U.S. patent application number 15/144429 was filed with the patent office on 2016-10-13 for methods for treating or preventing ophthalmological conditions.
The applicant listed for this patent is Ophthotech Corporation. Invention is credited to Douglas Brooks, Richard Everett, Samir Patel, Shane Xinxin Tian.
Application Number | 20160296550 15/144429 |
Document ID | / |
Family ID | 52277261 |
Filed Date | 2016-10-13 |
United States Patent
Application |
20160296550 |
Kind Code |
A1 |
Patel; Samir ; et
al. |
October 13, 2016 |
Methods for Treating or Preventing Ophthalmological Conditions
Abstract
The present invention relates to methods for treating and
preventing ophthalmological disease and disorders, comprising
administering Antagonist A or another pharmaceutically acceptable
salt thereof, optionally in combination with another treatment, to
a subject in need thereof. The present invention also relates to
methods for treating and preventing ophthalmological disease and
disorders, comprising administering an anti-C5 agent (e.g.,
ARC1905), optionally in combination with another treatment, to a
subject in need thereof.
Inventors: |
Patel; Samir; (Princeton,
NJ) ; Everett; Richard; (Randolph, NJ) ;
Brooks; Douglas; (Durham, NC) ; Tian; Shane
Xinxin; (Oakland, NJ) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Ophthotech Corporation |
New York |
NY |
US |
|
|
Family ID: |
52277261 |
Appl. No.: |
15/144429 |
Filed: |
May 2, 2016 |
Related U.S. Patent Documents
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Application
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Patent Number |
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14329702 |
Jul 11, 2014 |
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15144429 |
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61845936 |
Jul 12, 2013 |
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61845935 |
Jul 12, 2013 |
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61866502 |
Aug 15, 2013 |
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61866503 |
Aug 15, 2013 |
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61866507 |
Aug 15, 2013 |
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61911854 |
Dec 4, 2013 |
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61911860 |
Dec 4, 2013 |
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61911894 |
Dec 4, 2013 |
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61926848 |
Jan 13, 2014 |
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61926812 |
Jan 13, 2014 |
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61926825 |
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61931135 |
Jan 24, 2014 |
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61931116 |
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61931125 |
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61845938 |
Jul 12, 2013 |
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Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 27/02 20180101;
A61P 25/00 20180101; A61K 45/06 20130101; C12N 15/115 20130101;
A61K 31/7088 20130101; C12N 2310/351 20130101; A61P 9/10 20180101;
A61P 43/00 20180101; C12N 2310/16 20130101; A61K 9/0048 20130101;
C07K 2317/24 20130101; A61P 35/00 20180101; A61K 9/143 20130101;
A61P 9/00 20180101; A61K 39/3955 20130101; C07K 2317/76 20130101;
C12N 2310/314 20130101; C07K 16/22 20130101; C12N 2310/322
20130101; C12N 2320/31 20130101; C12N 2320/30 20130101; A61K 31/713
20130101; C12N 2310/321 20130101; C12N 2310/317 20130101; C07K
2317/55 20130101; A61K 39/3955 20130101; A61K 2300/00 20130101;
C12N 2310/322 20130101; C12N 2310/3533 20130101; C12N 2310/321
20130101; C12N 2310/3521 20130101; A61K 31/713 20130101; A61K
2300/00 20130101 |
International
Class: |
A61K 31/7088 20060101
A61K031/7088; A61K 9/00 20060101 A61K009/00; C12N 15/115 20060101
C12N015/115; A61K 9/14 20060101 A61K009/14; C07K 16/22 20060101
C07K016/22; A61K 39/395 20060101 A61K039/395; A61K 45/06 20060101
A61K045/06 |
Claims
1. A method for treating or preventing wet age-related macular
degeneration (wet AMD), comprising administering to a subject in
need thereof (a) Antagonist A or another pharmaceutically
acceptable salt thereof and (b) an VEGF antagonist, wherein (a) and
(b) are administered in an amount that is effective for treating or
preventing wet AMD, and wherein the administering occurs once every
month, .+-.about seven days, for a first administration period of
at least 3 consecutive months, followed by administering (a) and
(b) for a second administration period at a frequency of at least
every other month .+-.about seven days beginning at two months
.+-.about seven days after the day of the last month of the first
administration period on which (a) and (b) are administered.
2. The method of claim 1, wherein (a) and (b) are administered
within about 60 minutes of each other.
3. The method of claim 1, wherein the VEGF antagonist is
ranibizumab, bevacizumab, pegaptanib sodium, ESBA 1008 or
aflibercept.
4. The method of claim 1, wherein the VEGF antagonist is
ranibizumab or bevacizumab, wherein (a) and (b) are administered at
a frequency of once every month .+-.about seven days during the
second administration period and wherein the second administration
period is at least about nine months.
5. The method of claim 4, further comprising measuring the
subject's visual acuity.
6. The method of claim 5, further comprising administering to the
subject (a) and (b) in an amount that is effective for treating or
preventing wet AMD, until the subject's visual acuity on the last
two of any three consecutive months is .ltoreq.a five-ETDRS-letter
difference from the subject's visual acuity on the first of the
three consecutive months.
7. The method of claim 5, further comprising administering to the
subject (a) and (b) every other month in an amount that is
effective for treating or preventing wet AMD, wherein the subject's
visual acuity on the last two of any three consecutive months is
.ltoreq.a five-ETDRS-letter difference from the subject's visual
acuity on the first of the three consecutive months.
8. The method of claim 7, further comprising administering to the
subject (a) and (b) every month in an amount that is effective for
treating or preventing wet AMD, until the subject's visual acuity
on the last two of any three consecutive months is .ltoreq.a
five-ETDRS-letter difference from the subject's visual acuity on
the first of the three consecutive months.
9. The method of claim 1, wherein the VEGF antagonist is
aflibercept.
10. The method of claim 1, wherein the total number of months does
not exceed 24.
11. The method of claim 4, wherein the subject has intraretinal or
sub-retinal hemorrhage or a .gtoreq.50 .mu.m increase in foveal
intraretinal fluid at one month, .+-.about seven days, immediately
following the second administration period.
12. The method of claim 11, further comprising: administering to
the subject on each month .+-.about seven days, beginning on the
month that immediately follows the second administration period (a)
and (b) in an amount that is effective for treating or preventing
wet AMD, until the subject's visual acuity on the last two of any
three consecutive months that follow the 12 consecutive months is
.ltoreq.a five-ETDRS-letter difference from the subject's visual
acuity on the first of the three consecutive months.
13. The method of claim 12, wherein the total number of months does
not exceed 24.
14. The method of claim 1, wherein Antagonist A or another
pharmaceutically acceptable salt thereof is administered
intravitreally in an amount of about 1.5 mg/eye.
15. The method of claim 4, wherein the VEGF antagonist is
bevacizumab and is administered intravitreally in an amount of
about 1.25 mg/eye.
16. The method of claim 9, wherein the VEGF antagonist is
administered intravitreally in an amount of about 2 mg/eye.
17. The method of claim 4, wherein the VEGF antagonist is
ranibizumab and is administered intravitreally in an amount of
about 0.5 mg/eye.
18. The method of claim 1, further comprising administering an
anti-C5 agent.
19. The method of claim 1, further comprising administering (a) and
(b) on a month in which the subject has intraretinal or sub-retinal
hemorrhage or a .gtoreq.50 .mu.m increase in foveal intraretinal
fluid.
20. A method for treating or preventing sub-retinal fibrosis,
comprising administering to a subject in need thereof (a)
Antagonist A or another pharmaceutically acceptable salt thereof in
an amount that is effective for treating or preventing sub-retinal
fibrosis.
21. The method of claim 20, further comprising administering to the
subject (b) a VEGF antagonist, wherein (a) and (b) are administered
in an amount that is effective for treating or preventing
sub-retinal fibrosis.
22. The method of claim 20, wherein the subject has wet age-related
macular degeneration (wet AMD).
23. The method of claim 22, wherein the sub-retinal fibrosis is
associated with the wet AMD.
24. The method of claim 20, wherein administering Antagonist A or
another pharmaceutically acceptable salt thereof results in a
decrease in the size of sub-retinal hyper-reflective material
(SHRM) as evidenced by spectral domain optical coherence tomography
(SD-OCT) or results in stabilization of the subject's vision.
25. The method of claim 20, wherein Antagonist A or another
pharmaceutically acceptable salt thereof is administered
intravitreally in an amount of about 1.5 mg/eye.
26. The method of claim 21, wherein the VEGF antagonist is
bevacizumab, ranibizumab, aflibercept, pegaptanib sodium or
ESBA1008.
27. The method of claim 26, wherein the VEGF antagonist is
bevacizumab and is administered intravitreally in an amount of
about 1.25 mg/eye.
28. The method of claim 26, wherein the VEGF antagonist is
aflibercept and is administered intravitreally in an amount of
about 2 mg/eye.
29. The method of claim 26, wherein the VEGF antagonist is
ranibizumab and is administered intravitreally in an amount of
about 0.5 mg/eye.
30. The method of claim 21, further comprising administering an
anti-C5 agent.
31. A method for treating or preventing von Hippel-Lindau (VHL)
disease, comprising administering to a subject in need thereof
Antagonist A or another pharmaceutically acceptable salt thereof in
an amount that is effective for treating or preventing VHL
disease.
32. The method of claim 31, further comprising administering a VEGF
antagonist.
33. The method of claim 31, wherein Antagonist A or another
pharmaceutically acceptable salt thereof is administered
intravitreally in an amount of about 1.5 mg/eye.
34. The method of claim 32, wherein the VEGF antagonist is
bevacizumab and is administered intravitreally in an amount of
about 1.25 mg/eye.
35. The method of claim 32, wherein the VEGF antagonist is
aflibercept and is administered intravitreally in an amount of
about 2 mg/eye.
36. The method of claim 32, wherein the VEGF antagonist is
ranibizumab and is administered intravitreally in an amount of
about 0.5 mg/eye.
37. The method of claim 32, further comprising administering an
anti-C5 agent.
38. A composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; the average number of particles detected in the
composition after being stored at a temperature of about
2.0.degree. C. to about 8.0.degree. C. for at least about twelve
weeks does not exceed about 50 particles/mL, where the particles
have a diameter >about 10 .mu.m as measured by the microscopic
method particle count test described in (788) Particulate Matter in
Injections, Revised Bulletin, Official Oct. 1, 2011, The United
States Pharmacopeial Convention; and the composition is suitable
for intravitreal injection.
39. The composition of claim 38, wherein the composition comprises
an aqueous carrier, sodium chloride, monobasic sodium phosphate
monohydrate, dibasic sodium phosphate heptahydrate, or a
combination thereof.
40. The composition of claim 38, wherein the pH is about 7.5.
41. The composition of claim 38, wherein the composition is
buffered with hydrochloric acid.
42. The composition of claim 38, wherein the composition is
buffered with sodium hydroxide.
43. The composition of claim 38, wherein the average number of
particles detected in the composition after being stored at a
temperature of about 2.0.degree. C. to about 8.0.degree. C. for at
least about twelve weeks does not exceed 5 particles/mL, where the
particles have a diameter >25 .mu.m as measured by the
microscopic method particle count test described in (788)
Particulate Matter in Injections, Revised Bulletin, Official Oct.
1, 2011, The United States Pharmacopeial Convention.
44. The composition of claim 38, wherein the average number of
particles detected in the composition after being stored at a
temperature of about 2.0.degree. C. to about 8.0.degree. C. for at
least about twelve weeks does not exceed 2 particles/mL, where the
particles have a diameter >50 .mu.m as measured by the
microscopic method particle count test described in (788)
Particulate Matter in Injections, Revised Bulletin, Official Oct.
1, 2011, The United States Pharmacopeial Convention.
45. The composition of claim 39, wherein the composition comprises:
a) about 3% w/v of Antagonist A or another pharmaceutically
acceptable salt thereof; b) about 95.9% w/v of an aqueous carrier;
c) about 0.9% w/v sodium chloride; d) about 0.03% w/v monobasic
sodium phosphate monohydrate; and e) about 0.2% w/v dibasic sodium
phosphate heptahydrate.
46. The composition of claim 38, wherein the composition comprises
about 0.003-5.0 mg of Antagonist A or another pharmaceutically
acceptable salt thereof.
47. The composition of claim 46, wherein the composition is
suitable for a single intravitreal administration.
48. The composition of claim 45, wherein the composition comprises
about 0.03-3.0 mg of Antagonist A or another pharmaceutically
acceptable salt thereof.
49. The composition of claim 48, wherein the composition is
suitable for a single intravitreal administration.
50. The composition of claim 47 or 49, wherein the intravitreal
administration is via a 27-30 gauge needle.
51. A composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; at least about 50% of the Antagonist A or another
pharmaceutically acceptable salt thereof shows no sign of
decomposition or modification resulting in the formation of a new
chemical entity when stored at a temperature of from about
2.0.degree. C. to about 8.0.degree. C. for at least about 12 weeks;
and the composition is suitable for intravitreal injection.
52. The composition of claim 51, wherein the composition comprises
an aqueous carrier, sodium chloride, monobasic sodium phosphate
monohydrate, dibasic sodium phosphate heptahydrate, or a
combination thereof.
53. The composition of claim 51, wherein the pH is about 7.5.
54. The composition of claim 51, wherein the composition is
buffered with hydrochloric acid.
55. The composition of claim 51, wherein the composition is
buffered with sodium hydroxide.
56. The composition of claim 51, wherein at least about 70% of the
Antagonist A or another pharmaceutically acceptable salt shows no
sign of decomposition or modification resulting in the formation of
a new chemical entity when stored at a temperature of from about
2.0.degree. C. to about 8.0.degree. C. for at least about 12
weeks.
57. The composition of claim 51, wherein at least about 90% of the
Antagonist A or another pharmaceutically acceptable salt shows no
sign of decomposition or modification resulting in the formation of
a new chemical entity when stored at a temperature of from about
2.0.degree. C. to about 8.0.degree. C. for at least about 12
weeks.
58. The composition of claim 52, wherein the composition comprises:
a) about 3% w/v of Antagonist A or a pharmaceutically acceptable
salt thereof; b) about 95.9% w/v of an aqueous carrier; c) about
0.9% w/v sodium chloride; d) about 0.03% w/v monobasic sodium
phosphate monohydrate; and e) about 0.2% w/v dibasic sodium
phosphate heptahydrate.
59. The composition of claim 51, wherein the composition comprises
about 0.003-5.0 mg of Antagonist A or another pharmaceutically
acceptable salt thereof.
60. The composition of claim 59, wherein the composition is
suitable for a single intravitreal administration.
61. The composition of claim 59, wherein the composition comprises
about 0.03-3.0 mg of Antagonist A or another pharmaceutically
acceptable salt thereof.
62. The composition of claim 61, wherein the composition is
suitable for a single intravitreal administration.
63. The composition of claim 60 or 62, wherein the intravitreal
administration is via a 27-30 gauge needle.
64. A composition comprising: a) about 3% w/v of Antagonist A or
another pharmaceutically acceptable salt thereof; b) about 0.9% w/v
sodium chloride; c) about 0.03% w/v monobasic sodium phosphate
monohydrate; d) about 0.2% w/v dibasic sodium phosphate
heptahydrate; and e) an aqueous carrier.
65. The composition of claim 64, wherein the composition has a pH
of from about 5.0 to about 8.0.
66. The composition of claim 64, wherein the composition has a pH
of about 7.5.
67. The composition of claim 64, wherein the composition comprises
about 95.9% w/v of the pharmaceutically acceptable aqueous
carrier.
68. The composition of claim 64, wherein the composition comprises
about 0.003-5.0 mg of Antagonist A or another pharmaceutically
acceptable salt thereof.
69. The composition of claim 64, wherein the composition comprises
about 0.03-3.0 mg of Antagonist A or another pharmaceutically
acceptable salt thereof.
70. The composition of claim 64, wherein the composition is
suitable for intravitreal administration.
71. The composition of claim 70, wherein the composition is
suitable for a single intravitreal administration.
72. The composition of claim 70 or 71, wherein the intravitreal
administration is via a 27-30 gauge needle.
73. The composition of any one of claims 38, 51 and 64, wherein the
concentration of Antagonist A or the other pharmaceutically
acceptable salt in the composition is from about 5 mg/mL to about
50 mg/mL.
74. The composition of claim 73, wherein the concentration of
Antagonist A or the other pharmaceutically acceptable salt thereof
is about 30 mg/mL.
75. The composition of any one of claims 38, 51 and 64, wherein the
dosage of Antagonist A in the composition is about 1.5 mg in a
volume of 0.03 mL to 0.15 mL.
76. The composition of any one of claims 38, 51 and 64, wherein the
composition is contained in a single undivided container.
77. The composition of any one of claims 38, 51 and 64, wherein the
composition is in a unit dosage form.
78. A composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; the average number of particles detected in the
composition after being stored at a temperature of about
2.0.degree. C. to about 8.0.degree. C. for at least about twelve
weeks does not exceed about 50 particles/mL, where the particles
have a diameter >about 10 .mu.m as measured by the light
obscuration particle count test described in (788) Particulate
Matter in Injections, Revised Bulletin, Official Oct. 1, 2011, The
United States Pharmacopeial Convention; and the composition is
suitable for intravitreal injection.
79. The composition of claim 78, wherein the composition comprises
an aqueous carrier, sodium chloride, monobasic sodium phosphate
monohydrate, dibasic sodium phosphate heptahydrate, or a
combination thereof.
80. The composition of claim 78, wherein the pH is about 7.5.
81. The composition of claim 78, wherein the composition is
buffered with hydrochloric acid.
82. The composition of claim 78, wherein the composition is
buffered with sodium hydroxide.
83. The composition of claim 78, wherein the average number of
particles detected in the composition after being stored at a
temperature of about 2.0.degree. C. to about 8.0.degree. C. for at
least about twelve weeks does not exceed 5 particles/mL, where the
particles have a diameter >25 .mu.m as measured by the light
obscuration particle count test described in (788) Particulate
Matter in Injections, Revised Bulletin, Official Oct. 1, 2011, The
United States Pharmacopeial Convention.
84. The composition of claim 78, wherein the average number of
particles detected in the composition after being stored at a
temperature of about 2.0.degree. C. to about 8.0.degree. C. for at
least about twelve weeks does not exceed 2 particles/mL, where the
particles have a diameter >50 .mu.m as measured by the light
obscuration particle count test described in (788) Particulate
Matter in Injections, Revised Bulletin, Official Oct. 1, 2011, The
United States Pharmacopeial Convention.
85. The composition of claim 79, wherein the composition comprises:
a) about 3% w/v of Antagonist A or another pharmaceutically
acceptable salt thereof; b) about 95.9% w/v of an aqueous carrier;
c) about 0.9% w/v sodium chloride; d) about 0.03% w/v monobasic
sodium phosphate monohydrate; and e) about 0.2% w/v dibasic sodium
phosphate heptahydrate.
86. The composition of claim 78, wherein the composition comprises
about 0.003-5.0 mg of Antagonist A or another pharmaceutically
acceptable salt thereof.
87. The composition of claim 86, wherein the composition is
suitable for a single intravitreal administration.
88. The composition of claim 85, wherein the composition comprises
about 0.03-3.0 mg of Antagonist A or another pharmaceutically
acceptable salt thereof.
89. The composition of claim 88, wherein the composition is
suitable for a single intravitreal administration.
90. The composition of claim 87 or 89, wherein the intravitreal
administration is via a 27-30 gauge needle.
91. The composition of claim 78, wherein the concentration of
Antagonist A or the other pharmaceutically acceptable salt in the
composition is from about 5 mg/mL to about 50 mg/mL.
92. The composition of claim 91, wherein the concentration of
Antagonist A or the other pharmaceutically acceptable salt thereof
is about 30 mg/mL.
93. The composition of claim 78, wherein the dosage of Antagonist A
in the composition is about 1.5 mg in a volume of 0.03 mL to 0.15
mL.
94. The composition of claim 78, wherein the composition is
contained in a single undivided container.
95. The composition of claim 78, wherein the composition is in a
unit dosage form.
96. The method of claim 1, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; the average number of particles detected in the
composition after being stored at a temperature of about
2.0.degree. C. to about 8.0.degree. C. for at least about twelve
weeks does not exceed about 50 particles/mL, where the particles
have a diameter >about 10 .mu.m as measured by the microscopic
method particle count test described in (788) Particulate Matter in
Injections, Revised Bulletin, Official Oct. 1, 2011, The United
States Pharmacopeial Convention; and the composition is suitable
for intravitreal injection.
97. The method of claim 1, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; at least about 50% of the Antagonist A or another
pharmaceutically acceptable salt thereof shows no sign of
decomposition or modification resulting in the formation of a new
chemical entity when stored at a temperature of from about
2.0.degree. C. to about 8.0.degree. C. for at least about 12 weeks;
and the composition is suitable for intravitreal injection.
98. The method of claim 1, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) about 3% w/v of
Antagonist A or another pharmaceutically acceptable salt thereof;
b) about 0.9% w/v sodium chloride; c) about 0.03% w/v monobasic
sodium phosphate monohydrate; d) about 0.2% w/v dibasic sodium
phosphate heptahydrate; and e) an aqueous carrier.
99. The method of claim 1, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; the average number of particles detected in the
composition after being stored at a temperature of about
2.0.degree. C. to about 8.0.degree. C. for at least about twelve
weeks does not exceed about 50 particles/mL, where the particles
have a diameter >about 10 .mu.m as measured by the light
obscuration particle count test described in (788) Particulate
Matter in Injections, Revised Bulletin, Official Oct. 1, 2011, The
United States Pharmacopeial Convention; and the composition is
suitable for intravitreal injection.
100. The method of claim 20, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; the average number of particles detected in the
composition after being stored at a temperature of about
2.0.degree. C. to about 8.0.degree. C. for at least about twelve
weeks does not exceed about 50 particles/mL, where the particles
have a diameter >about 10 .mu.m as measured by the microscopic
method particle count test described in (788) Particulate Matter in
Injections, Revised Bulletin, Official Oct. 1, 2011, The United
States Pharmacopeial Convention; and the composition is suitable
for intravitreal injection.
101. The method of claim 20, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; at least about 50% of the Antagonist A or another
pharmaceutically acceptable salt thereof shows no sign of
decomposition or modification resulting in the formation of a new
chemical entity when stored at a temperature of from about
2.0.degree. C. to about 8.0.degree. C. for at least about 12 weeks;
and the composition is suitable for intravitreal injection.
102. The method of claim 20, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) about 3% w/v of
Antagonist A or another pharmaceutically acceptable salt thereof;
b) about 0.9% w/v sodium chloride; c) about 0.03% w/v monobasic
sodium phosphate monohydrate; d) about 0.2% w/v dibasic sodium
phosphate heptahydrate; and e) an aqueous carrier.
103. The method of claim 20, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; the average number of particles detected in the
composition after being stored at a temperature of about
2.0.degree. C. to about 8.0.degree. C. for at least about twelve
weeks does not exceed about 50 particles/mL, where the particles
have a diameter >about 10 .mu.m as measured by the light
obscuration particle count test described in (788) Particulate
Matter in Injections, Revised Bulletin, Official Oct. 1, 2011, The
United States Pharmacopeial Convention; and the composition is
suitable for intravitreal injection.
104. The method of claim 31, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; the average number of particles detected in the
composition after being stored at a temperature of about
2.0.degree. C. to about 8.0.degree. C. for at least about twelve
weeks does not exceed about 50 particles/mL, where the particles
have a diameter >about 10 .mu.m as measured by the microscopic
method particle count test described in (788) Particulate Matter in
Injections, Revised Bulletin, Official Oct. 1, 2011, The United
States Pharmacopeial Convention; and the composition is suitable
for intravitreal injection.
105. The method of claim 31, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; at least about 50% of the Antagonist A or another
pharmaceutically acceptable salt thereof shows no sign of
decomposition or modification resulting in the formation of a new
chemical entity when stored at a temperature of from about
2.0.degree. C. to about 8.0.degree. C. for at least about 12 weeks;
and the composition is suitable for intravitreal injection.
106. The method of claim 31, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) about 3% w/v of
Antagonist A or another pharmaceutically acceptable salt thereof;
b) about 0.9% w/v sodium chloride; c) about 0.03% w/v monobasic
sodium phosphate monohydrate; d) about 0.2% w/v dibasic sodium
phosphate heptahydrate; and e) an aqueous carrier.
107. The method of claim 31, wherein the antagonist A or another
pharmaceutically acceptable salt thereof is administered as a
component of a composition comprising: a) Antagonist A or another
pharmaceutically acceptable salt thereof; and b) a pharmaceutically
acceptable excipient, buffering agent, aqueous carrier, or
combination thereof, wherein the composition has a pH of from about
5.0 to about 8.0; the average number of particles detected in the
composition after being stored at a temperature of about
2.0.degree. C. to about 8.0.degree. C. for at least about twelve
weeks does not exceed about 50 particles/mL, where the particles
have a diameter >about 10 .mu.m as measured by the light
obscuration particle count test described in (788) Particulate
Matter in Injections, Revised Bulletin, Official Oct. 1, 2011, The
United States Pharmacopeial Convention; and the composition is
suitable for intravitreal injection.
Description
CROSS REFERENCE TO RELATED APPLICATIONS
[0001] This application is a continuation of U.S. application Ser.
No. 14/329,702, filed Jul. 11, 2014, which claims the benefit of
U.S. provisional application No. 61/845,938, filed Jul. 12, 2013,
61/845,935, filed Jul. 12, 2013, 61/845,936, filed Jul. 12, 2013,
61/866,502, filed Aug. 15, 2013, 61/866,503, filed Aug. 15, 2013,
61/866,507, filed Aug. 15, 2013, 61/911,854, filed Dec. 4, 2013,
61/911,860, filed Dec. 4, 2013, 61/911,894, filed Dec. 4, 2013,
61/926,812, filed Jan. 13, 2014, 61/926,825, filed Jan. 13, 2014,
61/926,848, filed Jan. 13, 2014, 61/931,116, filed Jan. 24, 2014,
61/931,125, filed Jan. 24, 2014, and 61/931,135, filed Jan. 24,
2014, each of which is incorporated by reference herein in its
entirety.
SEQUENCE LISTING
[0002] The Sequence Listing associated with this application is
provided in text format in lieu of a paper copy, and is hereby
incorporated by reference into the specification. The name of the
text file containing the Sequence Listing is
OPHT_012_07US_SeqList_ST25.txt. The text file is about 372 KB, was
created on May 2, 2016, and is being submitted electronically via
EFS-Web.
FIELD OF THE INVENTION
[0003] This invention relates to methods and compositions useful
for the treatment or prevention of an ophthalmological disease or
disorder, comprising administration of an effective amount of
Antagonist A or another pharmaceutically acceptable salt
thereof.
BACKGROUND OF THE INVENTION
[0004] Various disorders of the eye are characterized, caused by,
or result in choroidal, retinal or iris neovascularization or
retinal edema. One of these disorders is macular degeneration.
Age-related macular degeneration (AMD) is a disease that affects
approximately one in ten Americans over the age of 65. One type of
AMD, "wet-AMD," accounts only for approximately 10% of age-related
macular degeneration cases but results in approximately 90% of
cases of legal blindness from macular degeneration in the elderly.
Another disorder of the eye is diabetic retinopathy. Diabetic
retinopathy can affect up to 80% of all patients having diabetes
for 10 years or more and is the third leading cause of adult
blindness, accounting for almost 7% of blindness in the USA. Other
disorders include hypertensive retinopathy, central serous
chorioretinopathy, cystoid macular edema, Coats disease and ocular
or adnexal neoplasms such as choroidal hemangioma, retinal pigment
epithelial carcinoma, retinal vein occlusions and intraocular
lymphoma.
[0005] Therefore, although advances in the understanding of the
molecular events accompanying neovascularization have been made,
there exists a need to utilize this understanding to develop
improved methods for treating or preventing neovascular diseases
disorders, including ocular neovascular diseases and disorders such
as the neovascularization that occurs with AMD, diabetic
retinopathy, and retinal vein occlusions.
SUMMARY OF THE INVENTION
[0006] The present invention relates to methods and compositions
useful for the treatment or prevention of an ophthalmological
disease or disorder.
[0007] The present invention provides a method for treating or
preventing wet age-related macular degeneration (wet AMD),
comprising administering to a subject in need thereof (a)
Antagonist A or another pharmaceutically acceptable salt thereof
and (b) an VEGF antagonist, wherein (a) and (b) are administered in
an amount that is effective for treating or preventing wet AMD, and
wherein the administering occurs once every month, .+-.about seven
days, for a first administration period of at least 3 consecutive
months, followed by administering (a) and (b) for a second
administration period at a frequency of at least every other month
.+-.about seven days beginning at two months .+-.about seven days
after the day of the last month of the first administration period
on which (a) and (b) are administered.
[0008] Also provided herein is a method for treating or preventing
sub-retinal fibrosis, comprising administering to a subject in need
thereof (a) Antagonist A or another pharmaceutically acceptable
salt thereof in an amount that is effective for treating or
preventing sub-retinal fibrosis.
[0009] A method for treating or preventing von Hippel-Lindau (VHL)
disease, comprising administering to a subject in need thereof
Antagonist A or another pharmaceutically acceptable salt thereof in
an amount that is effective for treating or preventing VHL disease
is also provided herein.
BRIEF DESCRIPTION OF THE DRAWINGS
[0010] Reference is made to the following detailed description,
which sets forth illustrative embodiments and the accompanying
drawings of which:
[0011] FIGS. 1A-F show the chemical structure of Antagonist A,
wherein the 5' end of its aptamer (SEQ ID NO: 1) is modified with
Me(OCH.sub.2CH.sub.2).sub.nOC(O)NH(CH.sub.2).sub.4CH(NHC(O)O(CH.sub.2CH.s-
ub.2O).sub.nMe)C(O)NH(CH.sub.2).sub.6--, where n is about 450. The
designations {circle around (B)}-{circle around (F)} indicate a
continuation from a previous panel.
[0012] FIG. 2 shows a graph depicting the mean change in visual
acuity in wet AMD patients in a phase 2b clinical trial, who were
treated with 0.5 mg of Lucentis.RTM. alone or with 0.5 mg of
Lucentis.RTM. and either 1.5 mg of Antagonist A or 0.3 mg of
Antagonist A.
[0013] FIG. 3 shows a bar graph showing comparative visual-acuity
benefit in wet AMD patients with treatment with 0.5 mg of
Lucentis.RTM. and either 1.5 mg or 0.3 mg of Antagonist A as
compared to treatment with Lucentis.RTM. monotherapy (0.5 mg).
[0014] FIG. 4 shows a graph depicting the early and sustained
visual-acuity improvement over time in wet AMD patients treated
with Lucentis.RTM. monotherapy (0.5 mg) or with 0.5 mg of
Lucentis.RTM. and either 1.5 mg of Antagonist or 0.3 mg of
Antagonist A.
[0015] FIGS. 5A and 5B provide bar graphs showing that the
increased efficacy of treatment with 0.5 mg of Lucentis.RTM. and
either 1.5 mg or 0.3 mg of Antagonist A as compared to treatment
with Lucentis.RTM. monotherapy (0.5 mg) in patients with wet AMD is
independent of baseline lesion size or baseline vision. FIG. 5A
shows the mean change in visual acuity for patients in each of the
indicated baseline lesion quartiles, and FIG. 5B shows the mean
change in visual acuity for patients with the indicated baseline
vision.
[0016] FIGS. 6A and 6B provide bar graphs showing that the cohort
of patients treated with a combination of 0.5 mg of Lucentis.RTM.
and 1.5 mg of Antagonist A included a greater proportion of
patients with significant visual gain (FIG. 6A) and fewer patients
with visual loss (FIG. 6B) as compared to the cohort of patients
with treated Lucentis.RTM. monotherapy (0.5 mg).
[0017] FIGS. 7A-C provide bar graphs showing that patients treated
with 0.5 mg of Lucentis.RTM. and 1.5 mg of Antagonist A exhibited a
greater mean improvement in final visual acuity as compared to
patients treated with Lucentis.RTM. monotherapy (0.5 mg). FIG. 7A
shows the percentage of patients who demonstrated a visual acuity
of 20/40 or better; FIG. 7B shows the percentage of patients who
demonstrated a visual acuity of 20/25 or better; and FIG. 7C shows
the percentage of patients who demonstrated a visual acuity of
20/200 or worse.
[0018] FIGS. 8A and 8B provide bar graphs showing increased
reduction in choroidal neovascularization (CNV) lesion size in
small and large baseline CNV lesions in wet AMD patients treated
with both 0.5 mg of Lucentis.RTM. and 1.5 mg of Antagonist A as
compared to patients treated with Lucentis.RTM. monotherapy (0.5
mg). FIG. 8A shows the results in all patients, and FIG. 8B shows
the results in patients with a visual outcome >3-lines.
[0019] FIG. 9 shows a graph depicting the mean change in geographic
atrophy (GA) lesion area in dry AMD patients measured at 24 weeks
in patients treated with either a 0.3 mg or 1 mg dose of ARC1905
monthly from weeks 0 to 24 in a phase 2a trial.
[0020] FIG. 10 shows a graph depicting the mean change in GA lesion
area in dry AMD patients measured at 24 weeks and 48 weeks in
patients treated with either a 0.3 mg or 1 mg dose of ARC1905
monthly from weeks 0 to 48 in a phase 2a trial.
[0021] FIG. 11 shows Early Treatment for Diabetic Retinopathy Study
("ETDRS") Chart 1.
[0022] FIG. 12 shows Early Treatment for Diabetic Retinopathy Study
("ETDRS") Chart 2.
[0023] FIG. 13 shows Early Treatment for Diabetic Retinopathy Study
("ETDRS") Chart R.
DETAILED DESCRIPTION OF THE INVENTION
[0024] In certain aspects, the present invention provides new and
improved methods and compositions for treating and preventing
ophthalmological diseases and disorders, including, e.g., new uses,
combination therapies, treatment and dosing regimens, and
coformulations.
[0025] In one aspect, the invention provides methods for treating
or preventing an ophthalmological disease or disorder, comprising
administering to a subject in need thereof an effective amount of
Antagonist A or another pharmaceutically acceptable salt thereof.
In particular embodiments, the subject is administered Antagonist A
or another pharmaceutically acceptable salt thereof and not
administered an anti-C5 agent. In some embodiments, the subject is
administered Antagonist A or another pharmaceutically acceptable
salt thereof and not administered a VEGF antagonist.
[0026] In particular embodiments, the Antagonist A or another
pharmaceutically acceptable salt thereof is administered in
combination with a VEGF antagonist. In one embodiment, Antagonist A
or another pharmaceutically acceptable salt thereof is administered
in combination with ranibizumab, bevacizumab, aflibercept,
pegaptanib sodium, or ESBA1008.
[0027] In particular embodiments, the Antagonist A or another
pharmaceutically acceptable salt thereof is administered in
combination with a VEGF antagonist and an anti-C5 agent. In one
embodiment, Antagonist A or another pharmaceutically acceptable
salt thereof is administered in combination with a VEGF antagonist
(e.g., ranibizumab, bevacizumab, aflibercept, pegaptanib sodium, or
ESBA1008), and ARC1905.
[0028] The invention also provides treatment regimens, including
treatment and dosing regimens, related to the coadministration of
Antagonist A or another pharmaceutically acceptable salt thereof
and a VEGF antagonist, optionally also in combination with an
anti-C5 agent.
[0029] In further embodiments, another agent (e.g., an agent that
is not Antagonist A, VEGF antagonist or an anti-C5 agent) that is
useful for treating or preventing an ophthalmological disease or
disorder is administered. In some embodiments, the methods comprise
administering one or more (e.g., two) VEGF antagonists and/or one
or more (e.g., two) anti-C5 agents to the subject in need
thereof.
[0030] In another aspect, the invention provides methods for
treating or preventing an ophthalmological disease or disorder,
comprising administering to a subject in need thereof an effective
amount of an anti-C5 agent (e.g., ARC1905). In particular
embodiments, the subject is not administered Antagonist A or
another pharmaceutically acceptable salt thereof. In some
embodiments, the subject is not administered a VEGF antagonist.
[0031] In addition, the invention provides coformulations that
comprise Antagonist A or another pharmaceutically acceptable salt
thereof and a VEGF antagonist. In certain embodiments, the
coformulations further comprise an anti-C5 agent. In certain
embodiments, the coformulations are pharmaceutically compositions
comprising an effective amount of Antagonist A or another
pharmaceutically acceptable salt thereof and VEGF antagonist, and a
pharmaceutically acceptable carrier or vehicle. In certain
embodiments, the coformulations are pharmaceutically compositions
comprising an effective amount of Antagonist A or another
pharmaceutically acceptable salt thereof, VEGF antagonist, and
anti-C5 agent, and a pharmaceutically acceptable carrier or
vehicle.
[0032] In one embodiment, the present invention provides methods
for treating or preventing an ophthalmological disease or disorder,
comprising administering to a subject in need thereof Antagonist A
or another pharmaceutically acceptable salt thereof and optionally
a VEGF antagonist, wherein the methods further comprise performing
a surgery to treat the ophthalmological disease or disorder and/or
administration of an anti-C5 agent.
DEFINITIONS AND ABBREVIATIONS
[0033] As used herein, the following terms and phrases shall have
the meanings set forth below. Unless defined otherwise, all
technical and scientific terms used herein have the same meaning as
commonly understood to one of skill in the art to which this
invention belongs.
[0034] The term "about" when used in connection with a referenced
numeric indication means the referenced numeric indication plus or
minus up to 10% of that referenced numeric indication. For example,
"about 100" means from 90 to 110 and "about six" means from 5.4 to
6.6.
[0035] The term "antagonist" refers to an agent that inhibits,
either partially or fully, the activity or production of a target
molecule. In particular, the term "antagonist," as applied
selectively herein, means an agent capable of decreasing levels of
gene expression, mRNA levels, protein levels or protein activity of
the target molecule. Illustrative forms of antagonists include, for
example, proteins, polypeptides, peptides (such as cyclic
peptides), antibodies or antibody fragments, peptide mimetics,
nucleic acid molecules, antisense molecules, ribozymes, aptamers,
RNAi molecules, and small organic molecules. Illustrative
non-limiting mechanisms of antagonist inhibition include repression
of ligand synthesis and/or stability (e.g., using, antisense,
ribozymes or RNAi compositions targeting the ligand gene/nucleic
acid), blocking of binding of the ligand to its cognate receptor
(e.g., using anti-ligand aptamers, antibodies or a soluble, decoy
cognate receptor), repression of receptor synthesis and/or
stability (e.g., using, antisense, ribozymes or RNAi compositions
targeting the ligand receptor gene/nucleic acid), blocking of the
binding of the receptor to its cognate receptor (e.g., using
receptor antibodies) and blocking of the activation of the receptor
by its cognate ligand (e.g., using receptor tyrosine kinase
inhibitors). In addition, the antagonist may directly or indirectly
inhibit the target molecule.
[0036] The term "antibody fragment" includes a portion of an
antibody that is an antigen binding fragment or single chains
thereof. An antibody fragment can be a synthetically or genetically
engineered polypeptide. 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
V.sub.L, V.sub.H, C.sub.L and C.sub.H1 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 V.sub.H and C.sub.H1 domains; (iv) a Fv fragment
consisting of the V.sub.L and V.sub.H domains of a single arm of an
antibody, (v) a dAb fragment (Ward et al., (1989) Nature
341:544-546), which consists of a V.sub.H domain; and (vi) an
isolated complementarity determining region (CDR). Furthermore,
although the two domains of the Fv fragment, V.sub.L and V.sub.H,
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 V.sub.L and V.sub.H
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 fragment" of an antibody. These antibody
fragments are obtained using conventional techniques known to those
in the art, and the fragments can be screened for utility in the
same manner as whole antibodies.
[0037] The term "aptamer" refers to a peptide or nucleic acid that
has an inhibitory effect on a target. Inhibition of the target by
the aptamer can occur by binding of the target, by catalytically
altering the target, by reacting with the target in a way which
modifies the target or the functional activity of the target, by
ionically or covalently attaching to the target as in a suicide
inhibitor or by facilitating the reaction between the target and
another molecule. Aptamers can be peptides, ribonucleotides,
deoxyribonucleotides, other nucleic acids or a mixture of the
different types of nucleic acids. Aptamers can comprise one or more
modified amino acid, bases, sugars, polyethylene glycol spacers or
phosphate backbone units as described in further detail herein.
[0038] A nucleotide sequence is "complementary" to another
nucleotide sequence if each of the bases of the two sequences
matches, i.e., are capable of forming Watson Crick base pairs. The
complement of a nucleic acid strand can be the complement of a
coding strand or the complement of a non-coding strand.
[0039] The phrase "conserved residue" refers to an amino acid of a
group of amino acids having particular common properties. A
functional way to define common properties among individual amino
acids is to analyze the normalized frequencies of amino acid
changes among corresponding proteins of homologous organisms.
According to such analyses, groups of amino acids may be
characterized where amino acids within a group exchange
preferentially with each other, and therefore resemble each other
most in their impact on the overall protein structure (Schulz, G.
E. and R. H. Schirmer, Principles of Protein Structure,
Springer-Verlag). Examples of amino acid groups defined in this
manner include:
[0040] (i) a charged group, consisting of Glu and Asp, Lys, Arg and
His,
[0041] (ii) a positively-charged group, consisting of Lys, Arg and
His,
[0042] (iii) a negatively-charged group, consisting of Glu and
Asp,
[0043] (iv) an aromatic group, consisting of Phe, Tyr and Trp,
[0044] (v) a nitrogen ring group, consisting of His and Trp,
[0045] (vi) a large aliphatic nonpolar group, consisting of Val,
Leu and Ile,
[0046] (vii) a slightly-polar group, consisting of Met and Cys,
[0047] (viii) a small-residue group, consisting of Ser, Thr, Asp,
Asn, Gly, Ala, Glu, Gln and Pro,
[0048] (ix) an aliphatic group consisting of Val, Leu, Ile, Met and
Cys, and
[0049] (x) a small hydroxyl group consisting of Ser and Thr.
[0050] Members of each of the above groups are conserved
residues.
[0051] The term "label" includes, but is not limited to, a
radioactive isotope, a fluorophore, a chemiluminescent moiety, an
enzyme, an enzyme substrate, an enzyme cofactor, an enzyme
inhibitor, a dye, a metal ion, a ligand (e.g., biotin or a hapten)
and the like. Examples of fluorophore labels include fluorescein,
rhodamine, dansyl, umbelliferone, Texas red, luminol, NADPH,
alpha-beta-galactosidase and horseradish peroxidase.
[0052] The term "nucleic acid" refers to a polynucleotide such as
deoxyribonucleic acid (DNA) or ribonucleic acid (RNA). The term
also includes analogs of RNA or DNA made from nucleotide analogs,
and, as applicable to the embodiment being described, single (sense
or antisense) and double-stranded polynucleotides, ESTs,
chromosomes, cDNAs, mRNAs, and rRNAs.
[0053] The terms "RNA interference," "RNAi," "miRNA," and "siRNA"
refer to any method by which expression of a gene or gene product
is decreased by introducing into a target cell one or more
double-stranded RNAs, which are homologous to a gene of interest
(particularly to the messenger RNA of the gene of interest, e.g.,
PDGF or VEGF).
[0054] The term "neovascularization" refers to new blood vessel
formation in abnormal tissue or in abnormal positions.
[0055] The term "angiogenesis" refers to formation of new blood
vessels in normal or in abnormal tissue or positions.
[0056] The term "ophthalmological disease" includes diseases of the
eye and the ocular adnexa.
[0057] The term "ocular neovascular disorder" refers to an ocular
disorder characterized by neovascularization. In one embodiment,
the ocular neovascular disorder is a disorder other than cancer.
Examples of ocular neovascular disorders include diabetic
retinopathy and age-related macular degeneration.
[0058] The term "mammal" includes a human, monkey, cow, hog, sheep,
horse, dog, cat, rabbit, rat and mouse. In certain embodiments, a
subject is a mammal.
[0059] The term "PDGF" refers to a platelet-derived growth factor
that regulates cell growth or division. As used herein, the term
"PDGF" includes the various subtypes of PDGF including PDGF-B (see
SEQ ID NOS: 2 (nucleic acid) and 3 (polypeptide)), PDGF-A (see SEQ
ID NOS: 4 (nucleic acid) and 5 (polypeptide), PDGF-C (see SEQ ID
NOS: 6 (nucleic acid) and 7 (polypeptide)), PDGF-D, variants 1(see
SEQ ID NOS: 8 (nucleic acid) and 9 (polypeptide)) and 2 (see SEQ ID
NOS: 10 (nucleic acid) and 11 (polypeptide)), and dimerized forms
thereof, including PDGF-AA, PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD.
Platelet derived growth factors includes homo- or heterodimers of
A-chain (PDGF-A) and B-chain (PDGF-B) that exert their action via
binding to and dimerization of two related receptor tyrosine kinase
platelet-derived growth factor cell surface receptors (i.e.,
PDGFRs), PDGFR-.alpha. (see SEQ ID NOS: 12 (nucleic acid) and 13
(polypeptide)) and PDGFR-.beta. (see SEQ ID NOS: 14 (nucleic acid)
and 15 (polypeptide)). In addition, PDGF-C and PDGF-D, two
additional protease-activated ligands for the PDGFR complexes, have
been identified (Li et al., (2000) Nat. Cell. Biol. 2: 302-9;
Bergsten et al., (2001) Nat. Cell. Biol. 3: 512-6; and Uutele et
al., (2001) Circulation 103: 2242-47). Due to the different ligand
binding specificities of the PDGFRs, it is known that
PDGFR-.alpha./.alpha. binds PDGF-AA, PDGF-BB, PDGF-AB, and PDGF-CC;
PDGFR-.beta./.beta. binds PDGF-BB and PDGF-DD; whereas
PDGFR-.alpha./.beta. binds PDGF-AB, PDGF-BB, PDGF-CC, and PDGF-DD
(Betsholtz et al., (2001) BioEssays 23: 494-507). As used herein,
the term "PDGF" also refers to those members of the class of growth
factors that induce DNA synthesis and mitogenesis through the
binding and activation of a PDGFR on a responsive cell type. PDGFs
can effect, for example: directed cell migration (chemotaxis) and
cell activation; phospholipase activation; increased
phosphatidylinositol turnover and prostaglandin metabolism;
stimulation of both collagen and collagenase synthesis by
responsive cells; alteration of cellular metabolic activities,
including matrix synthesis, cytokine production, and lipoprotein
uptake; induction, indirectly, of a proliferative response in cells
lacking PDGF receptors; and potent vasoconstrictor activity. The
term "PDGF" can be used to refer to a "PDGF" polypeptide, a "PDGF"
encoding gene or nucleic acid, or a dimerized form thereof.
[0060] The term "PDGF-A" refers to an A chain polypeptide of PDGF
or its corresponding encoding gene or nucleic acid.
[0061] The term "PDGF-B" refers to a B chain polypeptide of PDGF or
its corresponding encoding gene or nucleic acid.
[0062] The term "PDGF-C" refers to a C chain polypeptide of PDGF or
its corresponding encoding gene or nucleic acid.
[0063] The term "PDGF-D" refers to a D chain polypeptide of PDGF or
its corresponding encoding gene or nucleic acid, including variants
1 and 2 of the D chain polypeptide of PDGF.
[0064] The term "PDGF-AA" refers to a dimer having two PDGF-A chain
polypeptides.
[0065] The term "PDGF-AB" refers to a dimer having one PDGF-A chain
polypeptide and one PDGF-B chain polypeptide.
[0066] The term "PDGF-BB" refers to a dimer having two PDGF-B chain
polypeptides.
[0067] The term "PDGF-CC" refers to a dimer having two PDGF-C chain
polypeptides.
[0068] The term "PDGF-DD" refers to a dimer having two PDGF-D chain
polypeptides.
[0069] The term "VEGF" refers to a vascular endothelial growth
factor that induces angiogenesis or an angiogenic process. As used
herein, the term "VEGF" includes the various subtypes of VEGF (also
known as vascular permeability factor (VPF) and VEGF-A) (see SEQ ID
NOS: 16 (nucleic acid) and 17 (polypeptide)) that arise by, e.g.,
alternative splicing of the VEGF-A/VPF gene including VEGF.sub.121,
VEGF.sub.165 and VEGF.sub.189. Further, as used herein, the term
"VEGF" includes VEGF-related angiogenic factors such as PIGF
(placenta growth factor), VEGF-B, VEGF-C, VEGF-D and VEGF-E, which
act through a cognate VEFG receptor (i.e., VEGFR) to induce
angiogenesis or an angiogenic process. The term "VEGF" includes any
member of the class of growth factors that binds to a VEGF receptor
such as VEGFR-1 (Flt-1) (see SEQ ID NOS: 18 (nucleic acid) and 19
(polypeptide)), VEGFR-2 (KDR/Flk-1) (see SEQ ID NOS: 20 (nucleic
acid) and 21 (polypeptide)), or VEGFR-3 (FLT-4). The term "VEGF"
can be used to refer to a "VEGF" polypeptide or a "VEGF" encoding
gene or nucleic acid.
[0070] The term "PDGF antagonist" refers to an agent that reduces,
or inhibits, either partially or fully, the activity or production
of a PDGF. In certain embodiments, the PDGF antagonist inhibits one
or more of PDGF-A, PDGF-B, PDGF-C and PDGF-D. In certain
embodiments, the PDGF antagonist inhibits one or more of PDGF-A,
PDGF-B, and PDGF-C. In some embodiments, the PDGF antagonist
inhibits a dimerized form of PDGF, such as PDGF-AA, PDGF-AB,
PDGF-BB, PDGF-CC, and PDGF-DD. In certain embodiments, the PDGF
antagonist inhibits PDGF-BB. In other embodiments, the PDGF
antagonist inhibits PDGF-AB. A PDGF antagonist can directly or
indirectly reduce or inhibit the activity or production of a
specific PDGF such as PDGF-B. Furthermore, "PDGF antagonists"
consistent with the above definition of "antagonist," include
agents that act on a PDGF ligand or its cognate receptor so as to
reduce or inhibit a PDGF-associated receptor signal. Examples of
"PDGF antagonists" include antisense molecules, ribozymes or RNAi
that target a PDGF nucleic acid; anti-PDGF aptamers, anti-PDGF
antibodies to PDGF itself or its receptor, or soluble PDGF receptor
decoys that prevent binding of a PDGF to its cognate receptor;
antisense molecules, ribozymes or RNAi that target a cognate PDGF
receptor (PDGFR) nucleic acid; anti-PDGFR aptamers or anti-PDGFR
antibodies that bind to a cognate PDGFR receptor; and PDGFR
tyrosine kinase inhibitors.
[0071] The term "VEGF antagonist" refers to an agent that reduces,
or inhibits, either partially or fully, the activity or production
of a VEGF. In certain embodiments, the VEGF antagonist inhibits one
or more of VEGF-A, VEGF-B, VEGF-C and VEGF-D. A VEGF antagonist can
directly or indirectly reduce or inhibit the activity or production
of a specific VEGF such as VEGF.sub.165. Furthermore, "VEGF
antagonists" consistent with the above definition of "antagonist,"
include agents that act on either a VEGF ligand or its cognate
receptor so as to reduce or inhibit a VEGF-associated receptor
signal. Examples of "VEGF antagonists" include antisense molecules,
ribozymes or RNAi that target a VEGF nucleic acid; anti-VEGF
aptamers, anti-VEGF antibodies to VEGF itself or its receptor, or
soluble VEGF receptor decoys that prevent binding of a VEGF to its
cognate receptor; antisense molecules, ribozymes, or RNAi that
target a cognate VEGF receptor (VEGFR) nucleic acid; anti-VEGFR
aptamers or anti-VEGFR antibodies that bind to a cognate VEGFR
receptor; and VEGFR tyrosine kinase inhibitors. In certain
embodiments, the VEGF antagonist is a peptide, e.g., a peptide
comprising three or more amino acid residues. In certain
embodiments, the VEGF antagonist is a bicyclic peptide.
[0072] The term "effective amount" when used in connection with an
active agent, refers to an amount of the active agent, e.g., a PDGF
antagonist, a VEGF antagonist or an anti-C5 agent, alone or in
combination with another active agent, that is useful to treat or
prevent an ophthalmological disease or disorder. The "effective
amount" can vary depending upon the mode of administration,
specific locus of the ophthalmological disease or disorder, the
age, body weight, and general health of the subject. The effective
amount of two or more active agents is the combined amount of the
active agents that is useful for treating or preventing an
ophthalmological disease or disorder, even if the amount of one of
the agents, in the absence of one or more of the other agents, is
ineffective to treat or prevent the ophthalmological disease or
disorder.
[0073] A "variant" of polypeptide X refers to a polypeptide having
the amino acid sequence of polypeptide X in which is altered in one
or more amino acid residues. The variant can have "conservative"
changes, wherein a substituted amino acid has similar structural or
chemical properties (e.g., replacement of leucine with isoleucine).
More rarely, a variant can have "nonconservative" changes (e.g.,
replacement of glycine with tryptophan). Analogous minor variations
may also include amino acid deletions or insertions, or both.
Guidance in determining which amino acid residues may be
substituted, inserted, or deleted without eliminating biological or
immunological activity can be determined using computer programs
well known in the art, for example, LASERGENE software
(DNASTAR).
[0074] The term "variant," when used in the context of a
polynucleotide sequence, can encompass a polynucleotide sequence
related to that of gene or the coding sequence thereof. This
definition also includes, for example, "allelic," "splice,"
"species," or "polymorphic" variants. A splice variant can have
significant identity to a reference molecule, but will generally
have a greater or lesser number of polynucleotides due to
alternative splicing of exons during mRNA processing. The
corresponding polypeptide can possess additional functional domains
or an absence of domains. Species variants are polynucleotide
sequences that vary from one species to another. The resulting
polypeptides generally will have significant amino acid identity
relative to each other. A polymorphic variant is a variation in the
polynucleotide sequence of a particular gene between individuals of
a given species.
[0075] The term "anti-C5 agent" refers to an agent that reduces, or
inhibits, either partially or fully, the activity or production of
a C5 complement protein or a variant thereof. An anti-C5 agent can
directly or indirectly reduce or inhibit the activity or production
of a C5 complement protein or variant thereof. An anti-C5 agent can
reduce or inhibit the conversion of C5 complement protein into its
component polypeptides C5a and C5b. Anti-C5 agents can also reduce
or inhibit the activity or production of C5a and/or C5b. Examples
of "anti-C5 agents" include antisense molecules, ribozymes or RNAi
that target a C5 nucleic acid; anti-C5 aptamers including anti-C5a
and anti-C5b aptamers, anti-C5 antibodies directed against C5, C5a,
C5b, or C5b-9, or soluble C5 receptor decoys that prevent binding
of a C5 complement protein or variant or fragment thereof (e.g.,
C5a or C5b) to a binding partner or receptor.
[0076] Agents Useful for Treatment or Prevention of an
Opthalmological Disease or Disorder
[0077] Antagonist A
[0078] Antagonist A is a PEGylated, anti-PDGF aptamer having the
sequence CAGGCUACGC GTAGAGCAUC ATGATCCUGT (SEQ ID NO: 1) (see
Example 3 of US Patent Application Publication No. 20050096257,
incorporated herein by reference in its entirety) having
2'-fluoro-2'-deoxyuridine at positions 6, 19 and 28;
2'-fluoro-2'-deoxycytidine at positions 8, 20, 26, and 27;
2'-O-Methyl-2'-deoxyguanosine at positions 9, 14, 16, and 29;
2'-O-Methyl-2'-deoxyadenosine at position 21; an inverted
orientation T (i.e., 3'-3'-linked) at position 30; and two
heaxethylene-glycol phosphoramidite linkages that join together the
9.sup.th and 10.sup.th nucleotides and 21.sup.st and 22.sup.nd
nucleotides via phosphodiester linkages between the linker and the
respective nucleotides.
[0079] The chemical name of Antagonist A is [(monomethoxy 20K
polyethylene glycol carbamoyl-N2-)(monomethoxy 20K polyethylene
glycol
carbamoyl-N6-)]-lysine-amido-6-hexandilyl-(1-5)-2'-deoxycytidylyl-(3'-5')-
-2'-deoxyadenylyl-(3'-5')-2'-deoxyguanylyl-(3'-5')-2'-deoxyguanylyl-(3'-5)-
-2'-deoxycytidylyl-(3'-5)-2'-deoxy-2'-fluorouridylyl-(3'-5')-2'-deoxyadeny-
lyl-(3'-5')-2'-deoxy-2'-fluorocytidylyl-(3'-5')-2'-deoxy-2'-methoxyguanyly-
l-(3'-1)-PO.sub.3-hexa(ethyloxy)-(18-5)-2'-deoxycytidylyl-(3'-5')-2'-deoxy-
guanylyl-(3'-5')-thymidylyl-(3'-5)-2'-deoxyadenylyl-(3'-5')-2'-deoxy-2'-me-
thoxyguanylyl-(3'-5)-2'-deoxyadenylyl-(3'-5)-2'-deoxy-2'-methoxyguanylyl-(-
3'-5)-2'-deoxycytidylyl-(3'-5)-2'-deoxyadenylyl-(3'-5)-2'-deoxy-2'-fluorou-
ridylyl-(3'-5)-2'-deoxy-2'-fluorocytidylyl-(3'-5)-2'-deoxy-2'-methoxyadeny-
lyl-(3'-1)-PO.sub.3-hexa(ethyloxy)-(18-5)-thymidylyl-(3'-5)-2'-deoxyguanyl-
yl-(3'-5)-2'-deoxyadenylyl-(3'-5)-thymidylyl-(3'-5)-2'-deoxy-2'-fluorocyti-
dylyl-(3'-5)-2'-deoxy-2'-fluorocytidylyl-(3'-5)-2'-deoxy-2'-fluorouridylyl-
-(3'-5)-2'-deoxy-2'-methoxyguanylyl-(3'-3)-thymidine.
[0080] The structure of Antagonist A is shown in FIG. 1.
[0081] The sequence of Antagonist A is:
[0082] 5'-[mPEG2 40 kD]-[HN--(CH.sub.2).sub.6O]
CAGGCU.sub.fAC.sub.fG.sub.m [PO.sub.3(CH.sub.2CH.sub.2O).sub.6]
CGTAG.sub.mAG.sub.mCAU.sub.fC.sub.fA.sub.m
[PO.sub.3(CH.sub.2CH.sub.2O).sub.6]TGATC.sub.fC.sub.fU.sub.fG.sub.m-[3T]--
3', whose aptamer sequence is set forth in (SEQ ID NO: 1),
[0083] where [3T] refers to an inverted thymidine nucleotide that
is attached to the 3' end of the oligonucleotide at the 3' position
on the ribose sugar, and [mPEG2 40 kD] represents two 20 kD
polyethylene glycol (PEG) polymer chains, in one embodiment two
about 20 kD PEG polymer chains, that are covalently attached to the
two amino groups of a lysine residue via carbamate linkages. This
moiety is in turn linked with the oligonucleotide via the amino
linker described below.
[0084] [HN--(CH.sub.2).sub.6O] represents a bifunctional
.alpha.-hydroxy-.omega.-amino linker that is covalently attached to
the PEG polymer via an amide bond. The linker is attached to the
oligonucleotide at the 5'-end of Antagonist A by a phosphodiester
linkage.
[0085] [PO.sub.3(CH.sub.2CH.sub.2O).sub.6] represents the
hexaethylene glycol (HEX) moieties that join segments of the
oligonucleotide via phosphodiester linkages. Antagonist A has two
HEX linkages that join together the 9.sup.th and 10.sup.th
nucleotides and 21.sup.st and 22.sup.nd nucleotides via
phosphodiester linkages between the linker and the respective
nucleotides.
[0086] C, A, G, and T represent the single letter code for the
2'-deoxy derivatives of cytosine, adenosine, guanosine, and
thymidine nucleic acids, respectively. Antagonist A has four
2'-deoxyribocytosine, six 2'-deoxyriboadenosine, four
2'-deoxyriboguanosine, and four 2'-deoxyribothymidine.
[0087] G.sub.m and A.sub.m represent 2'-methoxy substituted forms
of guanosine and adenosine, respectively. Antagonist A has four
2'-methoxyguanosines and one 2'-methoxyadenosine. C.sub.f and
U.sub.f represent the 2'-fluoro substituted forms of cytosine and
uridine, respectively. Antagonist A has four 2'-fluorocytosines and
three 2'-fluorouridines.
[0088] The phosphodiester linkages in the oligonucleotide, with the
exception of the 3'-terminus, connect the 5'- and 3'-oxygens of the
ribose ring with standard nucleoside phosphodiester linkages. The
phosphodiester linkage between the 3'-terminal thymidine and the
penultimate G.sub.m links their respective 3'-oxygens, which is
referred to as the 3',3'-cap.
[0089] Antagonist A has a molecular weight from 40,000 to 60,000
Daltons, in one embodiment from about 40,000 to about 60,000
Daltons, and can be colorless to slightly yellow in solution.
Antagonist A can be present in a solution of monobasic sodium
phosphate monohydrate and dibasic sodium phosphate heptahydrate as
buffering agents and sodium chloride as a tonicity adjuster.
Antagonist A is a hydrophilic polymer. The Antagonist A is soluble
in water and in phosphate-buffered saline (PBS), as assessed by
visual inspection, to at least 50 mg (based on oligonucleotide
weight)/mL solution.
[0090] Antagonist A can be synthesized using an iterative chemical
synthesis procedure to produce the oligonucleotide portion, which
is then covalently bonded to a pegylation reagent, as further
described in Example 4 of US Patent Publication NO.
2012/0100136.
[0091] Antagonist A is a persodium salt. Other pharmaceutically
acceptable salts, however, of Antagonist are useful in the
compositions and methods disclosed herein.
[0092] VEGF Antagonists
[0093] In some embodiments, the VEGF antagonist is ranibizumab
(commercially available under the trademark Lucentis.RTM.
(Genentech, San Francisco, Calif.); see FIG. 1 of U.S. Pat. No.
7,060,269 for the heavy chain and light chain variable region
sequences), bevacizumab (commercially available under the trademark
Avastin.RTM. (Genentech, San Francisco, Calif.); see FIG. 1 of U.S.
Pat. No. 6,054,297 for the heavy chain and light chain variable
region sequences), aflibercept (commercially available under the
trademark Eylea.RTM. (Regeneron, Tarrytown, N.Y.), KH902 VEGF
receptor-Fc fusion protein (see Zhang et al. (2008) Mol Vis.
14:37-49), 2C3 antibody (see U.S. Pat. No. 6,342,221, Column 8,
lines 48-67, Column 9, lines 1-21), ORA102 (available from Ora Bio,
Ltd.), pegaptanib (e.g., pegaptanib sodium; commercially available
under the trademark Macugen.RTM. (Valeant Pharmaceuticals,
Bridgewater, N.J.; see FIG. 1 of U.S. Pat. No. 6,051,698)),
bevasiranib (see Dejneka et al. (2008) Mol Vis. 14:997-1005),
SIRNA-027 (Shen et al. (2006) Gene Ther. 13:225-34), decursin (see
U.S. Pat. No. 6,525,089 (Column 3, lines 5-16)), decursinol (see
Ahn et al. (1997) Planta Med. 63:360-1), picropodophyllin (see
Economou (2008) Investigative Ophthalmology & Visual Science.
49:2620-6), guggulsterone (see Kim et al. (2008) Oncol. Rep.
20:1321-7), PLG101 (see Ahmadi and Lim (2008) Expert Opin
Pharmacother. 9:3045-52), PLG201 (see Ahmadi and Lim (2008)),
eicosanoid LXA4 (see Baker et al (2009) J Immun. 182:3819-26),
PTK787 (commercially available under the trademark Vitalanib.TM.;
see Barakat and Kaiser (2009) Expert Opin Investig Drugs
18:637-46), pazopanib (see Takahashi et al. (2009) Arch Ophthalmol.
127:494-9), axitinib (see Hu-Lowe et al. (2008) Clin Cancer Res.
14:7272-83), CDDO-Me (see Sogno et al. (2009) Recent Results Cancer
Res. 181:209-12), CDDO-Imm (see Sogno et al. (2009)), shikonin (see
Hisa et al. (1998) Anticancer Res. 18:783-90),
beta-hydroxyisovalerylshikonin (see Hisa et al. (1998)),
ganglioside GM3 (Chung et al. (2009) Glycobio. 19:229-39), DC101
antibody (see U.S. Pat. No. 6,448,077, Column 2, lines 61-65),
Mab25 antibody (see U.S. Pat. No. 6,448,077, Column 2, lines
61-65), Mab73 antibody (see U.S. Pat. No. 6,448,077, Column 2,
lines 61-65), 4A5 antibody (see U.S. Pat. No. 6,383,484, Column 12,
lines 50-54), 4E10 antibody (see U.S. Pat. No. 6,383,484, Column
10, lines 66-67, Column 11, lines 1-2), 5F12 antibody (see U.S.
Pat. No. 6,383,484, Column 10, lines 62-65), VA01 antibody (see
U.S. Pat. No. 5,730,977, Column 6, lines 26-30), BL2 antibody (U.S.
Pat. No. 5,730,977, Column 6, lines 30-32), VEGF-related protein
(see U.S. Pat. No. 6,451,764, FIG. 1), sFLT01 (see Pechan et al.
(2009) Gene Ther. 16:10-6), sFLT02 (see Pechan et al. (2009)),
Peptide B3 (see Lacal et al. (2008) Eur J Cancer 44:1914-21),
TG100801 (see Palanki et al. (2008) J Med Chem. 51:1546-59),
sorafenib (commercially available under the trademark Nexavar.TM.;
see Kernt et al. (2008) Acta Ophthalmol. 86:456-8), G6-31 antibody
(see Crawford et al. (2009) Cancer Cell 15:21-34), ESBA1008 (see
U.S. Pat. No. 8,349,322), tivozanib (see U.S. Pat. No. 6,821,987,
incorporated by reference in its entirety; Campas et al. (2009)
Drugs Fut 2009, 34(10): 793), or a pharmaceutically acceptable salt
thereof
[0094] In another embodiment, the VEGF antagonist is an antibody or
an antibody fragment which binds to an epitope VEGF-A (SEQ ID NO:
22) or VEGF-B (SEQ ID NO: 23), or any portion of the epitopes. In
one embodiment, the VEGF antagonist is an antibody or antibody
fragment that binds to one or more of an epitope of VEGF (e.g., SEQ
ID NOS: 22 and 23). In another embodiment, the VEGF antagonist is
an antibody or an antibody fragment which binds to an epitope of
VEGF, such as an epitope of VEGF-A, VEGF-B, VEGF-C, VEGF-D, or
VEGF-E. In some embodiments, the VEGF antagonist binds to an
epitope of VEGF such that binding of VEGF and VEGFR are inhibited.
In one embodiment, the epitope encompasses a component of the three
dimensional structure of VEGF that is displayed, such that the
epitope is exposed on the surface of the folded VEGF molecule. In
one embodiment, the epitope is a linear amino acid sequence from
VEGF.
[0095] In some embodiments, an inhibitory antibody directed against
VEGF is known in the art, e.g., those described in U.S. Pat. Nos.
6,524,583, 6,451,764 (VRP antibodies), U.S. Pat. Nos. 6,448,077,
6,416,758, 6,403,088 (to VEGF-C), U.S. Pat. No. 6,383,484 (to
VEGF-D), U.S. Pat. No. 6,342,221 (anti-VEGF antibodies), U.S. Pat.
Nos. 6,342,219 6,331,301 (VEGF-B antibodies), and U.S. Pat. No.
5,730,977, and PCT publications W096/30046, WO 97/44453, and WO
98/45331, the contents of which are incorporated by reference in
their entirety.
[0096] Other non-antibody VEGF antagonists include antibody
mimetics (e.g., Affibody.RTM. molecules, affilins, affitins,
anticalins, avimers, Kunitz domain peptides, and monobodies) with
VEGF antagonist activity. This includes recombinant binding
proteins comprising an ankyrin repeat domain that binds VEGF-A and
prevents it from binding to VEGFR-2. One example is MP0112, also
known as AGN 150998 (DARPin.RTM.). The ankyrin binding domain may
have an amino acid sequence of SEQ ID NO: 97.
[0097] Recombinant binding proteins comprising an ankyrin repeat
domain that binds VEGF-A and prevents it from binding to VEGFR-2
are described in more detail in WO2010/060748 and
WO2011/135067.
[0098] Further specific antibody mimetics with VEGF antagonist
activity are the 40 kD pegylated anticalin PRS-050 and the monobody
angiocept (CT-322).
[0099] The aforementioned non-antibody VEGF antagonist may be
modified to further improve their pharmacokinetic properties or
bioavailability. For example, a non-antibody VEGF antagonist may be
chemically modified (e.g., pegylated) to extend its in vivo
half-life. Alternatively or in addition, it may be modified by
glycosylation or the addition of further glycosylation sites not
present in the protein sequence of the natural protein from which
the VEGF antagonist was derived.
[0100] Other non-antibody VEGF antagonist immunoadhesin currently
in pre-clinical development is a recombinant human soluble VEGF
receptor fusion protein similar to VEGF-trap containing
extracellular ligand-binding domains 3 and 4 from VEGFR2/KDR, and
domain 2 from VEGFR1/Flt-1; these domains are fused to a human IgG
Fc protein fragment (Li et al., 2011 Molecular Vision 17:797-803).
This antagonist binds to isoforms VEGF-A. VEGF-B and VEGF-C. The
molecule is prepared using two different production processes
resulting in different glycosylation patterns on the final
proteins. The two glycoforms are referred to as KH902 (conbercept)
and KH906. The fusion protein can have the amino acid sequence of
SEQ ID NO: 98 and, like VEGF-trap, can be present as a dimer. This
fusion protein and related molecules are further characterized in
EP1767546.
[0101] Anti-C5 Agents
[0102] In certain embodiments, the anti-C5 agent modulates a
function of a C5 complement protein or a variant thereof. In some
embodiments, the anti-C5 agent inhibits a function of C5 complement
protein or a variant thereof. In one embodiment, the function
inhibited by the anti-C5 agent is C5 complement protein
cleavage.
[0103] A C5 complement protein variant as used herein encompasses a
variant that performs substantially the same function as a C5
complement protein function. A C5 complement protein variant in
some embodiments comprises substantially the same structure and in
some embodiments comprises at least 80% sequence identity, in some
embodiments at least 90% sequence identity, and in some embodiments
at least 95% sequence identity to the amino acid sequence of the C5
complement protein comprising the amino acid sequence SEQ ID NO:
24.
[0104] In some embodiments, the anti-C5 agent is selected from a
nucleic acid molecule, an aptamer, an antisense molecule, an RNAi
molecule, a protein, a peptide, a cyclic peptide, an antibody or
antibody fragment, a sugar, a polymer, or a small molecule. In
certain embodiments, the anti-C5 agent is an anti-C5 agent
described in PCT Patent Application Publication No. WO
2007/103549.
[0105] In particular embodiments, the anti-C5 agent is an anti-C5
aptamer. Aptamers are nucleic acid molecules having specific
binding affinity to molecules through interactions other than
classic Watson-Crick base pairing. Aptamers, like peptides
generated by phage display or monoclonal antibodies ("mAbs"), are
capable of specifically binding to selected targets and modulating
the target's activity, e.g., through binding aptamers may block
their target's ability to function. The aptamers may be unpegylated
or pegylated. In particular embodiments, the aptamers may contain
one or more 2' sugar modifications, such as 2'-O-alkyl (e.g.,
2'-O-methyl or 2'-O-methoxyethyl) or 2'-fluoro modifications.
[0106] Illustrative C5 specific aptamers include the aptamers
disclosed in PCT Publication No. WO 2007/103549, which is
incorporated by reference in its entirety. Illustrative C5 specific
aptamers include the aptamers ARC185 (SEQ ID NO: 25), ARC186 (SEQ
ID NO: 26), ARC188 (SEQ ID NO: 27), ARC189 (SEQ ID NO: 28), ARC243
(SEQ ID NO: 29), ARC244 (SEQ ID NO: 30), ARC250 (SEQ ID NO: 31),
ARC296 (SEQ ID NO: 32), ARC297 (SEQ ID NO: 33), ARC330 (SEQ ID NO:
34), ARC331(SEQ ID NO: 35), ARC332 (SEQ ID NO: 36), ARC333 (SEQ ID
NO: 37), ARC334 (SEQ ID NO: 38), ARC411 (SEQ ID NO: 39), ARC412
(SEQ ID NO: 40), ARC413 (SEQ ID NO: 41), ARC414 (SEQ ID NO: 42),
ARC415 (SEQ ID NO: 43), ARC416 (SEQ ID NO: 44), ARC417 (SEQ ID NO:
45), ARC418 (SEQ ID NO: 46), ARC419 (SEQ ID NO: 47), ARC420 (SEQ ID
NO: 48), ARC421 (SEQ ID NO: 49), ARC422 (SEQ ID NO: 50), ARC423
(SEQ ID NO: 51), ARC424 (SEQ ID NO: 52), ARC425 (SEQ ID NO: 53),
ARC426 (SEQ ID NO: 54), ARC427 (SEQ ID NO: 55), ARC428 (SEQ ID NO:
56), ARC429 (SEQ ID NO: 57), ARC430 (SEQ ID NO: 58), ARC431 (SEQ ID
NO: 59), ARC432 (SEQ ID NO: 60), ARC433 (SEQ ID NO: 61), ARC434
(SEQ ID NO: 62), ARC435 (SEQ ID NO: 63), ARC436 (SEQ ID NO: 64),
ARC437 (SEQ ID NO: 65), ARC438 (SEQ ID NO: 66), ARC439 (SEQ ID NO:
67), ARC440 (SEQ ID NO: 68), ARC457 (SEQ ID NO: 69), ARC458 (SEQ ID
NO: 70), ARC459 (SEQ ID NO: 71), ARC473 (SEQ ID NO: 72), ARC522
(SEQ ID NO: 73), ARC523 (SEQ ID NO: 74), ARC524 (SEQ ID NO: 75),
ARC525 (SEQ ID NO: 76), ARC532 (SEQ ID NO: 77), ARC543 (SEQ ID NO:
78), ARC544 (SEQ ID NO: 79), ARC550 (SEQ ID NO: 80), ARC551 (SEQ ID
NO: 81), ARC552 (SEQ ID NO: 82), ARC553 (SEQ ID NO: 83), ARC554
(SEQ ID NO: 84), ARC657 (SEQ ID NO: 85), ARC658 (SEQ ID NO: 86),
ARC672 (SEQ ID NO: 87), ARC706 (SEQ ID NO: 88), ARC913 (SEQ ID NO:
89), ARC874 (SEQ ID NO: 90), ARC954 (SEQ ID NO: 91), ARC1537 (SEQ
ID NO: 92), ARC1730 (SEQ ID NO: 93), or a pharmaceutically
acceptable salt thereof.
[0107] In some embodiments, the anti-C5 agent is an aptamer with
SEQ ID NO: 94, 95, or 96.
[0108] In a particular embodiment, the anti-C5 agent is a C5
specific aptamer comprising the nucleotide sequence of SEQ ID NO:
26 conjugated to a polyethylene glycol moiety via a linker. In some
embodiments, the polyethylene glycol moiety has a molecular weight
greater than about 10 kDa, particularly a molecular weight of about
20 kDa, more particularly about 30 kDa and more particularly about
40 kDa. In some embodiments, the polyethylene glycol moiety is
conjugated via a linker to the 5' end of the aptamer. In some
embodiments, the PEG conjugated to the 5' end of is a PEG of about
40 kDa molecular weight. In particular embodiments the about 40 kDa
PEG is a branched PEG. In some embodiments the branched about 40
kDa PEG is 1,3-bis(mPEG-[about 20 kDa])-propyl-2-(4'-butamide). In
other embodiments the branched about 40 kDa PEG is
2,3-bis(mPEG-[about 20 kDa])-propyl-1-carbamoyl.
[0109] In a particular embodiment, the C5 specific aptamer is a
compound, ARC187, having the structure set forth below:
##STR00001##
[0110] or a pharmaceutically acceptable salt thereof, where
Aptamer=
[0111] fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGf
UfUfUAfCf CfUmGfCmG-3T (SEQ ID NO: 26)
[0112] wherein fC and fU=2'-fluoro nucleotides, and mG and
mA=2'-OMe nucleotides and all other nucleotides are 2'-OH and where
3T indicates an inverted deoxy thymidine. In some embodiments, each
20 kDa mPEG of the above structure has a molecular weight of about
20 kDa.
[0113] In another particular embodiment, the C5 specific aptamer is
a compound, ARC1905, having the structure set forth below:
##STR00002##
[0114] or a pharmaceutically acceptable salt thereof, where
Aptamer=fCmGfCfCGfCmGmGfUfCfUfCmAmGmGfCGfCfUmGmAmGfUfCfUmGmAmGfUfUfUAfCf
CfUmGfCmG-3T (SEQ ID NO: 26)
[0115] wherein fC and fU=2'-fluoro nucleotides, and mG and
mA=2'-OMe nucleotides and all other nucleotides are 2'-OH and where
3T indicates and inverted deoxy thymidine. In some embodiments,
each 20 kDa mPEG of the above structure has a molecular weight of
about 20 kDa.
[0116] In other embodiments, the anti-C5 agent is an antisense
oligonucleotide or ribozyme targeted to C5 that effects C5
inhibition by inhibiting protein translation from the messenger RNA
or by targeting degradation of the corresponding C5 mRNA.
[0117] In still other embodiments, the anti-C5 agent is an anti-C5
RNA interference (RNAi) construct. Certain double stranded
oligonucleotides useful to effect RNAi against C5 complement
protein are less than 30 base pairs in length and may comprise
about 25, 24, 23, 22, 21, 20, 19, 18 or 17 base pairs of
ribonucleic acid and comprise a sequence with substantial sequence
identity to the mRNA sequence of complement C5 protein,
particularly human complement C5 protein. Optionally, the dsRNA
oligonucleotides may include 3' overhang ends. Non-limiting
illustrative 2-nucleotide 3' overhangs are composed of
ribonucleotide residues of any type and may even be composed of
2'-deoxythymidine resides, which lowers the cost of RNA synthesis
and may enhance nuclease resistance of siRNAs in the cell culture
medium and within transfected cells (see Elbashi et al., (2001)
Nature, 411: 494-8).
[0118] Other Agents for Treatment or Prevention of an
Ophthalmological Disease or Disorder
[0119] In another embodiment, another agent useful for treating or
preventing an ophthalmological disease or disorder is volociximab
or a pharmaceutically acceptable salt thereof (Ramakrishnan et al.
(2008) J Exp Ther Oncol. 5:273-86, which is hereby incorporated by
reference in its entirety).
[0120] In some embodiments, a plurality of aptamers can be
associated with a single Non-Immunogenic, High Molecular Weight
Compound, such as Polyalkylene Glycol or PEG, or a Lipophilic
Compound, such as a glycerolipid. The aptamers can all be to one
target or to different targets. In embodiments where a compound
comprises more than one PDGF aptamer, there can be an increase in
avidity due to multiple binding interactions with a target, such as
PDGF or VEGF. In yet further embodiments, a plurality of
Polyalkylene Glycol, PEG, glycerol lipid molecules can be attached
to each other. In these embodiments, one or more aptamers can be
associated with each Polyalkylene Glycol, PEG, or glycerol lipid.
This can result in an increase in avidity of each aptamer to its
target. In addition, in embodiments where there are aptamers to
PDGF or aptamers to PDGF and different Targets associated with
Polyalkylene Glycol, PEG, or glycerol lipid, a drug can also be
associated with, e.g., covalently bonded to, Polyalkylene Glycol,
PEG, or glycerol lipid. Thus the compound would provide targeted
delivery of the drug, with Polyalkylene Glycol, PEG, or glycerol
lipid serving as a Linker, optionally, with one or more additional
linkers.
[0121] Aptamers can be 5'-capped and/or 3'-capped with a 5'-5'
inverted nucleoside cap structure at the 5' end and/or a 3'-3'
inverted nucleoside cap structure at the 3' end. In several
embodiments, Antagonist A, Antagonist B, Antagonist C, Antagonist
D, pegaptanib, bevasiranib and Sirna-027 are 5' or 3'
end-capped.
[0122] Methods for Treating or Preventing an Ophthalmological
Disease or Disorder
[0123] The invention provides methods and compositions useful for
treating or preventing ophthalmological diseases and disorders,
including but not limited to any of the ophthalmological diseases
and disorders described herein.
[0124] In some embodiments, the methods for treating or preventing
an ophthalmological disease or disorder disclosed herein improve
retinal attachment success, improve visual acuity, or stabilize
vision. In some embodiments, the methods disclosed herein prevent
or retard the rate of further vision loss in a subject.
[0125] In some embodiments, administration of Antagonist A or
another pharmaceutically acceptable salt thereof in combination
with a VEGF antagonist or pharmaceutically acceptable salt thereof
and/or an anti-C5 agent improves retinal attachment success,
improves visual acuity, or stabilizes vision to a degree that is
greater than administration of Antagonist A or another
pharmaceutically acceptable salt thereof alone, the VEGF antagonist
or pharmaceutically acceptable salt thereof alone, or the anti-C5
agent alone. In some embodiments, the administration of Antagonist
A or another pharmaceutically acceptable salt thereof and the VEGF
antagonist or pharmaceutically acceptable salt thereof, and
optionally, an anti-C5 agent, has a synergistic effect in treating
or preventing an ophthalmological disease or disorder. For example,
the administration of both Antagonist A or another pharmaceutically
acceptable salt thereof and a VEGF antagonist or pharmaceutically
acceptable salt thereof can improve retinal attachment success,
improve visual acuity, or stabilize vision to a degree that is
greater than an additive effect of administering both Antagonist A
or another pharmaceutically acceptable salt thereof and the VEGF
antagonist or pharmaceutically acceptable salt thereof. In some
embodiments, administration of Antagonist A, alone or in
combination with a VEGF antagonist and/or an anti-C5 agent,
according to the methods described herein, e.g., treatment or
dosing regimens, improves retinal attachment success, improves
visual acuity, or stabilizes vision to a degree that is greater
than administration of Antagonist A, alone or in combination with a
VEGF antagonist and/or an anti-C5 agent, according to previously
described methods.
[0126] In particular embodiments, any of the methods and
compositions of the present invention are used to treat or prevent
an ophthalmological disease or disorder in particular subjects. For
example, in certain embodiments, subjects treated according to a
method described herein are defined or identified based on their
previous treatments for the disease or disorder, specific
manifestations of their disease or disorder being treated, and/or
other characteristics. In one embodiment, the subject has a defined
phenotype or medical history.
[0127] Accordingly, any of the methods described herein may further
comprise identifying the subject to be treated, such as by
determining whether the subject was previously administered a VEGF
antagonist for treating or preventing the disease or disorder or
whether the subject had previously failed monotherapy with a VEGF
antagonist, e.g., by inquiring of the subject or his health care
provider, or by reviewing the subject's medical records.
[0128] In one embodiment, the subject was previously treated with a
VEGF antagonist or anti-VEGF monotherapy for any ocular disease or
disorder for which a VEGF antagonist is used, or for any of the
ocular diseases or disorders described herein (e.g., wet-type
AMD).
[0129] In particular embodiments, the methods and compositions
described herein are useful for treating or preventing an
ophthalmological disease or disorder in a subject who is anti-VEGF
resistant, was previously administered or treated with anti-VEGF
monotherapy, does not respond or had not responded favorably or
adequately to anti-VEGF monotherapy, and/or failed monotherapy with
a VEGF antagonist. In some embodiments, a subject who failed
monotherapy is anti-VEGF resistant, has complement-mediated
inflammation, and/or did not respond adequately to anti-VEGF
monotherapy. In one embodiment, the subject who failed monotherapy
with a VEGF antagonist is a subject who experienced a poor visual
or anatomic outcome after treatment or administration with a VEGF
antagonist. In one embodiment, the subject did not exhibit improved
vision or exhibited reduced vision following anti-VEGF
monotherapy.
[0130] In certain embodiments, the subject does not respond or had
not responded favorably or adequately to anti-VEGF monotherapy, as
determined by the subject's vision loss or by the subject's lack of
significant vision gain following anti-VEGF monotherapy. In one
embodiment, the subject's lack of significant vision gain following
anti-VEGF monotherapy is determined by the subject's loss of
ability to read one or more, in some embodiments three or more, and
in some embodiments fifteen or more, letters of a standardized
chart of vision testing, e.g., the Early Treatment for Diabetic
Retinopathy Study Chart ("ETDRS chart"). In some embodiments, the
vision testing is as described in Early Treatment Diabetic
Retinopathy Study Research Group (ETDRS), Manual of Operations,
Baltimore: ETDRS Coordinating Center, University of Maryland.
Available from: National Technical Information Service, 5285 Port
Royal Road, Springfield, Va. 22161; Accession No. PB85 223006/AS;
Ferris et al., Am J Ophthalmol 94:91-96, 1982; or Example 4, as
described herein. In some embodiments, the vision testing uses one
or more charts available from
http://www.nei.nih.gov/photo/keyword.asp?conditions=Eye+Charts&match=all,
e.g., ETDRS visual acuity Chart 1, 2 and/or R.
[0131] In another embodiment, the subject's vision loss following
anti-VEGF monotherapy is determined by the subject's loss of
ability to read one or more, in some embodiments three or more,
letters or lines of a standardized chart of vision testing, e.g.,
the ETDRS chart, from baseline. In one embodiment, the subject's
lack of significant vision gain following anti-VEGF monotherapy is
determined by the subject's inability to read an additional one or
more, in some embodiment three or more, and in some embodiments
fifteen or more, letters of a standardized chart of vision testing,
e.g., the ETDRS chart, from baseline. In another embodiment, the
subject's lack of significant vision gain following anti-VEGF
monotherapy is determined by the subject's inability to read an
additional one or more, in some embodiments three or more, lines of
a standardized chart of visual testing, e.g., the ETDRS chart, from
baseline. In some embodiments, a subject's vision loss or lack of
significant vision gain is determined by the subject's visual loss
or anatomic signs of poor treatment response, for example,
persistent leakage, increased hemorrhage, persistent or increased
retinal pigment epithelium (RPE) detachment, signs of neovascular
activity, or growth of neovascularization or increased deposition
of abnormal matrix or fibrosis. In particular embodiments, a
subject's vision loss or lack of significant vision gain is
determined at 12 weeks or at 24 weeks following the initiation of
treatment.
[0132] In certain embodiments, the subject is anti-VEGF-resistant
to a VEGF antagonist, e.g., anti-VEGF monotherapy. In one
embodiment, a subject is anti-VEGF resistant if the subject was
previously administered with a VEGF antagonist, e.g., anti-VEGF
monotherapy, that did not result in the treatment or prevention of
the ophthalmological disease or disorder; resulted in only a
temporary treatment or prevention of the ophthalmological disease
or disorder and rendered the subject in further need of treatment
or prevention of the ophthalmological disease or disorder; or that
resulted in the subject's visual decline and rendered the subject
in further need of treatment or prevention of the ophthalmological
disease or disorder.
[0133] In another embodiment, a subject is anti-VEGF resistant if
the subject was previously treated or administered with an
anti-VEGF treatment, e.g., anti-VEGF monotherapy, and failed to
achieve any visual gain or experienced visual decline. In some
embodiments, the subject did not respond adequately to anti-VEGF
treatment. In one embodiment, the subject was administered the
anti-VEGF treatment for one year or longer. In some such
embodiments, the subject is in need of treatment for wet AMD.
[0134] Accordingly, the present invention provides methods for
treating, preventing, or stabilizing wet AMD in a subject, such as
a subject who has failed monotherapy with a VEGF antagonist (e.g.,
is anti-VEGF resistant, has complement-mediated inflammation,
and/or did not respond adequately to anti-VEGF monotherapy). In
particular embodiments, the methods comprise determining whether
the subject was previously administered or treated with anti-VEGF
monotherapy. In certain embodiments, anti-VEGF monotherapy means
administration of only one or more VEGF antagonists. In certain
embodiments, anti-VEGF monotherapy includes the optional
administration of other drugs that are not agents specifically
adapted for treating an ophthalmological disease or disorder, e.g,
wet AMD.
[0135] In certain embodiments, the methods and compositions
described herein are useful for treating or preventing an
ophthalmological disease or disorder in a subject that is
treatment-naive. In some embodiments, the subject is
treatment-naive if the subject was not previously treated for the
ophthalmological disease or disorder. In some embodiments, the
subject is treatment-naive if the subject was not previously
administered or treated with a VEGF antagonist or anti-VEGF
monotherapy ("anti-VEGF-treatment-naive"). In particular
embodiments, the methods further comprise determining whether the
subject was previously treated for the ophthalmological disease or
disorder or administered a VEGF antagonist or anti-VEGF
monotherapy, e.g., by inquiring of the subject or his or her health
care provider, or by reviewing the subject's medical records. In
certain embodiments, anti-VEGF monotherapy means administration of
only one or more VEGF antagonists. In certain embodiments,
anti-VEGF monotherapy includes the optional administration of other
drugs that are not agents specifically adapted for treating an
ophthalmological disease or disorder, e.g, wet AMD. In some
embodiments, the subject is treatment-naive if the subject was not
previously treated for AMD (e.g., wet AMD). In some embodiments,
the subject is treatment-naive if the subject was not previously
treated, or has underwent no previous treatment for AMD (e.g., wet
AMD) in either eye. In yet other embodiments, the subject is
treatment-naive if the subject was not previously treated, or has
underwent no previous treatment, for AMD (e.g., wet AMD; e.g., in
either eye) except for one or more oral supplements of vitamins and
minerals. In some embodiments, the subject is treatment-naive if
the subject was not previously administered a therapeutic agent
used for the treatment of AMD (e.g., wet AMD).
[0136] In certain embodiments, the subject has complement-mediated
inflammation. In certain embodiments, the subject is anti-VEGF
resistant and has complement-mediated inflammation. In certain
embodiments, the complement-mediated inflammation is present in an
eye of the subject. In certain embodiments, the complement-mediated
inflammation results from previous administration with anti-VEGF
monotherapy. In other embodiments, the subject has or has been
diagnosed with complement-mediated inflammation. In still other
embodiments, the subject did not respond adequately to anti-VEGF
monotherapy and has or has been diagnosed with complement-mediated
inflammation. In certain embodiments, complement-mediated
inflammation is diagnosed in the subject using a genetic screening
method. Such genetic screening methods are known to those of skill
in the art and include, but are not limited to, screening for
mutations in complement genes, such as complement factor H(CFH),
CFI, CFHR5, and MCP, BF, and C2 genes.
[0137] In certain embodiments, the methods and compositions
described herein are useful for treating or preventing an
ophthalmological disease or disorder in a subject who is newly
diagnosed with the ophthalmological disease or disorder. In some
embodiments, the subject is newly diagnosed if the subject was not
previously diagnosed for the ophthalmological disease or disorder.
In some embodiments, the subject is newly diagnosed with
age-related macular degeneration. In some embodiments, the subject
is newly diagnosed with dry age-related macular degeneration. In
some embodiments, the subject is newly diagnosed with wet-type AMD.
In particular embodiments, the methods further comprise determining
whether the subject was previously diagnosed for the
ophthalmological disease or disorder, e.g., by inquiring of the
subject or his or her health care provider, or by reviewing the
subject's medical records.
[0138] In some embodiments of the invention, the methods and
compositions described herein are useful for treating or preventing
an ophthalmological disease or disorder that is a neovascular
disorder. In other embodiments of the invention, the
ophthalmological disease or disorder results in retinal edema.
Illustrative ophthalmological diseases or disorders that can be
treated or prevented are described herein.
[0139] Treatment or Prevention of Age-Related Macular
Degeneration
[0140] In one embodiment, the ophthalmological disease or disorder
treated or prevented by any of the methods or compositions
described herein is age-related macular degeneration. Vision
changes that can be associated with macular degeneration include
distortions and/or blind spots (scotoma) detected using an Amsler
grid, changes in dark adaptation (diagnostic of rod cell health),
changes in color interpretation (diagnostic of cone cell health),
or a decrease in visual acuity. Examples of age-related macular
degeneration are nonneovascular (also known as "dry") and
neovascular (also known as "wet" or "exudative") macular
degeneration.
[0141] In one embodiment, the dry age-related macular degeneration
is associated with the formation of drusen. In one embodiment,
treating or preventing dry macular degeneration encompasses
treating or preventing an abnormality of the retinal pigment
epithelium and/or underlying vasculature, known as
choriocapilaries. Examples of abnormalities of the retinal pigment
epithelium include geographic atrophy, non-geographic atrophy,
focal hypopigmentation, and focal hyperpigmentation. In another
embodiment, treating or preventing wet age-related macular
degeneration encompasses treating or preventing choroidal
neovascularization or pigment epithelial detachment.
[0142] In one embodiment, the invention provides methods for
treating or preventing wet age-related macular degeneration.
Another aspect of the present invention is methods for treating,
preventing, or inhibiting a choroidal neovascular complex in a
subject, e.g., inhibiting the formation or growth of a choroidal
neovascular complex.
[0143] In another aspect of the invention, the invention provides
methods for treating or preventing choroidal neovascularization in
a subject. In some embodiments, the choroidal neovascularization is
subfoveal choroidal neovascularization. In some embodiments, the
subfoveal choroidal neovascularization is due to age-related
macular degeneration. In one embodiment, the subfoveal choroidal
neovascularization is secondary to exudative type AMD. In other
embodiments, the subfoveal choroidal neovascularization is present
in subjects who have exudative type AMD, and in other embodiments,
subfoveal choroidal neovascularization is present in subjects who
do not have exudative type AMD. In some embodiments, the subfoveal
choroidal neovascularization is secondary to inflammatory,
traumatic, myopic, idiopathic or neoplastic afflictions of the
macula.
[0144] In some embodiments, wet age-related macular degeneration is
classified according to the appearance of its choroidal
neovascularization (CNV), into classic, occult or mixed (classic
and occult) CNV types, as determined by an angiography, known as
fluorescence angiography. Classic, occult or mixed (classic and
occult) CNV classification can be based on the time, intensity and
level of definition of dye appearance, and leakage from the CNV, as
assessed by the fluorescein angiography. In some embodiments, the
subject has classic CNV (e.g., pure classic) or mixed CNV
(predominantly or minimally classic CNV). In some embodiments, the
subject has occult CNV (e.g., pure occult CNV).
[0145] The administration of Antagonist A or another
pharmaceutically acceptable salt thereof and the VEGF antagonist
and/or anti-C5 agent can have a synergistic effect in treating or
preventing classic CNV or occult CNV. For example, administration
of both Antagonist A or another pharmaceutically acceptable salt
thereof and the VEGF antagonist can improve visual acuity or
stabilize vision to a degree that is greater than an additive
effect of both Antagonist A or another pharmaceutically acceptable
salt thereof and the VEGF antagonist. In another example,
administration of both Antagonist A or another pharmaceutically
acceptable salt thereof and the VEGF antagonist can reduce CNV or
inhibit the growth of CNV to a greater degree than administration
of Antagonist A or another pharmaceutically acceptable salt thereof
or the VEGF antagonist. In some embodiments, administration of both
Antagonist A or another pharmaceutically acceptable salt thereof
and the VEGF antagonist can reduce CNV in a shorter timeframe or
with a lower dosage amount or frequency, as compared to the
timeframe or dosage amount with administration of Antagonist A or
another pharmaceutically acceptable salt thereof or the VEGF
antagonist. In some embodiments, administration of both Antagonist
A or another pharmaceutically acceptable salt thereof and the VEGF
antagonist can reduce CNV or inhibit the growth of CNV to a greater
degree than an additive effect of both Antagonist A or another
pharmaceutically acceptable salt thereof and the VEGF antagonist.
In some embodiments, administration of both Antagonist A or another
pharmaceutically acceptable salt thereof and the VEGF antagonist
can reduce CNV in a shorter timeframe or with a lower dosage amount
or frequency, as compared to an additive timeframe, dosage amount
or frequency with administration of both Antagonist A or another
pharmaceutically acceptable salt thereof and the VEGF
antagonist.
[0146] In one embodiment, the present invention provides methods
for treating, preventing, or stabilizing non-exudative type ("dry
type") AMD. In one embodiment, Antagonist A or another
pharmaceutically acceptable salt thereof, an anti-C5 agent, the
combination of Antagonist A or another pharmaceutically acceptable
salt thereof and an anti-C5 agent, or the combination of an anti-C5
agent and a VEGF antagonist is administered in an amount effective
to maintain about the same level of drusen or reduce the level of
drusen (e.g., amount, size, number, area and/or morphology) (e.g.,
size, number, area and/or morphology) as compared to the subject's
drusen level prior to administration of Antagonist A or another
pharmaceutically acceptable salt thereof, the anti-C5 agent, the
combination of Antagonist A or another pharmaceutically acceptable
salt thereof and the anti-C5 agent, or the combination of an
anti-C5 agent and a VEGF antagonist, respectively. In a particular
embodiment, the level of drusen is reduced by at least or about 5%,
at least or about 10%, at least or about 20%, at least or about
30%, at least or about 40%, or at least or about 50%.
[0147] In some embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof, an anti-C5 agent, the
combination of Antagonist A or another pharmaceutically acceptable
salt thereof and the anti-C5 agent, or the combination of the
anti-C5 agent and a VEGF antagonist is administered in an amount
effective to inhibit, slow, or prevent the progression of
non-exudative type AMD to geographic atrophy (GA). GA is an
advanced form of non-exudative type AMD. In other embodiments, the
Antagonist A or another pharmaceutically acceptable salt thereof
and/or the anti-C5 agent or a pharmaceutically acceptable salt
thereof is administered in an amount effective to reduce the growth
or area of a GA lesion over time as compared to that in a subject
not receiving Antagonist A or another pharmaceutically acceptable
salt thereof and/or the anti-C5 agent. In other embodiments, the
anti-C5 agent or a pharmaceutically acceptable salt thereof and a
VEGF antagonist is administered in an amount effective to reduce
the growth or area of a GA lesion over time as compared to that in
a subject not receiving the anti-C5 agent and/or the VEGF
antagonist. In a particular embodiment, the change in area or
growth of the geographic atrophy lesion over time is reduced by at
least or about 5%, at least or about 10%, at least or about 20%, at
least or about 30%, at least or about 40%, or at least or about
50%. Methods of identifying and assessing the size of geographic
lesions are known to those of skill in the art and include
autofluorescence imaging and optical coherence tomography.
[0148] In particular embodiments, a subject in whom non-exudative
AMD converts to exudative AMD, e.g., when new blood vessels invade
the overlying retina, is treated. The present invention further
provides methods for treating, preventing, or stabilizing drusen
retinopathy secondary to complement-mediated immune disorders,
including drusen retinopathy secondary to membranoproliferative
glomerulonephritis type II disease. In some embodiments, Antagonist
A or another pharmaceutically acceptable salt thereof and/or an
anti-C5 agent and/or a VEGF antagonist is administered in an amount
effective to reduce retinal drusen in subjects having or having
been diagnosed with membranoproliferative glomerulonephritis type
II disease or exudative-type AMD as compared to the level of
retinal drusen prior to administration of Antagonist A or another
pharmaceutically acceptable salt thereof and/or an anti-C5 agent
and/or a VEGF antagonist. In certain embodiments, the level of
drusen is reduced by at least or about 5%, at least or about 10%,
at least or about 20%, at least or about 30%, at least or about
40%, or at least or about 50%.
[0149] In one embodiment, the ophthalmological disease or disorder
is polypoidal choroidal vasculopathy (PCV), a variant of wet
AMD.
[0150] Treatment or Prevention of a Condition Associated with
Choroidal Neovascularization
[0151] In one embodiment, the ophthalmological disease or disorder
is a condition associated with choroidal neovascularization.
Examples of conditions associated with choroidal neovascularization
include a degenerative, inflammatory, traumatic or idiopathic
condition. Treating or preventing a degenerative disorder
associated with choroidal neovascularization also encompasses
treating or preventing a heredodegerative disorder. Examples of
heredodegenerative disorders include vitelliform macular dystrophy,
fundus flavimaculatus and optic nerve head drusen. Examples of
degenerative conditions associated with choroidal
neovascularization include myopic degeneration or angioid streaks.
In some embodiments, treating or preventing an inflammatory
disorder associated with choroidal neovascularization encompasses
treating or preventing ocular histoplasmosis syndrome, multifocal
choroiditis, serpininous choroiditis, toxoplasmosis, toxocariasis,
rubella, Vogt-Koyanagi-Harada syndrome, Behcet syndrome or
sympathetic ophthalmia. In some embodiments, treating or preventing
a traumatic disorder associated with choroidal neovascularization
encompasses treating or preventing choroidal rupture or a traumatic
condition caused by intense photocoagulation.
[0152] Treatment or Prevention of Proliferative Retinopathy
[0153] One particular aspect of the invention provides methods and
compositions for treating or preventing proliferative
vitreoretinopathy (PVR). In some embodiments, the PVR is a moderate
form. In other embodiments, the PVR is a severe form. In some
embodiments, the PVR is a recurrent form. In one embodiment, the
subject with PVR also has or had retinal detachment, or the subject
has PVR associated with retinal detachment, or PVR related scarring
(e.g., scarring resulting from PVR, e.g., retinal scarring). In
some embodiments, the PVR is characterized based on the
configuration of the retina and the location of the scar tissue,
such as in shown in Table 2 (See Lean J, et al. Classification of
proliferative vitreoretinopathy used in the silicone study. The
Silicone study group. Ophthalmology 1989; 96:765-771). Any of these
categories or types of PVR can be treated or prevented according to
the present invention.
TABLE-US-00001 TABLE 2 Classification of PVR Type Type of Location
no. contraction of PVR Summary of Clinical Signs 1 Focal Posterior
Starfold 2 Diffuse Posterior Confluent irregular retinal folds in
posterior retina; remainder of retina drawn posteriorly; optic disc
may not be visible 3 Sub-retinal Posterior "Napkin ring" around
disc or "clothesline" elevation of retina 4 Circumferential
Anterior Irregular retinal folds in the anterior retina; series of
radial folds more posteriorly; peripheral retina within vitreous
base stretched inward 5 Perpendicular Anterior Smooth
circumferential fold of retina at insertion of posterior hyaloid 6
Anterior Anterior Circumferential fold of retina at insertion of
posterior hyaloid pulled forward; trough of peripheral retina
anteriorly; ciliary processes stretched with possible hypotony;
iris retracted
[0154] The present methods for treating PVR can further comprise
administering another agent useful for treating PVR, such as a
corticosteriod; antineoplastic drug, such as 5-fluorouracil;
colchicine; retinoid; heparin; epidermal growth factor receptor
(EGFR) inhibitor, such as gefitinib or erlotinib.
[0155] Another aspect of the invention is methods for treating or
preventing a proliferative retinopathy, such as one related to PVR
(e.g., treating or preventing an ocular manifestation of a
proliferative retinopathy), such as proliferative diabetic
retinopathy, sickle cell retinopathy, post traumatic retinopathy,
hyperviscosity syndromes, Aortic arch syndromes, ocular ischemic
syndromes, carotid-cavernous fistula, multiple sclerosis, retinal
vasculitis, systemic lupus erythematosus, arteriolitis with SS-A
autoantibody, acute multifocal hemorrhagic vasculitis, vasculitis
resulting from infection, vasculitis resulting from Behcet's
disease, sarcoidosis, coagulopathies, sickling hemoglobinopathies,
AC and C-.beta. thalassemia, small vessel hyalinosis, incontinentia
pigmenti, Eales' disease, branch retinal artery or vein occlusion,
frosted branch angiitis, idiopathic retinal vasculitis, aneurysms,
neuroretinitis, retinal embolization, retinopathy of prematurity,
Uveitis, pars planitis, acute retinal necrosis, birdshot
retinochoroidopathy, long-standing retinal detachment, choroidal
melanoma, radiation retinopathy, familial exudative
vitreoretinopathy, inherited retinal venous beading, retinoschisis,
retinitis pigmentosa, or autosomal dominant
vitreoretinochoroidopathy.
[0156] Another aspect of the invention is methods for treating or
preventing a disease or condition that is a cause that results in
proliferative retinopathy or PVR. In one embodiment, post-retinal
detachment (e.g., that causes or results in PVR) is treated or
prevented. In another embodiment, proliferative diabetic
retinopathy (e.g., that causes or results in PVR) or sickle-cell
retinopathy (e.g., that causes or results in PVR), as well as
scarring caused by one or more of these disorders is treated or
prevented.
[0157] Treatment or Prevention of Glaucoma
[0158] In one embodiment, the opthalmological disease or disorder
is glaucoma. In one embodiment the glaucoma is open angle glaucoma,
primary open angle glaucoma, secondary open angle glaucoma, closed
angle glaucoma, glaucoma that is associated with diabetes, glaucoma
that is associated with diabetic retinopathy, angle closure
glaucoma, narrow angle glaucoma or acute glaucoma.
[0159] Treatment or Prevention of a Neoplasm
[0160] In one embodiment, the ophthalmological disease or disorder
is a neoplasm. Examples of neoplams include an eyelid tumor, a
conjunctival tumor, a choroidal tumor, an iris tumor, an optic
nerve tumor, a retinal tumor, an infiltrative intraocular tumor or
an orbital tumor. Examples of an eyelid tumor include basal cell
carcinoma, squamous carcinoma, sebaceous carcinoma, malignant
melanoma, capillary hemangioma, hydrocystoma, nevus or seborrheic
keratosis. Examples of a conjunctival tumor include conjunctival
Kaposi's sarcoma, squamous carcinoma, intraepithelial neoplasia of
the conjunctiva, epibular dermoid, lymphoma of the conjunctiva,
melanoma, pingueculum, or pterygium. Examples of a choroidal tumor
include choroidal nevus, choroidal hemangioma, metastatic choroidal
tumor, choroidal osteoma, choroidal melanoma, ciliary body melanoma
or nevus of Ota. Examples of an iris tumor include anterior uveal
metastasis, iris cyst, iris melanocytoma, iris melanoma, or pearl
cyst of the iris. Examples of an optic nerve tumor include optic
nerve melanocytoma, optic nerve sheath meningioma, choroidal
melanoma affecting the optic nerve, or circumpapillary metastasis
with optic neuropathy. Examples of a retinal tumor include retinal
pigment epithelial (RPE) hypertrophy, RPE adenoma, RPE carcinoma,
retinoblastoma, or hamartoma of the RPE. In some embodiments, the
present invention provides methods for inhibiting retinal pigment
epithelium (RPE) or glial cells, such as inhibiting the migration
of RPE or glial cells. Examples of an infiltrative intraocular
tumor include chronic lymphocytic leukemia, infiltrative
choroidopathy, or intraocular lymphoma. Examples of an orbital
tumor include adenoid cystic carcinoma of the lacrimal gland,
cavernous hemangioma of the orbit, lymphangioma of the orbit,
orbital mucocele, orbital pseudotumor, orbital rhabdomyosarcoma,
periocular hemangioma of childhood, or sclerosing orbital
psuedotumor.
[0161] Another aspect of the invention is methods for treating or
preventing von Hippel-Lindau (VHL) disease (e.g., treating or
preventing visual loss associated VHL disease). In some
embodiments, VHL disease is characterized by tumors. The tumors may
be malignant or benign. In another embodiment, a benign or
malignant tumor in the eye (e.g., ocular tumor) or a cyst (e.g., an
ocular cyst), associated with VHL is treated or prevented. In some
embodiments, the tumors are hemangioblastomas. In some embodiments,
the tumors are von Hippel angioma or retinal capillary hemangiomas
(e.g., juxtapapillary hemangioma).
[0162] In some embodiments, the subject with VHL disease has a
deficiency of the protein "pVHL."
[0163] In some embodiments, the VHL disease is severe (e.g., a
subject with severe VHL disease has a lesion that cannot be
effectively treated with a non-pharmacologic modality (e.g., laser
or cryotherapy), for example, as the lesion resides over or
adjacent to a significant neural structure (e.g., optic nerve,
macula, papillomacular bundle) that can be damaged with laser or
cryotherapy).
[0164] In some embodiments, the methods for treating or preventing
VHL disease comprise treating an ocular or non-ocular manifestation
(e.g., benign or malignant neoplasm or cyst of the kidney, adrenal
gland, pancreas, brain, spinal cord, inner ear, epididymis, or
broad ligament) of VHL.
[0165] In some embodiments, the subjected being treated has a
family history of VHL disease or one or more of retinal capillary
hemangioma (RCH), spinal or cerebellar hemangioblastoma,
pheochromocytoma, multiple pancreatic cysts, epididymal or broad
ligament cystadenoma, multiple renal cysts, and renal cell
carcinoma. In some embodiments, the subject has one or more RCH,
spinal and cerebellar hemangioblastoma, pheochromocytoma, multiple
pancreatic cysts, epididymal or broad ligament cystadenomas,
multiple renal cysts, or renal cell carcinoma before the age of 60
years. In some embodiments, the subject has two or more
hemangioblastomas of the retina or brain or a single
hemangioblastoma in association with a visceral manifestation, such
as kidney or pancreatic cysts; renal cell carcinoma; adrenal or
extra-adrenal pheochromocytomas; endolymphatic sac tumors;
papillary cystadenomas of the epididymis or broad ligament; or
neuroendocrine tumors of the pancreas. In some embodiments, the
subject has a disease-causing germline mutation in the VHL
gene.
[0166] In some embodiments, the subject has RCH that exhibit
activity, such as associated intra- or sub-retinal exudation or
lipid deposition (which may reflect ongoing vascular incompetence
and is not reflective of residual changes following previous
treatment or secondary to coexistent retinal traction); increased
size of the tumor compared to a previous time point as assessed by
fundus photography or fluorescein angiography (FA); associated
intra-, sub-, or pre-retinal hemorrhage not secondary to previous
treatment, as assessed by fundus photography or FA; appearance of
new feeder vessels or greater dilation or tortuosity of existing
feeder vessels compared to a previous time point; and/or vitreous
cell or haze indicative of vitreous exudation, in the absence of
other ocular features potentially responsible for such findings. In
some embodiments, the subject has RCH that is not readily treatable
using cryotherapy or thermal laser because of its size, posterior
location, poor previous response to conventional therapy, or other
factors.
[0167] In some embodiments, methods or compositions of the
invention are used to treat or prevent a complication of VHL,
visual dysfunction (e.g., from VHL), or a fibrous complication of
VHL (e.g., fibrous meningioma). In certain embodiments, the methods
or compositions of the present invention are used to treat a
manifestation of VHL as vascular proliferation that comprises fine,
superficial, juxtapapillary vessels that are often associated with
fibrovascular proliferation and epiretinal membrane formation.
[0168] Treatment or Prevention of Scarring or Fibrosis
[0169] Another aspect the invention provides methods for treating,
inhibiting or preventing scarring or fibrosis (e.g., scarring or
fibrosis is under the macular region of the retina). In some
embodiments, the scarring is a fibrovascular scar (e.g., in the
retina). In some embodiments, the fibrosis is hepatic, pulmonary or
renal fibrosis. In some embodiments, the fibrosis is ocular
fibrosis. In some embodiments, the fibrosis is sub-retinal fibrosis
(e.g., associated with neovascular AMD). In some embodiments, the
sub-retinal fibrosis is not associated with neovascular AMD. In
some embodiments, the fibrosis is subfoveal fibrosis. In some
embodiments, the subfoveal fibrosis is with retinal atrophy. In
some embodiments, subfoveal fibrosis or sub-retinal fibrosis
develops after administration of a VEGF antagonist, e.g., anti-VEGF
monotherapy.
[0170] In some embodiments, the scarring results from glaucoma
surgery, or follows glaucoma surgery, such as trabeculectomy,
filtering surgery (such as partial thickness filtering surgery),
glaucoma filtering procedures, minimally invasive glaucoma surgery,
glaucoma valve implant surgery, glaucoma seton surgery, glaucoma
tube shunt placement, glaucoma stent placement, or combined
cataract and glaucoma surgery. In some embodiments, the methods of
the present invention are useful to treat or prevent scarring
relating to or resulting from glaucoma surgery (e.g., that can
result in scar related proliferation). In some embodiments, the
scarring is sub-retinal scarring. In some embodiments, the scarring
is sub-retinal scarring that occurs following choroidal neovascular
regression.
[0171] In particular embodiments, methods for treating, inhibiting
or preventing sub-retinal fibrosis (e.g., reducing the formation of
sub-retinal fibrosis) comprise administering to a subject in need
thereof an effective amount of Antagonist A or another
pharmaceutically acceptable salt thereof and a VEGF antagonist. In
some embodiments, the subject has or is diagnosed with AMD (e.g.,
wet AMD). In some embodiments, the subject has or is diagnosed with
advanced wet AMD.
[0172] Treatment or Prevention of Other Ophthalmological Diseases
and Disorders
[0173] In certain embodiments, the ophthalmological disease or
disorder is a cataract (e.g., age-related cataract), diabetic
macula edema, macular telangiectasia (e.g., type 1 or 2 macular
telangiectasia), atrophic macular degeneration, chorioretinopathy
(e.g., central serous chorioretinopathy), retinal inflammatory
vasculopathy, pathological retinal angiogenesis, age-related
maculopathy, retinoblastoma, Pseudoxanthoma elasticum, a
vitreoretinal disease, choroidal sub-retinal neovascularization,
central serous chorioretinopathy, ischemic retinopathy,
hypertensive retinopathy or diabetic retinopathy (e.g.,
nonproliferative or proliferative diabetic retinopathy, such as
macular edema or macular ischemia), retinopathy of prematurity
(e.g., associated with abnormal growth of blood vessels in the
vascular bed supporting the developing retina), venous occlusive
disease (e.g., a retinal vein occlusion, branch retinal vein
occlusion or central retinal vein occlusion), arterial occlusive
disease (e.g., branch retinal artery occlusion (BRAO), central
retinal artery occlusion or ocular ischemic syndrome), central
serous chorioretinopathy (CSC), cystoid macular edema (CME) (e.g.,
affecting the central retina or macula, or after cataract surgery),
retinal telangiectasia (e.g., characterized by dilation and
tortuosity of retinal vessels and formation of multiple aneurysms,
idiopathic JXT, Leber's miliary aneurysms, or Coats' disease),
arterial macroaneurysm, retinal angiomatosis, radiation-induced
retinopathy (RIRP), or rubeosis iridis (e.g., associated with the
formation of neovascular glaucoma, diabetic retinopathy, central
retinal vein occlusion, ocular ischemic syndrome, or chronic
retinal detachment).
[0174] In other embodiments, the ophthalmological disease or
disorder is sickle cell disease (SCD), anemia, or sickle cell
retinopathy (e.g., non-neovascular or non-proliferative ocular
manifestations). In some embodiments, vaso-occlusive phenomena or
hemolysis associated with SCD is treated or prevented. In some
embodiments, ocular manifestations of SCD include vascular
occlusions in the conjunctiva, iris, retina, or choroid.
Non-neovascular or non-proliferative ocular manifestations can
include conjunctival vascular occlusions which transform smooth
vessels into comma-shaped fragments, iris atrophy, retinal "salmon
patch" hemorrhages, retinal pigmentary changes and other
abnormalities of the retinal vasculature, macula, choroid, and
optic disc. In some embodiments, neovascularization or the
proliferative ocular manifestation involves the growth of abnormal
vascular fronds which can lead to vitreous hemorrhage, retinal
detachment, epiretinal membranes, resulting in vision loss. In some
embodiments, the methods further comprise performing another
treatment, such as diathermy, cryotherapy, laser photocoagulation
or surgery (e.g., vitrectomy).
[0175] In one embodiment, the ophthalmological disease or disorder
is a condition associated with peripheral retinal
neovascularization. Examples of conditions associated with
peripheral retinal neovascularization include ischemic vascular
disease, inflammatory disease with possible ischemia, incontinentia
pigmenti, retinitis pigmentosa, retinoschisis or chronic retinal
detachment.
[0176] Examples of ischemic vascular disease include proliferative
diabetic retinopathy, branch retinal vein occlusion, branch retinal
arteriolar occlusion, carotid cavernous fistula, sickling
hemoglobinopathy, non-sickling hemoglobinopathy, IRVAN syndrome
(retinal vasculitic disorder characterized by idiopathic retinal
vasculitis, an aneurysm, and neuroretinitis), retinal embolization,
retinopathy of prematurity, familial exudative vitreoretinopathy,
hyperviscosity syndrome, aortic arch syndrome or Eales disease.
Examples of sickling hemoglobinopathy include SS hemoglobinopathy
and SC hemoglobinopathy. Examples of non-sickling hemoglobinopathy
include AC hemoglobinopathy and AS hemoglobinopathy. Examples of
hyperviscosity syndrome include leukemia, Waldenstrom
macroglobulinemia, multiple myeloma, polycythemia or
myeloproliferative disorder.
[0177] In some embodiments, treating or preventing an inflammatory
disease with possible ischemia encompasses treating or preventing
retinal vasculitis associated with systemic disease, retinal
vasculitis associated with an infectious agent, uveitis or birdshot
retinopathy. Examples of systemic diseases include systemic lupus
erythematosis, Behcet's disease, inflammatory bowel disease,
sarcoidosis, multiple sclerosis, Wegener's granulomatosis and
polyarteritis nodosa. Examples of infectious agents include a
bacterial agent that is the causative agent for syphilis,
tuberculosis, Lyme disease or cat-scratch disease, a virus such as
herpesvirus, or a parasite such as Toxocara canis or Toxoplasma
gondii. Examples of uveitis include pars planitis or Fuchs uveitis
syndrome.
[0178] Compositions for Therapeutic or Prophylactic
Administration
[0179] Antagonist A or another pharmaceutically acceptable salt
thereof, VEGF antagonists, or anti-C5 agents can be administered as
a component of a composition that further comprises a
pharmaceutically acceptable carrier or vehicle, e.g., a
pharmaceutical composition. In certain embodiments, each
therapeutic agent is administered to the subject in a separate
composition. However, in other embodiments, two or more therapeutic
agents may be administered to the subject in the same composition.
In one embodiment, a composition of the invention comprises an
effective amount of Antagonist A or another pharmaceutically
acceptable salt thereof, a VEGF antagonist, and/or an anti-C5 agent
and a pharmaceutically acceptable carrier or vehicle. In another
embodiment, a composition comprising Antagonist A or another
pharmaceutically acceptable salt thereof and another composition
comprising a VEGF antagonist are administered. In some embodiments,
another composition comprising an anti-C5 agent is administered. In
some embodiments, a composition comprising Antagonist A or another
pharmaceutically acceptable salt thereof and a VEGF antagonist is
administered. In some embodiments, another composition comprising
an anti-C5 agent is also administered.
[0180] Administration of each antagonist may be by any suitable
means that results in an amount of Antagonist A or another
pharmaceutically acceptable salt thereof, VEGF antagonist, and/or
anti-C5 agent that is effective for the treatment or prevention of
an ophthalmological disease or disorder. Each antagonist, for
example, can be admixed with a suitable carrier substance, and is
generally present in an amount of 1-95% by weight of the total
weight of the composition. The composition may be provided in a
dosage form that is suitable for ophthalmic, oral, parenteral
(e.g., intravenous, intramuscular, subcutaneous), rectal,
transdermal, nasal, or inhalant administration. In one embodiment,
the composition is in a form that is suitable for injection
directly in the eye. The composition may be in form of, e.g.,
tablets, capsules, pills, powders, granulates, suspensions,
emulsions, solutions, gels including hydrogels, pastes, ointments,
creams, plasters, delivery devices, suppositories, enemas,
injectables, implants, sprays, drops or aerosols. The compositions
comprising one or more antagonists can be formulated according to
conventional pharmaceutical practice (see, e.g., Remington: The
Science and Practice of Pharmacy, (20th ed.) ed. A. R. Gennaro,
2000, Lippincott Williams & Wilkins, Philadelphia, Pa. and
Encyclopedia of Pharmaceutical Technology, eds., J. Swarbrick and
J. C. Boylan, 1988-2002, Marcel Dekker, New York).
[0181] The compositions are, in one useful aspect, administered
parenterally (e.g., by intramuscular, intraperitoneal, intravenous,
intraocular, intravitreal, retro-bulbar, subconjunctival, subtenon
or subcutaneous injection or implant) or systemically. Formulations
for parenteral or systemic administration include sterile aqueous
or non-aqueous solutions, suspensions, or emulsions. A variety of
aqueous carriers can be used, e.g., water, buffered water, saline,
and the like. Examples of other suitable vehicles include
polypropylene glycol, polyethylene glycol, vegetable oils, gelatin,
hydrogels, hydrogenated naphalenes, and injectable organic esters,
such as ethyl oleate. Such formulations may also contain auxiliary
substances, such as preserving, wetting, buffering, emulsifying,
and/or dispersing agents. Biocompatible, biodegradable lactide
polymer, lactide/glycolide copolymer, or
polyoxyethylene-polyoxypropylene copolymers may be used to control
the release of the active ingredients.
[0182] Alternatively, the compositions can be administered by oral
ingestion. Compositions intended for oral use can be prepared in
solid or liquid forms, according to any method known to the art for
the manufacture of pharmaceutical compositions.
[0183] Solid dosage forms for oral administration include capsules,
tablets, pills, powders, and granules. Generally, these
pharmaceutical preparations contain active ingredients admixed with
non-toxic pharmaceutically acceptable excipients. These include,
for example, inert diluents, such as calcium carbonate, sodium
carbonate, lactose, sucrose, glucose, mannitol, cellulose, starch,
calcium phosphate, sodium phosphate, kaolin and the like. Binding
agents, buffering agents, and/or lubricating agents (e.g.,
magnesium stearate) may also be used. Tablets and pills can
additionally be prepared with enteric coatings. The compositions
may optionally contain sweetening, flavoring, coloring, perfuming,
and preserving agents in order to provide a more palatable
preparation.
[0184] Compositions useful for ophthalmic use include tablets
comprising one or more antagonists in admixture with a
pharmaceutically acceptable excipient. These excipients may be, for
example, inert diluents or fillers (e.g., sucrose and sorbitol),
lubricating agents, glidants, and antiadhesives (e.g., magnesium
stearate, zinc stearate, stearic acid, silicas, hydrogenated
vegetable oils, or talc).
[0185] The antagonists of the present invention may be admixed in a
tablet or other vehicle, or may be partitioned. In one example, one
antagonist is contained on the inside of the tablet, and the other
antagonist is on the outside, such that a substantial portion of
the other antagonist is released prior to the release of the
contained antagonist. If desired, antagonists in a tablet form may
be administered using a drug delivery device (see below).
[0186] For example, compositions of the present invention may be
administered intraocularly by intravitreal injection into the eye
as well as by subconjunctival and subtenon injections. Other routes
of administration include transcleral, retrobulbar,
intraperitoneal, intramuscular, and intravenous. Alternatively,
compositions can be administered using a drug delivery device or an
intraocular implant (see below).
[0187] In one embodiment, Antagonist A or another pharmaceutically
acceptable salt thereof or VEGF antagonist (e.g., ranibizumab,
bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008) is
administered intravitreally with a 30-gauge or 27-gauge needle. In
some embodiments, a 0.5 inch needle is used. In one embodiment,
Antagonist A or another pharmaceutically acceptable salt thereof is
administered intravitreally with a 30-gauge 0.5 inch needle and a
VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept,
pegaptanib sodium, or ESBA1008) is administered intravitreally with
a 27-gauge needle. In some embodiments, 50 .mu.L (1.5 mg in 0.05
mL) of Antagonist A or another pharmaceutically acceptable salt
thereof is administered intravitreally with a 30-gauge 0.5 inch
needle and 50 .mu.L of a VEGF antagonist (e.g., 0.5 mg of
ranibizumab, 1.25 mg of bevacizuamb, or 2.0 mg of aflibercept) is
administered intravitreally with a 27-gauge needle.
[0188] Liquid dosage forms for oral administration can include
pharmaceutically acceptable emulsions, solutions, suspensions,
syrups, and soft gelatin capsules. These forms can contain inert
diluents commonly used in the art, such as water or an oil medium,
and can also include adjuvants, such as wetting agents, emulsifying
agents, and suspending agents.
[0189] In some instances, the compositions can also be administered
topically, for example, by patch or by direct application to a
region, such as the epidermis or the eye, susceptible to or
affected by a neovascular disorder, or by iontophoresis.
[0190] In one embodiment, the compositions can comprise one or more
pharmaceutically acceptable excipients. In one embodiment,
excipients for compositions that comprise an antagonist include,
but are not limited to, buffering agents, nonionic surfactants,
preservatives, tonicity agents, sugars, amino acids, and
pH-adjusting agents. Suitable buffering agents include, but are not
limited to, monobasic sodium phosphate, dibasic sodium phosphate,
and sodium acetate. Suitable nonionic surfactants include, but are
not limited to, polyoxyethylene sorbitan fatty acid esters such as
polysorbate 20 and polysorbate 80. Suitable preservatives include,
but are not limited to, benzyl alcohol. Suitable tonicity agents
include, but are not limited to sodium chloride, mannitol, and
sorbitol. Suitable sugars include, but are not limited to,
.alpha.,.alpha.-trehalose. Suitable amino acids include, but are
not limited to glycine and histidine. Suitable pH-adjusting agents
include, but are not limited to, hydrochloric acid, acetic acid,
and sodium hydroxide. In one embodiment, the pH-adjusting agent or
agents are present in an amount effective to provide a pH of about
3 to about 8, about 4 to about 7, about 5 to about 6, about 6 to
about 7, or about 7 to about 7.5. In one embodiment, the
compositions do not comprise a preservative. In another embodiment,
the composition does not comprise an antimicrobial agent. In
another embodiment, the composition does not comprise a
bacteriostat. Suitable excipients for a VEGF antagonist also
include those described in U.S. Pat. No. 7,365,166, the contents of
which are herein incorporated by reference in their entirety.
[0191] In one embodiment, the composition is in the form of an
aqueous solution that is suitable for injection. In one embodiment,
a composition is in the form of an aqueous solution that is
suitable for injection. In one embodiment, a composition comprises
Antagonist A or another pharmaceutically acceptable salt thereof, a
buffering agent, a pH-adjusting agent, and water for injection. In
another embodiment, a composition comprises Antagonist A or another
pharmaceutically acceptable salt thereof, monobasic sodium
phosphate, dibasic sodium phosphate, sodium chloride, hydrochloride
acid, and sodium hydroxide.
[0192] In one embodiment, the composition comprises a VEGF
antagonist, a buffering agent, a sugar, a nonionic surfactant, and
water for injection. In another embodiment, the composition
comprises a VEGF antagonist, monobasic sodium phosphate, dibasic
sodium phosphate, .alpha.,.alpha.-trehalose dehydrate, and
polysorbate 20. In one embodiment, the composition comprises a VEGF
antagonist, a buffering agent, a pH-adjusting agent, a tonicity
agent, and water that is suitable for injection. In another
embodiment, the composition comprises a VEGF antagonist, monobasic
sodium phosphate, dibasic sodium phosphate, sodium chloride,
hydrochloric acid, and sodium hydroxide. In one embodiment, the
VEGF antagonist is a pegylated anti-VEGF aptamer, e.g., pegaptanib
sodium
[0193] In another embodiment, the VEGF antagonist is ranibizumab,
bevacizumab, aflibercept or ESBA1008. This invention provides the
pharmaceutically acceptable salts of the antagonists. An antagonist
of the present invention can possess a sufficiently basic
functional group, which can react with any of a number of inorganic
and organic acids, to form a pharmaceutically acceptable salt. A
pharmaceutically-acceptable acid addition salt is formed from a
pharmaceutically-acceptable acid, as is well known in the art. Such
salts include the pharmaceutically acceptable salts listed in
Journal of Pharmaceutical Science, 66, 2-19 (1977) and The Handbook
of Pharmaceutical Salts; Properties, Selection, and Use. P. H.
Stahl and C. G. Wermuth (ED.s), Verlag, Zurich (Switzerland) 2002,
which are hereby incorporated by reference in their entirety.
[0194] Examples of a pharmaceutically acceptable salts include
sulfate, citrate, acetate, oxalate, chloride, bromide, iodide,
nitrate, bisulfate, phosphate, acid phosphate, isonicotinate,
lactate, salicylate, acid citrate, tartrate, oleate, tannate,
pantothenate, bitartrate, ascorbate, succinate, maleate,
gentisinate, fumarate, gluconate, glucaronate, saccharate, formate,
benzoate, glutamate, methanesulfonate, ethanesulfonate,
benzenesulfonate, p-toluenesulfonate, camphorsulfonate, pamoate,
phenylacetate, trifluoroacetate, acrylate, chlorobenzoate,
dinitrobenzoate, hydroxybenzoate, methoxybenzoate, methylbenzoate,
o-acetoxybenzoate, naphthalene-2-benzoate, isobutyrate,
phenylbutyrate, .alpha.-hydroxybutyrate, butyne-1,4-dicarboxylate,
hexyne-1,4-dicarboxylate, caprate, caprylate, cinnamate,
glycollate, heptanoate, hippurate, malate, hydroxymaleate,
malonate, mandelate, mesylate, nicotinate, phthalate,
teraphthalate, propiolate, propionate, phenylpropionate, sebacate,
suberate, p-bromobenzenesulfonate, chlorobenzenesulfonate,
ethylsulfonate, 2-hydroxyethylsulfonate, methylsulfonate,
naphthalene-1-sulfonate, naphthalene-2-sulfonate,
naphthalene-1,5-sulfonate, xylenesulfonate, and tartarate salts.
The term "pharmaceutically acceptable salt" includes a hydrate of a
compound of the invention and also refers to a salt of an
antagonist of the present invention having an acidic functional
group, such as a carboxylic acid functional group or a hydrogen
phosphate functional group, and a base. Suitable bases include, but
are not limited to, hydroxides of alkali metals such as sodium,
potassium, and lithium; hydroxides of alkaline earth metal such as
calcium and magnesium; hydroxides of other metals, such as aluminum
and zinc; ammonia, and organic amines, such as unsubstituted or
hydroxy-substituted mono-, di-, or tri-alkylamines,
dicyclohexylamine; tributyl amine; pyridine; N-methyl,
N-ethylamine; diethylamine; triethylamine; mono-, bis-, or
tris-(2-OH-lower alkylamines), such as mono-; bis-, or
tris-(2-hydroxyethyl)amine, 2-hydroxy-tert-butylamine, or
tris-(hydroxymethyl)methylamine, N,N-di-lower
alkyl-N-(hydroxyl-lower alkyl)-amines, such as
N,N-dimethyl-N-(2-hydroxyethyl)amine or tri-(2-hydroxyethyl)amine;
N-methyl-D-glucamine; and amino acids such as arginine, lysine, and
the like. In one embodiment, the pharmaceutically acceptable salt
is a sodium salt. In another embodiment, the pharmaceutically
acceptable salt is a persodium salt.
[0195] The present invention further provides comprising Antagonist
A or another pharmaceutically acceptable salt thereof. In one
embodiment, the present compositions comprise about 30.0 mg of
Antagonist A or another pharmaceutically acceptable salt thereof,
about 0.3 mg of monobasic sodium phosphate monohydrate, about 2.1
mg of dibasic sodium phosphate heptahydrate and about 9.0 mg of
sodium chloride per about 1 mL. In some embodiments, hydrochloric
acid and/or sodium hydroxide are present as needed to adjust the pH
of the composition. In some embodiments, the pH is about pH 5.5 to
about pH 7.5 or about pH 6.0.
[0196] In some embodiments, the compositions comprise about 3%
(w/v) of Antagonist A or another pharmaceutically acceptable salt
thereof, about 0.03% (w/v) of monobasic sodium phosphate
monohydrate, about 0.2% (w/v) of dibasic sodium phosphate
heptahydrate, about 0.9% (w/v) of sodium chloride and about 95.9%
(w/v) of water. In some embodiments, hydrochloric acid and/or
sodium hydroxide are present as needed to adjust the pH of the
composition. In some embodiments, the pH is about pH 5.5 to about
pH 7.5 or about pH 6.0.
[0197] In certain embodiments, the concentration of Antagonist A or
another pharmaceutically acceptable salt thereof, a VEGF antagonist
(e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 or
pegaptanib sodium), and/or an anti-C5 agent (e.g., ARC1905 or a
pharmaceutically acceptable salt thereof) in a composition is about
0.002 mg/mL to about 50 mg/mL. In some embodiments, the
concentration of Antagonist A or another pharmaceutically
acceptable salt thereof, a VEGF antagonist (e.g., ranibizumab,
bevacizumab, aflibercept, ESBA1008 or pegaptanib sodium), and/or an
anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt
thereof) in a composition is less than or about 100 mg/mL, less
than about 50 mg/mL, less than about 40 mg/mL, less than about 30
mg/mL, less than about 25 mg/mL, less than about 20 mg/mL, less
than about 15 mg/mL, less than about 10 mg/mL, or less than about 5
mg/mL. In certain embodiments, the concentration of Antagonist A or
another pharmaceutically acceptable salt thereof, a VEGF antagonist
(e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 or
pegaptanib sodium), and/or an anti-C5 agent (e.g., ARC1905 or a
pharmaceutically acceptable salt thereof) in a composition is about
0.3 mg/mL to about 100 mg/mL, about 0.3 mg/mL to about 50 mg/mL,
about 0.3 mg/mL to about 40 mg/mL, about 0.3 mg/mL to about 30
mg/mL, about 0.3 to about 25 mg/mL, about 0.3 mg/mL to about 20
mg/mL, about 0.3 mg/mL to about 15 mg/mL, about 0.3 mg/mL to about
10 mg/mL, about 1 mg/mL to about 100 mg/mL, about 1 mg/mL to about
50 mg/mL, about 1 mg/mL to about 40 mg/mL, about 1 mg/mL to about
30 mg/mL, about 1 mg/mL to about 25 mg/mL, about 1 mg/mL to about
20 mg/mL, about 1 mg/mL to about 15 mg/mL, about 1 mg/mL to about
10 mg/mL, about 1 mg/mL to about 5 mg/mL, about 5 mg/mL to about
100 mg/mL, or about 5 mg/mL to about 50 mg/mL.
[0198] In certain embodiments, methods of the invention comprise
administering Antagonist A and optionally one or both of a VEGF
antagonist and an anti-C5 agent as a component of a pharmaceutical
composition. In one embodiment, the present invention provides
compositions comprising an effective amount of: (a) Antagonist A or
another pharmaceutically acceptable salt thereof; and (b) a VEGF
antagonist or a pharmaceutically acceptable salt thereof. In
certain embodiments, the compositions further comprise an effective
amount of an anti-C5 agent or a pharmaceutically acceptable salt
thereof. In some embodiments, the compositions stabilize one or
more of the Antagonist A or another pharmaceutically acceptable
salt thereof, the VEGF antagonist, and the anti-C5 agent. In
certain embodiments, the Antagonist A or another pharmaceutically
acceptable salt thereof, the VEGF antagonist and/or the anti-C5
agent does not adversely affect the activity of the other active
agent(s) present in the composition. In particular embodiments, at
least about 90% of one or more of the active agents in the
composition, e.g., Antagonist A or another pharmaceutically
acceptable salt thereof, VEGF antagonist, or anti-C5 agent, is
chemically stable when the composition is stored at a temperature
of from about 2.0.degree. C. to about 8.0.degree. C. for at least
about twelve weeks.
[0199] In particular embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof, the VEGF antagonist or
the anti-C5 agent is chemically stable when it shows no sign of
decomposition or modification resulting in formation of a new
chemical entity. In particular embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof, the VEGF antagonist or
the anti-C5 agent is chemically stable when at least about 50%, at
least about 60%, at least about 70%, at least about 80%, at least
about 90%, a least about 95%, or at least about 99% of Antagonist A
or another pharmaceutically acceptable salt thereof, the VEGF
antagonist or the anti-C5 agent shows no sign of decomposition or
modification resulting in formation of a new chemical entity, e.g.,
when stored at a temperature of from about 2.0.degree. C. to about
8.0.degree. C. for at least about twelve weeks.
[0200] In certain embodiments, the Antagonist A or another
pharmaceutically acceptable salt thereof does not adversely affect
the activity of the VEGF antagonist (e.g., ranibizumab,
bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008) or the
ARC1905 or a pharmaceutically acceptable salt thereof. In certain
embodiments, the VEGF antagonist (e.g., ranibizumab, bevacizumab,
aflibercept, pegaptanib sodium, or ESBA1008) does not adversely
affect the activity of the Antagonist A or another pharmaceutically
acceptable salt thereof, or ARC1905 or a pharmaceutically
acceptable salt thereof. In certain embodiments, ARC1905 or a
pharmaceutically acceptable salt thereof does not adversely affect
the activity of the Antagonist A or another pharmaceutically
acceptable salt thereof, or the VEGF antagonist (e.g., ranibizumab,
bevacizumab, aflibercept, pegaptanib sodium, or ESBA1008).
[0201] In particular embodiments, the compositions comprise
Antagonist A or another pharmaceutically acceptable salt thereof
and ranibizumab, bevacizumab, aflibercept, pegaptanib sodium or
ESBA1008, or a pharmaceutically acceptable salt thereof, and the
compositions are physically or chemically stable with respect to
both active agents at a particular pH or suitable for parenteral
administration. In particular embodiments, the compositions
comprise Antagonist A or another pharmaceutically acceptable salt
thereof ranibizumab, bevacizumab, aflibercept, pegaptanib sodium or
ESBA1008 or a pharmaceutically acceptable salt thereof and ARC1905
or a pharmaceutically acceptable salt thereof, and the compositions
are physically or chemically stable with respect to all active
agents at a particular pH or suitable for parenteral
administration. In particular embodiments, a composition is
physically stable if at least about 50%, at least about 60%, at
least about 70%, at least about 80%, at least about 90%, at least
about 95%, or at least about 99% of all active agents, i.e., the
Antagonist A or another pharmaceutically acceptable salt thereof,
the VEGF antagonist, and the anti-C5 agent (when present) present
in the composition show no sign of aggregation, precipitation or
denaturation upon visual examination of color or clarity, or as
measured by UV light scattering or by size exclusion chromatography
(SEC) or differential scanning calorimetry (DSC).
[0202] In particular embodiments, the compositions of the invention
are considered physically stable if after storage the average
number of particles detected does not exceed about 50 particles/mL,
where the particles have a diameter >about 10 .mu.m and does not
exceed 5 particles/mL, where the particles have a diameter >25
.mu.m, as measured by the Light Obscuration Particle Count Test
described in (788) Particulate Matter in Injections, Revised
Bulletin, Official Oct. 1, 2011, The United States Pharmacopeial
Convention.
[0203] In particular embodiments, the compositions are considered
physically stable if after storage the average number of particles
detected does not exceed 50 particles/mL, where the particles have
a diameter >10 .mu.m; does not exceed 5 particles/mL, where the
particles have a diameter >25 .mu.m; and does not exceed 2
particles/mL, where the particles have a diameter >50 .mu.m, as
measured by the microscopic method particle count test described in
(788) Particulate Matter in Injections, Revised Bulletin, Official
Oct. 1, 2011, The United States Pharmacopeial Convention.
[0204] In particular embodiments, the compositions comprise
Antagonist A or another pharmaceutically acceptable salt thereof, a
VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept,
ESBA1008 or pegaptanib sodium) and, optionally, an anti-C5 agent
(e.g., ARC1905 or a pharmaceutically acceptable salt thereof) and
are chemically stable for at least eight weeks or at least twelve
weeks at 25.degree. C. or for at least twelve weeks or at least
sixteen weeks or at least 24 weeks at 4.degree. C. In particular
embodiments, at least 80% of each of Antagonist A or another
pharmaceutically acceptable salt thereof, VEGF antagonist, and
anti-C5 agent (if present) show no sign of decomposition or
modification resulting in formation of a new chemical entity under
at least one of these conditions.
[0205] In particular embodiments, compositions comprise the
following: (1) Antagonist A or another pharmaceutically acceptable
salt thereof; (2) a VEGF antagonist; optionally, (3) an anti-C5
agent; (4) a buffer; optionally, (5) a tonicity modifier; and,
optionally, (6) a surfactant. In specific embodiments of such
compositions, the buffer is an acetate, phosphate, Tris or
histidine buffer, or a mixture thereof; the tonicity modifier is
sodium chloride, mannitol, sorbitol, or trehalose, or a mixture
thereof; and the surfactant is polysorbate 20. In various
embodiments, Antagonist A or another pharmaceutically acceptable
salt thereof is present in compositions of the invention at a
concentration of about 0.1 mg/mL to about 200 mg/mL; and the VEGF
antagonist is present at a concentration of about 0.1 mg/mL to
about 200 mg/mL. When present, the anti-C5 agent is present at a
concentration of about 0.1 mg/mL to about 200 mg/mL. The buffer is
present at a concentration of about 1 mM to about 200 mM; the
tonicity modifier is present at a concentration of about 10 mM to
about 200 mM (sodium chloride), about 1% to about 10% (w/v)
(sorbitol), or about 1% to about 20% (w/v) (trehalose); and the
surfactant, when present, is present at a concentration of about
0.005% to about 0.05% or a concentration of about 0.001% to about
0.05%.
[0206] In particular embodiments, the ratio of the concentration
(mass of Antagonist A or another pharmaceutically acceptable salt
thereof less that of its --R group/volume of composition) of
Antagonist A or another pharmaceutically acceptable salt thereof to
the concentration (mass/volume of composition) of the VEGF
antagonist (e.g., ranibizumab, bevacizumab, aflibercept, pegaptanib
sodium, or ESBA1008), ARC1905, or a pharmaceutically acceptable
salt thereof, present in the composition is less than, or less than
or equal to, 25.0, less than, or less than or equal to, 10.0, less
than, or less than or equal to, 9.0, less than, or less than or
equal to, 8.0, less than, or less than or equal to, 7.0, less than,
or less than or equal to, 6.0, less than, or less than or equal to,
5.0, less than, or less than or equal to, 4.0, less than, or less
than or equal to, 3.0, less than, or less than or equal to, 2.0 or
less than, or less than or equal to, 1.0. Antagonist A's --R group
is depicted in FIG. 1. In particular embodiments, the ratio of the
concentration (mass of Antagonist A or another pharmaceutically
acceptable salt thereof less that of its --R group/volume of
composition) of Antagonist A or another pharmaceutically acceptable
salt thereof to the concentration (mass/volume of composition) of
the VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept,
pegaptanib sodium, or ESBA1008), ARC1905, or a pharmaceutically
acceptable salt thereof, present in the composition is in the range
of about 1 to about 10, about 2 to about 5, about 3 about 4, or
about 5. In certain embodiments, the compositions comprise
Antagonist A or another pharmaceutically acceptable salt thereof, a
VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept,
pegaptanib sodium, or ESBA1008), and ARC1905 or a pharmaceutically
acceptable salt thereof.
[0207] In one particular embodiment, the compositions comprise
Antagonist A or another pharmaceutically acceptable salt thereof, a
VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept,
ESBA1008, or pegaptanib sodium), and, optionally, an anti-C5 agent
(e.g., ARC1905 or a pharmaceutically acceptable salt thereof),
wherein the ratio of the concentration of PDGF antagonist to the
concentration of VEGF antagonist (and/or anti-C5 agent) is less
than 2; and the compositions further comprise sodium chloride at a
concentration of about 10 mM to about 200 mM, histidine at a
concentration of about 1 mM to about 100 mM, and polysorbate (e.g.,
polysorbate 20) at a concentration of about 0.005% to about 0.05%,
where the pH of the composition is about 5.5 to about 7.0.
[0208] In certain embodiments, the compositions comprise one or
more of a tonicity modifier, a surfactant, and a buffer suitable to
achieve or maintain the particular pH or be suitable for parenteral
administration. Appropriate buffers include those described herein
as well as others known in the art, such as, e.g., Good's buffers,
e.g., MES.
[0209] In certain embodiments, the compositions comprise Antagonist
A or another pharmaceutically acceptable salt thereof, a VEGF
antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008
or pegaptanib sodium), and a tonicity modifier that is sorbitol or
sodium chloride, or mixtures thereof. In certain embodiments, the
compositions further comprise an anti-C5 agent (e.g., ARC1905 or a
pharmaceutically acceptable salt thereof). In particular
embodiments, the tonicity modifier is sorbitol, and the pH of the
composition is about 5.0 to about 8.0, about 5.0 to about 7.0,
about 6.0 or about 7.0. In particular embodiments, the tonicity
modifier is sodium chloride, and the pH of the composition is about
5.0 to about 8.0, about 5.0 to about 7.0, about 5.5 to about 7.5,
about 6.0 to about 8.0, about 8.0, about 7.0, or about 6.0. In
certain embodiments, the tonicity modifier is sorbitol at about 1%
to about 10% (w/v), or about 1% (w/v), about 2% (w/v), about 3%
(w/v), about 4% (w/v), about 5% (w/v), about 6% (w/v), about 7%
(w/v), about 8% (w/v), about 9% (w/v), or about 10% (w/v). In
particular embodiments, the tonicity modifier is sodium chloride at
a concentration of about 10 mM to about 200 mM, about 50 mM to 200
mM, about 75 mM to about 200 mM, about 50 mM to about 150 mM, about
100 mM, about 110 mM, about 120 mM, about 130 mM about 140 mM or
about 150 mM. In one embodiment, the tonicity modifier is sodium
chloride at a concentration of about 130 mM. In other embodiments,
the tonicity modifier is sodium chloride at a concentration of
about 75 mM or about 120 mM. With respect to tonicity modifier
concentration, "mM" refers to milimoles of the tonicity modifier
per liter of composition.
[0210] In certain embodiments, the compositions comprise Antagonist
A or another pharmaceutically acceptable salt thereof, a VEGF
antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008
or pegaptanib sodium), and a buffer capable of achieving or
maintaining the pH of the composition within a desired range. In
certain embodiments, the compositions further comprise an anti-C5
agent (e.g., ARC1905 or a pharmaceutically acceptable salt
thereof). In certain embodiments, the compositions comprise
histidine (e.g., L-histidine or a pharmaceutically acceptable salt
thereof) or phosphate as a buffer, e.g., sodium phosphate,
potassium phosphate, or both. In certain embodiments, the buffer is
present at a concentration of about 1 mM to about 200 mM, about 1
mM to about 150 mM, about 1 mM to about 20 mM, about 1 mM to about
10 mM, about 2 mM to about 100 mM, about 2 mM to about 20 mM, about
5 mM to about 20 mM, or about 10 mM. In particular embodiments, the
pH of the buffered composition is about 5.0 to about 8.0, about 5.0
to about 7.0, about 5.5 to about 7.5, about 5.5 to about 7.0, or
about 6.0. In one embodiment, the buffered composition has a pH of
about 5.5 to about 7.0. In certain embodiments, the buffer
comprises histidine at a concentration of about 1 mM to about 200
mM, about 1 mM to about 150 mM, about 2 mM to about 100 mM, about 5
mM to about 20 mM, or about 10 mM, and the buffered composition has
a pH of about 5.5 to about 7.0, or about 6.0. In one particular
embodiment, the buffer comprises histidine at a concentration of
about 10 mM and the pH of the histidine-buffered composition is
about 6.0. With respect to buffer concentration, "mM" refers to
millimoles of buffer (e.g., histidine) per liter of
composition.
[0211] In certain embodiments, the compositions comprise Antagonist
A or another pharmaceutically acceptable salt thereof, a VEGF
antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008
or pegaptanib sodium), and a buffer that comprises phosphate, alone
or in combination with histidine. In certain embodiments, the
compositions further comprise an anti-C5 agent (e.g., ARC1905 or a
pharmaceutically acceptable salt thereof). The phosphate buffer may
be, e.g., a sodium phosphate or potassium phosphate buffer. In
certain embodiments, the buffer comprises phosphate at a
concentration of about 1 mM to about 200 mM, about 1 mM to about 50
mM, about 2 mM to about 200 mM, about 2 mM to about 50 mM, about 5
mM to about 200 mM, about 5 mM to about 100 mM, about 5 mM to about
50 mM, about 10 mM to about 150 mM, about 10 mM to about 100 mM,
about 5 mM, about 10 mM, about 25 mM, or about 50 mM. In particular
embodiments, the pH of the buffered composition is about 5.0 to
about 8.0, about 6.0 to about 8.0, about 5.5 to about 7.5, about
5.5 to about 7.0, about 6.0, about 7.0, or about 8.0. In one
embodiment, the buffer comprises phosphate, and the buffered
composition has a pH of about 6.0 to about 8.0. In certain
embodiments, the buffer comprises phosphate at a concentration of
about 5 mM to about 200 mM, about 5 mM to about 150 mM, about 5 mM
to about 100 mM, about 5 mM, about 8 mM, about 10 mM, about 25 mM,
or about 50 mM, and the buffered composition has a pH of about 5.5
to about 7.5, about 5.5 to about 7.0, or about 6.0. In one
particular embodiment, the buffer comprises phosphate at a
concentration of about 10 mM, and the buffered composition has a pH
of about 6.2.
[0212] In certain embodiments, the compositions comprise Antagonist
A or another pharmaceutically acceptable salt thereof), a VEGF
antagonist (e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008
or pegaptanib sodium), and a surfactant. In certain embodiments,
the compositions further comprise an anti-C5 agent (e.g., ARC1905
or a pharmaceutically acceptable salt thereof). In particular
embodiments, the surfactant is polysorbate 20 at a concentration of
about 0.001% (w/v) to about 0.05% (w/v), about 0.002% (w/v) to
about 0.05% (w/v), about 0.005% (w/v) to about 0.05% (w/v), about
0.01% (w/v) to about 0.05% (w/v), or about 0.02% (w/v).
[0213] In one embodiment, the compositions comprise Antagonist A or
another pharmaceutically acceptable salt thereof, a VEGF antagonist
(e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 or
pegaptanib sodium), histidine, and NaCl. In certain embodiments,
the compositions further comprise an anti-C5 agent (e.g., ARC1905
or a pharmaceutically acceptable salt thereof). The composition may
further comprise polysorbate.
[0214] In certain embodiments, the compositions comprise an
effective amount of: (a) about 0.3 mg/mL to about 30 mg/mL of
Antagonist A or another pharmaceutically acceptable salt thereof;
(b) about 0.5 mg/mL to about 20 mg/mL of a VEGF antagonist (e.g.,
ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanib
sodium); and one or both of: (c) a buffer capable of achieving or
maintaining the pH of the compositions at about pH 5.0 to about pH
8.0; and (d) a tonicity modifier. In certain embodiments, the
compositions further comprise (e) about 0.3 mg/mL to about 30 mg/mL
of an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable
salt thereof). In certain embodiments, the buffer is about 1 mM to
about 20 mM L-histidine or about 1 mM to about 20 mM sodium
phosphate, and the tonicity modifier is about 10 mM to about 200 mM
NaCl, about 1% to about 20% (w/v) sorbitol, or about 1% to about
20% (w/v) trehalose. In particular embodiments, the compositions
further comprise: (f) about 0.001% (w/v) to about 0.05% (w/v)
surfactant.
[0215] In certain embodiments, the compositions comprise: (a) about
0.3 mg/mL to about 30 mg/mL of Antagonist A or another
pharmaceutically acceptable salt thereof; and (b) about 0.5 mg/mL
to about 20 mg/mL of a VEGF antagonist (e.g., ranibizumab,
bevacizumab, aflibercept, ESBA1008 or pegaptanib sodium). In
certain embodiments, the compositions further comprise (c) about
0.3 mg/mL to about 30 mg/mL of an anti-C5 agent (e.g., ARC1905 or a
pharmaceutically acceptable salt thereof). In certain embodiments,
any of these the compositions further comprise one or both of: (d)
about 1 mM to about 20 mM L-histidine; and (e) about 10 mM to about
200 mM NaCl. In further embodiments, the compositions further
comprise: (f) about 0.001% (w/v) to about 0.05% (w/v) surfactant,
which is optionally polysorbate. In a particular embodiment, the
compositions comprise: (a) about 0.3 mg/mL to about 30 mg/mL of
Antagonist A or another pharmaceutically acceptable salt thereof;
(b) about 0.5 mg/mL to about 20 mg/mL of a VEGF antagonist (e.g.,
ranibizumab, bevacizumab, aflibercept, ESBA1008 or pegaptanib
sodium); (c) about 1 mM to about 20 mM L-histidine; and (d) about
10 mM to about 200 mM NaCl, wherein the pH of the compositions is
about pH 5.0 to about pH 7.0. In certain embodiments, the
compositions further comprise (e) about 0.3 mg/mL to about 30 mg/mL
of an anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable
salt thereof). In certain embodiments, the compositions further
comprise: (f) about 0.01% (w/v) polysorbate 20.
[0216] In certain embodiments, compositions comprise: (a) about 1.0
mg/mL to about 100 mg/mL, or about 5.0 mg/mL to about 50 mg/mL of
Antagonist A or another pharmaceutically acceptable salt thereof);
and (b) about 1.0 mg/mL to about 50 mg/mL of a VEGF antagonist
(e.g., ranibizumab, bevacizumab, aflibercept, ESBA1008 or
pegaptanib sodium). In certain embodiments, the compositions
further comprise (c) about 1.0 mg/mL to about 100 mg/mL of an
anti-C5 agent (e.g., ARC1905 or a pharmaceutically acceptable salt
thereof). In other embodiments, any of the compositions further
comprise one or both of (d) about 1 mM to about 20 mM L-histidine;
and (e) about 10 mM to about 200 mM NaCl. In further embodiments,
any of the compositions further comprise: (f) about 0.001% (w/v) to
about 0.05% (w/v) surfactant, which is optionally polysorbate.
[0217] In certain embodiments, compositions comprise: (a) about 0.3
mg/mL to about 30 mg/mL of Antagonist A or another pharmaceutically
acceptable salt thereof); (b) about 0.5 mg/mL to about 20 mg/mL of
a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept,
ESBA1008 or pegaptanib sodium); and one or both of (c) a buffer
capable of achieving or maintaining the pH of the composition to
about pH 5.0 to about pH 8.0; and (d) a tonicity modifier. In
certain embodiments, the compositions further comprise about 0.3
mg/mL to about 30 mg/mL of an anti-C5 agent (e.g., ARC1905 or a
pharmaceutically acceptable salt thereof). In particular
embodiments, the buffer, where present, is about 1 mM to about 20
mM L-histidine or about 1 mM to about 20 mM sodium phosphate; and
the tonicity modifier, where present, is about 10 mM to about 200
mM NaCl, about 1% to about 20% (w/v) sorbitol, or about 1% to about
20% (w/v) trehalose. In certain embodiments, the buffer is about 1
mM to about 20 mM L-histidine; and the tonicity modifier is about
10 mM to about 200 mM NaCl, wherein the pH of the compositions is
about pH 5.0 to about pH 7.0.
[0218] Any of the compositions can also comprise a surfactant,
e.g., about 0.001% (w/v) to about 0.05% (w/v) surfactant.
[0219] In certain embodiments the compositions comprise: (a) about
3 mg/mL to about 90 mg/mLAntagonist A or another pharmaceutically
acceptable salt thereof; (b) about 1.0 mg/mL to about 30 mg/mL of a
VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept,
ESBA1008 or pegaptanib sodium); and one or both of (c) a buffer
capable of achieving or maintaining the pH of the compositions to
about pH 5.0 to about pH 8.0; and (d) a tonicity modifier. In
certain embodiments, any of the compositions further comprises (e)
about 3 mg/mL to about 90 mg/mL of an anti-C5 agent (e.g., ARC1905
or a pharmaceutically acceptable salt thereof). In particular
embodiments, the buffer, where present, comprises about 1 mM to
about 100 mM sodium phosphate or about 1.0 mM to about 10 mM
histidine.HCl; and the tonicity modifier, where present, is about
0.5% (w/v) to about 10% (w/v) trehalose.
[0220] In certain embodiments, a composition of the invention
comprises: (a) about 0.3 mg/mL to about 30 mg/mL Antagonist A or
another pharmaceutically acceptable salt thereof; (b) about 0.5
mg/mL to about 20 mg/mL ranibizumab or a pharmaceutically
acceptable salt thereof; and one or both of: (c) a buffer capable
of achieving or maintaining the pH of the composition at about pH
5.0 to about pH 8.0; and (d) a tonicity modifier. In certain
embodiments, the buffer is about 1 mM to about 20 mM L-histidine or
about 1 mM to about 20 mM sodium phosphate, and the tonicity
modifier is about 10 mM to about 200 mM NaCl, about 1% to about 20%
(w/v) sorbitol, or about 1% to about 20% (w/v) trehalose. In
particular embodiments, the composition of the invention further
comprises: (e) about 0.001% (w/v) to about 0.05% (w/v) surfactant.
In particular embodiments, the composition further comprises: (f)
an anti-C5 agent, another PDGF antagonist, or another VEGF
antagonist. In particular embodiments, the anti-C5 agent is ARC
186, ARC 187, or ARC1905, and the other VEGF antagonist is
bevacizumab or aflibercept.
[0221] In certain embodiments, a composition of the invention
comprises: (a) about 0.3 mg/mL to about 30 mg/mL Antagonist A or
another pharmaceutically acceptable salt thereof; and (b) about 0.5
mg/mL to about 25 mg/mL bevacizumab or a pharmaceutically
acceptable salt thereof; and one or both of: (c) a buffer capable
of achieving or maintaining the pH of the composition at about pH
5.0 to about pH 8.0; and (d) a tonicity modifier. In certain
embodiments, the buffer is about 5 mM to about 200 mM sodium
phosphate or about 5 mM to about 200 mM Tris.HCl, and the tonicity
modifier is about 10 mM to about 200 mM NaCl, about 1% to about 20%
(w/v) sorbitol, or about 1% to about 20% (w/v) trehalose. In
particular embodiments, the composition of the invention further
comprises: (e) about 0.001% (w/v) to about 0.05% (w/v) surfactant.
In particular embodiments, the composition further comprises: (f)
an anti-C5 agent, another PDGF antagonist, and/or another VEGF
antagonist. In particular embodiments, the anti-C5 agent is ARC186,
ARC187, or ARC1905, and the other VEGF antagonist is ranibizumab or
aflibercept.
[0222] In certain embodiments, a composition of the invention
comprises: (a) about 0.3 mg/mL to about 30 mg/mL Antagonist A or
another pharmaceutically acceptable salt thereof; (b) about 5 mg/mL
to about 40 mg/mL aflibercept or a pharmaceutically acceptable salt
thereof; and one or more of: (c) a buffer capable of achieving or
maintaining the pH of the composition at about pH 5.0 to about pH
8.0; (d) a tonicity modifier; and (e) 0 to about 10% (w/v) sucrose.
In certain embodiments, the buffer is about 5 mM to about 50 mM
phosphate, and the tonicity modifier is about 10 mM to about 200 mM
NaCl. In particular embodiments, the composition of the invention
further comprises: (f) about 0.001% (w/v) to about 0.05% (w/v)
surfactant. In particular embodiments, the composition further
comprises: (g) an anti-C5 agent, another PDGF antagonist, and/or
another VEGF antagonist. In particular embodiments, the anti-C5
agent is ARC186, ARC187, or ARC1905, and the other VEGF antagonist
is ranibizumab or bevacizumab.
[0223] In certain embodiments, a composition of the invention
comprises: (a) about 3 mg/mL to about 90 mg/mL Antagonist A or
another pharmaceutically acceptable salt thereof; (b) about 1.0
mg/mL to about 30 mg/mL ranibizumab or a pharmaceutically
acceptable salt thereof; and one or both of: (c) a buffer capable
of achieving or maintaining the pH of the composition at about pH
5.0 to about pH 8.0; and (d) a tonicity modifier. In certain
embodiments, the buffer comprises about 1 mM to about 100 mM sodium
phosphate or about 1.0 mM to about 10 mM histidine.HCl, and the
tonicity modifier is about 0.5% (w/v) to about 10% (w/v) trehalose.
In particular embodiments, the composition further comprises: (e)
an anti-C5 agent, another PDGF antagonist, and/or another VEGF
antagonist. In particular embodiments, the anti-C5 agent is ARC186,
ARC187, or ARC1905, and the other VEGF antagonist is bevacizumab or
aflibercept.
[0224] Illustrative compositions include F1-F31, as described in
Tables 3 and 4. Illustrative compositions are also described in PCT
Application Publication No. WO2013/181495. Any of these
compositions may further comprise an anti-C5 agent, such as ARC1905
or a pharmaceutically acceptable salt thereof.
TABLE-US-00002 TABLE 3 Composition Matrix for Illustrative
Antagonist A:Ranibizumab Compositions [Ant. A] [ran.] Polysorbate
Comp. Buffer pH Tonicity Modifier (mg/mL) (mg/mL) 20 (% w/v) F1 10
mM Sodium Phosphate 7.3 150 mM NaCl 3 0 0% F2 10 mM Sodium Acetate
5.0 5% (w/v) Sorbitol 3 5 0.01% F3 10 mM Sodium Acetate 5.0 130 mM
NaCl 3 5 0.01% F4 10 mM Histidine.HCl 5.5 10% (w/v) Trehalose 0 5
0.01% F5 10 mM Histidine.HCl 6.0 5% (w/v) Sorbitol 3 5 0.01% F6 10
mM Histidine.HCl 6.0 130 mM NaCl 3 5 0.01% F7 10 mM Sodium
Phosphate 7.0 5% (w/v) Sorbitol 3 5 0.01% F8 10 mM Sodium Phosphate
7.0 130 mM NaCl 3 5 0.01% F9 10 mM Tris.HCl 8.0 5% (w/v) Sorbitol 3
5 0.01% F10 10 mM Tris.HCl 8.0 130 mM NaCl 3 5 0.01% F11 5 mM
Sodium Phosphate + 6.5 75 mM NaCl + 3 5 0.005% 5 mM Histidine 5%
(w/v) Trehalose F27 10 mM Sodium Phosphate 7.3 150 mM NaCl 30 0 0%
F28 10 mM Histidine.HCl 5.5 10% (w/v) Trehalose 0 10 0.01% F29 10
mM Histidine.HCl 5.5 10% (w/v) Trehalose 0 40 0.01% F30 5 mM Sodium
Phosphate + 75 mM NaCl + 5% 15 5 0.005% 5 mM Histidine.HCl (w/v)
Trehalose F31 8 mM Sodium Phosphate + 120 mM NaCl + 2% 24 8 0.002%
2 mM Histidine.HCl (w/v) Trehalose "Ant. A" is Antagonist A; "ran."
is ranibizumab
TABLE-US-00003 TABLE 4 Composition Matrix for Illustrative
Antagonist A:Bevacizumab Compositions Antagonist A Concentration
Bevacizumab (mg/mL, oligo Concentration Comp. Buffer pH Tonicity
Modifier wt.) (mg/mL) Surfactant F12 10 mM 7.3 150 mM Sodium 30 0.0
0% Phosphate Chloride F13 50 mM 4 5% (w/v) Sorbitol 3 12.5 0.02%
Acetate Polysorbate 20 F14 50 mM 4 130 mM Sodium 3 12.5 0.02%
Acetate Chloride Polysorbate 20 F15 50 mM 5 5% (w/v) Sorbitol 3
12.5 0.02% Acetate Polysorbate 20 F16 50 mM 5 130 mM Sodium 3 12.5
0.02% Acetate Chloride Polysorbate 20 F17 50 mM 6 5% (w/v) Sorbitol
3 12.5 0.02% Phosphate Polysorbate 20 F18 50 mM 6.2 6% (w/v)
Trehalose 0 12.5 0.02% Phosphate Polysorbate 20 F19 50 mM 6 130 mM
Sodium 3 12.5 0.02% Phosphate Chloride Polysorbate 20 F20 50 mM 7
5% (w/v) Sorbitol 3 12.5 0.02% Phosphate Polysorbate 20 F21 50 mM 7
130 mM Sodium 3 12.5 0.02% Phosphate Chloride Polysorbate 20 F22 50
mM 8 5% (w/v) Sorbitol 3 12.5 0.02% Tris Polysorbate 20 F23 50 mM 8
130 mM Sodium 3 12.5 0.02% Tris Chloride Polysorbate 20 F24 30 mM
6.3 75 mM sodium 15 12.5 0.02% Phosphate Chloride + 3% (w/v)
Polysorbate 20 Trehalose F25 10 mM 7.3 150 mM Sodium 3 0.0 0%
Phosphate Chloride F26 30 mM 6.3 75 mM sodium 3 12.5 0.02%
Phosphate Chloride + 3% (w/v) Polysorbate 20 Trehalose
[0225] Administration and Dosage
[0226] The methods or compositions according to the invention can
be administered alone or in conjunction with another therapy and
can be provided at home, a doctor's office, a clinic, a hospital's
outpatient department, or a hospital. Treatment can begin at a
hospital so that the doctor can observe the therapy's effects
closely and make any adjustments that are needed. The duration of
the administration can depend on the type of ophthalmological
disease or disorder being treated or prevented, the age and
condition of the subject, the stage and type of the subject's
disease or disorder, and how the subject responds to the treatment.
Additionally, a subject having a greater risk of developing an
ophthalmological disease or disorder (e.g., a diabetic patient) can
receive treatment to inhibit or delay the onset of symptoms. In one
embodiment, the present methods or compositions allow for the
administration of a relatively lower dose of each antagonist.
[0227] The dosage and frequency of administration of each
antagonist can be controlled independently. For example, one
antagonist can be administered three times per day, while the other
antagonist can be administered once per day. Administration can be
performed in on-and-off cycles that include rest periods so that
the subject's body has a chance to recover from a side effect, if
any. The antagonists can also be present in the same
composition.
[0228] In other embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof and optionally, a VEGF
antagonist and/or anti-C5 agent are administered prior to, during,
and/or after another treatment. In one embodiment, Antagonist A or
another pharmaceutically acceptable salt thereof and the VEGF
antagonist and/or anti-C5 agent are administered concurrently, such
as in a co-formulation, prior to, during, and/or after the other
treatment. In other embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof and the VEGF antagonist
are administered sequentially, prior to, during, and/or after the
other treatment. In some embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof is administered prior to
the administration of the VEGF antagonist. In other embodiments,
Antagonist A or another pharmaceutically acceptable salt thereof is
administered subsequent to the administration of the VEGF
antagonist. In some embodiments, the other treatment is performing
surgery. Examples of other treatment include pneumatic retinopexy,
laser retinopexy, scleral buckling, and pars plana vitrectomy
(PPV), laser photocoagulation, or cryotherapy.
[0229] Administration of a composition disclosed herein with
performing another treatment can improve retinal attachment
success, improve visual acuity, reduce choroidal neovascularization
or stabilize vision to a degree that is greater than performing the
other treatment alone. For example, in some embodiments, the
administration of both Antagonist A or another pharmaceutically
acceptable salt thereof with performing another treatment can
improve retinal attachment success, improve visual acuity, or
stabilize vision to a degree that is greater than an additive
effect of both Antagonist A or another pharmaceutically acceptable
salt thereof with performing the other treatment. In some
embodiments, the synergistic effect is in reducing the size or
growth of a tumor (e.g., in treating or preventing VHL disease,
retinal capillary hemangioma, or von Hippel angioma). In some
embodiments, the synergistic effect is reducing or inhibiting
scarring or fibrosis (e.g., ocular scarring of fibrosis, such as
subretinal fibrosis).
[0230] Administration of both Antagonist A or another
pharmaceutically acceptable salt thereof and the VEGF antagonist
can improve retinal attachment success, improve visual acuity, or
stabilize vision to a degree that is greater than administration of
Antagonist A or another pharmaceutically acceptable salt thereof or
the VEGF antagonist. In some embodiments, the administration of
Antagonist A or another pharmaceutically acceptable salt thereof
and the VEGF antagonist can have a synergistic effect in treating
or preventing an ophthalmological disease or disorder. For example,
the administration of both Antagonist A or another pharmaceutically
acceptable salt thereof and the VEGF antagonist can improve retinal
attachment success, improve visual acuity, or stabilize vision to a
degree that is greater than an additive effect of administering
both Antagonist A or another pharmaceutically acceptable salt
thereof and the VEGF antagonist. In some embodiments, the
synergistic effect is in reducing the size or growth of a tumor
(e.g., in treating or preventing VHL disease, retinal capillary
hemangioma, or von Hippel angioma). In some embodiments, the
synergistic effect is reducing or inhibiting scarring or fibrosis
(e.g., ocular scarring of fibrosis, such as subretinal
fibrosis).
[0231] In some embodiments, the methods comprise administering
Antagonist A or another pharmaceutically acceptable salt thereof,
VEGF antagonist and anti-C5 agent, in which two or more of
Antagonist A or another pharmaceutically acceptable salt thereof,
the VEGF antagonist and the anti-C5 agent are present in the same
composition. In certain embodiments, the PDGF antagonist and the
VEGF antagonist are present in the same composition; in certain
embodiments, Antagonist A or another pharmaceutically acceptable
salt thereof and the anti-C5 agent are present in the same
composition; and in certain embodiments, the VEGF antagonist and
the anti-C5 agent are present in the same composition. In some
embodiments, all three of Antagonist A or another pharmaceutically
acceptable salt thereof, the VEGF antagonist and the anti-C5 agent
are present in the same composition.
[0232] In some embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof, the VEGF antagonist and
the anti-C5 agent are administered sequentially. In one embodiment,
Antagonist A or another pharmaceutically acceptable salt thereof is
administered prior to the VEGF antagonist or the anti-C5 agent. In
one embodiment, the VEGF antagonist is administered prior to
Antagonist A or another pharmaceutically acceptable salt thereof or
the anti-C5 agent. In one embodiment, the anti-C5 agent is
administered prior to the VEGF antagonist or Antagonist A or
another pharmaceutically acceptable salt thereof. In one
embodiment, Antagonist A or another pharmaceutically acceptable
salt thereof is administered prior to the VEGF antagonist and
anti-C5 agent. In one embodiment, the VEGF antagonist is
administered prior to Antagonist A or another pharmaceutically
acceptable salt thereof and the -C5 agent. In one embodiment, the
anti-C5 agent is administered prior to the VEGF antagonist and PDGF
antagonist.
[0233] In certain embodiments, the subject is administered two or
more active agents (e.g., Antagonist A or another pharmaceutically
acceptable salt thereof and a VEGF antagonist) in a staggered
dosing regimen, wherein one or more of the two or more active
agents is administered before another one or more of the two or
more active agents is administered to the subject.
[0234] In certain embodiments, the one or more active agent(s) is
administered at least one day before the other one or more active
agent(s). Accordingly, in some embodiments the present methods
comprise administering on one or more days Antagonist A or another
pharmaceutically acceptable salt thereof, one or more VEGF
antagonists or one or more anti-C5 agents.
[0235] In one embodiment, the order of administration is:
Antagonist A or another pharmaceutically acceptable salt thereof,
followed by VEGF antagonist, followed by anti-C5 agent. In another
embodiment, the order of administration is: Antagonist A or another
pharmaceutically acceptable salt thereof, followed by anti-C5
agent, followed by VEGF antagonist. In another embodiment, the
order of administration is: VEGF antagonist, followed by anti-C5
agent, followed by Antagonist A or another pharmaceutically
acceptable salt thereof. In another embodiment, the order of
administration is: VEGF antagonist, followed by Antagonist A or
another pharmaceutically acceptable salt thereof, followed by
anti-C5 agent. In yet another embodiment the order of
administration is: anti-C5 agent, followed by Antagonist A or
another pharmaceutically acceptable salt thereof, followed by VEGF
antagonist. In another embodiment the order of administration is:
anti-C5 agent, followed by VEGF antagonist, followed by PDGF
antagonist.
[0236] In some embodiments, the Antagonist A or another
pharmaceutically acceptable salt thereof and the VEGF antagonist
are administered concurrently, and the anti-C5 agent is
administered prior to or subsequent to administration of the PDGF
antagonist and VEGF antagonist. In some embodiments, Antagonist A
or another pharmaceutically acceptable salt thereof and the anti-C5
agent are administered concurrently, and the VEGF antagonist is
administered prior to or subsequent to administration of Antagonist
A or another pharmaceutically acceptable salt thereof and the VEGF
antagonist. In some embodiments, the VEGF antagonist and anti-C5
agent are administered concurrently, and Antagonist A or another
pharmaceutically acceptable salt thereof is administered prior to
or subsequent to administration of the anti-C5 agent and VEGF
antagonist.
[0237] In other embodiments, the order of administration is:
Antagonist A or another pharmaceutically acceptable salt thereof,
followed by VEGF antagonist and anti-C5 agent, wherein the VEGF
antagonist and anti-C5 agent are present in the same composition.
In another embodiment, the order of administration is: VEGF
antagonist, followed by anti-C5 agent and Antagonist A or another
pharmaceutically acceptable salt thereof, wherein the anti-C5 agent
and PDGF antagonist are present in the same composition. In yet
another embodiment the order of administration is: anti-C5 agent,
followed by Antagonist A or another pharmaceutically acceptable
salt thereof and VEGF antagonist, wherein the PDGF antagonist and
VEGF antagonist are present in the same composition.
[0238] In still other embodiments, the order of administration is:
Antagonist A or another pharmaceutically acceptable salt thereof
and VEGF antagonist, wherein Antagonist A or another
pharmaceutically acceptable salt thereof and the VEGF antagonist
are present in the same composition, followed by anti-C5 agent. In
another embodiment, the order of administration is: Antagonist A or
another pharmaceutically acceptable salt thereof and anti-C5 agent,
wherein Antagonist A or another pharmaceutically acceptable salt
thereof and the anti-C5 agent are present in the same composition,
followed by VEGF antagonist. In another embodiment, the order of
administration is: VEGF antagonist and anti-C5 agent, wherein the
VEGF antagonist and anti-C5 agent are present in the same
composition, followed by Antagonist A or another pharmaceutically
acceptable salt thereof.
[0239] For example, Antagonist A or another pharmaceutically
acceptable salt thereof can be administered prior to or subsequent
to administration of a VEGF antagonist and/or an anti-C5 agent; a
VEGF antagonist can be administered prior to or subsequent to
administration of Antagonist A or another pharmaceutically
acceptable salt thereof and/or anti-C5 agent; or an anti-C5 agent
can be administered prior to or subsequent to administration of
Antagonist A or another pharmaceutically acceptable salt thereof
and/or a VEGF antagonist.
[0240] In some embodiments, the present methods comprise
administering a first agent prior to administering a second agent.
In some embodiments, the present methods comprise administering a
first agent prior to administering a second agent and administering
the second agent prior to administering a third agent.
[0241] In some embodiments, the present methods comprise
concurrently administering a first agent and a second agent. In
some embodiments, the present methods comprise concurrently
administering a first agent and a second agent prior to
administering a third agent.
[0242] In some embodiments, the present methods comprise
administering a first agent prior to concurrently administering a
second agent and third agent.
[0243] In some embodiments, the present methods comprise
concurrently administering a first agent, a second agent and a
third agent.
[0244] Illustrative groups of first agent, second agent and third
agent are set forth below in Tables 5 and 6.
TABLE-US-00004 TABLE 5 Group First Agent Second Agent Third Agent A
Antagonist A or another VEGF antagonist Anti-C5 Agent
pharmaceutically acceptable salt thereof B Antagonist A or another
Anti-C5 Agent VEGF antagonist pharmaceutically acceptable salt
thereof C VEGF antagonist Antagonist A or another Anti-C5 Agent
pharmaceutically acceptable salt thereof D VEGF antagonist Anti-C5
Agent Antagonist A or another pharmaceutically acceptable salt
thereof E Anti-C5 Agent Antagonist A or another VEGF antagonist
pharmaceutically acceptable salt thereof F Anti-C5 Agent VEGF
antagonist Antagonist A or another pharmaceutically acceptable salt
thereof
TABLE-US-00005 TABLE 6 Group First Agent Second Agent Third Agent A
Antagonist A ranibizumab ARC1905 B Antagonist A bevacizumab ARC1905
C Antagonist A aflibercept ARC1905 D Antagonist A pegaptanib sodium
ARC1905 E Antagonist A ESBA1008 ARC1905 F Antagonist A ARC1905
ranibizumab G Antagonist A ARC1905 bevacizumab H Antagonist A
ARC1905 aflibercept I Antagonist A ARC1905 pegaptanib sodium J
Antagonist A ARC1905 ESBA1008 K ranibizumab Antagonist A ARC1905 L
bevacizumab Antagonist A ARC1905 M aflibercept Antagonist A ARC1905
N pegaptanib sodium Antagonist A ARC1905 O ESBA1008 Antagonist A
ARC1905 P ranibizumab ARC1905 Antagonist A Q bevacizumab ARC1905
Antagonist A R aflibercept ARC1905 Antagonist A S pegaptanib sodium
ARC1905 Antagonist A T ESBA1008 ARC1905 Antagonist A U ARC1905
Antagonist A ranibizumab V ARC1905 Antagonist A bevacizumab W
ARC1905 Antagonist A aflibercept X ARC1905 Antagonist A pegaptanib
sodium Y ARC1905 Antagonist A ESBA1008 Z ARC1905 ranibizumab
Antagonist A AA ARC1905 bevacizumab Antagonist A AB ARC1905
aflibercept Antagonist A AC ARC1905 pegaptanib sodium Antagonist A
AD ARC1905 ESBA1008 Antagonist A
[0245] In some embodiments, the present methods comprise
administering Antagonist A or another pharmaceutically acceptable
salt thereof and two or more VEGF antagonists. In some embodiments,
the present methods comprise administering Antagonist A or another
pharmaceutically acceptable salt thereof and two or more anti-C5
agents. In some embodiments, the present methods comprise
administering a VEGF antagonist and two or more anti-C5 agents.
[0246] In some embodiments, the present methods comprise
administering Antagonist A or another pharmaceutically acceptable
salt thereof prior to administering two or more VEGF antagonists.
In some embodiments, the present methods comprise administering
Antagonist A or another pharmaceutically acceptable salt thereof
prior to administering a first VEGF antagonist and administering
the first VEGF antagonist prior to administering a second VEGF
antagonist.
[0247] In some embodiments, the present methods comprise
concurrently administering Antagonist A or another pharmaceutically
acceptable salt thereof and a VEGF antagonist. In some embodiments,
the present methods comprise concurrently administering Antagonist
A or another pharmaceutically acceptable salt thereof and a first
VEGF antagonist prior to administering a second VEGF
antagonist.
[0248] In some embodiments, the present methods comprise
administering Antagonist A or another pharmaceutically acceptable
salt thereof prior to concurrently administering a first VEGF
antagonist and a second VEGF antagonist.
[0249] In some embodiments, the present methods comprise
concurrently administering Antagonist A or another pharmaceutically
acceptable salt thereof, a first VEGF antagonist and a second VEGF
antagonist.
[0250] In some embodiments, the present methods comprise
administering a VEGF antagonist prior to administering two PDGF
antagonists (e.g., Antagonist A or another pharmaceutically
acceptable salt thereof and another PDGF antagonist). In some
embodiments, the present methods comprise administering a VEGF
antagonist prior to administering a first PDGF antagonist and
administering the first PDGF antagonist prior to administering a
second PDGF antagonist.
[0251] In some embodiments, the present methods comprise
concurrently administering a VEGF antagonist and Antagonist A or
another pharmaceutically acceptable salt thereof. In some
embodiments, the present methods comprise concurrently
administering a VEGF antagonist and a first PDGF antagonist prior
to administering a second PDGF antagonist.
[0252] In some embodiments, the present methods comprise
administering a VEGF antagonist prior to concurrently administering
a first PDGF antagonist and a second PDGF antagonist.
[0253] In some embodiments, the present methods comprise
concurrently administering a VEGF antagonist, a first PDGF
antagonist and a second PDGF antagonist.
[0254] In some embodiments, the present methods comprise
administering Antagonist A or another pharmaceutically acceptable
salt thereof prior to administering two or more anti-C5 agents. In
some embodiments, the present methods comprise administering
Antagonist A or another pharmaceutically acceptable salt thereof
prior to administering a first anti-C5 agent and administering the
first anti-C5 agent prior to administering a second anti-C5
agent.
[0255] In some embodiments, the present methods comprise
concurrently administering Antagonist A or another pharmaceutically
acceptable salt thereof and an anti-C5 agent. In some embodiments,
the present methods comprise concurrently administering Antagonist
A or another pharmaceutically acceptable salt thereof and a first
anti-C5 agent prior to administering a second anti-C5 agent.
[0256] In some embodiments, the present methods comprise
administering Antagonist A or another pharmaceutically acceptable
salt thereof prior to concurrently administering a first anti-C5
agent and a second anti-C5 agent.
[0257] In some embodiments, the present methods comprise
concurrently administering Antagonist A or another pharmaceutically
acceptable salt thereof, a first anti-C5 agent and a second anti-C5
agent.
[0258] In some embodiments, the present methods comprise
administering an anti-C5 agent prior to administering two or more
PDGF antagonists. In some embodiments, the present methods comprise
administering an anti-C5 agent prior to administering a first PDGF
antagonist and administering the first PDGF antagonist prior to
administering a second PDGF antagonist.
[0259] In some embodiments, the present methods comprise
concurrently administering an anti-C5 agent and Antagonist A or
another pharmaceutically acceptable salt thereof. In some
embodiments, the present methods comprise concurrently
administering an anti-C5 agent and a first PDGF antagonist prior to
administering a second PDGF antagonist.
[0260] In some embodiments, the present methods comprise
administering an anti-C5 agent prior to concurrently administering
a first PDGF antagonist and a second PDGF antagonist.
[0261] In some embodiments, the present methods comprise
concurrently administering an anti-C5 agent, a first PDGF
antagonist and a second PDGF antagonist.
[0262] In some embodiments, the present methods comprise
administering a VEGF antagonist prior to administering two or more
anti-C5 agents. In some embodiments, the present methods comprise
administering a VEGF antagonist prior to administering a first
anti-C5 agent and administering the first anti-C5 agent prior to
administering a second anti-C5 agent.
[0263] In some embodiments, the present methods comprise
concurrently administering a VEGF antagonist and an anti-C5 agent.
In some embodiments, the present methods comprise concurrently
administering a VEGF antagonist and a first anti-C5 agent prior to
administering a second anti-C5 agent.
[0264] In some embodiments, the present methods comprise
administering a VEGF antagonist prior to concurrently administering
a first anti-C5 agent and a second anti-C5 agent.
[0265] In some embodiments, the present methods comprise
concurrently administering a VEGF antagonist, a first anti-C5 agent
and a second anti-C5 agent.
[0266] In some embodiments, the present methods comprise
administering an anti-C5 agent prior to administering two or more
VEGF antagonists. In some embodiments, the present methods comprise
administering an anti-C5 agent prior to administering a first VEGF
antagonist and administering the first VEGF antagonist prior to
administering a second VEGF antagonist.
[0267] In some embodiments, the present methods comprise
concurrently administering an anti-C5 agent and a VEGF antagonist.
In some embodiments, the present methods comprise concurrently
administering an anti-C5 agent and a first VEGF antagonist prior to
administering a second VEGF antagonist.
[0268] In some embodiments, the present methods comprise
administering an anti-C5 agent prior to concurrently administering
a first VEGF antagonist and a second VEGF antagonist.
[0269] In some embodiments, the present methods comprise
concurrently administering an anti-C5 agent, a first VEGF
antagonist and a second VEGF antagonist.
[0270] In some embodiments, the first agent and second agent are
PDGF antagonists, which can be the same or different. In some
embodiment, the first agent and second agent are VEGF antagonists,
which can be the same or different. In some embodiments, the first
agent and second agent are anti-C5 agents, which can be the same or
different.
[0271] In some embodiments, the first agent and third agent are
PDGF antagonists, which can be the same or different. In some
embodiment, the first agent and third agent are VEGF antagonists,
which can be the same or different. In some embodiments, the first
agent and third agent are anti-C5 agents, which can be the same or
different.
[0272] In some embodiments, the second agent and third agent are
PDGF antagonists, which can be the same or different. In some
embodiment, the second agent and third agent are VEGF antagonists,
which can be the same or different. In some embodiments, the second
agent and third agent are anti-C5 agents, which can be the same or
different.
[0273] Illustrative groups of first agent, second agent and third
agent are set forth below in Tables 7, 8, 9 and 10.
TABLE-US-00006 TABLE 7 Group First Agent Second Agent Third Agent A
PDGF Antagonist VEGF antagonist VEGF antagonist B VEGF antagonist
PDGF Antagonist VEGF antagonist C VEGF antagonist VEGF antagonist
PDGF Antagonist D PDGF Antagonist Anti-C5 Agent Anti-C5 Agent E
Anti-C5 Agent PDGF Antagonist Anti-C5 Agent F Anti-C5 Agent Anti-C5
Agent PDGF Antagonist G PDGF Antagonist PDGF Antagonist VEGF
antagonist H PDGF Antagonist VEGF antagonist PDGF Antagonist I VEGF
antagonist PDGF Antagonist PDGF Antagonist J PDGF Antagonist PDGF
Antagonist Anti-C5 Agent K PDGF Antagonist Anti-C5 Agent PDGF
Antagonist L Anti-C5 Agent PDGF Antagonist PDGF Antagonist
TABLE-US-00007 TABLE 8 Group First Agent Second Agent Third Agent A
PDGF Antagonist First VEGF antagonist Second VEGF antagonist B
First VEGF antagonist PDGF Antagonist Second VEGF antagonist C
First VEGF antagonist Second VEGF antagonist PDGF Antagonist D PDGF
Antagonist First Anti-C5 Agent Second Anti-C5 Agent E First Anti-C5
Agent PDGF Antagonist Second Anti-C5 Agent F First Anti-C5 Agent
Second Anti-C5 Agent PDGF Antagonist G First PDGF Antagonist Second
PDGF Antagonist VEGF antagonist H First PDGF Antagonist VEGF
antagonist Second PDGF Antagonist I VEGF antagonist First PDGF
Antagonist Second PDGF Antagonist J First PDGF Antagonist Second
PDGF Antagonist Anti-C5 Agent K First PDGF Antagonist Anti-C5 Agent
Second PDGF Antagonist L Anti-C5 Agent First PDGF Antagonist Second
PDGF Antagonist
TABLE-US-00008 TABLE 9 Group First Agent Second Agent Third Agent A
Antagonist A ranibizumab Antagonist A B Antagonist A ranibizumab
ranibizumab C Antagonist A bevacizumab Antagonist A D Antagonist A
bevacizumab bevacizumab E Antagonist A aflibercept Antagonist A F
Antagonist A aflibercept aflibercept G Antagonist A pegaptanib
sodium Antagonist A H Antagonist A pegaptanib sodium pegaptanib
sodium I Antagonist A ESBA1008 Antagonist A J Antagonist A ESBA1008
ESBA1008 K Antagonist A ARC1905 Antagonist A L Antagonist A ARC1905
ARC1905 M ranibizumab Antagonist A ranibizumab N ranibizumab
Antagonist A Antagonist A O bevacizumab Antagonist A bevacizumab P
bevacizumab Antagonist A Antagonist A Q aflibercept Antagonist A
aflibercept R aflibercept Antagonist A Antagonist A S pegaptanib
sodium Antagonist A pegaptanib sodium T pegaptanib sodium
Antagonist A Antagonist A U ESBA1008 Antagonist A ESBA1008 V
ESBA1008 Antagonist A Antagonist A W ARC1905 Antagonist A ARC1905 X
ARC1905 Antagonist A Antagonist A Y ranibizumab ranibizumab
Antagonist A Z bevacizumab bevacizumab Antagonist A AA aflibercept
aflibercept Antagonist A AB pegaptanib sodium pegaptanib sodium
Antagonist A AC ESBA1008 ESBA1008 Antagonist A AD ARC1905 ARC1905
Antagonist A AE ranibizumab ranibizumab bevacizumab AF ranibizumab
bevacizumab ranibizumab AG ranibizumab ranibizumab aflibercept AH
ranibizumab aflibercept ranibizumab AI ranibizumab ranibizumab
pegaptanib sodium AJ ranibizumab pegaptanib sodium ranibizumab AK
ranibizumab ranibizumab ESBA1008 AL ranibizumab ESBA1008
ranibizumab AM ranibizumab ranibizumab ARC1905 AN ranibizumab
ARC1905 ranibizumab AO bevacizumab bevacizumab ranibizumab AP
bevacizumab ranibizumab bevacizumab AQ bevacizumab bevacizumab
aflibercept AR bevacizumab aflibercept bevacizumab AS bevacizumab
bevacizumab pegaptanib sodium AT bevacizumab pegaptanib sodium
bevacizumab AU bevacizumab bevacizumab ESBA1008 AV bevacizumab
ESBA1008 bevacizumab AW bevacizumab bevacizumab ARC1905 AX
bevacizumab ARC1905 bevacizumab AY aflibercept aflibercept
ranibizumab AZ aflibercept ranibizumab aflibercept BA aflibercept
aflibercept bevacizumab BB aflibercept bevacizumab aflibercept BC
aflibercept aflibercept pegaptanib sodium BD aflibercept pegaptanib
sodium aflibercept BE aflibercept aflibercept ESBA1008 BF
aflibercept ESBA1008 aflibercept BG aflibercept aflibercept ARC1905
BH aflibercept ARC1905 aflibercept BI pegaptanib sodium pegaptanib
sodium ranibizumab BJ pegaptanib sodium ranibizumab pegaptanib
sodium BK pegaptanib sodium pegaptanib sodium bevacizumab BL
pegaptanib sodium bevacizumab pegaptanib sodium BM pegaptanib
sodium pegaptanib sodium aflibercept BN pegaptanib sodium
aflibercept pegaptanib sodium BO pegaptanib sodium pegaptanib
sodium ESBA1008 BP pegaptanib sodium ESBA1008 pegaptanib sodium BQ
pegaptanib sodium pegaptanib sodium ARC1905 BR pegaptanib sodium
ARC1905 pegaptanib sodium BS ESBA1008 ESBA1008 ranibizumab BT
ESBA1008 ranibizumab ESBA1008 BU ESBA1008 ESBA1008 bevacizumab BV
ESBA1008 bevacizumab ESBA1008 BW ESBA1008 ESBA1008 aflibercept BX
ESBA1008 aflibercept ESBA1008 BY ESBA1008 ESBA1008 pegaptanib
sodium BZ ESBA1008 pegaptanib sodium ESBA1008 CA ESBA1008 ESBA1008
ARC1905 CB ESBA1008 ARC1905 ESBA1008 CC ARC1905 ARC1905 ranibizumab
CD ARC1905 ranibizumab ARC1905 CE ARC1905 ARC1905 bevacizumab CF
ARC1905 bevacizumab ARC1905 CO ARC1905 ARC1905 aflibercept CH
ARC1905 aflibercept ARC1905 CI ARC1905 ARC1905 pegaptanib sodium CJ
ARC1905 pegaptanib sodium ARC1905 CK ARC1905 ARC1905 ESBA1008 CL
ARC1905 ESBA1008 ESBA1008
TABLE-US-00009 TABLE 10 Group First Agent Second Agent Third Agent
A Antagonist A ranibizumab bevacizumab B Antagonist A ranibizumab
aflibercept C Antagonist A ranibizumab pegaptanib sodium D
Antagonist A bevacizumab aflibercept E Antagonist A bevacizumab
pegaptanib sodium F Antagonist A aflibercept pegaptanib sodium G
ranibizumab bevacizumab Antagonist A H ranibizumab aflibercept
Antagonist A I ranibizumab pegaptanib sodium Antagonist A J
bevacizumab aflibercept Antagonist A K bevacizumab pegaptanib
sodium Antagonist A L aflibercept pegaptanib sodium Antagonist A M
ranibizumab Antagonist A bevacizumab N ranibizumab Antagonist A
aflibercept O ranibizumab Antagonist A pegaptanib sodium P
bevacizumab Antagonist A aflibercept Q bevacizumab Antagonist A
pegaptanib sodium R aflibercept Antagonist A pegaptanib sodium S
bevacizumab ranibizumab Antagonist A T aflibercept ranibizumab
Antagonist A U pegaptanib sodium ranibizumab Antagonist A V
aflibercept bevacizumab Antagonist A W pegaptanib sodium
bevacizumab Antagonist A X pegaptanib sodium aflibercept Antagonist
A Y bevacizumab Antagonist A ranibizumab Z aflibercept Antagonist A
ranibizumab AA pegaptanib sodium Antagonist A ranibizumab AB
aflibercept Antagonist A bevacizumab AC pegaptanib sodium
Antagonist A bevacizumab AD pegaptanib sodium Antagonist A
aflibercept AE Antagonist A ARC187 ARC1905 AF Antagonist A ARC1905
ARC187 AG ARC187 ARC1905 Antagonist A AH ARC1905 ARC187 Antagonist
A AI ARC187 Antagonist A ARC1905 AJ ARC1905 Antagonist A ARC187
[0274] In one embodiment, two or more agents are administered
concurrently. In one embodiment, the two or more agents
administered concurrently are present in the same composition. In
another embodiment, the two or more agents administered
concurrently are each present in a separate composition.
[0275] In certain embodiments, the time period from administration
of a first agent to administration of a second agent is at least 1
min, at least 5 min, at least 10 min, at least 15 min, at least 30
min, or at least one hour. In certain embodiments, the time period
from administration of a first agent to administration of a second
agent is between 1 min and 2 hours, between 5 min and 2 hours,
between 10 min and 2 hours, between 15 min and 2 hours, between 30
min and 2 hours, between 45 min and 2 hours, between 1 hour and 2
hours, or between 30 min and 1 hour. In certain embodiments, the
time period from administration of a first agent to administration
of a second agent is about 1 min, about 2 min, about 3 min, about 5
min, about 10 min, about 15 min, about 20 min, about 25 min, about
30 min, about 35 min, about 40 min, about 45 min, about 50 min,
about 55 min, about 60 min, about 90 min, or about 120 min. In
certain embodiments, a second agent is administered within 90 days,
30 days, 10 days, 5 days, 2 days, 1 day, 24 hours, 1 hour, 30
minutes, 10 minutes, 5 minutes or one minute after administration
of a second agent.
[0276] In certain embodiments, the time period from administration
of a second agent to administration of a third agent is at least 1
min, at least 5 min, at least 10 min, at least 15 min, at least 30
min, or at least one hour. In certain embodiments, the time period
between administration of a second agent and administration of a
third agent is between 1 min and 2 hours, between 5 min and 2
hours, between 10 min and 2 hours, between 15 min and 2 hours,
between 30 min and 2 hours, between 45 min and 2 hours, between 1
hour and 2 hours, or between 30 min and 1 hour. In certain
embodiments, the time period between administration of a second
agent and administration of a third agent is about 1 min, about 2
min, about 3 min, about 5 min, about 10 min, about 15 min, about 20
min, about 25 min, about 30 min, about 35 min, about 40 min, about
45 min, about 50 min, about 55 min, about 60 min, about 90 min, or
about 120 min. In certain embodiments, a third agent is
administered within 90 days, 30 days, 10 days, 5 days, 2 days, 1
day, 24 hours, 1 hour, 30 minutes, 10 minutes, 5 minutes or one
minute after administration of a second agent.
[0277] In certain embodiments, the time period between concurrent
administration of a first agent and a second agent and
administration of a third agent is at least 1 min, at least 5 min,
at least 10 min, at least 15 min, at least 30 min, or at least one
hour. In certain embodiments, the time period between concurrent
administration of a first agent and a second agent and
administration of a third agent is between 1 min and 2 hours,
between 5 min and 2 hours, between 10 min and 2 hours, between 15
min and 2 hours, between 30 min and 2 hours, between 45 min and 2
hours, between 1 hour and 2 hours, or between 30 min and 1 hour. In
certain embodiments, the time period from concurrent administration
of a first agent and a second agent to administration of a third
agent is about 1 min, about 2 min, about 3 min, about 5 min, about
10 min, about 15 min, about 20 min, about 25 min, about 30 min,
about 35 min, about 40 min, about 45 min, about 50 min, about 55
min, about 60 min, about 90 min, or about 120 min. In certain
embodiments, administration of a third agent is within 90 days, 30
days, 10 days, 5 days, 2 days, 1 day, 24 hours, 1 hour, 30 minutes,
10 minutes, 5 minutes or one minute of concurrent administration of
a first agent and a second agent.
[0278] In certain embodiments, the time period from administration
of a first agent to concurrent administration a second agent and a
third agent is at least 1 min, at least 5 min, at least 10 min, at
least 15 min, at least 30 min, or at least one hour. In certain
embodiments, the time period from administration of a first agent
to concurrent administration of a second agent and a third agent is
between 1 min and 2 hours, between 5 min and 2 hours, between 10
min and 2 hours, between 15 min and 2 hours, between 30 min and 2
hours, between 45 min and 2 hours, between 1 hour and 2 hours, or
between 30 min and 1 hour. In certain embodiments, the time period
from administration of a first agent to concurrent administration
of a second agent and a third agent is about 1 min, about 2 min,
about 3 min, about 5 min, about 10 min, about 15 min, about 20 min,
about 25 min, about 30 min, about 35 min, about 40 min, about 45
min, about 50 min, about 55 min, about 60 min, about 90 min, or
about 120 min. In certain embodiments, concurrent administration of
a second agent and a third agent is within 90 days, 30 days, 10
days, 5 days, 2 days, 1 day, 24 hours, 1 hour, 30 minutes, 10
minutes, 5 minutes or one minute of administration of a first
agent.
[0279] The administration of two or more, such as three or more,
active agents (e.g., Antagonist A or another pharmaceutically
acceptable salt thereof, a VEGF antagonist and an anti-C5 agent)
can have a synergistic effect in treating or preventing a disease
or disorder, e.g., an ophthalmological disease or disorder. For
example, administration of Antagonist A or another pharmaceutically
acceptable salt thereof, VEGF antagonist and anti-C5 agent (or any
two of these active agents) can improve retinal attachment success,
improve visual acuity, reduce choroidal neovascularization or
stabilize vision to a degree that is greater than an additive
effect of the active agents.
[0280] In certain embodiments, the invention provides methods for
treating or preventing an ophthalmological disease or disorder,
comprising administering to a subject in need thereof one or more,
in some embodiments two or more or three or more, active agents via
an apparatus. In other embodiments, the methods further comprise
performing surgery on the subject. In other embodiments, the
methods further comprise administering another active agent, such
as an antineoplastic drug, including but not limited to any of
those described herein. In particular embodiments, the methods
further comprise administering another active agent and performing
surgery on the subject.
[0281] In some embodiments, administration of Antagonist A or
another pharmaceutically acceptable salt thereof, and optionally a
VEGF antagonist and/or an anti-C5 agent to a subject results in
improved vision, such as increased visual acuity. In some
embodiments, the subject experienced moderate vision loss, defined
as losing 15 letters or more from baseline on ETDRS visual acuity
testing, measured at week 24, prior to treatment with Antagonist A
or another pharmaceutically acceptable salt thereof.
[0282] In some embodiments, visual acuity testing is as described
in Early Treatment Diabetic Retinopathy Study Research Group
(ETDRS), Manual of Operations, Baltimore: ETDRS Coordinating
Center, University of Maryland. Available from: National Technical
Information Service, 5285 Port Royal Road, Springfield, Va. 22161;
Accession No. PB85 223006/AS; Ferris et al., Am J Ophthalmol
94:91-96, 1982; or or Example 4, as described herein. In some
embodiments, the visual acuity testing uses one or more charts
available from
http://www.nei.nih.gov/photo/keyword.asp?conditions=Eye+Charts&match=all,
e.g., ETDRS visual acuity Chart 1, 2 and/or R.
[0283] In other embodiments, administration of Antagonist A or
another pharmaceutically acceptable salt thereof and a VEGF
antagonist results in fewer ocular adverse events, a decrease in
size of RCH (e.g., measured by fundus photography and FA), a
decrease in exudation (measured by fundus photography, OCT, and
FA), or a decrease in epiretinal proliferation or retinal traction
(assessed by fundus photography), compared to those experienced by
a subject who was not administered with Antagonist A or another
pharmaceutically acceptable salt thereof. In some embodiments, the
subject does not require, and the methods do not comprise, ablative
treatment of RCH or ocular surgery.
[0284] In some embodiments, administration of Antagonist A or
another pharmaceutically acceptable salt thereof, and optionally a
VEGF antagonist and/or an anti-C5 agent, to a subject results in
improved vision independent of baseline lesion size or baseline
vision, compared to vision of a subject who was not administered
with Antagonist A or another pharmaceutically acceptable salt
thereof, or compared to a subject administered anti-VEGF
monotherapy. In some embodiments, administration of Antagonist A or
another pharmaceutically acceptable salt thereof, and optionally a
VEGF antagonist and/or an anti-C5 agent, to a subject results in
the subject having a visual acuity of 20/40 or better, or 20/25 or
better vision. In some embodiments, administration of Antagonist A
or another pharmaceutically acceptable salt thereof, and optionally
a VEGF antagonist and/or an anti-C5 agent to a subject results in
an increased reduction in CNV size in the subject, compared to CNV
size in a patient who was not administered with Antagonist A or
another pharmaceutically acceptable salt thereof, or compared to a
subject administered anti-VEGF monotherapy. In some embodiments,
administration of Antagonist A or another pharmaceutically
acceptable salt thereof, and optionally a VEGF antagonist and/or an
anti-C5 agent, to a subject results in a reduction in CNV size
(e.g., reduction in disc area (DA) size). In some embodiments,
administration of Antagonist A or another pharmaceutically
acceptable salt thereof, and optionally a VEGF antagonist and/or an
anti-C5 agent to a subject result in an increased reduction in DA
in the subject, compared to DA in a patient who was not
administered with Antagonist A or another pharmaceutically
acceptable salt thereof, or compared to a subject administered
anti-VEGF monotherapy. In some embodiments, the increased reduction
in CNV size is in subjects with small baseline CNV, e.g., less than
or equal to 1.62 DA (disc area). In some embodiments, the increased
reduction in CNV size (e.g., in disc area) is in subjects with
large baseline CNV, e.g., greater than 1.62 DA. In some
embodiments, administration of Antagonist A or another
pharmaceutically acceptable salt thereof, and optionally a VEGF
antagonist and/or an anti-C5 agent, to a subject results in
neovascular regression. In some embodiments, administration of
Antagonist A or another pharmaceutically acceptable salt thereof,
and optionally a VEGF antagonist and/or an anti-C5 agent, to a
subject results in reduced neovascular growth, compared to that
occurring in a subject who was not administered with Antagonist A
or another pharmaceutically acceptable salt thereof, or compared to
a subject administered anti-VEGF monotherapy. In some embodiments,
the reduced neovascular growth is anti-fibrosis. In some
embodiments, administration of Antagonist A or another
pharmaceutically acceptable salt thereof, and optionally a VEGF
antagonist and/or an anti-C5 agent, to a subject results in a
decrease in or absence of hyper-reflective material, e.g.,
sub-retinal hyper-reflective material, such as a decrease in the
size of sub-retinal hyper-reflective material (SHRM) as evidenced
by spectral domain optical coherence tomography (SD-OCT). In some
embodiments, administration of Antagonist A or another
pharmaceutically acceptable salt thereof, and optionally a VEGF
antagonist and/or an anti-C5 agent, to a subject results in an
increase in resolution of hyper-reflective material, e.g.,
sub-retinal hyper-reflective material, such as compared to a
subject who was not administered with Antagonist A or another
pharmaceutically acceptable salt thereof, or compared to a subject
administered a VEGF antagonist, anti-VEGF monotherapy, and/or an
anti-C5 agent.
[0285] In some embodiments, a subject with improved vision has a
greater than 3-line, 4-line or 5-line gain in visual acuity. In one
embodiment, a subject's visual acuity is determined using a
protocol such as the Early Treatment for Diabetic Retinopathy Study
("ETDRS") or the Age-Related Eye Disease Study ("AREDS") protocol.
In some embodiments, visual acuity is measured using a modified
ETDRS and/or AREDS protocol, such as the measurement of visual
acuity described in Ferris et al., Am J Ophthalmol 94:91-96, 1982.
In some embodiments, visual acuity is measured as described in
Early Treatment Diabetic Retinopathy Study Research Group (ETDRS),
Manual of Operations, Baltimore: ETDRS Coordinating Center,
University of Maryland. Available from: National Technical
Information Service, 5285 Port Royal Road, Springfield, Va. 22161;
Accession No. PB85 223006/AS. In other embodiments, visual acuity
testing is measured as described in Example 4 below. In some
embodiments, the visual acuity testing uses one or more charts
available from
http://www.nei.nih.gov/photo/keyword.asp?conditions=Eye+Charts&match=all,
e.g., ETDRS visual acuity Chart 1, 2 and/or R.
[0286] In one embodiment, a subject's visual acuity is determined
by one or more of the following procedures: (1) measurement of
best-corrected visual acuity (BCVA) with required manifest
refraction; (2) measurement of corrected visual acuity with
conditional manifest refraction; or (3) measurement of corrected
visual acuity without manifest refraction.
[0287] In one embodiment, each of the PDGF and VEGF antagonists is
administered in an amount effective to treat or prevent an
ophthalmological disease or disorder. The amount of antagonist that
is admixed with the carrier materials to produce a single dosage
can vary depending upon the subject being treated and the
particular mode of administration.
[0288] The dosage of each antagonist can depend on several factors
including the severity of the condition, whether the condition is
to be treated or prevented, and the age, weight, and health of the
person to be treated. Additionally, pharmacogenomic (the effect of
genotype on the pharmacokinetic, pharmacodynamic or efficacy
profile of a therapeutic) information about a particular patient
may affect dosage used. Furthermore, the exact individual dosages
can be adjusted somewhat depending on a variety of factors,
including the specific combination of antagonists being
administered, the time of administration, the route of
administration, the nature of the formulation, the rate of
excretion, the particular ophthalmological disease or disorder
being treated, the severity of the disorder, and the anatomical
location of the neovascular disorder. Some variations in the dosage
can be expected.
[0289] Generally, when orally administered to a subject, the dosage
of an antagonist of the present invention is normally 0.001
mg/kg/day to 100 mg/kg/day, 0.01 mg/kg/day to 50 mg/kg/day, or 0.1
mg/kg/day to 10 mg/kg/day. Generally, when orally administered to a
human, the dosage of an antagonist of the present invention is
normally 0.001 mg to 300 mg per day, 1 mg to 200 mg per day, or 5
mg to 50 mg per day. Dosages up to 200 mg per day may be necessary.
For administration of an antagonist of the present invention by
parenteral injection, the dosage is normally 0.1 mg to 250 mg per
day, 1 mg to 20 mg per day, or 3 mg to 5 mg per day. Injections may
be given up to four times daily. In some embodiments, the dosage of
a PDGF or VEGF antagonist for use in the present invention is
normally 0.1 mg to 1500 mg per day, or 0.5 mg to 10 mg per day, or
0.5 mg to 5 mg per day. A dosage of up to 3000 mg per day can be
administered.
[0290] In some embodiments, for administration by parenteral
injection of a three active agents (e.g., Antagonist A or another
pharmaceutically acceptable salt thereof, VEGF antagonist and an
anti-C5 agent or other combination disclosed herein), the dosage of
each of the PDGF antagonist, VEGF antagonist and anti-C5 agent, is
typically 0.1 mg to 250 mg per day, 1 mg to 20 mg per day, or 3 mg
to 5 mg per day. Injections may be given up to four times daily.
Generally, when parenterally administered, the dosage of Antagonist
A or another pharmaceutically acceptable salt thereof, VEGF
antagonist, or anti-C5 agent is typically 0.1 mg to 1500 mg per
day, or 0.5 mg to 10 mg per day, or 0.5 mg to 5 mg per day. A
dosage of at least up to 3000 mg per day can be administered.
[0291] In some embodiments, in which Antagonist A or another
pharmaceutically acceptable salt thereof, VEGF antagonist and/or
anti-C5 agent are ophthalmologically administered to a human, for
example intravitreally, the dosage of each of Antagonist A or
another pharmaceutically acceptable salt thereof, VEGF antagonist
and anti-C5 agent is typically 0.003 mg to 5.0 mg per eye per
administration, or 0.03 mg to 3.0 mg per eye per administration, or
0.1 mg to 1.0 mg per eye per administration. In one embodiment, the
dosage of each of Antagonist A or another pharmaceutically
acceptable salt thereof, VEGF antagonist and anti-C5 agent is about
0.03 mg, about 0.3 mg, about 0.5 mg, about 1.0 mg, about 1.25 mg,
about 1.5 mg, about 2.0 mg or about 3.0 mg per eye. In one
embodiment, the dosage Antagonist A or another pharmaceutically
acceptable salt thereof is about 0.03 mg, about 0.3 mg, about 0.5
mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 2.0 mg, about
3.0 mg, or about 4.0 mg per eye. In another embodiment, the dosage
of a VEGF antagonist (e.g., ranibizumab, bevacizumab, aflibercept,
ESBA1008 or pegaptanib sodium) is about 0.03 mg, about 0.3 mg,
about 0.5 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg, about 1.65
mg, about 2.0 mg, about 3.0 mg, or about 4.0 mg per eye. In another
embodiment, the dosage of the anti-C5 agent (e.g., ARC1905 or a
pharmaceutically acceptable salt thereof) is about 0.03 mg, about
0.3 mg, about 0.5 mg, about 1.0 mg, about 1.25 mg, about 1.5 mg,
about 1.65 mg, about 2.0 mg, about 3.0 mg, or about 4.0 per
eye.
[0292] In certain embodiments where a subject is administered both
Antagonist A or another pharmaceutically acceptable salt thereof
and a VEGF antagonist, and optionally an anti-C5 agent, the dosage
of Antagonist A or another pharmaceutically acceptable salt
thereof) is about 1.5 mg, and the dosage of the VEGF antagonist
(e.g., ranibizumab) is about 0.5 mg. In certain embodiments where a
subject is administered both Antagonist A or another
pharmaceutically acceptable salt thereof and a VEGF antagonist, the
dosage of Antagonist A or another pharmaceutically acceptable salt
thereofis about 3.0 mg, and the dosage of the VEGF antagonist
(e.g., ranibizumab) is about 0.5 mg. In certain embodiments, a
subject is administered both Antagonist A or another
pharmaceutically acceptable salt thereof and a VEGF antagonist,
wherein the dosage of Antagonist A or another pharmaceutically
acceptable salt thereof) is about 1.5 mg, and the dosage of the
VEGF antagonist (e.g., bevacizumab) is about 1.25 mg. In certain
embodiments, a subject is administered both Antagonist A or another
pharmaceutically acceptable salt thereof and a VEGF antagonist,
wherein the dosage of Antagonist A or another pharmaceutically
acceptable salt thereof is about 3.0 mg, and the dosage of the VEGF
antagonist (e.g., bevacizumab) is about 1.25 mg. In certain
embodiments, a subject is administered both Antagonist A or another
pharmaceutically acceptable salt thereof and a VEGF antagonist,
wherein the dosage of Antagonist A or another pharmaceutically
acceptable salt thereof is about 1.5 mg, and the dosage of the VEGF
antagonist (e.g., aflibercept) is about 2.0 mg. In certain
embodiments, a subject is administered both Antagonist A or another
pharmaceutically acceptable salt thereof and a VEGF antagonist,
wherein the dosage of Antagonist A or another pharmaceutically
acceptable salt thereof is about 3.0 mg, and the dosage of the VEGF
antagonist (e.g., aflibercept) is about 2.0 mg. In certain
embodiments, a subject is administered both Antagonist A or another
pharmaceutically acceptable salt thereof and a VEGF antagonist,
wherein the dosage of Antagonist A or another pharmaceutically
acceptable salt thereof is about 1.5 mg, and the dosage of the VEGF
antagonist, e.g., pegaptanib sodium, is about 1.65 mg. In certain
embodiments, a subject is administered both Antagonist A or another
pharmaceutically acceptable salt thereof and a VEGF antagonist,
wherein the dosage of Antagonist A or another pharmaceutically
acceptable salt thereof is about 3.0 mg, and the dosage of the VEGF
antagonist, e.g., pegaptanib sodium, is about 1.65 mg.
[0293] The dosage can range from about 0.01 mL to about 0.2 mL
administered per eye, or about 0.03 mL to about 0.15 mL
administered per eye, or about 0.05 mL to about 0.10 mL
administered per eye.
[0294] Antagonist A or a pharmaceutically acceptable salt thereof
can be delivered intravitreally at up to about 30 mg/ml with
injection volumes up to 100 .mu.L.
[0295] Illustrative Antagonist A/VEGF antagonist combination pairs
and their dosages are set forth in Table 11:
TABLE-US-00010 TABLE 11 Combination No. PDGF Antagonist VEGF
Antagonist 1 Antagonist A ranibizumab (about 1.5 mg) (about 0.5 mg)
2 Antagonist A ranibizumab (about 3.0 mg) (about 0.5 mg) 3
Antagonist A bevacizumab (about 1.5 mg) (about 1.25 mg) 4
Antagonist A bevacizumab (about 3.0 mg) (about 1.25 mg) 5
Antagonist A aflibercept (about 1.5 mg) (about 2.0 mg) 6 Antagonist
A aflibercept (about 3.0 mg) (about 2.0 mg) 7 Antagonist A
pegaptanib sodium (about 3.0 mg) (about 1.65 mg) 8 Antagonist A
pegaptanib sodium (about 3.0 mg) (about 1.65 mg)
[0296] In particular embodiments wherein the subject is
administered an anti-C5 agent in combination with Antagonist A or
another pharmaceutically acceptable salt thereof and the VEGF
antagonist, the anti-C5 agent may be administered at a dosage of
about 0.03 mg, about 0.3 mg, about 0.5 mg, about 1.0 mg, about 1.25
mg, about 1.5 mg, about 2.0 mg or about 3.0 mg per eye.
[0297] In certain embodiments, ocular dosages of compositions
comprising anti-C5 aptamers, such as ARC1905 and ARC187, or a
pharmaceutically acceptable salt thereof, can range from about 0.01
mg to about 5 mg/eye or from about 0.1 mg to about 3 mg/eye. For
instance, ocular dosages of compositions comprising ARC1905,
ARC187, or a pharmaceutically acceptable salt thereof may be about
0.01 mg, about 0.03 mg, about 0.05 mg, about 0.1 mg, about 0.3 mg,
about 0.5 mg, about 1 mg, about 1.5 mg, about 2 mg, about 2.5 mg,
about 3 mg, about 3.5 mg, about 4 mg, about 4.5 mg, or about 5 mg.
Such dosages may be administered ocularly, for example by
intravitreal injection, weekly, biweekly, monthly, or quarterly,
optionally by a sustained release device or formulation. In some
embodiments, the anti-C5 aptamers (e.g., ARC1905, ARC187, or a
pharmaceutically acceptable salt thereof) can be administered in
multiple injections (e.g., intravitreal injections) over a period
of months separated by varying time intervals. In certain such
embodiments, initial injections received early in the treatment
regimen are separated by a shorter interval than injections
received later in the treatment regimen. For instance, one dosage
regimen, particularly useful in methods for treating, preventing,
or stabilizing AMD (e.g., non-exudative type AMD or geographic
atrophy), comprises administering initial injections at the start
of treatment (e.g., first two, three, four, or five injections) of
anti-C5 aptamer (e.g., ARC1905, ARC187, or a pharmaceutically
acceptable salt thereof) on a monthly basis and administering
subsequent injections at longer intervals (e.g., every three, four,
five, or six months). By way of example, the first three injections
of anti-C5 aptamer are administered to a subject every month,
whereas the fourth and fifth injections are administered three or
four months after the previous injection. Intervals between
injections of anti-C5 aptamer may be adjusted based on the
subject's response to treatment as measured, for example, by change
in geographic atrophy lesion size or improvement or stabilization
of visual acuity.
[0298] In some embodiments, an anti-C5 aptamer is administered to a
subject with a VEGF antagonist, wherein the dosage of the anti-C5
aptamer is about 0.03 mg, and the dosage of the VEGF antagonist,
e.g., ranibizumab, is about 0.5 mg. In certain embodiments, a
subject is administered both an anti-C5 aptamer and a VEGF
antagonist, wherein the dosage of the anti-C5 aptamer is about 1.0
mg, and the dosage of the VEGF antagonist, e.g., ranibizumab, is
about 0.5 mg. In certain embodiments, a subject is administered
both an anti-C5 aptamer and a VEGF antagonist, wherein the dosage
of the anti-C5 aptamer is about 2.0 mg, and the dosage of the VEGF
antagonist, e.g., ranibizumab, is about 0.5 mg.
[0299] In some embodiments, an anti-C5 aptamer is administered to a
subject with a VEGF antagonist, wherein the dosage of the anti-C5
aptamer is about 0.03 mg, and the dosage of the VEGF antagonist,
e.g., bevacizumab, is about 1.25 mg. In certain embodiments, a
subject is administered both an anti-C5 aptamer and a VEGF
antagonist, wherein the dosage of the anti-C5 aptamer is about 1.0
mg, and the dosage of the VEGF antagonist, e.g., bevacizumab, is
about 1.25 mg. In certain embodiments, a subject is administered
both an anti-C5 aptamer and a VEGF antagonist, wherein the dosage
of the anti-C5 aptamer is about 2.0 mg, and the dosage of the VEGF
antagonist, e.g., bevacizumab, is about 1.25 mg.
[0300] In some embodiments, an anti-C5 aptamer is administered to a
subject with a VEGF antagonist, wherein the dosage of the anti-C5
aptamer is about 0.03 mg, and the dosage of the VEGF antagonist,
e.g., aflibercept, is about 2.0 mg. In certain embodiments, a
subject is administered both an anti-C5 aptamer and a VEGF
antagonist, wherein the dosage of the anti-C5 aptamer is about 1.0
mg, and the dosage of the VEGF antagonist, e.g., aflibercept, is
about 2.0 mg. In certain embodiments, a subject is administered
both an anti-C5 aptamer and a VEGF antagonist, wherein the dosage
of the anti-C5 aptamer is about 2.0 mg, and the dosage of the VEGF
antagonist, e.g., aflibercept, is about 2.0 mg.
[0301] Administration of each antagonist can, independently, be one
to four times daily or one to four times per month or one to six
times per year or once every two, three, four or five years.
Administration can be for the duration of one day or one month, two
months, three months, six months, one year, two years, three years,
and may even be for the life of the patient. In one embodiment, the
administration is performed once a month for three months. Chronic,
long-term administration will be indicated in many cases. The
dosage may be administered as a single dose or divided into
multiple doses. In general, the desired dosage should be
administered at set intervals for a prolonged period, usually at
least over several weeks or months, although longer periods of
administration of several months or years or more may be
needed.
[0302] In addition to treating pre-existing ophthalmological
diseases and disorders, the compositions can be administered
prophylactically in order to prevent or slow the onset of these
disease and disorders. The term "prevent" encompasses inhibiting or
delaying the onset or progression of a disease or disorder. In
prophylactic applications, the composition can be administered to a
patient susceptible to or otherwise at risk of a particular
ophthalmological disease or disorder.
[0303] In one embodiment, Antagonist A or another pharmaceutically
acceptable salt thereof and the VEGF antagonist are administered to
a subject in need of treatment therewith, typically in the form of
an injectable pharmaceutical composition. Antagonist A or another
pharmaceutically acceptable salt thereof and VEGF antagonist can be
administered either in separate compositions or in a pharmaceutical
composition comprising both the PDGF antagonist and VEGF
antagonist. The administration can be by injection, for example by
intraocular injection, or by using a drug delivery device.
Parenteral, systemic, or transdermal administration is also within
the scope of the invention. The administration of Antagonist A or
another pharmaceutically acceptable salt thereof and the VEGF
antagonist can be sequential in time or concurrent. When
administered sequentially, the administration of each can be by the
same or different route. In one embodiment, Antagonist A or another
pharmaceutically acceptable salt thereof is administered within 90
days, 30 days, 10 days, 5 days, 24 hours, 1 hour, 30 minutes, 10
minutes, 5 minutes or one minute of administration of a VEGF
antagonist. Where Antagonist A or another pharmaceutically
acceptable salt thereof is administered prior to the VEGF
antagonist, the VEGF antagonist is administered within a time and
in an amount such that the total amount of Antagonist A or another
pharmaceutically acceptable salt thereof and VEGF antagonist is
effective to treat or prevent an ophthalmological disease or
disorder. Where the VEGF antagonist is administered prior to
Antagonist A or another pharmaceutically acceptable salt thereof,
Antagonist A or another pharmaceutically acceptable salt thereof is
administered within a time and in an amount such that the total
amount of Antagonist A or another pharmaceutically acceptable salt
thereof and VEGF antagonist is effective to treat or prevent an
ophthalmological disease or disorder.
[0304] In one embodiment, Antagonist A or another pharmaceutically
acceptable salt thereof or VEGF antagonist (e.g., ranibizumab,
bevacizumab, pegaptanib sodium, ESBA1008 or aflibercept) is
administered intravitreally with a 30-gauge or 27-gauge needle. In
some embodiments, a 0.5 inch needle is used. In one embodiment,
Antagonist A or another pharmaceutically acceptable salt thereof is
administered intravitreally with a 30-gauge 0.5 inch needle and a
VEGF antagonist (e.g., ranibizumab, bevacizumab, pegaptanib sodium,
ESBA1008 or aflibercept) is administered intravitreally with a
27-gauge needle. In some embodiments, 504, (1.5 mg in 0.05 mL) of
Antagonist A or another pharmaceutically acceptable salt thereof is
administered intravitreally with a 30-gauge 0.5 inch needle and
504, (0.5 mg in 0.05 mL) of a VEGF antagonist (e.g., ranibizumab,
bevacizumab, pegaptanib sodium or aflibercept) is administered
intravitreally with a 27-gauge needle.
[0305] In certain embodiments where Antagonist A or another
pharmaceutically acceptable salt thereof such as Antagonist A or
another pharmaceutically acceptable salt thereof is used in
combination with a VEGF antagonist, such as ranibizumab,
bevacizumab, ESBA1008, pegaptanib sodium or aflibercept, one of
these two agents is first administered to the subject, and then the
other agent is administered to the subject. In particular
embodiments, the two agents are both administered to the same eye
of the subject. In particular embodiments, the two agents are both
administered to both eyes of the subject. The two agents may be
administered to an eye in either order, i.e., Antagonist A or
another pharmaceutically acceptable salt thereof may be
administered first, and then the VEGF antagonist administered, or
the VEGF antagonist may be administered first, and then Antagonist
A or another pharmaceutically acceptable salt thereof administered.
The agent administered second may be administered immediately
following administration of the agent administered first, or the
agent administered second may be administered after a time period
following administration of the agent administered first.
[0306] In certain embodiments, the time period from administration
of the first agent to administration of the second agent is at
least 1 min, at least 5 min, at least 10 min, at least 15 min, at
least 30 min, or at least one hour. In certain embodiments, the
time period from administration of the first agent to
administration of the second agent is between 1 min and 2 hours,
between 5 min and 2 hours, between 10 min and 2 hours, between 15
min and 2 hours, between 30 min and 2 hours, between 45 min and 2
hours, between 1 hour and 2 hours, or between 30 min and 1 hour. In
certain embodiments, the time period from administration of the
first agent to administration of the second agent is about 1 min,
about 2 min, about 3 min, about 5 min, about 10 min, about 15 min,
about 20 min, about 25 min, about 30 min, about 35 min, about 40
min, about 45 min, about 50 min, about 55 min, about 60 min, about
90 min, or about 120 min.
[0307] In certain embodiments, the present invention provides
methods for treating or preventing any of the ophthalmological
diseases described herein, comprising providing to a subject in
need thereof Antagonist A or another pharmaceutically acceptable
salt thereof at a first time point, and providing to the subject a
VEGF antagonist, e.g., aflibercept, bevacizumab, ranibizumab,
ESBA1008, or pegaptanib sodium, at a second time point, wherein the
amount of time between the first time point and the second time
point is about 1 min, about 2 min, about 5 min, about 10 min, about
15 min, about 20 min, about 25 min, about 30 min, about 40 min,
about 50 min, about 60 min, about 90 min, about 2 hours, about 4
hours, about 6 hours, about 8 hours, about 12 hours, about 24
hours, about 36 hours, about 48 hours, about three days, about four
days, about five days, about six days, or about seven days.
[0308] In certain embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof and the VEGF antagonist
are administered intravitreally. In certain embodiments, about 1.5
mg or 3.0 mg of Antagonist A or another pharmaceutically acceptable
salt thereof to an eye, and about 0.5 mg, about 1.25 mg, about 1.65
mg, or about 2.0 mg of the VEGF antagonist is administered to an
eye. In some embodiments, the VEGF antagonist is administered
intravitreally about 30 minutes after Antagonist A or another
pharmaceutically acceptable salt thereof is administered
intravitreally. In some embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof is administered
intravitreally about 30 minutes after the VEGF antagonist is
administered intravitreally.
[0309] In one embodiment, a VEGF antagonist is administered to at
least one eye of the subject, about 1 hour is allowed to elapse
following administration of the VEGF antagonist, and then
Antagonist A or another pharmaceutically acceptable salt thereof is
administered to the same eye. In one embodiment, Antagonist A or
another pharmaceutically acceptable salt thereof is administered to
at least one eye of the subject, about 1 hour is allowed to lapse
following administration of the PDGF antagonist, and then a VEGF
antagonist is administered to the same eye.
[0310] In certain embodiments, the PDGF antagonist and the VEGF
antagonist are administered to each eye in a total combined volume
of less than or about 50 .mu.L, less than or about 60 .mu.L, less
than or about 70 .mu.L, less than or about 80 .mu.L, less than or
about 90 .mu.L, less than or about 100 .mu.L, less than or about
120 .mu.L, less than or about 150 .mu.L, or less than or about 200
.mu.L.
[0311] In certain embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof, VEGF antagonist and
anti-C5 agent are administered intraocularly, e.g., intravitreally.
In particular embodiments, Antagonist A or another pharmaceutically
acceptable salt thereof, VEGF antagonist and anti-C5 agent are
administered to the mammal via a single injection, e.g., a single
intraocular or intravitreal injection. In particular embodiments,
Antagonist A or another pharmaceutically acceptable salt thereof,
VEGF antagonist and anti-C5 agent are administered sequentially. In
certain embodiments, two or more of Antagonist A or another
pharmaceutically acceptable salt thereof, a VEGF antagonist and an
anti-C5 agent are administered at the same time, e.g., in the same
composition. In particular embodiments, one of Antagonist A or
another pharmaceutically acceptable salt thereof, a VEGF antagonist
and an anti-C5 agent is administered, and within about 30 seconds,
one or two of others are subsequently administered. In particular
embodiments, all three of Antagonist A or another pharmaceutically
acceptable salt thereof, a VEGF antagonist and an anti-C5 agent are
administered within about 30 seconds or one minute of each other.
In other embodiments, one of Antagonist A or another
pharmaceutically acceptable salt thereof, a VEGF antagonist and an
anti-C5 agent is administered, and one or both of the others are
administered about 1 min, about 2 min, about 5 min, about 10 min,
about 15 min, about 20 min, about 25 min, about 30 min, about 40
min, about 50 min, about 60 min, about 90 min, about 2 hours, about
4 hours, about 6 hours, about 8 hours, about 12 hours, about 24
hours, about 36 hours, about 48 hours, about three days, about four
days, about five days, about six days, or about seven days later.
In other embodiments, one or two of Antagonist A or another
pharmaceutically acceptable salt thereof, VEGF antagonist and
anti-C5 agent are administered, and the other is administered about
1 min, about 2 min, about 5 min, about 10 min, about 15 min, about
20 min, about 25 min, about 30 min, about 40 min, about 50 min,
about 60 min, about 90 min, about 2 hours, about 4 hours, about 6
hours, about 8 hours, about 12 hours, about 24 hours, about 36
hours, about 48 hours, about three days, about four days, about
five days, about six days, or about seven days later. In certain
embodiments, one of the PDGF antagonist, VEGF antagonist and
anti-C5 agent is administered; and another is administered about 1
min, about 2 min, about 5 min, about 10 min, about 15 min, about 20
min, about 25 min, about 30 min, about 40 min, about 50 min, about
60 min, about 90 min, about 2 hours, about 4 hours, about 6 hours,
about 8 hours, about 12 hours, about 24 hours, about 36 hours,
about 48 hours, about three days, about four days, about five days,
about six days, or about seven days later; and the remaining one is
administered about 1 min, about 2 min, about 5 min, about 10 min,
about 15 min, about 20 min, about 25 min, about 30 min, about 40
min, about 50 min, about 60 min, about 90 min, about 2 hours, about
4 hours, about 6 hours, about 8 hours, about 12 hours, about 24
hours, about 36 hours, about 48 hours, about three days, about four
days, about five days, about six days, or about seven days later.
In certain embodiments wherein two of Antagonist A or another
pharmaceutically acceptable salt thereof, VEGF antagonist and
anti-C5 agent are present in the same composition, the composition
is administered and the PDGF antagonist, VEGF antagonist or anti-C5
agent that is not present in the composition is administered about
1 min, about 2 min, about 5 min, about 10 min, about 15 min, about
20 min, about 25 min, about 30 min, about 40 min, about 50 min,
about 60 min, about 90 min, about 2 hours, about 4 hours, about 6
hours, about 8 hours, about 12 hours, about 24 hours, about 36
hours, about 48 hours, about three days, about four days, about
five days, about six days, or about seven days later. In other
embodiments wherein two of Antagonist A or another pharmaceutically
acceptable salt thereof, VEGF antagonist and anti-C5 agent are
present in the same composition, Antagonist A or another
pharmaceutically acceptable salt thereof, VEGF antagonist or
anti-C5 agent that is not present in the composition is
administered, and the composition is administered about 1 min,
about 2 min, about 5 min, about 10 min, about 15 min, about 20 min,
about 25 min, about 30 min, about 40 min, about 50 min, about 60
min, about 90 min, about 2 hours, about 4 hours, about 6 hours,
about 8 hours, about 12 hours, about 24 hours, about 36 hours,
about 48 hours, about three days, about four days, about five days,
about six days, or about seven days later.
[0312] In certain embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof, e.g., Antagonist A or
another pharmaceutically acceptable salt thereof, is administered
about every 24 hours for two or more, three or more, four or more,
five or more, six or more, or seven or more days, and a VEGF
antagonist, e.g., aflibercept, bevacizumab, ESBA1008, pegaptanib
sodium or ranimizumab, is administered about 48 hours following the
first administration of Antagonist A or another pharmaceutically
acceptable salt thereof. In certain embodiments, Antagonist A or
another pharmaceutically acceptable salt thereof is administered on
each of four successive days, i.e., day 1, day 2, day 3 and day 4,
and the VEGF antagonist (e.g., bevacizumab, ranicizumab, ESBA1008,
pegaptanib sodium or aflibercept) is administered on the third day,
i.e., day 3. In particular embodiments, a composition comprising
Antagonist A or another pharmaceutically acceptable salt thereof,
e.g., Antagonist A or another pharmaceutically acceptable salt
thereof, is administered to a subject, and a composition comprising
a VEGF antagonist is administered to the subject about forty-eight
hours later.
[0313] In one embodiment, about 50 mg/kg of Antagonist A or another
pharmaceutically acceptable salt thereof (e.g., Antagonist A or
another pharmaceutically acceptable salt thereof) is administered,
e.g., intraperitoneally, on day 1, day 2, day 3 and day 4, and
about 1 mg/kg of a VEGF antagonist (e.g., bevacizumab, ranibizumab,
ESBA1008, pegaptanib sodium, or aflibercept) is administered on day
3. In one embodiment, about 50 mg/kg of Antagonist A or another
pharmaceutically acceptable salt thereof (e.g., Antagonist A or
another pharmaceutically acceptable salt thereof) is administered
on day 1, day 2, day 3 and day 4, and about 5 mg/kg of a VEGF
antagonist (e.g., bevacizumab, ranibizumab, ESBA1008, pegaptanib
sodium, or aflibercept) is administered on day 3.
[0314] In one embodiment, about 50 mg/kg of Antagonist A or another
pharmaceutically acceptable salt thereof is administered on day 1,
day 2, day 3 and day 4, and about 1 mg/kg of aflibercept is
administered on day 3. In one embodiment, about 50 mg/kg of
Antagonist A or another pharmaceutically acceptable salt thereof is
administered on day 1, day 2, day 3 and day 4, and about 5 mg/kg of
aflibercept is administered on day 3.
[0315] In one embodiment, about 0.03 mg, about 0.3 mg, about 0.5
mg, about 1.0 mg, about 1.5 mg or about 3.0 mg of Antagonist A or
another pharmaceutically acceptable salt thereof (e.g., Antagonist
A or another pharmaceutically acceptable salt thereof) is
administered intravitreally on day 1, day 2, day 3 and day 4, and
about 0.5 mg, about 1.0 mg, about 1.5 mg, about 1.65 mg, about 3.0
mg, or about 4.0 mg of a VEGF antagonist (e.g., bevacizumab,
ranibizumab, ESBA1008, pegaptanib sodium, or aflibercept) is
administered intravitreally on day 3. In one embodiment, about 0.3
mg or about 1.5 mg of Antagonist A or another pharmaceutically
acceptable salt thereof is administered intravitreally on day 1,
day 2, day 3 and day 4, and about 0.5 mg of ranibizumab is
administered intravitreally on day 3. In one embodiment, about 0.3
mg or about 1.5 mg of Antagonist A or another pharmaceutically
acceptable salt thereof is administered intravitreally on day 1,
day 2, day 3 and day 4, and about 1.25 mg of bevacizumab is
administered intravitreally on day 3. In one embodiment, about 0.3
mg or about 1.5 mg of Antagonist A or another pharmaceutically
acceptable salt thereof is administered intravitreally on day 1,
day 2, day 3 and day 4, and about 2.0 mg of aflibercept is
administered intravitreally on day 3. In one embodiment, about 0.3
mg or about 1.5 mg of Antagonist A or another pharmaceutically
acceptable salt thereof is administered intravitreally on day 1,
day 2, day 3 and day 4, and about 1.65 mg of pegaptanib sodium is
administered intravitreally on day 3.
[0316] In some embodiments, Antagonist A or another
pharmaceutically acceptable salt thereof and VEGF antagonist are
administered every four weeks or every 30 days, for six treatments.
In some embodiments, the VEGF antagonist is ranibizumab. In some
embodiments, 0.3 mg of Antagonist A or another pharmaceutically
acceptable salt thereof and 0.5 mg of ranibizumab are administered
every four weeks or every 30 days, for six treatments. In some
embodiments, 1.5 mg of Antagonist A or another pharmaceutically
acceptable salt thereof and 0.5 mg of ranibizumab are administered
every four weeks or every 30 days, for six treatments.
[0317] In some embodiments, 0.3 mg of Antagonist A or another
pharmaceutically acceptable salt thereof and 1.25 mg of
bevacizumab, 2.0 mg of aflibercept, or 1.65 mg of pegaptanib sodium
are administered every four weeks or every 30 days, for six
treatments. In some embodiments, 1.5 mg of Antagonist A or another
pharmaceutically acceptable salt thereof and 1.25 mg of
bevacizumab, 2.0 mg of aflibercept, or 1.65 mg of pegaptanib sodium
are administered every four weeks or every 30 days, for six
treatments.
[0318] In some embodiments, the methods comprise administering
Antagonist A or another pharmaceutically acceptable salt thereof,
bevacizumab and aflibercept. In some embodiments, the methods
comprise administering Antagonist A or another pharmaceutically
acceptable salt thereof, bevacizumab and aflibercept every four
weeks or every 30 days, for six treatments. In some embodiments,
the methods comprise administering 1.5 mg of Antagonist A or
another pharmaceutically acceptable salt thereof, 1.25 mg of
bevacizumab, and 2 mg of aflibercept. In some embodiments, the
methods comprise administering 1.5 mg of Antagonist A or another
pharmaceutically acceptable salt thereof, 1.25 mg of bevacizumab,
and 2 mg of aflibercept every four weeks or every 30 days, for six
treatments.
[0319] In some embodiments, the methods comprise administering to a
subject in need thereof (a) Antagonist A or another
pharmaceutically acceptable salt thereof and (b) an VEGF
antagonist, wherein (a) and (b) are administered in an amount that
is effective for treating or preventing an ocular condition (e.g.,
wet AMD), and wherein the administering occurs once every month,
.+-.about seven days, for 12 consecutive months.
[0320] In some embodiments, the methods comprise administering to a
subject in need thereof (a) Antagonist A or another
pharmaceutically acceptable salt thereof and (b) an VEGF
antagonist, wherein: (a) and (b) are administered in an amount that
is effective for treating or preventing an ocular condition (e.g.,
wet AMD); and the administering occurs once every month, .+-.about
seven days, for a first 12 consecutive months, and immediately
thereafter once every two months, .+-.about seven days, for a
second 12 consecutive months, commencing on the second month of the
second 12 consecutive months.
[0321] In some embodiments, the methods comprise administering to a
subject in need thereof (a) Antagonist A or another
pharmaceutically acceptable salt thereof and (b) an VEGF
antagonist, wherein: (a) and (b) are administered in an amount that
is effective for treating or preventing an ocular condition (e.g.,
wet AMD); and the administering occurs once every month, .+-.about
seven days, for 24 consecutive months is also provided herein.
[0322] In some embodiments, the methods comprise administering to a
subject in need thereof (a) Antagonist A or another
pharmaceutically acceptable salt thereof and (b) an VEGF
antagonist, wherein: (a) and (b) are administered in an amount that
is effective for treating or preventing an ocular condition (e.g.,
wet AMD); and the administering occurs once every month, .+-.about
seven days, for three consecutive months, and immediately
thereafter once every two months, .+-.about seven days, for 12
consecutive months, commencing on the second month of the 12
consecutive months.
[0323] In some embodiments, the methods comprise continuous
treatment, continuous and discontinuous treatments, and/or
retreatments, e.g., for the treatment or preventing of wet-type AMD
or subfoveal neovascular AMD. In some embodiments, continuous
treatment comprises administering to Antagonist A or another
pharmaceutically acceptable salt thereof and an anti-VEGF agent
monthly (.+-.7 days) for at least 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, or 12 consecutive months. In some embodiments, Antagonist A or
a pharmaceutically acceptable salt thereof is administered within
about 1 min, about 2 min, about 5 min, about 10 min, about 15 min,
about 20 min, about 25 min, about 30 min, about 40 min, about 50
min, about 60 min, about 90 min, about 2 hours, about 4 hours,
about 6 hours, about 8 hours, about 12 hours of administration of
the VEGF antagonist. In some embodiments, the VEGF antagonist is
administered prior to administration of Antagonist A or a
pharmaceutically acceptable salt thereof. In other embodiments,
Antagonist A or a pharmaceutically acceptable salt thereof is
administered prior to administration of the VEGF antagonist. In
some embodiments, Antagonist A or a pharmaceutically acceptable
salt thereof and a VEGF antagonist are administered as a
co-formulation. In some embodiments, the amount of Antagonist A or
a pharmaceutically acceptable salt thereof administered is about
1.5 mg/eye and the amount of VEGF antagonist administered is about
0.5 mg/eye (e.g., ranibizumab), about 1.25 mg/eye (e.g.,
bevacizumab), about 1.65 mg/eye (e.g., pegaptanib sodium), or about
2.0 mg/eye (e.g., aflibercept).
[0324] In some embodiments, the methods further comprise measuring
the subject's visual acuity. In some embodiments, the subject's
visual acuity is measured once every month, .+-.about seven days.
In some embodiments, visual acuity is stable when it is stable for
three consecutive months. In some embodiments, visual acuity is
stable when at each of the last two of the three consecutive
months, visual acuity is within 5 ETDRS letters (better or worse)
of the subject's visual acuity at the first of the three
consecutive months (i.e., the month immediately preceding the first
of the two consecutive following months).
[0325] In some embodiments, a subject is administered in accordance
with the present methods until the subject's visual acuity is
stable. In some embodiments, a subject is administered in
accordance with the present methods until the subject's visual
acuity is stable for three consecutive months. In some embodiments,
a subject is administered in accordance with the present methods
until the subject's visual acuity at each of the last two of the
three consecutive months is .ltoreq.a five-ETDRS-letter difference
from the subject's visual acuity of the first of the three
consecutive months. In some embodiments, a subject is administered
in accordance with the present methods until the subject
experiences no new or significant intraretinal or sub-retinal
hemorrhage, or no increase of .gtoreq.50 .mu.m in foveal
intraretinal fluid. In some embodiments, a subject is administered
in accordance with the present methods until the subject's visual
acuity measured at each of the last two of the three consecutive
months is .ltoreq.a five-ETDRS-letter difference from the subject's
visual acuity of the first of the three consecutive months, and the
subject experiences no new or significant intraretinal or
sub-retinal hemorrhage, and no increase of .gtoreq.50 .mu.m in
foveal intraretinal fluid.
[0326] In some embodiments, discontinuous treatment is administered
after continuous treatment, in which discontinuous treatment is
based on a physician's discretion, and the subject has stabilized
vision as determined by .ltoreq.a five-ETDRS-letter difference in
the subject's visual acuity after continuous and discontinuous
treatment.
[0327] In some embodiments, subjects with a loss of visual acuity
of >5 ETDRS letters from the previous monthly assessment, new
and significant intraretinal or sub-retinal hemorrhage, and/or an
increase of .gtoreq.50 .mu.m in foveal intraretinal fluid are
retreated.
[0328] In some embodiments, the continuous method comprises
administering Antagonist A or another pharmaceutically acceptable
salt thereof and a VEGF antagonist in an amount that is effective
for treating or preventing wet AMD, wherein the administering
occurs once every month, .+-.about seven days, for 12 consecutive
months. In some embodiments, the methods further comprise measuring
the subject's visual acuity at one month, .+-.about seven days,
immediately following the 12 consecutive months, wherein the
subject's visual acuity measured on the twelfth of the 12
consecutive months and the one month immediately following the 12
consecutive months is .ltoreq.a five-ETDRS-letter difference in the
subject's visual acuity measured on the eleventh of the 12
consecutive months.
[0329] In some embodiments, the methods further comprise measuring
the subject's visual acuity once every month, .+-.about seven days,
on each of an additional 11 consecutive months. In some
embodiments, the subject's visual acuity measured on any two
consecutive months of the additional 11 consecutive months is
.ltoreq.a five-ETDRS-letter difference in the subject's visual
acuity measured on a month immediately preceding the two
consecutive months.
[0330] In some embodiments, the subject's visual acuity measured on
the twelfth of the 12 consecutive months and the one month
immediately following the 12 consecutive months is not .ltoreq.a
five-ETDRS-letter difference in the subject's visual acuity
measured on the eleventh of the 12 consecutive months and the
subject is retreated. In some embodiments, retreatment comprises
administering to the patient on the one month immediately following
the 12 consecutive months Antagonist A or another pharmaceutically
acceptable salt thereof and a VEGF antagonist in an amount that is
effective for treating or preventing wet AMD, measuring the
patient's visual acuity on a month, .+-.about seven days,
immediately following the one month immediately following the 12
consecutive months, and administering to the subject on each
immediately following month Antagonist A or another
pharmaceutically acceptable salt thereof and a VEGF antagonist in
an amount that is effective for treating or preventing wet AMD,
until the subject's visual acuity on any two consecutive following
months is .ltoreq.a five-ETDRS-letter difference in the subject's
visual acuity measured on a month immediately preceding the first
of the two consecutive following months. In some embodiments, the
total number of months does not exceed 24.
[0331] In some embodiments, wherein the subject's visual acuity
measured on the one month immediately following the 12 consecutive
months is not .ltoreq.a five-ETDRS-letter difference in the
subject's visual acuity measured on the twelfth of the 12
consecutive months and is not solely attributable to newly
diagnosed foveal atrophy or worsening ocular media opacity, the
method further comprises administering to the subject on the one
month immediately following the 12 consecutive months Antagonist A
or another pharmaceutically acceptable salt thereof and a VEGF
antagonist in an amount that is effective for treating or
preventing wet AMD; and administering to the subject on each
immediately following month (a) and (b) in an amount that is
effective for treating or preventing wet AMD, until the subject's
visual acuity measured on any two consecutive following months is
.ltoreq.a five-ETDRS-letter difference in the subject's visual
acuity measured on a month immediately preceding the first of the
two consecutive following months. In some embodiments, the total
number of months does not exceed 24.
[0332] In some embodiments, wherein the subject presents
intraretinal or sub-retinal hemorrhage or a .gtoreq.50 .mu.m
increase in foveal intraretinal fluid at one month, .+-.about seven
days, immediately following the 12 consecutive months, the method
further comprises administering to the subject on the one month
immediately following the 12 consecutive months Antagonist A or
another pharmaceutically acceptable salt thereof an a VEGF
antagonist in an amount that is effective for treating or
preventing wet AMD; and administering to the subject on each
immediately following month (a) and (b) in an amount that is
effective for treating or preventing wet AMD, until the subject's
visual acuity measured on any two consecutive following months is
.ltoreq.a five-ETDRS-letter difference in the subject's visual
acuity measured on a month immediately preceding the first of the
two consecutive following months. In some embodiments, the total
number of months does not exceed 24.
[0333] Also provided herein is a method comprising administering
Antagonist A or another pharmaceutically acceptable salt thereof
and a VEGF antagonist intravitreally once every month, .+-.about
seven days, for a first 12 consecutive months, and immediately
thereafter once every two months, .+-.about seven days, for a
second 12 consecutive months, commencing on the second month of the
second 12 consecutive months. In some embodiments, Antagonist A or
a pharmaceutically acceptable salt thereof is administered within
about 1 min, about 2 min, about 5 min, about 10 min, about 15 min,
about 20 min, about 25 min, about 30 min, about 40 min, about 50
min, about 60 min, about 90 min, about 2 hours, about 4 hours,
about 6 hours, about 8 hours, about 12 hours of administration of
the VEGF antagonist. In some embodiments, the VEGF antagonist is
administered prior to administration of Antagonist A or a
pharmaceutically acceptable salt thereof. In other embodiments,
Antagonist A or a pharmaceutically acceptable salt thereof is
administered prior to administration of the VEGF antagonist. In
some embodiments, Antagonist A or a pharmaceutically acceptable
salt thereof and a VEGF antagonist are administered as a
co-formulation. In some embodiments, the amount of Antagonist A or
a pharmaceutically acceptable salt thereof administered is about
1.5 mg/eye and the amount of VEGF antagonist administered is about
0.5 mg/eye (e.g., ranibizumab), about 1.25 mg/eye (e.g.,
bevacizumab), about 1.65 mg/eye (e.g., pegaptanib sodium), or about
2.0 mg/eye (e.g., aflibercept).
[0334] In some embodiments, the method further comprises measuring
the subject's visual acuity once every month, .+-.about seven days,
during the first 12 consecutive months and second 12 consecutive
months. In some embodiments, the subject's visual acuity measured
on any one of the first, third, fifth, seven, ninth and eleventh
months of the second consecutive 12 months decreased at least five
ETDRS letters relative to the patient's visual acuity measured on
the month immediately preceding the first, third, fifth, seven,
ninth or eleventh month of the second consecutive 12 months.
[0335] In some embodiments, the methods further comprises
administering to the subject an amount of Antagonist A or a
pharmaceutically acceptable salt thereof and a VEGF antagonist
effective for treating or preventing wet AMD on the month in which
the subject's visual acuity measured the decrease of at least five
ETDRS letters relative to the patient's visual acuity measured on
the immediately preceding month.
[0336] In some embodiments, the method further comprises
administering Antagonist A or a pharmaceutically acceptable salt
thereof and a VEGF antagonist on any one of the first, third,
fifth, seven, ninth and eleventh months of the second consecutive
12 months.
[0337] In some embodiments, the decrease in visual acuity is
attributed to solely newly diagnosed foveal atrophy or opacified
ocular media.
[0338] In some embodiments, the subject presents intraretinal or
sub-retinal hemorrhage or a .gtoreq.50 .mu.m increase in foveal
intraretinal fluid on any one of the first, third, fifth, seven,
ninth and eleventh months of the second consecutive 12 months.
[0339] In some embodiments, the method further comprises
administering Antagonist A or a pharmaceutically acceptable salt
thereof and a VEGF antagonist on month in which the subject
presents intraretinal or sub-retinal hemorrhage or a .gtoreq.50
.mu.m increase in foveal intraretinal fluid.
[0340] Also provided herein is a method comprising administering
Antagonist A or another pharmaceutically acceptable salt thereof
and a VEGF antagonist intravitreally once every month, .+-.about
seven days, for 24 consecutive months. In other embodiments,
Antagonist A or another pharmaceutically acceptable salt thereof
and a VEGF antagonist are administered intravitreally once a month
for three months and then every other month for the next 21 months.
In some embodiments, Antagonist A or a pharmaceutically acceptable
salt thereof is administered within about 1 min, about 2 min, about
5 min, about 10 min, about 15 min, about 20 min, about 25 min,
about 30 min, about 40 min, about 50 min, about 60 min, about 90
min, about 2 hours, about 4 hours, about 6 hours, about 8 hours,
about 12 hours of administration of the VEGF antagonist. In some
embodiments, the VEGF antagonist is administered prior to
administration of Antagonist A or a pharmaceutically acceptable
salt thereof. In other embodiments, Antagonist A or a
pharmaceutically acceptable salt thereof is administered prior to
administration of the VEGF antagonist. In some embodiments,
Antagonist A or a pharmaceutically acceptable salt thereof and a
VEGF antagonist are administered as a co-formulation. In some
embodiments, the amount of Antagonist A or a pharmaceutically
acceptable salt thereof administered is about 1.5 mg/eye and the
amount of VEGF antagonist administered is about 0.5 mg/eye (e.g.,
ranibizumab), about 1.25 mg/eye (e.g., bevacizumab), about 1.65
mg/eye (e.g., pegaptanib sodium), or about 2.0 mg/eye (e.g.,
aflibercept).
[0341] In some embodiments, the methods comprise administering to a
subject in need thereof (a) Antagonist A or another
pharmaceutically acceptable salt thereof and (b) an VEGF
antagonist, wherein (a) and (b) are administered in an amount that
is effective for treating or preventing an ophthalmological disease
or disorder (e.g., wet AMD), and wherein the administering occurs
once every month, .+-.about seven days, for a first administration
period of at least 3 consecutive months, followed by administering
(a) and (b) for a second administration period at a frequency of at
least every other month .+-.about seven days beginning at two
months .+-.about seven days after the day of the last month of the
first administration period on which (a) and (b) are administered.
In some embodiments, the first administration period is for at
least 6 consecutive months. In some embodiments, the VEGF
antagonist is ranibizumab or bevacizumab, wherein (a) and (b) are
administered at a frequency of once every month .+-.about seven
days during the second administration period and wherein the second
administration period is at least about nine months.
[0342] In some embodiments, the methods further comprise measuring
the subject's visual acuity on a day that is prior to and within
about one month of administration of (a) and (b). In some
embodiments, the methods further comprise administering to the
subject (a) and (b) in an amount that is effective for treating or
preventing an ophthalmological disease or disorder (e.g., wet AMD),
until the subject's visual acuity on any two consecutive following
months is .ltoreq.a five-ETDRS-letter difference in the subject's
visual acuity measured on a month immediately preceding the first
of the two consecutive following months.
[0343] In some embodiments, the method further comprise
administering to the subject (a) and (b) every other month in an
amount that is effective for treating or preventing an
ophthalmological disease or disorder (e.g., wet AMD), until the
subject's visual acuity on any two consecutive visual acuity
assessments is not .ltoreq.a five-ETDRS-letter difference in the
subject's visual acuity measured on a visual acuity assessment
immediately preceding the first of the two consecutive visual
acuity assessments.
[0344] In other embodiments, the methods further comprise
administering to the subject (a) and (b) every month in an amount
that is effective for treating or preventing an ophthalmological
disease or disorder (e.g., wet AMD), until the subject's visual
acuity on any two consecutive following months is .ltoreq.a
five-ETDRS-letter difference in the subject's visual acuity
measured on a month immediately preceding the first of the two
consecutive following months.
[0345] In some embodiments, the methods comprise administering to a
subject in need thereof (a) Antagonist A or another
pharmaceutically acceptable salt thereof and (b) aflibercept,
wherein (a) and (b) are administered in an amount that is effective
for treating or preventing an ophthalmological disease or disorder
(e.g., wet AMD), and wherein the administering occurs once every
month, .+-.about seven days, for a first administration period of
at least 3 consecutive months, followed by administering (a) and
(b) for a second administration period at a frequency of at least
every other month .+-.about seven days beginning at two months
.+-.about seven days after the day of the last month of the first
administration period on which (a) and (b) are administered.
[0346] In some embodiments, the subject has intraretinal or
sub-retinal hemorrhage or a .gtoreq.50 .mu.m increase in foveal
intraretinal fluid at one month, .+-.about seven days, immediately
following the second administration period. In some embodiments,
the methods further comprise administering to the subject on each
month .+-.about seven days, beginning on the month that immediately
follows the second administration period (a) and (b) in an amount
that is effective for treating or preventing wet AMD, until the
subject's visual acuity measured on any two consecutive months that
follow the 12 consecutive months is .ltoreq.a five-ETDRS-letter
difference in the subject's visual acuity measured on a month
immediately preceding the first of the two consecutive months.
[0347] In some embodiments, the total number of months of treatment
does not exceed 24.
[0348] Pharmaceutical compositions according to the invention may
be formulated to release Antagonist A or another pharmaceutically
acceptable salt thereof, a VEGF antagonist, or an anti-C5 agent,
substantially immediately upon administration or at any
predetermined time period after administration, using controlled
release formulations. For example, a pharmaceutical composition can
be provided in sustained-release form. The use of immediate or
sustained release compositions depends on the nature of the
condition being treated. If the condition consists of an acute
disorder, treatment with an immediate release form can be utilized
over a prolonged release composition. For certain preventative or
long-term treatments, a sustained released composition can also be
appropriate.
[0349] Administration of one or both of the antagonists of, or an
anti-C5 agent, in controlled release formulations can be useful
where the antagonist, either alone or in combination, has (i) a
narrow therapeutic index (e.g., the difference between the plasma
concentration leading to harmful side effects or toxic reactions
and the plasma concentration leading to a therapeutic effect is
small; generally, the therapeutic index, TI, is defined as the
ratio of median lethal dose (LD.sub.50) to median effective dose
(ED.sub.50)); (ii) a narrow absorption window in the
gastro-intestinal tract; or (iii) a short biological half-life, so
that frequent dosing during a day is required in order to sustain
the plasma level at a therapeutic level.
[0350] Many strategies can be pursued to obtain controlled release
in which the rate of release outweighs the rate of degradation or
metabolism of the therapeutic antagonist. For example, controlled
release can be obtained by the appropriate selection of formulation
parameters and ingredients, including, e.g., appropriate controlled
release compositions and coatings. Examples include single or
multiple unit tablet or capsule compositions, oil solutions,
suspensions, emulsions, microcapsules, microspheres, nanoparticles,
patches, and liposomes. Methods for preparing such sustained or
controlled release formulations are well known in the art.
[0351] Antagonist A or another pharmaceutically acceptable salt
thereof, the VEGF antagonist, or the anti-C5 agent can also be
delivered using a drug-delivery device such as an implant. Such
implants can be biodegradable and/or biocompatible, or can be
non-biodegradable. The implants can be permeable to Antagonist A or
another pharmaceutically acceptable salt thereof, the VEGF
antagonist, or the anti-C5 agent. Ophthalmic drug delivery devices
can be inserted into a chamber of the eye, such as the anterior or
posterior chamber or can be implanted in or on the sclera,
choroidal space, or an avascularized region exterior to the
vitreous. In one embodiment, the implant can be positioned over an
avascular region, such as on the sclera, so as to allow for
transcleral diffusion of Antagonist A or another pharmaceutically
acceptable salt thereof, the VEGF antagonist, or the anti-C5 agent
to the desired site of treatment, e.g., the intraocular space and
macula of the eye. Furthermore, the site of transcleral diffusion
can be proximal to a site of neovascularization such as a site
proximal to the macula. Suitable drug delivery devices are
described, for example, in U.S. Publication Nos. 2008/0286334;
2008/0145406; 2007/0184089; 2006/0233860; 2005/0244500;
2005/0244471; and 2005/0244462, and U.S. Pat. Nos. 6,808,719 and
5,322,691, the contents of each of which is herein incorporated by
reference in its entirety.
[0352] In one embodiment, the implant comprises Antagonist A or
another pharmaceutically acceptable salt thereof and/or VEGF
antagonist dispersed in a biodegradable polymer matrix. The matrix
can comprise PLGA (polylactic acid-polyglycolic acid copolymer), an
ester-end capped polymer, an acid end-capped polymer, or a mixture
thereof. In another embodiment, the implant comprises Antagonist A
or another pharmaceutically acceptable salt thereof and/or a VEGF
antagonist, a surfactant, and lipophilic compound. The lipophilic
compound can be present in an amount of about 80-99% by weight of
the implant. Suitable lipophilic compounds include, but are not
limited to, glyceryl palmitostearate, diethylene glycol
monostearate, propylene glycol monostearate, glyceryl monostearate,
glyceryl monolinoleate, glyceryl monooleate, glyceryl
monopalmitate, glyceryl monolaurate, glyceryl dilaurate, glyceryl
monomyristate, glyceryl dimyristate, glyceryl monopalmitate,
glyceryl dipalmitate, glyceryl monostearate, glyceryl distearate,
glyceryl monooleate, glyceryl dioleate, glyceryl monolinoleate,
glyceryl dilinoleate, glyceryl monoarachidate, glyceryl
diarachidate, glyceryl monobehenate, glyceryl dibehenate, and
mixtures thereof. In another embodiment, the implant comprises
Antagonist A or another pharmaceutically acceptable salt thereof
and/or a VEGF antagonist housed within a hollow sleeve. The PDGF
antagonist or VEGF antagonist, or both, are delivered to the eye by
inserting the sleeve into the eye, releasing the implant from the
sleeve into the eye, and then removing the sleeve from the eye. An
example of this delivery device is described in U.S. Publication
No. 2005/0244462, which is hereby incorporated by reference in its
entirety.
[0353] In one embodiment, the implant is a flexible ocular insert
device adapted for the controlled sustained release of Antagonist A
or another pharmaceutically acceptable salt thereof and/or a VEGF
antagonist into the eye. In one embodiment, the device includes an
elongated body of a polymeric material in the form of a rod or tube
containing Antagonist A or another pharmaceutically acceptable salt
thereof, VEGF antagonist or both, and with at least two anchoring
protrusions extending radially outwardly from the body. The device
may have a length of at least 8 mm and the diameter of its body
portion including the protrusions does not exceed 1.9 mm. The
sustained release mechanism can, for example, be by diffusion or by
osmosis or bioerosion. The insert device can be inserted into the
upper or lower formix of the eye so as to be independent of
movement of the eye by virtue of the formix anatomy. The
protrusions can be of various shapes such as, for example, ribs,
screw threads, dimples or bumps, truncated cone-shaped segments or
winding braid segments. In a further embodiment, the polymeric
material for the body is selected as one which swells in a liquid
environment. Thus a device of smaller initial size can be employed.
The insert device can be of a size and configuration such that,
upon insertion into the upper or lower formix, the device remains
out of the field of vision so as to be well retained in place and
imperceptible by a recipient over a prolonged period of use. The
device can be retained in the upper or lower formix for 7 to 14
days or longer. An example of this device is described in U.S. Pat.
No. 5,322,691, which is hereby incorporated by reference in its
entirety.
[0354] Kits
[0355] The invention relates to kits comprising one or more
pharmaceutical compositions and instructions for use. At least two
antagonists can be formulated together or in separate compositions
and in individual dosage amounts. The antagonists are also useful
when formulated as pharmaceutically acceptable salts. In one
embodiment, the kits comprise a composition comprising Antagonist A
or another pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier or vehicle and another
composition comprising a VEGF antagonist and a pharmaceutically
acceptable carrier or vehicle. In another embodiment, the kits
comprise a composition comprising a VEGF antagonist, Antagonist A
or another pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier or vehicle. Each of the kits'
compositions can be contained in a container. In some embodiments,
the kits comprise an anti-C5 agent.
[0356] The kits can comprise (1) an amount of Antagonist A or
another pharmaceutically acceptable salt thereof and a
pharmaceutically acceptable carrier, vehicle, or diluent in a first
unit dosage form; (2) an amount of a VEGF antagonist and a
pharmaceutically acceptable carrier, vehicle, or diluent in a
second unit dosage form; and (3) a container. The container can be
used to separate components and include, for example, a divided
bottle or a divided foil packet. The separate antagonist
compositions may also, if desired, be contained within a single,
undivided container. In some embodiments, the kits comprise an
anti-C5 agent.
[0357] The kits can also comprise directions for the administration
of the antagonists. The kits are particularly advantageous when the
separate components are administered in different dosage forms, are
administered at different dosage levels, or when titration of the
individual antagonists is desired.
EXAMPLES
Example 1
Antagonist a and Ranibizumab Combination Therapy for Treating
Subfoveal Neovascular Lesions Secondary to Neovascular Age Related
Macular Degeneration (NVAMD)
[0358] In this study, 449 subjects with subfoveal neovascular
lesions secondary to NVAMD received six monthly intravitreous
injections of Antagonist A given in combination with ranibizumab
(administered as Lucentis.RTM., commercially available from
Genentech, South San Francisco, Calif.). Antagonist A was injected
as the formulation shown in Table 12. The primary efficacy endpoint
in the study was the mean change in visual acuity from baseline at
the week 24 visit. As pre-specified in the analysis plan, the
Hochberg procedure (Hochberg, Y. (1988). A sharper Bonferroni
procedure for multiple tests of significance. Biometrika. 75,
800-802) was employed to account for multiple dose comparisons.
[0359] The subjects were randomized in a 1:1:1 ratio to the groups
shown in Table 13.
TABLE-US-00011 TABLE 12 Antagonist A Formulation 30 mg/mL Reference
to Solution Percent Name of Ingredient Standards Function
Composition (w/v) Antagonist A In-house standard Drug substance
30.0 mg 3% Monobasic Sodium USP/Ph. Eur pH buffering 0.3 mg 0.03%
Phosphate Monohydrate agent Dibasic Sodium Phosphate USP/Ph. Eur pH
buffering 2.1 mg 0.2% Heptahydrate agent Sodium Chloride USP/Ph.
Eur Tonicity adjuster 9.0 mg 0.9% Hydrochloric Acid NF/Ph. Eur pH
adjuster As needed Sodium Hydroxide NF/Ph. Eur pH adjuster As
needed Water for Injection USP/Ph. Eur Diluent q.s. 95.9% Nitrogen
NF/Ph. Eur Inert gas overlay -- -- Total Volume 1 ml Volume in
Final Drug 230 microliters Product Presentation
TABLE-US-00012 TABLE 13 Antagonist A and Ranibizumab Combination
Therapy for Subfoveal Neovascular Lesions Secondary to NVAMD
Treatment Groups Group No. Group Name Treatment Regimen 1
Combination Subjects were administered Therapy 0.3 mg/eye of
Antagonist A (0.3 mg) and 0.5 mg/eye of Lucentis .RTM. 2
Combination Subjects were administered Therapy 1.5 mg/eye of
Antagonist A (1.5 mg) and 0.5 mg/eye of Lucentis .RTM. 3
Ranibizumab Subjects were administered Monotherapy Antagonist A
Sham and 0.5 mg/eye of Lucentis .RTM.
[0360] Combination therapy proved superior in terms of mean visual
gain when compared to eyes that were treated with anti-VEGF
monotherapy. Subjects treated with Lucentis.RTM. and either 1.5
mg/eye or 0.3 mg/eye Antagonist A showed an increase in visual
acuity compared with those treated with Lucentis.RTM. alone (FIG.
2). The combination of 1.5 mg/eye of Antagonist A and 0.5 mg of
Lucentis.RTM. met the pre-specified, alpha protected primary
endpoint of superiority in mean change of visual acuity gain
compared to ranibizumab monotherapy from baseline to 24 weeks (10.6
ETDRS letters at week 24, compared to 6.5 letters, p=0.019,
representing a 62% additional benefit). (FIG. 3) Subjects treated
with Lucentis.RTM. and either 1.5 mg or 0.3 mg Antagonist A showed
a 62% comparative benefit from baseline compared to treatment with
Lucentis.RTM. alone.
[0361] In addition, the mean change in vision over time
demonstrated the benefit of combination therapy at each measured
time point over 24 weeks. (FIG. 4) That benefit was sustained
during the study and demonstrated increasing differentiation of the
curves at study closure.
[0362] Treatment with 0.5 mg of Lucentis.RTM. and either 1.5 mg or
0.3 mg Antagonist A in wet AMD patients also had increased efficacy
as compared to patients treated with Lucentis.RTM. alone,
independent of baseline lesion size or vision. (FIGS. 5A and
5B)
[0363] A greater percentage of subjects in the Combination Therapy
(1.5 mg) group achieved enhanced visual outcomes compared to those
in the Ranibizumab Monotherapy group with respect to multiple
treatment endpoints at week 24, as shown in FIG. 6A, and Table
14.
TABLE-US-00013 TABLE 14 Percentage of Subjects in the Combination
Therapy (1.5 mg) Group and Ranibizumab Monotherapy Group with
Visual Acuity Improvement Percentage of Patients Combination
Ranibizumab Therapy (1.5 mg) Monotherapy >3-lines of visual
acuity 36.4% 28.6% improvement >4-lines of visual acuity 19.9%
11.6% improvement >5-lines of visual acuity 11.9% 4.1%
improvement >20/40 vision after treatment 37.0% 31.9% >20/25
vision after treatment 12.3% 5.6%
[0364] Moreover, fewer subjects in the Combination Therapy (1.5 mg)
group demonstrated a loss of visual acuity as compared to the
number of subjects in the Ranibizumab Monotherapy group at week 24,
as shown in FIG. 6B and Table 15.
TABLE-US-00014 TABLE 15 Percentage of Subjects in the Combination
Therapy (1.5 mg) Group and Ranibizumab Monotherapy Group with
Visual Acuity Loss Percentage of Patients Combination Ranibizumab
Treatment Endpoint Therapy (1.5 mg) Monotherapy >1-lines of
visual acuity loss 8.3% 21.5% >2-lines of visual acuity loss
3.4% 12.5% <20/125 vision after treatment 19.2% 27.8% <20/200
vision after treatment 10.3% 13.9%
[0365] Subjects treated with Lucentis.RTM. and 1.5 mg Antagonist A
showed improved final visual acuity compared to patients treated
with Lucentis.RTM. monotherapy. (FIG. 7) Subjects in the
Combination Therapy (1.5 mg) group also showed increased reduction
in CNV size in small and large baseline CNV as compared to subjects
in the Ranibizumab Monotherapy group (FIGS. 8A and 8B).
[0366] Combination therapy was well tolerated. There were no events
of endophthalmitis, retinal detachment, retinal tear or iatrogenic
traumatic cataract after a total of 4431 intravitreal injections
(1776 administrations of Antagonist A and 2655 administrations of
Lucentis.RTM.). As expected, mean intraocular pressure (TOP)
increased after each intravitreal injection consistent with a
volume effect. However, mean TOP in all arms returned to
pre-injection levels at the next visit, including at the end of the
study. The systemic safety profile of combination therapy was
similar to that of ranibizumab monotherapy.
[0367] The results of the trial show statistically significant
superior efficacy of the combination treatment with Antagonist A
and ranibizumab over Lucentis.RTM. (ranibizumab) monotherapy for
the treatment of wet AMD.
Example 2
ARC1905 for the Treatment of Wet AMD
[0368] Forty-three patients with subfoveal neovascular AMD received
six monthly administrations of ARC1905 (0.3 mg/eye, 1 mg/eye or 2
mg/eye) in combination with Lucentis. The mean change in visual
acuity at week 24 was an increase of +13.6, +11.7 and +15.3 letters
at the doses of 0.3 mg, 1 mg and 2 mg, respectively. Furthermore,
46%, 47% and 60% of patients gained 3 or more lines of visual
acuity at the doses of 0.3 mg, 1 mg, and 2 mg, respectively.
Example 3
ARC1905 for the Treatment and Prevention of Dry AMD
[0369] Forty-seven patients with dry AMD were enrolled to receive
five intravitreal injections of either 0.3 mg/eye or 1.0 mg/eye of
ARC1905 over a 36-week treatment period. FIG. 9 shows the mean
change in geographic atrophy (GA) lesion area in dry AMD patients
measured at week 24 in patients treated with either 0.3 mg or 1.0
mg doses of ARC1905 at weeks 0, 4, and 8. FIG. 10 shows the mean
change in GA lesion in dry AMD patients measured at week 24 and
week 48 in patients treated with either 0.3 mg or 1.0 mg doses of
ARC1905 at weeks 0, 4, 8, 24, and 36. The results show a
dose-dependent reduction in growth of the GA lesion, indicating
ARC1905 can slow the progression of GA in non-exudative type AMD
patients
Example 4
Visual Acuity Testing Using ETDRS Chart
[0370] Best-corrected visual acuity is measured using standard
charts, lighting, and procedures. Best correction is determined by
careful refraction at that visit.
[0371] Chart 1 (FIG. 11) is used for testing the visual acuity of
the right eye. Chart 2 (FIG. 12) is used for testing the left eye.
Chart R (FIG. 13) is used for testing refraction. Subjects do not
see any of the charts before the examination.
[0372] A distance of 4 meters is between the subject's eyes and the
visual acuity chart. With the box light off, not more than 15
foot-candles of light (161.4 Lux) fall on the center of the chart.
To measure the amount of light, the room is set up for visual
acuity testing, but with the box light off. The light meter is
placed at the fourth line from the top of the chart, with its back
against the chart and the reading is taken. If more than one lane
is available for testing visual acuity, the visual acuity of an
individual subject should be measured in the same lane at each
visit. If different lanes are used to test visual acuity, they each
meet the same standards.
[0373] Retroilluminated ETDRS charts are used. The illuminator box
is either wall-mounted or mounted on a stand (available from
Lighthouse Low Vision Services). The light box is mounted at a
height such that the top of the third row letter is 49.+-.2 inches
from the floor.
[0374] The visual acuity light box is equipped with two 20-watt
fluorescent tubes (available from General Electric Cool Daylight)
and a ballast which partially covers the tubes. Because the
illumination of fluorescent tubes generally diminishes by 5 percent
during the first 100 hours and by another 5 percent during the next
2000 hours, new tubes are kept on for 4 days (96 hours)
continuously, and replaced once a year.
[0375] A sticker is placed on the back of the light box, indicating
the date on which the present tubes were installed. A spare set of
burned in bulbs is available.
[0376] Each tube is partly covered by a 14-inch fenestrated sleeve,
which is open in the back. This serves as a baffle to reduce
illumination. Each sleeve is centered on the tube with the opening
towards the back.
[0377] All eyes are tested at 4 meters first, even if the
refraction was performed at 1 meter. The subject is seated
comfortably directly in front of the chart so that the eyes remain
at the 4 meter distance. Testing begins with the right eye. The
subject's left eye is occluded. A folded tissue or eye pad lightly
taped over the eye behind the trial frame serves as an effective
occluder that allows eccentric fixation without inadvertent use of
the covered eye. After testing the right eye, occlusion of the
right eye is done before Chart 2 is put up for testing the left
eye.
[0378] The lens correction from the subjective refraction is in the
trial frame worn by the subject.
[0379] The subject is asked to read the letters slowly,
approximately one letter per second. The subject is told that only
one chance is given to read each letter on the chart. If the
subject is unsure about the identity of the letter, then the
subject is encouraged to guess.
[0380] The subject begins by reading the top line of the chart and
continue reading every letter on each smaller line, from left to
right on each line. The examiner circles every correct letter read
and totals each line and the whole column (0 if no letters are
correct) on the data collection form. An X is put through letters
read incorrectly. Letters, for which no guess was attempted, are
not circled. When a subject reaches a level where he/she cannot
guess, the examiner may stop the test provided that the subject has
made errors on previous guesses, which is a clear indication that
the best visual acuity has been obtained.
[0381] When a subject cannot read at least 20 letters on the chart
at 4.0 meters, the subject is tested at 1.0 meter. The distance
from the subject to the chart should be measured again using the
rigid one meter stick. The distance is measured from the outer
canthus to the center of the fourth letter (right eye) or the
second letter (left eye) of the third line of the chart. The
spherical correction in the trial frame should be changed by adding
+0.75 to correct for the closer test distance. The subject may
fixate eccentrically or turn or shake his/her head to improve
visual acuity. If this is done, the examiner ensures that the
fellow eye remains occluded both centrally and peripherally and
that the subject does not move forward in the chair. Particular
care should be taken to ensure the subject does not move forward
when testing at 1 meter. The subject is reminded to blink.
[0382] The examiner does not tell the subject if a letter was
identified correctly. The subject may be encouraged by neutral
comments, such as "good", "next", and "OK".
[0383] The examiner does not stand close to the chart during
testing. The examiner's attention is focused on the subject and the
data collection form. If the subject has difficulty locating the
next line to read, the examiner may go up to the chart and point to
the next line to be read, and then moves away from the chart.
[0384] When it is possible to measure the visual acuity of the eye
at 4.0 meters (i.e., 20 or more letters read at 4 meters), the
visual acuity score for that eye is recorded as the number of
letters correct plus 30. The subject gets credit for the 30 1M
letters even though they did not have to read them. Otherwise, the
visual acuity score is the number of letters read correctly at 1.0
meter plus the number, if any, read at 4M. If no letters are read
correctly at either 4.0 meters or 1 meter, then the visual acuity
score is recorded as 0.
INCORPORATION BY REFERENCE
[0385] All publications and patent applications disclosed in this
specification are herein incorporated by reference to the same
extent as if each individual publication or patent application was
specifically and individually indicated to be incorporated by
reference.
Sequence CWU 1
1
98130DNAArtificial SequenceSynthetic anti-PDGF aptamer 1caggcuacgc
gtagagcauc atgatccugt 3022137DNAHomo sapiens 2ccctgcctgc ctccctgcgc
acccgcagcc tcccccgctg cctccctagg gctcccctcc 60ggccgccagc gcccattttt
cattccctag atagagatac tttgcgcgca cacacataca 120tacgcgcgca
aaaaggaaaa aaaaaaaaaa aagcccaccc tccagcctcg ctgcaaagag
180aaaaccggag cagccgcagc tcgcagctcg cagcccgcag cccgcagagg
acgcccagag 240cggcgagcgg gcgggcagac ggaccgacgg actcgcgccg
cgtccacctg tcggccgggc 300ccagccgagc gcgcagcggg cacgccgcgc
gcgcggagca gccgtgcccg ccgcccgggc 360ccgccgccag ggcgcacacg
ctcccgcccc cctacccggc ccgggcggga gtttgcacct 420ctccctgccc
gggtgctcga gctgccgttg caaagccaac tttggaaaaa gttttttggg
480ggagacttgg gccttgaggt gcccagctcc gcgctttccg attttggggg
cctttccaga 540aaatgttgca aaaaagctaa gccggcgggc agaggaaaac
gcctgtagcc ggcgagtgaa 600gacgaaccat cgactgccgt gttccttttc
ctcttggagg ttggagtccc ctgggcgccc 660ccacacggct agacgcctcg
gctggttcgc gacgcagccc cccggccgtg gatgctgcac 720tcgggctcgg
gatccgccca ggtagcggcc tcggacccag gtcctgcgcc caggtcctcc
780cctgcccccc agcgacggag ccggggccgg gggcggcggc gccgggggca
tgcgggtgag 840ccgcggctgc agaggcctga gcgcctgatc gccgcggacc
cgagccgagc ccacccccct 900ccccagcccc ccaccctggc cgcgggggcg
gcgcgctcga tctacgcgtt cggggccccg 960cggggccggg cccggagtcg
gcatgaatcg ctgctgggcg ctcttcctgt ctctctgctg 1020ctacctgcgt
ctggtcagcg ccgaggggga ccccattccc gaggagcttt atgagatgct
1080gagtgaccac tcgatccgct cctttgatga tctccaacgc ctgctgcacg
gagaccccgg 1140agaggaagat ggggccgagt tggacctgaa catgacccgc
tcccactctg gaggcgagct 1200ggagagcttg gctcgtggaa gaaggagcct
gggttccctg accattgctg agccggccat 1260gatcgccgag tgcaagacgc
gcaccgaggt gttcgagatc tcccggcgcc tcatagaccg 1320caccaacgcc
aacttcctgg tgtggccgcc ctgtgtggag gtgcagcgct gctccggctg
1380ctgcaacaac cgcaacgtgc agtgccgccc cacccaggtg cagctgcgac
ctgtccaggt 1440gagaaagatc gagattgtgc ggaagaagcc aatctttaag
aaggccacgg tgacgctgga 1500agaccacctg gcatgcaagt gtgagacagt
ggcagctgca cggcctgtga cccgaagccc 1560ggggggttcc caggagcagc
gagccaaaac gccccaaact cgggtgacca ttcggacggt 1620gcgagtccgc
cggcccccca agggcaagca ccggaaattc aagcacacgc atgacaagac
1680ggcactgaag gagacccttg gagcctaggg gcatcggcag gagagtgtgt
gggcagggtt 1740atttaatatg gtatttgctg tattgccccc atggggcctt
ggagtagata atattgtttc 1800cctcgtccgt ctgtctcgat gcctgattcg
gacggccaat ggtgcctccc ccacccctcc 1860acgtgtccgt ccacccttcc
atcagcgggt ctcctcccag cggcctccgg ctcttgccca 1920gcagctcaag
aagaaaaaga aggactgaac tccatcgcca tcttcttccc ttaactccaa
1980gaacttggga taagagtgtg agagagactg atggggtcgc tctttggggg
aaacgggttc 2040cttcccctgc acctggcctg ggccacacct gagcgctgtg
gactgtcctg aggagccctg 2100aggacctctc agcatagcct gcctgatccc tgaaccc
21373241PRTHomo sapiens 3Met Asn Arg Cys Trp Ala Leu Phe Leu Ser
Leu Cys Cys Tyr Leu Arg 1 5 10 15 Leu Val Ser Ala Glu Gly Asp Pro
Ile Pro Glu Glu Leu Tyr Glu Met 20 25 30 Leu Ser Asp His Ser Ile
Arg Ser Phe Asp Asp Leu Gln Arg Leu Leu 35 40 45 His Gly Asp Pro
Gly Glu Glu Asp Gly Ala Glu Leu Asp Leu Asn Met 50 55 60 Thr Arg
Ser His Ser Gly Gly Glu Leu Glu Ser Leu Ala Arg Gly Arg 65 70 75 80
Arg Ser Leu Gly Ser Leu Thr Ile Ala Glu Pro Ala Met Ile Ala Glu 85
90 95 Cys Lys Thr Arg Thr Glu Val Phe Glu Ile Ser Arg Arg Leu Ile
Asp 100 105 110 Arg Thr Asn Ala Asn Phe Leu Val Trp Pro Pro Cys Val
Glu Val Gln 115 120 125 Arg Cys Ser Gly Cys Cys Asn Asn Arg Asn Val
Gln Cys Arg Pro Thr 130 135 140 Gln Val Gln Leu Arg Pro Val Gln Val
Arg Lys Ile Glu Ile Val Arg 145 150 155 160 Lys Lys Pro Ile Phe Lys
Lys Ala Thr Val Thr Leu Glu Asp His Leu 165 170 175 Ala Cys Lys Cys
Glu Thr Val Ala Ala Ala Arg Pro Val Thr Arg Ser 180 185 190 Pro Gly
Gly Ser Gln Glu Gln Arg Ala Lys Thr Pro Gln Thr Arg Val 195 200 205
Thr Ile Arg Thr Val Arg Val Arg Arg Pro Pro Lys Gly Lys His Arg 210
215 220 Lys Phe Lys His Thr His Asp Lys Thr Ala Leu Lys Glu Thr Leu
Gly 225 230 235 240 Ala 42305DNAHomo sapiens 4ttcttggggc tgatgtccgc
aaatatgcag aattaccggc cgggtcgctc ctgaagccag 60cgcggggagc gagcgcggcg
gcggccagca ccgggaacgc accgaggaag aagcccagcc 120cccgccctcc
gccccttccg tccccacccc ctacccggcg gcccaggagg ctccccggct
180gcggcgcgca ctccctgttt ctcctcctcc tggctggcgc tgcctgcctc
tccgcactca 240ctgctcgccg ggcgccgtcc gccagctccg tgctccccgc
gccaccctcc tccgggccgc 300gctccctaag ggatggtact gaatttcgcc
gccacaggag accggctgga gcgcccgccc 360cgcgcctcgc ctctcctccg
agcagccagc gcctcgggac gcgatgagga ccttggcttg 420cctgctgctc
ctcggctgcg gatacctcgc ccatgttctg gccgaggaag ccgagatccc
480ccgcgaggtg atcgagaggc tggcccgcag tcagatccac agcatccggg
acctccagcg 540actcctggag atagactccg tagggagtga ggattctttg
gacaccagcc tgagagctca 600cggggtccac gccactaagc atgtgcccga
gaagcggccc ctgcccattc ggaggaagag 660aagcatcgag gaagctgtcc
ccgctgtctg caagaccagg acggtcattt acgagattcc 720tcggagtcag
gtcgacccca cgtccgccaa cttcctgatc tggcccccgt gcgtggaggt
780gaaacgctgc accggctgct gcaacacgag cagtgtcaag tgccagccct
cccgcgtcca 840ccaccgcagc gtcaaggtgg ccaaggtgga atacgtcagg
aagaagccaa aattaaaaga 900agtccaggtg aggttagagg agcatttgga
gtgcgcctgc gcgaccacaa gcctgaatcc 960ggattatcgg gaagaggaca
cggatgtgag gtgaggatga gccgcagccc tttcctggga 1020catggatgta
catggcgtgt tacattcctg aacctactat gtacggtgct ttattgccag
1080tgtgcggtct ttgttctcct ccgtgaaaaa ctgtgtccga gaacactcgg
gagaacaaag 1140agacagtgca catttgttta atgtgacatc aaagcaagta
ttgtagcact cggtgaagca 1200gtaagaagct tccttgtcaa aaagagagag
agagagagag agagagaaaa caaaaccaca 1260aatgacaaaa acaaaacgga
ctcacaaaaa tatctaaact cgatgagatg gagggtcgcc 1320ccgtgggatg
gaagtgcaga ggtctcagca gactggattt ctgtccgggt ggtcacaggt
1380gcttttttgc cgaggatgca gagcctgctt tgggaacgac tccagagggg
tgctggtggg 1440ctctgcaggg cccgcaggaa gcaggaatgt cttggaaacc
gccacgcgaa ctttagaaac 1500cacacctcct cgctgtagta tttaagccca
tacagaaacc ttcctgagag ccttaagtgg 1560tttttttttt tgtttttgtt
ttgttttttt tttttttgtt tttttttttt tttttttttt 1620ttacaccata
aagtgattat taagcttcct tttactcttt ggctagcttt tttttttttt
1680tttttttttt ttttttttaa ttatctcttg gatgacattt acaccgataa
cacacaggct 1740gctgtaactg tcaggacagt gcgacggtat ttttcctagc
aagatgcaaa ctaatgagat 1800gtattaaaat aaacatggta tacctaccta
tgcatcattt cctaaatgtt tctggctttg 1860tgtttctccc ttaccctgct
ttatttgtta atttaagcca ttttgaaaga actatgcgtc 1920aaccaatcgt
acgccgtccc tgcggcacct gccccagagc ccgtttgtgg ctgagtgaca
1980acttgttccc cgcagtgcac acctagaatg ctgtgttccc acgcggcacg
tgagatgcat 2040tgccgcttct gtctgtgttg ttggtgtgcc ctggtgccgt
ggtggcggtc actccctctg 2100ctgccagtgt ttggacagaa cccaaattct
ttatttttgg taagatattg tgctttacct 2160gtattaacag aaatgtgtgt
gtgtggtttg tttttttgta aaggtgaagt ttgtatgttt 2220acctaatatt
acctgttttg tatacctgag agcctgctat gttcttcttt tgttgatcca
2280aaattaaaaa aaaaatacca ccaac 23055196PRTHomo sapiens 5Met Arg
Thr Leu Ala Cys Leu Leu Leu Leu Gly Cys Gly Tyr Leu Ala 1 5 10 15
His Val Leu Ala Glu Glu Ala Glu Ile Pro Arg Glu Val Ile Glu Arg 20
25 30 Leu Ala Arg Ser Gln Ile His Ser Ile Arg Asp Leu Gln Arg Leu
Leu 35 40 45 Glu Ile Asp Ser Val Gly Ser Glu Asp Ser Leu Asp Thr
Ser Leu Arg 50 55 60 Ala His Gly Val His Ala Thr Lys His Val Pro
Glu Lys Arg Pro Leu 65 70 75 80 Pro Ile Arg Arg Lys Arg Ser Ile Glu
Glu Ala Val Pro Ala Val Cys 85 90 95 Lys Thr Arg Thr Val Ile Tyr
Glu Ile Pro Arg Ser Gln Val Asp Pro 100 105 110 Thr Ser Ala Asn Phe
Leu Ile Trp Pro Pro Cys Val Glu Val Lys Arg 115 120 125 Cys Thr Gly
Cys Cys Asn Thr Ser Ser Val Lys Cys Gln Pro Ser Arg 130 135 140 Val
His His Arg Ser Val Lys Val Ala Lys Val Glu Tyr Val Arg Lys 145 150
155 160 Lys Pro Lys Leu Lys Glu Val Gln Val Arg Leu Glu Glu His Leu
Glu 165 170 175 Cys Ala Cys Ala Thr Thr Ser Leu Asn Pro Asp Tyr Arg
Glu Glu Asp 180 185 190 Thr Asp Val Arg 195 6 3018DNAHomo sapiens
6gcccggagag ccgcatctat tggcagcttt gttattgatc agaaactgct cgccgccgac
60ttggcttcca gtctggctgc gggcaaccct tgagttttcg cctctgtcct gtcccccgaa
120ctgacaggtg ctcccagcaa cttgctgggg acttctcgcc gctcccccgc
gtccccaccc 180cctcattcct ccctcgcctt cacccccacc cccaccactt
cgccacagct caggatttgt 240ttaaaccttg ggaaactggt tcaggtccag
gttttgcttt gatccttttc aaaaactgga 300gacacagaag agggctctag
gaaaaagttt tggatgggat tatgtggaaa ctaccctgcg 360attctctgct
gccagagcag gctcggcgct tccaccccag tgcagccttc ccctggcggt
420ggtgaaagag actcgggagt cgctgcttcc aaagtgcccg ccgtgagtga
gctctcaccc 480cagtcagcca aatgagcctc ttcgggcttc tcctgctgac
atctgccctg gccggccaga 540gacaggggac tcaggcggaa tccaacctga
gtagtaaatt ccagttttcc agcaacaagg 600aacagaacgg agtacaagat
cctcagcatg agagaattat tactgtgtct actaatggaa 660gtattcacag
cccaaggttt cctcatactt atccaagaaa tacggtcttg gtatggagat
720tagtagcagt agaggaaaat gtatggatac aacttacgtt tgatgaaaga
tttgggcttg 780aagacccaga agatgacata tgcaagtatg attttgtaga
agttgaggaa cccagtgatg 840gaactatatt agggcgctgg tgtggttctg
gtactgtacc aggaaaacag atttctaaag 900gaaatcaaat taggataaga
tttgtatctg atgaatattt tccttctgaa ccagggttct 960gcatccacta
caacattgtc atgccacaat tcacagaagc tgtgagtcct tcagtgctac
1020ccccttcagc tttgccactg gacctgctta ataatgctat aactgccttt
agtaccttgg 1080aagaccttat tcgatatctt gaaccagaga gatggcagtt
ggacttagaa gatctatata 1140ggccaacttg gcaacttctt ggcaaggctt
ttgtttttgg aagaaaatcc agagtggtgg 1200atctgaacct tctaacagag
gaggtaagat tatacagctg cacacctcgt aacttctcag 1260tgtccataag
ggaagaacta aagagaaccg ataccatttt ctggccaggt tgtctcctgg
1320ttaaacgctg tggtgggaac tgtgcctgtt gtctccacaa ttgcaatgaa
tgtcaatgtg 1380tcccaagcaa agttactaaa aaataccacg aggtccttca
gttgagacca aagaccggtg 1440tcaggggatt gcacaaatca ctcaccgacg
tggccctgga gcaccatgag gagtgtgact 1500gtgtgtgcag agggagcaca
ggaggatagc cgcatcacca ccagcagctc ttgcccagag 1560ctgtgcagtg
cagtggctga ttctattaga gaacgtatgc gttatctcca tccttaatct
1620cagttgtttg cttcaaggac ctttcatctt caggatttac agtgcattct
gaaagaggag 1680acatcaaaca gaattaggag ttgtgcaaca gctcttttga
gaggaggcct aaaggacagg 1740agaaaaggtc ttcaatcgtg gaaagaaaat
taaatgttgt attaaataga tcaccagcta 1800gtttcagagt taccatgtac
gtattccact agctgggttc tgtatttcag ttctttcgat 1860acggcttagg
gtaatgtcag tacaggaaaa aaactgtgca agtgagcacc tgattccgtt
1920gccttgctta actctaaagc tccatgtcct gggcctaaaa tcgtataaaa
tctggatttt 1980tttttttttt tttgctcata ttcacatatg taaaccagaa
cattctatgt actacaaacc 2040tggtttttaa aaaggaacta tgttgctatg
aattaaactt gtgtcgtgct gataggacag 2100actggatttt tcatatttct
tattaaaatt tctgccattt agaagaagag aactacattc 2160atggtttgga
agagataaac ctgaaaagaa gagtggcctt atcttcactt tatcgataag
2220tcagtttatt tgtttcattg tgtacatttt tatattctcc ttttgacatt
ataactgttg 2280gcttttctaa tcttgttaaa tatatctatt tttaccaaag
gtatttaata ttctttttta 2340tgacaactta gatcaactat ttttagcttg
gtaaattttt ctaaacacaa ttgttatagc 2400cagaggaaca aagatgatat
aaaatattgt tgctctgaca aaaatacatg tatttcattc 2460tcgtatggtg
ctagagttag attaatctgc attttaaaaa actgaattgg aatagaattg
2520gtaagttgca aagacttttt gaaaataatt aaattatcat atcttccatt
cctgttattg 2580gagatgaaaa taaaaagcaa cttatgaaag tagacattca
gatccagcca ttactaacct 2640attccttttt tggggaaatc tgagcctagc
tcagaaaaac ataaagcacc ttgaaaaaga 2700cttggcagct tcctgataaa
gcgtgctgtg ctgtgcagta ggaacacatc ctatttattg 2760tgatgttgtg
gttttattat cttaaactct gttccataca cttgtataaa tacatggata
2820tttttatgta cagaagtatg tctcttaacc agttcactta ttgtactctg
gcaatttaaa 2880agaaaatcag taaaatattt tgcttgtaaa atgcttaata
tcgtgcctag gttatgtggt 2940gactatttga atcaaaaatg tattgaatca
tcaaataaaa gaatgtggct attttgggga 3000gaaaattaaa aaaaaaaa
30187345PRTHomo sapiens 7Met Ser Leu Phe Gly Leu Leu Leu Leu Thr
Ser Ala Leu Ala Gly Gln 1 5 10 15 Arg Gln Gly Thr Gln Ala Glu Ser
Asn Leu Ser Ser Lys Phe Gln Phe 20 25 30 Ser Ser Asn Lys Glu Gln
Asn Gly Val Gln Asp Pro Gln His Glu Arg 35 40 45 Ile Ile Thr Val
Ser Thr Asn Gly Ser Ile His Ser Pro Arg Phe Pro 50 55 60 His Thr
Tyr Pro Arg Asn Thr Val Leu Val Trp Arg Leu Val Ala Val 65 70 75 80
Glu Glu Asn Val Trp Ile Gln Leu Thr Phe Asp Glu Arg Phe Gly Leu 85
90 95 Glu Asp Pro Glu Asp Asp Ile Cys Lys Tyr Asp Phe Val Glu Val
Glu 100 105 110 Glu Pro Ser Asp Gly Thr Ile Leu Gly Arg Trp Cys Gly
Ser Gly Thr 115 120 125 Val Pro Gly Lys Gln Ile Ser Lys Gly Asn Gln
Ile Arg Ile Arg Phe 130 135 140 Val Ser Asp Glu Tyr Phe Pro Ser Glu
Pro Gly Phe Cys Ile His Tyr 145 150 155 160 Asn Ile Val Met Pro Gln
Phe Thr Glu Ala Val Ser Pro Ser Val Leu 165 170 175 Pro Pro Ser Ala
Leu Pro Leu Asp Leu Leu Asn Asn Ala Ile Thr Ala 180 185 190 Phe Ser
Thr Leu Glu Asp Leu Ile Arg Tyr Leu Glu Pro Glu Arg Trp 195 200 205
Gln Leu Asp Leu Glu Asp Leu Tyr Arg Pro Thr Trp Gln Leu Leu Gly 210
215 220 Lys Ala Phe Val Phe Gly Arg Lys Ser Arg Val Val Asp Leu Asn
Leu 225 230 235 240 Leu Thr Glu Glu Val Arg Leu Tyr Ser Cys Thr Pro
Arg Asn Phe Ser 245 250 255 Val Ser Ile Arg Glu Glu Leu Lys Arg Thr
Asp Thr Ile Phe Trp Pro 260 265 270 Gly Cys Leu Leu Val Lys Arg Cys
Gly Gly Asn Cys Ala Cys Cys Leu 275 280 285 His Asn Cys Asn Glu Cys
Gln Cys Val Pro Ser Lys Val Thr Lys Lys 290 295 300 Tyr His Glu Val
Leu Gln Leu Arg Pro Lys Thr Gly Val Arg Gly Leu 305 310 315 320 His
Lys Ser Leu Thr Asp Val Ala Leu Glu His His Glu Glu Cys Asp 325 330
335 Cys Val Cys Arg Gly Ser Thr Gly Gly 340 345 8 3997DNAHomo
sapiens 8tctcaggggc cgcggccggg gctggagaac gctgctgctc cgctcgcctg
ccccgctaga 60ttcggcgctg cccgccccct gcagcctgtg ctgcagctgc cggccaccgg
agggggcgaa 120caaacaaacg tcaacctgtt gtttgtcccg tcaccattta
tcagctcagc accacaagga 180agtgcggcac ccacacgcgc tcggaaagtt
cagcatgcag gaagtttggg gagagctcgg 240cgattagcac agcgacccgg
gccagcgcag ggcgagcgca ggcggcgaga gcgcagggcg 300gcgcggcgtc
ggtcccggga gcagaacccg gctttttctt ggagcgacgc tgtctctagt
360cgctgatccc aaatgcaccg gctcatcttt gtctacactc taatctgcgc
aaacttttgc 420agctgtcggg acacttctgc aaccccgcag agcgcatcca
tcaaagcttt gcgcaacgcc 480aacctcaggc gagatgagag caatcacctc
acagacttgt accgaagaga tgagaccatc 540caggtgaaag gaaacggcta
cgtgcagagt cctagattcc cgaacagcta ccccaggaac 600ctgctcctga
catggcggct tcactctcag gagaatacac ggatacagct agtgtttgac
660aatcagtttg gattagagga agcagaaaat gatatctgta ggtatgattt
tgtggaagtt 720gaagatatat ccgaaaccag taccattatt agaggacgat
ggtgtggaca caaggaagtt 780cctccaagga taaaatcaag aacgaaccaa
attaaaatca cattcaagtc cgatgactac 840tttgtggcta aacctggatt
caagatttat tattctttgc tggaagattt ccaacccgca 900gcagcttcag
agaccaactg ggaatctgtc acaagctcta tttcaggggt atcctataac
960tctccatcag taacggatcc cactctgatt gcggatgctc tggacaaaaa
aattgcagaa 1020tttgatacag tggaagatct gctcaagtac ttcaatccag
agtcatggca agaagatctt 1080gagaatatgt atctggacac ccctcggtat
cgaggcaggt cataccatga ccggaagtca 1140aaagttgacc tggataggct
caatgatgat gccaagcgtt acagttgcac tcccaggaat 1200tactcggtca
atataagaga agagctgaag ttggccaatg tggtcttctt tccacgttgc
1260ctcctcgtgc agcgctgtgg aggaaattgt ggctgtggaa ctgtcaactg
gaggtcctgc 1320acatgcaatt cagggaaaac cgtgaaaaag tatcatgagg
tattacagtt tgagcctggc 1380cacatcaaga ggaggggtag agctaagacc
atggctctag ttgacatcca gttggatcac 1440catgaacgat gtgattgtat
ctgcagctca agaccacctc gataagagaa tgtgcacatc 1500cttacattaa
gcctgaaaga acctttagtt taaggagggt gagataagag acccttttcc
1560taccagcaac caaacttact actagcctgc aatgcaatga acacaagtgg
ttgctgagtc 1620tcagccttgc tttgttaatg ccatggcaag tagaaaggta
tatcatcaac ttctatacct 1680aagaatatag gattgcattt aataatagtg
tttgaggtta tatatgcaca aacacacaca 1740gaaatatatt catgtctatg
tgtatataga tcaaatgttt tttttggtat atataaccag 1800gtacaccaga
gcttacatat gtttgagtta gactcttaaa atcctttgcc aaaataaggg
1860atggtcaaat atatgaaaca tgtctttaga aaatttagga gataaattta
tttttaaatt 1920ttgaaacaca aaacaatttt gaatcttgct ctcttaaaga
aagcatcttg tatattaaaa 1980atcaaaagat gaggctttct tacatataca
tcttagttga ttattaaaaa aggaaaaata 2040tggtttccag agaaaaggcc
aatacctaag cattttttcc atgagaagca ctgcatactt 2100acctatgtgg
actataataa
cctgtctcca aaaccatgcc ataataatat aagtgcttta 2160gaaattaaat
cattgtgttt tttatgcatt ttgctgaggc atgcttattc atttaacacc
2220tatctcaaaa acttacttag aaggtttttt attatagtcc tacaaaagac
aatgtataag 2280ctgtaacaga attttgaatt gtttttcttt gcaaaacccc
tccacaaaag caaatccttt 2340caagaatggc atgggcattc tgtatgaacc
tttccagatg gtgttcagtg aaagatgtgg 2400gtagttgaga acttaaaaag
tgaacattga aacatcgacg taactggaaa ttaggtggga 2460tatttgatag
gatccatatc taataatgga ttcgaactct ccaaactaca ccaattaatt
2520taatgtatct tgcttttgtg ttcccgtctt tttgaaatat agacatggat
ttataatggc 2580attttatatt tggcaggcca tcatagatta tttacaacct
aaaagctttt gtgtatcaaa 2640aaaatcacat tttattaatg taaatttcta
atcgtatact tgctcactgt tctgatttcc 2700tgtttctgaa ccaagtaaaa
tcagtcctag aggctatggt tcttaatcta tggagcttgc 2760tttaagaagc
cagttgtcaa ttgtggtaac acaagtttgg ccctgctgtc ctactgttta
2820atagaaaact gttttacatt ggttaatggt atttagagta attttttctc
tctgcctcct 2880ttgtgtctgt tttaaaggag actaactcca ggagtaggaa
atgattcatc atcctccaaa 2940gcaagaggct taagagagaa acaccgaaat
tcagatagct cagggactgc taacagagaa 3000ctacattttt cttattgcct
tgaaagttaa aaggaaagca gatttcttca gtgactttgt 3060ggtcctacta
actacaacca gtttgggtga cagggctggt aaagtcccag tgttagatga
3120gtgacctaaa tatacttaga tttctaagta tggtgctctc aggtccaagt
tcaactattc 3180ttaagcagtg caattcttcc cagttatttg agatgaaaga
tctctgctta ttgaagatgt 3240accttctaaa actttcctaa aagtgtctga
tgtttttact caagagggga gtggtaaaat 3300taaatactct attgttcaat
tctctaaaat cccagaacac aatcagaaat agctcaggca 3360gacactaata
attaagaacg ctcttcctct tcataactgc tttgcaagtt tcctgtgaaa
3420acatcagttt cctgtaccaa agtcaaaatg aacgttacat cactctaacc
tgaacagctc 3480acaatgtagc tgtaaatata aaaaatgaga gtgttctacc
cagttttcaa taaaccttcc 3540aggctgcaat aaccagcaag gttttcagtt
aaagccctat ctgcactttt tatttattag 3600ctgaaatgta agcaggcata
ttcactcact tttctttgcc tttcctgaga gttttattaa 3660aacttctccc
ttggttacct gttatctttt gcacttctaa catgtagcca ataaatctat
3720ttgatagcca tcaaaggaat aaaaagctgg ccgtacaaat tacatttcaa
aacaaaccct 3780aataaatcca catttccgca tggctcattc acctggaata
atgcctttta ttgaatatgt 3840tcttataggg caaaacactt tcataagtag
agttttttat gttttttgtc atatcggtaa 3900catgcagctt tttcctctca
tagcattttc tatagcgaat gtaatatgcc tcttatcttc 3960atgaaaaata
aatattgctt ttgaacaaaa ctaaaaa 39979370PRTHomo sapiens 9Met His Arg
Leu Ile Phe Val Tyr Thr Leu Ile Cys Ala Asn Phe Cys 1 5 10 15 Ser
Cys Arg Asp Thr Ser Ala Thr Pro Gln Ser Ala Ser Ile Lys Ala 20 25
30 Leu Arg Asn Ala Asn Leu Arg Arg Asp Glu Ser Asn His Leu Thr Asp
35 40 45 Leu Tyr Arg Arg Asp Glu Thr Ile Gln Val Lys Gly Asn Gly
Tyr Val 50 55 60 Gln Ser Pro Arg Phe Pro Asn Ser Tyr Pro Arg Asn
Leu Leu Leu Thr 65 70 75 80 Trp Arg Leu His Ser Gln Glu Asn Thr Arg
Ile Gln Leu Val Phe Asp 85 90 95 Asn Gln Phe Gly Leu Glu Glu Ala
Glu Asn Asp Ile Cys Arg Tyr Asp 100 105 110 Phe Val Glu Val Glu Asp
Ile Ser Glu Thr Ser Thr Ile Ile Arg Gly 115 120 125 Arg Trp Cys Gly
His Lys Glu Val Pro Pro Arg Ile Lys Ser Arg Thr 130 135 140 Asn Gln
Ile Lys Ile Thr Phe Lys Ser Asp Asp Tyr Phe Val Ala Lys 145 150 155
160 Pro Gly Phe Lys Ile Tyr Tyr Ser Leu Leu Glu Asp Phe Gln Pro Ala
165 170 175 Ala Ala Ser Glu Thr Asn Trp Glu Ser Val Thr Ser Ser Ile
Ser Gly 180 185 190 Val Ser Tyr Asn Ser Pro Ser Val Thr Asp Pro Thr
Leu Ile Ala Asp 195 200 205 Ala Leu Asp Lys Lys Ile Ala Glu Phe Asp
Thr Val Glu Asp Leu Leu 210 215 220 Lys Tyr Phe Asn Pro Glu Ser Trp
Gln Glu Asp Leu Glu Asn Met Tyr 225 230 235 240 Leu Asp Thr Pro Arg
Tyr Arg Gly Arg Ser Tyr His Asp Arg Lys Ser 245 250 255 Lys Val Asp
Leu Asp Arg Leu Asn Asp Asp Ala Lys Arg Tyr Ser Cys 260 265 270 Thr
Pro Arg Asn Tyr Ser Val Asn Ile Arg Glu Glu Leu Lys Leu Ala 275 280
285 Asn Val Val Phe Phe Pro Arg Cys Leu Leu Val Gln Arg Cys Gly Gly
290 295 300 Asn Cys Gly Cys Gly Thr Val Asn Trp Arg Ser Cys Thr Cys
Asn Ser 305 310 315 320 Gly Lys Thr Val Lys Lys Tyr His Glu Val Leu
Gln Phe Glu Pro Gly 325 330 335 His Ile Lys Arg Arg Gly Arg Ala Lys
Thr Met Ala Leu Val Asp Ile 340 345 350 Gln Leu Asp His His Glu Arg
Cys Asp Cys Ile Cys Ser Ser Arg Pro 355 360 365 Pro Arg 370
103979DNAHomo sapiens 10tctcaggggc cgcggccggg gctggagaac gctgctgctc
cgctcgcctg ccccgctaga 60ttcggcgctg cccgccccct gcagcctgtg ctgcagctgc
cggccaccgg agggggcgaa 120caaacaaacg tcaacctgtt gtttgtcccg
tcaccattta tcagctcagc accacaagga 180agtgcggcac ccacacgcgc
tcggaaagtt cagcatgcag gaagtttggg gagagctcgg 240cgattagcac
agcgacccgg gccagcgcag ggcgagcgca ggcggcgaga gcgcagggcg
300gcgcggcgtc ggtcccggga gcagaacccg gctttttctt ggagcgacgc
tgtctctagt 360cgctgatccc aaatgcaccg gctcatcttt gtctacactc
taatctgcgc aaacttttgc 420agctgtcggg acacttctgc aaccccgcag
agcgcatcca tcaaagcttt gcgcaacgcc 480aacctcaggc gagatgactt
gtaccgaaga gatgagacca tccaggtgaa aggaaacggc 540tacgtgcaga
gtcctagatt cccgaacagc taccccagga acctgctcct gacatggcgg
600cttcactctc aggagaatac acggatacag ctagtgtttg acaatcagtt
tggattagag 660gaagcagaaa atgatatctg taggtatgat tttgtggaag
ttgaagatat atccgaaacc 720agtaccatta ttagaggacg atggtgtgga
cacaaggaag ttcctccaag gataaaatca 780agaacgaacc aaattaaaat
cacattcaag tccgatgact actttgtggc taaacctgga 840ttcaagattt
attattcttt gctggaagat ttccaacccg cagcagcttc agagaccaac
900tgggaatctg tcacaagctc tatttcaggg gtatcctata actctccatc
agtaacggat 960cccactctga ttgcggatgc tctggacaaa aaaattgcag
aatttgatac agtggaagat 1020ctgctcaagt acttcaatcc agagtcatgg
caagaagatc ttgagaatat gtatctggac 1080acccctcggt atcgaggcag
gtcataccat gaccggaagt caaaagttga cctggatagg 1140ctcaatgatg
atgccaagcg ttacagttgc actcccagga attactcggt caatataaga
1200gaagagctga agttggccaa tgtggtcttc tttccacgtt gcctcctcgt
gcagcgctgt 1260ggaggaaatt gtggctgtgg aactgtcaac tggaggtcct
gcacatgcaa ttcagggaaa 1320accgtgaaaa agtatcatga ggtattacag
tttgagcctg gccacatcaa gaggaggggt 1380agagctaaga ccatggctct
agttgacatc cagttggatc accatgaacg atgtgattgt 1440atctgcagct
caagaccacc tcgataagag aatgtgcaca tccttacatt aagcctgaaa
1500gaacctttag tttaaggagg gtgagataag agaccctttt cctaccagca
accaaactta 1560ctactagcct gcaatgcaat gaacacaagt ggttgctgag
tctcagcctt gctttgttaa 1620tgccatggca agtagaaagg tatatcatca
acttctatac ctaagaatat aggattgcat 1680ttaataatag tgtttgaggt
tatatatgca caaacacaca cagaaatata ttcatgtcta 1740tgtgtatata
gatcaaatgt tttttttggt atatataacc aggtacacca gagcttacat
1800atgtttgagt tagactctta aaatcctttg ccaaaataag ggatggtcaa
atatatgaaa 1860catgtcttta gaaaatttag gagataaatt tatttttaaa
ttttgaaaca caaaacaatt 1920ttgaatcttg ctctcttaaa gaaagcatct
tgtatattaa aaatcaaaag atgaggcttt 1980cttacatata catcttagtt
gattattaaa aaaggaaaaa tatggtttcc agagaaaagg 2040ccaataccta
agcatttttt ccatgagaag cactgcatac ttacctatgt ggactataat
2100aacctgtctc caaaaccatg ccataataat ataagtgctt tagaaattaa
atcattgtgt 2160tttttatgca ttttgctgag gcatgcttat tcatttaaca
cctatctcaa aaacttactt 2220agaaggtttt ttattatagt cctacaaaag
acaatgtata agctgtaaca gaattttgaa 2280ttgtttttct ttgcaaaacc
cctccacaaa agcaaatcct ttcaagaatg gcatgggcat 2340tctgtatgaa
cctttccaga tggtgttcag tgaaagatgt gggtagttga gaacttaaaa
2400agtgaacatt gaaacatcga cgtaactgga aattaggtgg gatatttgat
aggatccata 2460tctaataatg gattcgaact ctccaaacta caccaattaa
tttaatgtat cttgcttttg 2520tgttcccgtc tttttgaaat atagacatgg
atttataatg gcattttata tttggcaggc 2580catcatagat tatttacaac
ctaaaagctt ttgtgtatca aaaaaatcac attttattaa 2640tgtaaatttc
taatcgtata cttgctcact gttctgattt cctgtttctg aaccaagtaa
2700aatcagtcct agaggctatg gttcttaatc tatggagctt gctttaagaa
gccagttgtc 2760aattgtggta acacaagttt ggccctgctg tcctactgtt
taatagaaaa ctgttttaca 2820ttggttaatg gtatttagag taattttttc
tctctgcctc ctttgtgtct gttttaaagg 2880agactaactc caggagtagg
aaatgattca tcatcctcca aagcaagagg cttaagagag 2940aaacaccgaa
attcagatag ctcagggact gctaacagag aactacattt ttcttattgc
3000cttgaaagtt aaaaggaaag cagatttctt cagtgacttt gtggtcctac
taactacaac 3060cagtttgggt gacagggctg gtaaagtccc agtgttagat
gagtgaccta aatatactta 3120gatttctaag tatggtgctc tcaggtccaa
gttcaactat tcttaagcag tgcaattctt 3180cccagttatt tgagatgaaa
gatctctgct tattgaagat gtaccttcta aaactttcct 3240aaaagtgtct
gatgttttta ctcaagaggg gagtggtaaa attaaatact ctattgttca
3300attctctaaa atcccagaac acaatcagaa atagctcagg cagacactaa
taattaagaa 3360cgctcttcct cttcataact gctttgcaag tttcctgtga
aaacatcagt ttcctgtacc 3420aaagtcaaaa tgaacgttac atcactctaa
cctgaacagc tcacaatgta gctgtaaata 3480taaaaaatga gagtgttcta
cccagttttc aataaacctt ccaggctgca ataaccagca 3540aggttttcag
ttaaagccct atctgcactt tttatttatt agctgaaatg taagcaggca
3600tattcactca cttttctttg cctttcctga gagttttatt aaaacttctc
ccttggttac 3660ctgttatctt ttgcacttct aacatgtagc caataaatct
atttgatagc catcaaagga 3720ataaaaagct ggccgtacaa attacatttc
aaaacaaacc ctaataaatc cacatttccg 3780catggctcat tcacctggaa
taatgccttt tattgaatat gttcttatag ggcaaaacac 3840tttcataagt
agagtttttt atgttttttg tcatatcggt aacatgcagc tttttcctct
3900catagcattt tctatagcga atgtaatatg cctcttatct tcatgaaaaa
taaatattgc 3960ttttgaacaa aactaaaaa 397911364PRTHomo sapiens 11Met
His Arg Leu Ile Phe Val Tyr Thr Leu Ile Cys Ala Asn Phe Cys 1 5 10
15 Ser Cys Arg Asp Thr Ser Ala Thr Pro Gln Ser Ala Ser Ile Lys Ala
20 25 30 Leu Arg Asn Ala Asn Leu Arg Arg Asp Asp Leu Tyr Arg Arg
Asp Glu 35 40 45 Thr Ile Gln Val Lys Gly Asn Gly Tyr Val Gln Ser
Pro Arg Phe Pro 50 55 60 Asn Ser Tyr Pro Arg Asn Leu Leu Leu Thr
Trp Arg Leu His Ser Gln 65 70 75 80 Glu Asn Thr Arg Ile Gln Leu Val
Phe Asp Asn Gln Phe Gly Leu Glu 85 90 95 Glu Ala Glu Asn Asp Ile
Cys Arg Tyr Asp Phe Val Glu Val Glu Asp 100 105 110 Ile Ser Glu Thr
Ser Thr Ile Ile Arg Gly Arg Trp Cys Gly His Lys 115 120 125 Glu Val
Pro Pro Arg Ile Lys Ser Arg Thr Asn Gln Ile Lys Ile Thr 130 135 140
Phe Lys Ser Asp Asp Tyr Phe Val Ala Lys Pro Gly Phe Lys Ile Tyr 145
150 155 160 Tyr Ser Leu Leu Glu Asp Phe Gln Pro Ala Ala Ala Ser Glu
Thr Asn 165 170 175 Trp Glu Ser Val Thr Ser Ser Ile Ser Gly Val Ser
Tyr Asn Ser Pro 180 185 190 Ser Val Thr Asp Pro Thr Leu Ile Ala Asp
Ala Leu Asp Lys Lys Ile 195 200 205 Ala Glu Phe Asp Thr Val Glu Asp
Leu Leu Lys Tyr Phe Asn Pro Glu 210 215 220 Ser Trp Gln Glu Asp Leu
Glu Asn Met Tyr Leu Asp Thr Pro Arg Tyr 225 230 235 240 Arg Gly Arg
Ser Tyr His Asp Arg Lys Ser Lys Val Asp Leu Asp Arg 245 250 255 Leu
Asn Asp Asp Ala Lys Arg Tyr Ser Cys Thr Pro Arg Asn Tyr Ser 260 265
270 Val Asn Ile Arg Glu Glu Leu Lys Leu Ala Asn Val Val Phe Phe Pro
275 280 285 Arg Cys Leu Leu Val Gln Arg Cys Gly Gly Asn Cys Gly Cys
Gly Thr 290 295 300 Val Asn Trp Arg Ser Cys Thr Cys Asn Ser Gly Lys
Thr Val Lys Lys 305 310 315 320 Tyr His Glu Val Leu Gln Phe Glu Pro
Gly His Ile Lys Arg Arg Gly 325 330 335 Arg Ala Lys Thr Met Ala Leu
Val Asp Ile Gln Leu Asp His His Glu 340 345 350 Arg Cys Asp Cys Ile
Cys Ser Ser Arg Pro Pro Arg 355 360 12 6574DNAHomo sapiens
12aagagcaaaa agcgaaggcg caatctggac actgggagat tcggagcgca gggagtttga
60gagaaacttt tattttgaag agaccaaggt tgaggggggg cttatttcct gacagctatt
120tacttagagc aaatgattag ttttagaagg atggactata acattgaatc
aattacaaaa 180cgcggttttt gagcccatta ctgttggagc tacagggaga
gaaacagagg aggagactgc 240aagagatcat tggaggccgt gggcacgctc
tttactccat gtgtgggaca ttcattgcgg 300aataacatcg gaggagaagt
ttcccagagc tatggggact tcccatccgg cgttcctggt 360cttaggctgt
cttctcacag ggctgagcct aatcctctgc cagctttcat taccctctat
420ccttccaaat gaaaatgaaa aggttgtgca gctgaattca tccttttctc
tgagatgctt 480tggggagagt gaagtgagct ggcagtaccc catgtctgaa
gaagagagct ccgatgtgga 540aatcagaaat gaagaaaaca acagcggcct
ttttgtgacg gtcttggaag tgagcagtgc 600ctcggcggcc cacacagggt
tgtacacttg ctattacaac cacactcaga cagaagagaa 660tgagcttgaa
ggcaggcaca tttacatcta tgtgccagac ccagatgtag cctttgtacc
720tctaggaatg acggattatt tagtcatcgt ggaggatgat gattctgcca
ttataccttg 780tcgcacaact gatcccgaga ctcctgtaac cttacacaac
agtgaggggg tggtacctgc 840ctcctacgac agcagacagg gctttaatgg
gaccttcact gtagggccct atatctgtga 900ggccaccgtc aaaggaaaga
agttccagac catcccattt aatgtttatg ctttaaaagc 960aacatcagag
ctggatctag aaatggaagc tcttaaaacc gtgtataagt caggggaaac
1020gattgtggtc acctgtgctg tttttaacaa tgaggtggtt gaccttcaat
ggacttaccc 1080tggagaagtg aaaggcaaag gcatcacaat gctggaagaa
atcaaagtcc catccatcaa 1140attggtgtac actttgacgg tccccgaggc
cacggtgaaa gacagtggag attacgaatg 1200tgctgcccgc caggctacca
gggaggtcaa agaaatgaag aaagtcacta tttctgtcca 1260tgagaaaggt
ttcattgaaa tcaaacccac cttcagccag ttggaagctg tcaacctgca
1320tgaagtcaaa cattttgttg tagaggtgcg ggcctaccca cctcccagga
tatcctggct 1380gaaaaacaat ctgactctga ttgaaaatct cactgagatc
accactgatg tggaaaagat 1440tcaggaaata aggtatcgaa gcaaattaaa
gctgatccgt gctaaggaag aagacagtgg 1500ccattatact attgtagctc
aaaatgaaga tgctgtgaag agctatactt ttgaactgtt 1560aactcaagtt
ccttcatcca ttctggactt ggtcgatgat caccatggct caactggggg
1620acagacggtg aggtgcacag ctgaaggcac gccgcttcct gatattgagt
ggatgatatg 1680caaagatatt aagaaatgta ataatgaaac ttcctggact
attttggcca acaatgtctc 1740aaacatcatc acggagatcc actcccgaga
caggagtacc gtggagggcc gtgtgacttt 1800cgccaaagtg gaggagacca
tcgccgtgcg atgcctggct aagaatctcc ttggagctga 1860gaaccgagag
ctgaagctgg tggctcccac cctgcgttct gaactcacgg tggctgctgc
1920agtcctggtg ctgttggtga ttgtgatcat ctcacttatt gtcctggttg
tcatttggaa 1980acagaaaccg aggtatgaaa ttcgctggag ggtcattgaa
tcaatcagcc cagatggaca 2040tgaatatatt tatgtggacc cgatgcagct
gccttatgac tcaagatggg agtttccaag 2100agatggacta gtgcttggtc
gggtcttggg gtctggagcg tttgggaagg tggttgaagg 2160aacagcctat
ggattaagcc ggtcccaacc tgtcatgaaa gttgcagtga agatgctaaa
2220acccacggcc agatccagtg aaaaacaagc tctcatgtct gaactgaaga
taatgactca 2280cctggggcca catttgaaca ttgtaaactt gctgggagcc
tgcaccaagt caggccccat 2340ttacatcatc acagagtatt gcttctatgg
agatttggtc aactatttgc ataagaatag 2400ggatagcttc ctgagccacc
acccagagaa gccaaagaaa gagctggata tctttggatt 2460gaaccctgct
gatgaaagca cacggagcta tgttatttta tcttttgaaa acaatggtga
2520ctacatggac atgaagcagg ctgatactac acagtatgtc cccatgctag
aaaggaaaga 2580ggtttctaaa tattccgaca tccagagatc actctatgat
cgtccagcct catataagaa 2640gaaatctatg ttagactcag aagtcaaaaa
cctcctttca gatgataact cagaaggcct 2700tactttattg gatttgttga
gcttcaccta tcaagttgcc cgaggaatgg agtttttggc 2760ttcaaaaaat
tgtgtccacc gtgatctggc tgctcgcaac gtcctcctgg cacaaggaaa
2820aattgtgaag atctgtgact ttggcctggc cagagacatc atgcatgatt
cgaactatgt 2880gtcgaaaggc agtacctttc tgcccgtgaa gtggatggct
cctgagagca tctttgacaa 2940cctctacacc acactgagtg atgtctggtc
ttatggcatt ctgctctggg agatcttttc 3000ccttggtggc accccttacc
ccggcatgat ggtggattct actttctaca ataagatcaa 3060gagtgggtac
cggatggcca agcctgacca cgctaccagt gaagtctacg agatcatggt
3120gaaatgctgg aacagtgagc cggagaagag accctccttt taccacctga
gtgagattgt 3180ggagaatctg ctgcctggac aatataaaaa gagttatgaa
aaaattcacc tggacttcct 3240gaagagtgac catcctgctg tggcacgcat
gcgtgtggac tcagacaatg catacattgg 3300tgtcacctac aaaaacgagg
aagacaagct gaaggactgg gagggtggtc tggatgagca 3360gagactgagc
gctgacagtg gctacatcat tcctctgcct gacattgacc ctgtccctga
3420ggaggaggac ctgggcaaga ggaacagaca cagctcgcag acctctgaag
agagtgccat 3480tgagacgggt tccagcagtt ccaccttcat caagagagag
gacgagacca ttgaagacat 3540cgacatgatg gatgacatcg gcatagactc
ttcagacctg gtggaagaca gcttcctgta 3600actggcggat tcgaggggtt
ccttccactt ctggggccac ctctggatcc cgttcagaaa 3660accactttat
tgcaatgcag aggttgagag gaggacttgg ttgatgttta aagagaagtt
3720cccagccaag ggcctcgggg agcgttctaa atatgaatga atgggatatt
ttgaaatgaa 3780ctttgtcagt gttgcctctt gcaatgcctc agtagcatct
cagtggtgtg tgaagtttgg 3840agatagatgg ataagggaat aataggccac
agaaggtgaa ctttgtgctt caaggacatt 3900ggtgagagtc caacagacac
aatttatact gcgacagaac ttcagcattg taattatgta 3960aataactcta
accaaggctg tgtttagatt gtattaacta tcttctttgg acttctgaag
4020agaccactca atccatccat gtacttccct cttgaaacct gatgtcagct
gctgttgaac 4080tttttaaaga agtgcatgaa aaaccatttt tgaaccttaa
aaggtactgg tactatagca 4140ttttgctatc ttttttagtg ttaaagagat
aaagaataat aattaaccaa ccttgtttaa 4200tagatttggg tcatttagaa
gcctgacaac tcattttcat attgtaatct atgtttataa
4260tactactact gttatcagta atgctaaatg tgtaataatg taacatgatt
tccctccaga 4320gaaagcacaa tttaaaacaa tccttactaa gtaggtgatg
agtttgacag tttttgacat 4380ttatattaaa taacatgttt ctctataaag
tatggtaata gctttagtga attaaattta 4440gttgagcata gagaacaaag
taaaagtagt gttgtccagg aagtcagaat ttttaactgt 4500actgaatagg
ttccccaatc catcgtatta aaaaacaatt aactgccctc tgaaataatg
4560ggattagaaa caaacaaaac tcttaagtcc taaaagttct caatgtagag
gcataaacct 4620gtgctgaaca taacttctca tgtatattac ccaatggaaa
atataatgat cagcaaaaag 4680actggatttg cagaagtttt tttttttttt
ttcttcatgc ctgatgaaag ctttggcgac 4740cccaatatat gtattttttg
aatctatgaa cctgaaaagg gtcagaagga tgcccagaca 4800tcagcctcct
tctttcaccc cttaccccaa agagaaagag tttgaaactc gagaccataa
4860agatattctt tagtggaggc tggatgtgca ttagcctgga tcctcagttc
tcaaatgtgt 4920gtggcagcca ggatgactag atcctgggtt tccatccttg
agattctgaa gtatgaagtc 4980tgagggaaac cagagtctgt atttttctaa
actccctggc tgttctgatc ggccagtttt 5040cggaaacact gacttaggtt
tcaggaagtt gccatgggaa acaaataatt tgaactttgg 5100aacagggttg
gcattcaacc acgcaggaag cctactattt aaatccttgg cttcaggtta
5160gtgacattta atgccatcta gctagcaatt gcgaccttaa tttaactttc
cagtcttagc 5220tgaggctgag aaagctaaag tttggttttg acaggttttc
caaaagtaaa gatgctactt 5280cccactgtat gggggagatt gaactttccc
cgtctcccgt cttctgcctc ccactccata 5340ccccgccaag gaaaggcatg
tacaaaaatt atgcaattca gtgttccaag tctctgtgta 5400accagctcag
tgttttggtg gaaaaaacat tttaagtttt actgataatt tgaggttaga
5460tgggaggatg aattgtcaca tctatccaca ctgtcaaaca ggttggtgtg
ggttcattgg 5520cattctttgc aatactgctt aattgctgat accatatgaa
tgaaacatgg gctgtgatta 5580ctgcaatcac tgtgctatcg gcagatgatg
ctttggaaga tgcagaagca ataataaagt 5640acttgactac ctactggtgt
aatctcaatg caagccccaa ctttcttatc caactttttc 5700atagtaagtg
cgaagactga gccagattgg ccaattaaaa acgaaaacct gactaggttc
5760tgtagagcca attagacttg aaatacgttt gtgtttctag aatcacagct
caagcattct 5820gtttatcgct cactctccct tgtacagcct tattttgttg
gtgctttgca ttttgatatt 5880gctgtgagcc ttgcatgaca tcatgaggcc
ggatgaaact tctcagtcca gcagtttcca 5940gtcctaacaa atgctcccac
ctgaatttgt atatgactgc atttgtgtgt gtgtgtgtgt 6000tttcagcaaa
ttccagattt gtttcctttt ggcctcctgc aaagtctcca gaagaaaatt
6060tgccaatctt tcctactttc tatttttatg atgacaatca aagccggcct
gagaaacact 6120atttgtgact ttttaaacga ttagtgatgt ccttaaaatg
tggtctgcca atctgtacaa 6180aatggtccta tttttgtgaa gagggacata
agataaaatg atgttataca tcaatatgta 6240tatatgtatt tctatataga
cttggagaat actgccaaaa catttatgac aagctgtatc 6300actgccttcg
tttatatttt tttaactgtg ataatcccca caggcacatt aactgttgca
6360cttttgaatg tccaaaattt atattttaga aataataaaa agaaagatac
ttacatgttc 6420ccaaaacaat ggtgtggtga atgtgtgaga aaaactaact
tgatagggtc taccaataca 6480aaatgtatta cgaatgcccc tgttcatgtt
tttgttttaa aacgtgtaaa tgaagatctt 6540tatatttcaa taaatgatat
ataatttaaa gtta 6574131089PRTHomo sapiens 13Met Gly Thr Ser His Pro
Ala Phe Leu Val Leu Gly Cys Leu Leu Thr 1 5 10 15 Gly Leu Ser Leu
Ile Leu Cys Gln Leu Ser Leu Pro Ser Ile Leu Pro 20 25 30 Asn Glu
Asn Glu Lys Val Val Gln Leu Asn Ser Ser Phe Ser Leu Arg 35 40 45
Cys Phe Gly Glu Ser Glu Val Ser Trp Gln Tyr Pro Met Ser Glu Glu 50
55 60 Glu Ser Ser Asp Val Glu Ile Arg Asn Glu Glu Asn Asn Ser Gly
Leu 65 70 75 80 Phe Val Thr Val Leu Glu Val Ser Ser Ala Ser Ala Ala
His Thr Gly 85 90 95 Leu Tyr Thr Cys Tyr Tyr Asn His Thr Gln Thr
Glu Glu Asn Glu Leu 100 105 110 Glu Gly Arg His Ile Tyr Ile Tyr Val
Pro Asp Pro Asp Val Ala Phe 115 120 125 Val Pro Leu Gly Met Thr Asp
Tyr Leu Val Ile Val Glu Asp Asp Asp 130 135 140 Ser Ala Ile Ile Pro
Cys Arg Thr Thr Asp Pro Glu Thr Pro Val Thr 145 150 155 160 Leu His
Asn Ser Glu Gly Val Val Pro Ala Ser Tyr Asp Ser Arg Gln 165 170 175
Gly Phe Asn Gly Thr Phe Thr Val Gly Pro Tyr Ile Cys Glu Ala Thr 180
185 190 Val Lys Gly Lys Lys Phe Gln Thr Ile Pro Phe Asn Val Tyr Ala
Leu 195 200 205 Lys Ala Thr Ser Glu Leu Asp Leu Glu Met Glu Ala Leu
Lys Thr Val 210 215 220 Tyr Lys Ser Gly Glu Thr Ile Val Val Thr Cys
Ala Val Phe Asn Asn 225 230 235 240 Glu Val Val Asp Leu Gln Trp Thr
Tyr Pro Gly Glu Val Lys Gly Lys 245 250 255 Gly Ile Thr Met Leu Glu
Glu Ile Lys Val Pro Ser Ile Lys Leu Val 260 265 270 Tyr Thr Leu Thr
Val Pro Glu Ala Thr Val Lys Asp Ser Gly Asp Tyr 275 280 285 Glu Cys
Ala Ala Arg Gln Ala Thr Arg Glu Val Lys Glu Met Lys Lys 290 295 300
Val Thr Ile Ser Val His Glu Lys Gly Phe Ile Glu Ile Lys Pro Thr 305
310 315 320 Phe Ser Gln Leu Glu Ala Val Asn Leu His Glu Val Lys His
Phe Val 325 330 335 Val Glu Val Arg Ala Tyr Pro Pro Pro Arg Ile Ser
Trp Leu Lys Asn 340 345 350 Asn Leu Thr Leu Ile Glu Asn Leu Thr Glu
Ile Thr Thr Asp Val Glu 355 360 365 Lys Ile Gln Glu Ile Arg Tyr Arg
Ser Lys Leu Lys Leu Ile Arg Ala 370 375 380 Lys Glu Glu Asp Ser Gly
His Tyr Thr Ile Val Ala Gln Asn Glu Asp 385 390 395 400 Ala Val Lys
Ser Tyr Thr Phe Glu Leu Leu Thr Gln Val Pro Ser Ser 405 410 415 Ile
Leu Asp Leu Val Asp Asp His His Gly Ser Thr Gly Gly Gln Thr 420 425
430 Val Arg Cys Thr Ala Glu Gly Thr Pro Leu Pro Asp Ile Glu Trp Met
435 440 445 Ile Cys Lys Asp Ile Lys Lys Cys Asn Asn Glu Thr Ser Trp
Thr Ile 450 455 460 Leu Ala Asn Asn Val Ser Asn Ile Ile Thr Glu Ile
His Ser Arg Asp 465 470 475 480 Arg Ser Thr Val Glu Gly Arg Val Thr
Phe Ala Lys Val Glu Glu Thr 485 490 495 Ile Ala Val Arg Cys Leu Ala
Lys Asn Leu Leu Gly Ala Glu Asn Arg 500 505 510 Glu Leu Lys Leu Val
Ala Pro Thr Leu Arg Ser Glu Leu Thr Val Ala 515 520 525 Ala Ala Val
Leu Val Leu Leu Val Ile Val Ile Ile Ser Leu Ile Val 530 535 540 Leu
Val Val Ile Trp Lys Gln Lys Pro Arg Tyr Glu Ile Arg Trp Arg 545 550
555 560 Val Ile Glu Ser Ile Ser Pro Asp Gly His Glu Tyr Ile Tyr Val
Asp 565 570 575 Pro Met Gln Leu Pro Tyr Asp Ser Arg Trp Glu Phe Pro
Arg Asp Gly 580 585 590 Leu Val Leu Gly Arg Val Leu Gly Ser Gly Ala
Phe Gly Lys Val Val 595 600 605 Glu Gly Thr Ala Tyr Gly Leu Ser Arg
Ser Gln Pro Val Met Lys Val 610 615 620 Ala Val Lys Met Leu Lys Pro
Thr Ala Arg Ser Ser Glu Lys Gln Ala 625 630 635 640 Leu Met Ser Glu
Leu Lys Ile Met Thr His Leu Gly Pro His Leu Asn 645 650 655 Ile Val
Asn Leu Leu Gly Ala Cys Thr Lys Ser Gly Pro Ile Tyr Ile 660 665 670
Ile Thr Glu Tyr Cys Phe Tyr Gly Asp Leu Val Asn Tyr Leu His Lys 675
680 685 Asn Arg Asp Ser Phe Leu Ser His His Pro Glu Lys Pro Lys Lys
Glu 690 695 700 Leu Asp Ile Phe Gly Leu Asn Pro Ala Asp Glu Ser Thr
Arg Ser Tyr 705 710 715 720 Val Ile Leu Ser Phe Glu Asn Asn Gly Asp
Tyr Met Asp Met Lys Gln 725 730 735 Ala Asp Thr Thr Gln Tyr Val Pro
Met Leu Glu Arg Lys Glu Val Ser 740 745 750 Lys Tyr Ser Asp Ile Gln
Arg Ser Leu Tyr Asp Arg Pro Ala Ser Tyr 755 760 765 Lys Lys Lys Ser
Met Leu Asp Ser Glu Val Lys Asn Leu Leu Ser Asp 770 775 780 Asp Asn
Ser Glu Gly Leu Thr Leu Leu Asp Leu Leu Ser Phe Thr Tyr 785 790 795
800 Gln Val Ala Arg Gly Met Glu Phe Leu Ala Ser Lys Asn Cys Val His
805 810 815 Arg Asp Leu Ala Ala Arg Asn Val Leu Leu Ala Gln Gly Lys
Ile Val 820 825 830 Lys Ile Cys Asp Phe Gly Leu Ala Arg Asp Ile Met
His Asp Ser Asn 835 840 845 Tyr Val Ser Lys Gly Ser Thr Phe Leu Pro
Val Lys Trp Met Ala Pro 850 855 860 Glu Ser Ile Phe Asp Asn Leu Tyr
Thr Thr Leu Ser Asp Val Trp Ser 865 870 875 880 Tyr Gly Ile Leu Leu
Trp Glu Ile Phe Ser Leu Gly Gly Thr Pro Tyr 885 890 895 Pro Gly Met
Met Val Asp Ser Thr Phe Tyr Asn Lys Ile Lys Ser Gly 900 905 910 Tyr
Arg Met Ala Lys Pro Asp His Ala Thr Ser Glu Val Tyr Glu Ile 915 920
925 Met Val Lys Cys Trp Asn Ser Glu Pro Glu Lys Arg Pro Ser Phe Tyr
930 935 940 His Leu Ser Glu Ile Val Glu Asn Leu Leu Pro Gly Gln Tyr
Lys Lys 945 950 955 960 Ser Tyr Glu Lys Ile His Leu Asp Phe Leu Lys
Ser Asp His Pro Ala 965 970 975 Val Ala Arg Met Arg Val Asp Ser Asp
Asn Ala Tyr Ile Gly Val Thr 980 985 990 Tyr Lys Asn Glu Glu Asp Lys
Leu Lys Asp Trp Glu Gly Gly Leu Asp 995 1000 1005 Glu Gln Arg Leu
Ser Ala Asp Ser Gly Tyr Ile Ile Pro Leu Pro 1010 1015 1020 Asp Ile
Asp Pro Val Pro Glu Glu Glu Asp Leu Gly Lys Arg Asn 1025 1030 1035
Arg His Ser Ser Gln Thr Ser Glu Glu Ser Ala Ile Glu Thr Gly 1040
1045 1050 Ser Ser Ser Ser Thr Phe Ile Lys Arg Glu Asp Glu Thr Ile
Glu 1055 1060 1065 Asp Ile Asp Met Met Asp Asp Ile Gly Ile Asp Ser
Ser Asp Leu 1070 1075 1080 Val Glu Asp Ser Phe Leu 1085
145718DNAHomo sapiens 14ctcctgaggc tgccagcagc cagcagtgac tgcccgccct
atctgggacc caggatcgct 60ctgtgagcaa cttggagcca gagaggagat caacaaggag
gaggagagag ccggcccctc 120agccctgctg cccagcagca gcctgtgctc
gccctgccca acgcagacag ccagacccag 180ggcggcccct ctggcggctc
tgctcctccc gaaggatgct tggggagtga ggcgaagctg 240ggccgctcct
ctcccctaca gcagccccct tcctccatcc ctctgttctc ctgagccttc
300aggagcctgc accagtcctg cctgtccttc tactcagctg ttacccactc
tgggaccagc 360agtctttctg ataactggga gagggcagta aggaggactt
cctggagggg gtgactgtcc 420agagcctgga actgtgccca caccagaagc
catcagcagc aaggacacca tgcggcttcc 480gggtgcgatg ccagctctgg
ccctcaaagg cgagctgctg ttgctgtctc tcctgttact 540tctggaacca
cagatctctc agggcctggt cgtcacaccc ccggggccag agcttgtcct
600caatgtctcc agcaccttcg ttctgacctg ctcgggttca gctccggtgg
tgtgggaacg 660gatgtcccag gagcccccac aggaaatggc caaggcccag
gatggcacct tctccagcgt 720gctcacactg accaacctca ctgggctaga
cacgggagaa tacttttgca cccacaatga 780ctcccgtgga ctggagaccg
atgagcggaa acggctctac atctttgtgc cagatcccac 840cgtgggcttc
ctccctaatg atgccgagga actattcatc tttctcacgg aaataactga
900gatcaccatt ccatgccgag taacagaccc acagctggtg gtgacactgc
acgagaagaa 960aggggacgtt gcactgcctg tcccctatga tcaccaacgt
ggcttttctg gtatctttga 1020ggacagaagc tacatctgca aaaccaccat
tggggacagg gaggtggatt ctgatgccta 1080ctatgtctac agactccagg
tgtcatccat caacgtctct gtgaacgcag tgcagactgt 1140ggtccgccag
ggtgagaaca tcaccctcat gtgcattgtg atcgggaatg aggtggtcaa
1200cttcgagtgg acataccccc gcaaagaaag tgggcggctg gtggagccgg
tgactgactt 1260cctcttggat atgccttacc acatccgctc catcctgcac
atccccagtg ccgagttaga 1320agactcgggg acctacacct gcaatgtgac
ggagagtgtg aatgaccatc aggatgaaaa 1380ggccatcaac atcaccgtgg
ttgagagcgg ctacgtgcgg ctcctgggag aggtgggcac 1440actacaattt
gctgagctgc atcggagccg gacactgcag gtagtgttcg aggcctaccc
1500accgcccact gtcctgtggt tcaaagacaa ccgcaccctg ggcgactcca
gcgctggcga 1560aatcgccctg tccacgcgca acgtgtcgga gacccggtat
gtgtcagagc tgacactggt 1620tcgcgtgaag gtggcagagg ctggccacta
caccatgcgg gccttccatg aggatgctga 1680ggtccagctc tccttccagc
tacagatcaa tgtccctgtc cgagtgctgg agctaagtga 1740gagccaccct
gacagtgggg aacagacagt ccgctgtcgt ggccggggca tgccccagcc
1800gaacatcatc tggtctgcct gcagagacct caaaaggtgt ccacgtgagc
tgccgcccac 1860gctgctgggg aacagttccg aagaggagag ccagctggag
actaacgtga cgtactggga 1920ggaggagcag gagtttgagg tggtgagcac
actgcgtctg cagcacgtgg atcggccact 1980gtcggtgcgc tgcacgctgc
gcaacgctgt gggccaggac acgcaggagg tcatcgtggt 2040gccacactcc
ttgcccttta aggtggtggt gatctcagcc atcctggccc tggtggtgct
2100caccatcatc tcccttatca tcctcatcat gctttggcag aagaagccac
gttacgagat 2160ccgatggaag gtgattgagt ctgtgagctc tgacggccat
gagtacatct acgtggaccc 2220catgcagctg ccctatgact ccacgtggga
gctgccgcgg gaccagcttg tgctgggacg 2280caccctcggc tctggggcct
ttgggcaggt ggtggaggcc acggctcatg gcctgagcca 2340ttctcaggcc
acgatgaaag tggccgtcaa gatgcttaaa tccacagccc gcagcagtga
2400gaagcaagcc cttatgtcgg agctgaagat catgagtcac cttgggcccc
acctgaacgt 2460ggtcaacctg ttgggggcct gcaccaaagg aggacccatc
tatatcatca ctgagtactg 2520ccgctacgga gacctggtgg actacctgca
ccgcaacaaa cacaccttcc tgcagcacca 2580ctccgacaag cgccgcccgc
ccagcgcgga gctctacagc aatgctctgc ccgttgggct 2640ccccctgccc
agccatgtgt ccttgaccgg ggagagcgac ggtggctaca tggacatgag
2700caaggacgag tcggtggact atgtgcccat gctggacatg aaaggagacg
tcaaatatgc 2760agacatcgag tcctccaact acatggcccc ttacgataac
tacgttccct ctgcccctga 2820gaggacctgc cgagcaactt tgatcaacga
gtctccagtg ctaagctaca tggacctcgt 2880gggcttcagc taccaggtgg
ccaatggcat ggagtttctg gcctccaaga actgcgtcca 2940cagagacctg
gcggctagga acgtgctcat ctgtgaaggc aagctggtca agatctgtga
3000ctttggcctg gctcgagaca tcatgcggga ctcgaattac atctccaaag
gcagcacctt 3060tttgccttta aagtggatgg ctccggagag catcttcaac
agcctctaca ccaccctgag 3120cgacgtgtgg tccttcggga tcctgctctg
ggagatcttc accttgggtg gcacccctta 3180cccagagctg cccatgaacg
agcagttcta caatgccatc aaacggggtt accgcatggc 3240ccagcctgcc
catgcctccg acgagatcta tgagatcatg cagaagtgct gggaagagaa
3300gtttgagatt cggcccccct tctcccagct ggtgctgctt ctcgagagac
tgttgggcga 3360aggttacaaa aagaagtacc agcaggtgga tgaggagttt
ctgaggagtg accacccagc 3420catccttcgg tcccaggccc gcttgcctgg
gttccatggc ctccgatctc ccctggacac 3480cagctccgtc ctctatactg
ccgtgcagcc caatgagggt gacaacgact atatcatccc 3540cctgcctgac
cccaaacccg aggttgctga cgagggccca ctggagggtt cccccagcct
3600agccagctcc accctgaatg aagtcaacac ctcctcaacc atctcctgtg
acagccccct 3660ggagccccag gacgaaccag agccagagcc ccagcttgag
ctccaggtgg agccggagcc 3720agagctggaa cagttgccgg attcggggtg
ccctgcgcct cgggcggaag cagaggatag 3780cttcctgtag ggggctggcc
cctaccctgc cctgcctgaa gctccccccc tgccagcacc 3840cagcatctcc
tggcctggcc tgaccgggct tcctgtcagc caggctgccc ttatcagctg
3900tccccttctg gaagctttct gctcctgacg tgttgtgccc caaaccctgg
ggctggctta 3960ggaggcaaga aaactgcagg ggccgtgacc agccctctgc
ctccagggag gccaactgac 4020tctgagccag ggttccccca gggaactcag
ttttcccata tgtaagatgg gaaagttagg 4080cttgatgacc cagaatctag
gattctctcc ctggctgaca ggtggggaga ccgaatccct 4140ccctgggaag
attcttggag ttactgaggt ggtaaattaa cttttttctg ttcagccagc
4200tacccctcaa ggaatcatag ctctctcctc gcacttttat ccacccagga
gctagggaag 4260agaccctagc ctccctggct gctggctgag ctagggccta
gccttgagca gtgttgcctc 4320atccagaaga aagccagtct cctccctatg
atgccagtcc ctgcgttccc tggcccgagc 4380tggtctgggg ccattaggca
gcctaattaa tgctggaggc tgagccaagt acaggacacc 4440cccagcctgc
agcccttgcc cagggcactt ggagcacacg cagccatagc aagtgcctgt
4500gtccctgtcc ttcaggccca tcagtcctgg ggctttttct ttatcaccct
cagtcttaat 4560ccatccacca gagtctagaa ggccagacgg gccccgcatc
tgtgatgaga atgtaaatgt 4620gccagtgtgg agtggccacg tgtgtgtgcc
agtatatggc cctggctctg cattggacct 4680gctatgaggc tttggaggaa
tccctcaccc tctctgggcc tcagtttccc cttcaaaaaa 4740tgaataagtc
ggacttatta actctgagtg ccttgccagc actaacattc tagagtattc
4800caggtggttg cacatttgtc cagatgaagc aaggccatat accctaaact
tccatcctgg 4860gggtcagctg ggctcctggg agattccaga tcacacatca
cactctgggg actcaggaac 4920catgcccctt ccccaggccc ccagcaagtc
tcaagaacac agctgcacag gccttgactt 4980agagtgacag ccggtgtcct
ggaaagcccc cagcagctgc cccagggaca tgggaagacc 5040acgggacctc
tttcactacc cacgatgacc tccgggggta tcctgggcaa aagggacaaa
5100gagggcaaat gagatcacct cctgcagccc accactccag cacctgtgcc
gaggtctgcg 5160tcgaagacag aatggacagt gaggacagtt atgtcttgta
aaagacaaga agcttcagat 5220gggtacccca agaaggatgt gagaggtggg
cgctttggag gtttgcccct cacccaccag 5280ctgccccatc cctgaggcag
cgctccatgg gggtatggtt ttgtcactgc ccagacctag 5340cagtgacatc
tcattgtccc cagcccagtg ggcattggag gtgccagggg agtcagggtt
5400gtagccaaga cgcccccgca cggggagggt tgggaagggg gtgcaggaag
ctcaacccct 5460ctgggcacca accctgcatt gcaggttggc accttacttc
cctgggatcc ccagagttgg 5520tccaaggagg
gagagtgggt tctcaatacg gtaccaaaga tataatcacc taggtttaca
5580aatattttta ggactcacgt taactcacat ttatacagca gaaatgctat
tttgtatgct 5640gttaagtttt tctatctgtg tacttttttt taagggaaag
attttaatat taaacctggt 5700gcttctcact cacaaaaa 5718151106PRTHomo
sapiens 15Met Arg Leu Pro Gly Ala Met Pro Ala Leu Ala Leu Lys Gly
Glu Leu 1 5 10 15 Leu Leu Leu Ser Leu Leu Leu Leu Leu Glu Pro Gln
Ile Ser Gln Gly 20 25 30 Leu Val Val Thr Pro Pro Gly Pro Glu Leu
Val Leu Asn Val Ser Ser 35 40 45 Thr Phe Val Leu Thr Cys Ser Gly
Ser Ala Pro Val Val Trp Glu Arg 50 55 60 Met Ser Gln Glu Pro Pro
Gln Glu Met Ala Lys Ala Gln Asp Gly Thr 65 70 75 80 Phe Ser Ser Val
Leu Thr Leu Thr Asn Leu Thr Gly Leu Asp Thr Gly 85 90 95 Glu Tyr
Phe Cys Thr His Asn Asp Ser Arg Gly Leu Glu Thr Asp Glu 100 105 110
Arg Lys Arg Leu Tyr Ile Phe Val Pro Asp Pro Thr Val Gly Phe Leu 115
120 125 Pro Asn Asp Ala Glu Glu Leu Phe Ile Phe Leu Thr Glu Ile Thr
Glu 130 135 140 Ile Thr Ile Pro Cys Arg Val Thr Asp Pro Gln Leu Val
Val Thr Leu 145 150 155 160 His Glu Lys Lys Gly Asp Val Ala Leu Pro
Val Pro Tyr Asp His Gln 165 170 175 Arg Gly Phe Ser Gly Ile Phe Glu
Asp Arg Ser Tyr Ile Cys Lys Thr 180 185 190 Thr Ile Gly Asp Arg Glu
Val Asp Ser Asp Ala Tyr Tyr Val Tyr Arg 195 200 205 Leu Gln Val Ser
Ser Ile Asn Val Ser Val Asn Ala Val Gln Thr Val 210 215 220 Val Arg
Gln Gly Glu Asn Ile Thr Leu Met Cys Ile Val Ile Gly Asn 225 230 235
240 Glu Val Val Asn Phe Glu Trp Thr Tyr Pro Arg Lys Glu Ser Gly Arg
245 250 255 Leu Val Glu Pro Val Thr Asp Phe Leu Leu Asp Met Pro Tyr
His Ile 260 265 270 Arg Ser Ile Leu His Ile Pro Ser Ala Glu Leu Glu
Asp Ser Gly Thr 275 280 285 Tyr Thr Cys Asn Val Thr Glu Ser Val Asn
Asp His Gln Asp Glu Lys 290 295 300 Ala Ile Asn Ile Thr Val Val Glu
Ser Gly Tyr Val Arg Leu Leu Gly 305 310 315 320 Glu Val Gly Thr Leu
Gln Phe Ala Glu Leu His Arg Ser Arg Thr Leu 325 330 335 Gln Val Val
Phe Glu Ala Tyr Pro Pro Pro Thr Val Leu Trp Phe Lys 340 345 350 Asp
Asn Arg Thr Leu Gly Asp Ser Ser Ala Gly Glu Ile Ala Leu Ser 355 360
365 Thr Arg Asn Val Ser Glu Thr Arg Tyr Val Ser Glu Leu Thr Leu Val
370 375 380 Arg Val Lys Val Ala Glu Ala Gly His Tyr Thr Met Arg Ala
Phe His 385 390 395 400 Glu Asp Ala Glu Val Gln Leu Ser Phe Gln Leu
Gln Ile Asn Val Pro 405 410 415 Val Arg Val Leu Glu Leu Ser Glu Ser
His Pro Asp Ser Gly Glu Gln 420 425 430 Thr Val Arg Cys Arg Gly Arg
Gly Met Pro Gln Pro Asn Ile Ile Trp 435 440 445 Ser Ala Cys Arg Asp
Leu Lys Arg Cys Pro Arg Glu Leu Pro Pro Thr 450 455 460 Leu Leu Gly
Asn Ser Ser Glu Glu Glu Ser Gln Leu Glu Thr Asn Val 465 470 475 480
Thr Tyr Trp Glu Glu Glu Gln Glu Phe Glu Val Val Ser Thr Leu Arg 485
490 495 Leu Gln His Val Asp Arg Pro Leu Ser Val Arg Cys Thr Leu Arg
Asn 500 505 510 Ala Val Gly Gln Asp Thr Gln Glu Val Ile Val Val Pro
His Ser Leu 515 520 525 Pro Phe Lys Val Val Val Ile Ser Ala Ile Leu
Ala Leu Val Val Leu 530 535 540 Thr Ile Ile Ser Leu Ile Ile Leu Ile
Met Leu Trp Gln Lys Lys Pro 545 550 555 560 Arg Tyr Glu Ile Arg Trp
Lys Val Ile Glu Ser Val Ser Ser Asp Gly 565 570 575 His Glu Tyr Ile
Tyr Val Asp Pro Met Gln Leu Pro Tyr Asp Ser Thr 580 585 590 Trp Glu
Leu Pro Arg Asp Gln Leu Val Leu Gly Arg Thr Leu Gly Ser 595 600 605
Gly Ala Phe Gly Gln Val Val Glu Ala Thr Ala His Gly Leu Ser His 610
615 620 Ser Gln Ala Thr Met Lys Val Ala Val Lys Met Leu Lys Ser Thr
Ala 625 630 635 640 Arg Ser Ser Glu Lys Gln Ala Leu Met Ser Glu Leu
Lys Ile Met Ser 645 650 655 His Leu Gly Pro His Leu Asn Val Val Asn
Leu Leu Gly Ala Cys Thr 660 665 670 Lys Gly Gly Pro Ile Tyr Ile Ile
Thr Glu Tyr Cys Arg Tyr Gly Asp 675 680 685 Leu Val Asp Tyr Leu His
Arg Asn Lys His Thr Phe Leu Gln His His 690 695 700 Ser Asp Lys Arg
Arg Pro Pro Ser Ala Glu Leu Tyr Ser Asn Ala Leu 705 710 715 720 Pro
Val Gly Leu Pro Leu Pro Ser His Val Ser Leu Thr Gly Glu Ser 725 730
735 Asp Gly Gly Tyr Met Asp Met Ser Lys Asp Glu Ser Val Asp Tyr Val
740 745 750 Pro Met Leu Asp Met Lys Gly Asp Val Lys Tyr Ala Asp Ile
Glu Ser 755 760 765 Ser Asn Tyr Met Ala Pro Tyr Asp Asn Tyr Val Pro
Ser Ala Pro Glu 770 775 780 Arg Thr Cys Arg Ala Thr Leu Ile Asn Glu
Ser Pro Val Leu Ser Tyr 785 790 795 800 Met Asp Leu Val Gly Phe Ser
Tyr Gln Val Ala Asn Gly Met Glu Phe 805 810 815 Leu Ala Ser Lys Asn
Cys Val His Arg Asp Leu Ala Ala Arg Asn Val 820 825 830 Leu Ile Cys
Glu Gly Lys Leu Val Lys Ile Cys Asp Phe Gly Leu Ala 835 840 845 Arg
Asp Ile Met Arg Asp Ser Asn Tyr Ile Ser Lys Gly Ser Thr Phe 850 855
860 Leu Pro Leu Lys Trp Met Ala Pro Glu Ser Ile Phe Asn Ser Leu Tyr
865 870 875 880 Thr Thr Leu Ser Asp Val Trp Ser Phe Gly Ile Leu Leu
Trp Glu Ile 885 890 895 Phe Thr Leu Gly Gly Thr Pro Tyr Pro Glu Leu
Pro Met Asn Glu Gln 900 905 910 Phe Tyr Asn Ala Ile Lys Arg Gly Tyr
Arg Met Ala Gln Pro Ala His 915 920 925 Ala Ser Asp Glu Ile Tyr Glu
Ile Met Gln Lys Cys Trp Glu Glu Lys 930 935 940 Phe Glu Ile Arg Pro
Pro Phe Ser Gln Leu Val Leu Leu Leu Glu Arg 945 950 955 960 Leu Leu
Gly Glu Gly Tyr Lys Lys Lys Tyr Gln Gln Val Asp Glu Glu 965 970 975
Phe Leu Arg Ser Asp His Pro Ala Ile Leu Arg Ser Gln Ala Arg Leu 980
985 990 Pro Gly Phe His Gly Leu Arg Ser Pro Leu Asp Thr Ser Ser Val
Leu 995 1000 1005 Tyr Thr Ala Val Gln Pro Asn Glu Gly Asp Asn Asp
Tyr Ile Ile 1010 1015 1020 Pro Leu Pro Asp Pro Lys Pro Glu Val Ala
Asp Glu Gly Pro Leu 1025 1030 1035 Glu Gly Ser Pro Ser Leu Ala Ser
Ser Thr Leu Asn Glu Val Asn 1040 1045 1050 Thr Ser Ser Thr Ile Ser
Cys Asp Ser Pro Leu Glu Pro Gln Asp 1055 1060 1065 Glu Pro Glu Pro
Glu Pro Gln Leu Glu Leu Gln Val Glu Pro Glu 1070 1075 1080 Pro Glu
Leu Glu Gln Leu Pro Asp Ser Gly Cys Pro Ala Pro Arg 1085 1090 1095
Ala Glu Ala Glu Asp Ser Phe Leu 1100 1105 163626DNAHomo sapiens
16tcgcggaggc ttggggcagc cgggtagctc ggaggtcgtg gcgctggggg ctagcaccag
60cgctctgtcg ggaggcgcag cggttaggtg gaccggtcag cggactcacc ggccagggcg
120ctcggtgctg gaatttgata ttcattgatc cgggttttat ccctcttctt
ttttcttaaa 180catttttttt taaaactgta ttgtttctcg ttttaattta
tttttgcttg ccattcccca 240cttgaatcgg gccgacggct tggggagatt
gctctacttc cccaaatcac tgtggatttt 300ggaaaccagc agaaagagga
aagaggtagc aagagctcca gagagaagtc gaggaagaga 360gagacggggt
cagagagagc gcgcgggcgt gcgagcagcg aaagcgacag gggcaaagtg
420agtgacctgc ttttgggggt gaccgccgga gcgcggcgtg agccctcccc
cttgggatcc 480cgcagctgac cagtcgcgct gacggacaga cagacagaca
ccgcccccag ccccagctac 540cacctcctcc ccggccggcg gcggacagtg
gacgcggcgg cgagccgcgg gcaggggccg 600gagcccgcgc ccggaggcgg
ggtggagggg gtcggggctc gcggcgtcgc actgaaactt 660ttcgtccaac
ttctgggctg ttctcgcttc ggaggagccg tggtccgcgc gggggaagcc
720gagccgagcg gagccgcgag aagtgctagc tcgggccggg aggagccgca
gccggaggag 780ggggaggagg aagaagagaa ggaagaggag agggggccgc
agtggcgact cggcgctcgg 840aagccgggct catggacggg tgaggcggcg
gtgtgcgcag acagtgctcc agccgcgcgc 900gctccccagg ccctggcccg
ggcctcgggc cggggaggaa gagtagctcg ccgaggcgcc 960gaggagagcg
ggccgcccca cagcccgagc cggagaggga gcgcgagccg cgccggcccc
1020ggtcgggcct ccgaaaccat gaactttctg ctgtcttggg tgcattggag
ccttgccttg 1080ctgctctacc tccaccatgc caagtggtcc caggctgcac
ccatggcaga aggaggaggg 1140cagaatcatc acgaagtggt gaagttcatg
gatgtctatc agcgcagcta ctgccatcca 1200atcgagaccc tggtggacat
cttccaggag taccctgatg agatcgagta catcttcaag 1260ccatcctgtg
tgcccctgat gcgatgcggg ggctgctgca atgacgaggg cctggagtgt
1320gtgcccactg aggagtccaa catcaccatg cagattatgc ggatcaaacc
tcaccaaggc 1380cagcacatag gagagatgag cttcctacag cacaacaaat
gtgaatgcag accaaagaaa 1440gatagagcaa gacaagaaaa aaaatcagtt
cgaggaaagg gaaaggggca aaaacgaaag 1500cgcaagaaat cccggtataa
gtcctggagc gttccctgtg ggccttgctc agagcggaga 1560aagcatttgt
ttgtacaaga tccgcagacg tgtaaatgtt cctgcaaaaa cacagactcg
1620cgttgcaagg cgaggcagct tgagttaaac gaacgtactt gcagatgtga
caagccgagg 1680cggtgagccg ggcaggagga aggagcctcc ctcagggttt
cgggaaccag atctctcacc 1740aggaaagact gatacagaac gatcgataca
gaaaccacgc tgccgccacc acaccatcac 1800catcgacaga acagtcctta
atccagaaac ctgaaatgaa ggaagaggag actctgcgca 1860gagcactttg
ggtccggagg gcgagactcc ggcggaagca ttcccgggcg ggtgacccag
1920cacggtccct cttggaattg gattcgccat tttatttttc ttgctgctaa
atcaccgagc 1980ccggaagatt agagagtttt atttctggga ttcctgtaga
cacacccacc cacatacata 2040catttatata tatatatatt atatatatat
aaaaataaat atctctattt tatatatata 2100aaatatatat attctttttt
taaattaaca gtgctaatgt tattggtgtc ttcactggat 2160gtatttgact
gctgtggact tgagttggga ggggaatgtt cccactcaga tcctgacagg
2220gaagaggagg agatgagaga ctctggcatg atcttttttt tgtcccactt
ggtggggcca 2280gggtcctctc ccctgcccag gaatgtgcaa ggccagggca
tgggggcaaa tatgacccag 2340ttttgggaac accgacaaac ccagccctgg
cgctgagcct ctctacccca ggtcagacgg 2400acagaaagac agatcacagg
tacagggatg aggacaccgg ctctgaccag gagtttgggg 2460agcttcagga
cattgctgtg ctttggggat tccctccaca tgctgcacgc gcatctcgcc
2520cccaggggca ctgcctggaa gattcaggag cctgggcggc cttcgcttac
tctcacctgc 2580ttctgagttg cccaggagac cactggcaga tgtcccggcg
aagagaagag acacattgtt 2640ggaagaagca gcccatgaca gctccccttc
ctgggactcg ccctcatcct cttcctgctc 2700cccttcctgg ggtgcagcct
aaaaggacct atgtcctcac accattgaaa ccactagttc 2760tgtcccccca
ggagacctgg ttgtgtgtgt gtgagtggtt gaccttcctc catcccctgg
2820tccttccctt cccttcccga ggcacagaga gacagggcag gatccacgtg
cccattgtgg 2880aggcagagaa aagagaaagt gttttatata cggtacttat
ttaatatccc tttttaatta 2940gaaattaaaa cagttaattt aattaaagag
tagggttttt tttcagtatt cttggttaat 3000atttaatttc aactatttat
gagatgtatc ttttgctctc tcttgctctc ttatttgtac 3060cggtttttgt
atataaaatt catgtttcca atctctctct ccctgatcgg tgacagtcac
3120tagcttatct tgaacagata tttaattttg ctaacactca gctctgccct
ccccgatccc 3180ctggctcccc agcacacatt cctttgaaat aaggtttcaa
tatacatcta catactatat 3240atatatttgg caacttgtat ttgtgtgtat
atatatatat atatgtttat gtatatatgt 3300gattctgata aaatagacat
tgctattctg ttttttatat gtaaaaacaa aacaagaaaa 3360aatagagaat
tctacatact aaatctctct ccttttttaa ttttaatatt tgttatcatt
3420tatttattgg tgctactgtt tatccgtaat aattgtgggg aaaagatatt
aacatcacgt 3480ctttgtctct agtgcagttt ttcgagatat tccgtagtac
atatttattt ttaaacaacg 3540acaaagaaat acagatatat cttaaaaaaa
aaaaagcatt ttgtattaaa gaatttaatt 3600ctgatctcaa aaaaaaaaaa aaaaaa
362617395PRTHomo sapiens 17Met Thr Asp Arg Gln Thr Asp Thr Ala Pro
Ser Pro Ser Tyr His Leu 1 5 10 15 Leu Pro Gly Arg Arg Arg Thr Val
Asp Ala Ala Ala Ser Arg Gly Gln 20 25 30 Gly Pro Glu Pro Ala Pro
Gly Gly Gly Val Glu Gly Val Gly Ala Arg 35 40 45 Gly Val Ala Leu
Lys Leu Phe Val Gln Leu Leu Gly Cys Ser Arg Phe 50 55 60 Gly Gly
Ala Val Val Arg Ala Gly Glu Ala Glu Pro Ser Gly Ala Ala 65 70 75 80
Arg Ser Ala Ser Ser Gly Arg Glu Glu Pro Gln Pro Glu Glu Gly Glu 85
90 95 Glu Glu Glu Glu Lys Glu Glu Glu Arg Gly Pro Gln Trp Arg Leu
Gly 100 105 110 Ala Arg Lys Pro Gly Ser Trp Thr Gly Glu Ala Ala Val
Cys Ala Asp 115 120 125 Ser Ala Pro Ala Ala Arg Ala Pro Gln Ala Leu
Ala Arg Ala Ser Gly 130 135 140 Arg Gly Gly Arg Val Ala Arg Arg Gly
Ala Glu Glu Ser Gly Pro Pro 145 150 155 160 His Ser Pro Ser Arg Arg
Gly Ser Ala Ser Arg Ala Gly Pro Gly Arg 165 170 175 Ala Ser Glu Thr
Met Asn Phe Leu Leu Ser Trp Val His Trp Ser Leu 180 185 190 Ala Leu
Leu Leu Tyr Leu His His Ala Lys Trp Ser Gln Ala Ala Pro 195 200 205
Met Ala Glu Gly Gly Gly Gln Asn His His Glu Val Val Lys Phe Met 210
215 220 Asp Val Tyr Gln Arg Ser Tyr Cys His Pro Ile Glu Thr Leu Val
Asp 225 230 235 240 Ile Phe Gln Glu Tyr Pro Asp Glu Ile Glu Tyr Ile
Phe Lys Pro Ser 245 250 255 Cys Val Pro Leu Met Arg Cys Gly Gly Cys
Cys Asn Asp Glu Gly Leu 260 265 270 Glu Cys Val Pro Thr Glu Glu Ser
Asn Ile Thr Met Gln Ile Met Arg 275 280 285 Ile Lys Pro His Gln Gly
Gln His Ile Gly Glu Met Ser Phe Leu Gln 290 295 300 His Asn Lys Cys
Glu Cys Arg Pro Lys Lys Asp Arg Ala Arg Gln Glu 305 310 315 320 Lys
Lys Ser Val Arg Gly Lys Gly Lys Gly Gln Lys Arg Lys Arg Lys 325 330
335 Lys Ser Arg Tyr Lys Ser Trp Ser Val Pro Cys Gly Pro Cys Ser Glu
340 345 350 Arg Arg Lys His Leu Phe Val Gln Asp Pro Gln Thr Cys Lys
Cys Ser 355 360 365 Cys Lys Asn Thr Asp Ser Arg Cys Lys Ala Arg Gln
Leu Glu Leu Asn 370 375 380 Glu Arg Thr Cys Arg Cys Asp Lys Pro Arg
Arg 385 390 395 184017DNAHomo sapiens 18atggtcagct actgggacac
cggggtcctg ctgtgcgcgc tgctcagctg tctgcttctc 60acaggatcta gttcaggttc
aaaattaaaa gatcctgaac tgagtttaaa aggcacccag 120cacatcatgc
aagcaggcca gacactgcat ctccaatgca ggggggaagc agcccataaa
180tggtctttgc ctgaaatggt gagtaaggaa agcgaaaggc tgagcataac
taaatctgcc 240tgtggaagaa atggcaaaca attctgcagt actttaacct
tgaacacagc tcaagcaaac 300cacactggct tctacagctg caaatatcta
gctgtaccta cttcaaagaa gaaggaaaca 360gaatctgcaa tctatatatt
tattagtgat acaggtagac ctttcgtaga gatgtacagt 420gaaatccccg
aaattataca catgactgaa ggaagggagc tcgtcattcc ctgccgggtt
480acgtcaccta acatcactgt tactttaaaa aagtttccac ttgacacttt
gatccctgat 540ggaaaacgca taatctggga cagtagaaag ggcttcatca
tatcaaatgc aacgtacaaa 600gaaatagggc ttctgacctg tgaagcaaca
gtcaatgggc atttgtataa gacaaactat 660ctcacacatc gacaaaccaa
tacaatcata gatgtccaaa taagcacacc acgcccagtc 720aaattactta
gaggccatac tcttgtcctc aattgtactg ctaccactcc cttgaacacg
780agagttcaaa tgacctggag ttaccctgat gaaaaaaata agagagcttc
cgtaaggcga 840cgaattgacc aaagcaattc ccatgccaac atattctaca
gtgttcttac tattgacaaa 900atgcagaaca aagacaaagg actttatact
tgtcgtgtaa ggagtggacc atcattcaaa 960tctgttaaca cctcagtgca
tatatatgat aaagcattca tcactgtgaa acatcgaaaa 1020cagcaggtgc
ttgaaaccgt agctggcaag cggtcttacc ggctctctat gaaagtgaag
1080gcatttccct cgccggaagt tgtatggtta aaagatgggt tacctgcgac
tgagaaatct 1140gctcgctatt tgactcgtgg ctactcgtta attatcaagg
acgtaactga agaggatgca 1200gggaattata caatcttgct gagcataaaa
cagtcaaatg
tgtttaaaaa cctcactgcc 1260actctaattg tcaatgtgaa accccagatt
tacgaaaagg ccgtgtcatc gtttccagac 1320ccggctctct acccactggg
cagcagacaa atcctgactt gtaccgcata tggtatccct 1380caacctacaa
tcaagtggtt ctggcacccc tgtaaccata atcattccga agcaaggtgt
1440gacttttgtt ccaataatga agagtcctct atcctggatg ctgacagcaa
catgggaaac 1500agaattgaga gcatcactca gcgcatggca ataatagaag
gaaagaataa gatggctagc 1560accttggttg tggctgactc tagaatttct
ggaatctaca tttgcatagc ttccaataaa 1620gttgggactg tgggaagaaa
cataagcttt tatatcacag atgtgccaaa tgggtttcat 1680gttaacttgg
aaaaaatgcc gacggaagga gaggacctga aactgtcttg cacagttaac
1740aagttcttat acagagacgt tacttggatt ttactgcgga cagttaataa
cagaacaatg 1800cactacagta ttagcaagca aaaaatggcc atcactaagg
agcactccat cactcttaat 1860cttaccatca tgaatgtttc cctgcaagat
tcaggcacct atgcctgcag agccaggaat 1920gtatacacag gggaagaaat
cctccagaag aaagaaatta caatcagaga tcaggaagca 1980ccatacctcc
tgcgaaacct cagtgatcac acagtggcca tcagcagttc caccacttta
2040gactgtcatg ctaatggtgt ccccgagcct cagatcactt ggtttaaaaa
caaccacaaa 2100atacaacaag agcctggaat tattttagga ccaggaagca
gcacgctgtt tattgaaaga 2160gtcacagaag aggatgaagg tgtctatcac
tgcaaagcca ccaaccagaa gggctctgtg 2220gaaagttcag catacctcac
tgttcaagga acctcggaca agtctaatct ggagctgatc 2280actctaacat
gcacctgtgt ggctgcgact ctcttctggc tcctattaac cctctttatc
2340cgaaaaatga aaaggtcttc ttctgaaata aagactgact acctatcaat
tataatggac 2400ccagatgaag ttcctttgga tgagcagtgt gagcggctcc
cttatgatgc cagcaagtgg 2460gagtttgccc gggagagact taaactgggc
aaatcacttg gaagaggggc ttttggaaaa 2520gtggttcaag catcagcatt
tggcattaag aaatcaccta cgtgccggac tgtggctgtg 2580aaaatgctga
aagagggggc cacggccagc gagtacaaag ctctgatgac tgagctaaaa
2640atcttgaccc acattggcca ccatctgaac gtggttaacc tgctgggagc
ctgcaccaag 2700caaggagggc ctctgatggt gattgttgaa tactgcaaat
atggaaatct ctccaactac 2760ctcaagagca aacgtgactt attttttctc
aacaaggatg cagcactaca catggagcct 2820aagaaagaaa aaatggagcc
aggcctggaa caaggcaaga aaccaagact agatagcgtc 2880accagcagcg
aaagctttgc gagctccggc tttcaggaag ataaaagtct gagtgatgtt
2940gaggaagagg aggattctga cggtttctac aaggagccca tcactatgga
agatctgatt 3000tcttacagtt ttcaagtggc cagaggcatg gagttcctgt
cttccagaaa gtgcattcat 3060cgggacctgg cagcgagaaa cattctttta
tctgagaaca acgtggtgaa gatttgtgat 3120tttggccttg cccgggatat
ttataagaac cccgattatg tgagaaaagg agatactcga 3180cttcctctga
aatggatggc tcctgaatct atctttgaca aaatctacag caccaagagc
3240gacgtgtggt cttacggagt attgctgtgg gaaatcttct ccttaggtgg
gtctccatac 3300ccaggagtac aaatggatga ggacttttgc agtcgcctga
gggaaggcat gaggatgaga 3360gctcctgagt actctactcc tgaaatctat
cagatcatgc tggactgctg gcacagagac 3420ccaaaagaaa ggccaagatt
tgcagaactt gtggaaaaac taggtgattt gcttcaagca 3480aatgtacaac
aggatggtaa agactacatc ccaatcaatg ccatactgac aggaaatagt
3540gggtttacat actcaactcc tgccttctct gaggacttct tcaaggaaag
tatttcagct 3600ccgaagttta attcaggaag ctctgatgat gtcagatatg
taaatgcttt caagttcatg 3660agcctggaaa gaatcaaaac ctttgaagaa
cttttaccga atgccacctc catgtttgat 3720gactaccagg gcgacagcag
cactctgttg gcctctccca tgctgaagcg cttcacctgg 3780actgacagca
aacccaaggc ctcgctcaag attgacttga gagtaaccag taaaagtaag
3840gagtcggggc tgtctgatgt cagcaggccc agtttctgcc attccagctg
tgggcacgtc 3900agcgaaggca agcgcaggtt cacctacgac cacgctgagc
tggaaaggaa aatcgcgtgc 3960tgctccccgc ccccagacta caactcggtg
gtcctgtact ccaccccacc catctag 4017191338PRTHomo sapiens 19Met Val
Ser Tyr Trp Asp Thr Gly Val Leu Leu Cys Ala Leu Leu Ser 1 5 10 15
Cys Leu Leu Leu Thr Gly Ser Ser Ser Gly Ser Lys Leu Lys Asp Pro 20
25 30 Glu Leu Ser Leu Lys Gly Thr Gln His Ile Met Gln Ala Gly Gln
Thr 35 40 45 Leu His Leu Gln Cys Arg Gly Glu Ala Ala His Lys Trp
Ser Leu Pro 50 55 60 Glu Met Val Ser Lys Glu Ser Glu Arg Leu Ser
Ile Thr Lys Ser Ala 65 70 75 80 Cys Gly Arg Asn Gly Lys Gln Phe Cys
Ser Thr Leu Thr Leu Asn Thr 85 90 95 Ala Gln Ala Asn His Thr Gly
Phe Tyr Ser Cys Lys Tyr Leu Ala Val 100 105 110 Pro Thr Ser Lys Lys
Lys Glu Thr Glu Ser Ala Ile Tyr Ile Phe Ile 115 120 125 Ser Asp Thr
Gly Arg Pro Phe Val Glu Met Tyr Ser Glu Ile Pro Glu 130 135 140 Ile
Ile His Met Thr Glu Gly Arg Glu Leu Val Ile Pro Cys Arg Val 145 150
155 160 Thr Ser Pro Asn Ile Thr Val Thr Leu Lys Lys Phe Pro Leu Asp
Thr 165 170 175 Leu Ile Pro Asp Gly Lys Arg Ile Ile Trp Asp Ser Arg
Lys Gly Phe 180 185 190 Ile Ile Ser Asn Ala Thr Tyr Lys Glu Ile Gly
Leu Leu Thr Cys Glu 195 200 205 Ala Thr Val Asn Gly His Leu Tyr Lys
Thr Asn Tyr Leu Thr His Arg 210 215 220 Gln Thr Asn Thr Ile Ile Asp
Val Gln Ile Ser Thr Pro Arg Pro Val 225 230 235 240 Lys Leu Leu Arg
Gly His Thr Leu Val Leu Asn Cys Thr Ala Thr Thr 245 250 255 Pro Leu
Asn Thr Arg Val Gln Met Thr Trp Ser Tyr Pro Asp Glu Lys 260 265 270
Asn Lys Arg Ala Ser Val Arg Arg Arg Ile Asp Gln Ser Asn Ser His 275
280 285 Ala Asn Ile Phe Tyr Ser Val Leu Thr Ile Asp Lys Met Gln Asn
Lys 290 295 300 Asp Lys Gly Leu Tyr Thr Cys Arg Val Arg Ser Gly Pro
Ser Phe Lys 305 310 315 320 Ser Val Asn Thr Ser Val His Ile Tyr Asp
Lys Ala Phe Ile Thr Val 325 330 335 Lys His Arg Lys Gln Gln Val Leu
Glu Thr Val Ala Gly Lys Arg Ser 340 345 350 Tyr Arg Leu Ser Met Lys
Val Lys Ala Phe Pro Ser Pro Glu Val Val 355 360 365 Trp Leu Lys Asp
Gly Leu Pro Ala Thr Glu Lys Ser Ala Arg Tyr Leu 370 375 380 Thr Arg
Gly Tyr Ser Leu Ile Ile Lys Asp Val Thr Glu Glu Asp Ala 385 390 395
400 Gly Asn Tyr Thr Ile Leu Leu Ser Ile Lys Gln Ser Asn Val Phe Lys
405 410 415 Asn Leu Thr Ala Thr Leu Ile Val Asn Val Lys Pro Gln Ile
Tyr Glu 420 425 430 Lys Ala Val Ser Ser Phe Pro Asp Pro Ala Leu Tyr
Pro Leu Gly Ser 435 440 445 Arg Gln Ile Leu Thr Cys Thr Ala Tyr Gly
Ile Pro Gln Pro Thr Ile 450 455 460 Lys Trp Phe Trp His Pro Cys Asn
His Asn His Ser Glu Ala Arg Cys 465 470 475 480 Asp Phe Cys Ser Asn
Asn Glu Glu Ser Ser Ile Leu Asp Ala Asp Ser 485 490 495 Asn Met Gly
Asn Arg Ile Glu Ser Ile Thr Gln Arg Met Ala Ile Ile 500 505 510 Glu
Gly Lys Asn Lys Met Ala Ser Thr Leu Val Val Ala Asp Ser Arg 515 520
525 Ile Ser Gly Ile Tyr Ile Cys Ile Ala Ser Asn Lys Val Gly Thr Val
530 535 540 Gly Arg Asn Ile Ser Phe Tyr Ile Thr Asp Val Pro Asn Gly
Phe His 545 550 555 560 Val Asn Leu Glu Lys Met Pro Thr Glu Gly Glu
Asp Leu Lys Leu Ser 565 570 575 Cys Thr Val Asn Lys Phe Leu Tyr Arg
Asp Val Thr Trp Ile Leu Leu 580 585 590 Arg Thr Val Asn Asn Arg Thr
Met His Tyr Ser Ile Ser Lys Gln Lys 595 600 605 Met Ala Ile Thr Lys
Glu His Ser Ile Thr Leu Asn Leu Thr Ile Met 610 615 620 Asn Val Ser
Leu Gln Asp Ser Gly Thr Tyr Ala Cys Arg Ala Arg Asn 625 630 635 640
Val Tyr Thr Gly Glu Glu Ile Leu Gln Lys Lys Glu Ile Thr Ile Arg 645
650 655 Asp Gln Glu Ala Pro Tyr Leu Leu Arg Asn Leu Ser Asp His Thr
Val 660 665 670 Ala Ile Ser Ser Ser Thr Thr Leu Asp Cys His Ala Asn
Gly Val Pro 675 680 685 Glu Pro Gln Ile Thr Trp Phe Lys Asn Asn His
Lys Ile Gln Gln Glu 690 695 700 Pro Gly Ile Ile Leu Gly Pro Gly Ser
Ser Thr Leu Phe Ile Glu Arg 705 710 715 720 Val Thr Glu Glu Asp Glu
Gly Val Tyr His Cys Lys Ala Thr Asn Gln 725 730 735 Lys Gly Ser Val
Glu Ser Ser Ala Tyr Leu Thr Val Gln Gly Thr Ser 740 745 750 Asp Lys
Ser Asn Leu Glu Leu Ile Thr Leu Thr Cys Thr Cys Val Ala 755 760 765
Ala Thr Leu Phe Trp Leu Leu Leu Thr Leu Phe Ile Arg Lys Met Lys 770
775 780 Arg Ser Ser Ser Glu Ile Lys Thr Asp Tyr Leu Ser Ile Ile Met
Asp 785 790 795 800 Pro Asp Glu Val Pro Leu Asp Glu Gln Cys Glu Arg
Leu Pro Tyr Asp 805 810 815 Ala Ser Lys Trp Glu Phe Ala Arg Glu Arg
Leu Lys Leu Gly Lys Ser 820 825 830 Leu Gly Arg Gly Ala Phe Gly Lys
Val Val Gln Ala Ser Ala Phe Gly 835 840 845 Ile Lys Lys Ser Pro Thr
Cys Arg Thr Val Ala Val Lys Met Leu Lys 850 855 860 Glu Gly Ala Thr
Ala Ser Glu Tyr Lys Ala Leu Met Thr Glu Leu Lys 865 870 875 880 Ile
Leu Thr His Ile Gly His His Leu Asn Val Val Asn Leu Leu Gly 885 890
895 Ala Cys Thr Lys Gln Gly Gly Pro Leu Met Val Ile Val Glu Tyr Cys
900 905 910 Lys Tyr Gly Asn Leu Ser Asn Tyr Leu Lys Ser Lys Arg Asp
Leu Phe 915 920 925 Phe Leu Asn Lys Asp Ala Ala Leu His Met Glu Pro
Lys Lys Glu Lys 930 935 940 Met Glu Pro Gly Leu Glu Gln Gly Lys Lys
Pro Arg Leu Asp Ser Val 945 950 955 960 Thr Ser Ser Glu Ser Phe Ala
Ser Ser Gly Phe Gln Glu Asp Lys Ser 965 970 975 Leu Ser Asp Val Glu
Glu Glu Glu Asp Ser Asp Gly Phe Tyr Lys Glu 980 985 990 Pro Ile Thr
Met Glu Asp Leu Ile Ser Tyr Ser Phe Gln Val Ala Arg 995 1000 1005
Gly Met Glu Phe Leu Ser Ser Arg Lys Cys Ile His Arg Asp Leu 1010
1015 1020 Ala Ala Arg Asn Ile Leu Leu Ser Glu Asn Asn Val Val Lys
Ile 1025 1030 1035 Cys Asp Phe Gly Leu Ala Arg Asp Ile Tyr Lys Asn
Pro Asp Tyr 1040 1045 1050 Val Arg Lys Gly Asp Thr Arg Leu Pro Leu
Lys Trp Met Ala Pro 1055 1060 1065 Glu Ser Ile Phe Asp Lys Ile Tyr
Ser Thr Lys Ser Asp Val Trp 1070 1075 1080 Ser Tyr Gly Val Leu Leu
Trp Glu Ile Phe Ser Leu Gly Gly Ser 1085 1090 1095 Pro Tyr Pro Gly
Val Gln Met Asp Glu Asp Phe Cys Ser Arg Leu 1100 1105 1110 Arg Glu
Gly Met Arg Met Arg Ala Pro Glu Tyr Ser Thr Pro Glu 1115 1120 1125
Ile Tyr Gln Ile Met Leu Asp Cys Trp His Arg Asp Pro Lys Glu 1130
1135 1140 Arg Pro Arg Phe Ala Glu Leu Val Glu Lys Leu Gly Asp Leu
Leu 1145 1150 1155 Gln Ala Asn Val Gln Gln Asp Gly Lys Asp Tyr Ile
Pro Ile Asn 1160 1165 1170 Ala Ile Leu Thr Gly Asn Ser Gly Phe Thr
Tyr Ser Thr Pro Ala 1175 1180 1185 Phe Ser Glu Asp Phe Phe Lys Glu
Ser Ile Ser Ala Pro Lys Phe 1190 1195 1200 Asn Ser Gly Ser Ser Asp
Asp Val Arg Tyr Val Asn Ala Phe Lys 1205 1210 1215 Phe Met Ser Leu
Glu Arg Ile Lys Thr Phe Glu Glu Leu Leu Pro 1220 1225 1230 Asn Ala
Thr Ser Met Phe Asp Asp Tyr Gln Gly Asp Ser Ser Thr 1235 1240 1245
Leu Leu Ala Ser Pro Met Leu Lys Arg Phe Thr Trp Thr Asp Ser 1250
1255 1260 Lys Pro Lys Ala Ser Leu Lys Ile Asp Leu Arg Val Thr Ser
Lys 1265 1270 1275 Ser Lys Glu Ser Gly Leu Ser Asp Val Ser Arg Pro
Ser Phe Cys 1280 1285 1290 His Ser Ser Cys Gly His Val Ser Glu Gly
Lys Arg Arg Phe Thr 1295 1300 1305 Tyr Asp His Ala Glu Leu Glu Arg
Lys Ile Ala Cys Cys Ser Pro 1310 1315 1320 Pro Pro Asp Tyr Asn Ser
Val Val Leu Tyr Ser Thr Pro Pro Ile 1325 1330 1335 20 5830DNAHomo
sapiens 20actgagtccc gggaccccgg gagagcggtc agtgtgtggt cgctgcgttt
cctctgcctg 60cgccgggcat cacttgcgcg ccgcagaaag tccgtctggc agcctggata
tcctctccta 120ccggcacccg cagacgcccc tgcagccgcc ggtcggcgcc
cgggctccct agccctgtgc 180gctcaactgt cctgcgctgc ggggtgccgc
gagttccacc tccgcgcctc cttctctaga 240caggcgctgg gagaaagaac
cggctcccga gttctgggca tttcgcccgg ctcgaggtgc 300aggatgcaga
gcaaggtgct gctggccgtc gccctgtggc tctgcgtgga gacccgggcc
360gcctctgtgg gtttgcctag tgtttctctt gatctgccca ggctcagcat
acaaaaagac 420atacttacaa ttaaggctaa tacaactctt caaattactt
gcaggggaca gagggacttg 480gactggcttt ggcccaataa tcagagtggc
agtgagcaaa gggtggaggt gactgagtgc 540agcgatggcc tcttctgtaa
gacactcaca attccaaaag tgatcggaaa tgacactgga 600gcctacaagt
gcttctaccg ggaaactgac ttggcctcgg tcatttatgt ctatgttcaa
660gattacagat ctccatttat tgcttctgtt agtgaccaac atggagtcgt
gtacattact 720gagaacaaaa acaaaactgt ggtgattcca tgtctcgggt
ccatttcaaa tctcaacgtg 780tcactttgtg caagataccc agaaaagaga
tttgttcctg atggtaacag aatttcctgg 840gacagcaaga agggctttac
tattcccagc tacatgatca gctatgctgg catggtcttc 900tgtgaagcaa
aaattaatga tgaaagttac cagtctatta tgtacatagt tgtcgttgta
960gggtatagga tttatgatgt ggttctgagt ccgtctcatg gaattgaact
atctgttgga 1020gaaaagcttg tcttaaattg tacagcaaga actgaactaa
atgtggggat tgacttcaac 1080tgggaatacc cttcttcgaa gcatcagcat
aagaaacttg taaaccgaga cctaaaaacc 1140cagtctggga gtgagatgaa
gaaatttttg agcaccttaa ctatagatgg tgtaacccgg 1200agtgaccaag
gattgtacac ctgtgcagca tccagtgggc tgatgaccaa gaagaacagc
1260acatttgtca gggtccatga aaaacctttt gttgcttttg gaagtggcat
ggaatctctg 1320gtggaagcca cggtggggga gcgtgtcaga atccctgcga
agtaccttgg ttacccaccc 1380ccagaaataa aatggtataa aaatggaata
ccccttgagt ccaatcacac aattaaagcg 1440gggcatgtac tgacgattat
ggaagtgagt gaaagagaca caggaaatta cactgtcatc 1500cttaccaatc
ccatttcaaa ggagaagcag agccatgtgg tctctctggt tgtgtatgtc
1560ccaccccaga ttggtgagaa atctctaatc tctcctgtgg attcctacca
gtacggcacc 1620actcaaacgc tgacatgtac ggtctatgcc attcctcccc
cgcatcacat ccactggtat 1680tggcagttgg aggaagagtg cgccaacgag
cccagccaag ctgtctcagt gacaaaccca 1740tacccttgtg aagaatggag
aagtgtggag gacttccagg gaggaaataa aattgaagtt 1800aataaaaatc
aatttgctct aattgaagga aaaaacaaaa ctgtaagtac ccttgttatc
1860caagcggcaa atgtgtcagc tttgtacaaa tgtgaagcgg tcaacaaagt
cgggagagga 1920gagagggtga tctccttcca cgtgaccagg ggtcctgaaa
ttactttgca acctgacatg 1980cagcccactg agcaggagag cgtgtctttg
tggtgcactg cagacagatc tacgtttgag 2040aacctcacat ggtacaagct
tggcccacag cctctgccaa tccatgtggg agagttgccc 2100acacctgttt
gcaagaactt ggatactctt tggaaattga atgccaccat gttctctaat
2160agcacaaatg acattttgat catggagctt aagaatgcat ccttgcagga
ccaaggagac 2220tatgtctgcc ttgctcaaga caggaagacc aagaaaagac
attgcgtggt caggcagctc 2280acagtcctag agcgtgtggc acccacgatc
acaggaaacc tggagaatca gacgacaagt 2340attggggaaa gcatcgaagt
ctcatgcacg gcatctggga atccccctcc acagatcatg 2400tggtttaaag
ataatgagac ccttgtagaa gactcaggca ttgtattgaa ggatgggaac
2460cggaacctca ctatccgcag agtgaggaag gaggacgaag gcctctacac
ctgccaggca 2520tgcagtgttc ttggctgtgc aaaagtggag gcatttttca
taatagaagg tgcccaggaa 2580aagacgaact tggaaatcat tattctagta
ggcacggcgg tgattgccat gttcttctgg 2640ctacttcttg tcatcatcct
acggaccgtt aagcgggcca atggagggga actgaagaca 2700ggctacttgt
ccatcgtcat ggatccagat gaactcccat tggatgaaca ttgtgaacga
2760ctgccttatg atgccagcaa atgggaattc cccagagacc ggctgaagct
aggtaagcct 2820cttggccgtg gtgcctttgg ccaagtgatt gaagcagatg
cctttggaat tgacaagaca 2880gcaacttgca ggacagtagc agtcaaaatg
ttgaaagaag gagcaacaca cagtgagcat 2940cgagctctca tgtctgaact
caagatcctc attcatattg gtcaccatct caatgtggtc 3000aaccttctag
gtgcctgtac caagccagga gggccactca tggtgattgt ggaattctgc
3060aaatttggaa acctgtccac ttacctgagg agcaagagaa atgaatttgt
cccctacaag 3120accaaagggg cacgattccg tcaagggaaa gactacgttg
gagcaatccc tgtggatctg 3180aaacggcgct tggacagcat caccagtagc
cagagctcag ccagctctgg atttgtggag 3240gagaagtccc tcagtgatgt
agaagaagag gaagctcctg aagatctgta taaggacttc 3300ctgaccttgg
agcatctcat ctgttacagc ttccaagtgg ctaagggcat ggagttcttg
3360gcatcgcgaa agtgtatcca cagggacctg
gcggcacgaa atatcctctt atcggagaag 3420aacgtggtta aaatctgtga
ctttggcttg gcccgggata tttataaaga tccagattat 3480gtcagaaaag
gagatgctcg cctccctttg aaatggatgg ccccagaaac aatttttgac
3540agagtgtaca caatccagag tgacgtctgg tcttttggtg ttttgctgtg
ggaaatattt 3600tccttaggtg cttctccata tcctggggta aagattgatg
aagaattttg taggcgattg 3660aaagaaggaa ctagaatgag ggcccctgat
tatactacac cagaaatgta ccagaccatg 3720ctggactgct ggcacgggga
gcccagtcag agacccacgt tttcagagtt ggtggaacat 3780ttgggaaatc
tcttgcaagc taatgctcag caggatggca aagactacat tgttcttccg
3840atatcagaga ctttgagcat ggaagaggat tctggactct ctctgcctac
ctcacctgtt 3900tcctgtatgg aggaggagga agtatgtgac cccaaattcc
attatgacaa cacagcagga 3960atcagtcagt atctgcagaa cagtaagcga
aagagccggc ctgtgagtgt aaaaacattt 4020gaagatatcc cgttagaaga
accagaagta aaagtaatcc cagatgacaa ccagacggac 4080agtggtatgg
ttcttgcctc agaagagctg aaaactttgg aagacagaac caaattatct
4140ccatcttttg gtggaatggt gcccagcaaa agcagggagt ctgtggcatc
tgaaggctca 4200aaccagacaa gcggctacca gtccggatat cactccgatg
acacagacac caccgtgtac 4260tccagtgagg aagcagaact tttaaagctg
atagagattg gagtgcaaac cggtagcaca 4320gcccagattc tccagcctga
ctcggggacc acactgagct ctcctcctgt ttaaaaggaa 4380gcatccacac
cccaactccc ggacatcaca tgagaggtct gctcagattt tgaagtgttg
4440ttctttccac cagcaggaag tagccgcatt tgattttcat ttcgacaaca
gaaaaaggac 4500ctcggactgc agggagccag tcttctaggc atatcctgga
agaggcttgt gacccaagaa 4560tgtgtctgtg tcttctccca gtgttgacct
gatcctcttt tttcattcat ttaaaaagca 4620ttatcatgcc cctgctgcgg
gtctcaccat gggtttagaa caaagagctt caagcaatgg 4680ccccatcctc
aaagaagtag cagtacctgg ggagctgaca cttctgtaaa actagaagat
4740aaaccaggca acgtaagtgt tcgaggtgtt gaagatggga aggatttgca
gggctgagtc 4800tatccaagag gctttgttta ggacgtgggt cccaagccaa
gccttaagtg tggaattcgg 4860attgatagaa aggaagacta acgttacctt
gctttggaga gtactggagc ctgcaaatgc 4920attgtgtttg ctctggtgga
ggtgggcatg gggtctgttc tgaaatgtaa agggttcaga 4980cggggtttct
ggttttagaa ggttgcgtgt tcttcgagtt gggctaaagt agagttcgtt
5040gtgctgtttc tgactcctaa tgagagttcc ttccagaccg ttagctgtct
ccttgccaag 5100ccccaggaag aaaatgatgc agctctggct ccttgtctcc
caggctgatc ctttattcag 5160aataccacaa agaaaggaca ttcagctcaa
ggctccctgc cgtgttgaag agttctgact 5220gcacaaacca gcttctggtt
tcttctggaa tgaataccct catatctgtc ctgatgtgat 5280atgtctgaga
ctgaatgcgg gaggttcaat gtgaagctgt gtgtggtgtc aaagtttcag
5340gaaggatttt acccttttgt tcttccccct gtccccaacc cactctcacc
ccgcaaccca 5400tcagtatttt agttatttgg cctctactcc agtaaacctg
attgggtttg ttcactctct 5460gaatgattat tagccagact tcaaaattat
tttatagccc aaattataac atctattgta 5520ttatttagac ttttaacata
tagagctatt tctactgatt tttgcccttg ttctgtcctt 5580tttttcaaaa
aagaaaatgt gttttttgtt tggtaccata gtgtgaaatg ctgggaacaa
5640tgactataag acatgctatg gcacatatat ttatagtctg tttatgtaga
aacaaatgta 5700atatattaaa gccttatata taatgaactt tgtactattc
acattttgta tcagtattat 5760gtagcataac aaaggtcata atgctttcag
caattgatgt cattttatta aagaacattg 5820aaaaacttga 5830211356PRTHomo
sapiens 21Met Gln Ser Lys Val Leu Leu Ala Val Ala Leu Trp Leu Cys
Val Glu 1 5 10 15 Thr Arg Ala Ala Ser Val Gly Leu Pro Ser Val Ser
Leu Asp Leu Pro 20 25 30 Arg Leu Ser Ile Gln Lys Asp Ile Leu Thr
Ile Lys Ala Asn Thr Thr 35 40 45 Leu Gln Ile Thr Cys Arg Gly Gln
Arg Asp Leu Asp Trp Leu Trp Pro 50 55 60 Asn Asn Gln Ser Gly Ser
Glu Gln Arg Val Glu Val Thr Glu Cys Ser 65 70 75 80 Asp Gly Leu Phe
Cys Lys Thr Leu Thr Ile Pro Lys Val Ile Gly Asn 85 90 95 Asp Thr
Gly Ala Tyr Lys Cys Phe Tyr Arg Glu Thr Asp Leu Ala Ser 100 105 110
Val Ile Tyr Val Tyr Val Gln Asp Tyr Arg Ser Pro Phe Ile Ala Ser 115
120 125 Val Ser Asp Gln His Gly Val Val Tyr Ile Thr Glu Asn Lys Asn
Lys 130 135 140 Thr Val Val Ile Pro Cys Leu Gly Ser Ile Ser Asn Leu
Asn Val Ser 145 150 155 160 Leu Cys Ala Arg Tyr Pro Glu Lys Arg Phe
Val Pro Asp Gly Asn Arg 165 170 175 Ile Ser Trp Asp Ser Lys Lys Gly
Phe Thr Ile Pro Ser Tyr Met Ile 180 185 190 Ser Tyr Ala Gly Met Val
Phe Cys Glu Ala Lys Ile Asn Asp Glu Ser 195 200 205 Tyr Gln Ser Ile
Met Tyr Ile Val Val Val Val Gly Tyr Arg Ile Tyr 210 215 220 Asp Val
Val Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val Gly Glu 225 230 235
240 Lys Leu Val Leu Asn Cys Thr Ala Arg Thr Glu Leu Asn Val Gly Ile
245 250 255 Asp Phe Asn Trp Glu Tyr Pro Ser Ser Lys His Gln His Lys
Lys Leu 260 265 270 Val Asn Arg Asp Leu Lys Thr Gln Ser Gly Ser Glu
Met Lys Lys Phe 275 280 285 Leu Ser Thr Leu Thr Ile Asp Gly Val Thr
Arg Ser Asp Gln Gly Leu 290 295 300 Tyr Thr Cys Ala Ala Ser Ser Gly
Leu Met Thr Lys Lys Asn Ser Thr 305 310 315 320 Phe Val Arg Val His
Glu Lys Pro Phe Val Ala Phe Gly Ser Gly Met 325 330 335 Glu Ser Leu
Val Glu Ala Thr Val Gly Glu Arg Val Arg Ile Pro Ala 340 345 350 Lys
Tyr Leu Gly Tyr Pro Pro Pro Glu Ile Lys Trp Tyr Lys Asn Gly 355 360
365 Ile Pro Leu Glu Ser Asn His Thr Ile Lys Ala Gly His Val Leu Thr
370 375 380 Ile Met Glu Val Ser Glu Arg Asp Thr Gly Asn Tyr Thr Val
Ile Leu 385 390 395 400 Thr Asn Pro Ile Ser Lys Glu Lys Gln Ser His
Val Val Ser Leu Val 405 410 415 Val Tyr Val Pro Pro Gln Ile Gly Glu
Lys Ser Leu Ile Ser Pro Val 420 425 430 Asp Ser Tyr Gln Tyr Gly Thr
Thr Gln Thr Leu Thr Cys Thr Val Tyr 435 440 445 Ala Ile Pro Pro Pro
His His Ile His Trp Tyr Trp Gln Leu Glu Glu 450 455 460 Glu Cys Ala
Asn Glu Pro Ser Gln Ala Val Ser Val Thr Asn Pro Tyr 465 470 475 480
Pro Cys Glu Glu Trp Arg Ser Val Glu Asp Phe Gln Gly Gly Asn Lys 485
490 495 Ile Glu Val Asn Lys Asn Gln Phe Ala Leu Ile Glu Gly Lys Asn
Lys 500 505 510 Thr Val Ser Thr Leu Val Ile Gln Ala Ala Asn Val Ser
Ala Leu Tyr 515 520 525 Lys Cys Glu Ala Val Asn Lys Val Gly Arg Gly
Glu Arg Val Ile Ser 530 535 540 Phe His Val Thr Arg Gly Pro Glu Ile
Thr Leu Gln Pro Asp Met Gln 545 550 555 560 Pro Thr Glu Gln Glu Ser
Val Ser Leu Trp Cys Thr Ala Asp Arg Ser 565 570 575 Thr Phe Glu Asn
Leu Thr Trp Tyr Lys Leu Gly Pro Gln Pro Leu Pro 580 585 590 Ile His
Val Gly Glu Leu Pro Thr Pro Val Cys Lys Asn Leu Asp Thr 595 600 605
Leu Trp Lys Leu Asn Ala Thr Met Phe Ser Asn Ser Thr Asn Asp Ile 610
615 620 Leu Ile Met Glu Leu Lys Asn Ala Ser Leu Gln Asp Gln Gly Asp
Tyr 625 630 635 640 Val Cys Leu Ala Gln Asp Arg Lys Thr Lys Lys Arg
His Cys Val Val 645 650 655 Arg Gln Leu Thr Val Leu Glu Arg Val Ala
Pro Thr Ile Thr Gly Asn 660 665 670 Leu Glu Asn Gln Thr Thr Ser Ile
Gly Glu Ser Ile Glu Val Ser Cys 675 680 685 Thr Ala Ser Gly Asn Pro
Pro Pro Gln Ile Met Trp Phe Lys Asp Asn 690 695 700 Glu Thr Leu Val
Glu Asp Ser Gly Ile Val Leu Lys Asp Gly Asn Arg 705 710 715 720 Asn
Leu Thr Ile Arg Arg Val Arg Lys Glu Asp Glu Gly Leu Tyr Thr 725 730
735 Cys Gln Ala Cys Ser Val Leu Gly Cys Ala Lys Val Glu Ala Phe Phe
740 745 750 Ile Ile Glu Gly Ala Gln Glu Lys Thr Asn Leu Glu Ile Ile
Ile Leu 755 760 765 Val Gly Thr Ala Val Ile Ala Met Phe Phe Trp Leu
Leu Leu Val Ile 770 775 780 Ile Leu Arg Thr Val Lys Arg Ala Asn Gly
Gly Glu Leu Lys Thr Gly 785 790 795 800 Tyr Leu Ser Ile Val Met Asp
Pro Asp Glu Leu Pro Leu Asp Glu His 805 810 815 Cys Glu Arg Leu Pro
Tyr Asp Ala Ser Lys Trp Glu Phe Pro Arg Asp 820 825 830 Arg Leu Lys
Leu Gly Lys Pro Leu Gly Arg Gly Ala Phe Gly Gln Val 835 840 845 Ile
Glu Ala Asp Ala Phe Gly Ile Asp Lys Thr Ala Thr Cys Arg Thr 850 855
860 Val Ala Val Lys Met Leu Lys Glu Gly Ala Thr His Ser Glu His Arg
865 870 875 880 Ala Leu Met Ser Glu Leu Lys Ile Leu Ile His Ile Gly
His His Leu 885 890 895 Asn Val Val Asn Leu Leu Gly Ala Cys Thr Lys
Pro Gly Gly Pro Leu 900 905 910 Met Val Ile Val Glu Phe Cys Lys Phe
Gly Asn Leu Ser Thr Tyr Leu 915 920 925 Arg Ser Lys Arg Asn Glu Phe
Val Pro Tyr Lys Thr Lys Gly Ala Arg 930 935 940 Phe Arg Gln Gly Lys
Asp Tyr Val Gly Ala Ile Pro Val Asp Leu Lys 945 950 955 960 Arg Arg
Leu Asp Ser Ile Thr Ser Ser Gln Ser Ser Ala Ser Ser Gly 965 970 975
Phe Val Glu Glu Lys Ser Leu Ser Asp Val Glu Glu Glu Glu Ala Pro 980
985 990 Glu Asp Leu Tyr Lys Asp Phe Leu Thr Leu Glu His Leu Ile Cys
Tyr 995 1000 1005 Ser Phe Gln Val Ala Lys Gly Met Glu Phe Leu Ala
Ser Arg Lys 1010 1015 1020 Cys Ile His Arg Asp Leu Ala Ala Arg Asn
Ile Leu Leu Ser Glu 1025 1030 1035 Lys Asn Val Val Lys Ile Cys Asp
Phe Gly Leu Ala Arg Asp Ile 1040 1045 1050 Tyr Lys Asp Pro Asp Tyr
Val Arg Lys Gly Asp Ala Arg Leu Pro 1055 1060 1065 Leu Lys Trp Met
Ala Pro Glu Thr Ile Phe Asp Arg Val Tyr Thr 1070 1075 1080 Ile Gln
Ser Asp Val Trp Ser Phe Gly Val Leu Leu Trp Glu Ile 1085 1090 1095
Phe Ser Leu Gly Ala Ser Pro Tyr Pro Gly Val Lys Ile Asp Glu 1100
1105 1110 Glu Phe Cys Arg Arg Leu Lys Glu Gly Thr Arg Met Arg Ala
Pro 1115 1120 1125 Asp Tyr Thr Thr Pro Glu Met Tyr Gln Thr Met Leu
Asp Cys Trp 1130 1135 1140 His Gly Glu Pro Ser Gln Arg Pro Thr Phe
Ser Glu Leu Val Glu 1145 1150 1155 His Leu Gly Asn Leu Leu Gln Ala
Asn Ala Gln Gln Asp Gly Lys 1160 1165 1170 Asp Tyr Ile Val Leu Pro
Ile Ser Glu Thr Leu Ser Met Glu Glu 1175 1180 1185 Asp Ser Gly Leu
Ser Leu Pro Thr Ser Pro Val Ser Cys Met Glu 1190 1195 1200 Glu Glu
Glu Val Cys Asp Pro Lys Phe His Tyr Asp Asn Thr Ala 1205 1210 1215
Gly Ile Ser Gln Tyr Leu Gln Asn Ser Lys Arg Lys Ser Arg Pro 1220
1225 1230 Val Ser Val Lys Thr Phe Glu Asp Ile Pro Leu Glu Glu Pro
Glu 1235 1240 1245 Val Lys Val Ile Pro Asp Asp Asn Gln Thr Asp Ser
Gly Met Val 1250 1255 1260 Leu Ala Ser Glu Glu Leu Lys Thr Leu Glu
Asp Arg Thr Lys Leu 1265 1270 1275 Ser Pro Ser Phe Gly Gly Met Val
Pro Ser Lys Ser Arg Glu Ser 1280 1285 1290 Val Ala Ser Glu Gly Ser
Asn Gln Thr Ser Gly Tyr Gln Ser Gly 1295 1300 1305 Tyr His Ser Asp
Asp Thr Asp Thr Thr Val Tyr Ser Ser Glu Glu 1310 1315 1320 Ala Glu
Leu Leu Lys Leu Ile Glu Ile Gly Val Gln Thr Gly Ser 1325 1330 1335
Thr Ala Gln Ile Leu Gln Pro Asp Ser Gly Thr Thr Leu Ser Ser 1340
1345 1350 Pro Pro Val 1355 2216PRTHomo sapiens 22Cys Asn Asp Glu
Gly Leu Glu Cys Val Pro Thr Glu Glu Ser Asn Ile 1 5 10 15
2316PRTHomo sapiens 23Cys Pro Asp Asp Gly Leu Glu Cys Val Pro Thr
Gly Gln His Gln Val 1 5 10 15 241676PRTHomo sapiens 24Met Gly Leu
Leu Gly Ile Leu Cys Phe Leu Ile Phe Leu Gly Lys Thr 1 5 10 15 Trp
Gly Gln Glu Gln Thr Tyr Val Ile Ser Ala Pro Lys Ile Phe Arg 20 25
30 Val Gly Ala Ser Glu Asn Ile Val Ile Gln Val Tyr Gly Tyr Thr Glu
35 40 45 Ala Phe Asp Ala Thr Ile Ser Ile Lys Ser Tyr Pro Asp Lys
Lys Phe 50 55 60 Ser Tyr Ser Ser Gly His Val His Leu Ser Ser Glu
Asn Lys Phe Gln 65 70 75 80 Asn Ser Ala Ile Leu Thr Ile Gln Pro Lys
Gln Leu Pro Gly Gly Gln 85 90 95 Asn Pro Val Ser Tyr Val Tyr Leu
Glu Val Val Ser Lys His Phe Ser 100 105 110 Lys Ser Lys Arg Met Pro
Ile Thr Tyr Asp Asn Gly Phe Leu Phe Ile 115 120 125 His Thr Asp Lys
Pro Val Tyr Thr Pro Asp Gln Ser Val Lys Val Arg 130 135 140 Val Tyr
Ser Leu Asn Asp Asp Leu Lys Pro Ala Lys Arg Glu Thr Val 145 150 155
160 Leu Thr Phe Ile Asp Pro Glu Gly Ser Glu Val Asp Met Val Glu Glu
165 170 175 Ile Asp His Ile Gly Ile Ile Ser Phe Pro Asp Phe Lys Ile
Pro Ser 180 185 190 Asn Pro Arg Tyr Gly Met Trp Thr Ile Lys Ala Lys
Tyr Lys Glu Asp 195 200 205 Phe Ser Thr Thr Gly Thr Ala Tyr Phe Glu
Val Lys Glu Tyr Val Leu 210 215 220 Pro His Phe Ser Val Ser Ile Glu
Pro Glu Tyr Asn Phe Ile Gly Tyr 225 230 235 240 Lys Asn Phe Lys Asn
Phe Glu Ile Thr Ile Lys Ala Arg Tyr Phe Tyr 245 250 255 Asn Lys Val
Val Thr Glu Ala Asp Val Tyr Ile Thr Phe Gly Ile Arg 260 265 270 Glu
Asp Leu Lys Asp Asp Gln Lys Glu Met Met Gln Thr Ala Met Gln 275 280
285 Asn Thr Met Leu Ile Asn Gly Ile Ala Gln Val Thr Phe Asp Ser Glu
290 295 300 Thr Ala Val Lys Glu Leu Ser Tyr Tyr Ser Leu Glu Asp Leu
Asn Asn 305 310 315 320 Lys Tyr Leu Tyr Ile Ala Val Thr Val Ile Glu
Ser Thr Gly Gly Phe 325 330 335 Ser Glu Glu Ala Glu Ile Pro Gly Ile
Lys Tyr Val Leu Ser Pro Tyr 340 345 350 Lys Leu Asn Leu Val Ala Thr
Pro Leu Phe Leu Lys Pro Gly Ile Pro 355 360 365 Tyr Pro Ile Lys Val
Gln Val Lys Asp Ser Leu Asp Gln Leu Val Gly 370 375 380 Gly Val Pro
Val Thr Leu Asn Ala Gln Thr Ile Asp Val Asn Gln Glu 385 390 395 400
Thr Ser Asp Leu Asp Pro Ser Lys Ser Val Thr Arg Val Asp Asp Gly 405
410 415 Val Ala Ser Phe Val Leu Asn Leu Pro Ser Gly Val Thr Val Leu
Glu 420 425 430 Phe Asn Val Lys Thr Asp Ala Pro Asp Leu Pro Glu Glu
Asn Gln Ala 435 440 445 Arg Glu Gly Tyr Arg Ala Ile Ala Tyr Ser Ser
Leu Ser Gln Ser Tyr 450 455 460 Leu Tyr Ile Asp Trp Thr Asp Asn His
Lys Ala Leu Leu Val Gly Glu 465 470 475 480 His Leu Asn Ile Ile Val
Thr Pro Lys Ser Pro Tyr Ile Asp Lys Ile 485 490 495 Thr His Tyr Asn
Tyr Leu Ile Leu Ser Lys Gly Lys Ile Ile His Phe 500
505 510 Gly Thr Arg Glu Lys Phe Ser Asp Ala Ser Tyr Gln Ser Ile Asn
Ile 515 520 525 Pro Val Thr Gln Asn Met Val Pro Ser Ser Arg Leu Leu
Val Tyr Tyr 530 535 540 Ile Val Thr Gly Glu Gln Thr Ala Glu Leu Val
Ser Asp Ser Val Trp 545 550 555 560 Leu Asn Ile Glu Glu Lys Cys Gly
Asn Gln Leu Gln Val His Leu Ser 565 570 575 Pro Asp Ala Asp Ala Tyr
Ser Pro Gly Gln Thr Val Ser Leu Asn Met 580 585 590 Ala Thr Gly Met
Asp Ser Trp Val Ala Leu Ala Ala Val Asp Ser Ala 595 600 605 Val Tyr
Gly Val Gln Arg Gly Ala Lys Lys Pro Leu Glu Arg Val Phe 610 615 620
Gln Phe Leu Glu Lys Ser Asp Leu Gly Cys Gly Ala Gly Gly Gly Leu 625
630 635 640 Asn Asn Ala Asn Val Phe His Leu Ala Gly Leu Thr Phe Leu
Thr Asn 645 650 655 Ala Asn Ala Asp Asp Ser Gln Glu Asn Asp Glu Pro
Cys Lys Glu Ile 660 665 670 Leu Arg Pro Arg Arg Thr Leu Gln Lys Lys
Ile Glu Glu Ile Ala Ala 675 680 685 Lys Tyr Lys His Ser Val Val Lys
Lys Cys Cys Tyr Asp Gly Ala Cys 690 695 700 Val Asn Asn Asp Glu Thr
Cys Glu Gln Arg Ala Ala Arg Ile Ser Leu 705 710 715 720 Gly Pro Arg
Cys Ile Lys Ala Phe Thr Glu Cys Cys Val Val Ala Ser 725 730 735 Gln
Leu Arg Ala Asn Ile Ser His Lys Asp Met Gln Leu Gly Arg Leu 740 745
750 His Met Lys Thr Leu Leu Pro Val Ser Lys Pro Glu Ile Arg Ser Tyr
755 760 765 Phe Pro Glu Ser Trp Leu Trp Glu Val His Leu Val Pro Arg
Arg Lys 770 775 780 Gln Leu Gln Phe Ala Leu Pro Asp Ser Leu Thr Thr
Trp Glu Ile Gln 785 790 795 800 Gly Val Gly Ile Ser Asn Thr Gly Ile
Cys Val Ala Asp Thr Val Lys 805 810 815 Ala Lys Val Phe Lys Asp Val
Phe Leu Glu Met Asn Ile Pro Tyr Ser 820 825 830 Val Val Arg Gly Glu
Gln Ile Gln Leu Lys Gly Thr Val Tyr Asn Tyr 835 840 845 Arg Thr Ser
Gly Met Gln Phe Cys Val Lys Met Ser Ala Val Glu Gly 850 855 860 Ile
Cys Thr Ser Glu Ser Pro Val Ile Asp His Gln Gly Thr Lys Ser 865 870
875 880 Ser Lys Cys Val Arg Gln Lys Val Glu Gly Ser Ser Ser His Leu
Val 885 890 895 Thr Phe Thr Val Leu Pro Leu Glu Ile Gly Leu His Asn
Ile Asn Phe 900 905 910 Ser Leu Glu Thr Trp Phe Gly Lys Glu Ile Leu
Val Lys Thr Leu Arg 915 920 925 Val Val Pro Glu Gly Val Lys Arg Glu
Ser Tyr Ser Gly Val Thr Leu 930 935 940 Asp Pro Arg Gly Ile Tyr Gly
Thr Ile Ser Arg Arg Lys Glu Phe Pro 945 950 955 960 Tyr Arg Ile Pro
Leu Asp Leu Val Pro Lys Thr Glu Ile Lys Arg Ile 965 970 975 Leu Ser
Val Lys Gly Leu Leu Val Gly Glu Ile Leu Ser Ala Val Leu 980 985 990
Ser Gln Glu Gly Ile Asn Ile Leu Thr His Leu Pro Lys Gly Ser Ala 995
1000 1005 Glu Ala Glu Leu Met Ser Val Val Pro Val Phe Tyr Val Phe
His 1010 1015 1020 Tyr Leu Glu Thr Gly Asn His Trp Asn Ile Phe His
Ser Asp Pro 1025 1030 1035 Leu Ile Glu Lys Gln Lys Leu Lys Lys Lys
Leu Lys Glu Gly Met 1040 1045 1050 Leu Ser Ile Met Ser Tyr Arg Asn
Ala Asp Tyr Ser Tyr Ser Val 1055 1060 1065 Trp Lys Gly Gly Ser Ala
Ser Thr Trp Leu Thr Ala Phe Ala Leu 1070 1075 1080 Arg Val Leu Gly
Gln Val Asn Lys Tyr Val Glu Gln Asn Gln Asn 1085 1090 1095 Ser Ile
Cys Asn Ser Leu Leu Trp Leu Val Glu Asn Tyr Gln Leu 1100 1105 1110
Asp Asn Gly Ser Phe Lys Glu Asn Ser Gln Tyr Gln Pro Ile Lys 1115
1120 1125 Leu Gln Gly Thr Leu Pro Val Glu Ala Arg Glu Asn Ser Leu
Tyr 1130 1135 1140 Leu Thr Ala Phe Thr Val Ile Gly Ile Arg Lys Ala
Phe Asp Ile 1145 1150 1155 Cys Pro Leu Val Lys Ile Asp Thr Ala Leu
Ile Lys Ala Asp Asn 1160 1165 1170 Phe Leu Leu Glu Asn Thr Leu Pro
Ala Gln Ser Thr Phe Thr Leu 1175 1180 1185 Ala Ile Ser Ala Tyr Ala
Leu Ser Leu Gly Asp Lys Thr His Pro 1190 1195 1200 Gln Phe Arg Ser
Ile Val Ser Ala Leu Lys Arg Glu Ala Leu Val 1205 1210 1215 Lys Gly
Asn Pro Pro Ile Tyr Arg Phe Trp Lys Asp Asn Leu Gln 1220 1225 1230
His Lys Asp Ser Ser Val Pro Asn Thr Gly Thr Ala Arg Met Val 1235
1240 1245 Glu Thr Thr Ala Tyr Ala Leu Leu Thr Ser Leu Asn Leu Lys
Asp 1250 1255 1260 Ile Asn Tyr Val Asn Pro Val Ile Lys Trp Leu Ser
Glu Glu Gln 1265 1270 1275 Arg Tyr Gly Gly Gly Phe Tyr Ser Thr Gln
Asp Thr Ile Asn Ala 1280 1285 1290 Ile Glu Gly Leu Thr Glu Tyr Ser
Leu Leu Val Lys Gln Leu Arg 1295 1300 1305 Leu Ser Met Asp Ile Asp
Val Ser Tyr Lys His Lys Gly Ala Leu 1310 1315 1320 His Asn Tyr Lys
Met Thr Asp Lys Asn Phe Leu Gly Arg Pro Val 1325 1330 1335 Glu Val
Leu Leu Asn Asp Asp Leu Ile Val Ser Thr Gly Phe Gly 1340 1345 1350
Ser Gly Leu Ala Thr Val His Val Thr Thr Val Val His Lys Thr 1355
1360 1365 Ser Thr Ser Glu Glu Val Cys Ser Phe Tyr Leu Lys Ile Asp
Thr 1370 1375 1380 Gln Asp Ile Glu Ala Ser His Tyr Arg Gly Tyr Gly
Asn Ser Asp 1385 1390 1395 Tyr Lys Arg Ile Val Ala Cys Ala Ser Tyr
Lys Pro Ser Arg Glu 1400 1405 1410 Glu Ser Ser Ser Gly Ser Ser His
Ala Val Met Asp Ile Ser Leu 1415 1420 1425 Pro Thr Gly Ile Ser Ala
Asn Glu Glu Asp Leu Lys Ala Leu Val 1430 1435 1440 Glu Gly Val Asp
Gln Leu Phe Thr Asp Tyr Gln Ile Lys Asp Gly 1445 1450 1455 His Val
Ile Leu Gln Leu Asn Ser Ile Pro Ser Ser Asp Phe Leu 1460 1465 1470
Cys Val Arg Phe Arg Ile Phe Glu Leu Phe Glu Val Gly Phe Leu 1475
1480 1485 Ser Pro Ala Thr Phe Thr Val Tyr Glu Tyr His Arg Pro Asp
Lys 1490 1495 1500 Gln Cys Thr Met Phe Tyr Ser Thr Ser Asn Ile Lys
Ile Gln Lys 1505 1510 1515 Val Cys Glu Gly Ala Ala Cys Lys Cys Val
Glu Ala Asp Cys Gly 1520 1525 1530 Gln Met Gln Glu Glu Leu Asp Leu
Thr Ile Ser Ala Glu Thr Arg 1535 1540 1545 Lys Gln Thr Ala Cys Lys
Pro Glu Ile Ala Tyr Ala Tyr Lys Val 1550 1555 1560 Ser Ile Thr Ser
Ile Thr Val Glu Asn Val Phe Val Lys Tyr Lys 1565 1570 1575 Ala Thr
Leu Leu Asp Ile Tyr Lys Thr Gly Glu Ala Val Ala Glu 1580 1585 1590
Lys Asp Ser Glu Ile Thr Phe Ile Lys Lys Val Thr Cys Thr Asn 1595
1600 1605 Ala Glu Leu Val Lys Gly Arg Gln Tyr Leu Ile Met Gly Lys
Glu 1610 1615 1620 Ala Leu Gln Ile Lys Tyr Asn Phe Ser Phe Arg Tyr
Ile Tyr Pro 1625 1630 1635 Leu Asp Ser Leu Thr Trp Ile Glu Tyr Trp
Pro Arg Asp Thr Thr 1640 1645 1650 Cys Ser Ser Cys Gln Ala Phe Leu
Ala Asn Leu Asp Glu Phe Ala 1655 1660 1665 Glu Asp Ile Phe Leu Asn
Gly Cys 1670 1675 2542RNAArtificial SequenceSynthetic C5 specific
aptamer 25gacgaugcgg ucucaugcgu cgagugugag uuuaccuucg uc
422638DNAArtificial SequenceSynthetic C5 specific aptamer
26cgccgcgguc ucaggcgcug agucugaguu accugcgt 382744RNAArtificial
SequenceSynthetic C5 specific aptamer 27aggacgaugc ggucucaugc
gucgagugug aguuuaccuu cguc 442840RNAArtificial SequenceSynthetic C5
specific aptamer 28agcgccgcgg ucucaggcgc ugagucugag uuuaccugcg
402946RNAArtificial SequenceSynthetic C5 specific aptamer
29ggcgauuacu gggacggacu cgcgauguga gcccagacga cucgcc
463040RNAArtificial SequenceSynthetic C5 specific aptamer
30ggcuucugaa gauuauuucg cgaugugaac uccagacccc 403140RNAArtificial
SequenceSynthetic C5 specific aptamer 31ggcgccgcgg ucucaggcgc
ugagucugag uuuaccugcg 403239DNAArtificial SequenceSynthetic C5
specific aptamer 32cgccgcgguc tcaggcgcug agtctgaguu uaccugcgt
393339DNAArtificial SequenceSynthetic C5 specific aptamer
33cgccgcgguc tcaggcgcug agtctgaguu uaccugcgt 393438DNAArtificial
SequenceSynthetic C5 specific aptamer 34cgccgcgguc tcaggcgcug
agtctgaguu uaccugcg 383538DNAArtificial SequenceSynthetic C5
specific aptamer 35cgccgcgguc tcaggcgcug agtctgaguu uaccugcg
383638DNAArtificial SequenceSynthetic C5 specific aptamer
36cgccgcgguc tcaggcgcug agtctgaguu uaccugcg 383738DNAArtificial
SequenceSynthetic C5 specific aptamer 37cgccgcgguc tcaggcgcug
agtctgaguu uaccugcg 383838DNAArtificial SequenceSynthetic C5
specific aptamer 38cgccgcgguc tcaggcgcug agtctgaguu uaccugcg
383938DNAArtificial SequenceSynthetic C5 specific aptamer
39cgccgcgguc tcaggcgcug agtctgaguu uaccugcg 384037DNAArtificial
SequenceSynthetic C5 specific aptamer 40cgccgcgguc tcaggcgcug
agtctgaguu uacugcg 374138DNAArtificial SequenceSynthetic C5
specific aptamer 41cgccgcgguc tcaggcgcug agtctgaguu uaccugcg
384237DNAArtificial SequenceSynthetic C5 specific aptamer
42cgccgcgguc tcaggcgcug agtctgaguu uacugcg 374338DNAArtificial
SequenceSynthetic C5 specific aptamer 43cgccgcgguc tcaggcgcug
agtctgaguu uaccugcg 384438DNAArtificial SequenceSynthetic C5
specific aptamer 44cgccgcgguc tcaggcgcug agtctgaguu uaccugcg
384538DNAArtificial SequenceSynthetic C5 specific aptamer
45cgccgcgguc tcaggcgcug agtctgaguu uaccugcg 384638DNAArtificial
SequenceSynthetic C5 specific aptamer 46cgccgcgguc tcaggcgcug
agtctgaguu uaccugcg 384738DNAArtificial SequenceSynthetic C5
specific aptamer 47cgccgcgguc tcaggcgctg agtctgaguu uaccugcg
384838DNAArtificial SequenceSynthetic C5 specific aptamer
48cgccgcgguc tcaggcgctg agtctgaguu uaccugcg 384938DNAArtificial
SequenceSynthetic C5 specific aptamer 49cgccgcgguc tcaggcgcug
agtctgagtu uaccugcg 385038DNAArtificial SequenceSynthetic C5
specific aptamer 50cgccgcgguc tcaggcgcug agtctgagut uaccugcg
385138DNAArtificial SequenceSynthetic C5 specific aptamer
51cgccgcgguc tcaggcgcug agtctgaguu taccugcg 385238DNAArtificial
SequenceSynthetic C5 specific aptamer 52cgccgcgguc tcaggcgcug
agtctgagtt taccugcg 385338DNAArtificial SequenceSynthetic C5
specific aptamer 53cgccgcgguc tcaggcgcug agtctgaguu uacctgcg
385438DNAArtificial SequenceSynthetic C5 specific aptamer
54cgccgcgguc tcaggcgcug agtctgaguu uaccugcg 385538DNAArtificial
SequenceSynthetic C5 specific aptamer 55cgccgcgguc tcaggcgcug
agtctgaguu uaccugcg 385638DNAArtificial SequenceSynthetic C5
specific aptamer 56cgccgcgguc tcaggcgcug agtctgaguu uaccugcg
385738DNAArtificial SequenceSynthetic C5 specific aptamer
57cgccgcgguc tcaggcgcug agtctgaguu uaccugcg 385837DNAArtificial
SequenceSynthetic C5 specific aptamer 58cgcgcggucu caggcgcuga
gucugaguuu accugcg 375938DNAArtificial SequenceSynthetic C5
specific aptamer 59cgccgcgguc ucaggcgcug agucugaguu uaccugcg
386038DNAArtificial SequenceSynthetic C5 specific aptamer
60cgccgcgguc ucaggcgcug agucugaguu uaccugcg 386138DNAArtificial
SequenceSynthetic C5 specific aptamer 61cgccgcgguc tcaggcgcug
agtctgaguu uaccugcg 386238DNAArtificial SequenceSynthetic C5
specific aptamer 62cgccgcgguc tcaggcgcug agtctgaguu uaccugcg
386338DNAArtificial SequenceSynthetic C5 specific aptamer
63cgccgcgguc tcaggcgcug agtctgaguu uaccugcg 386438DNAArtificial
SequenceSynthetic C5 specific aptamer 64cgccgcgguc tcaggcgcug
agtctgaguu uaccugcg 386538DNAArtificial SequenceSynthetic C5
specific aptamer 65cgccgcgguc tcaggcgcug agtctgaguu uaccugcg
386638DNAArtificial SequenceSynthetic C5 specific aptamer
66cgccgcgguc tcaggcgcug agtctgaguu uaccugcg 386738DNAArtificial
SequenceSynthetic C5 specific aptamer 67cgccgcgguc tcaggcgcug
agtctgaguu uaccugcg 386838DNAArtificial SequenceSynthetic C5
specific aptamer 68cgccgcgguc tcaggcgcug agtctgaguu uaccugcg
386940DNAArtificial SequenceSynthetic C5 specific aptamer
69gcgucgcggu ctcaggcgcu gagtctgagu uuaccuacgc 407038DNAArtificial
SequenceSynthetic C5 specific aptamer 70gggcgcgguc tcaggcgcug
agtctgaguu uaccuccc 387139DNAArtificial SequenceSynthetic C5
specific aptamer 71gcgccgcggu ctcaggcgcu gagtctgagu uuacugcgc
397243DNAArtificial SequenceSynthetic C5 specific aptamer
72ggacgccgcg gucucaggcg cugagucugg uuuacugcgu cut
437342DNAArtificial SequenceSynthetic C5 specific aptamer
73ggcgccgcgg uctcaggcgc ugagtctgag tuuacctgcg cc
427440DNAArtificial SequenceSynthetic C5 specific aptamer
74ggcgccgcgg uctcaggcgc ugagtctgat tacctgcgcc 407542DNAArtificial
SequenceSynthetic C5 specific aptamer 75ggcgccgcgg tctcaggcgc
ugagtctgag tttacctgcg cc 427642DNAArtificial SequenceSynthetic C5
specific aptamer 76ggcgccgcgg tcucaggcgc ugagucugag tttacctgcg cc
427740RNAArtificial SequenceSynthetic C5 specific aptamer
77agcgccgcgg ucucaggcgc ugagucugag uuuaccugcg 407842DNAArtificial
SequenceSynthetic C5 specific aptamer 78ggcgccgcgg uctcaggcgc
ugagtctgag uuuaccugcg cc 427942RNAArtificial SequenceSynthetic C5
specific aptamer 79ggcgccgcgg ucucaggcgc ugagucugag uuuaccugcg cc
428039DNAArtificial SequenceSynthetic C5 specific aptamer
80cgccgcgguc ucaggcgcug agucugaguu uaccugcgt 398139DNAArtificial
SequenceSynthetic C5 specific aptamer 81cgccgcgguc ucaggcgcug
agucugaguu uaccugcgt 398239DNAArtificial SequenceSynthetic C5
specific aptamer 82cgccgcgguc ucaggcgcug agucugagtu uaccugcgt
398339DNAArtificial SequenceSynthetic C5 specific aptamer
83cgccgcgguc ucaggcgcug agucugaguu uaccugcgt 398439DNAArtificial
SequenceSynthetic C5 specific aptamer 84cgccgcgguc ucaggcgcug
agucugagtu uaccugcgt
398539DNAArtificial SequenceSynthetic C5 specific aptamer
85cgccgcgguc ucaggcgcug agucugaguu uaccugcgt 398639DNAArtificial
SequenceSynthetic C5 specific aptamer 86cgccgcgguc ucaggcgcug
agucugaguu uaccugcgt 398739DNAArtificial SequenceSynthetic C5
specific aptamer 87cgccgcgguc ucaggcgcug agucugaguu uaccugcgt
398839DNAArtificial SequenceSynthetic C5 specific aptamer
88cgccgcgguc ucaggcgcug agucugaguu uaccugcgt 398975RNAArtificial
SequenceSynthetic C5 specific aptamer 89gggagaggag agaacguucu
accuugguuu ggcacaggca uacauacgca ggggucgauc 60gaucgaucau cgaug
759032RNAArtificial SequenceSynthetic C5 specific aptamer
90ccuugguuug gcacaggcau acauacgcag gg 329147RNAArtificial
SequenceSynthetic C5 specific aptamer 91cguucuaccu ugguuuggca
caggcauaca uacgcagggg ucgaucg 479239DNAArtificial SequenceSynthetic
C5 specific aptamer 92cgccgcgguc ucaggcgcug agucugaguu uaccugcgt
399338RNAArtificial SequenceSynthetic C5 specific aptamer
93cgccgcgguc ucaggcgcug agucugaguu uaccugcg 389480RNAArtificial
SequenceSynthetic C5 specific aptamer 94gggagaggag agaacguucu
accuugguuu ggcccaggca uauauacgca gggauugauc 60cguuacgacu agcaucgaug
809579RNAArtificial SequenceSynthetic C5 specific aptamer
95gggagaggag agaacguucu accuuagguu cgcacuguca uacauacaca cgggcaaucg
60guuacgacua gcaucgaug 799675RNAArtificial SequenceSynthetic C5
specific aptamer 96gggagaggag agaacguucu accuugguuu ggcncaggca
uanauacgca cgggucgauc 60gguuacgacu agcau 7597126PRTUnknownankyrin
binding domain 97Gly Ser Asp Leu Gly Lys Lys Leu Leu Glu Ala Ala
Arg Ala Gly Gln 1 5 10 15 Asp Asp Glu Val Arg Ile Leu Met Ala Asn
Gly Ala Asp Val Asn Thr 20 25 30 Ala Asp Ser Thr Gly Trp Thr Pro
Leu His Leu Ala Val Pro Trp Gly 35 40 45 His Leu Glu Ile Val Glu
Val Leu Leu Lys Tyr Gly Ala Asp Val Asn 50 55 60 Ala Lys Asp Phe
Gln Gly Trp Thr Pro Leu His Leu Ala Ala Ala Ile 65 70 75 80 Gly His
Gln Glu Ile Val Glu Val Leu Leu Lys Asn Gly Ala Asp Val 85 90 95
Asn Ala Gln Asp Lys Phe Gly Lys Thr Ala Phe Asp Ile Ser Ile Asp 100
105 110 Asn Gly Asn Glu Asp Leu Ala Glu Ile Leu Gln Lys Ala Ala 115
120 125 98552PRTArtificial Sequencerecombinant human soluble VEGF
receptor fusion protein 98Met Val Ser Tyr Trp Asp Thr Gly Val Leu
Leu Cys Ala Leu Leu Ser 1 5 10 15 Cys Leu Leu Leu Thr Gly Ser Ser
Ser Gly Gly Arg Pro Phe Val Glu 20 25 30 Met Tyr Ser Glu Ile Pro
Glu Ile Ile His Met Thr Glu Gly Arg Glu 35 40 45 Leu Val Ile Pro
Cys Arg Val Thr Ser Pro Asn Ile Thr Val Thr Leu 50 55 60 Lys Lys
Phe Pro Leu Asp Thr Leu Ile Pro Asp Gly Lys Arg Ile Ile 65 70 75 80
Trp Asp Ser Arg Lys Gly Phe Ile Ile Ser Asn Ala Thr Tyr Lys Glu 85
90 95 Ile Gly Leu Leu Thr Cys Glu Ala Thr Val Asn Gly His Leu Tyr
Lys 100 105 110 Thr Asn Tyr Leu Thr His Arg Gln Thr Asn Thr Ile Ile
Asp Val Val 115 120 125 Leu Ser Pro Ser His Gly Ile Glu Leu Ser Val
Gly Glu Lys Leu Val 130 135 140 Leu Asn Cys Thr Ala Arg Thr Glu Leu
Asn Val Gly Ile Asp Phe Asn 145 150 155 160 Trp Glu Tyr Pro Ser Ser
Lys His Gln His Lys Lys Leu Val Asn Arg 165 170 175 Asp Leu Lys Thr
Gln Ser Gly Ser Glu Met Lys Lys Phe Leu Ser Thr 180 185 190 Leu Thr
Ile Asp Gly Val Thr Arg Ser Asp Gln Gly Leu Tyr Thr Cys 195 200 205
Ala Ala Ser Ser Gly Leu Met Thr Lys Lys Asn Ser Thr Phe Val Arg 210
215 220 Val His Glu Lys Pro Phe Val Ala Phe Gly Ser Gly Met Glu Ser
Leu 225 230 235 240 Val Glu Ala Thr Val Gly Glu Arg Val Arg Leu Pro
Ala Lys Tyr Leu 245 250 255 Gly Tyr Pro Pro Pro Glu Ile Lys Trp Tyr
Lys Asn Gly Ile Pro Leu 260 265 270 Glu Ser Asn His Thr Ile Lys Ala
Gly His Val Leu Thr Ile Met Glu 275 280 285 Val Ser Glu Arg Asp Thr
Gly Asn Tyr Thr Val Ile Leu Thr Asn Pro 290 295 300 Ile Ser Lys Glu
Lys Gln Ser His Val Val Ser Leu Val Val Tyr Val 305 310 315 320 Pro
Pro Gly Pro Gly Asp Lys Thr His Thr Cys Pro Leu Cys Pro Ala 325 330
335 Pro Glu Leu Leu Gly Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro
340 345 350 Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys
Val Val 355 360 365 Val Asp Val Ser His Glu Asp Pro Glu Val Lys Phe
Asn Trp Tyr Val 370 375 380 Asp Gly Val Glu Val His Asn Ala Lys Thr
Lys Pro Arg Glu Glu Gln 385 390 395 400 Tyr Asn Ser Thr Tyr Arg Val
Val Ser Val Leu Thr Val Leu His Gln 405 410 415 Asp Trp Leu Asn Gly
Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala 420 425 430 Leu Pro Ala
Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro 435 440 445 Arg
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu Leu Thr 450 455
460 Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser
465 470 475 480 Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu
Asn Asn Tyr 485 490 495 Lys Ala Thr Pro Pro Val Leu Asp Ser Asp Gly
Ser Phe Phe Leu Tyr 500 505 510 Ser Lys Leu Thr Val Asp Lys Ser Arg
Trp Gln Gln Gly Asn Val Phe 515 520 525 Ser Cys Ser Val Met His Glu
Ala Leu His Asn His Tyr Thr Gln Lys 530 535 540 Ser Leu Ser Leu Ser
Pro Gly Lys 545 550
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References