
70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
60 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 60 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Glu Arg Gly Phe 85 90 95 Thr Gly Ser Met Val Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 61
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 61 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
62 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 62 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Thr 85 90 95 His Pro Leu Thr Ile Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 63
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 63 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
64 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 64 Ser Tyr Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Ser 85 90 95 His Pro Ala Leu Thr Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 65
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 65 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser
115 <210> SEQ ID NO 66 <211> LENGTH: 112 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
66 Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln
1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly
Ser Asn 20 25 30 Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala
Pro Lys Leu Leu 35 40 45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly
Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala
Ser Leu Ala Ile Thr Gly Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp
Tyr Tyr Cys Gln Ser Tyr Asp Arg Gly Thr 85 90 95 His Pro Leu Thr
Met Phe Gly Thr Gly Thr Lys Val Thr Val Leu Gly 100 105 110
<210> SEQ ID NO 67 <211> LENGTH: 115 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 67 Gln
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Lys Thr His Gly Ser His
Asp Asn Trp Gly Gln Gly Thr Met Val Thr 100 105 110 Val Ser Ser 115
<210> SEQ ID NO 68 <211> LENGTH: 112 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 68 Gln
Ser Val Leu Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10
15 Arg Val Thr Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn
20 25 30 Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys
Leu Leu 35 40 45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro
Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu
Ala Ile Thr Gly Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr
Cys Gln Ser Tyr Asp Arg Gly Thr 85 90 95 His Pro Leu Thr Met Phe
Gly Thr Gly Thr Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ
ID NO 69 <211> LENGTH: 115 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 69 Gln Val Gln Leu Val
Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly
Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40
45 Ala Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val
50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr
Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
Val Tyr Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly
Gln Gly Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ
ID NO 70 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 70 Gln Ser Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Thr 85 90 95 His Pro Ala Leu Leu Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 71
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 71 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Glu Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
72 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 72 Gln Ser Val Leu Thr
Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr
Ile Ser Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr
Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40
45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser
50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly
Leu Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr
Asp Arg Gly Thr 85 90 95 His Pro Ala Leu Leu Phe Gly Thr Gly Thr
Lys Val Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 73
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 73 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly
Thr Met Val Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO
74 <211> LENGTH: 112 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens
<400> SEQUENCE: 74 Gln Ser Val Leu Thr Gln Pro Pro Ser Val
Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly
Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Lys Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asn
Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln 65 70 75 80
Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Arg Gly Thr 85
90 95 His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys Val Thr Val Leu
Gly 100 105 110 <210> SEQ ID NO 75 <211> LENGTH: 115
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 75 Gln Val Gln Leu Val Gln Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Lys Thr His Gly Ser His Asp Asn Trp Gly Gln Gly Thr Met Val
Thr 100 105 110 Val Ser Ser 115 <210> SEQ ID NO 76
<211> LENGTH: 112 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 76 Gln Ser Val Leu Thr Gln Pro
Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser
Cys Ser Gly Ser Arg Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Lys
Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile
Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55
60 Gly Ser Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Thr Gly Leu Gln
65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Asp Arg
Tyr Thr 85 90 95 His Pro Ala Leu Leu Phe Gly Thr Gly Thr Lys Val
Thr Val Leu Gly 100 105 110 <210> SEQ ID NO 77 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 77 Ser Gly Ser Tyr Asp Tyr 1 5 <210>
SEQ ID NO 78 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 78 His Gly
Ser His Asp Asn 1 5 <210> SEQ ID NO 79 <211> LENGTH: 6
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 79 His Gly Ser Tyr Asp Tyr 1 5 <210>
SEQ ID NO 80 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 80 Arg Arg
Arg Ser Asn Tyr 1 5 <210> SEQ ID NO 81 <211> LENGTH: 6
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 81 Ser Gly Ser Ile Asp Tyr 1 5 <210>
SEQ ID NO 82 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 82 His Gly
Ser His Asp Asp 1 5 <210> SEQ ID NO 83 <211> LENGTH: 6
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 83 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 84 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 84 Thr Thr
His Gly Ser His Asp Asn Trp Gly Gln Gly 1 5 10 <210> SEQ ID
NO 85 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 85 Ala Lys His Gly Ser
His Asp Asn Trp Gly Gln Gly 1 5 10 <210> SEQ ID NO 86
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 86 Thr Thr His Gly Ser His Asp
Asn Trp Ser Gln Gly 1 5 10 <210> SEQ ID NO 87 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 87 Thr Thr His Gly Ser His Asp Thr Trp Gly
Gln Gly 1 5 10 <210> SEQ ID NO 88 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 88 Lys Thr His Gly Ser His Asp Asn Trp Gly
Gln Gly 1 5 10 <210> SEQ ID NO 89 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 89 Lys Thr His Gly Ser His Asp Asn Trp Gly
His Gly 1 5 10 <210> SEQ ID NO 90 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 90 Thr Thr His Gly Ser His Asp Asn Trp Ser
Gln Gly 1 5 10 <210> SEQ ID NO 91 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 91 Thr Thr His Arg Ser His Asn Asn Trp Gly
Gln Gly 1 5 10
<210> SEQ ID NO 92 <211> LENGTH: 8 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 92 Thr
Thr His Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 93
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 93 Thr Thr His Gly Ser His Asp
Thr 1 5 <210> SEQ ID NO 94 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
94 Thr Lys His Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 95
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 95 Thr Thr Gln Gly Arg His Asp
Asn 1 5 <210> SEQ ID NO 96 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
96 Lys Thr Arg Gly Arg His Asp Asn 1 5 <210> SEQ ID NO 97
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 97 Thr Thr His Gly Ser His Asp
Lys 1 5 <210> SEQ ID NO 98 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
98 Thr Thr His Gly Ser His Asp Asp 1 5 <210> SEQ ID NO 99
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 99 Lys Thr His Gly Ser His Asp
Asn 1 5 <210> SEQ ID NO 100 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
100 Lys Thr His Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 101
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 101 Thr Thr His Gly Ser His Asp
Asn 1 5 <210> SEQ ID NO 102 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
102 Thr Thr Ser Gly Ser Tyr Asp Tyr 1 5 <210> SEQ ID NO 103
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 103 Thr Thr His Gly Ser His Asp
Asn 1 5 <210> SEQ ID NO 104 <211> LENGTH: 8 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
104 Thr Thr His Gly Ser Gln Asp Asn 1 5 <210> SEQ ID NO 105
<211> LENGTH: 8 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 105 Ala Thr His Gly Ser Gln Asp
Asn 1 5 <210> SEQ ID NO 106 <211> LENGTH: 6 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
106 His Gly Ser Gln Asp Thr 1 5 <210> SEQ ID NO 107
<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 107 Ser Gly Ser Tyr Asp Tyr 1 5
<210> SEQ ID NO 108 <211> LENGTH: 6 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 108
His Gly Ser Gln Asp Asn 1 5 <210> SEQ ID NO 109 <211>
LENGTH: 9 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 109 Cys Lys Thr His Gly Ser His Asp Asn 1 5
<210> SEQ ID NO 110 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 110
Gln Ser Tyr Asp Ser Ser Leu Arg Gly Ser Arg Val 1 5 10 <210>
SEQ ID NO 111 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 111 Gln
Ser Tyr Asp Arg Gly Phe Thr Gly Ser Arg Val 1 5 10 <210> SEQ
ID NO 112 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 112 Gln Ser Tyr Asp
Ser Ser Leu Arg Gly Ser Arg Val 1 5 10 <210> SEQ ID NO 113
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 113 Gln Ser Tyr Asp Ser Ser Leu
Thr Gly Ser Arg Val 1 5 10 <210> SEQ ID NO 114 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 114 Gln Ser Tyr Asp Ser Ser Leu Trp Gly Ser
Arg Val 1 5 10
<210> SEQ ID NO 115 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 115
Gln Thr Tyr Asp Ile Ser Glu Ser Gly Ser Arg Val 1 5 10 <210>
SEQ ID NO 116 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 116 Gln
Ser Tyr Asp Arg Gly Phe Thr Gly Ser Arg Val 1 5 10 <210> SEQ
ID NO 117 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 117 Gln Thr Tyr Asp
Arg Gly Phe Thr Gly Ser Arg Val 1 5 10 <210> SEQ ID NO 118
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 118 Gln Thr Tyr Asp Lys Gly Phe
Thr Gly Ser Ser Val 1 5 10 <210> SEQ ID NO 119 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 119 Gln Ser Tyr Asp Arg Arg Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 120 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 120 Gln Ser Tyr Asp Trp Asn Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 121 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 121 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 122 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 122 Gln Ser Tyr Asp Asn Gly Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 123 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 123 Gln Ser Tyr Asp Asn Ala Val Thr Ala Ser
Lys Val 1 5 10 <210> SEQ ID NO 124 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 124 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 125 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 125 Gln Ser Tyr Asp Ser Ser Leu Trp Gly Thr
Arg Val 1 5 10 <210> SEQ ID NO 126 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 126 Gln Ser Tyr Asp Arg Asp Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 127 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 127 Gln Ser Tyr Glu Arg Gly Phe Thr Gly Ser
Met Val 1 5 10 <210> SEQ ID NO 128 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 128 Gln Ser Tyr Asp Asn Gly Phe Thr Gly Ala
Arg Val 1 5 10 <210> SEQ ID NO 129 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 129 Gln Ser Tyr Asp Arg Arg Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 130 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 130 Gln Thr Tyr Asp Lys Gly Phe Thr Gly Ser
Ser Val 1 5 10 <210> SEQ ID NO 131 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 131 Gln Ser Tyr Asp Arg Asp Phe Thr Gly Thr
Arg Val 1 5 10 <210> SEQ ID NO 132 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 132 Gln Ser Tyr Asp Arg Gly Phe Tyr Gly Ser
Met Val 1 5 10 <210> SEQ ID NO 133 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 133 Gln Thr Tyr Asp Lys Gly Phe Thr Gly Ser
Ser Val 1 5 10 <210> SEQ ID NO 134 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 134 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ala
Arg Val 1 5 10 <210> SEQ ID NO 135 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 135 Gln Ser Tyr Glu Arg Gly Phe Thr Gly Ala
Arg Val 1 5 10 <210> SEQ ID NO 136 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 136 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 137 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 137
Gln Ser Tyr Asp Arg Gly Phe Thr Gly Phe Lys Val Phe 1 5 10
<210> SEQ ID NO 138 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 138
Gln Ser Tyr Asp Arg Gly Phe Val Ser Ala Tyr Val Phe 1 5 10
<210> SEQ ID NO 139 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 139
Gln Ser Tyr Asp Arg Gly Leu Thr Val Thr Lys Val Phe 1 5 10
<210> SEQ ID NO 140 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 140
Gln Ser Tyr Asp Arg Gly Tyr Thr Ala Ser Arg Val Phe 1 5 10
<210> SEQ ID NO 141 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 141
Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser Lys Val Phe 1 5 10
<210> SEQ ID NO 142 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 142
Gln Ser Tyr Asp Arg Gly Leu Thr Gly Phe Arg Val Phe 1 5 10
<210> SEQ ID NO 143 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 143
Gln Ser Tyr Asp Arg Gly Phe Thr Gly Tyr Lys Val Phe 1 5 10
<210> SEQ ID NO 144 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 144
Gln Ser Tyr Asp Arg Gly Leu Thr Gly Tyr Arg Leu Phe 1 5 10
<210> SEQ ID NO 145 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 145
Gln Ser Tyr Asp Arg Gly Phe Thr Asp Tyr Lys Val Phe 1 5 10
<210> SEQ ID NO 146 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 146
Gln Ser Tyr Asp Arg Gly Phe Thr Gly Pro Arg Leu Phe 1 5 10
<210> SEQ ID NO 147 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 147
Gln Ser Tyr Asp Arg Gly Leu Thr Gly Ser Arg Val Phe 1 5 10
<210> SEQ ID NO 148 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 148
Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ala Arg Val Trp 1 5 10
<210> SEQ ID NO 149 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 149
Gln Ser Tyr Asp Arg Gly Phe Thr Gly Tyr Arg Val Phe 1 5 10
<210> SEQ ID NO 150 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 150
Gln Ser Tyr Asp Arg Gly Phe Thr Gly Pro Arg Val Phe 1 5 10
<210> SEQ ID NO 151 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 151
Gln Ser Tyr Asp Arg Gly Met Thr Ser Ser Arg Val Phe 1 5 10
<210> SEQ ID NO 152 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 152
Gln Ser Tyr Asp Arg Asp Ser Thr Gly Ser Arg Val Phe 1 5 10
<210> SEQ ID NO 153 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 153
Gln Ser Tyr Asp Ser Ser Leu Arg Gly Ser Arg Val Phe 1 5 10
<210> SEQ ID NO 154 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 154
His Ser Tyr Asp Ser Asp Phe Thr Gly Ser Arg Val Phe 1 5 10
<210> SEQ ID NO 155 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 155
His Ser Ser Glu Ser Gly Phe Thr Gly Ser Arg Val Phe 1 5 10
<210> SEQ ID NO 156 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 156
His Ser Tyr Asp Asn Arg Phe Thr Gly Ser Arg Val Phe 1 5 10
<210> SEQ ID NO 157 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 157
His Ser Tyr Asp Ser Arg Phe Thr Gly Ser Arg Val Phe 1 5 10
<210> SEQ ID NO 158 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 158
Gln Ser Tyr Asp Ser Glu Phe Thr Gly Ser Arg Val Phe 1 5 10
<210> SEQ ID NO 159 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 159
Gln Ser Tyr Asp Thr Gly Phe Thr Gly Ser Arg Val Phe 1 5 10
<210> SEQ ID NO 160 <211> LENGTH: 13 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 160 His Ser Tyr Asp Ser Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 161 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 161 Gln Ser Tyr Asp Thr Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 162 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 162 His Ser Tyr Asp Thr Lys Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 163 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 163 His Ser Ser Asp Ser Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 164 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 164 Gln Ser Tyr Asp Ser Asp Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 165 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 165 His Ser Tyr Glu Ser Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 166 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 166 Gln Ser Tyr Asp Ala Pro Trp Ser Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 167 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 167 Gln Ser Tyr Asp Ser Asp Phe Thr Gly Ser
Lys Val Phe 1 5 10 <210> SEQ ID NO 168 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 168 His Thr Asn Asp Ser Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 169 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 169 His Ser Tyr Asp Thr Arg Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 170 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 170 Gln Ser Tyr Asp Met Arg Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 171 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 171 His Ser Ser Asp Ser Asp Ser Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 172 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 172 Gln Ser Tyr Asn Thr Asp Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 173 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 173 Gln Ser Tyr Asp Ser Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 174 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 174 His Ser Tyr Asp Met Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 175 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 175 His Ser Tyr Asp Asn Gly Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 176 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 176 His Ser His Asp Arg Asp Phe Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 177 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 177 Gln Ser Tyr Asp Ser Ser Leu Arg Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 178 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 178 Gln Ser Tyr Asp Arg Gly Ile His Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 179 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 179 Gln Ser Tyr Asp Ser Gly Phe Pro Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 180 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 180 Gln Ser Tyr Asp Ile Gly Ser Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 181 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 181 Gln Ser Tyr Asp Ser Gly Leu Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 182 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 182 Gln Ser Tyr Asp Ile Gly Met Thr Gly Ser
Arg Val Phe 1 5 10 <210> SEQ ID NO 183 <211> LENGTH: 13
<212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 183 Gln
Ser Tyr Asp Ile Gly Leu Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 184 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 184 Gln
Ser Tyr Asp Ser Gly Val Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 185 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 185 Gln
Ser Tyr Asp Arg Gly Leu Thr Ala Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 186 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 186 Gln
Ser Tyr Asp Thr Gly Leu Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 187 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 187 Gln
Ser Tyr Asp Thr Ala Leu Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 188 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 188 Gln
Ser Tyr Asp Ile Arg Phe Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 189 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 189 Gln
Ser Tyr Asp Ile Arg Ser Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 190 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 190 Gln
Ser Tyr Asp Asn Arg Leu Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 191 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 191 Gln
Ser Tyr Glu Thr Ser Phe Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 192 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 192 Gln
Ser Tyr Asp Ser Ser Ser Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 193 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 193 Gln
Ser Tyr Asp Ser Gly Phe Thr Ala Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 194 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 194 Gln
Thr Tyr Asp Lys Gly Phe Thr Gly Ser Ser Val Phe 1 5 10 <210>
SEQ ID NO 195 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 195 Gln
Ser Tyr Asp Asn Gly Phe Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 196 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 196 Gln
Ser Tyr Asp Thr Gly Phe Thr Lys Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 197 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 197 Gln
Ser Tyr Asp Ser Asp Val Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 198 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 198 Gln
Ser Tyr Asp Ala Gly Phe Thr Gly Ser Arg Val Phe 1 5 10 <210>
SEQ ID NO 199 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 199 Gln
Ser Tyr Asp Arg Gly Thr His Pro Ser Met Leu 1 5 10 <210> SEQ
ID NO 200 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 200 Gln Ser Tyr Asp
Arg Gly Thr Thr Pro Arg Pro Met 1 5 10 <210> SEQ ID NO 201
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 201 Gln Ser Tyr Asp Arg Gly Arg
Asn Pro Ala Leu Thr 1 5 10 <210> SEQ ID NO 202 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 202 Gln Ser Tyr Asp Arg Gly Thr His Pro Trp
Leu His 1 5 10 <210> SEQ ID NO 203 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 203 Gln Ser Tyr Asp Arg Gly Asn Ser Pro Ala
Thr Val 1 5 10 <210> SEQ ID NO 204 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 204 Gln Ser Tyr Asp Arg Gly Thr Phe Pro Ser
Pro Gln 1 5 10 <210> SEQ ID NO 205 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 205 Gln Ser Tyr Asp Arg Gly Leu Asn Pro Ser
Ala Thr 1 5 10 <210> SEQ ID NO 206
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 206 Gln Ser Tyr Asp Arg Gly Lys
Ser Asn Lys Met Leu 1 5 10 <210> SEQ ID NO 207 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 207 Gln Ser Tyr Asp Arg Gly His Thr Ala His
Leu Tyr 1 5 10 <210> SEQ ID NO 208 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 208 Gln Ser Tyr Asp Arg Gly Gln Thr Pro Ser
Ile Thr 1 5 10 <210> SEQ ID NO 209 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 209 Gln Ser Tyr Asp Arg Gly Tyr Pro Arg Asn
Ile Leu 1 5 10 <210> SEQ ID NO 210 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 210 Gln Ser Tyr Asp Arg Gly Ile Thr Pro Gly
Leu Ala 1 5 10 <210> SEQ ID NO 211 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 211 Gln Ser Tyr Asp Arg Gly Gln Pro His Ala
Val Leu 1 5 10 <210> SEQ ID NO 212 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 212 Gln Ser Tyr Asp Arg Gly Asn Ser Pro Ile
Pro Thr 1 5 10 <210> SEQ ID NO 213 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 213 Gln Ser Tyr Asp Arg Gly Thr Pro Asn Asn
Ser Phe 1 5 10 <210> SEQ ID NO 214 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 214 Gln Ser Tyr Asp Ser Gly Val Asp Pro Gly
Pro Tyr 1 5 10 <210> SEQ ID NO 215 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 215 Gln Ser Tyr Asp Arg Gly Arg Pro Arg His
Ala Leu 1 5 10 <210> SEQ ID NO 216 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 216 Gln Ser Tyr Asp Arg Gly Pro Tyr His Pro
Ile Arg 1 5 10 <210> SEQ ID NO 217 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 217 Gln Ser Tyr Asp Arg Gly Pro His Thr Gln
Pro Thr 1 5 10 <210> SEQ ID NO 218 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 218 Gln Ser Tyr Asp Arg Gly His Asn Asn Phe
Ser Pro 1 5 10 <210> SEQ ID NO 219 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 219 Gln Ser Tyr Asp Arg Gly Pro Thr His Leu
Pro His 1 5 10 <210> SEQ ID NO 220 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 220 Gln Ser Tyr Asp Arg Gly Thr Pro Ser Tyr
Pro Thr 1 5 10 <210> SEQ ID NO 221 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 221 Gln Ser Tyr Asp Ser Gly Thr Ser Asn Leu
Leu Pro 1 5 10 <210> SEQ ID NO 222 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 222 Gln Ser Tyr Asp Arg Gly Asp Ser Asn His
Asp Leu 1 5 10 <210> SEQ ID NO 223 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 223 Gln Ser Tyr Asp Arg Gly Leu Pro Arg Leu
Thr His 1 5 10 <210> SEQ ID NO 224 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 224 Gln Ser Tyr Asp Arg Gly Ile Pro Thr Ser
Tyr Leu 1 5 10 <210> SEQ ID NO 225 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 225 Gln Ser Tyr Asp Arg Gly Leu Arg Val Gln
Ala Pro 1 5 10 <210> SEQ ID NO 226 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 226 Gln Ser Tyr Asp Arg Gly Leu Ser Asp Ser
Pro Leu 1 5 10 <210> SEQ ID NO 227 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 227 Gln Ser Tyr Asp Ser Gly Ser Leu Arg Arg
Ile Leu 1 5 10 <210> SEQ ID NO 228 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 228 Gln Ser Tyr Asp Arg Gly Pro Ala Arg Thr
Ser Pro 1 5 10
<210> SEQ ID NO 229 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 229
Gln Ser Tyr Asp Arg Gly Arg Ala Ala His Pro Gln 1 5 10 <210>
SEQ ID NO 230 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 230 Gln
Ser Tyr Asp Arg Gly Thr Gln Pro Ala Asx Ile 1 5 10 <210> SEQ
ID NO 231 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 231 Gln Ser Tyr Asp
Arg Gly Thr His Pro Thr Met Ile 1 5 10 <210> SEQ ID NO 232
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 232 Gln Ser Tyr Asp Arg Gly Arg
Ile Pro Ala Asx Thr 1 5 10 <210> SEQ ID NO 233 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 233 Gln Ser Tyr Asp Arg Gly Thr His Pro Val
Pro Ala 1 5 10 <210> SEQ ID NO 234 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 234 Gln Ser Tyr Asp Arg Gly Ser Asx Pro Ile
Pro Ala 1 5 10 <210> SEQ ID NO 235 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 235 Gln Ser Tyr Asp Arg Gly Thr His Pro Val
Pro Ala 1 5 10 <210> SEQ ID NO 236 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 236 Gln Ser Tyr Asp Arg Gly Thr His Pro Thr
Met Tyr 1 5 10 <210> SEQ ID NO 237 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 237 Gln Ser Tyr Asp Arg Gly His His Tyr Thr
Thr Phe 1 5 10 <210> SEQ ID NO 238 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 238 Gln Ser Tyr Asp Arg Gly Ser His Pro Ala
Ala Glu 1 5 10 <210> SEQ ID NO 239 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 239 Gln Ser Tyr Asp Arg Gly Thr Ile Pro Ser
Ile Glu 1 5 10 <210> SEQ ID NO 240 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 240 Gln Ser Tyr Asp Arg Gly Ser Ser Pro Ala
Ile Met 1 5 10 <210> SEQ ID NO 241 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 241 Gln Ser Tyr Asp Arg Gly Ile Trp Pro Asn
Leu Asn 1 5 10 <210> SEQ ID NO 242 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 242 Gln Ser Tyr Asp Arg Gly Thr His Pro Asn
Leu Asn 1 5 10 <210> SEQ ID NO 243 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 243 Gln Ser Tyr Asp Arg Gly Thr His Pro Ser
Ile Ser 1 5 10 <210> SEQ ID NO 244 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 244 Gln Ser Tyr Asp Arg Gly Ser Ala Pro Met
Ile Asn 1 5 10 <210> SEQ ID NO 245 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 245 Gln Ser Tyr Asp Arg Gly His His Pro Ala
Met Ser 1 5 10 <210> SEQ ID NO 246 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 246 Gln Ser Tyr Asp Arg Gly Thr His Pro Ser
Ile Thr 1 5 10 <210> SEQ ID NO 247 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 247 Gln Ser Tyr Asp Arg Gly Thr Asp Pro Ala
Ile Val 1 5 10 <210> SEQ ID NO 248 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 248 Gln Ser Tyr Asp Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 249 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 249 Gln Ser Tyr Asp Arg Gly Ser His Pro Ala
Leu Thr 1 5 10 <210> SEQ ID NO 250 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 250 Gln Ser Tyr Asp Arg Gly Thr Thr Pro Ala
Pro Glu 1 5 10 <210> SEQ ID NO 251 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 251 Gln Ser Tyr Asp Arg Gly Ser His Pro Thr
Leu Ile
1 5 10 <210> SEQ ID NO 252 <211> LENGTH: 12 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
252 Gln Ser Tyr Asp Arg Gly Thr His Pro Ser Met Leu 1 5 10
<210> SEQ ID NO 253 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 253
Gln Ser Tyr Asp Arg Gly Thr Thr Pro Arg Pro Met 1 5 10 <210>
SEQ ID NO 254 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 254 Gln
Ser Tyr Asp Arg Gly Arg Leu Pro Ala Gln Thr 1 5 10 <210> SEQ
ID NO 255 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 255 Gln Ser Tyr Asp
Arg Gly Thr His Pro Leu Thr Ile 1 5 10 <210> SEQ ID NO 256
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 256 Gln Ser Tyr Asp Arg Gly Gln
Thr Pro Ser Ile Thr 1 5 10 <210> SEQ ID NO 257 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 257 Gln Ser Tyr Asp Arg Gly Thr His Phe Gln
Met Tyr 1 5 10 <210> SEQ ID NO 258 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 258 Gln Ser Tyr Asp Arg Gly Arg Asn Pro Ala
Leu Thr 1 5 10 <210> SEQ ID NO 259 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 259 Gln Ser Tyr Asp Arg Gly Thr His Pro Leu
Thr Met 1 5 10 <210> SEQ ID NO 260 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 260 Gln Ser Tyr Asp Arg Gly Thr His Pro Leu
Thr Met 1 5 10 <210> SEQ ID NO 261 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 261 Gln Ser Tyr Asp Ser Gly Tyr Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 262 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 262 Gln Ser Tyr Asp Ser Gly Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 263 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 263 Gln Ser Tyr Asp Ser Arg Phe Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 264 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 264 Gln Ser Tyr Pro Asp Gly Thr Pro Ala Ser
Arg Val 1 5 10 <210> SEQ ID NO 265 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 265 Gln Ser Tyr Ser Thr His Met Pro Ile Ser
Arg Val 1 5 10 <210> SEQ ID NO 266 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 266 Gln Ser Tyr Asp Ser Gly Ser Thr Gly Ser
Arg Val 1 5 10 <210> SEQ ID NO 267 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 267 Gln Ser Tyr Pro Asn Ser Tyr Pro Ile Ser
Arg Val 1 5 10 <210> SEQ ID NO 268 <211> LENGTH: 10
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 268 Gln Ser Tyr Ile Arg Ala Pro Gln Gln Val 1
5 10 <210> SEQ ID NO 269 <211> LENGTH: 12 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
269 Gln Ser Tyr Leu Lys Ser Arg Ala Phe Ser Arg Val 1 5 10
<210> SEQ ID NO 270 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 270
Gln Ser Tyr Asp Ser Arg Phe Thr Gly Ser Arg Val 1 5 10 <210>
SEQ ID NO 271 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 271 Gln
Ser Tyr Asp Arg Gly Phe Thr Gly Ser Met Val 1 5 10 <210> SEQ
ID NO 272 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 272 Gln Ser Tyr Asp
Arg Gly Phe Thr Gly Ser Met Val 1 5 10 <210> SEQ ID NO 273
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 273 Gln Ser Tyr Asp Arg Gly Phe
Thr Gly Phe Asp Gly 1 5 10 <210> SEQ ID NO 274 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 274
Gln Ser Tyr Asp Arg Gly Thr Ala Pro Ala Leu Ser 1 5 10 <210>
SEQ ID NO 275 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 275 Gln
Ser Tyr Asp Arg Gly Ser Tyr Pro Ala Leu Arg 1 5 10 <210> SEQ
ID NO 276 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 276 Gln Ser Tyr Asp
Arg Gly Asn Trp Pro Asn Ser Asn 1 5 10 <210> SEQ ID NO 277
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 277 Gln Ser Tyr Asp Arg Gly Thr
Ala Pro Ser Leu Leu 1 5 10 <210> SEQ ID NO 278 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 278 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Met Val 1 5 10 <210> SEQ ID NO 279 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 279 Gln Ser Tyr Asp Arg Gly Thr Thr Pro Arg
Ile Arg 1 5 10 <210> SEQ ID NO 280 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 280 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Met Val 1 5 10 <210> SEQ ID NO 281 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 281 Gln Ser Tyr Asp Arg Gly Phe Thr Gly Ser
Met Val 1 5 10 <210> SEQ ID NO 282 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 282 Gln Ser Tyr Asp Arg Gly Met Ile Pro Ala
Leu Thr 1 5 10 <210> SEQ ID NO 283 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 283 Gln Ser Tyr Asp Arg Asn Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 284 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 284 Gln Ser Tyr Asp Arg Phe Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 285 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 285 Gln Ser Tyr Asp Arg Tyr Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 286 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 286 Gln Ser Tyr Asp Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 287 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 287 Gln Ser Tyr Asp Arg Tyr Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 288 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 288 Phe Thr Phe Glu Ser Tyr Gly Met His 1 5
<210> SEQ ID NO 289 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 289
Phe Thr Phe Ser Ser Tyr Gly Met His 1 5 <210> SEQ ID NO 290
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 290 Phe Thr Phe Tyr Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 291 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 291 Phe Thr Phe His Ser Tyr Gly Met His 1 5
<210> SEQ ID NO 292 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 292
Phe Thr Phe Lys Ser Tyr Gly Met His 1 5 <210> SEQ ID NO 293
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 293 Phe Thr Phe Arg Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 294 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 294 Phe Thr Phe Asn Ser Tyr Gly Met His 1 5
<210> SEQ ID NO 295 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 295
Phe Thr Phe Thr Ser Tyr Gly Met His 1 5 <210> SEQ ID NO 296
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 296 Phe Thr Phe Gly Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 297 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 297 Phe Thr Phe Val Ser Tyr Gly Met His 1 5
<210> SEQ ID NO 298 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 298
Phe Thr Phe Ile Ser Tyr Gly Met His 1 5 <210> SEQ ID NO 299
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 299 Phe Thr Phe Trp Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 300 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 300 Phe Thr Phe Ser Glu Tyr Gly Met His 1 5
<210> SEQ ID NO 301 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 301
Phe Thr Phe Ser Cys Tyr Gly Met His 1 5 <210> SEQ ID NO 302
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 302 Phe Thr Phe Ser Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 303 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 303 Phe Thr Phe Ser Tyr Tyr Gly Met His 1 5
<210> SEQ ID NO 304 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 304
Phe Thr Phe Ser His Tyr Gly Met His 1 5 <210> SEQ ID NO 305
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 305 Phe Thr Phe Ser Arg Tyr Gly
Met His 1 5 <210> SEQ ID NO 306 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 306 Phe Thr Phe Ser Asn Tyr Gly Met His 1 5
<210> SEQ ID NO 307 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 307
Phe Thr Phe Ser Gln Tyr Gly Met His 1 5 <210> SEQ ID NO 308
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 308 Phe Thr Phe Ser Thr Tyr Gly
Met His 1 5 <210> SEQ ID NO 309 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 309 Phe Thr Phe Ser Ala Tyr Gly Met His 1 5
<210> SEQ ID NO 310 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 310
Phe Thr Phe Ser Ile Tyr Gly Met His 1 5 <210> SEQ ID NO 311
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 311 Phe Thr Phe Ser Ser Glu Gly
Met His 1 5 <210> SEQ ID NO 312 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 312 Phe Thr Phe Ser Ser Cys Gly Met His 1 5
<210> SEQ ID NO 313 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 313
Phe Thr Phe Ser Ser Ser Gly Met His 1 5 <210> SEQ ID NO 314
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 314 Phe Thr Phe Ser Ser Tyr Gly
Met His 1 5 <210> SEQ ID NO 315 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 315 Phe Thr Phe Ser Ser His Gly Met His 1 5
<210> SEQ ID NO 316 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 316
Phe Thr Phe Ser Ser Arg Gly Met His 1 5 <210> SEQ ID NO 317
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 317 Phe Thr Phe Ser Ser Asn Gly
Met His 1 5 <210> SEQ ID NO 318 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 318 Phe Thr Phe Ser Ser Thr Gly Met His 1 5
<210> SEQ ID NO 319 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 319
Phe Thr Phe Ser Ser Ala Gly Met His 1 5 <210> SEQ ID NO 320
<211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 320 Phe Thr Phe Ser Ser Val Gly Met His 1 5
<210> SEQ ID NO 321 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 321
Phe Thr Phe Ser Ser Leu Gly Met His 1 5 <210> SEQ ID NO 322
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 322 Phe Thr Phe Ser Ser Ile Gly
Met His 1 5 <210> SEQ ID NO 323 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 323 Phe Thr Phe Ser Ser Tyr Asp Met His 1 5
<210> SEQ ID NO 324 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 324
Phe Thr Phe Ser Ser Tyr Glu Met His 1 5 <210> SEQ ID NO 325
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 325 Phe Thr Phe Ser Ser Tyr Cys
Met His 1 5 <210> SEQ ID NO 326 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 326 Phe Thr Phe Ser Ser Tyr Ser Met His 1 5
<210> SEQ ID NO 327 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 327
Phe Thr Phe Ser Ser Tyr Tyr Met His 1 5 <210> SEQ ID NO 328
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 328 Phe Thr Phe Ser Ser Tyr Asn
Met His 1 5 <210> SEQ ID NO 329 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 329 Phe Thr Phe Ser Ser Tyr Gly Met His 1 5
<210> SEQ ID NO 330 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 330
Phe Thr Phe Ser Ser Tyr Ala Met His 1 5 <210> SEQ ID NO 331
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 331 Phe Thr Phe Ser Ser Tyr Val
Met His 1 5 <210> SEQ ID NO 332 <211> LENGTH: 9
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 332 Phe Thr Phe Ser Ser Tyr Met Met His 1 5
<210> SEQ ID NO 333 <211> LENGTH: 9 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 333
Phe Thr Phe Ser Ser Tyr Ile Met His 1 5 <210> SEQ ID NO 334
<211> LENGTH: 9 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 334 Phe Thr Phe Ser Ser Tyr Pro
Met His 1 5 <210> SEQ ID NO 335 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 335 Glu Ile Arg Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 336
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 336 Cys Ile Arg Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 337 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 337 Tyr Ile Arg Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 338 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 338
His Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 339 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 339 Lys Ile Arg Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 340
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 340 Asn Ile Arg Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 341 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 341 Gln Ile Arg Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15
Gly <210> SEQ ID NO 342 <211> LENGTH: 17 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
342 Thr Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys
1 5 10 15 Gly <210> SEQ ID NO 343 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 343 Leu Ile Arg Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 344
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 344 Phe Ile Arg Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 345 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 345 Phe Ile Glu Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 346 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 346
Phe Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 347 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 347 Phe Ile Tyr Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 348
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 348 Phe Ile His Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 349 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 349 Phe Ile Lys Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 350 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 350
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 351 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 351 Phe Ile Gln Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 352
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 352 Phe Ile Thr Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 353 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 353 Phe Ile Gly Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 354 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 354
Phe Ile Ala Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 355 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 355 Phe Ile Val Tyr Asp Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 356
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 356 Phe Ile Leu Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 357 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 357 Phe Ile Trp Tyr
Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 358 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 358
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 359 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 359 Phe Ile Arg Tyr Glu Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 360
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 360 Phe Ile Arg Tyr Ser Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 361
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 361 Phe Ile Arg Tyr Tyr Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 362 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 362 Phe Ile Arg Tyr
Lys Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 363 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 363
Phe Ile Arg Tyr Arg Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 364 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 364 Phe Ile Arg Tyr Asn Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 365
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 365 Phe Ile Arg Tyr Gln Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 366 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 366 Phe Ile Arg Tyr
Thr Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 367 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 367
Phe Ile Arg Tyr Ala Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 368 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 368 Phe Ile Arg Tyr Val Gly Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 369
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 369 Phe Ile Arg Tyr Leu Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 370 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 370 Phe Ile Arg Tyr
Ile Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 371 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 371
Phe Ile Arg Tyr Phe Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 372 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 372 Phe Ile Arg Tyr Asp Asp Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 373
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 373 Phe Ile Arg Tyr Asp Glu Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 374 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 374 Phe Ile Arg Tyr
Asp Ser Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 375 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 375
Phe Ile Arg Tyr Asp Tyr Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 376 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 376 Phe Ile Arg Tyr Asp Lys Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 377
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 377 Phe Ile Arg Tyr Asp Arg Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 378 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 378 Phe Ile Arg Tyr
Asp Asn Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 379 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 379
Phe Ile Arg Tyr Asp Gln Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 380 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 380 Phe Ile Arg Tyr Asp Thr Ser Asn Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 381
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 381 Phe Ile Arg Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 382 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 382 Phe Ile Arg Tyr
Asp Val Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 383 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 383
Phe Ile Arg Tyr Asp Phe Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 384 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 384 Phe Ile Arg Tyr Asp Gly Ser Ser Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 385
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 385 Phe Ile Arg Tyr Asp Gly Ser
Tyr Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 386 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 386 Phe Ile Arg Tyr
Asp Gly Ser His Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 387 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 387
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 388 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 388 Phe Ile Arg Tyr Asp Gly Ser Thr Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 389
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 389 Phe Ile Arg Tyr Asp Gly Ser
Gly Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 390 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 390 Phe Ile Arg Tyr
Asp Gly Ser Met Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 391 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 391
Phe Ile Arg Tyr Asp Gly Ser Leu Lys Tyr Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 392 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 392 Phe Ile Arg Tyr Asp Gly Ser Ile Lys Tyr
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 393
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 393 Phe Ile Arg Tyr Asp Gly Ser
Pro Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 394 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 394 Phe Ile Arg Tyr
Asp Gly Ser Phe Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 395 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 395
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Glu Tyr Ala Asp Ser Val Lys 1 5
10 15 Gly <210> SEQ ID NO 396 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 396 Phe Ile Arg Tyr Asp Gly Ser Asn Lys Ser
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 397
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 397 Phe Ile Arg Tyr Asp Gly Ser
Asn Lys Tyr Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 398 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 398 Phe Ile Arg Tyr
Asp Gly Ser Asn Lys Asn Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 399 <211> LENGTH: 17 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 399
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Val Tyr Ala Asp Ser Val Lys 1 5
10 15
Gly <210> SEQ ID NO 400 <211> LENGTH: 17 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
400 Phe Ile Arg Tyr Asp Gly Ser Asn Lys Leu Tyr Ala Asp Ser Val Lys
1 5 10 15 Gly <210> SEQ ID NO 401 <211> LENGTH: 17
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 401 Phe Ile Arg Tyr Asp Gly Ser Asn Lys Ile
Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ ID NO 402
<211> LENGTH: 17 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 402 Phe Ile Arg Tyr Asp Gly Ser
Asn Lys Pro Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly <210> SEQ
ID NO 403 <211> LENGTH: 17 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 403 Phe Ile Arg Tyr
Asp Gly Ser Asn Lys Phe Tyr Ala Asp Ser Val Lys 1 5 10 15 Gly
<210> SEQ ID NO 404 <211> LENGTH: 6 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 404
Glu Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 405 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 405 Ser Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 406 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 406 His
Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 407 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 407 Lys Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 408 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 408 Gln
Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 409 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 409 Thr Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 410 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 410 Ala
Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 411 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 411 Leu Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 412 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 412 Pro
Gly Ser His Asp Asn 1 5 <210> SEQ ID NO 413 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 413 Phe Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 414 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 414 His
Asp Ser His Asp Asn 1 5 <210> SEQ ID NO 415 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 415 His Cys Ser His Asp Asn 1 5 <210>
SEQ ID NO 416 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 416 His
His Ser His Asp Asn 1 5 <210> SEQ ID NO 417 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 417 His Arg Ser His Asp Asn 1 5 <210>
SEQ ID NO 418 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 418 His
Thr Ser His Asp Asn 1 5 <210> SEQ ID NO 419 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 419 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 420 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 420 His
Val Ser His Asp Asn 1 5 <210> SEQ ID NO 421 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 421 His Met Ser His Asp Asn
1 5 <210> SEQ ID NO 422 <211> LENGTH: 6 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
422 His Leu Ser His Asp Asn 1 5 <210> SEQ ID NO 423
<211> LENGTH: 6 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 423 His Ile Ser His Asp Asn 1 5
<210> SEQ ID NO 424 <211> LENGTH: 6 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 424
His Pro Ser His Asp Asn 1 5 <210> SEQ ID NO 425 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 425 His Trp Ser His Asp Asn 1 5 <210>
SEQ ID NO 426 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 426 His
Gly Asp His Asp Asn 1 5 <210> SEQ ID NO 427 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 427 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 428 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 428 His
Gly Tyr His Asp Asn 1 5 <210> SEQ ID NO 429 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 429 His Gly His His Asp Asn 1 5 <210>
SEQ ID NO 430 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 430 His
Gly Arg His Asp Asn 1 5 <210> SEQ ID NO 431 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 431 His Gly Asn His Asp Asn 1 5 <210>
SEQ ID NO 432 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 432 His
Gly Thr His Asp Asn 1 5 <210> SEQ ID NO 433 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 433 His Gly Gly His Asp Asn 1 5 <210>
SEQ ID NO 434 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 434 His
Gly Ala His Asp Asn 1 5 <210> SEQ ID NO 435 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 435 His Gly Ile His Asp Asn 1 5 <210>
SEQ ID NO 436 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 436 His
Gly Pro His Asp Asn 1 5 <210> SEQ ID NO 437 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 437 His Gly Trp His Asp Asn 1 5 <210>
SEQ ID NO 438 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 438 His
Gly Phe His Asp Asn 1 5 <210> SEQ ID NO 439 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 439 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 440 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 440 His
Gly Ser Arg Asp Asn 1 5 <210> SEQ ID NO 441 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 441 His Gly Ser Thr Asp Asn 1 5 <210>
SEQ ID NO 442 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 442 His
Gly Ser Ala Asp Asn 1 5 <210> SEQ ID NO 443 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 443 His Gly Ser Val Asp Asn 1 5 <210>
SEQ ID NO 444 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 444
His Gly Ser Leu Asp Asn 1 5 <210> SEQ ID NO 445 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 445 His Gly Ser Ile Asp Asn 1 5 <210>
SEQ ID NO 446 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 446 His
Gly Ser Phe Asp Asn 1 5 <210> SEQ ID NO 447 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 447 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 448 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 448 His
Gly Ser His Ser Asn 1 5 <210> SEQ ID NO 449 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 449 His Gly Ser His Tyr Asn 1 5 <210>
SEQ ID NO 450 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 450 His
Gly Ser His His Asn 1 5 <210> SEQ ID NO 451 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 451 His Gly Ser His Arg Asn 1 5 <210>
SEQ ID NO 452 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 452 His
Gly Ser His Asn Asn 1 5 <210> SEQ ID NO 453 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 453 His Gly Ser His Gly Asn 1 5 <210>
SEQ ID NO 454 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 454 His
Gly Ser His Ala Asn 1 5 <210> SEQ ID NO 455 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 455 His Gly Ser His Val Asn 1 5 <210>
SEQ ID NO 456 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 456 His
Gly Ser His Ile Asn 1 5 <210> SEQ ID NO 457 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 457 His Gly Ser His Asp Ser 1 5 <210>
SEQ ID NO 458 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 458 His
Gly Ser His Asp His 1 5 <210> SEQ ID NO 459 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 459 His Gly Ser His Asp Lys 1 5 <210>
SEQ ID NO 460 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 460 His
Gly Ser His Asp Arg 1 5 <210> SEQ ID NO 461 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 461 His Gly Ser His Asp Asn 1 5 <210>
SEQ ID NO 462 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 462 His
Gly Ser His Asp Thr 1 5 <210> SEQ ID NO 463 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 463 His Gly Ser His Asp Gly 1 5 <210>
SEQ ID NO 464 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 464 His
Gly Ser His Asp Ala 1 5 <210> SEQ ID NO 465 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 465 His Gly Ser His Asp Leu 1 5 <210>
SEQ ID NO 466 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 466 His
Gly Ser His Asp Ile 1 5 <210> SEQ ID NO 467 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens
<400> SEQUENCE: 467 His Gly Ser His Asp Pro 1 5 <210>
SEQ ID NO 468 <211> LENGTH: 6 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 468 His
Gly Ser His Asp Trp 1 5 <210> SEQ ID NO 469 <211>
LENGTH: 6 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 469 His Gly Ser His Asp Phe 1 5 <210>
SEQ ID NO 470 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 470 Ser
Gly Gly Arg Ser Asn Ile Gly Asp Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 471 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 471 Ser
Gly Gly Arg Ser Asn Ile Gly Cys Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 472 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 472 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 473 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 473 Ser
Gly Gly Arg Ser Asn Ile Gly Tyr Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 474 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 474 Ser
Gly Gly Arg Ser Asn Ile Gly Lys Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 475 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 475 Ser
Gly Gly Arg Ser Asn Ile Gly Arg Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 476 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 476 Ser
Gly Gly Arg Ser Asn Ile Gly Asn Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 477 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 477 Ser
Gly Gly Arg Ser Asn Ile Gly Thr Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 478 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 478 Ser
Gly Gly Arg Ser Asn Ile Gly Pro Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 479 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 479 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asp Thr Val Lys 1 5 10 <210>
SEQ ID NO 480 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 480 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Glu Thr Val Lys 1 5 10 <210>
SEQ ID NO 481 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 481 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Ser Thr Val Lys 1 5 10 <210>
SEQ ID NO 482 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 482 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Tyr Thr Val Lys 1 5 10 <210>
SEQ ID NO 483 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 483 Ser
Gly Gly Arg Ser Asn Ile Gly Ser His Thr Val Lys 1 5 10 <210>
SEQ ID NO 484 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 484 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Lys Thr Val Lys 1 5 10 <210>
SEQ ID NO 485 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 485 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Asn Thr Val Lys 1 5 10 <210>
SEQ ID NO 486 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 486 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Gln Thr Val Lys 1 5 10 <210>
SEQ ID NO 487 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 487 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Thr Thr Val Lys 1 5 10 <210>
SEQ ID NO 488 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 488 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Gly Thr Val Lys 1 5 10 <210>
SEQ ID NO 489 <211> LENGTH: 13 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 489 Ser
Gly Gly Arg Ser Asn Ile Gly Ser Met Thr Val Lys 1 5 10 <210>
SEQ ID NO 490 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 490 Ser Gly Gly Arg Ser Asn Ile Gly Ser Ile
Thr Val Lys 1 5 10 <210> SEQ ID NO 491 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 491 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Asp Val Lys 1 5 10 <210> SEQ ID NO 492 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 492 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Cys Val Lys 1 5 10 <210> SEQ ID NO 493 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 493 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Ser Val Lys 1 5 10 <210> SEQ ID NO 494 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 494 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Tyr Val Lys 1 5 10 <210> SEQ ID NO 495 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 495 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
His Val Lys 1 5 10 <210> SEQ ID NO 496 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 496 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Lys Val Lys 1 5 10 <210> SEQ ID NO 497 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 497 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Arg Val Lys 1 5 10 <210> SEQ ID NO 498 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 498 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Asn Val Lys 1 5 10 <210> SEQ ID NO 499 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 499 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Gln Val Lys 1 5 10 <210> SEQ ID NO 500 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 500 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Thr Val Lys 1 5 10 <210> SEQ ID NO 501 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 501 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Ala Val Lys 1 5 10 <210> SEQ ID NO 502 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 502 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Val Val Lys 1 5 10 <210> SEQ ID NO 503 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 503 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Leu Val Lys 1 5 10 <210> SEQ ID NO 504 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 504 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Ile Val Lys 1 5 10 <210> SEQ ID NO 505 <211> LENGTH: 13
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 505 Ser Gly Gly Arg Ser Asn Ile Gly Ser Asn
Pro Val Lys 1 5 10 <210> SEQ ID NO 506 <211> LENGTH: 7
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 506 Asp Asn Asp Gln Arg Pro Ser 1 5
<210> SEQ ID NO 507 <211> LENGTH: 7 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 507
Glu Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 508
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 508 Cys Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 509 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
509 Ser Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 510
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 510 Tyr Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 511 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
511 His Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 512
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 512 Lys Asn Asp Gln Arg Pro Ser
1 5
<210> SEQ ID NO 513 <211> LENGTH: 7 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 513
Arg Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 514
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 514 Asn Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 515 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
515 Gln Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 516
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 516 Thr Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 517 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
517 Gly Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 518
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 518 Ala Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 519 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
519 Val Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 520
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 520 Met Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 521 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
521 Leu Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 522
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 522 Ile Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 523 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
523 Pro Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 524
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 524 Trp Asn Asp Gln Arg Pro Ser
1 5 <210> SEQ ID NO 525 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
525 Phe Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 526
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 526 Gly Asn Asp Ser Arg Pro Ser
1 5 <210> SEQ ID NO 527 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
527 Gly Asn Asp Tyr Arg Pro Ser 1 5 <210> SEQ ID NO 528
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 528 Gly Asn Asp Arg Arg Pro Ser
1 5 <210> SEQ ID NO 529 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
529 Gly Asn Asp Gln Arg Pro Ser 1 5 <210> SEQ ID NO 530
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 530 Gly Asn Asp Thr Arg Pro Ser
1 5 <210> SEQ ID NO 531 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
531 Gly Asn Asp Ala Arg Pro Ser 1 5 <210> SEQ ID NO 532
<211> LENGTH: 7 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 532 Gly Asn Asp Ile Arg Pro Ser
1 5 <210> SEQ ID NO 533 <211> LENGTH: 7 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
533 Gly Asn Asp Pro Arg Pro Ser 1 5 <210> SEQ ID NO 534
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 534 Gln Ser Tyr Asp Arg Gly Thr
His Pro Ala Leu Leu 1 5 10 <210> SEQ ID NO 535 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 535 Gln Ser Tyr Cys Arg Gly Thr His Pro Ala
Leu Leu 1 5 10
<210> SEQ ID NO 536 <211> LENGTH: 12 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 536
Gln Ser Tyr Ser Arg Gly Thr His Pro Ala Leu Leu 1 5 10 <210>
SEQ ID NO 537 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 537 Gln
Ser Tyr Tyr Arg Gly Thr His Pro Ala Leu Leu 1 5 10 <210> SEQ
ID NO 538 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 538 Gln Ser Tyr Asn
Arg Gly Thr His Pro Ala Leu Leu 1 5 10 <210> SEQ ID NO 539
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 539 Gln Ser Tyr Gln Arg Gly Thr
His Pro Ala Leu Leu 1 5 10 <210> SEQ ID NO 540 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 540 Gln Ser Tyr Thr Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 541 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 541 Gln Ser Tyr Gly Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 542 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 542 Gln Ser Tyr Ala Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 543 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 543 Gln Ser Tyr Leu Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 544 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 544 Gln Ser Tyr Ile Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 545 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 545 Gln Ser Tyr Trp Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 546 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 546 Gln Ser Tyr Phe Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 547 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 547 Gln Ser Tyr Asp Asp Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 548 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 548 Gln Ser Tyr Asp Cys Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 549 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 549 Gln Ser Tyr Asp Ser Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 550 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 550 Gln Ser Tyr Asp Tyr Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 551 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 551 Gln Ser Tyr Asp Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 552 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 552 Gln Ser Tyr Asp Asn Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 553 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 553 Gln Ser Tyr Asp Gln Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 554 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 554 Gln Ser Tyr Asp Thr Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 555 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 555 Gln Ser Tyr Asp Gly Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 556 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 556 Gln Ser Tyr Asp Ala Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 557 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 557 Gln Ser Tyr Asp Val Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 558 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 558
Gln Ser Tyr Asp Met Gly Thr His Pro Ala Leu Leu 1 5 10 <210>
SEQ ID NO 559 <211> LENGTH: 12 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 559 Gln
Ser Tyr Asp Leu Gly Thr His Pro Ala Leu Leu 1 5 10 <210> SEQ
ID NO 560 <211> LENGTH: 12 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 560 Gln Ser Tyr Asp
Ile Gly Thr His Pro Ala Leu Leu 1 5 10 <210> SEQ ID NO 561
<211> LENGTH: 12 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 561 Gln Ser Tyr Asp Pro Gly Thr
His Pro Ala Leu Leu 1 5 10 <210> SEQ ID NO 562 <211>
LENGTH: 12 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 562 Gln Ser Tyr Asp Trp Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 563 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 563 Gln Ser Tyr Asp Arg Asp Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 564 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 564 Gln Ser Tyr Asp Arg Cys Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 565 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 565 Gln Ser Tyr Asp Arg Ser Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 566 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 566 Gln Ser Tyr Asp Arg Tyr Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 567 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 567 Gln Ser Tyr Asp Arg His Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 568 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 568 Gln Ser Tyr Asp Arg Arg Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 569 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 569 Gln Ser Tyr Asp Arg Asn Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 570 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 570 Gln Ser Tyr Asp Arg Gln Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 571 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 571 Gln Ser Tyr Asp Arg Thr Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 572 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 572 Gln Ser Tyr Asp Arg Gly Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 573 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 573 Gln Ser Tyr Asp Arg Ala Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 574 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 574 Gln Ser Tyr Asp Arg Val Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 575 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 575 Gln Ser Tyr Asp Arg Leu Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 576 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 576 Gln Ser Tyr Asp Arg Ile Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 577 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 577 Gln Ser Tyr Asp Arg Pro Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 578 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 578 Gln Ser Tyr Asp Arg Trp Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 579 <211> LENGTH: 12
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 579 Gln Ser Tyr Asp Arg Phe Thr His Pro Ala
Leu Leu 1 5 10 <210> SEQ ID NO 580 <400> SEQUENCE: 580
000 <210> SEQ ID NO 581 <400> SEQUENCE: 581 000
<210> SEQ ID NO 582
<400> SEQUENCE: 582 000 <210> SEQ ID NO 583 <400>
SEQUENCE: 583 000 <210> SEQ ID NO 584 <400> SEQUENCE:
584 000 <210> SEQ ID NO 585 <400> SEQUENCE: 585 000
<210> SEQ ID NO 586 <400> SEQUENCE: 586 000 <210>
SEQ ID NO 587 <400> SEQUENCE: 587 000 <210> SEQ ID NO
588 <400> SEQUENCE: 588 000 <210> SEQ ID NO 589
<400> SEQUENCE: 589 000 <210> SEQ ID NO 590 <400>
SEQUENCE: 590 000 <210> SEQ ID NO 591 <400> SEQUENCE:
591 000 <210> SEQ ID NO 592 <400> SEQUENCE: 592 000
<210> SEQ ID NO 593 <400> SEQUENCE: 593 000 <210>
SEQ ID NO 594 <211> LENGTH: 100 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 594 Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp His
20 25 30 Tyr Met Asp Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Gly Arg Thr Arg Asn Lys Ala Asn Ser Tyr Thr Thr
Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
Asp Asp Ser Lys Asn Ser 65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu
Lys Thr Glu Asp Thr Ala Val Tyr 85 90 95 Tyr Cys Ala Arg 100
<210> SEQ ID NO 595 <211> LENGTH: 100 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 595
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
His 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Gln Gly Lys Gly Leu
Glu Leu Val 35 40 45 Gly Leu Ile Arg Asn Lys Ala Asn Ser Tyr Thr
Thr Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Leu Thr Ile Ser
Arg Glu Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Ser Ser
Leu Lys Thr Glu Asp Leu Ala Val Tyr 85 90 95 Tyr Cys Ala Arg 100
<210> SEQ ID NO 596 <211> LENGTH: 100 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 596
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
His 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Gln Gly Lys Gly Leu
Glu Leu Val 35 40 45 Gly Leu Ile Arg Asn Lys Ala Asn Ser Tyr Thr
Thr Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Leu Thr Ile Ser
Arg Glu Asp Ser Lys Asn Thr 65 70 75 80 Met Tyr Leu Gln Met Ser Asn
Leu Lys Thr Glu Asp Leu Ala Val Tyr 85 90 95 Tyr Cys Ala Arg 100
<210> SEQ ID NO 597 <211> LENGTH: 100 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 597
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
His 20 25 30 Tyr Met Ser Trp Val Arg Gln Ala Gln Gly Lys Gly Leu
Glu Leu Val 35 40 45 Gly Leu Ile Arg Asn Lys Ala Asn Ser Tyr Thr
Thr Glu Tyr Ala Ala 50 55 60 Ser Val Lys Gly Arg Leu Thr Ile Ser
Arg Glu Asp Ser Lys Asn Thr 65 70 75 80 Leu Tyr Leu Gln Met Ser Ser
Leu Lys Thr Glu Asp Leu Ala Val Tyr 85 90 95 Tyr Cys Ala Arg 100
<210> SEQ ID NO 598 <211> LENGTH: 98 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 598
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Arg 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp
Tyr 20 25 30 Ala Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Gly Ile Ser Trp Asn Ser Gly Ser Ile Gly
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Leu Tyr Tyr Cys 85 90 95 Ala Lys <210>
SEQ ID NO 599 <211> LENGTH: 98 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 599 Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Arg Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Asp Asp Tyr
20 25 30 Gly Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu
Trp Val 35 40 45 Ser Gly Ile Asn Trp Asn Gly Gly Ser Thr Gly Tyr
Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn
Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Thr Ala Leu Tyr His Cys 85 90 95
Ala Arg <210> SEQ ID NO 600 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 600 Glu Val Gln Leu Val Glu Ser Gly Gly Val
Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Asp Asp Tyr 20 25 30 Thr Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Leu Ile Ser
Trp Asp Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Thr Glu Asp Thr Ala Leu Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 601 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 601 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser
Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 602 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 602 Gln Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp Ile Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser
Ser Ser Ser Ser Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 603 <211> LENGTH: 100
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 603 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Lys Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Gly Ser 20 25 30 Ala Met His Trp Val Arg
Gln Ala Ser Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg Ile Arg
Ser Lys Ala Asn Ser Tyr Ala Thr Ala Tyr Ala Ala 50 55 60 Ser Val
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65 70 75 80
Ala Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala Val Tyr 85
90 95 Tyr Cys Thr Arg 100 <210> SEQ ID NO 604 <211>
LENGTH: 100 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 604 Glu Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly Arg
Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55 60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65
70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 605
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 605 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly
Arg Ile Glu Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55
60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 606
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 606 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly
Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55
60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 607
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 607 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly
Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asn Tyr Ala Ala 50 55
60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 608
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 608 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Asn
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly
Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55
60
Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr 65
70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 609
<211> LENGTH: 100 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 609 Glu Val Gln Leu Val Glu Ser
Gly Gly Ala Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asn Ala 20 25 30 Trp Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Gly
Arg Ile Lys Ser Lys Thr Asp Gly Gly Thr Thr Asp Tyr Ala Ala 50 55
60 Pro Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asp Ser Lys Asn Thr
65 70 75 80 Leu Tyr Leu Gln Met Asn Ser Leu Lys Thr Glu Asp Thr Ala
Val Tyr 85 90 95 Tyr Cys Thr Thr 100 <210> SEQ ID NO 610
<211> LENGTH: 98 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 610 Glu Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Pro Ala Ser Gly Phe Thr Phe Ser Asn His 20 25 30 Tyr Met Ser
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Tyr Ile Ser Gly Asp Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Asn Asn Ser Pro Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Val Lys <210> SEQ ID NO 611 <211>
LENGTH: 98 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 611 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asn His 20 25 30 Tyr Thr Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ser Ser
Gly Asn Ser Gly Tyr Thr Asn Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Val Lys <210> SEQ ID NO 612 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 612 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asn Ser 20 25 30 Asp Met Asn Trp Val His
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Val Ser
Trp Asn Gly Ser Arg Thr His Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Ile Ile Ser Arg Asp Asn Ser Arg Asn Thr Leu Tyr 65 70 75 80
Leu Gln Thr Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Val Arg <210> SEQ ID NO 613 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 613 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asn Ser 20 25 30 Asp Met Asn Trp Ala Arg
Lys Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Val Ser
Trp Asn Gly Ser Arg Thr His Tyr Val Asp Ser Val 50 55 60 Lys Arg
Arg Phe Ile Ile Ser Arg Asp Asn Ser Arg Asn Ser Leu Tyr 65 70 75 80
Leu Gln Lys Asn Arg Arg Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85
90 95 Val Arg <210> SEQ ID NO 614 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 614 Thr Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Glu Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asn Ser 20 25 30 Asp Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Gly Val Ser
Trp Asn Gly Ser Arg Thr His Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Ile Ile Ser Arg Asp Asn Ser Arg Asn Phe Leu Tyr 65 70 75 80
Gln Gln Met Asn Ser Leu Arg Pro Glu Asp Met Ala Val Tyr Tyr Cys 85
90 95 Val Arg <210> SEQ ID NO 615 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 615 Glu Val His Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ala Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Asn Tyr 20 25 30 Asp Met His Trp Val Arg
Gln Ala Thr Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Asn Gly
Thr Ala Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 616 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 616 Glu Val Gln Leu Val Glu Thr Gly Gly Gly
Leu Ile Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Val Ser Ser Asn 20 25 30 Tyr Met Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Val Ile Tyr
Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 617 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 617 Glu Val Gln Leu Val Gln Ser Gly Gly Gly
Leu Val His Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45
Ser Ala Ile Gly Thr Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val Lys 50
55 60 Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
Leu 65 70 75 80 Gln Met Asn Ser Leu Arg Ala Glu Asp Met Ala Val Tyr
Tyr Cys Ala 85 90 95 Arg <210> SEQ ID NO 618 <211>
LENGTH: 97 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 618 Glu Val Gln Leu Val Gln Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Gly
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly
Thr Gly Gly Gly Thr Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 619 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 619 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser
Gly Ser Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 620 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 620 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Ala Ile Ser
Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Val Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Val Lys <210> SEQ ID NO 621 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 621 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Ala Ile Ser
Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Val Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Val Lys <210> SEQ ID NO 622 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 622 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Ala Ile Ser
Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asn Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Gly Ser Leu Arg Ala Glu Asp Met Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 623 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 623 Glu Val Gln Leu Leu Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met Ser Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Ser
Gly Ser Gly Gly Ser Thr Tyr Tyr Gly Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 624 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 624 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Thr Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 625 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 625 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 626 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 626 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75
80
Leu Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 627 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 627 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 628 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 628 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 629 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 629 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 630 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 630 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 631 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 631 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 632 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 632 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 633 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 633 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Ala Ile Ser
Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Val Gln Met Ser Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Val Lys <210> SEQ ID NO 634 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 634 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ser Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Tyr Val 35 40 45 Ser Ala Ile Ser
Ser Asn Gly Gly Ser Thr Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 635 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 635 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Ala Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 636 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 636 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 637 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 637 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ala Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 638 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 638 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Asp Met His Trp Val Arg
Gln Ala Thr Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ala Ile Gly
Thr Ala Gly Asp Thr Tyr Tyr Pro Gly Ser Val Lys 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Glu Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Arg Ala Gly Asp Thr Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 639 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 639 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Glu Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser
Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 640 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 640 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Leu Arg Ala Arg Leu Cys Ile Thr Val 85
90 95 Arg Glu <210> SEQ ID NO 641 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 641 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 642 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 642 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 643 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 643 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 644 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 644 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 645 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 645 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20
25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp
Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
Lys Asn Arg Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg <210> SEQ ID NO
646 <211> LENGTH: 98 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 646 Gln Val Gln Leu
Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser
Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn
Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
Ala Val Tyr Tyr Cys 85 90 95 Ala Arg <210> SEQ ID NO 647
<211> LENGTH: 98 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 647 Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg <210> SEQ ID NO 648 <211>
LENGTH: 98 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 648 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Gly Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 649 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 649 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Phe Ile Arg
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 650 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 650 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 651 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 651 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 652 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 652 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Lys <210> SEQ ID NO 653 <211> LENGTH: 95
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 653 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Ser
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Arg Lys 85 90
95 <210> SEQ ID NO 654 <211> LENGTH: 98 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
654 Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln Pro Gly Arg
1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser
Ser Tyr 20 25 30 Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly
Leu Glu Trp Val 35 40 45 Ala Val Ile Ser Tyr Asp Gly Ser Asn Lys
Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr 65
70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg <210> SEQ ID NO 655 <211>
LENGTH: 98 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 655 Gln Val Gln Leu Val Glu Ser Gly Gly Gly
Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Val Ile Trp
Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Ala 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ser Thr Asn Thr Leu Phe 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 656 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 656 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser
Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 657 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 657 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser
Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 658 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 658 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser
Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val Lys 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 659 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 659 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Ser Ile Ser
Ser Ser Ser Ser Tyr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 660 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 660 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr Ile Ser
Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 661 <211> LENGTH: 97
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 661 Glu Asp Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Pro Ser Cys Ala Ala
Ser Gly Phe Ala Phe Ser Ser Tyr 20 25 30 Val Leu His Trp Val Arg
Arg Ala Pro Gly Lys Gly Pro Glu Trp Val 35 40 45 Ser Ala Ile Gly
Thr Gly Gly Asp Thr Tyr Tyr Ala Asp Ser Val Met 50 55 60 Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ala Lys Lys Ser Leu Tyr Leu 65 70 75 80
Gln Met Asn Ser Leu Ile Ala Glu Asp Met Ala Val Tyr Tyr Cys Ala 85
90 95 Arg <210> SEQ ID NO 662 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 662 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Val Trp Val 35 40 45 Ser Arg Ile Asn
Ser Asp Gly Ser Ser Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg <210> SEQ ID NO 663 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 663 Glu Val Gln Leu Val Glu Ser Gly Gly Gly
Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys Ala Ala
Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met His Trp Val Arg
Gln Ala Pro Gly Lys Gly Leu Val Trp Val 35 40 45 Ser Arg Ile Asn
Ser Asp Gly Ser Ser Thr Ser Tyr Ala Asp Ser Val 50 55 60 Lys Gly
Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Thr Leu Tyr 65 70 75 80
Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85
90 95 Ala Arg
<210> SEQ ID NO 664 <211> LENGTH: 98 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 664
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr
Tyr Val Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg <210>
SEQ ID NO 665 <211> LENGTH: 98 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 665 Glu
Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10
15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr
20 25 30 Trp Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Val
Trp Val 35 40 45 Ser Arg Ile Asn Ser Asp Gly Ser Ser Thr Ser Tyr
Ala Asp Ser Met 50 55 60 Lys Gly Gln Phe Thr Ile Ser Arg Asp Asn
Ala Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala
Glu Asp Met Ala Val Tyr Tyr Cys 85 90 95 Thr Arg <210> SEQ ID
NO 666 <211> LENGTH: 98 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 666 Glu Val Gln Leu
Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu
Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30
Trp Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35
40 45 Ala Asn Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser
Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn
Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr
Ala Val Tyr Tyr Cys 85 90 95 Ala Arg <210> SEQ ID NO 667
<211> LENGTH: 98 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 667 Gln Val Gln Leu Val Gln Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Phe Ile Arg Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Lys Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Thr Thr <210> SEQ ID NO 668 <211>
LENGTH: 98 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 668 Gln Ser Val Leu Thr Gln Pro Pro Ser Val
Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly
Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Tyr Val Ser Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Asp Asn
Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Gln 65 70 75 80
Thr Gly Asp Glu Ala Asp Tyr Tyr Cys Gly Thr Trp Asp Ser Ser Leu 85
90 95 Ser Ala <210> SEQ ID NO 669 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 669 Gln Ser Val Leu Thr Gln Pro Pro Ser Val
Ser Ala Ala Pro Gly Gln 1 5 10 15 Lys Val Thr Ile Ser Cys Ser Gly
Ser Ser Ser Asp Met Gly Asn Tyr 20 25 30 Ala Val Ser Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Glu Asn
Asn Lys Arg Pro Ser Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Thr Leu Gly Ile Thr Gly Leu Trp 65 70 75 80
Pro Glu Asp Glu Ala Asp Tyr Tyr Cys Leu Ala Trp Asp Thr Ser Pro 85
90 95 Arg Ala <210> SEQ ID NO 670 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 670 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala
Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly
Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Thr Val Asn Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Ser Asn
Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85
90 95 Asn Gly <210> SEQ ID NO 671 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 671 Gln Ser Val Leu Thr Gln Pro Pro Ser Ala
Ser Gly Thr Pro Gly Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly
Ser Ser Ser Asn Ile Gly Ser Asn 20 25 30 Tyr Val Tyr Trp Tyr Gln
Gln Leu Pro Gly Thr Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Arg Asn
Asn Gln Arg Pro Ser Gly Val Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Arg 65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85
90 95 Ser Gly <210> SEQ ID NO 672 <211> LENGTH: 98
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 672 Gln Ser Val Leu Thr Gln Pro Pro Ser Val
Ser Glu Ala Pro Arg Gln 1 5 10 15 Arg Val Thr Ile Ser Cys Ser Gly
Ser Ser Ser Asn Ile Gly Asn Asn 20 25 30 Ala Val Asn Trp Tyr Gln
Gln Leu Pro Gly Lys Ala Pro Lys Leu Leu 35 40 45 Ile Tyr Tyr Asp
Asp Leu Leu Pro Ser Gly Val Ser Asp Arg Phe Ser 50 55 60 Gly Ser
Lys Ser Gly Thr Ser Ala Ser Leu Ala Ile Ser Gly Leu Gln 65 70 75 80
Ser Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ala Trp Asp Asp Ser Leu 85
90 95 Asn Gly <210> SEQ ID NO 673 <211> LENGTH: 99
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 673 Gln Ser Val Leu Thr Gln Pro Pro Ser Val
Ser Gly Ala Pro Gly Gln
1 5 10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly
Ala Gly 20 25 30 Tyr Val Val His Trp Tyr Gln Gln Leu Pro Gly Thr
Ala Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser
Gly Val Pro Asp Gln Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser
Ala Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ser Glu Asp Glu Ala
Asp Tyr Tyr Cys Lys Ala Trp Asp Asn Ser 85 90 95 Leu Asn Ala
<210> SEQ ID NO 674 <211> LENGTH: 99 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 674
Gln Ser Val Val Thr Gln Pro Pro Ser Val Ser Gly Ala Pro Gly Gln 1 5
10 15 Arg Val Thr Ile Ser Cys Thr Gly Ser Ser Ser Asn Ile Gly Ala
Gly 20 25 30 Tyr Asp Val His Trp Tyr Gln Gln Leu Pro Gly Thr Ala
Pro Lys Leu 35 40 45 Leu Ile Tyr Gly Asn Ser Asn Arg Pro Ser Gly
Val Pro Asp Arg Phe 50 55 60 Ser Gly Ser Lys Ser Gly Thr Ser Ala
Ser Leu Ala Ile Thr Gly Leu 65 70 75 80 Gln Ala Glu Asp Glu Ala Asp
Tyr Tyr Cys Gln Ser Tyr Asp Ser Ser 85 90 95 Leu Ser Gly
<210> SEQ ID NO 675 <211> LENGTH: 98 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 675
Ser Tyr Val Leu Thr Gln Pro Pro Ser Val Ser Gly Thr Pro Gly Gln 1 5
10 15 Arg Val Thr Ile Ser Cys Ser Gly Gly Arg Ser Asn Ile Gly Ser
Asn 20 25 30 Thr Val Lys Trp Tyr Gln Gln Leu Pro Gly Thr Ala Pro
Lys Leu Leu 35 40 45 Ile Tyr Gly Asn Asp Gln Arg Pro Ser Gly Val
Pro Asp Arg Phe Ser 50 55 60 Gly Ser Lys Ser Gly Thr Ser Ala Ser
Leu Ala Ile Thr Gly Val Gln 65 70 75 80 Ala Glu Asp Glu Ala Asp Tyr
Tyr Cys Gln Ser Tyr Asp Ser Ser Leu 85 90 95 Arg Gly
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