U.S. patent application number 16/354615 was filed with the patent office on 2019-07-04 for antibodies to m-csf.
The applicant listed for this patent is Amgen Fremont Inc., Warner-Lambert Company LLC. Invention is credited to Vahe Bedian, Madhav Narasimha Devalaraja, Ian Foltz, Mary Haak-Frendscho, Sirid-Aimee Kellermann, Joseph Edwin Low, James Leslie Mobley.
Application Number | 20190202905 16/354615 |
Document ID | / |
Family ID | 33300142 |
Filed Date | 2019-07-04 |
![](/patent/app/20190202905/US20190202905A1-20190704-D00001.png)
![](/patent/app/20190202905/US20190202905A1-20190704-D00002.png)
![](/patent/app/20190202905/US20190202905A1-20190704-D00003.png)
![](/patent/app/20190202905/US20190202905A1-20190704-D00004.png)
![](/patent/app/20190202905/US20190202905A1-20190704-D00005.png)
![](/patent/app/20190202905/US20190202905A1-20190704-D00006.png)
![](/patent/app/20190202905/US20190202905A1-20190704-D00007.png)
![](/patent/app/20190202905/US20190202905A1-20190704-D00008.png)
![](/patent/app/20190202905/US20190202905A1-20190704-D00009.png)
![](/patent/app/20190202905/US20190202905A1-20190704-D00010.png)
![](/patent/app/20190202905/US20190202905A1-20190704-D00011.png)
View All Diagrams
United States Patent
Application |
20190202905 |
Kind Code |
A1 |
Bedian; Vahe ; et
al. |
July 4, 2019 |
ANTIBODIES TO M-CSF
Abstract
The present invention relates to antibodies and antigen-binding
portions thereof that specifically bind to a M-CSF, preferably
human M-CSF, and that function to inhibit a M-CSF. The invention
also relates to human anti-M-CSF antibodies and antigen-binding
portions thereof. The invention also relates to antibodies that are
chimeric, bispecific, derivatized, single chain antibodies or
portions of fusion proteins. The invention also relates to isolated
heavy and light chain immunoglobulins derived from human anti-M-CSF
antibodies and nucleic acid molecules encoding such
immunoglobulins. The present invention also relates to methods of
making human anti-M-CSF antibodies, compositions comprising these
antibodies and methods of using the antibodies and compositions for
diagnosis and treatment. The invention also provides gene therapy
methods using nucleic acid molecules encoding the heavy and/or
light immunoglobulin molecules that comprise the human anti-M-CSF
antibodies. The invention also relates to transgenic animals and
transgenic plants comprising nucleic acid molecules of the present
invention.
Inventors: |
Bedian; Vahe; (East Lyme,
CT) ; Devalaraja; Madhav Narasimha; (Ann Arbor,
MI) ; Foltz; Ian; (Burnaby, CA) ;
Haak-Frendscho; Mary; (San Francisco, CA) ;
Kellermann; Sirid-Aimee; (Menlo Park, CA) ; Low;
Joseph Edwin; (Ann Arbor, MI) ; Mobley; James
Leslie; (Brighton, MI) |
|
Applicant: |
Name |
City |
State |
Country |
Type |
Amgen Fremont Inc.
Warner-Lambert Company LLC |
Thousand Oaks
Morris Plains |
CA
NJ |
US
US |
|
|
Family ID: |
33300142 |
Appl. No.: |
16/354615 |
Filed: |
March 15, 2019 |
Related U.S. Patent Documents
|
|
|
|
|
|
Application
Number |
Filing Date |
Patent Number |
|
|
15614237 |
Jun 5, 2017 |
10280219 |
|
|
16354615 |
|
|
|
|
14923655 |
Oct 27, 2015 |
9718883 |
|
|
15614237 |
|
|
|
|
13458820 |
Apr 27, 2012 |
|
|
|
14923655 |
|
|
|
|
12748602 |
Mar 29, 2010 |
8188249 |
|
|
13458820 |
|
|
|
|
11894560 |
Aug 20, 2007 |
7728113 |
|
|
12748602 |
|
|
|
|
11375221 |
Mar 13, 2006 |
7326414 |
|
|
11894560 |
|
|
|
|
10938353 |
Sep 9, 2004 |
7592430 |
|
|
11375221 |
|
|
|
|
60502163 |
Sep 10, 2003 |
|
|
|
Current U.S.
Class: |
1/1 |
Current CPC
Class: |
A61P 19/08 20180101;
C07K 2317/14 20130101; A61P 43/00 20180101; A61P 13/12 20180101;
C07K 2317/21 20130101; A61K 38/193 20130101; A61P 9/00 20180101;
A61P 11/00 20180101; A61P 27/02 20180101; A61K 39/395 20130101;
A61P 39/02 20180101; A61P 31/04 20180101; A61P 3/00 20180101; A61P
19/02 20180101; A61P 25/00 20180101; A61K 2039/505 20130101; A61P
3/10 20180101; A61P 7/02 20180101; C07K 2317/73 20130101; A61P 1/04
20180101; A61P 17/02 20180101; A61P 17/04 20180101; C07K 2317/92
20130101; A61P 17/00 20180101; G06Q 40/04 20130101; G06Q 50/12
20130101; A61P 19/10 20180101; G06Q 30/0601 20130101; A61P 1/00
20180101; A61P 19/06 20180101; A61P 35/00 20180101; A61P 35/02
20180101; A61P 19/00 20180101; C07K 16/24 20130101; A61P 29/00
20180101; G06Q 30/02 20130101; Y02A 50/412 20180101; A61P 33/06
20180101; A61P 37/00 20180101; A61P 17/06 20180101; C07K 16/243
20130101; Y02A 50/30 20180101; A61P 37/08 20180101; C07K 2317/56
20130101; C07K 2317/76 20130101; A61P 17/16 20180101; A61P 21/00
20180101; A61P 25/28 20180101; A61P 37/06 20180101; A61P 9/10
20180101; A61P 11/06 20180101; C07K 2317/565 20130101 |
International
Class: |
C07K 16/24 20060101
C07K016/24; A61K 39/395 20060101 A61K039/395; G06Q 30/06 20060101
G06Q030/06; A61K 38/19 20060101 A61K038/19; G06Q 30/02 20060101
G06Q030/02; G06Q 50/12 20060101 G06Q050/12; G06Q 40/04 20060101
G06Q040/04 |
Claims
1-6. (canceled)
7. A monoclonal antibody that specifically binds M-CSF, wherein the
antibody is selected from the group consisting of: a) an antibody
comprising the heavy chain amino acid sequence set forth in SEQ ID
NO: 2 and the light chain amino acid sequence set forth in SEQ ID
NO: 4, without the signal sequences; b) an antibody comprising the
heavy chain amino acid sequence set forth in SEQ ID NO: 6 and the
light chain amino acid sequence set forth in SEQ ID NO: 8, without
the signal sequences; c) an antibody comprising the heavy chain
amino acid sequence set forth in SEQ ID NO: 10 and the light chain
amino acid sequence set forth in SEQ ID NO: 12, without the signal
sequences; d) an antibody comprising the heavy chain amino acid
sequence set forth in SEQ ID NO: 14 and the light chain amino acid
sequence set forth in SEQ ID NO: 16, without the signal sequences;
e) an antibody comprising the heavy chain amino acid sequence set
forth in SEQ ID NO: 18 and the light chain amino acid sequence set
forth in SEQ ID NO: 20, without the signal sequences; f) an
antibody comprising the heavy chain amino acid sequence set forth
in SEQ ID NO: 22 and the light chain amino acid sequence set forth
in SEQ ID NO: 24, without the signal sequences; g) an antibody
comprising the heavy chain amino acid sequence set forth in SEQ ID
NO: 26 and the light chain amino acid sequence set forth in SEQ ID
NO: 28, without the signal sequences; h) an antibody comprising the
heavy chain amino acid sequence set forth in SEQ ID NO: 38 and the
light chain amino acid sequence set forth in SEQ ID NO: 28, without
the signal sequences; i) an antibody comprising the heavy chain
amino acid sequence set forth in SEQ ID NO: 54 and the light chain
amino acid sequence set forth in SEQ ID NO: 56, without the signal
sequences; j) an antibody comprising the heavy chain amino acid
sequence set forth in SEQ ID NO: 74 and the light chain amino acid
sequence set forth in SEQ ID NO: 56, without the signal sequences;
k) an antibody comprising the heavy chain amino acid sequence set
forth in SEQ ID NO: 78 and the light chain amino acid sequence set
forth in SEQ ID NO: 56, without the signal sequences; l) an
antibody comprising the heavy chain amino acid sequence set forth
in SEQ ID NO: 82 and the light chain amino acid sequence set forth
in SEQ ID NO: 28, without the signal sequences; m) an antibody
comprising the heavy chain amino acid sequence set forth in SEQ ID
NO: 102 and the light chain amino acid sequence set forth in SEQ ID
NO: 28, without the signal sequences; n) an antibody comprising the
heavy chain amino acid sequence set forth in SEQ ID NO: 30 and the
light chain amino acid sequence set forth in SEQ ID NO: 32, without
the signal sequences; o) an antibody comprising the heavy chain
amino acid sequence set forth in SEQ ID NO: 30 and the light chain
amino acid sequence set forth in SEQ ID NO: 44, without the signal
sequences; p) an antibody comprising the heavy chain amino acid
sequence set forth in SEQ ID NO: 58 and the light chain amino acid
sequence set forth in SEQ ID NO: 60, without the signal sequences;
q) an antibody comprising the heavy chain amino acid sequence set
forth in SEQ ID NO: 62 and the light chain amino acid sequence set
forth in SEQ ID NO: 60, without the signal sequences; r) an
antibody comprising the heavy chain amino acid sequence set forth
in SEQ ID NO: 90 and the light chain amino acid sequence set forth
in SEQ ID NO: 44, without the signal sequences; s) an antibody
comprising the heavy chain amino acid sequence set forth in SEQ ID
NO: 94 and the light chain amino acid sequence set forth in SEQ ID
NO: 60, without the signal sequences; t) an antibody comprising the
heavy chain amino acid sequence set forth in SEQ ID NO: 98 and the
light chain amino acid sequence set forth in SEQ ID NO: 32, without
the signal sequences; u) an antibody comprising the heavy chain
amino acid sequence set forth in SEQ ID NO: 34 and the light chain
amino acid sequence set forth in SEQ ID NO: 36, without the signal
sequences; v) an antibody comprising the heavy chain amino acid
sequence set forth in SEQ ID NO: 46 and the light chain amino acid
sequence set forth in SEQ ID NO: 48, without the signal sequences;
w) an antibody comprising the heavy chain amino acid sequence set
forth in SEQ ID NO: 50 and the light chain amino acid sequence set
forth in SEQ ID NO: 52, without the signal sequences; x) an
antibody comprising the heavy chain amino acid sequence set forth
in SEQ ID NO: 66 and the light chain amino acid sequence set forth
in SEQ ID NO: 52, without the signal sequences; y) an antibody
comprising the heavy chain amino acid sequence set forth in SEQ ID
NO: 70 and the light chain amino acid sequence set forth in SEQ ID
NO: 52, without the signal sequences; and z) an antibody comprising
the heavy chain amino acid sequence set forth in SEQ ID NO: 86 and
the light chain amino acid sequence set forth in SEQ ID NO: 48,
without the signal sequences.
8.-19. (canceled)
20. The monoclonal antibody or antigen-binding portion according to
claim 7, wherein the C-terminal lysine of the heavy chain of said
antibody or antigen-binding portion is not present.
21. A pharmaceutical composition, comprising the antibody or
antigen-binding portion according to claim 7 or 20 and a
pharmaceutically acceptable carrier.
22. (canceled)
23. A method for treating a condition selected from the group
consisting of arthritis, psoriatic arthritis, ankylosing
spondylitis, Reiter's syndrome, rheumatoid arthritis, gout,
traumatic arthritis, rubella arthritis and acute synovitis and
other arthritic conditions, sepsis, septic shock, endotoxic shock,
gram negative sepsis, toxic shock syndrome, Alzheimer's disease,
stroke, neurotrauma, asthma, adult respiratory distress syndrome,
cerebral malaria, chronic pulmonary inflammatory disease,
silicosis, pulmonary sarcoidosis, bone resorption disease,
osteoporosis, restenosis, cardiac and renal reperfusion injury,
thrombosis, glomerularonephritis, diabetes, graft vs. host
reaction, allograft rejection, inflammatory bowel disease, Crohn's
disease, ulcerative colitis, multiple sclerosis, muscle
degeneration, eczema, contact dermatitis, psoriasis, sunburn and
conjunctivitis shock in a subject, including a human, comprising
the step of administering to said subject in need thereof a
therapeutically effective amount of the antibody or antigen-binding
portion thereof according to claim 7 or 20 or the pharmaceutical
composition according to claim 21, wherein said antibody or portion
inhibits M-CSF.
24.-25. (canceled)
26. A method for treating a solid tumor such as a sarcoma, a
carcinoma or a lymphoma in a subject, including a human, comprising
the step of administering to said subject the antibody or
antigen-binding portion thereof according to claim 7 or 20 or the
pharmaceutical composition according to claim 21, wherein said
antibody or antigen-binding portion inhibits M-CSF binding to
c-fms.
27. An isolated cell line that produces the antibody or
antigen-binding portion thereof according to claim 7 or 20 or the
heavy chain or light chain of said antibody or said antigen-binding
portions thereof.
28. (canceled)
29. An isolated nucleic acid molecule comprising a nucleotide
sequence that encodes the heavy chain or an antigen-binding portion
thereof or the light chain or an antigen-binding portion thereof of
an antibody according to claim 7 or 20.
30. A vector comprising the nucleic acid molecule according to
claim 29, wherein the vector optionally comprises an expression
control sequence operably linked to said nucleic acid molecule.
31. A host cell comprising the vector according to claim 30 or the
nucleic acid molecule according to claim 29.
32. The host cell according to claim 31 comprising a nucleic acid
molecule encoding the heavy chain and a nucleic acid molecule
encoding the light chain of an antibody or antigen-binding portion
according to claim 7 or 20.
33. A method of making an anti-M-CSF antibody or antigen-binding
portion thereof, comprising culturing the host cell according to
claim 32 or the cell line according to claim 27 under suitable
conditions and recovering said antibody or antigen-binding
portions.
34. (canceled)
Description
[0001] This application is a continuation of Ser. No. 15/614,237,
filed Jun. 5, 2017, which is a divisional of U.S. application Ser.
No. 14/923,655, filed Oct. 27, 2015, now U.S. Pat. No. 9,718,883,
which is a divisional of U.S. application Ser. No. 13/458,820,
filed Apr. 27, 2012, which is a continuation of U.S. application
Ser. No. 12/748,602, filed Mar. 29, 2010, now U.S. Pat. No.
8,188,249, which is a continuation of U.S. application Ser. No.
11/894,560, filed Aug. 20, 2007, now U.S. Pat. No. 7,728,113, which
is a continuation of U.S. application Ser. No. 11/375,221, filed
Mar. 13, 2006, now U.S. Pat. No. 7,326,414, which is a continuation
of U.S. application Ser. No. 10/938,353, filed Sep. 9, 2004, now
U.S. Pat. No. 7,592,430, which claims the benefit of U.S.
Provisional Application 60/502,163, filed Sep. 10, 2003. Each of
the above-identified applications is incorporated herein by
reference in its entirety.
[0002] The instant application contains a Sequence Listing which
has been submitted via EFS-Web and is hereby incorporated by
reference in its entirety. Said ASCII text file, created on Mar.
15, 2019, is named 000659-0052-108-SL.txt, and is 172,120 bytes in
size.
BACKGROUND OF THE INVENTION
[0003] Macrophage colony stimulating factor (M-CSF) is a member of
the family of proteins referred to as colony stimulating factors
(CSFs). M-CSF is a secreted or a cell surface glycoprotein
comprised of two subunits that are joined by a disulfide bond with
a total molecular mass varying from 40 to 90 kD ((Stanley E. R., et
al., Mol. Reprod. Dev., 46:4-10 (1997)). Similar to other CSFs,
M-CSF is produced by macrophages, monocytes, and human joint tissue
cells, such as chondrocytes and synovial fibroblasts, in response
to proteins such as interleukin-1 or tumor necrosis factor-alpha.
M-CSF stimulates the formation of macrophage colonies from
pluripotent hematopoietic progenitor stem cells (Stanley E. R., et
al., Mol. Reprod. Dev., 46:4-10 (1997)).
[0004] M-CSF typically bind to its receptor, c-fins, in order to
exert a biological effect. c-fins contains five extracellular Ig
domains, one transmembrane domain, and an intracellular domain with
two kinase domains. Upon M-CSF binding to c-fms, the receptor
homo-dimerizes and initiates a cascade of signal transduction
pathways including the JAK/STAT, PI3K, and ERK pathways.
[0005] M-CSF is an important regulator of the function, activation,
and survival of monocytes/macrophages. A number of animal models
have confirmed the role of M-CSF in various diseases, including
rheumatoid arthritis (RA) and cancer. Macrophages comprise key
effector cells in RA. The degree of synovial macrophage
infiltration in RA has been shown to closely correlate with the
extent of underlying joint destruction. M-CSF, endogenously
produced in the rheumatoid joint by monocytes/macrophages,
fibroblasts, and endothelial cells, acts on cells of the
monocyte/macrophage lineage to promote their survival and
differentiation into bone destroying osteoclasts, and enhance
pro-inflammatory cellular functions such as cytotoxicity,
superoxide production, phagocytosis, chemotaxis and secondary
cytokine production. For example, treatment with M-CSF in the rat
streptococcus agalactiae sonicate-induced experimental arthritis
model lead to enhanced pathology (Abd, A. H., et al., Lymphokine
Cytokine Res. 10:43-50 (1991)). Similarly, subcutaneous injections
of M-CSF in a murine model of collagen-induced arthritis (CIA),
which is a model for RA, resulted in a significant exacerbation of
the RA disease symptoms (Campbell I. K., et al., J. Leuk. Biol.
68:144-150 (2000)). Furthermore, MRL/lpr mice that are highly
susceptible to RA and other autoimmune diseases have elevated basal
M-CSF serum concentrations (Yui M. A., et al., Am. J. Pathol.
139:255-261 (1991)). The requirement for endogenous M-CSF in
maintaining CIA was demonstrated by a significant reduction in the
severity of established disease by M-CSF neutralizing mouse
monoclonal antibody (Campbell I. K., et al., J. Leuk. Biol.
68:144-150 (2000)).
[0006] With respect to cancer, inhibition of colony stimulating
factors by antisense oligonucleotides suppresses tumor growth in
embryonic and colon tumor xenografts in mice by decelerating
macrophage-mediated ECM breakdown (Seyedhossein, A., et al., Cancer
Research, 62:5317-5324 (2002)).
[0007] M-CSF binding to c-fins and its subsequent activation of
monocyte/macrophages is important in a number of disease states. In
addition to RA and cancer, the other examples of M-CSF-related
disease states include osteoporosis, destructive arthritis,
atherogenesis, glomerulonephritis, Kawasaki disease, and HIV-1
infection, in which monocytes/macrophages and related cell types
play a role. For instance, osteoclasts are similar to macrophages
and are regulated in part by M-CSF. Growth and differentiation
signals induced by M-CSF in the initial stages of osteoclast
maturation are essential for their subsequent osteoclastic activity
in bone.
[0008] Osteoclast mediated bone loss, in the form of both focal
bone erosions and more diffuse juxta-articular osteoporosis, is a
major unsolved problem in RA. The consequences of this bone loss
include joint deformities, functional disability, increased risk of
bone fractures and increased mortality. M-CSF is uniquely essential
for osteoclastogenesis and experimental blockade of this cytokine
in animal models of arthritis successfully abrogates joint
destruction. Similar destructive pathways are known to operate in
other forms of destructive arthritis such as psoriatic arthritis,
and could represent venues for similar intervention.
[0009] Postmenopausal bone loss results from defective bone
remodeling secondary to an uncoupling of bone formation from
exuberant osteoclast mediated bone resorption as a consequence of
estrogen deficiency. In-vivo neutralization of M-CSF using a
blocking antibody has been shown in mice to completely prevent the
rise in osteoclast numbers, the increase in bone resorption and the
resulting bone loss induced by ovariectomy.
[0010] Several lines of evidence point to a central role for M-CSF
in atherogenesis, and in proliferative intimal hyperplasia after
mechanical trauma to the arterial wall. All the major cell types in
atherosclerotic lesions have been shown to express M-CSF, and this
is further up-regulated by exposure to oxidized lipoprotein.
Blockade of M-CSF signaling with a neutralizing c-fins antibody
reduces the accumulation of macrophage-derived foam cells in the
aortic root of apolipoprotein E deficient mice maintained on a high
fat diet.
[0011] In both experimental and human glomerulonephritis,
glomerular M-CSF expression has been found to co-localize with
local macrophage accumulation, activation and proliferation and
correlate with the extent of glomerular injury and proteinuria.
Blockade of M-CSF signaling via an antibody directed against its
receptor c-fins significantly down-regulates local macrophage
accumulation in mice during the renal inflammatory response induced
by experimental unilateral ureteric obstruction.
[0012] Kawasaki disease (KD) is an acute, febrile, pediatric
vasculitis of unknown cause. Its most common and serious
complications involve the coronary vasculature in the form of
aneurismal dilatation. Serum M-CSF levels are significantly
elevated in acute phase Kawasaki's disease, and normalize following
treatment with intravenous immunoglobulin. Giant cell arthritis
(GCA) is an inflammatory vasculopathy mainly occurring in the
elderly in which T cells and macrophages infiltrate the walls of
medium and large arteries leading to clinical consequences that
include blindness and stroke secondary to arterial occlusion. The
active involvement of macrophages in GCA is evidenced by the
presence of elevated levels of macrophage derived inflammatory
mediators within vascular lesions.
[0013] M-CSF has been reported to render human monocyte derived
macrophages more susceptible to HIV-1 infection in vitro. In a
recent study, M-CSF increased the frequency with which
monocyte-derived macrophages became infected, the amount of HIV
mRNA expressed per infected cell, and the level of proviral DNA
expressed per infected culture.
[0014] Given the role of M-CSF in various diseases, a method for
inhibiting M-CSF activity is desirable.
[0015] There is a critical need for therapeutic anti-M-CSF
antibodies.
SUMMARY OF THE INVENTION
[0016] The present invention provides isolated human antibodies or
antigen-binding portions thereof that specifically bind human M-CSF
and acts as a M-CSF antagonist and compositions comprising said
antibody or portion.
[0017] The invention also provides for compositions comprising the
heavy and/or light chain, the variable regions thereof, or
antigen-binding portions thereof an anti-M-CSF antibody, or nucleic
acid molecules encoding an antibody, antibody chain or variable
region thereof the invention effective in such treatment and a
pharmaceutically acceptable carrier. In certain embodiments, the
compositions may further comprise another component, such as a
therapeutic agent or a diagnostic agent. Diagnostic and therapeutic
methods are also provided by the invention. In certain embodiments,
the compositions are used in a therapeutically effective amount
necessary to treat or prevent a particular disease or
condition.
[0018] The invention also provides methods for treating or
preventing a variety of diseases and conditions such as, but not
limited to, inflammation, cancer, atherogenesis, neurological
disorders and cardiac disorders with an effective amount of an
anti-M-CSF antibody of the invention, or antigen binding portion
thereof, nucleic acids encoding said antibody, or heavy and/or
light chain, the variable regions, or antigen-binding portions
thereof.
[0019] The invention provides isolated cell lines, such as a
hybridomas, that produce anti-M-CSF antibodies or antigen-binding
portions thereof.
[0020] The invention also provides nucleic acid molecules encoding
the heavy and/or light chains of anti-M-CSF antibodies, the
variable regions thereof, or the antigen-binding portions
thereof.
[0021] The invention provides vectors and host cells comprising the
nucleic acid molecules, as well as methods of recombinantly
producing the polypeptides encoded by the nucleic acid
molecules.
[0022] Non-human transgenic animals or plants that express the
heavy and/or light chains, or antigen-binding portions thereof, of
anti-M-CSF antibodies are also provided.
BRIEF DESCRIPTION OF THE DRAWINGS
[0023] FIGS. 1A and 1B are graphs illustrating that the anti-M-CSF
antibodies resulted in a dose-related decrease in total monocyte
counts in male and female monkeys over time. The monocyte counts
were determined by light scatter using an Abbott Diagnostics Inc.
Cell Dyn system. Monocyte counts were monitored from 24 hours
through 3 weeks after administration of vehicle or antibody 8.10.3
at 0, 0.1, 1 or 5 mg/kg in a dose volume of 3.79 mL/kg over an
approximately 5 minute period.
[0024] FIG. 1A male monkeys.
[0025] FIG. 1B female monkeys.
[0026] FIGS. 2A and 2B are graphs illustrating that anti-M-CSF
treatment resulted in a reduction in the percentage of CD14+CD16+
monocytes, in male and female monkeys. 0-21 days after
administration of vehicle or antibody 8.10.3 at 0, 0.1, 1 or 5
mg/kg in a dose volume of 3.79 mL/kg over an approximately 5 minute
period. For each monkey tested, the percentage of monocytes within
the CD14+CD16+ subset was determined after each blood draw, on days
1, 3, 7, 14 and 21 after 8.10.3 injection.
[0027] FIG. 2A male monkeys.
[0028] FIG. 2B female monkeys.
[0029] FIG. 3 is a graph illustrating that anti-M-CSF treatment
resulted in a decrease in the percentage change of total monocytes
at all doses of antibody 8.10.3F as compared to pre-test levels of
monocytes.
[0030] FIG. 3 shows data collected from experiments using antibody
8.10.3F.
[0031] FIGS. 4A-4ZZ provide sequence alignments of the predicted
amino acid sequences of light and heavy chain variable regions from
twenty-six anti-M-CSF antibodies compared with the germline amino
acid sequences of the corresponding variable region genes.
Differences between the antibody sequences and the germline gene
sequences are indicated in bold-faced type. Dashes represent no
change from germline. The underlined sequences in each alignment
represent, from left to right, the FR1, CDR1, FR2, CDR2, FR3, CDR3
AND FR4 sequences. FIG. 4A shows an alignment of the predicted
amino acid sequence of the light chain variable region for antibody
252 (residues 21-127 of SEQ ID NO: 4) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0032] FIG. 4B shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 88
(residues 21-127 of SEQ ID NO: 8) to the germline V.sub..kappa.O12,
J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0033] FIG. 4C shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 100
(residues 21-127 of SEQ ID NO: 12) to the germline V.sub..kappa.L2,
J.sub..kappa.3 sequence (SEQ ID NO: 107).
[0034] FIG. 4D shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 3.8.3
(residues 23-130 of SEQ ID NO: 16) to the germline V.sub..kappa.L5,
J.sub..kappa.3 sequence (SEQ ID NO: 109).
[0035] FIG. 4E shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 2.7.3
(residues 23-130 of SEQ ID NO: 20) to the germline V.sub..kappa.L5,
J.sub..kappa.4 sequence (SEQ ID NO: 117).
[0036] FIG. 4F shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 1.120.1
(residues 21-134 of SEQ ID NO: 24) to the germline V.sub..kappa.B3,
J.sub..kappa.1 sequence (SEQ ID NO: 112).
[0037] FIG. 4G shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 252
(residues 20-136 of SEQ ID NO: 2) to the germline V.sub.H3-11,
D.sub.H7-27 J.sub.H6 sequence (SEQ ID NO: 106).
[0038] FIG. 4H shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 88
(residues 20-138 of SEQ ID NO: 6) to the germline V.sub.H3-7,
D.sub.H6-13, J.sub.H4 sequence (SEQ ID NO: 105).
[0039] FIG. 4I shows the alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 100
(residues 20-141 of SEQ ID NO: 10) to the germline V.sub.H3-23,
D.sub.H1-26, J.sub.H4 sequence (SEQ ID NO: 104).
[0040] FIG. 4J shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 3.8.3
(residues 20-135 of SEQ ID NO: 14) to the germline V.sub.H3-11,
D.sub.H7-27, J.sub.H4 sequence (SEQ ID NO: 108).
[0041] FIG. 4K shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 2.7.3
(residues 20-137 of SEQ ID NO: 18) to the germline V.sub.H3-33,
D.sub.H1-26, J.sub.H4 sequence (SEQ ID NO: 110).
[0042] FIG. 4L shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 1.120.1
(residues 20-139 of SEQ ID NO: 22) to the germline V.sub.H1-18,
D.sub.H4-23, J.sub.H4 sequence (SEQ ID NO: 111).
[0043] FIG. 4M shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 8.10.3
(residues 21-129 of SEQ ID NO: 44) to the germline
V.sub..kappa.A27, J.sub..kappa.4 sequence (SEQ ID NO: 114).
[0044] FIG. 4N shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 8.10.3
(residues 20-141 of SEQ ID NO: 30) to the germline V.sub.H3-48,
D.sub.H1-26, J.sub.H4b sequence (SEQ ID NO: 113).
[0045] FIG. 4O shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.14.4
(residues 23-130 of SEQ ID NO: 28) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0046] FIG. 4P shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.14.4
(residues 20-135 of SEQ ID NO: 38) to the germline V.sub.H3-11,
D.sub.H7-27, J.sub.H4b sequence (SEQ ID NO: 116).
[0047] FIG. 4Q shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.7.2
(residues 23-130 of SEQ ID NO: 48) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0048] FIG. 4R shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.7.2
(residues 20-136 of SEQ ID NO: 46) to the germline V.sub.H3-11,
D.sub.H6-13, J.sub.H6b sequence (SEQ ID NO: 115).
[0049] FIG. 4S shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.14.41
(residues 23-130 of SEQ ID NO: 28) to the germline V.sub..kappa.O12
J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0050] FIG. 4T shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.14.41
(residues 20-135 of SEQ ID NO: 26) to the germline V.sub.H3-11,
D.sub.H7-27, J.sub.H4b sequence (SEQ ID NO: 116).
[0051] FIG. 4U shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 8.10.3F
(residues 21-129 of SEQ ID NO: 32) to the germline
V.sub..kappa.A27, J.sub..kappa.4 sequence (SEQ ID NO: 114).
[0052] FIG. 4V shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 8.10.3F
(residues 20-141 of SEQ ID NO: 30) to the germline V.sub.H3-48,
D.sub.H1-26, J.sub.H4b sequence (SEQ ID NO: 113).
[0053] FIG. 4W shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.7.2IF
(residues 23-130 of SEQ ID NO: 36) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0054] FIG. 4X shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.7.2IF
(residues 20-136 of SEQ ID NO: 34) to the germline V.sub.H3-11,
D.sub.H6-13, J.sub.H6b sequence (SEQ ID NO: 115).
[0055] FIG. 4Y shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.7.2C-Ser
(residues 23-130 of SEQ ID NO: 52) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0056] FIG. 4Z shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.7.2C-Ser
(residues 20-136 of SEQ ID NO: 50) to the germline V.sub.H3-11,
D.sub.H6-13, J.sub.H6b sequence (SEQ ID NO: 115).
[0057] FIG. 4AA shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody
9.14.4C-Ser (residues 23-130 of SEQ ID NO: 56) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0058] FIG. 4BB shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody
9.14.4C-Ser (residues 20-135 of SEQ ID NO: 54) to the germline
V.sub.H3-11, D.sub.H7-27, J.sub.H4b sequence (SEQ ID NO: 116).
[0059] FIG. 4CC shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody
8.10.3C-Ser (residues 21-129 of SEQ ID NO: 60) to the germline
V.sub..kappa.A27, J.sub..kappa.4 sequence (SEQ ID NO: 114).
[0060] FIG. 4DD shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody
8.10.3C-Ser (residues 20-141 of SEQ ID NO: 58) to the germline
V.sub.H3-48, D.sub.H1-26, J.sub.H4b sequence (SEQ ID NO: 113).
[0061] FIG. 4EE shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 8.10.3-CG2
(residues 21-129 of SEQ ID NO: 60) to the germline
V.sub..kappa.A27, J.sub..kappa.4 sequence (SEQ ID NO: 114).
[0062] FIG. 4FF shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 8.10.3-CG2
(residues 20-141 of SEQ ID NO: 62) to the germline V.sub.H3-48,
D.sub.H1-26, J.sub.H4b sequence (SEQ ID NO: 113).
[0063] FIG. 4GG shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.7.2-CG2
(residues 23-130 of SEQ ID NO: 52) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0064] FIG. 4HH shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.7.2-CG2
(residues 20-136 of SEQ ID NO: 66) to the germline V.sub.H3-11,
D.sub.H6-13, J.sub.H6b sequence (SEQ ID NO: 115).
[0065] FIG. 4II shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.7.2-CG4
(residues 23-130 of SEQ ID NO: 52) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0066] FIG. 4JJ shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.7.2-CG4
(residues 20-135 of SEQ ID NO: 70) to the germline V.sub.H3-11,
D.sub.H6-13, J.sub.H6b sequence (SEQ ID NO: 115).
[0067] FIG. 4KK shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.14.4-CG2
(residues 23-130 of SEQ ID NO: 56) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0068] FIG. 4LL shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.14.4-CG2
(residues 20-135 of SEQ ID NO: 74) to the germline V.sub.H3-11,
D.sub.H7-27, J.sub.H4b sequence (SEQ ID NO: 116).
[0069] FIG. 4MM shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.14.4-CG4
(residues 23-130 of SEQ ID NO: 56) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0070] FIG. 4NN shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.14.4-CG4
(residues 20-135 of SEQ ID NO: 78) to the germline V.sub.H3-11,
D.sub.H7-27, J.sub.H4b sequence (SEQ ID NO: 116).
[0071] FIG. 4OO shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.14.4-Ser
(residues 23-130 of SEQ ID NO: 28) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0072] FIG. 4PP shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.14.4-Ser
(residues 20-135 of SEQ ID NO: 82) to the germline V.sub.H3-11,
D.sub.H7-27, J.sub.H4b sequence (SEQ ID NO: 116).
[0073] FIG. 4QQ shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.7.2-Ser
(residues 23-130 of SEQ ID NO: 48) to the germline
V.sub..kappa.O12, J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0074] FIG. 4RR shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.7.2-Ser
(residues 20-136 of SEQ ID NO: 86) to the germline V.sub.H3-11,
D.sub.H6-13, J.sub.H6b sequence (SEQ ID NO: 115).
[0075] FIG. 4SS shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 8.10.3-Ser
(residues 21-129 of SEQ ID NO: 44) to the germline
V.sub..kappa.A27, J.sub..kappa.4 sequence (SEQ ID NO: 114).
[0076] FIG. 4TT shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 8.10.3-Ser
(residues 20-141 of SEQ ID NO: 90) to the germline V.sub.H3-48,
D.sub.H1-26, J.sub.H4b sequence (SEQ ID NO: 113).
[0077] FIG. 4UU shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 8.10.3-CG4
(residues 21-129 of SEQ ID NO: 60) to the germline
V.sub..kappa.A27, J.sub..kappa.4 sequence (SEQ ID NO: 114).
[0078] FIG. 4VV shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 8.10.3-CG4
(residues 20-141 of SEQ ID NO: 94) to the germline V.sub.H3-48,
D.sub.H1-26, J.sub.H4b sequence (SEQ ID NO: 113).
[0079] FIG. 4WW shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 9.14.4G1
(residues 23-130 of SEQ ID NO: 28) to the germline V.sub..kappa.O12
J.sub..kappa.3 sequence (SEQ ID NO: 103).
[0080] FIG. 4XX shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 9.14.4G1
(residues 20-135 of SEQ ID NO: 102) to the germline V.sub.H3-11,
D.sub.H7-27, J.sub.H4b sequence (SEQ ID NO: 116).
[0081] FIG. 4YY shows an alignment of the predicted amino acid
sequence of the light chain variable region for antibody 8.10.3FG1
(residues 21-129 of SEQ ID NO:32) to the germline V.sub..kappa.A27,
J.sub..kappa.4 sequence (SEQ ID NO: 114).
[0082] FIG. 4ZZ shows an alignment of the predicted amino acid
sequence of the heavy chain variable region for antibody 8.10.3FG1
(residues 20-141 of SEQ ID NO: 98) to the germline V.sub.H3-48,
D.sub.H1-26, J.sub.H4b sequence (SEQ ID NO: 113).
DETAILED DESCRIPTION OF THE INVENTION
Definitions and General Techniques
[0083] Unless otherwise defined herein, scientific and technical
terms used in connection with the present invention shall have the
meanings that are commonly understood by those of ordinary skill in
the art. Further, unless otherwise required by context, singular
terms shall include pluralities and plural terms shall include the
singular. Generally, nomenclatures used in connection with, and
techniques of, cell and tissue culture, molecular biology,
immunology, microbiology, genetics and protein and nucleic acid
chemistry and hybridization described herein are those well known
and commonly used in the art.
[0084] The methods and techniques of the present invention are
generally performed according to conventional methods well known in
the art and as described in various general and more specific
references that are cited and discussed throughout the present
specification unless otherwise indicated. See, e.g., Sambrook et
al., Molecular Cloning: A Laboratory Manual, 2d ed., Cold Spring
Harbor Laboratory Press, Cold Spring Harbor, N.Y. (1989) and
Ausubel et al., Current Protocols in Molecular Biology, Greene
Publishing Associates (1992), and Harlow and Lane Antibodies: A
Laboratory Manual, Cold Spring Harbor Laboratory Press, Cold Spring
Harbor, N.Y. (1990), which are incorporated herein by reference.
Enzymatic reactions and purification techniques are performed
according to manufacturer's specifications, as commonly
accomplished in the art or as described herein. The nomenclatures
used in connection with, and the laboratory procedures and
techniques of, analytical chemistry, synthetic organic chemistry,
and medicinal and pharmaceutical chemistry described herein are
those well known and commonly used in the art. Standard techniques
are used for chemical syntheses, chemical analyses, pharmaceutical
preparation, formulation, and delivery, and treatment of
patients.
[0085] The following terms, unless otherwise indicated, shall be
understood to have the following meanings:
[0086] The term "polypeptide" encompasses native or artificial
proteins, protein fragments and polypeptide analogs of a protein
sequence. A polypeptide may be monomeric or polymeric.
[0087] The term "isolated protein", "isolated polypeptide" or
"isolated antibody" is a protein, polypeptide or antibody that by
virtue of its origin or source of derivation has one to four of the
following: (1) is not associated with naturally associated
components that accompany it in its native state, (2) is free of
other proteins from the same species, (3) is expressed by a cell
from a different species, or (4) does not occur in nature. Thus, a
polypeptide that is chemically synthesized or synthesized in a
cellular system different from the cell from which it naturally
originates will be "isolated" from its naturally associated
components. A protein may also be rendered substantially free of
naturally associated components by isolation, using protein
purification techniques well known in the art.
[0088] Examples of isolated antibodies include an anti-M-CSF
antibody that has been affinity purified using M-CSF, an anti-M-CSF
antibody that has been synthesized by a hybridoma or other cell
line in vitro, and a human anti-M-CSF antibody derived from a
transgenic mouse.
[0089] A protein or polypeptide is "substantially pure,"
"substantially homogeneous," or "substantially purified" when at
least about 60 to 75% of a sample exhibits a single species of
polypeptide. The polypeptide or protein may be monomeric or
multimeric. A substantially pure polypeptide or protein will
typically comprise about 50%, 60%, 70%, 80% or 90% W/W of a protein
sample, more usually about 95%, and preferably will be over 99%
pure. Protein purity or homogeneity may be indicated by a number of
means well known in the art, such as polyacrylamide gel
electrophoresis of a protein sample, followed by visualizing a
single polypeptide band upon staining the gel with a stain well
known in the art. For certain purposes, higher resolution may be
provided by using HPLC or other means well known in the art for
purification.
[0090] The term "polypeptide fragment" as used herein refers to a
polypeptide that has an amino-terminal and/or carboxy-terminal
deletion, but where the remaining amino acid sequence is identical
to the corresponding positions in the naturally-occurring sequence.
In some embodiments, fragments are at least 5, 6, 8 or 10 amino
acids long. In other embodiments, the fragments are at least 14, at
least 20, at least 50, or at least 70, 80, 90, 100, 150 or 200
amino acids long.
[0091] The term "polypeptide analog" as used herein refers to a
polypeptide that comprises a segment that has substantial identity
to a portion of an amino acid sequence and that has at least one of
the following properties: (1) specific binding to M-CSF under
suitable binding conditions, (2) ability to inhibit M-CSF.
[0092] Typically, polypeptide analogs comprise a conservative amino
acid substitution (or insertion or deletion) with respect to the
normally-occurring sequence. Analogs typically are at least 20 or
25 amino acids long, preferably at least 50, 60, 70, 80, 90, 100,
150 or 200 amino acids long or longer, and can often be as long as
a full-length polypeptide.
[0093] In certain embodiments, amino acid substitutions of the
antibody or antigen-binding portion thereof are those which: (1)
reduce susceptibility to proteolysis, (2) reduce susceptibility to
oxidation, (3) alter binding affinity for forming protein
complexes, or (4) confer or modify other physicochemical or
functional properties of such analogs. Analogs can include various
muteins of a sequence other than the normally-occurring peptide
sequence. For example, single or multiple amino acid substitutions
(preferably conservative amino acid substitutions) may be made in
the normally-occurring sequence, preferably in the portion of the
polypeptide outside the domain(s) forming intermolecular
contacts.
[0094] A conservative amino acid substitution should not
substantially change the structural characteristics of the parent
sequence; e.g., a replacement amino acid should not alter the
anti-parallel .beta.-sheet that makes up the immunoglobulin binding
domain that occurs in the parent sequence, or disrupt other types
of secondary structure that characterizes the parent sequence. In
general, glycine and proline analogs would not be used in an
anti-parallel .beta.-sheet. Examples of art-recognized polypeptide
secondary and tertiary structures are described in Proteins,
Structures and Molecular Principles (Creighton, Ed., W. H. Freeman
and Company, New York (1984)); Introduction to Protein Structure
(C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y.
(1991)); and Thornton et al., Nature 354:105 (1991), which are each
incorporated herein by reference.
[0095] Non-peptide analogs are commonly used in the pharmaceutical
industry as drugs with properties analogous to those of the
template peptide. These types of non-peptide compound are termed
"peptide mimetics" or "peptidomimetics." Fauchere, J. Adv. Drug
Res. 15:29 (1986); Veber and Freidinger, TINS p.392 (1985); and
Evans et al., J. Med. Chem. 30:1229 (1987), which are incorporated
herein by reference. Such compounds are often developed with the
aid of computerized molecular modeling. Peptide mimetics that are
structurally similar to therapeutically useful peptides may be used
to produce an equivalent therapeutic or prophylactic effect.
Generally, peptidomimetics are structurally similar to a paradigm
polypeptide (i.e., a polypeptide that has a desired biochemical
property or pharmacological activity), such as a human antibody,
but have one or more peptide linkages optionally replaced by a
linkage selected from the group consisting of: --CH.sub.2NH--,
--CH.sub.2S--, --CH.sub.2--CH.sub.2--, --CH.dbd.CH-- (cis and
trans), --COCH.sub.2--, --CH(OH)CH.sub.2--, and --CH.sub.2SO--, by
methods well known in the art. Systematic substitution of one or
more amino acids of a consensus sequence with a D-amino acid of the
same type (e.g., D-lysine in place of L-lysine) may also be used to
generate more stable peptides. In addition, constrained peptides
comprising a consensus sequence or a substantially identical
consensus sequence variation may be generated by methods known in
the art (Rizo and Gierasch, Ann. Rev. Biochem. 61:387 (1992),
incorporated herein by reference); for example, by adding internal
cysteine residues capable of forming intramolecular disulfide
bridges which cyclize the peptide.
[0096] An "antibody" refers to an intact antibody or an
antigen-binding portion that competes with the intact antibody for
specific binding. See generally, Fundamental Immunology, Ch. 7
(Paul, W., ed., 2nd ed. Raven Press, N.Y. (1989)) (incorporated by
reference in its entirety for all purposes). Antigen-binding
portions may be produced by recombinant DNA techniques or by
enzymatic or chemical cleavage of intact antibodies. In some
embodiments, antigen-binding portions include Fab, Fab',
F(ab').sub.2, Fd, Fv, dAb, and complementarity determining region
(CDR) fragments, single-chain antibodies (scFv), chimeric
antibodies, diabodies and polypeptides that contain at least a
portion of an antibody that is sufficient to confer specific
antigen binding to the polypeptide.
[0097] From N-terminus to C-terminus, both the mature light and
heavy chain variable domains comprise the regions FR1, CDR1, FR2,
CDR2, FR3, CDR3 and FR4. The assignment of amino acids to each
domain is in accordance with the definitions of Kabat, Sequences of
Proteins of Immunological Interest (National Institutes of Health,
Bethesda, Md. (1987 and 1991)), Chothia & Lesk, J. Mol. Biol.
196:901-917 (1987), or Chothia et al., Nature 342:878-883
(1989).
[0098] As used herein, an antibody that is referred to by number is
the same as a monoclonal antibody that is obtained from the
hybridoma of the same number. For example, monoclonal antibody
3.8.3 is the same antibody as one obtained from hybridoma
3.8.3.
[0099] As used herein, a Fd fragment means an antibody fragment
that consists of the V.sub.H and C.sub.H1 domains; an Fv fragment
consists of the V.sub.L and V.sub.H domains of a single arm of an
antibody; and a dAb fragment (Ward et al., Nature 341:544-546
(1989)) consists of a V.sub.H domain.
[0100] In some embodiments, the antibody is a single-chain antibody
(scFv) in which a V.sub.L and V.sub.H domains are paired to form a
monovalent molecules via a synthetic linker that enables them to be
made as a single protein chain. (Bird et al., Science 242:423-426
(1988) and Huston et al., Proc. Natl. Acad. Sci. USA 85:5879-5883
(1988).) In some embodiments, the antibodies are diabodies, i.e.,
are bivalent antibodies in which V.sub.H and V.sub.L domains are
expressed on a single polypeptide chain, but using a linker that is
too short to allow for pairing between the two domains on the same
chain, thereby forcing the domains to pair with complementary
domains of another chain and creating two antigen binding sites.
(See e.g., Holliger P. et al., Proc. Natl. Acad. Sci. USA
90:6444-6448 (1993), and Poljak R. J. et al., Structure 2:1121-1123
(1994).) In some embodiments, one or more CDRs from an antibody of
the invention may be incorporated into a molecule either covalently
or noncovalently to make it an immunoadhesin that specifically
binds to M-CSF. In such embodiments, the CDR(s) may be incorporated
as part of a larger polypeptide chain, may be covalently linked to
another polypeptide chain, or may be incorporated
noncovalently.
[0101] In embodiments having one or more binding sites, the binding
sites may be identical to one another or may be different.
[0102] As used herein, the term "human antibody" means any antibody
in which the variable and constant domain sequences are human
sequences. The term encompasses antibodies with sequences derived
from human genes, but which have been changed, e.g. to decrease
possible immunogenicity, increase affinity, eliminate cysteines
that might cause undesirable folding, etc. The term emcompasses
such antibodies produced recombinantly in non-human cells, which
might impart glycosylation not typical of human cells. These
antibodies may be prepared in a variety of ways, as described
below.
[0103] The term "chimeric antibody" as used herein means an
antibody that comprises regions from two or more different
antibodies. In one embodiment, one or more of the CDRs are derived
from a human anti-M-CSF antibody. In another embodiment, all of the
CDRs are derived from a human anti-M-CSF antibody. In another
embodiment, the CDRs from more than one human anti-M-CSF antibodies
are combined in a chimeric antibody. For instance, a chimeric
antibody may comprise a CDR1 from the light chain of a first human
anti-M-CSF antibody, a CDR2 from the light chain of a second human
anti-M-CSF antibody and a CDR3 from the light chain of a third
human anti-M-CSF antibody, and the CDRs from the heavy chain may be
derived from one or more other anti-M-CSF antibodies. Further, the
framework regions may be derived from one of the anti-M-CSF
antibodies from which one or more of the CDRs are taken or from one
or more different human antibodies.
[0104] Fragments or analogs of antibodies or immunoglobulin
molecules can be readily prepared by those of ordinary skill in the
art following the teachings of this specification. Preferred amino-
and carboxy-termini of fragments or analogs occur near boundaries
of functional domains. Structural and functional domains can be
identified by comparison of the nucleotide and/or amino acid
sequence data to public or proprietary sequence databases.
Preferably, computerized comparison methods are used to identify
sequence motifs or predicted protein conformation domains that
occur in other proteins of known structure and/or function. Methods
to identify protein sequences that fold into a known
three-dimensional structure are known. See Bowie et al., Science
253:164 (1991).
[0105] The term "surface plasmon resonance", as used herein, refers
to an optical phenomenon that allows for the analysis of real-time
biospecific interactions by detection of alterations in protein
concentrations within a biosensor matrix, for example using the
BIACORE.RTM. protein interaction analysis equipment (Pharmacia
Biosensor AB, Uppsala, Sweden and Piscataway, N.J.). For further
descriptions, see Jonsson U. et al., Ann. Biol. Clin. 51:19-26
(1993); Jonsson U. et al., Biotechniques 11:620-627 (1991); Jonsson
B. et al., J. Mol. Recognit. 8:125-131 (1995); and Johnsson B. et
al., Anal. Biochem. 198:268-277 (1991).
[0106] The term "K.sub.D" refers to the equilibrium dissociation
constant of a particular antibody-antigen interaction.
[0107] The term "epitope" includes any protein determinant capable
of specific binding to an immunoglobulin or T-cell receptor or
otherwise interacting with a molecule. Epitopic determinants
generally consist of chemically active surface groupings of
molecules such as amino acids or sugar side chains and generally
have specific three dimensional structural characteristics, as well
as specific charge characteristics. An epitope may be "linear" or
"conformational." In a linear epitope, all of the points of
interaction between the protein and the interacting molecule (such
as an antibody) occur linearally along the primary amino acid
sequence of the protein. In a conformational epitope, the points of
interaction occur across amino acid residues on the protein that
are separated from one another. An antibody is said to specifically
bind an antigen when the dissociation constant is .ltoreq.1 mM,
preferably .ltoreq.100 nM and most preferably .ltoreq.10 nM. In
certain embodiments, the K.sub.D is 1 pM to 500 pM. In other
embodiments, the K.sub.D is between 500 pM to 1 .mu.M. In other
embodiments, the K.sub.D is between 1 .mu.M to 100 nM. In other
embodiments, the K.sub.D is between 100 mM to 10 nM. Once a desired
epitope on an antigen is determined, it is possible to generate
antibodies to that epitope, e.g., using the techniques described in
the present invention. Alternatively, during the discovery process,
the generation and characterization of antibodies may elucidate
information about desirable epitopes. From this information, it is
then possible to competitively screen antibodies for binding to the
same epitope. An approach to achieve this is to conduct
cross-competition studies to find antibodies that competitively
bind with one another, e.g., the antibodies compete for binding to
the antigen. A high throughout process for "binning" antibodies
based upon their cross-competition is described in International
Patent Application No. WO 03/48731.
[0108] As used herein, the twenty conventional amino acids and
their abbreviations follow conventional usage. See Immunology--A
Synthesis (2.sup.nd Edition, E. S. Golub and D. R. Gren, Eds.,
Sinauer Associates, Sunderland, Mass. (1991)), which is
incorporated herein by reference.
[0109] The term "polynucleotide" as referred to herein means a
polymeric form of nucleotides of at least 10 bases in length,
either ribonucleotides or deoxynucleotides or a modified form of
either type of nucleotide. The term includes single and double
stranded forms.
[0110] The term "isolated polynucleotide" as used herein means a
polynucleotide of genomic, cDNA, or synthetic origin or some
combination thereof, which by virtue of its origin or source of
derivation, the "isolated polynucleotide" has one to three of the
following: (1) is not associated with all or a portion of a
polynucleotides with which the "isolated polynucleotide" is found
in nature, (2) is operably linked to a polynucleotide to which it
is not linked in nature, or (3) does not occur in nature as part of
a larger sequence.
[0111] The term "oligonucleotide" as used herein includes naturally
occurring, and modified nucleotides linked together by naturally
occurring and non-naturally occurring oligonucleotide linkages.
Oligonucleotides are a polynucleotide subset generally comprising a
length of 200 bases or fewer. Preferably oligonucleotides are 10 to
60 bases in length and most preferably 12, 13, 14, 15, 16, 17, 18,
19, or 20 to 40 bases in length. Oligonucleotides are usually
single stranded, e.g. for primers and probes; although
oligonucleotides may be double stranded, e.g. for use in the
construction of a gene mutant. Oligonucleotides of the invention
can be either sense or antisense oligonucleotides.
[0112] The term "naturally occurring nucleotides" as used herein
includes deoxyribonucleotides and ribonucleotides. The term
"modified nucleotides" as used herein includes nucleotides with
modified or substituted sugar groups and the like. The term
"oligonucleotide linkages" referred to herein includes
oligonucleotides linkages such as phosphorothioate,
phosphorodithioate, phosphoroselenoate, phosphorodiselenoate,
phosphoroanilothioate, phoshoraniladate, phosphoroamidate, and the
like. See e.g., LaPlanche et al., Nucl. Acids Res. 14:9081 (1986);
Stec et al., J. Am. Chem. Soc. 106:6077 (1984); Stein et al., Nucl.
Acids Res. 16:3209 (1988); Zon et al., Anti-Cancer Drug Design
6:539 (1991); Zon et al., Oligonucleotides and Analogues: A
Practical Approach, pp. 87-108 (F. Eckstein, Ed., Oxford University
Press, Oxford England (1991)); U.S. Pat. No. 5,151,510; Uhlmann and
Peyman, Chemical Reviews 90:543 (1990), the disclosures of which
are hereby incorporated by reference. An oligonucleotide can
include a label for detection, if desired.
[0113] "Operably linked" sequences include both expression control
sequences that are contiguous with the gene of interest and
expression control sequences that act in trans or at a distance to
control the gene of interest. The term "expression control
sequence" as used herein means polynucleotide sequences that are
necessary to effect the expression and processing of coding
sequences to which they are ligated. Expression control sequences
include appropriate transcription initiation, termination, promoter
and enhancer sequences; efficient RNA processing signals such as
splicing and polyadenylation signals; sequences that stabilize
cytoplasmic mRNA; sequences that enhance translation efficiency
(i.e., Kozak consensus sequence); sequences that enhance protein
stability; and when desired, sequences that enhance protein
secretion. The nature of such control sequences differs depending
upon the host organism; in prokaryotes, such control sequences
generally include promoter, ribosomal binding site, and
transcription termination sequence; in eukaryotes, generally, such
control sequences include promoters and transcription termination
sequence. The term "control sequences" is intended to include, at a
minimum, all components whose presence is essential for expression
and processing, and can also include additional components whose
presence is advantageous, for example, leader sequences and fusion
partner sequences.
[0114] The term "vector", as used herein, means a nucleic acid
molecule capable of transporting another nucleic acid to which it
has been linked. In some embodiments, the vector is a plasmid,
i.e., a circular double stranded DNA loop into which additional DNA
segments may be ligated. In some embodiments, the vector is a viral
vector, wherein additional DNA segments may be ligated into the
viral genome. In some embodiments, the vectors are capable of
autonomous replication in a host cell into which they are
introduced (e.g., bacterial vectors having a bacterial origin of
replication and episomal mammalian vectors). In other embodiments,
the vectors (e.g., non-episomal mammalian vectors) can be
integrated into the genome of a host cell upon introduction into
the host cell, and thereby are replicated along with the host
genome. Moreover, certain vectors are capable of directing the
expression of genes to which they are operatively linked. Such
vectors are referred to herein as "recombinant expression vectors"
(or simply, "expression vectors").
[0115] The term "recombinant host cell" (or simply "host cell"), as
used herein, means a cell into which a recombinant expression
vector has been introduced. It should be understood that
"recombinant host cell" and "host cell" mean not only the
particular subject cell but also the progeny of such a cell.
Because certain modifications may occur in succeeding generations
due to either mutation or environmental influences, such progeny
may not, in fact, be identical to the parent cell, but are still
included within the scope of the term "host cell" as used
herein.
[0116] The term "selectively hybridize" referred to herein means to
detectably and specifically bind. Polynucleotides, oligonucleotides
and fragments thereof in accordance with the invention selectively
hybridize to nucleic acid strands under hybridization and wash
conditions that minimize appreciable amounts of detectable binding
to nonspecific nucleic acids. "High stringency" or "highly
stringent" conditions can be used to achieve selective
hybridization conditions as known in the art and discussed herein.
One example of "high stringency" or "highly stringent" conditions
is the incubation of a polynucleotide with another polynucleotide,
wherein one polynucleotide may be affixed to a solid surface such
as a membrane, in a hybridization buffer of 6.times.SSPE or SSC,
50% formamide, 5.times.Denhardt's reagent, 0.5% SDS, 100 .mu.g/ml
denatured, fragmented salmon sperm DNA at a hybridization
temperature of 42.degree. C. for 12-16 hours, followed by twice
washing at 55.degree. C. using a wash buffer of 1.times.SSC, 0.5%
SDS. See also Sambrook et al., supra, pp. 9.50-9.55.
[0117] The term "percent sequence identity" in the context of
nucleic acid sequences means the percent of residues when a first
contiguous sequence is compared and aligned for maximum
correspondence to a second contiguous sequence. The length of
sequence identity comparison may be over a stretch of at least
about nine nucleotides, usually at least about 18 nucleotides, more
usually at least about 24 nucleotides, typically at least about 28
nucleotides, more typically at least about 32 nucleotides, and
preferably at least about 36, 48 or more nucleotides. There are a
number of different algorithms known in the art which can be used
to measure nucleotide sequence identity. For instance,
polynucleotide sequences can be compared using FASTA, Gap or
Bestfit, which are programs in Wisconsin Package Version 10.0,
Genetics Computer Group (GCG), Madison, Wis. FASTA, which includes,
e.g., the programs FASTA2 and FASTA3, provides alignments and
percent sequence identity of the regions of the best overlap
between the query and search sequences (Pearson, Methods Enzymol.
183:63-98 (1990); Pearson, Methods Mol. Biol. 132:185-219 (2000);
Pearson, Methods Enzymol. 266:227-258 (1996); Pearson, J. Mol.
Biol. 276:71-84 (1998); herein incorporated by reference). Unless
otherwise specified, default parameters for a particular program or
algorithm are used. For instance, percent sequence identity between
nucleic acid sequences can be determined using FASTA with its
default parameters (a word size of 6 and the NOPAM factor for the
scoring matrix) or using Gap with its default parameters as
provided in GCG Version 6.1, herein incorporated by reference.
[0118] A reference to a nucleotide sequence encompasses its
complement unless otherwise specified. Thus, a reference to a
nucleic acid having a particular sequence should be understood to
encompass its complementary strand, with its complementary
sequence.
[0119] The term "percent sequence identity" means a ratio,
expressed as a percent of the number of identical residues over the
number of residues compared.
[0120] The term "substantial similarity" or "substantial sequence
similarity," when referring to a nucleic acid or fragment thereof,
means that when optimally aligned with appropriate nucleotide
insertions or deletions with another nucleic acid (or its
complementary strand), there is nucleotide sequence identity in at
least about 85%, preferably at least about 90%, and more preferably
at least about 95%, 96%, 97%, 98% or 99% of the nucleotide bases,
as measured by any well-known algorithm of sequence identity, such
as FASTA, BLAST or Gap, as discussed above.
[0121] As applied to polypeptides, the term "substantial identity"
means that two peptide sequences, when optimally aligned, such as
by the programs GAP or BESTFIT using default gap weights, as
supplied with the programs, share at least 70%, 75% or 80% sequence
identity, preferably at least 90% or 95% sequence identity, and
more preferably at least 97%, 98% or 99% sequence identity. In
certain embodiments, residue positions that are not identical
differ by conservative amino acid substitutions. A "conservative
amino acid substitution" is one in which an amino acid residue is
substituted by another amino acid residue having a side chain R
group with similar chemical properties (e.g., charge or
hydrophobicity). In general, a conservative amino acid substitution
will not substantially change the functional properties of a
protein. In cases where two or more amino acid sequences differ
from each other by conservative substitutions, the percent sequence
identity may be adjusted upwards to correct for the conservative
nature of the substitution. Means for making this adjustment are
well-known to those of skill in the art. See, e.g., Pearson,
Methods Mol. Biol. 243:307-31 (1994). Examples of groups of amino
acids that have side chains with similar chemical properties
include 1) aliphatic side chains: glycine, alanine, valine,
leucine, and isoleucine; 2) aliphatic-hydroxyl side chains: serine
and threonine; 3) amide-containing side chains: asparagine and
glutamine; 4) aromatic side chains: phenylalanine, tyrosine, and
tryptophan; 5) basic side chains: lysine, arginine, and histidine;
6) acidic side chains: aspartic acid and glutamic acid; and 7)
sulfur-containing side chains: cysteine and methionine.
Conservative amino acids substitution groups are:
valine-leucine-isoleucine, phenylalanine-tyrosine, lysine-arginine,
alanine-valine, glutamate-aspartate, and asparagine-glutamine.
[0122] Alternatively, a conservative replacement is any change
having a positive value in the PAM250 log-likelihood matrix
disclosed in Gonnet et al., Science 256:1443-45 (1992), herein
incorporated by reference. A "moderately conservative" replacement
is any change having a nonnegative value in the PAM250
log-likelihood matrix.
[0123] Sequence identity for polypeptides, is typically measured
using sequence analysis software. Protein analysis software matches
sequences using measures of similarity assigned to various
substitutions, deletions and other modifications, including
conservative amino acid substitutions. For instance, GCG contains
programs such as "Gap" and "Bestfit" which can be used with default
parameters, as specified with the programs, to determine sequence
homology or sequence identity between closely related polypeptides,
such as homologous polypeptides from different species of organisms
or between a wild type protein and a mutein thereof. See, e.g., GCG
Version 6.1. Polypeptide sequences also can be compared using FASTA
using default or recommended parameters, see GCG Version 6.1.
(University of Wisconsin Wis.) FASTA (e.g., FASTA2 and FASTA3)
provides alignments and percent sequence identity of the regions of
the best overlap between the query and search sequences (Pearson,
Methods Enzymol. 183:63-98 (1990); Pearson, Methods Mol. Biol.
132:185-219 (2000)). Another preferred algorithm when comparing a
sequence of the invention to a database containing a large number
of sequences from different organisms is the computer program
BLAST, especially blastp or tblastn, using default parameters, as
supplied with the programs. See, e.g., Altschul et al., J. Mol.
Biol. 215:403-410 (1990); Altschul et al., Nucleic Acids Res.
25:3389-402 (1997).
[0124] The length of polypeptide sequences compared for homology
will generally be at least about 16 amino acid residues, usually at
least about 20 residues, more usually at least about 24 residues,
typically at least about 28 residues, and preferably more than
about 35 residues. When searching a database containing sequences
from a large number of different organisms, it is preferable to
compare amino acid sequences.
[0125] As used herein, the terms "label" or "labeled" refers to
incorporation of another molecule in the antibody. In one
embodiment, the label is a detectable marker, e.g., incorporation
of a radiolabeled amino acid or attachment to a polypeptide of
biotinyl moieties that can be detected by marked avidin (e.g.,
streptavidin containing a fluorescent marker or enzymatic activity
that can be detected by optical or colorimetric methods). In
another embodiment, the label or marker can be therapeutic, e.g., a
drug conjugate or toxin. Various methods of labeling polypeptides
and glycoproteins are known in the art and may be used. Examples of
labels for polypeptides include, but are not limited to, the
following: radioisotopes or radionuclides (e.g., .sup.3H, .sup.14C,
.sup.15N, .sup.35S, .sup.90Y, .sup.99Tc, .sup.111In, .sup.125I,
.sup.131I) fluorescent labels (e.g., FITC, rhodamine, lanthanide
phosphors), enzymatic labels (e.g., horseradish peroxidase,
.beta.-galactosidase, luciferase, alkaline phosphatase),
chemiluminescent markers, biotinyl groups, predetermined
polypeptide epitopes recognized by a secondary reporter (e.g.,
leucine zipper pair sequences, binding sites for secondary
antibodies, metal binding domains, epitope tags), magnetic agents,
such as gadolinium chelates, toxins such as pertussis toxin, taxol,
cytochalasin B, gramicidin D, ethidium bromide, emetine, mitomycin,
etoposide, tenoposide, vincristine, vinblastine, colchicin,
doxorubicin, daunorubicin, dihydroxy anthracin dione, mitoxantrone,
mithramycin, actinomycin D, 1-dehydrotestosterone, glucocorticoids,
procaine, tetracaine, lidocaine, propranolol, and puromycin and
analogs or homologs thereof. In some embodiments, labels are
attached by spacer arms of various lengths to reduce potential
steric hindrance.
[0126] Throughout this specification and claims, the word
"comprise," or variations such as "comprises" or "comprising," will
be understood to imply the inclusion of a stated integer or group
of integers but not the exclusion of any other integer or group of
integers.
Human Anti-M-CSF Antibodies and Characterization Thereof
[0127] In one embodiment, the invention provides humanized
anti-M-CSF antibodies. In another embodiment, the invention
provides human anti-M-CSF antibodies. In some embodiments, human
anti-M-CSF antibodies are produced by immunizing a non-human
transgenic animal, e.g., a rodent, whose genome comprises human
immunoglobulin genes so that the rodent produces human
antibodies.
[0128] An anti-M-CSF antibody of the invention can comprise a human
kappa or a human lamda light chain or an amino acid sequence
derived therefrom. In some embodiments comprising a kappa light
chain, the light chain variable domain (V.sub.L) is encoded in part
by a human V.sub..kappa.O12, V.sub..kappa.L2, V.sub..kappa.L5,
V.sub..kappa.A27 or V.sub..kappa.B3 gene and a J.sub..kappa.1,
J.sub..kappa.2, or J.sub..kappa.4 gene. In particular embodiments
of the invention, the light chain variable domain is encoded by
V.sub..kappa.O12/J.sub..kappa.3, V.sub..kappa.L2/J.sub..kappa.3,
V.sub..kappa.L5/J.sub..kappa.3, V.sub..kappa.L5/J.sub..kappa.4,
V.sub..kappa.A27/J.sub..kappa.4 or V.sub..kappa.B3/J.sub..kappa.1
gene.
[0129] In some embodiments, the V.sub.L of the M-CSF antibody
comprises one or more amino acid substitutions relative to the
germline amino acid sequence. In some embodiments, the V.sub.L of
the anti-M-CSF antibody comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10
amino acid substitutions relative to the germline amino acid
sequence. In some embodiments, one or more of those substitutions
from germline is in the CDR regions of the light chain. In some
embodiments, the amino acid substitutions relative to germline are
at one or more of the same positions as the substitutions relative
to germline in any one or more of the V.sub.L of antibodies 252,
88, 100, 3.8.3, 2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4,
8.10.3, 9.7.2, 9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2,
9.7.2-CG2, 9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser,
9.7.2-Ser, 8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1. For
example, the V.sub.L of the anti-M-CSF antibody may contain one or
more amino acid substitutions compared to germline found in the
V.sub.L of antibody 88, and other amino acid substitutions compared
to germline found in the V.sub.L of antibody 252 which utilizes the
same V.sub..kappa. gene as antibody 88. In some embodiments, the
amino acid changes are at one or more of the same positions but
involve a different mutation than in the reference antibody.
[0130] In some embodiments, amino acid changes relative to germline
occur at one or more of the same positions as in any of the V.sub.L
of antibodies 252, 88, 100, 3.8.3, 2.7.3, 1.120.1, 9.14.41,
8.10.3F, 9.7.2IF, 9.14.4, 8.10.3, 9.7.2, 9.7.2C-Ser, 9.14.4C-Ser,
8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2, 9.7.2-CG4, 9.14.4-CG2,
9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser, 8.10.3-Ser, 8.10.3-CG4,
8.10.3FG1 or 9.14.4G1, but the changes may represent conservative
amino acid substitutions at such position(s) relative to the amino
acid in the reference antibody. For example, if a particular
position in one of these antibodies is changed relative to germline
and is glutamate, one may substitute aspartate at that position.
Similarly, if an amino acid substitution compared to germline is
serine, one may substitute threonine for serine at that position.
Conservative amino acid substitutions are discussed supra.
[0131] In some embodiments, the light chain of the human anti-M-CSF
antibody comprises the amino acid sequence that is the same as the
amino acid sequence of the V.sub.L of antibody 252 (SEQ ID NO: 4),
88 (SEQ ID NO: 8), 100 (SEQ ID NO: 12), 3.8.3 (SEQ ID NO: 16),
2.7.3 (SEQ ID NO: 20), 1.120.1 (SEQ ID NO: 24), 9.14.41 (SEQ ID NO:
28), 8.10.3F (SEQ ID NO: 32), 9.7.2IF (SEQ ID NO: 36), 9.14.4 (SEQ
ID NO: 28), 8.10.3 (SEQ ID NO: 44), 9.7.2 (SEQ ID NO: 48),
9.7.2C-Ser (SEQ ID NO: 52), 9.14.4C-Ser (SEQ ID NO: 56),
8.10.3C-Ser (SEQ ID NO: 60), 8.10.3-CG2 (SEQ ID NO: 60), 9.7.2-CG2
(SEQ ID NO: 52), 9.7.2-CG4 (SEQ ID NO: 52), 9.14.4-CG2 (SEQ ID NO:
56), 9.14.4-CG4 (SEQ ID NO: 56), 9.14.4-Ser (SEQ ID NO: 28),
9.7.2-Ser (SEQ ID NO: 48), 8.10.3-Ser (SEQ ID NO: 44), 8.10.3-CG4
(SEQ ID NO: 60) 8.10.3FG1 (SEQ ID NO: 32) or 9.14.4G1 (SEQ ID NO:
28), or said amino acid sequence having up to 1, 2, 3, 4, 5, 6, 7,
8, 9, or 10 conservative amino acid substitutions and/or a total of
up to 3 non-conservative amino acid substitutions. In some
embodiments, the light chain comprises the amino acid sequence from
the beginning of the CDR1 to the end of the CDR3 of any one of the
foregoing antibodies.
[0132] In some embodiments, the light chain of the anti-M-CSF
antibody comprises at least the light chain CDR1, CDR2 or CDR3 of a
germline or antibody sequence, as described herein. In another
embodiment, the light chain may comprise a CDR1, CDR2 or CDR3
regions of an antibody independently selected from 252, 88, 100,
3.8.3, 2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3,
9.7.2, 9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2,
9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser,
8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1, or CDR regions each
having less than 4 or less than 3 conservative amino acid
substitutions and/or a total of three or fewer non-conservative
amino acid substitutions. In other embodiments, the light chain of
the anti-M-CSF antibody comprises the light chain CDR1, CDR2 or
CDR3, each of which are independently selected from the CDR1, CDR2
and CDR3 regions of an antibody having a light chain variable
region comprising the amino acid sequence of the V.sub.L region
selected from SEQ ID NOS: 4, 8, 12, 16, 20, 24, 28, 32, 36, 44, 48,
52, 56 or 60, or encoded by a nucleic acid molecule encoding the
V.sub.L region selected from SEQ ID NOS: 3, 7, 11, 27, 31, 35, 43
or 47. The light chain of the anti-M-CSF antibody may comprise the
CDR1, CDR2 and CDR3 regions of an antibody comprising the amino
acid sequence of the V.sub.L region selected from 252, 88, 100,
3.8.3, 2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3,
9.7.2, 9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2,
9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser,
8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1 or SEQ ID NOS: 4, 8,
12, 16, 20, 24, 28, 32, 36, 44, 48, 52, 56 or 60.
[0133] In some embodiments, the light chain comprises the CDR1,
CDR2 and CDR3 regions of antibody 252, 88, 100, 3.8.3, 2.7.3,
1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3, 9.7.2,
9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2,
9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser,
8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1, or said CDR regions
each having less than 4 or less than 3 conservative amino acid
substitutions and/or a total of three or fewer non-conservative
amino acid substitutions.
[0134] With regard to the heavy chain, in some embodiments, the
variable region of the heavy chain amino acid sequence is encoded
in part by a human V.sub.H3-11, V.sub.H3-23, V.sub.H3-7,
V.sub.H1-18, V.sub.H3-33, V.sub.H3-48 gene and a J.sub.H4,
J.sub.H6, J.sub.H4b, or J.sub.H6b gene. In a particular embodiment
of the invention, the heavy chain variable region is encoded by
V.sub.H3-11/D.sub.H7-27/J.sub.H6, V.sub.H3-7/D.sub.H6-13/J.sub.H4,
V.sub.H3-23/D.sub.H1-26/J.sub.H4, V.sub.H3-11/D.sub.H7-27/J.sub.H4,
V.sub.H3-33/D.sub.H1-26/J.sub.H4, V.sub.H1-18/D.sub.H4-23/J.sub.H4,
V.sub.H3-11/D.sub.H7-27/J.sub.H4b,
V.sub.H3-48/D.sub.H1-26/J.sub.H4b,
V.sub.H3-11/D.sub.H6-13/J.sub.H6b,
V.sub.H3-11/D.sub.H7-27/J.sub.H4b,
V.sub.H3-48/D.sub.H1-6/J.sub.H4b, or
V.sub.H3-11/D.sub.H6-13/J.sub.H6b gene. In some embodiments, the
V.sub.H of the anti-M-CSF antibody contains one or more amino acid
substitutions, deletions or insertions (additions) relative to the
germline amino acid sequence. In some embodiments, the variable
domain of the heavy chain comprises 1, 2, 3, 4, 5, 6, 7, 8, 9, 10,
11, 12, 13, 14, 15, 16, 17, or 18 mutations from the germline amino
acid sequence. In some embodiments, the mutation(s) are
non-conservative substitutions compared to the germline amino acid
sequence. In some embodiments, the mutations are in the CDR regions
of the heavy chain. In some embodiments, the amino acid changes are
made at one or more of the same positions as the mutations from
germline in any one or more of the V.sub.H of antibodies 252, 88,
100, 3.8.3, 2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.21F, 9.14.4,
8.10.3, 9.7.2, 9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2,
9.7.2-CG2, 9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser,
9.7.2-Ser, 8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1. In other
embodiments, the amino acid changes are at one or more of the same
positions but involve a different mutation than in the reference
antibody.
[0135] In some embodiments, the heavy chain comprises an amino acid
sequence of the variable domain (V.sub.H) of antibody 252 (SEQ ID
NO: 2), 88 (SEQ ID NO: 6), 100 (SEQ ID NO: 10), 3.8.3 (SEQ ID NO:
14), 2.7.3 (SEQ. ID NO: 18), 1.120.1 (SEQ. ID NO: 22), 9.14.41 (SEQ
ID NO: 26), 8.10.3F (SEQ ID NO: 30), 9.7.21F (SEQ ID NO: 34),
9.14.4 (SEQ ID NO: 38), 8.10.3 (SEQ ID NO: 30), 9.7.2 (SEQ ID NO:
46), 9.7.2C-Ser (SEQ ID NO: 50), 9.14.4C-Ser (SEQ ID NO: 54),
8.10.3C-Ser (SEQ ID NO: 58), 8.10.3-CG2 (SEQ ID NO: 62), 9.7.2-CG2
(SEQ ID NO: 66), 9.7.2-CG4 (SEQ ID NO: 70), 9.14.4-CG2 (SEQ ID NO:
74), 9.14.4-CG4 (SEQ ID NO: 78), 9.14.4-Ser (SEQ ID NO: 82),
9.7.2-Ser (SEQ ID NO: 86), 8.10.3-Ser (SEQ ID NO: 90) 8.10.3-CG4
(SEQ ID NO: 94), 8.10.3FG1 (SEQ ID NO: 98) or 9.14.4G1 (SEQ ID NO:
102), or said amino acid sequence having up to 1, 2, 3, 4, 5, 6, 7,
8, 9, or 10 conservative amino acid substitutions and/or a total of
up to 3 non-conservative amino acid substitutions. In some
embodiments, the heavy chain comprises the amino acid sequence from
the beginning of the CDR1 to the end of the CDR3 of any one of the
foregoing antibodies.
[0136] In some embodiments, the heavy chain comprises the heavy
chain CDR1, CDR2 and CDR3 regions of antibody 252, 88, 100, 3.8.3,
2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.21F, 9.14.4, 8.10.3, 9.7.2,
9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2,
9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser,
8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1, or said CDR regions
each having less than 8, less than 6, less than 4, or less than 3
conservative amino acid substitutions and/or a total of three or
fewer non-conservative amino acid substitutions.
[0137] In some embodiments, the heavy chain comprises a germline or
antibody CDR3, as described above, of an antibody sequence as
described herein, and may also comprise the CDR1 and CDR2 regions
of a germline sequence, or may comprise a CDR1 and CDR2 of an
antibody sequence, each of which are independently selected from an
antibody comprising a heavy chain of an antibody selected from 252,
88, 100, 3.8.3, 2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4,
8.10.3, 9.7.2, 9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2,
9.7.2-CG2, 9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser,
9.7.2-Ser, 8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1. In
another embodiment, the heavy chain comprises a CDR3 of an antibody
sequence as described herein, and may also comprise the CDR1 and
CDR2 regions, each of which are independently selected from a CDR1
and CDR2 region of a heavy chain variable region comprising an
amino acid sequence of the V.sub.H region selected from SEQ ID NOS:
2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 46, 50, 54, 58, 62, 66, 70,
74, 78, 82, 86, 90, 94, 98 or 102, or encoded by a nucleic acid
sequence encoding the V.sub.H region selected from SEQ ID NOS: 1,
5, 9, 25, 29, 33, 37, 45, 97 or 101. In another embodiment, the
antibody comprises a light chain as disclosed above and a heavy
chain as disclosed above.
[0138] One type of amino acid substitution that may be made is to
change one or more cysteines in the antibody, which may be
chemically reactive, to another residue, such as, without
limitation, alanine or serine. In one embodiment, there is a
substitution of a non-canonical cysteine. The substitution can be
in a framework region of a variable domain or in the constant
domain of an antibody. In another embodiment, the cysteine is in a
non-canonical region of the antibody.
[0139] Another type of amino acid substitution that may be made is
to remove any potential proteolytic sites in the antibody,
particularly those that are in a CDR or framework region of a
variable domain or in the constant domain of an antibody.
Substitution of cysteine residues and removal of proteolytic sites
may decrease the risk of any heterogeneity in the antibody product
and thus increase its homogeneity. Another type of amino acid
substitution is elimination of asparagine-glycine pairs, which form
potential deamidation sites, by altering one or both of the
residues.
[0140] In some embodiments, the C-terminal lysine of the heavy
chain of the anti-M-CSF antibody of the invention is not present
(Lewis D. A., et al., Anal. Chem, 66(5): 585-95 (1994)). In various
embodiments of the invention, the heavy and light chains of the
anti-M-CSF antibodies may optionally include a signal sequence.
[0141] In one aspect, the invention relates to inhibiting human
anti-M-CSF monoclonal antibodies and the cell lines engineered to
produce them. Table 1 lists the sequence identifiers (SEQ ID NOS)
of the nucleic acids that encode the variable region of the heavy
and light chains and the corresponding predicted amino acid
sequences for the monoclonal antibodies: 252, 88, 100, 3.8.3,
2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3 and
9.7.2. Additional variant antibodies 9.7.2C-Ser, 9.14.4C-Ser,
8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2, 9.7.2-CG4, 9.14.4-CG2,
9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser, 8.10.3-Ser, 8.10.3-CG4 8.10.3FG1
or 9.14.4G1 could be made by methods known to one skilled in the
art.
TABLE-US-00001 TABLE 1 HUMAN ANTI-M-CSF ANTIBODIES SEQUENCE
IDENTIFIER (SEQ ID NOS:) Full Length Heavy Light MAb DNA Protein
DNA Protein 252 1 2 3 4 88 5 6 7 8 100 9 10 11 12 3.8.3 14 16 2.7.3
18 20 1.120.1 22 24 9.14.4I 25 26 27 28 9.14.4 37 38 27 28
9.14.4C-Ser 54 56 9.14.4-CG2 74 56 9.14.4-CG4 78 56 9.14.4-Ser 82
27 28 9.14.4-G1 101 102 27 28 8.10.3F 29 30 31 32 8.10.3 29 30 43
44 8.10.3C-Ser 58 60 8.10.3-CG2 62 60 8.10.3-Ser 90 43 44
8.10.3-CG4 94 60 8.10.3FG1 97 98 31 32 9.7.2IF 33 34 35 36 9.7.2 45
46 47 48 9.7.2C-Ser 50 52 9.7.2-CG2 66 52 9.7.2-CG4 70 52 9.7.2-Ser
86 47 48
Class and Subclass of Anti-M-CSF Antibodies
[0142] The class and subclass of anti-M-CSF antibodies may be
determined by any method known in the art. In general, the class
and subclass of an antibody may be determined using antibodies that
are specific for a particular class and subclass of antibody. Such
antibodies are commercially available. The class and subclass can
be determined by ELISA, or Western Blot as well as other
techniques. Alternatively, the class and subclass may be determined
by sequencing all or a portion of the constant domains of the heavy
and/or light chains of the antibodies, comparing their amino acid
sequences to the known amino acid sequences of various class and
subclasses of immunoglobulins, and determining the class and
subclass of the antibodies.
[0143] In some embodiments, the anti-M-CSF antibody is a monoclonal
antibody. The anti-M-CSF antibody can be an IgG, an IgM, an IgE, an
IgA, or an IgD molecule. In preferred embodiments, the anti-M-CSF
antibody is an IgG and is an IgG1, IgG2, IgG3 or IgG4 subclass. In
other preferred embodiments, the antibody is subclass IgG2 or IgG4.
In another preferred embodiment, the antibody is subclass IgG1.
Species and Molecular Selectivity
[0144] In another aspect of the invention, the anti-M-CSF
antibodies demonstrate both species and molecule selectivity. In
some embodiments, the anti-M-CSF antibody binds to human,
cynomologus monkey and mouse M-CSF. Following the teachings of the
specification, one may determine the species selectivity for the
anti-M-CSF antibody using methods well known in the art. For
instance, one may determine the species selectivity using Western
blot, FACS, ELISA, RIA, a cell proliferation assay, or a M-CSF
receptor binding assay. In a preferred embodiment, one may
determine the species selectivity using a cell proliferation assay
or ELISA. In some embodiments, the anti-M-CSF antibodies bind to
human secreted isoforms of M-CSF and membrane bound isoforms of
M-CSF.
[0145] In another embodiment, the anti-M-CSF antibody has a
selectivity for M-CSF that is at least 100 times greater than its
selectivity for GM-/G-CSF. In some embodiments, the anti-M-CSF
antibody does not exhibit any appreciable specific binding to any
other protein other than M-CSF. One can determine the selectivity
of the anti-M-CSF antibody for M-CSF using methods well known in
the art following the teachings of the specification. For instance
one can determine the selectivity using Western blot, FACS, ELISA,
or RIA.
Identification of M-CSF Epitopes Recognized by Anti-M-CSF
Antibodies
[0146] The invention provides a human anti-M-CSF monoclonal
antibody that binds to M-CSF and competes with, cross-competes with
and/or binds the same epitope and/or binds to M-CSF with the same
K.sub.D as (a) an antibody selected from 252, 88, 100, 3.8.3,
2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3, 9.7.2,
9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2,
9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser,
8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1; (b) an antibody that
comprises a heavy chain variable region having an amino acid
sequence of SEQ ID NO: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 46,
50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98 or 102; (c) an
antibody that comprises a light chain variable region having an
amino acid sequence of SEQ ID NO: 4, 8, 12, 16, 20, 24, 28, 32, 36,
44, 48, 52, 56 or 60; (d) an antibody that comprises both a heavy
chain variable region as defined in (b) and a light chain variable
region as defined in (c).
[0147] One can determine whether an antibody binds to the same
epitope, competes for binding with, cross competes for binding with
or has the same K.sub.D an anti-M-CSF antibody by using methods
known in the art. In one embodiment, one allows the anti-M-CSF
antibody of the invention to bind to M-CSF under saturating
conditions and then measures the ability of the test antibody to
bind to M-CSF. If the test antibody is able to bind to M-CSF at the
same time as the anti-M-CSF antibody, then the test antibody binds
to a different epitope as the anti-M-CSF antibody. However, if the
test antibody is not able to bind to M-CSF at the same time, then
the test antibody binds to the same epitope, an overlapping
epitope, or an epitope that is in close proximity to the epitope
bound by the human anti-M-CSF antibody. This experiment can be
performed using ELISA, RIA, or FACS. In a preferred embodiment, the
experiment is performed using BIACORE.RTM. protein interaction
analysis equipment.
Binding Affinity of Anti-M-CSF Antibodies to M-CSF
[0148] In some embodiments of the invention, the anti-M-CSF
antibodies bind to M-CSF with high affinity. In some embodiments,
the anti-M-CSF antibody binds to M-CSF with a K.sub.D of
1.times.10.sup.-7M or less. In other preferred embodiments, the
antibody binds to M-CSF with a K.sub.D of 1.times.10.sup.-8 M,
1.times.10.sup.-9M, 1.times.10.sup.-10 M, 1.times.10.sup.-11 M,
1.times.10.sup.-12M or less. In certain embodiments, the K.sub.D is
1 pM to 500 pM. In other embodiments, the K.sub.D is between 500 pM
to 1 .mu.M. In other embodiments, the K.sub.D is between 1 .mu.M to
100 nM. In other embodiments, the K.sub.D is between 100 mM to 10
nM. In an even more preferred embodiment, the antibody binds to
M-CSF with substantially the same K.sub.D as an antibody selected
from 252, 88, 100, 3.8.3, 2.7.3, 1.120.1, 9.14.41, 8.10.3F,
9.7.2IF, 9.14.4, 8.10.3, 9.7.2, 9.7.2C-Ser, 9.14.4C-Ser,
8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2, 9.7.2-CG4, 9.14.4-CG2,
9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser, 8.10.3-Ser, 8.10.3-CG4,
8.10.3FG1 or 9.14.4G1. In another preferred embodiment, the
antibody binds to M-CSF with substantially the same K.sub.D as an
antibody that comprises a CDR2 of a light chain, and/or a CDR3 of a
heavy chain from an antibody selected from 252, 88, 100, 3.8.3,
2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3, 9.7.2,
9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2,
9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser,
8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1. In still another
preferred embodiment, the antibody binds to M-CSF with
substantially the same K.sub.D as an antibody that comprises a
heavy chain variable region having an amino acid sequence of SEQ ID
NO: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 46, 50, 54, 58, 62, 66,
70, 74, 78, 82, 86, 90, 94, 98 or 102, or that comprises a light
chain variable region having an amino acid sequence of SEQ ID NO:
4, 8, 12, 16, 20, 24, 28, 32, 36, 44, 48, 52, 56 or 60. In another
preferred embodiment, the antibody binds to M-CSF with
substantially the same K.sub.D as an antibody that comprises a
CDR2, and may optionally comprise a CDR1 and/or CDR3, of a light
chain variable region having an amino acid sequence of the V.sub.L
region of SEQ ID NO: 4, 8, 12, 16, 20, 24, 28, 32, 36, 44, 48, 52,
56 or 60, or that comprises a CDR3, and may optionally comprise a
CDR1 and/or CDR2, of a heavy chain variable region having an amino
acid sequence of the V.sub.H region of SEQ ID NO: 2, 6, 10, 14, 18,
22, 26, 30, 34, 38, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90,
94, 98 or 102.
[0149] In some embodiments, the anti-M-CSF antibody has a low
dissociation rate. In some embodiments, the anti-M-CSF antibody has
an k.sub.off of 2.0.times.10.sup.-4 s.sup.-1 or lower. In other
preferred embodiments, the antibody binds to M-CSF with a k.sub.off
of 2.0.times.10.sup.-5 or a k.sub.off 2.0.times.10.sup.-6 s.sup.-1
or lower. In some embodiments, the k.sub.off is substantially the
same as an antibody described herein, such as an antibody selected
from 252, 88, 100, 3.8.3, 2.7.3, 1.120.1, 9.14.41, 8.10.3F,
9.7.2IF, 9.14.4, 8.10.3, 9.7.2, 9.7.2C-Ser, 9.14.4C-Ser,
8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2, 9.7.2-CG4, 9.14.4-CG2,
9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser, 8.10.3-Ser, 8.10.3-CG4,
8.10.3FG1 or 9.14.4G1. In some embodiments, the antibody binds to
M-CSF with substantially the same k.sub.off as an antibody that
comprises (a) a CDR3, and may optionally comprise a CDR1 and/or
CDR2, of a heavy chain of an antibody selected from 252, 88, 100,
3.8.3, 2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3,
9.7.2, 9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2,
9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser,
8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1; or (b) a CDR2, and
may optionally comprise a CDR1 and/or CDR3, of a light chain from
an antibody selected from 252, 88, 100, 3.8.3, 2.7.3, 1.120.1,
9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3, 9.7.2, 9.7.2C-Ser,
9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2, 9.7.2-CG4,
9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser, 8.10.3-Ser,
8.10.3-CG4, 8.10.3FG1 or 9.14.4G1. In some embodiments, the
antibody binds to M-CSF with substantially the same k.sub.off as an
antibody that comprises a heavy chain variable region having an
amino acid sequence of SEQ ID NO: 2, 6, 10, 14, 18, 22, 26, 30, 34,
38, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98 or 102;
or that comprises a light chain variable region having an amino
acid sequence of SEQ ID NO: 4, 8, 12, 16, 20, 24, 28, 32, 36, 44,
48, 52, 56 or 60; In another preferred embodiment, the antibody
binds to M-CSF with substantially the same k.sub.off as an antibody
that comprises a CDR2, and may optionally comprise a CDR1 and/or
CDR3, of a light chain variable region having an amino acid
sequence of SEQ ID NO: 4, 8, 12, 16, 20, 24, 28, 32, 36, 44, 48,
52, 56 or 60; or a CDR3, and may optionally comprise a CDR1 and/or
CDR2, of a heavy chain variable region having an amino acid
sequence of SEQ ID NO: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 46,
50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98 or 102.
[0150] The binding affinity and dissociation rate of an anti-M-CSF
antibody to a M-CSF can be determined by methods known in the art.
The binding affinity can be measured by competitive ELISAs, RIAs,
surface plasmon resonance (e.g., by using BIACORE.RTM. protein
interaction analysis equipment). The dissociation rate can be
measured by surface plasmon resonance. Preferably, the binding
affinity and dissociation rate is measured by surface plasmon
resonance. More preferably, the binding affinity and dissociation
rate are measured using BIACORE.RTM. protein interaction analysis
equipment. Example VI exemplifies a method for determining affinity
constants of anti-M-CSF monoclonal antibodies by BIACORE.RTM.
protein interaction analysis equipment.
Inhibition of M-CSF Activity by Anti-M-CSF Antibody
[0151] Inhibition of M-CSF Binding to c-Fins
[0152] In another embodiment, the invention provides an anti-M-CSF
antibody that inhibits the binding of a M-CSF to c-fins receptor
and blocks or prevents activation of c-fins. In an preferred
embodiment, the M-CSF is human. In another preferred embodiment,
the anti-M-CSF antibody is a human antibody. The IC.sub.50 can be
measured by ELISA, RIA, and cell based assays such as a cell
proliferation assay, a whole blood monocyte shape change assay, or
a receptor binding inhibition assay. In one embodiment, the
antibody or portion thereof inhibits cell proliferation with an
IC.sub.50 of no more than 8.0.times.10.sup.-7 M, preferably no more
than 3.times.10.sup.-7 M, or more preferably no more than
8.times.10.sup.-7 M as measured by a cell proliferation assay. In
another embodiment, the IC.sub.50 as measured by a monocyte shape
change assay is no more than 2.times.10.sup.-6 M, preferably no
more than 9.0.times.10.sup.-7 M, or more preferably no more than
9.times.10.sup.-8 M. In another preferred embodiment, the IC.sub.50
as measured by a receptor binding assay is no more than
2.times.10.sup.-6M, preferably no more than 8.0.times.10.sup.-7 M,
or more preferably no more than 7.0.times.10.sup.-8 M. Examples
III, IV, and V exemplify various types of assays.
[0153] In another aspect anti-M-CSF antibodies of the invention
inhibit monocyte/macrophage cell proliferation in response to a
M-CSF by at least 20%, more preferably 40%, 45%, 50%, 55%, 60%,
65%, 70%, 80%, 85%, 90%, 95% or 100% compared to the proliferation
of cell in the absence of antibody.
Methods of Producing Antibodies and Antibody Producing Cell
Lines
Immunization
[0154] In some embodiments, human antibodies are produced by
immunizing a non-human animal comprising in its genome some or all
of human immuno-globulin heavy chain and light chain loci with a
M-CSF antigen. In a preferred embodiment, the non-human animal is a
XENOMOUSE.RTM. transgenic mouse that makes human antibodies
(Abgenix Inc., Fremont, Calif.). Another non-human animal that may
be used is a transgenic mouse produced by Medarex (Medarex, Inc.,
Princeton, N.J.).
[0155] XENOMOUSE.RTM. transgenic mice that make human antibodies
are engineered mouse strains that comprise large fragments of human
immunoglobulin heavy chain and light chain loci and are deficient
in mouse antibody production. See, e.g., Green et al., Nature
Genetics 7:13-21 (1994) and U.S. Pat. Nos. 5,916,771, 5,939,598,
5,985,615, 5,998,209, 6,075,181, 6,091,001, 6,114,598, 6,130,364,
6,162,963 and 6,150,584. See also WO 91/10741, WO 94/02602, WO
96/34096, WO 96/33735, WO 98/16654, WO 98/24893, WO 98/50433, WO
99/45031, WO 99/53049, WO 00/09560, and WO 00/037504.
[0156] In another aspect, the invention provides a method for
making anti-M-CSF antibodies from non-human, non-mouse animals by
immunizing non-human transgenic animals that comprise human
immunoglobulin loci with a M-CSF antigen. One can produce such
animals using the methods described in the above-cited documents.
The methods disclosed in these documents can be modified as
described in U.S. Pat. No. 5,994,619. U.S. Pat. No. 5,994,619
describes methods for producing novel cultural inner cell mass
(CICM) cells and cell lines, derived from pigs and cows, and
transgenic CICM cells into which heterologous DNA has been
inserted. CICM transgenic cells can be used to produce cloned
transgenic embryos, fetuses, and offspring. The '619 patent also
describes the methods of producing the transgenic animals, that are
capable of transmitting the heterologous DNA to their progeny. In
preferred embodiments, the non-human animals are rats, sheep, pigs,
goats, cattle or horses.
[0157] XENOMOUSE.RTM. transgenic mice that make human antibodies
produce an adult-like human repertoire of fully human antibodies
and generate antigen-specific human antibodies. In some
embodiments, the XENOMOUSE.RTM. transgenic mice that make human
antibodies contain approximately 80% of the human antibody V gene
repertoire through introduction of megabase sized, germline
configuration yeast artificial chromosome (YAC) fragments of the
human heavy chain loci and kappa light chain loci. In other
embodiments, XENOMOUSE.RTM. transgenic mice that make human
antibodies further contain approximately all of the lambda light
chain locus. See Mendez et al., Nature Genetics 15:146-156 (1997),
Green and Jakobovits, J. Exp. Med. 188:483-495 (1998), and WO
98/24893, the disclosures of which are hereby incorporated by
reference.
[0158] In some embodiments, the non-human animal comprising human
immunoglobulin genes are animals that have a human immunoglobulin
"minilocus". In the minilocus approach, an exogenous Ig locus is
mimicked through the inclusion of individual genes from the Ig
locus. Thus, one or more V.sub.H genes, one or more D.sub.H genes,
one or more J.sub.H genes, a mu constant domain, and a second
constant domain (preferably a gamma constant domain) are formed
into a construct for insertion into an animal. This approach is
described, inter alia, in U.S. Pat. Nos. 5,545,807, 5,545,806,
5,569,825, 5,625,126, 5,633,425, 5,661,016, 5,770,429, 5,789,650,
5,814,318, 5,591,669, 5,612,205, 5,721,367, 5,789,215, and
5,643,763, hereby incorporated by reference.
[0159] In another aspect, the invention provides a method for
making humanized anti-M-CSF antibodies. In some embodiments,
non-human animals are immunized with a M-CSF antigen as described
below under conditions that permit antibody production.
Antibody-producing cells are isolated from the animals, fused with
myelomas to produce hybridomas, and nucleic acids encoding the
heavy and light chains of an anti-M-CSF antibody of interest are
isolated. These nucleic acids are subsequently engineered using
techniques known to those of skill in the art and as described
further below to reduce the amount of non-human sequence, i.e., to
humanize the antibody to reduce the immune response in humans
[0160] In some embodiments, the M-CSF antigen is isolated and/or
purified M-CSF. In a preferred embodiment, the M-CSF antigen is
human M-CSF. In some embodiments, the M-CSF antigen is a fragment
of M-CSF. In some embodiments, the M-CSF fragment is the
extracellular domain of M-CSF. In some embodiments, the M-CSF
fragment comprises at least one epitope of M-CSF. In other
embodiments, the M-CSF antigen is a cell that expresses or
overexpresses M-CSF or an immunogenic fragment thereof on its
surface. In some embodiments, the M-CSF antigen is a M-CSF fusion
protein. M-CSF can be purified from natural sources using known
techniques. Recombinant M-CSF is commercially available.
[0161] Immunization of animals can be by any method known in the
art. See, e.g., Harlow and Lane, Antibodies: A Laboratory Manual,
New York: Cold Spring Harbor Press, 1990. Methods for immunizing
non-human animals such as mice, rats, sheep, goats, pigs, cattle
and horses are well known in the art. See, e.g., Harlow and Lane,
supra, and U.S. Pat. No. 5,994,619. In a preferred embodiment, the
M-CSF antigen is administered with an adjuvant to stimulate the
immune response. Exemplary adjuvants include complete or incomplete
Freund's adjuvant, RIBI (muramyl dipeptides) or ISCOM
(immunostimulating complexes). Such adjuvants may protect the
polypeptide from rapid dispersal by sequestering it in a local
deposit, or they may contain substances that stimulate the host to
secrete factors that are chemotactic for macrophages and other
components of the immune system. Preferably, if a polypeptide is
being administered, the immunization schedule will involve two or
more administrations of the polypeptide, spread out over several
weeks. Example I exemplifies a method for producing anti-M-CSF
monoclonal antibodies in XENOMOUSE.RTM. transgenic mice that make
human antibodies.
Production of Antibodies and Antibody Producing Cell Lines
[0162] After immunization of an animal with a M-CSF antigen,
antibodies and/or antibody-producing cells can be obtained from the
animal. In some embodiments, anti-M-CSF antibody-containing serum
is obtained from the animal by bleeding or sacrificing the animal.
The serum may be used as it is obtained from the animal, an
immunoglobulin fraction may be obtained from the serum, or the
anti-M-CSF antibodies may be purified from the serum.
[0163] In some embodiments, antibody-producing immortalized cell
lines are prepared from cells isolated from the immunized animal.
After immunization, the animal is sacrificed and lymph node and/or
splenic B cells are immortalized. Methods of immortalizing cells
include, but are not limited to, transfecting them with oncogenes,
infecting them with an oncogenic virus, cultivating them under
conditions that select for immortalized cells, subjecting them to
carcinogenic or mutating compounds, fusing them with an
immortalized cell, e.g., a myeloma cell, and inactivating a tumor
suppressor gene. See, e.g., Harlow and Lane, supra. If fusion with
myeloma cells is used, the myeloma cells preferably do not secrete
immunoglobulin polypeptides (a non-secretory cell line).
Immortalized cells are screened using M-CSF, a portion thereof, or
a cell expressing M-CSF. In a preferred embodiment, the initial
screening is performed using an enzyme-linked immunoassay (ELISA)
or a radioimmunoassay. An example of ELISA screening is provided in
WO 00/37504, incorporated herein by reference.
[0164] Anti-M-CSF antibody-producing cells, e.g., hybridomas, are
selected, cloned and further screened for desirable
characteristics, including robust growth, high antibody production
and desirable antibody characteristics, as discussed further below.
Hybridomas can be expanded in vivo in syngeneic animals, in animals
that lack an immune system, e.g., nude mice, or in cell culture in
vitro. Methods of selecting, cloning and expanding hybridomas are
well known to those of ordinary skill in the art.
[0165] In a preferred embodiment, the immunized animal is a
non-human animal that expresses human immunoglobulin genes and the
splenic B cells are fused to a myeloma cell line from the same
species as the non-human animal. In a more preferred embodiment,
the immunized animal is a XENOMOUSE.RTM. transgenic mouse that
makes human antibodies and the myeloma cell line is a non-secretory
mouse myeloma. In an even more preferred embodiment, the myeloma
cell line is P3-X63-AG8-653. See, e.g., Example I.
[0166] Thus, in one embodiment, the invention provides methods of
producing a cell line that produces a human monoclonal antibody or
a fragment thereof directed to M-CSF comprising (a) immunizing a
non-human transgenic animal described herein with M-CSF, a portion
of M-CSF or a cell or tissue expressing M-CSF; (b) allowing the
transgenic animal to mount an immune response to M-CSF; (c)
isolating B lymphocytes from a transgenic animal; (d) immortalizing
the B lymphocytes; (e) creating individual monoclonal populations
of the immortalized B lymphocytes; and (f) screening the
immortalized B lymphocytes to identify an antibody directed to
M-CSF.
[0167] In another aspect, the invention provides hybridomas that
produce an human anti-M-CSF antibody. In a preferred embodiment,
the hybridomas are mouse hybridomas, as described above. In other
embodiments, the hybridomas are produced in a non-human, non-mouse
species such as rats, sheep, pigs, goats, cattle or horses. In
another embodiment, the hybridomas are human hybridomas.
[0168] In another preferred embodiment, a transgenic animal is
immunized with M-CSF, primary cells, e.g., spleen or peripheral
blood cells, are isolated from an immunized transgenic animal and
individual cells producing antibodies specific for the desired
antigen are identified. Polyadenylated mRNA from each individual
cell is isolated and reverse transcription polymerase chain
reaction (RT-PCR) is performed using sense primers that anneal to
variable region sequences, e.g., degenerate primers that recognize
most or all of the FR1 regions of human heavy and light chain
variable region genes and antisense primers that anneal to constant
or joining region sequences. cDNAs of the heavy and light chain
variable regions are then cloned and expressed in any suitable host
cell, e.g., a myeloma cell, as chimeric antibodies with respective
immunoglobulin constant regions, such as the heavy chain and
.kappa. or .lamda. constant domains. See Babcook, J. S. et al.,
Proc. Natl. Acad. Sci. USA 93:7843-48, 1996, herein incorporated by
reference. Anti M-CSF antibodies may then be identified and
isolated as described herein.
[0169] In another embodiment, phage display techniques can be used
to provide libraries containing a repertoire of antibodies with
varying affinities for M-CSF. For production of such repertoires,
it is unnecessary to immortalize the B cells from the immunized
animal. Rather, the primary B cells can be used directly as a
source of DNA. The mixture of cDNAs obtained from B cell, e.g.,
derived from spleens, is used to prepare an expression library, for
example, a phage display library transfected into E. coli. The
resulting cells are tested for immunoreactivity to M-CSF.
Techniques for the identification of high affinity human antibodies
from such libraries are described by Griffiths et al., EMBO J.,
13:3245-3260 (1994); Nissim et al., ibid, pp. 692-698 and by
Griffiths et al., ibid, 12:725-734. Ultimately, clones from the
library are identified which produce binding affinities of a
desired magnitude for the antigen and the DNA encoding the product
responsible for such binding is recovered and manipulated for
standard recombinant expression. Phage display libraries may also
be constructed using previously manipulated nucleotide sequences
and screened in a similar fashion. In general, the cDNAs encoding
heavy and light chains are independently supplied or linked to form
Fv analogs for production in the phage library.
[0170] The phage library is then screened for the antibodies with
the highest affinities for M-CSF and the genetic material recovered
from the appropriate clone. Further rounds of screening can
increase affinity of the original antibody isolated.
[0171] In another aspect, the invention provides hybridomas that
produce an human anti-M-CSF antibody. In a preferred embodiment,
the hybridomas are mouse hybridomas, as described above. In other
embodiments, the hybridomas are produced in a non-human, non-mouse
species such as rats, sheep, pigs, goats, cattle or horses. In
another embodiment, the hybridomas are human hybridomas.
Nucleic Acids, Vectors, Host Cells, and Recombinant Methods of
Making Antibodies
Nucleic Acids
[0172] The present invention also encompasses nucleic acid
molecules encoding anti-M-CSF antibodies. In some embodiments,
different nucleic acid molecules encode a heavy chain and a light
chain of an anti-M-CSF immunoglobulin. In other embodiments, the
same nucleic acid molecule encodes a heavy chain an a light chain
of an anti-M-CSF immunoglobulin. In one embodiment, the nucleic
acid encodes a M-CSF antibody of the invention.
[0173] In some embodiments, the nucleic acid molecule encoding the
variable domain of the light chain comprises a human
V.sub..kappa.L5, O12, L2, B3, A27 gene and a J.kappa.1, J.kappa.2,
J.kappa.3, or J.kappa.4 gene.
[0174] In some embodiments, the nucleic acid molecule encoding the
light chain, encodes an amino acid sequence comprising 1, 2, 3, 4,
5, 6, 7, 8, 9, or 10 mutations from the germline amino acid
sequence. In some embodiments, the nucleic acid molecule comprises
a nucleotide sequence that encodes a V.sub.L amino acid sequence
comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, or 10 non-conservative amino
acid substitutions and/or 1, 2, or 3 non-conservative substitutions
compared to germline sequence. Substitutions may be in the CDR
regions, the framework regions, or in the constant domain.
[0175] In some embodiments, the nucleic acid molecule encodes a
V.sub.L amino acid sequence comprising one or more variants
compared to germline sequence that are identical to the variations
found in the V.sub.L of one of the antibodies 252, 88, 100, 3.8.3,
2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3, 9.7.2,
9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2,
9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser,
8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1.
[0176] In some embodiments, the nucleic acid molecule encodes at
least three amino acid mutations compared to the germline sequence
found in the V.sub.L of one of the antibodies 252, 88, 100, 3.8.3,
2.7.3, 1.120.1, 9.14.4, 8.10.3, or 9.7.2.
[0177] In some embodiments, the nucleic acid molecule comprises a
nucleotide sequence that encodes the V.sub.L amino acid sequence of
monoclonal antibody 252 (SEQ ID NO: 4), 88 (SEQ ID NO: 8), 100 (SEQ
ID NO: 12), 3.8.3 (SEQ ID NO: 16), 2.7.3 (SEQ ID NO: 20), 1.120.1
(SEQ ID NO: 24), 9.14.41 (SEQ ID NO: 28), 8.10.3F (SEQ ID NO: 32),
9.7.21E (SEQ ID NO: 36), 9.14.4 (SEQ ID NO: 28), 8.10.3 (SEQ ID NO:
44), 9.7.2 (SEQ ID NO: 48), 9.7.2C-Ser (SEQ ID NO: 52), 9.14.4C-Ser
(SEQ ID NO: 56), 8.10.3C-Ser (SEQ ID NO: 60), 8.10.3-CG2 (SEQ ID
NO: 60), 9.7.2-CG2 (SEQ ID NO: 52), 9.7.2-CG4 (SEQ ID NO: 52),
9.14.4-CG2 (SEQ ID NO: 56), 9.14.4-CG4 (SEQ ID NO: 56), 9.14.4-Ser
(SEQ ID NO: 28), 9.7.2-Ser (SEQ ID NO: 48), 8.10.3-Ser (SEQ ID NO:
44), 8.10.3-CG4 (SEQ ID NO: 60) 8.10.3FG1 (SEQ ID NO: 32) or
9.14.4G1 (SEQ ID NO: 28), or a portion thereof. In some
embodiments, said portion comprises at least the CDR2 region. In
some embodiments, the nucleic acid encodes the amino acid sequence
of the light chain CDRs of said antibody. In some embodiments, said
portion is a contiguous portion comprising CDR1-CDR3.
[0178] In some embodiments, the nucleic acid molecule comprises a
nucleotide sequence that encodes the light chain amino acid
sequence of one of SEQ ID NOS: 4, 8, 12, 16, 20, 24, 28, 32, 36,
44, 48, 52, 56 or 60. In some preferred embodiments, the nucleic
acid molecule comprises the light chain nucleotide sequence of SEQ
ID NOS: 3, 7, 11, 27, 31, 35, 43 or 47, or a portion thereof.
[0179] In some embodiments, the nucleic acid molecule encodes a
V.sub.L amino acid sequence that is at least 70%, 75%, 80%, 85%,
90%, 95%, 97%, 98% or 99% identical to a V.sub.L amino acid
sequence shown in FIG. 1 or to a V.sub.L amino acid sequences of
any one of antibodies 252, 88, 100, 3.8.3, 2.7.3, 1.120.1, 9.14.41,
8.10.3F, 9.7.2IF, 9.14.4, 8.10.3, 9.7.2, 9.7.2C-Ser, 9.14.4C-Ser,
8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2, 9.7.2-CG4, 9.14.4-CG2,
9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser, 8.10.3-Ser, 8.10.3-CG4,
8.10.3FG1 or 9.14.4G1, or an amino acid sequence of any one of SEQ
ID NOS: 4, 8, 12, 16, 20, 24, 28, 32, 36, 44, 48, 52, 56 or 60.
Nucleic acid molecules of the invention include nucleic acids that
hybridize under highly stringent conditions, such as those
described above, to a nucleic acid sequence encoding the light
chain amino acid sequence of SEQ ID NOS: 4, 8, 12, 16, 20, 24, 28,
32, 36, 44, 48, 52, 56 or 60, or that has the light chain nucleic
acid sequence of SEQ ID NOS: 3, 7, 11, 27, 31, 35, 43 or 47.
[0180] In another embodiment, the nucleic acid encodes a
full-length light chain of an antibody selected from 252, 88, 100,
3.8.3, 2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3,
9.7.2, 9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2,
9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser,
8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1, or a light chain
comprising the amino acid sequence of SEQ ID NOS: 4, 8, 12, 16, 20,
24, 28, 32, 36, 44, 48, 52, 56 or 60 and a constant region of a
light chain, or a light chain comprising a mutation. Further, the
nucleic acid may comprise the light chain nucleotide sequence of
SEQ ID NOS: 3, 7, 11, 27, 31, 35, 43 or 47 and the nucleotide
sequence encoding a constant region of a light chain, or a nucleic
acid molecule encoding a light chain comprise a mutation.
[0181] In another preferred embodiment, the nucleic acid molecule
encodes the variable domain of the heavy chain (V.sub.H) that
comprises a human V.sub.H1-18, 3-33, 3-11, 3-23, 3-48, or 3-7 gene
sequence or a sequence derived therefrom. In various embodiments,
the nucleic acid molecule comprises a human V.sub.H1-18 gene, a
D.sub.H4-23 gene and a human J.sub.H4 gene; a human V.sub.H3-33
gene, a human D.sub.H1-26 gene and a human J.sub.H4 gene; a human
V.sub.H3-11 gene, a human D.sub.H7-27 gene and a human J.sub.H4
gene; a human V.sub.H3-11 gene, a human D.sub.H 7-27 gene and a
human J.sub.H6 gene; a human V.sub.H3-23 gene, a human D.sub.H1-26
gene and a human J.sub.H4 gene; a human V.sub.H 3-7 gene, a human
D.sub.H6-13 gene and a human J.sub.H4 gene; a human V.sub.H3-11
gene, a human D.sub.H7-27 gene, and a human J.sub.H4b gene; a human
V.sub.H3-48 gene, a human D.sub.H1-26 gene, and a human J.sub.H4b
gene; a human V.sub.H3-11 gene, a human D.sub.H6-13 gene, and a
human J.sub.H6b gene, or a sequence derived from the human
genes.
[0182] In some embodiments, the nucleic acid molecule encodes an
amino acid sequence comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11,
12, 13, 14, 15, 16, 17 or 18 mutations compared to the germline
amino acid sequence of the human V, D or J genes. In some
embodiments, said mutations are in the V.sub.H region. In some
embodiments, said mutations are in the CDR regions.
[0183] In some embodiments, the nucleic acid molecule encodes one
or more amino acid mutations compared to the germline sequence that
are identical to amino acid mutations found in the V.sub.H of
monoclonal antibody 252, 88, 100, 3.8.3, 2.7.3, 1.120.1, 9.14.41,
8.10.3F, 9.7.2IF, 9.14.4, 8.10.3, 9.7.2, 9.7.2C-Ser, 9.14.4C-Ser,
8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2, 9.7.2-CG4, 9.14.4-CG2,
9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser, 8.10.3-Ser, 8.10.3-CG4,
8.10.3FG1 or 9.14.4G1. In some embodiments, the nucleic acid
encodes at least three amino acid mutations compared to the
germline sequences that are identical to at least three amino acid
mutations found in one of the above-listed monoclonal
antibodies.
[0184] In some embodiments, the nucleic acid molecule comprises a
nucleotide sequence that encodes at least a portion of the V.sub.H
amino acid sequence of antibody 252 (SEQ ID NO: 2), 88 (SEQ ID NO:
6), 100 (SEQ ID NO: 10), 3.8.3 (SEQ ID NO: 14), 2.7.3 (SEQ ID NO:
18), 1.120.1 (SEQ ID NO: 22), 9.14.41 (SEQ ID NO: 26), 8.10.3F (SEQ
ID NO: 30), 9.7.21E (SEQ ID NO: 34), 9.14.4 (SEQ ID NO: 38), 8.10.3
(SEQ ID NO: 30), 9.7.2 (SEQ ID NO: 46), 9.7.2C-Ser (SEQ ID NO: 50),
9.14.4C-Ser (SEQ ID NO: 54), 8.10.3C-Ser (SEQ ID NO: 58),
8.10.3-CG2 (SEQ ID NO: 62), 9.7.2-CG2 (SEQ ID NO: 66), 9.7.2-CG4
(SEQ ID NO: 70), 9.14.4-CG2 (SEQ ID NO: 74), 9.14.4-CG4 (SEQ ID NO:
78), 9.14.4-Ser (SEQ ID NO: 82), 9.7.2-Ser (SEQ ID NO: 86),
8.10.3-Ser (SEQ ID NO: 90), 8.10.3-CG4 (SEQ ID NO: 94), 8.10.3FG1
(SEQ ID NO: 98) or 9.14.4-G1 (SEQ ID NO: 102), or said sequence
having conservative amino acid mutations and/or a total of three or
fewer non-conservative amino acid substitutions. In various
embodiments the sequence encodes one or more CDR regions,
preferably a CDR3 region, all three CDR regions, a contiguous
portion including CDR1-CDR3, or the entire V.sub.H region.
[0185] In some embodiments, the nucleic acid molecule comprises a
heavy chain nucleotide sequence that encodes the amino acid
sequence of one of SEQ ID NOS: 2, 6, 10, 14, 18, 22, 26, 30, 34,
38, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98 or 102.
In some preferred embodiments, the nucleic acid molecule comprises
at least a portion of the heavy chain nucleotide sequence of SEQ ID
NO: 1, 5, 9, 25, 29, 33, 37, 45, 97 or 101. In some embodiments,
said portion encodes the V.sub.H region, a CDR3 region, all three
CDR regions, or a contiguous region including CDR1-CDR3.
[0186] In some embodiments, the nucleic acid molecule encodes a
V.sub.H amino acid sequence that is at least 70%, 75%, 80%, 85%,
90%, 95%, 97%, 98% or 99% identical to the V.sub.H amino acid
sequences shown in FIGS. 4A-4ZZ or to a V.sub.H amino acid sequence
of any one of SEQ ID NOS: 2, 6, 10, 14, 18, 22, 26, 30, 34, 38, 46,
50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98 or 102. Nucleic
acid molecules of the invention include nucleic acids that
hybridize under highly stringent conditions, such as those
described above, to a nucleotide sequence encoding the heavy chain
amino acid sequence of SEQ ID NOS: 2, 6, 10, 14, 18, 22, 26, 30,
34, 38, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94, 98 or
102 or that has the nucleotide sequence of SEQ ID NOS: 1, 5, 9, 25,
29, 33, 37, 45, 97 or 101.
[0187] In another embodiment, the nucleic acid encodes a
full-length heavy chain of an antibody selected from 252, 88, 100,
3.8.3, 2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3,
9.7.2, 9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2,
9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser,
8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1, or a heavy chain
having the amino acid sequence of SEQ ID NOS: 2, 6, 10, 14, 18, 22,
26, 30, 34, 38, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94,
98 or 102 and a constant region of a heavy chain, or a heavy chain
comprising a mutation. Further, the nucleic acid may comprise the
heavy chain nucleotide sequence of SEQ ID NOS: 1, 5, 9, 25, 29, 33,
37, 45, 97 or 101 and a nucleotide sequence encoding a constant
region of a light chain, or a nucleic acid molecule encoding a
heavy chain comprising a mutation.
[0188] A nucleic acid molecule encoding the heavy or entire light
chain of an anti-M-CSF antibody or portions thereof can be isolated
from any source that produces such antibody. In various
embodiments, the nucleic acid molecules are isolated from a B cell
isolated from an animal immunized with M-CSF or from an
immortalized cell derived from such a B cell that expresses an
anti-M-CSF antibody. Methods of isolating mRNA encoding an antibody
are well-known in the art. See, e.g., Sambrook et al. The mRNA may
be used to produce cDNA for use in the polymerase chain reaction
(PCR) or cDNA cloning of antibody genes. In a preferred embodiment,
the nucleic acid molecule is isolated from a hybridoma that has as
one of its fusion partners a human immunoglobulin-producing cell
from a non-human transgenic animal. In an even more preferred
embodiment, the human immunoglobulin producing cell is isolated
from a XENOMOUSE.RTM. transgenic mouse that makes human antibodies.
In another embodiment, the human immunoglobulin-producing cell is
from a non-human, non-mouse transgenic animal, as described above.
In another embodiment, the nucleic acid is isolated from a
non-human, non-transgenic animal. The nucleic acid molecules
isolated from a non-human, non-transgenic animal may be used, e.g.,
for humanized antibodies.
[0189] In some embodiments, a nucleic acid encoding a heavy chain
of an anti-M-CSF antibody of the invention can comprise a
nucleotide sequence encoding a V.sub.H domain of the invention
joined in-frame to a nucleotide sequence encoding a heavy chain
constant domain from any source. Similarly, a nucleic acid molecule
encoding a light chain of an anti-M-CSF antibody of the invention
can comprise a nucleotide sequence encoding a V.sub.L domain of the
invention joined in-frame to a nucleotide sequence encoding a light
chain constant domain from any source.
[0190] In a further aspect of the invention, nucleic acid molecules
encoding the variable domain of the heavy (V.sub.H) and light
(V.sub.L) chains are "converted" to full-length antibody genes. In
one embodiment, nucleic acid molecules encoding the V.sub.H or
V.sub.L domains are converted to full-length antibody genes by
insertion into an expression vector already encoding heavy chain
constant (C.sub.H) or light chain (C.sub.L) constant domains,
respectively, such that the V.sub.H segment is operatively linked
to the C.sub.H segment(s) within the vector, and the V.sub.L
segment is operatively linked to the C.sub.L segment within the
vector. In another embodiment, nucleic acid molecules encoding the
V.sub.H and/or V.sub.L domains are converted into full-length
antibody genes by linking, e.g., ligating, a nucleic acid molecule
encoding a V.sub.H and/or V.sub.L domains to a nucleic acid
molecule encoding a C.sub.H and/or C.sub.L domain using standard
molecular biological techniques. Nucleic acid sequences of human
heavy and light chain immunoglobulin constant domain genes are
known in the art. See, e.g., Kabat et al., Sequences of Proteins of
Immunological Interest, 5th Ed., NIH Publ. No. 91-3242, 1991.
Nucleic acid molecules encoding the full-length heavy and/or light
chains may then be expressed from a cell into which they have been
introduced and the anti-M-CSF antibody isolated.
[0191] The nucleic acid molecules may be used to recombinantly
express large quantities of anti-M-CSF antibodies. The nucleic acid
molecules also may be used to produce chimeric antibodies,
bispecific antibodies, single chain antibodies, immunoadhesins,
diabodies, mutated antibodies and antibody derivatives, as
described further below. If the nucleic acid molecules are derived
from a non-human, non-transgenic animal, the nucleic acid molecules
may be used for antibody humanization, also as described below.
[0192] In another embodiment, a nucleic acid molecule of the
invention is used as a probe or PCR primer for a specific antibody
sequence. For instance, the nucleic acid can be used as a probe in
diagnostic methods or as a PCR primer to amplify regions of DNA
that could be used, inter alia, to isolate additional nucleic acid
molecules encoding variable domains of anti-M-CSF antibodies. In
some embodiments, the nucleic acid molecules are oligonucleotides.
In some embodiments, the oligonucleotides are from highly variable
regions of the heavy and light chains of the antibody of interest.
In some embodiments, the oligonucleotides encode all or a part of
one or more of the CDRs of antibody 252, 88, 100, 3.8.3, 2.7.3, or
1.120.1, or variants thereof described herein.
Vectors
[0193] The invention provides vectors comprising nucleic acid
molecules that encode the heavy chain of an anti-M-CSF antibody of
the invention or an antigen-binding portion thereof. The invention
also provides vectors comprising nucleic acid molecules that encode
the light chain of such antibodies or antigen-binding portion
thereof. The invention further provides vectors comprising nucleic
acid molecules encoding fusion proteins, modified antibodies,
antibody fragments, and probes thereof.
[0194] In some embodiments, the anti-M-CSF antibodies, or
antigen-binding portions of the invention are expressed by
inserting DNAs encoding partial or full-length light and heavy
chains, obtained as described above, into expression vectors such
that the genes are operatively linked to necessary expression
control sequences such as transcriptional and transnational control
sequences. Expression vectors include plasmids, retroviruses,
adenoviruses, adeno-associated viruses (AAV), plant viruses such as
cauliflower mosaic virus, tobacco mosaic virus, cosmids, YACs, EBV
derived episomes, and the like. The antibody gene is ligated into a
vector such that transcriptional and transnational control
sequences within the vector serve their intended function of
regulating the transcription and translation of the antibody gene.
The expression vector and expression control sequences are chosen
to be compatible with the expression host cell used. The antibody
light chain gene and the antibody heavy chain gene can be inserted
into separate vectors. In a preferred embodiment, both genes are
inserted into the same expression vector. The antibody genes are
inserted into the expression vector by standard methods (e.g.,
ligation of complementary restriction sites on the antibody gene
fragment and vector, or blunt end ligation if no restriction sites
are present).
[0195] A convenient vector is one that encodes a functionally
complete human C.sub.H or C.sub.L immunoglobulin sequence, with
appropriate restriction sites engineered so that any V.sub.H or
V.sub.L sequence can easily be inserted and expressed, as described
above. In such vectors, splicing usually occurs between the splice
donor site in the inserted J region and the splice acceptor site
preceding the human C domain, and also at the splice regions that
occur within the human C.sub.H exons. Polyadenylation and
transcription termination occur at native chromosomal sites
downstream of the coding regions. The recombinant expression vector
also can encode a signal peptide that facilitates secretion of the
antibody chain from a host cell. The antibody chain gene may be
cloned into the vector such that the signal peptide is linked
in-frame to the amino terminus of the immunoglobulin chain. The
signal peptide can be an immunoglobulin signal peptide or a
heterologous signal peptide (i.e., a signal peptide from a
non-immunoglobulin protein).
[0196] In addition to the antibody chain genes, the recombinant
expression vectors of the invention carry regulatory sequences that
control the expression of the antibody chain genes in a host cell.
It will be appreciated by those skilled in the art that the design
of the expression vector, including the selection of regulatory
sequences may depend on such factors as the choice of the host cell
to be transformed, the level of expression of protein desired, etc.
Preferred regulatory sequences for mammalian host cell expression
include viral elements that direct high levels of protein
expression in mammalian cells, such as promoters and/or enhancers
derived from retroviral LTRs, cytomegalovirus (CMV) (such as the
CMV promoter/enhancer), Simian Virus 40 (SV40) (such as the SV40
promoter/enhancer), adenovirus, (e.g., the adenovirus major late
promoter (AdMLP)), polyoma and strong mammalian promoters such as
native immunoglobulin and actin promoters. For further description
of viral regulatory elements, and sequences thereof, see e.g., U.S.
Pat. Nos. 5,168,062, 4,510,245 and 4,968,615. Methods for
expressing antibodies in plants, including a description of
promoters and vectors, as well as transformation of plants is known
in the art. See, e.g., U.S. Pat. No. 6,517,529, herein incorporated
by reference. Methods of expressing polypeptides in bacterial cells
or fungal cells, e.g., yeast cells, are also well known in the
art.
[0197] In addition to the antibody chain genes and regulatory
sequences, the recombinant expression vectors of the invention may
carry additional sequences, such as sequences that regulate
replication of the vector in host cells (e.g., origins of
replication) and selectable marker genes. The selectable marker
gene facilitates selection of host cells into which the vector has
been introduced (see e.g., U.S. Pat. Nos. 4,399,216, 4,634,665 and
5,179,017). For example, typically the selectable marker gene
confers resistance to drugs, such as G418, hygromycin or
methotrexate, on a host cell into which the vector has been
introduced. Preferred selectable marker genes include the
dihydrofolate reductase (DHFR) gene (for use in dhfr-host cells
with methotrexate selection/amplification), the neomycin resistance
gene (for G418 selection), and the glutamate synthetase gene.
Non-Hybridoma Host Cells and Methods of Recombinantly Producing
Protein
[0198] Nucleic acid molecules encoding anti-M-CSF antibodies and
vectors comprising these nucleic acid molecules can be used for
transfection of a suitable mammalian, plant, bacterial or yeast
host cell. Transformation can be by any known method for
introducing polynucleotides into a host cell. Methods for
introduction of heterologous polynucleotides into mammalian cells
are well known in the art and include dextran-mediated
transfection, calcium phosphate precipitation, polybrene-mediated
transfection, protoplast fusion, electroporation, encapsulation of
the polynucleotide(s) in liposomes, and direct microinjection of
the DNA into nuclei. In addition, nucleic acid molecules may be
introduced into mammalian cells by viral vectors. Methods of
transforming cells are well known in the art. See, e.g., U.S. Pat.
Nos. 4,399,216, 4,912,040, 4,740,461, and 4,959,455 (which patents
are hereby incorporated herein by reference). Methods of
transforming plant cells are well known in the art, including,
e.g., Agrobacterium-mediated transformation, biolistic
transformation, direct injection, electroporation and viral
transformation. Methods of transforming bacterial and yeast cells
are also well known in the art.
[0199] Mammalian cell lines available as hosts for expression are
well known in the art and include many immortalized cell lines
available from the American Type Culture Collection (ATCC). These
include, inter alia, Chinese hamster ovary (CHO) cells, NSO, SP2
cells, HeLa cells, baby hamster kidney (BHK) cells, monkey kidney
cells (COS), human hepatocellular carcinoma cells (e.g., Hep G2),
A549 cells, and a number of other cell lines. Cell lines of
particular preference are selected through determining which cell
lines have high expression levels. Other cell lines that may be
used are insect cell lines, such as Sf9 cells. When recombinant
expression vectors encoding antibody genes are introduced into
mammalian host cells, the antibodies are produced by culturing the
host cells for a period of time sufficient to allow for expression
of the antibody in the host cells or, more preferably, secretion of
the antibody into the culture medium in which the host cells are
grown. Antibodies can be recovered from the culture medium using
standard protein purification methods. Plant host cells include,
e.g., Nicotiana, Arabidopsis, duckweed, corn, wheat, potato, etc.
Bacterial host cells include E. coli and Streptomyces species.
Yeast host cells include Schizosaccharomyces pombe, Saccharomyces
cerevisiae and Pichia pastoris.
[0200] Further, expression of antibodies of the invention (or other
moieties therefrom) from production cell lines can be enhanced
using a number of known techniques. For example, the glutamine
synthetase gene expression system (the GS system) is a common
approach for enhancing expression under certain conditions. The GS
system is discussed in whole or part in connection with European
Patent Nos. 0 216 846, 0 256 055, and 0 323 997 and European Patent
Application No. 89303964.4.
[0201] It is possible that antibodies expressed by different cell
lines or in transgenic animals will have different glycosylation
from each other. However, all antibodies encoded by the nucleic
acid molecules provided herein, or comprising the amino acid
sequences provided herein are part of the instant invention,
regardless of the glycosylation state or pattern or modification of
the antibodies.
Transgenic Animals and Plants
[0202] Anti-M-CSF antibodies of the invention also can be produced
transgenically through the generation of a mammal or plant that is
transgenic for the immunoglobulin heavy and light chain sequences
of interest and production of the antibody in a recoverable form
therefrom. In connection with the transgenic production in mammals,
anti-M-CSF antibodies can be produced in, and recovered from, the
milk of goats, cows, or other mammals. See, e.g., U.S. Pat. Nos.
5,827,690, 5,756,687, 5,750,172, and 5,741,957. In some
embodiments, non-human transgenic animals that comprise human
immunoglobulin loci are immunized with M-CSF or an immunogenic
portion thereof, as described above. Methods for making antibodies
in plants, yeast or fungi/algae are described, e.g., in U.S. Pat.
Nos. 6,046,037 and 5,959,177.
[0203] In some embodiments, non-human transgenic animals or plants
are produced by introducing one or more nucleic acid molecules
encoding an anti-M-CSF antibody of the invention into the animal or
plant by standard transgenic techniques. See Hogan and U.S. Pat.
No. 6,417,429, supra. The transgenic cells used for making the
transgenic animal can be embryonic stem cells or somatic cells. The
transgenic non-human organisms can be chimeric, nonchimeric
heterozygotes, and nonchimeric homozygotes. See, e.g., Hogan et
al., Manipulating the Mouse Embryo: A Laboratory Manual 2ed., Cold
Spring Harbor Press (1999); Jackson et al., Mouse Genetics and
Transgenics: A Practical Approach, Oxford University Press (2000);
and Pinkert, Transgenic Animal Technology: A Laboratory Handbook,
Academic Press (1999). In some embodiments, the transgenic
non-human animals have a targeted disruption and replacement by a
targeting construct that encodes a heavy chain and/or a light chain
of interest. In a preferred embodiment, the transgenic animals
comprise and express nucleic acid molecules encoding heavy and
light chains that specifically bind to M-CSF, preferably human
M-CSF. In some embodiments, the transgenic animals comprise nucleic
acid molecules encoding a modified antibody such as a single-chain
antibody, a chimeric antibody or a humanized antibody. The
anti-M-CSF antibodies may be made in any transgenic animal. In a
preferred embodiment, the non-human animals are mice, rats, sheep,
pigs, goats, cattle or horses. The non-human transgenic animal
expresses said encoded polypeptides in blood, milk, urine, saliva,
tears, mucus and other bodily fluids.
Phage Display Libraries
[0204] The invention provides a method for producing an anti-M-CSF
antibody or antigen-binding portion thereof comprising the steps of
synthesizing a library of human antibodies on phage, screening the
library with M-CSF or a portion thereof, isolating phage that bind
M-CSF, and obtaining the antibody from the phage. By way of
example, one method for preparing the library of antibodies for use
in phage display techniques comprises the steps of immunizing a
non-human animal comprising human immunoglobulin loci with M-CSF or
an antigenic portion thereof to create an immune response,
extracting antibody producing cells from the immunized animal;
isolating RNA from the extracted cells, reverse transcribing the
RNA to produce cDNA, amplifying the cDNA using a primer, and
inserting the cDNA into a phage display vector such that antibodies
are expressed on the phage. Recombinant anti-M-CSF antibodies of
the invention may be obtained in this way.
[0205] Recombinant anti-M-CSF human antibodies of the invention can
be isolated by screening a recombinant combinatorial antibody
library. Preferably the library is a scFv phage display library,
generated using human V.sub.L and V.sub.H cDNAs prepared from mRNA
isolated from B cells. Methodologies for preparing and screening
such libraries are known in the art. There are commercially
available kits for generating phage display libraries (e.g., the
Pharmacia Recombinant Phage Antibody System, catalog no.
27-9400-01; and the Stratagene SURFZAP.RTM. phage display kit,
catalog no. 240612). There also are other methods and reagents that
can be used in generating and screening antibody display libraries
(see, e.g., U.S. Pat. No. 5,223,409; PCT Publication Nos. WO
92/18619, WO 91/17271, WO 92/20791, WO 92/15679, WO 93/01288, WO
92/01047, WO 92/09690; Fuchs et al., Bio/Technology 9:1370-1372
(1991); Hay et al., Hum. Antibod. Hybridomas 3:81-85 (1992); Huse
et al., Science 246:1275-1281 (1989); McCafferty et al., Nature
348:552-554 (1990); Griffiths et al., EMBO J. 12:725-734 (1993);
Hawkins et al., J. Mol. Biol. 226:889-896 (1992); Clackson et al.,
Nature 352:624-628 (1991); Gram et al., Proc. Natl. Acad. Sci. USA
89:3576-3580 (1992); Garrad et al., Bio/Technology 9:1373-1377
(1991); Hoogenboom et al., Nuc. Acid Res. 19:4133-4137 (1991); and
Barbas et al., Proc. Natl. Acad. Sci. USA 88:7978-7982 (1991).
[0206] In one embodiment, to isolate human anti-M-CSF antibodies
with the desired characteristics, a human anti-M-CSF antibody as
described herein is first used to select human heavy and light
chain sequences having similar binding activity toward M-CSF, using
the epitope imprinting methods described in PCT Publication No. WO
93/06213. The antibody libraries used in this method are preferably
scFv libraries prepared and screened as described in PCT
Publication No. WO 92/01047, McCafferty et al., Nature 348:552-554
(1990); and Griffiths et al., EMBO J. 12:725-734 (1993). The scFv
antibody libraries preferably are screened using human M-CSF as the
antigen.
[0207] Once initial human V.sub.L and V.sub.H domains are selected,
"mix and match" experiments are performed, in which different pairs
of the initially selected V.sub.L and V.sub.H segments are screened
for M-CSF binding to select preferred V.sub.L/V.sub.H pair
combinations. Additionally, to further improve the quality of the
antibody, the V.sub.L and V.sub.H segments of the preferred
V.sub.L/V.sub.H pair(s) can be randomly mutated, preferably within
the CDR3 region of V.sub.H and/or V.sub.L, in a process analogous
to the in vivo somatic mutation process responsible for affinity
maturation of antibodies during a natural immune response. This in
vitro affinity maturation can be accomplished by amplifying V.sub.H
and V.sub.L domains using PCR primers complimentary to the V.sub.H
CDR3 or V.sub.L CDR3, respectively, which primers have been
"spiked" with a random mixture of the four nucleotide bases at
certain positions such that the resultant PCR products encode
V.sub.H and V.sub.L segments into which random mutations have been
introduced into the V.sub.H and/or V.sub.L CDR3 regions. These
randomly mutated V.sub.H and V.sub.L segments can be re-screened
for binding to M-CSF.
[0208] Following screening and isolation of an anti-M-CSF antibody
of the invention from a recombinant immunoglobulin display library,
nucleic acids encoding the selected antibody can be recovered from
the display package (e.g., from the phage genome) and subcloned
into other expression vectors by standard recombinant DNA
techniques. If desired, the nucleic acid can further be manipulated
to create other antibody forms of the invention, as described
below. To express a recombinant human antibody isolated by
screening of a combinatorial library, the DNA encoding the antibody
is cloned into a recombinant expression vector and introduced into
a mammalian host cells, as described above.
Class Switching
[0209] Another aspect of the invention provides a method for
converting the class or subclass of an anti-M-CSF antibody to
another class or subclass. In some embodiments, a nucleic acid
molecule encoding a V.sub.L or V.sub.H that does not include any
nucleic acid sequences encoding C.sub.L or C.sub.H is isolated
using methods well-known in the art. The nucleic acid molecule then
is operatively linked to a nucleic acid sequence encoding a C.sub.L
or C.sub.H from a desired immunoglobulin class or subclass. This
can be achieved using a vector or nucleic acid molecule that
comprises a C.sub.L or C.sub.H chain, as described above. For
example, an anti-M-CSF antibody that was originally IgM can be
class switched to an IgG. Further, the class switching may be used
to convert one IgG subclass to another, e.g., from IgG1 to IgG2.
Another method for producing an antibody of the invention
comprising a desired isotype comprises the steps of isolating a
nucleic acid encoding a heavy chain of an anti-M-CSF antibody and a
nucleic acid encoding a light chain of an anti-M-CSF antibody,
isolating the sequence encoding the V.sub.H region, ligating the
V.sub.H sequence to a sequence encoding a heavy chain constant
domain of the desired isotype, expressing the light chain gene and
the heavy chain construct in a cell, and collecting the anti-M-CSF
antibody with the desired isotype.
[0210] In some embodiments, anti-M-CSF antibodies of the invention
have the serine at position 228 (according to the EU-numbering
convention) of the heavy chain changed to a proline. Accordingly,
the CPSC sub-sequence in the Fc region of IgG4 becomes CPPC, which
is the sub-sequence in IgG1. (Aalberse, R. C. and Schuurman, J.,
Immunology, 105:9-19 (2002)). For example, the serine at residue
243 SEQ ID NO: 46 (which corresponds to reside 228 in the
EU-numbering convention) would become proline. Similarly, the
serine at residue 242 of SEQ ID NO: 38 (which corresponds to reside
228 in the EU-numbering convention) would become proline. In some
embodiments, the framework region of the IgG4 antibody can be
back-mutated to the germline framework sequence. Some embodiments
comprise both the back-mutates framework region and the serine to
proline change in the Fc region. See, e.g., SEQ ID NO: 54 (antibody
9.14.4C-Ser) and SEQ ID NO: 58 (antibody 8.10.3C-Ser) in Table
1.
Deimmunized Antibodies
[0211] Another way of producing antibodies with reduced
immunogenicity is the deimmunization of antibodies. In another
aspect of the invention, the antibody may be deimmunized using the
techniques described in, e.g., PCT Publication Nos. WO98/52976 and
WO00/34317 (which incorporated herein by reference in their
entirety).
Mutated Antibodies
[0212] In another embodiment, the nucleic acid molecules, vectors
and host cells may be used to make mutated anti-M-CSF antibodies.
The antibodies may be mutated in the variable domains of the heavy
and/or light chains, e.g., to alter a binding property of the
antibody. For example, a mutation may be made in one or more of the
CDR regions to increase or decrease the K.sub.D of the antibody for
M-CSF, to increase or decrease k.sub.off, or to alter the binding
specificity of the antibody. Techniques in site-directed
mutagenesis are well-known in the art. See, e.g., Sambrook et al.
and Ausubel et al., supra. In a preferred embodiment, mutations are
made at an amino acid residue that is known to be changed compared
to germline in a variable domain of an anti-M-CSF antibody. In
another embodiment, one or more mutations are made at an amino acid
residue that is known to be changed compared to the germline in a
CDR region or framework region of a variable domain, or in a
constant domain of a monoclonal antibody 252, 88, 100, 3.8.3,
2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.21F, 9.14.4, 8.10.3, 9.7.2,
9.7.2C-Ser, 9.14.4C-Ser, 8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2,
9.7.2-CG4, 9.14.4-CG2, 9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser,
8.10.3-Ser, 8.10.3-CG4, 8.10.3FG1 or 9.14.4G1. In another
embodiment, one or more mutations are made at an amino acid residue
that is known to be changed compared to the germline in a CDR
region or framework region of a variable domain of a heavy chain
amino acid sequence selected from SEQ ID NOS: 2, 6, 10, 14, 18, 22,
26, 30, 34, 38, 46, 50, 54, 58, 62, 66, 70, 74, 78, 82, 86, 90, 94,
98 or 102, or whose heavy chain nucleotide sequence is presented in
SEQ ID NOS: 1, 5, 9, 25, 29, 33, 37, 45, 97 or 101. In another
embodiment, one or more mutations are made at an amino acid residue
that is known to be changed compared to the germline in a CDR
region or framework region of a variable domain of a light chain
amino acid sequence selected from SEQ ID NOS: 4, 8, 12, 16, 20, 24,
28, 32, 36, 44, 48, 52, 56 or 60, or whose light chain nucleotide
sequence is presented in SEQ ID NOS: 3, 7, 11, 27, 31, 35, 43 or
47.
[0213] In one embodiment, the framework region is mutated so that
the resulting framework region(s) have the amino acid sequence of
the corresponding germline gene. A mutation may be made in a
framework region or constant domain to increase the half-life of
the anti-M-CSF antibody. See, e.g., PCT Publication No. WO
00/09560, herein incorporated by reference. A mutation in a
framework region or constant domain also can be made to alter the
immunogenicity of the antibody, to provide a site for covalent or
non-covalent binding to another molecule, or to alter such
properties as complement fixation, FcR binding and
antibody-dependent cell-mediated cytotoxicity (ADCC). According to
the invention, a single antibody may have mutations in any one or
more of the CDRs or framework regions of the variable domain or in
the constant domain.
[0214] In some embodiments, there are from 1 to 8 including any
number in between, amino acid mutations in either the V.sub.H or
V.sub.L domains of the mutated anti-M-CSF antibody compared to the
anti-M-CSF antibody prior to mutation. In any of the above, the
mutations may occur in one or more CDR regions. Further, any of the
mutations can be conservative amino acid substitutions. In some
embodiments, there are no more than 5, 4, 3, 2, or 1 amino acid
changes in the constant domains.
Modified Antibodies
[0215] In another embodiment, a fusion antibody or immunoadhesin
may be made that comprises all or a portion of an anti-M-CSF
antibody of the invention linked to another polypeptide. In a
preferred embodiment, only the variable domains of the anti-M-CSF
antibody are linked to the polypeptide. In another preferred
embodiment, the V.sub.H domain of an anti-M-CSF antibody is linked
to a first polypeptide, while the V.sub.L domain of an anti-M-CSF
antibody is linked to a second polypeptide that associates with the
first polypeptide in a manner such that the V.sub.H and V.sub.L
domains can interact with one another to form an antibody binding
site. In another preferred embodiment, the V.sub.H domain is
separated from the V.sub.L domain by a linker such that the V.sub.H
and V.sub.L domains can interact with one another (see below under
Single Chain Antibodies). The V.sub.H-linker-V.sub.L antibody is
then linked to the polypeptide of interest. The fusion antibody is
useful for directing a polypeptide to a M-CSF-expressing cell or
tissue. The polypeptide may be a therapeutic agent, such as a
toxin, growth factor or other regulatory protein, or may be a
diagnostic agent, such as an enzyme that may be easily visualized,
such as horseradish peroxidase. In addition, fusion antibodies can
be created in which two (or more) single-chain antibodies are
linked to one another. This is useful if one wants to create a
divalent or polyvalent antibody on a single polypeptide chain, or
if one wants to create a bispecific antibody.
[0216] To create a single chain antibody, (scFv) the V.sub.H- and
V.sub.L-encoding DNA fragments are operatively linked to another
fragment encoding a flexible linker, e.g., encoding the amino acid
sequence (Gly.sub.4-Ser).sub.3, such that the V.sub.H and V.sub.L
sequences can be expressed as a contiguous single-chain protein,
with the V.sub.L and V.sub.H domains joined by the flexible linker.
See, e.g., Bird et al., Science 242:423-426 (1988); Huston et al.,
Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988); McCafferty et al.,
Nature 348:552-554 (1990). The single chain antibody may be
monovalent, if only a single V.sub.H and V.sub.L are used,
bivalent, if two V.sub.H and V.sub.L are used, or polyvalent, if
more than two V.sub.H and V.sub.L are used. Bispecific or
polyvalent antibodies may be generated that bind specifically to
M-CSF and to another molecule.
[0217] In other embodiments, other modified antibodies may be
prepared using anti-M-CSF antibody-encoding nucleic acid molecules.
For instance, "Kappa bodies" (Ill et al., Protein Eng. 10: 949-57
(1997)), "Minibodies" (Martin et al., EMBO J. 13: 5303-9 (1994)),
"Diabodies" (Holliger et al., Proc. Natl. Acad. Sci. USA 90:
6444-6448 (1993)), or "Janusins" (Traunecker et al., EMBO J.
10:3655-3659 (1991) and Traunecker et al., Int. J. Cancer (Suppl.)
7:51-52 (1992)) may be prepared using standard molecular biological
techniques following the teachings of the specification.
[0218] Bispecific antibodies or antigen-binding fragments can be
produced by a variety of methods including fusion of hybridomas or
linking of Fab' fragments. See, e.g., Songsivilai & Lachmann,
Clin. Exp. Immunol. 79: 315-321 (1990), Kostelny et al., J.
Immunol. 148:1547-1553 (1992). In addition, bispecific antibodies
may be formed as "diabodies" or "Janusins." In some embodiments,
the bispecific antibody binds to two different epitopes of M-CSF.
In some embodiments, the bispecific antibody has a first heavy
chain and a first light chain from monoclonal antibody 252, 88,
100, 3.8.3, 2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4,
8.10.3, or 9.7.2 and an additional antibody heavy chain and light
chain. In some embodiments, the additional light chain and heavy
chain also are from one of the above-identified monoclonal
antibodies, but are different from the first heavy and light
chains.
[0219] In some embodiments, the modified antibodies described above
are prepared using one or more of the variable domains or CDR
regions from a human anti-M-CSF monoclonal antibody provided
herein, from an amino acid sequence of said monoclonal antibody, or
from a heavy chain or light chain encoded by a nucleic acid
sequence encoding said monoclonal antibody.
Derivatized and Labeled Antibodies
[0220] An anti-M-CSF antibody or antigen-binding portion of the
invention can be derivatized or linked to another molecule (e.g.,
another peptide or protein). In general, the antibodies or portion
thereof is derivatized such that the M-CSF binding is not affected
adversely by the derivatization or labeling. Accordingly, the
antibodies and antibody portions of the invention are intended to
include both intact and modified forms of the human anti-M-CSF
antibodies described herein. For example, an antibody or antibody
portion of the invention can be functionally linked (by chemical
coupling, genetic fusion, noncovalent association or otherwise) to
one or more other molecular entities, such as another antibody
(e.g., a bispecific antibody or a diabody), a detection agent, a
cytotoxic agent, a pharmaceutical agent, and/or a protein or
peptide that can mediate associate of the antibody or antibody
portion with another molecule (such as a streptavidin core region
or a polyhistidine tag).
[0221] One type of derivatized antibody is produced by crosslinking
two or more antibodies (of the same type or of different types,
e.g., to create bispecific antibodies). Suitable crosslinkers
include those that are heterobifunctional, having two distinctly
reactive groups separated by an appropriate spacer (e.g.,
m-maleimidobenzoyl-N-hydroxysuccinimide ester) or homobifunctional
(e.g., disuccinimidyl suberate). Such linkers are available from
Pierce Chemical Company, Rockford, Ill.
[0222] Another type of derivatized antibody is a labeled antibody.
Useful detection agents with which an antibody or antigen-binding
portion of the invention may be derivatized include fluorescent
compounds, including fluorescein, fluorescein isothiocyanate,
rhodamine, 5-dimethylamine-1-napthalenesulfonyl chloride,
phycoerythrin, lanthanide phosphors and the like. An antibody can
also be labeled with enzymes that are useful for detection, such as
horseradish peroxidase, .beta.-galactosidase, luciferase, alkaline
phosphatase, glucose oxidase and the like. When an antibody is
labeled with a detectable enzyme, it is detected by adding
additional reagents that the enzyme uses to produce a reaction
product that can be discerned. For example, when the agent
horseradish peroxidase is present, the addition of hydrogen
peroxide and diaminobenzidine leads to a colored reaction product,
which is detectable. An antibody can also be labeled with biotin,
and detected through indirect measurement of avidin or streptavidin
binding. An antibody can also be labeled with a predetermined
polypeptide epitope recognized by a secondary reporter (e.g.,
leucine zipper pair sequences, binding sites for secondary
antibodies, metal binding domains, epitope tags). In some
embodiments, labels are attached by spacer arms of various lengths
to reduce potential steric hindrance.
[0223] An anti-M-CSF antibody can also be labeled with a
radiolabeled amino acid. The radiolabeled anti-M-CSF antibody can
be used for both diagnostic and therapeutic purposes. For instance,
the radiolabeled anti-M-CSF antibody can be used to detect
M-CSF-expressing tumors by x-ray or other diagnostic techniques.
Further, the radiolabeled anti-M-CSF antibody can be used
therapeutically as a toxin for cancerous cells or tumors. Examples
of labels for polypeptides include, but are not limited to, the
following radioisotopes or radionuclides --.sup.3H, .sup.14C,
.sup.15N, .sup.35S, .sup.90Y, .sup.99Tc, .sup.111In, .sup.125I, and
.sup.131I.
[0224] An anti-M-CSF antibody can also be derivatized with a
chemical group such as polyethylene glycol (PEG), a methyl or ethyl
group, or a carbohydrate group. These groups are useful to improve
the biological characteristics of the antibody, e.g., to increase
serum half-life or to increase tissue binding.
Pharmaceutical Compositions and Kits
[0225] The invention also relates to compositions comprising a
human anti-M-CSF antagonist antibody for the treatment of subjects
in need of treatment for rheumatoid arthritis, osteoporosis, or
atherosclerosis. In some embodiments, the subject of treatment is a
human. In other embodiments, the subject is a veterinary subject.
Hyperproliferative disorders where monocytes play a role that may
be treated by an antagonist anti-M-CSF antibody of the invention
can involve any tissue or organ and include but are not limited to
brain, lung, squamous cell, bladder, gastric, pancreatic, breast,
head, neck, liver, renal, ovarian, prostate, colorectal,
esophageal, gynecological, nasopharynx, or thyroid cancers,
melanomas, lymphomas, leukemias or multiple myelomas. In
particular, human antagonist anti-M-CSF antibodies of the invention
are useful to treat or prevent carcinomas of the breast, prostate,
colon and lung.
[0226] This invention also encompasses compositions for the
treatment of a condition selected from the group consisting of
arthritis, psoriatic arthritis, Reiter's syndrome, gout, traumatic
arthritis, rubella arthritis and acute synovitis, rheumatoid
arthritis, rheumatoid spondylitis, ankylosing spondylitis,
osteoarthritis, gouty arthritis and other arthritic conditions,
sepsis, septic shock, endotoxic shock, gram negative sepsis, toxic
shock syndrome, Alzheimer's disease, stroke, neurotrauma, asthma,
adult respiratory distress syndrome, cerebral malaria, chronic
pulmonary inflammatory disease, silicosis, pulmonary sarcoidosis,
bone resorption disease, osteoporosis, restenosis, cardiac and
renal reperfusion injury, thrombosis, glomerularonephritis,
diabetes, graft vs. host reaction, allograft rejection,
inflammatory bowel disease, Crohn's disease, ulcerative colitis,
multiple sclerosis, muscle degeneration, eczema, contact
dermatitis, psoriasis, sunburn, or conjunctivitis shock in a
mammal, including a human, comprising an amount of a human
anti-M-CSF monoclonal antibody of the invention effective in such
treatment and a pharmaceutically acceptable carrier.
[0227] Treatment may involve administration of one or more
antagonist anti-M-CSF monoclonal antibodies of the invention, or
antigen-binding fragments thereof, alone or with a pharmaceutically
acceptable carrier. As used herein, "pharmaceutically acceptable
carrier" means any and all solvents, dispersion media, coatings,
antibacterial and antifungal agents, isotonic and absorption
delaying agents, and the like that are physiologically compatible.
Some examples of pharmaceutically acceptable carriers are water,
saline, phosphate buffered saline, dextrose, glycerol, ethanol and
the like, as well as combinations thereof. In many cases, it will
be preferable to include isotonic agents, for example, sugars,
polyalcohols such as mannitol, sorbitol, or sodium chloride in the
composition. Additional examples of pharmaceutically acceptable
substances are wetting agents or minor amounts of auxiliary
substances such as wetting or emulsifying agents, preservatives or
buffers, which enhance the shelf life or effectiveness of the
antibody.
[0228] Anti-M-CSF antibodies of the invention and compositions
comprising them, can be administered in combination with one or
more other therapeutic, diagnostic or prophylactic agents.
Additional therapeutic agents include other anti-neoplastic,
anti-tumor, anti-angiogenic or chemotherapeutic agents. Such
additional agents may be included in the same composition or
administered separately. In some embodiments, one or more
inhibitory anti-M-CSF antibodies of the invention can be used as a
vaccine or as adjuvants to a vaccine.
[0229] The compositions of this invention may be in a variety of
forms, for example, liquid, semi-solid and solid dosage forms, such
as liquid solutions (e.g., injectable and infusible solutions),
dispersions or suspensions, tablets, pills, powders, liposomes and
suppositories. The preferred form depends on the intended mode of
administration and therapeutic application. Typical preferred
compositions are in the form of injectable or infusible solutions,
such as compositions similar to those used for passive immunization
of humans. The preferred mode of administration is parenteral
(e.g., intravenous, subcutaneous, intraperitoneal, intramuscular).
In a preferred embodiment, the antibody is administered by
intravenous infusion or injection. In another preferred embodiment,
the antibody is administered by intramuscular or subcutaneous
injection. In another embodiment, the invention includes a method
of treating a subject in need thereof with an antibody or an
antigen-binding portion thereof that specifically binds to M-CSF
comprising the steps of: (a) administering an effective amount of
an isolated nucleic acid molecule encoding the heavy chain or the
antigen-binding portion thereof, an isolated nucleic acid molecule
encoding the light chain or the antigen-binding portion thereof, or
both the nucleic acid molecules encoding the light chain and the
heavy chain or antigen-binding portions thereof; and (b) expressing
the nucleic acid molecule.
[0230] Therapeutic compositions typically must be sterile and
stable under the conditions of manufacture and storage. The
composition can be formulated as a solution, microemulsion,
dispersion, liposome, or other ordered structure suitable to high
drug concentration. Sterile injectable solutions can be prepared by
incorporating the anti-M-CSF antibody in the required amount in an
appropriate solvent with one or a combination of ingredients
enumerated above, as required, followed by filtered sterilization.
Generally, dispersions are prepared by incorporating the active
compound into a sterile vehicle that contains a basic dispersion
medium and the required other ingredients from those enumerated
above. In the case of sterile powders for the preparation of
sterile injectable solutions, the preferred methods of preparation
are vacuum drying and freeze-drying that yields a powder of the
active ingredient plus any additional desired ingredient from a
previously sterile-filtered solution thereof. The proper fluidity
of a solution can be maintained, for example, by the use of a
coating such as lecithin, by the maintenance of the required
particle size in the case of dispersion and by the use of
surfactants. Prolonged absorption of injectable compositions can be
brought about by including in the composition an agent that delays
absorption, for example, monostearate salts and gelatin.
[0231] The antibodies of the present invention can be administered
by a variety of methods known in the art, although for many
therapeutic applications, the preferred route/mode of
administration is subcutaneous, intramuscular, or intravenous
infusion. As will be appreciated by the skilled artisan, the route
and/or mode of administration will vary depending upon the desired
results.
[0232] In certain embodiments, the antibody compositions active
compound may be prepared with a carrier that will protect the
antibody against rapid release, such as a controlled release
formulation, including implants, transdermal patches, and
microencapsulated delivery systems. Biodegradable, biocompatible
polymers can be used, such as ethylene vinyl acetate,
polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and
polylactic acid. Many methods for the preparation of such
formulations are patented or generally known to those skilled in
the art. See, e.g., Sustained and Controlled Release Drug Delivery
Systems (J. R. Robinson, ed., Marcel Dekker, Inc., New York,
1978).
[0233] In certain embodiments, an anti-M-CSF antibody of the
invention can be orally administered, for example, with an inert
diluent or an assimilable edible carrier. The compound (and other
ingredients, if desired) can also be enclosed in a hard or soft
shell gelatin capsule, compressed into tablets, or incorporated
directly into the subject's diet. For oral therapeutic
administration, the anti-M-CSF antibodies can be incorporated with
excipients and used in the form of ingestible tablets, buccal
tablets, troches, capsules, elixirs, suspensions, syrups, wafers,
and the like. To administer a compound of the invention by other
than parenteral administration, it may be necessary to coat the
compound with, or co-administer the compound with, a material to
prevent its inactivation.
[0234] Additional active compounds also can be incorporated into
the compositions. In certain embodiments, an anti-M-CSF antibody of
the invention is co-formulated with and/or co-administered with one
or more additional therapeutic agents. These agents include
antibodies that bind other targets, antineoplastic agents,
antitumor agents, chemotherapeutic agents, peptide analogues that
inhibit M-CSF, soluble c-fins that can bind M-CSF, one or more
chemical agents that inhibit M-CSF, anti-inflammatory agents,
anti-coagulants, agents that lower blood pressure (i.e,
angiotensin-converting enzyme (ACE) inhibitors). Such combination
therapies may require lower dosages of the anti-M-CSF antibody as
well as the co-administered agents, thus avoiding possible
toxicities or complications associated with the various
monotherapies.
[0235] Inhibitory anti-M-CSF antibodies of the invention and
compositions comprising them also may be administered in
combination with other therapeutic regimens, in particular in
combination with radiation treatment for cancer. The compounds of
the present invention may also be used in combination with
anticancer agents such as endostatin and angiostatin or cytotoxic
drugs such as adriamycin, daunomycin, cis-platinum, etoposide,
taxol, taxotere and alkaloids, such as vincristine, farnesyl
transferase inhibitors, VEGF inhibitors, and antimetabolites such
as methotrexate.
[0236] The compounds of the invention may also be used in
combination with antiviral agents such as VIRACEPT.RTM. (nelfinavir
mesylate), AZT, aciclovir and famciclovir, and antisepsis compounds
such as Valant.
[0237] The compositions of the invention may include a
"therapeutically effective amount" or a "prophylactically effective
amount" of an antibody or antigen-binding portion of the invention.
A "therapeutically effective amount" refers to an amount effective,
at dosages and for periods of time necessary, to achieve the
desired therapeutic result. A therapeutically effective amount of
the antibody or antibody portion may vary according to factors such
as the disease state, age, sex, and weight of the individual, and
the ability of the antibody or antibody portion to elicit a desired
response in the individual. A therapeutically effective amount is
also one in which any toxic or detrimental effects of the antibody
or antibody portion are outweighed by the therapeutically
beneficial effects. A "prophylactically effective amount" refers to
an amount effective, at dosages and for periods of time necessary,
to achieve the desired prophylactic result. Typically, since a
prophylactic dose is used in subjects prior to or at an earlier
stage of disease, the prophylactically effective amount will be
less than the therapeutically effective amount.
[0238] Dosage regimens can be adjusted to provide the optimum
desired response (e.g., a therapeutic or prophylactic response).
For example, a single bolus can be administered, several divided
doses can be administered over time or the dose can be
proportionally reduced or increased as indicated by the exigencies
of the therapeutic situation. It is especially advantageous to
formulate parenteral compositions in dosage unit form for ease of
administration and uniformity of dosage. Dosage unit form as used
herein refers to physically discrete units suited as unitary
dosages for the mammalian subjects to be treated; each unit
containing a predetermined quantity of active compound calculated
to produce the desired therapeutic effect in association with the
required pharmaceutical carrier The specification for the dosage
unit forms of the invention are dictated by and directly dependent
on (a) the unique characteristics of the anti-M-CSF antibody or
portion and the particular therapeutic or prophylactic effect to be
achieved, and (b) the limitations inherent in the art of
compounding such an antibody for the treatment of sensitivity in
individuals.
[0239] An exemplary, non-limiting range for a therapeutically or
prophylactically effective amount of an antibody or antibody
portion of the invention is 0.025 to 50 mg/kg, more preferably 0.1
to 50 mg/kg, more preferably 0.1-25, 0.1 to 10 or 0.1 to 3 mg/kg.
It is to be noted that dosage values may vary with the type and
severity of the condition to be alleviated. It is to be further
understood that for any particular subject, specific dosage
regimens should be adjusted over time according to the individual
need and the professional judgment of the person administering or
supervising the administration of the compositions, and that dosage
ranges set forth herein are exemplary only and are not intended to
limit the scope or practice of the claimed composition.
[0240] Another aspect of the present invention provides kits
comprising an anti-M-CSF antibody or antigen-binding portion of the
invention or a composition comprising such an antibody or portion.
A kit may include, in addition to the antibody or composition,
diagnostic or therapeutic agents. A kit also can include
instructions for use in a diagnostic or therapeutic method. In a
preferred embodiment, the kit includes the antibody or a
composition comprising it and a diagnostic agent that can be used
in a method described below. In another preferred embodiment, the
kit includes the antibody or a composition comprising it and one or
more therapeutic agents that can be used in a method described
below. One embodiment of the invention is a kit comprising a
container, instructions on the administration of an anti-M-CSF
antibody to a human suffering from an inflammatory disease, or
instructions for measuring the number of CD14+CD16+ monocytes in a
biological sample and an anti-M-CSF antibody.
[0241] This invention also relates to compositions for inhibiting
abnormal cell growth in a mammal comprising an amount of an
antibody of the invention in combination with an amount of a
chemotherapeutic agent, wherein the amounts of the compound, salt,
solvate, or prodrug, and of the chemotherapeutic agent are together
effective in inhibiting abnormal cell growth. Many chemotherapeutic
agents are known in the art. In some embodiments, the
chemotherapeutic agent is selected from the group consisting of
mitotic inhibitors, alkylating agents, anti-metabolites,
intercalating antibiotics, growth factor inhibitors, cell cycle
inhibitors, enzymes, topoisomerase inhibitors, biological response
modifiers, anti-hormones, e.g. anti-androgens, and
anti-angiogenesis agents.
[0242] Anti-angiogenic agents, such as MMP-2
(matrix-metalloproteinase 2) inhibitors, MMP-9
(matrix-metalloproteinase 9) inhibitors, and COX-II (cyclooxygenase
II) inhibitors, can be used in conjunction with an anti-M-CSF
antibody of the invention. Examples of useful COX-II inhibitors
include CELEBREX.RTM. (celecoxib), valdecoxib, and rofecoxib.
Examples of useful matrix metalloproteinase inhibitors are
described in WO 96/33172 (published Oct. 24, 1996), WO 96/27583
(published Mar. 7, 1996), European Patent Application No.
97304971.1 (filed Jul. 8, 1997), European Patent Application No.
99308617.2 (filed Oct. 29, 1999), WO 98/07697 (published Feb. 26,
1998), WO 98/03516 (published Jan. 29, 1998), WO 98/34918
(published Aug. 13, 1998), WO 98/34915 (published Aug. 13, 1998),
WO 98/33768 (published Aug. 6, 1998), WO 98/30566 (published Jul.
16, 1998), European Patent Publication 606,046 (published Jul. 13,
1994), European Patent Publication 931,788 (published Jul. 28,
1999), WO 90/05719 (published May 31, 1990), WO 99/52910 (published
Oct. 21, 1999), WO 99/52889 (published Oct. 21, 1999), WO 99/29667
(published Jun. 17, 1999), PCT International Application No.
PCT/M98/01113 (filed Jul. 21, 1998), European Patent Application
No. 99302232.1 (filed Mar. 25, 1999), Great Britain patent
application number 9912961.1 (filed Jun. 3, 1999), U.S. Provisional
Application No. 60/148,464 (filed Aug. 12, 1999), U.S. Pat. No.
5,863,949 (issued Jan. 26, 1999), U.S. Pat. No. 5,861,510 (issued
Jan. 19, 1999), and European Patent Publication 780,386 (published
Jun. 25, 1997), all of which are incorporated herein in their
entireties by reference. Preferred MMP inhibitors are those that do
not demonstrate arthralgia. More preferred, are those that
selectively inhibit MMP-2 and/or MMP-9 relative to the other
matrix-metalloproteinases (i.e. MMP-1, MMP-3, MMP-4, MMP-5, MMP-6,
MMP-7, MMP-8, MMP-10, MMP-11, MMP-12, and MMP-13). Some specific
examples of MMP inhibitors useful in the present invention are
AG-3340, RO 32-3555, RS 13-0830, and the compounds recited in the
following list:
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclopentyl-
)-amino]-propionic acid;
3-exo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]o-
ctane-3-carboxylic acid hydroxyamide; (2R, 3R)
1-[4-(2-chloro-4-fluoro-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-pi-
peridine-2-carboxylic acid hydroxyamide;
4-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxyl-
ic acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-cyclobutyl)-
-amino]-propionic acid;
4-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-4-carboxyl-
ic acid hydroxyamide; (R)
3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-tetrahydro-pyran-3-carboxyl-
ic acid hydroxyamide; (2R, 3R)
1-[4-(4-fluoro-2-methyl-benzyloxy)-benzenesulfonyl]-3-hydroxy-3-methyl-pi-
peridine-2-carboxylic acid hydroxyamide;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(1-hydroxycarbamoyl-1-methyl-et-
hyl)-amino]-propionic acid;
3-[[4-(4-fluoro-phenoxy)-benzenesulfonyl]-(4-hydroxycarbamoyl-tetrahydro--
pyran-4-yl)-amino]-propionic acid;
3-exo-3-[4-(4-chloro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]o-
ctane-3-carboxylic acid hydroxyamide;
3-endo-3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-8-oxa-bicyclo[3.2.1]-
octane-3-carboxylic acid hydroxyamide; and (R)
3-[4-(4-fluoro-phenoxy)-benzenesulfonylamino]-tetrahydro-furan-3-carboxyl-
ic acid hydroxyamide; and pharmaceutically acceptable salts and
solvates of said compounds.
[0243] A compound comprising a human anti-M-CSF monoclonal antibody
of the invention can also be used with signal transduction
inhibitors, such as agents that can inhibit EGF-R (epidermal growth
factor receptor) responses, such as EGF-R antibodies, EGF
antibodies, and molecules that are EGF-R inhibitors; VEGF (vascular
endothelial growth factor) inhibitors, such as VEGF receptors and
molecules that can inhibit VEGF; and erbB2 receptor inhibitors,
such as organic molecules or antibodies that bind to the erbB2
receptor, for example, HERCEPTIN.RTM. (trastuzumab) (Genentech,
Inc.). EGF-R inhibitors are described in, for example in WO
95/19970 (published Jul. 27, 1995), WO 98/14451 (published Apr. 9,
1998), WO 98/02434 (published Jan. 22, 1998), and U.S. Pat. No.
5,747,498 (issued May 5, 1998), and such substances can be used in
the present invention as described herein. EGFR-inhibiting agents
include, but are not limited to, the monoclonal antibodies C225 and
anti-EGFR 22Mab (ImClone Systems Incorporated), ABX-EGF
(Abgenix/Cell Genesys), EMD-7200 (Merck KgaA), EMD-5590 (Merck
KgaA), MDX-447/H-477 (Medarex Inc. and Merck KgaA), and the
compounds ZD-1834, ZD-1838 and ZD-1839 (AstraZeneca), PKI-166
(Novartis), PKI-166/CGP-75166 (Novartis), PTK 787 (Novartis), CP
701 (Cephalon), leflunomide (Pharmacia/Sugen), CI-1033 (Warner
Lambert Parke Davis), CI-1033/PD 183,805 (Warner Lambert Parke
Davis), CL-387,785 (Wyeth-Ayerst), BBR-1611 (Boehringer Mannheim
GmbH/Roche), Naamidine A (Bristol Myers Squibb), RC-3940-II
(Pharmacia), BMX-1382 (Boehringer Ingelheim), OLX-103 (Merck &
Co.), VRCTC-310 (Ventech Research), EGF fusion toxin (Seragen
Inc.), DAB-389 (Seragen/Lilgand), ZM-252808 (Imperial Cancer
Research Fund), RG-50864 (INSERM), LFM-A12 (Parker Hughes Cancer
Center), WHI-P97 (Parker Hughes Cancer Center), GW-282974 (Glaxo),
KT-8391 (Kyowa Hakko) and EGF-R Vaccine (York Medical/Centro de
Immunologia Molecular (CIM)). These and other EGF-R-inhibiting
agents can be used in the present invention.
[0244] VEGF inhibitors, for example SU-5416 and SU-6668 (Sugen
Inc.), AVASTIN.RTM. (bevacizumab) (Genentech), SH-268 (Schering),
and NX-1838 (NeXstar) can also be combined with the compound of the
present invention. VEGF inhibitors are described in, for example in
WO 99/24440 (published May 20, 1999), PCT International Application
PCT/M99/00797 (filed May 3, 1999), in WO 95/21613 (published Aug.
17, 1995), WO 99/61422 (published Dec. 2, 1999), U.S. Pat. No.
5,834,504 (issued Nov. 10, 1998), WO 98/50356 (published Nov. 12,
1998), U.S. Pat. No. 5,883,113 (issued Mar. 16, 1999), U.S. Pat.
No. 5,886,020 (issued Mar. 23, 1999), U.S. Pat. No. 5,792,783
(issued Aug. 11, 1998), WO 99/10349 (published Mar. 4, 1999), WO
97/32856 (published Sep. 12, 1997), WO 97/22596 (published Jun. 26,
1997), WO 98/54093 (published Dec. 3, 1998), WO 98/02438 (published
Jan. 22, 1998), WO 99/16755 (published Apr. 8, 1999), and WO
98/02437 (published Jan. 22, 1998), all of which are incorporated
herein in their entireties by reference. Other examples of some
specific VEGF inhibitors useful in the present invention are IM862
(Cytran Inc.); anti-VEGF monoclonal antibody of Genentech, Inc.;
and angiozyme, a synthetic ribozyme from Ribozyme and Chiron. These
and other VEGF inhibitors can be used in the present invention as
described herein. ErbB2 receptor inhibitors, such as GW-282974
(Glaxo Wellcome plc), and the monoclonal antibodies AR-209 (Aronex
Pharmaceuticals Inc.) and 2B-1 (Chiron), can furthermore be
combined with the compound of the invention, for example those
indicated in WO 98/02434 (published Jan. 22, 1998), WO 99/35146
(published Jul. 15, 1999), WO 99/35132 (published Jul. 15, 1999),
WO 98/02437 (published Jan. 22, 1998), WO 97/13760 (published Apr.
17, 1997), WO 95/19970 (published Jul. 27, 1995), U.S. Pat. No.
5,587,458 (issued Dec. 24, 1996), and U.S. Pat. No. 5,877,305
(issued Mar. 2, 1999), which are all hereby incorporated herein in
their entireties by reference. ErbB2 receptor inhibitors useful in
the present invention are also described in U.S. Pat. No. 6,465,449
(issued Oct. 15, 2002), and in U.S. Pat. No. 6,284,764 (issued Sep.
4, 2001), both of which are incorporated in their entireties herein
by reference. The erbB2 receptor inhibitor compounds and substance
described in the aforementioned PCT applications, U.S. patents, and
U.S. provisional applications, as well as other compounds and
substances that inhibit the erbB2 receptor, can be used with the
compound of the present invention in accordance with the present
invention.
[0245] Anti-survival agents include anti-IGF-IR antibodies and
anti-integrin agents, such as anti-integrin antibodies.
[0246] Anti-inflammatory agents can be used in conjunction with an
anti-M-CSF antibody of the invention. For the treatment of
rheumatoid arthritis, the human anti-M-CSF antibodies of the
invention may be combined with agents such as TNF-.alpha.
inhibitors such as TNF drugs (such as REMICADE.RTM. (infliximab),
CDP-870 and HUMIRA.RTM. (adalimumab)) and TNF receptor
immunoglobulin molecules (such as ENBREL.RTM. (etanercept)), IL-1
inhibitors, receptor antagonists or soluble IL-1ra (e.g.
KINERET.RTM. (anakinra) or ICE inhibitors), COX-2 inhibitors (such
as celecoxib, rofecoxib, valdecoxib and etoricoxib),
metalloprotease inhibitors (preferably MMP-13 selective
inhibitors), p2X7 inhibitors, .alpha.2.delta. ligands (such as
NEUROTIN.RTM. (gabapentin) and LYRICA.RTM. (pregabalin), low dose
methotrexate, leflunomide, hydroxychloroquine, d-penicillamine,
auranofin or parenteral or oral gold. The compounds of the
invention can also be used in combination with existing therapeutic
agents for the treatment of osteoarthritis. Suitable agents to be
used in combination include standard non-steroidal
anti-inflammatory agents (hereinafter NSAID's) such as piroxicam,
diclofenac, propionic acids such as naproxen, flurbiprofen,
fenoprofen, ketoprofen and ibuprofen, fenamates such as mefenamic
acid, indomethacin, sulindac, apazone, pyrazolones such as
phenylbutazone, salicylates such as aspirin, COX-2 inhibitors such
as celecoxib, valdecoxib, rofecoxib and etoricoxib, analgesics and
intraarticular therapies such as corticosteroids and hyaluronic
acids such as hyalgan and synvisc.
[0247] Anti-coagulant agents can be used in conjunction with an
anti-M-CSF antibody of the invention. Examples of anti-coagulant
agents include, but are not limited to, COUMADIN.RTM. (warfarin
sodium), heparin, and LOVENOX.RTM. (enoxaparin sodium).
[0248] The human anti-M-CSF antibodies of the present invention may
also be used in combination with cardiovascular agents such as
calcium channel blockers, lipid lowering agents such as statins,
fibrates, beta-blockers, Ace inhibitors, Angiotensin-2 receptor
antagonists and platelet aggregation inhibitors. The compounds of
the present invention may also be used in combination with CNS
agents such as antidepressants (such as sertraline),
anti-Parkinsonian drugs (such as deprenyl, L-dopa, REQUIP.RTM.
(ropinirole HCl), MIRAPEX.RTM. (pramipexole dihydrochloride), MAOB
inhibitors such as selegine and rasagiline, comP inhibitors such as
Tasmar, A-2 inhibitors, dopamine reuptake inhibitors, NMDA
antagonists, Nicotine agonists, Dopamine agonists and inhibitors of
neuronal nitric oxide synthase), and anti-Alzheimer's drugs such as
donepezil, tacrine, .alpha.2.delta. LIGANDS (such as NEUROTIN.RTM.
(gabapentin) and LYRICA.RTM. (pregabalin)) inhibitors, COX-2
inhibitors, propentofylline or metryfonate.
[0249] The human anti-M-CSF antibodies of the present invention may
also be used in combination with osteoporosis agents such as
roloxifene, droloxifene, lasofoxifene or fosomax and
immunosuppressant agents such as FK-506 and rapamycin.
Diagnostic Methods of Use
[0250] In another aspect, the invention provides diagnostic
methods. The anti-M-CSF antibodies can be used to detect M-CSF in a
biological sample in vitro or in vivo. In one embodiment, the
invention provides a method for diagnosing the presence or location
of a M-CSF-expressing tumor in a subject in need thereof,
comprising the steps of injecting the antibody into the subject,
determining the expression of M-CSF in the subject by localizing
where the antibody has bound, comparing the expression in the
subject with that of a normal reference subject or standard, and
diagnosing the presence or location of the tumor.
[0251] The anti-M-CSF antibodies can be used in a conventional
immunoassay, including, without limitation, an ELISA, an RIA, FACS,
tissue immunohistochemistry, Western blot or immunoprecipitation.
The anti-M-CSF antibodies of the invention can be used to detect
M-CSF from humans. In another embodiment, the anti-M-CSF antibodies
can be used to detect M-CSF from primates such as cynomologus
monkey, rhesus monkeys, chimpanzees or apes. The invention provides
a method for detecting M-CSF in a biological sample comprising
contacting a biological sample with an anti-M-CSF antibody of the
invention and detecting the bound antibody. In one embodiment, the
anti-M-CSF antibody is directly labeled with a detectable label. In
another embodiment, the anti-M-CSF antibody (the first antibody) is
unlabeled and a second antibody or other molecule that can bind the
anti-M-CSF antibody is labeled. As is well known to one of skill in
the art, a second antibody is chosen that is able to specifically
bind the particular species and class of the first antibody. For
example, if the anti-M-CSF antibody is a human IgG, then the
secondary antibody could be an anti-human-IgG. Other molecules that
can bind to antibodies include, without limitation, Protein A and
Protein G, both of which are available commercially, e.g., from
Pierce Chemical Co.
[0252] Suitable labels for the antibody or secondary antibody have
been disclosed supra, and include various enzymes, prosthetic
groups, fluorescent materials, luminescent materials and
radioactive materials. Examples of suitable enzymes include
horseradish peroxidase, alkaline phosphatase, .beta.-galactosidase,
or acetylcholinesterase; examples of suitable prosthetic group
complexes include streptavidin/biotin and avidin/biotin; examples
of suitable fluorescent materials include umbelliferone,
fluorescein, fluorescein isothiocyanate, rhodamine,
dichlorotriazinylamine fluorescein, dansyl chloride or
phycoerythrin; an example of a luminescent material includes
luminol; and examples of suitable radioactive material include
.sup.125I, .sup.131I, .sup.35S or .sup.3H.
[0253] In other embodiments, M-CSF can be assayed in a biological
sample by a competition immunoassay utilizing M-CSF standards
labeled with a detectable substance and an unlabeled anti-M-CSF
antibody. In this assay, the biological sample, the labeled M-CSF
standards and the anti-M-CSF antibody are combined and the amount
of labeled M-CSF standard bound to the unlabeled antibody is
determined. The amount of M-CSF in the biological sample is
inversely proportional to the amount of labeled M-CSF standard
bound to the anti-M-CSF antibody.
[0254] One can use the immunoassays disclosed above for a number of
purposes. For example, the anti-M-CSF antibodies can be used to
detect M-CSF in cells or on the surface of cells in cell culture,
or secreted into the tissue culture medium. The anti-M-CSF
antibodies can be used to determine the amount of M-CSF on the
surface of cells or secreted into the tissue culture medium that
have been treated with various compounds. This method can be used
to identify compounds that are useful to inhibit or activate M-CSF
expression or secretion. According to this method, one sample of
cells is treated with a test compound for a period of time while
another sample is left untreated. If the total level of M-CSF is to
be measured, the cells are lysed and the total M-CSF level is
measured using one of the immunoassays described above. The total
level of M-CSF in the treated versus the untreated cells is
compared to determine the effect of the test compound.
[0255] An immunoassay for measuring total M-CSF levels is an ELISA
or Western blot. If the cell surface level of M-CSF is to be
measured, the cells are not lysed, and the M-CSF cell surface
levels can be measured using one of the immunoassays described
above. An immunoassay for determining cell surface levels of M-CSF
can include the steps of labeling the cell surface proteins with a
detectable label, such as biotin or .sup.125I, immunoprecipitating
the M-CSF with an anti-M-CSF antibody and then detecting the
labeled M-CSF. Another immunoassay for determining the localization
of M-CSF, e.g., cell surface levels, can be immunohistochemistry.
Methods such as ELISA, RIA, Western blot, immunohistochemistry,
cell surface labeling of integral membrane proteins and
immunoprecipitation are well known in the art. See, e.g., Harlow
and Lane, supra. In addition, the immunoassays can be scaled up for
high throughput screening in order to test a large number of
compounds for inhibition or activation of M-CSF.
[0256] Another example of an immunoassay for measuring secreted
M-CSF levels can be an antigen capture assay, ELISA,
immunohistochemistry assay, Western blot and the like using
antibodies of the invention. If secreted M-CSF is to be measured,
cell culture media or body fluid, such as blood serum, urine, or
synovial fluid, can be assayed for secreted M-CSF and/or cells can
be lysed to release produced, but not yet secreted M-CSF. An
immunoassay for determining secreted levels of M-CSF includes the
steps of labeling the secreted proteins with a detectable label,
such as biotin or .sup.125I, immunoprecipitating the M-CSF with an
anti-M-CSF antibody and then detecting the labeled M-CSF. Another
immunoassay for determining secreted levels of M-CSF can include
the steps of (a) pre-binding anti-M-CSF antibodies to the surface
of a microtiter plate; (b) adding tissue culture cell media or body
fluid containing the secreted M-CSF to the wells of the microtiter
plate to bind to the anti-M-CSF antibodies; (c) adding an antibody
that will detect the anti-M-CSF antibody, e.g., anti-M-CSF labeled
with digoxigenin that binds to an epitope of M-CSF different from
the anti-M-CSF antibody of step (a); (d) adding an antibody to
digoxigenin conjugated to peroxidase; and (e) adding a peroxidase
substrate that will yield a colored reaction product that can be
quantitated to determine the level of secreted M-CSF in tissue
culture cell media or a body fluid sample. Methods such as ELISA,
RIA, Western blot, immunohistochemistry, and antigen capture assay
are well known in the art. See, e.g., Harlow and Lane, supra. In
addition, the immunoassays can be scaled up for high throughput
screening in order to test a large number of compounds for
inhibition or activation of M-CSF.
[0257] The anti-M-CSF antibodies of the invention can also be used
to determine the levels of cell surface M-CSF in a tissue or in
cells derived from the tissue. In some embodiments, the tissue is
from a diseased tissue. In some embodiments, the tissue can be a
tumor or a biopsy thereof. In some embodiments of the method, a
tissue or a biopsy thereof can be excised from a patient. The
tissue or biopsy can then be used in an immunoassay to determine,
e.g., total M-CSF levels, cell surface levels of M-CSF, or
localization of M-CSF by the methods discussed above.
[0258] The method can comprise the steps of administering a
detectably labeled anti-M-CSF antibody or a composition comprising
them to a patient in need of such a diagnostic test and subjecting
the patient to imaging analysis to determine the location of the
M-CSF-expressing tissues. Imaging analysis is well known in the
medical art, and includes, without limitation, x-ray analysis,
magnetic resonance imaging (MRI) or computed tomography (CE). The
antibody can be labeled with any agent suitable for in vivo
imaging, for example a contrast agent, such as barium, which can be
used for x-ray analysis, or a magnetic contrast agent, such as a
gadolinium chelate, which can be used for MRI or CE. Other labeling
agents include, without limitation, radioisotopes, such as
.sup.99Tc. In another embodiment, the anti-M-CSF antibody will be
unlabeled and will be imaged by administering a second antibody or
other molecule that is detectable and that can bind the anti-M-CSF
antibody. In an embodiment, a biopsy is obtained from the patient
to determine whether the tissue of interest expresses M-CSF.
[0259] The anti-M-CSF antibodies of the invention can also be used
to determine the secreted levels of M-CSF in a body fluid such as
blood serum, urine, or synovial fluid derived from a tissue. In
some embodiments, the body fluid is from a diseased tissue. In some
embodiments, the body fluid is from a tumor or a biopsy thereof. In
some embodiments of the method, body fluid is removed from a
patient. The body fluid is then used in an immunoassay to determine
secreted M-CSF levels by the methods discussed above. One
embodiment of the invention is a method of assaying for the
activity of a M-CSF antagonist comprising: administering a M-CSF
antagonist to a primate or human subject and measuring the number
of CD14+CD16+ monocytes in a biological sample.
Therapeutic Methods of Use
[0260] In another embodiment, the invention provides a method for
inhibiting M-CSF activity by administering an anti-M-CSF antibody
to a patient in need thereof. Any of the types of antibodies
described herein may be used therapeutically. In a preferred
embodiment, the anti-M-CSF antibody is a human, chimeric or
humanized antibody. In another preferred embodiment, the M-CSF is
human and the patient is a human patient. Alternatively, the
patient may be a mammal that expresses a M-CSF that the anti-M-CSF
antibody cross-reacts with. The antibody may be administered to a
non-human mammal expressing a M-CSF with which the antibody
cross-reacts (i.e. a primate) for veterinary purposes or as an
animal model of human disease. Such animal models may be useful for
evaluating the therapeutic efficacy of antibodies of this
invention.
[0261] As used herein, the term "a disorder in which M-CSF activity
is detrimental" is intended to include diseases and other disorders
in which the presence of high levels of M-CSF in a subject
suffering from the disorder has been shown to be or is suspected of
being either responsible for the pathophysiology of the disorder or
a factor that contributes to a worsening of the disorder. Such
disorders may be evidenced, for example, by an increase in the
levels of M-CSF secreted and/or on the cell surface or increased
tyrosine autophosphorylation of c-fins in the affected cells or
tissues of a subject suffering from the disorder. The increase in
M-CSF levels may be detected, for example, using an anti-M-CSF
antibody as described above.
[0262] In one embodiment, an anti-M-CSF antibody may be
administered to a patient who has a c-fins-expressing tumor or a
tumor that secretes M-CSF and/or that expresses M-CSF on its cell
surface. Preferably, the tumor expresses a level of c-fins or M-CSF
that is higher than a normal tissue. The tumor may be a solid tumor
or may be a non-solid tumor, such as a lymphoma. In a more
preferred embodiment, an anti-M-CSF antibody may be administered to
a patient who has a c-fins-expressing tumor, a M-CSF-expressing
tumor, or a tumor that secretes M-CSF that is cancerous. Further,
the tumor may be cancerous. In an even more preferred embodiment,
the tumor is a cancer of lung, breast, prostate or colon. In
another preferred embodiment, the anti-M-CSF antibody administered
to a patient results in M-CSF no longer bound to the c-fins
receptor. In a highly preferred embodiment, the method causes the
tumor not to increase in weight or volume or to decrease in weight
or volume. In another embodiment, the method causes c-fins on tumor
cells to not be bound by M-CSF. In another embodiment, the method
causes M-CSF on tumor cells to not be bound to c-fins. In another
embodiment, the method causes secreted M-CSF of the tumor cells to
not be bound to c-fins. In a preferred embodiment, the antibody is
selected from 252, 88, 100, 3.8.3, 2.7.3, 1.120.1, 9.14.41,
8.10.3F, 9.7.2IF, 9.14.4, 8.10.3, 9.7.2, 9.7.2C-Ser, 9.14.4C-Ser,
8.10.3C-Ser, 8.10.3-CG2, 9.7.2-CG2, 9.7.2-CG4, 9.14.4-CG2,
9.14.4-CG4, 9.14.4-Ser, 9.7.2-Ser, 8.10.3-Ser, 8.10.3-CG4,
8.10.3FG1 or 9.14.4G1, or comprises a heavy chain, light chain or
antigen binding region thereof.
[0263] In another preferred embodiment, an anti-M-CSF antibody may
be administered to a patient who expresses inappropriately high
levels of M-CSF. It is known in the art that high-level expression
of M-CSF can lead to a variety of common cancers. In one
embodiment, said method relates to the treatment of cancer such as
brain, squamous cell, bladder, gastric, pancreatic, breast, head,
neck, esophageal, prostate, colorectal, lung, renal, kidney,
ovarian, gynecological or thyroid cancer. Patients that can be
treated with a compounds of the invention according to the methods
of this invention include, for example, patients that have been
diagnosed as having lung cancer, bone cancer, pancreatic cancer,
skin cancer, cancer of the head and neck, cutaneous or intraocular
melanoma, uterine cancer, ovarian cancer, rectal cancer, cancer of
the anal region, stomach cancer, colon cancer, breast cancer,
gynecologic tumors (e.g., uterine sarcomas, carcinoma of the
fallopian tubes, carcinoma of the endometrium, carcinoma of the
cervix, carcinoma of the vagina or carcinoma of the vulva),
Hodgkin's disease, cancer of the esophagus, cancer of the small
intestine, cancer of the endocrine system (e.g., cancer of the
thyroid, parathyroid or adrenal glands), sarcomas of soft tissues,
cancer of the urethra, cancer of the penis, prostate cancer,
chronic or acute leukemia, solid tumors (e.g., sarcomas, carcinomas
or lymphomas that are cancers of body tissues other than blood,
bone marrow or the lymphatic system), solid tumors of childhood,
lymphocytic lymphomas, cancer of the bladder, cancer of the kidney
or ureter (e.g., renal cell carcinoma, carcinoma of the renal
pelvis), or neoplasms of the central nervous system (e.g., primary
CNS lymphoma, spinal axis tumors, brain stem gliomas or pituitary
adenomas). In a more preferred embodiment, the anti-M-CSF antibody
is administered to a patient with breast cancer, prostate cancer,
lung cancer or colon cancer. In an even more preferred embodiment,
the method causes the cancer to stop proliferating abnormally, or
not to increase in weight or volume or to decrease in weight or
volume.
[0264] The antibody may be administered once, but more preferably
is administered multiple times. For example, the antibody may be
administered from three times daily to once every six months or
longer. The administering may be on a schedule such as three times
daily, twice daily, once daily, once every two days, once every
three days, once weekly, once every two weeks, once every month,
once every two months, once every three months and once every six
months. The antibody may also be administered continuously via a
minipump. The antibody may be administered via an oral, mucosal,
buccal, intranasal, inhalable, intravenous, subcutaneous,
intramuscular, parenteral, intratumor or topical route. The
antibody may be administered at the site of the tumor or inflamed
body part, into the tumor or inflamed body part, or at a site
distant from the site of the tumor or inflamed body part. The
antibody may be administered once, at least twice or for at least
the period of time until the condition is treated, palliated or
cured. The antibody generally will be administered for as long as
the tumor is present provided that the antibody causes the tumor or
cancer to stop growing or to decrease in weight or volume or until
the inflamed body part is healed. The antibody will generally be
administered as part of a pharmaceutical composition as described
supra. The dosage of antibody will generally be in the range of
0.1-100 mg/kg, more preferably 0.5-50 mg/kg, more preferably 1-20
mg/kg, and even more preferably 1-10 mg/kg. The serum concentration
of the antibody may be measured by any method known in the art.
[0265] In another aspect, the anti-M-CSF antibody may be
co-administered with other therapeutic agents, such as
anti-inflammatory agents, anti-coagulant agents, agents that will
lower or reduce blood pressure, anti-neoplastic drugs or molecules,
to a patient who has a hyperproliferative disorder, such as cancer
or a tumor. In one aspect, the invention relates to a method for
the treatment of the hyperproliferative disorder in a mammal
comprising administering to said mammal a therapeutically effective
amount of a compound of the invention in combination with an
anti-tumor agent selected from the group consisting of, but not
limited to, mitotic inhibitors, alkylating agents,
anti-metabolites, intercalating agents, growth factor inhibitors,
cell cycle inhibitors, enzymes, topoisomerase inhibitors,
biological response modifiers, anti-hormones, kinase inhibitors,
matrix metalloprotease inhibitors, genetic therapeutics and
anti-androgens. In a more preferred embodiment, the antibody may be
administered with an antineoplastic agent, such as adriamycin or
taxol. In another preferred embodiment, the antibody or combination
therapy is administered along with radiotherapy, chemotherapy,
photodynamic therapy, surgery or other immunotherapy. In yet
another preferred embodiment, the antibody will be administered
with another antibody. For example, the anti-M-CSF antibody may be
administered with an antibody or other agent that is known to
inhibit tumor or cancer cell proliferation, e.g., an antibody or
agent that inhibits erbB2 receptor, EGF-R, CD20 or VEGF.
[0266] Co-administration of the antibody with an additional
therapeutic agent (combination therapy) encompasses administering a
pharmaceutical composition comprising the anti-M-CSF antibody and
the additional therapeutic agent and administering two or more
separate pharmaceutical compositions, one comprising the anti-M-CSF
antibody and the other(s) comprising the additional therapeutic
agent(s). Further, although co-administration or combination
therapy generally means that the antibody and additional
therapeutic agents are administered at the same time as one
another, it also encompasses instances in which the antibody and
additional therapeutic agents are administered at different times.
For instance, the antibody may be administered once every three
days, while the additional therapeutic agent is administered once
daily. Alternatively, the antibody may be administered prior to or
subsequent to treatment of the disorder with the additional
therapeutic agent. Similarly, administration of the anti-M-CSF
antibody may be administered prior to or subsequent to other
therapy, such as radiotherapy, chemotherapy, photodynamic therapy,
surgery or other immunotherapy
[0267] The antibody and one or more additional therapeutic agents
(the combination therapy) may be administered once, twice or at
least the period of time until the condition is treated, palliated
or cured. Preferably, the combination therapy is administered
multiple times. The combination therapy may be administered from
three times daily to once every six months. The administering may
be on a schedule such as three times daily, twice daily, once
daily, once every two days, once every three days, once weekly,
once every two weeks, once every month, once every two months, once
every three months and once every six months, or may be
administered continuously via a minipump. The combination therapy
may be administered via an oral, mucosal, buccal, intranasal,
inhalable, intravenous, subcutaneous, intramuscular, parenteral,
intratumor or topical route. The combination therapy may be
administered at a site distant from the site of the tumor. The
combination therapy generally will be administered for as long as
the tumor is present provided that the antibody causes the tumor or
cancer to stop growing or to decrease in weight or volume.
[0268] In a still further embodiment, the anti-M-CSF antibody is
labeled with a radiolabel, an immunotoxin or a toxin, or is a
fusion protein comprising a toxic peptide. The anti-M-CSF antibody
or anti-M-CSF antibody fusion protein directs the radiolabel,
immunotoxin, toxin or toxic peptide to the M-CSF-expressing cell.
In a preferred embodiment, the radiolabel, immunotoxin, toxin or
toxic peptide is internalized after the anti-M-CSF antibody binds
to the M-CSF on the surface of the target cell.
[0269] In another aspect, the anti-M-CSF antibody may be used to
treat noncancerous states in which high levels of M-CSF and/or
M-CSF have been associated with the noncancerous state or disease.
In one embodiment, the method comprises the step of administering
an anti-M-CSF antibody to a patient who has a noncancerous
pathological state caused or exacerbated by high levels of M-CSF
and/or M-CSF levels or activity. In a more preferred embodiment,
the anti-M-CSF antibody slows the progress of the noncancerous
pathological state. In a more preferred embodiment, the anti-M-CSF
antibody stops or reverses, at least in part, the noncancerous
pathological state.
Gene Therapy
[0270] The nucleic acid molecules of the instant invention can be
administered to a patient in need thereof via gene therapy. The
therapy may be either in vivo or ex vivo. In a preferred
embodiment, nucleic acid molecules encoding both a heavy chain and
a light chain are administered to a patient. In a more preferred
embodiment, the nucleic acid molecules are administered such that
they are stably integrated into chromosomes of B cells because
these cells are specialized for producing antibodies. In a
preferred embodiment, precursor B cells are transfected or infected
ex vivo and re-transplanted into a patient in need thereof. In
another embodiment, precursor B cells or other cells are infected
in vivo using a virus known to infect the cell type of interest.
Typical vectors used for gene therapy include liposomes, plasmids
and viral vectors. Exemplary viral vectors are retroviruses,
adenoviruses and adeno-associated viruses. After infection either
in vivo or ex vivo, levels of antibody expression can be monitored
by taking a sample from the treated patient and using any
immunoassay known in the art or discussed herein.
[0271] In a preferred embodiment, the gene therapy method comprises
the steps of administering an isolated nucleic acid molecule
encoding the heavy chain or an antigen-binding portion thereof of
an anti-M-CSF antibody and expressing the nucleic acid molecule. In
another embodiment, the gene therapy method comprises the steps of
administering an isolated nucleic acid molecule encoding the light
chain or an antigen-binding portion thereof of an anti-M-CSF
antibody and expressing the nucleic acid molecule. In a more
preferred method, the gene therapy method comprises the steps of
administering of an isolated nucleic acid molecule encoding the
heavy chain or an antigen-binding portion thereof and an isolated
nucleic acid molecule encoding the light chain or the
antigen-binding portion thereof of an anti-M-CSF antibody of the
invention and expressing the nucleic acid molecules. The gene
therapy method may also comprise the step of administering another
anti-cancer agent, such as taxol or adriamycin.
[0272] In order that this invention may be better understood, the
following examples are set forth. These examples are for purposes
of illustration only and are not to be construed as limiting the
scope of the invention in any manner.
Example I
Generation of Cell Lines Producing Anti-M-CSF Antibody
[0273] Antibodies of the invention were prepared, selected, and
assayed as follows:
Immunization and Hybridoma Generation
[0274] Eight to ten week old XENOMOUSE.RTM. transgenic mice that
make human antibodies were immunized intraperitoneally or in their
hind footpads with human M-CSF (10 .mu.g/dose/mouse). This dose was
repeated five to seven times over a three to eight week period.
Four days before fusion, the mice were given a final injection of
human M-CSF in PBS. The spleen and lymph node lymphocytes from
immunized mice were fused with the non-secretory myeloma
P3-X63-Ag8.653 cell line, and the fused cells were subjected to HAT
selection as previously described (Galfre and Milstein, Methods
Enzymol. 73:3-46, 1981). A panel of hybridomas all secreting M-CSF
specific human IgG2 and IgG4 antibodies was recovered. Antibodies
also were generated using XENOMAX.RTM. antibody selection
technology as described in Babcook, J. S. et al., Proc. Natl. Acad.
Sci. USA 93:7843-48, 1996. Nine cell lines engineered to produce
antibodies of the invention were selected for further study and
designated 252, 88, 100, 3.8.3, 2.7.3, 1.120.1, 9.14.4, 8.10.3 and
9.7.2. The hybridomas were deposited under terms in accordance with
the Budapest Treaty with the American Type Culture Collection
(ATCC), 10801 University Blvd., Manassas, Va. 20110-2209 on Aug. 8,
2003. The hybridomas have been assigned the following accession
numbers:
TABLE-US-00002 Hybridoma 3.8.3 (LN 15891) PTA-5390 Hybridoma 2.7.3
(LN 15892) PTA-5391 Hybridoma 1.120.1 (LN 15893) PTA-5392 Hybridoma
9.7.2 (LN 15894) PTA-5393 Hybridoma 9.14.4 (LN 15895) PTA-5394
Hybridoma 8.10.3 (LN 15896) PTA-5395 Hybridoma 88-gamma (UC 25489)
PTA-5396 Hybridoma 88-kappa (UC 25490) PTA-5397 Hybridoma 100-gamma
(UC 25491) PTA-5398 Hybridoma 100-kappa (UC 25492) PTA-5399
Hybridoma 252-gamma (UC 25493) PTA-5400 Hybridoma 252-kappa (UC
25494) PTA-5401
Example II
Gene Utilization Analysis
[0275] DNA encoding the heavy and light chains of monoclonal
antibodies 252, 88, 100, 3.8.3, 2.7.3, 1,120.1, 9.14.4, 8.10.3 and
9.7.2 was cloned from the respective hybridoma cell lines and the
DNA sequences were determined by methods known to one skilled in
the art. Additionally, DNA from the hybridoma cell lines 9.14.4,
8.10.3 and 9.7.2 was mutated at specific framework regions in the
variable domain and/or isotype-switched to obtain, for example,
9.14.41, 8.10.3F, and 9.7.2IF, respectively. From nucleic acid
sequence and predicted amino acid sequence of the antibodies, the
identity of the gene usage for each antibody chain was determined
("VBASE"). Table 2 sets forth the gene utilization of selected
antibodies in accordance with the invention:
TABLE-US-00003 TABLE 2 Heavy and Light Chain Gene Utilization Heavy
Chain Kappa Light Chain Clone SEQ ID NO: V.sub.H D.sub.H J.sub.H
SEQ ID NO: V.kappa. J.kappa. 252 1, 2 3-11 7-27 6 3, 4 O12 3 88 5,
6 3-7 6-13 4 7, 8 O12 3 100 9, 10 3-23 1-26 4 11, 12 L2 3 3.8.3 14
3-11 7-27 4 16 L5 3 2.7.3 18 3-33 1-26 4 20 L5 4 1.120.1 22 1-18
4-23 4 24 B3 1 9.14.4I 25, 26 3-11 7-27 4b 27, 28 O12 3 8.10.3F 29,
30 3-48 1-26 4b 31, 32 A27 4 9.7.2IF 33, 34 3-11 6-13 6b 35, 36 O12
3 9.14.4 37, 38 3-11 7-27 4b 27, 28 O12 3 8.10.3 29, 30 3-48 1-26
4b 43, 44 A27 4 9.7.2 45, 46 3-11 6-13 6b 47, 48 O12 3 8.10.3FG1
97, 98 3-48 1-26 4b 31, 32 A27 4 9.14.4G1 101, 102 3-11 7-27 4b 27,
28 O12 3 9.14.4C-Ser 54 3-11 7-27 4b 56 O12 3 9.14.4-CG2 74 3-11
7-27 4b 56 O12 3 9.14.4-CG4 78 3-11 7-27 4b 56 O12 3 8.10.3C-Ser 58
3-48 1-26 4b 60 A27 4 8.10.3-CG2 62 3-48 1-26 4b 60 A27 4
8.10.3-CG4 94 3-48 1-26 4b 60 A27 4 8.10.3-Ser 90 3-48 1-26 4b 43,
44 A27 4 9.7.2C-Ser 50 3-11 6-13 6b 52 O12 3 9.7.2-CG2 66 3-11 6-13
6b 52 O12 3 9.7.2-CG4 70 3-11 6-13 6b 52 O12 3 9.7.2-Ser 86 3-11
6-13 6b 47, 48 O12 3 9.14.4-Ser 82 3-11 7-27 4b 27, 28 O12 3
[0276] Mutagenesis of specific residues of the heavy and light
chains was carried out by designing primers and using the
QuickChange Site Directed Mutagenesis Kit from Stratagene,
according to the manufacturer's instructions. Mutations were
confirmed by automated sequencing, and mutagenized inserts were
subcloned into expression vectors. The expression vectors were
transfected into HEK293 cells to produce enough of the antibodies
for characterization.
Example III
M-CSF Mouse Monocytic Cell Proliferation Assay
[0277] In vitro assays were conducted to measure M-CSF-dependent
mouse monocytic cell proliferation in the presence of anti-M-CSF
antibodies to determine the degree of inhibition by anti-M-CSF
antibodies.
[0278] Mouse monocytic cells, M-NFS-60 cells, from American Type
Culture Collection (ATCC) (Manassas, Va.), were obtained and
maintained in RPMI-1640 medium containing 2 mM L-glutamine (ATCC),
10% heat inactivated fetal bovine serum (FBS) (Invitrogen,
Carlsbad, Calif.), 0.05 mM 2-mercaptoethanol (Sigma, St. Louis Mo.)
(assay medium), with 15 ng/ml human M-CSF. M-NSF-60 cells were
split to 5.times.10.sup.4 for next day use or to 2.5.times.10.sup.4
for use in 2 days. Prior to use in the assay, the cells were washed
three times with RPMI-1640, counted and the volume adjusted with
assay medium to yield 2.times.10.sup.5 cells/ml. All conditions
were conducted in triplicate in 96-well treated tissue culture
plates (Corning, Corning, N.Y.). To each well 50 .mu.l of the
washed cells, either 100 pM or 1000 pM M-CSF in a volume of 25
.mu.l and test or control antibody at various concentrations in a
volume of 25 .mu.l in acetate buffer (140 mM sodium chloride, 20 mM
sodium acetate, and 0.2 mg/ml polysorbate 80, pH 5.5) to a final
volume of 100 .mu.l was added. Antibodies of the invention were
tested alone and with human M-CFS. The plates were incubated for 24
hours (hrs) at 37.degree. C. with 5% CO.sub.2.
[0279] After 24 hrs, 10 .mu.l/well of 0.5 .mu.Ci .sup.3H-thymidine
(Amersham Biosciences, Piscataway, N.J.) was added and pulsed with
the cells for 3 hrs. To detect the amount of incorporated
thymidine, the cells were harvested onto pre-wet unifilter GF/C
filterplates (Packard, Meriden, Conn.) and washed 10 times with
water. The plates were allowed to dry overnight. Bottom seals were
added to the filterplates. Next, 45 .mu.l Microscint 20 (Packard,
Meriden, Conn.) per well was added. After a top seal was added, the
plates were counted in a Trilux microbeta counter (Wallac, Norton,
Ohio).
[0280] These experiments demonstrate that anti-M-CSF antibodies of
the invention inhibit mouse monocytic cell proliferation in
response to M-CSF. Further, by using various concentrations of
antibodies, the IC.sub.50 for inhibition of mouse nonocytic cell
proliferation was determined for antibodies 252, 88, 100, 3.8.3,
2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3, and
9.7.2 (Cell Proliferation Assay, Table 3a and Table 3b).
TABLE-US-00004 TABLE 3a Antibody 252 88 100 3.8.3 2.7.3 1.120.1
M-CSF Mouse 1.86 .times. 10.sup.-10 2.31 .times. 10.sup.-10 7.44
.times. 10.sup.-10 7.3 .times. 10.sup.-11 1.96 .times. 10.sup.-10
1.99 .times. 10.sup.-10 Monocytic Cell Proliferation Assay
[IC.sub.50, M] Human Whole 8.67 .times. 10.sup.-10 5.80 .times.
10.sup.-10 1.53 .times. 10.sup.-10 8.6 .times. 10.sup.-11 7.15
.times. 10.sup.-10 8.85 .times. 10.sup.-10 Blood Monocyte
Activation Assay [IC.sub.50, M] Receptor Binding 7.47 .times.
10.sup.-10 4.45 .times. 10.sup.-10 1.252 .times. 10.sup.-9 7.0
.times. 10.sup.-11 3.08 .times. 10.sup.-10 1.57 .times. 10.sup.-10
Inhibition Assay [IC.sub.50, M ]
TABLE-US-00005 TABLE 3b Antibody 9.14.4I 8.10.3F 9.7.2IF 9.14.4
8.10.3 9.7.2 M-CSF Mouse 2.02 .times. 10.sup.-10 4.13 .times.
10.sup.-10 7.37 .times. 10.sup.-10 2.02 .times. 10.sup.-10 4.13
.times. 10.sup.-10 7.37 .times. 10.sup.-10 Monocytic Cell
Proliferation Assay [IC.sub.50, M] Human Whole 2.49 .times.
10.sup.-10 4.46 .times. 10.sup.-10 1.125 .times. 10.sup.-9 6.48
.times. 10.sup.-10 2.8 .times. 10.sup.-10 1.98 .times. 10.sup.-10
Blood Monocyte Activation Assay [IC.sub.50, M] Receptor Binding
2.97 .times. 10.sup.-10 9.8 .times. 10.sup.-11 5.29 .times.
10.sup.-10 4.1 .times. 10.sup.-11 1.5 .times. 10.sup.-9 6 .times.
10.sup.-12 Inhibition Assay [IC.sub.50, M]
Example IV
Human Whole Blood Monocyte Activation Assay
[0281] In vitro assays were conducted to measure M-CSF dependent
monocyte shape changes in the presence of anti-M-CSF antibodies to
determine if the anti-M-CSF antibodies were capable of inhibiting
whole blood monocyte activation and their degree of inhibition of
monocyte shape changes.
[0282] In individual wells of a 96-well tissue culture plate, 6
.mu.l of 1.7 nM anti-M-CSF and 94 .mu.l of whole human blood for a
final concentration of 102 pM anti-M-CSF antibody were mixed. The
plates were incubated at 37.degree. C. in a CO.sub.2 tissue culture
incubator. Next, the plates were removed from the incubator. To
each well, 100 .mu.l of a fixative solution (0.5% formalin in
phosphate buffered saline without MgCl.sub.2 or CaCl.sub.2)) was
added and the plates were incubated for 10 minutes at room
temperature. For each sample, 180 .mu.l from each well and 1 ml of
Red Cell Lysis Buffer were mixed. The tubes were vortexed for 2
seconds. Next, the samples were incubated at 37.degree. C. for 5
minutes in a shaking water bath to lyse the red blood cells, but to
leave monocytes intact. Immediately following this incubation, the
samples were read on a fluorescence-activated cell scanning (FACS)
machine (BD Beckman FACS) and data was analyzed using FACS Station
Software Version 3.4.
[0283] These experiments demonstrate that anti-M-CSF antibodies of
the invention inhibit monocyte shape changes compared to control
samples. Using the monocyte shape change assay, the IC.sub.50 was
determined for antibodies 252, 88, 100, 3.8.3, 2.7.3, 1.120.1,
9.14.41, 8.10.3F, 9.7.21F, 9.14.4, 8.10.3, and 9.7.2 (Human Whole
Blood Monocyte Activation, Table 3a and Table 3b).
Example V
c-Fins Receptor Binding Inhibition Assay
[0284] In vitro assays were conducted to measure M-CSF binding to
c-fins receptor in the presence of anti-M-CSF antibodies to
determine if the anti-M-CSF antibodies were capable of inhibiting
M-CSF binding to c-fins receptor and their degree of
inhibition.
[0285] NIH-3T3 cells transfected with human c-fins or M-NSF-60
cells maintained in Dulbecco's phosphate buffered saline without
magnesium or calcium were washed. NIH-3T3 cells were removed from
tissue culture plates with 5 mM ethylene-diamine-tetra-acetate
(EDTA), pH 7.4. The NIH-3T3 cells were returned to the tissue
culture incubator for 1-2 minutes and the flask(s) were tapped to
loosen the cells. The NIH-3T3 cells and the M-NSF-60 cells were
transferred to 50 ml tubes and washed twice with reaction buffer
(lx RPMI without sodium bicarbonate containing 50 mM
N-2-Hydroxyethylpiperazine-N'-2-ethanesulfonic acid (HEPES), pH
7.4). Next, the NIH-3T3 cells were resuspended in reaction buffer
for a final concentration of 1.5.times.10.sup.5 cell/ml. The
M-NSF-60 cells were resuspended in a reaction buffer for a final
concentration of 2.5.times.10.sup.6 cell s/ml.
[0286] For the assay, 9 .mu.l of a sterile 0.4 M sucrose solution,
100 .mu.l of .sup.125I-M-CSF (Amersham, IMQ7228v) at a final
concentration of 200 pM in RPMI-1640 containing 50 mM HEPES (pH
7.4), 0.2% bovine serum albumin, and 100 .mu.l of unlabeled M-CSF
at a final concentration of 200 nM were mixed in a binding tube.
Next, 50 .mu.l/tube of increasing concentrations of a test antibody
was added. In order to determine non-specific binding of the
antibodies, we included samples to which we also added 200 nM
M-CSF. To control tubes, we did not add antibody. Next, 15,000
NIH-3T3 cells or 250,000 M-NSF-60 cells were added per tube. All
tubes were incubated at room temperature for 3 hrs and subjected to
centrifugation at 10,000 rpm for 2 min. The tips of the tubes
containing the cell pellets were cut off and the amount of M-CSF
bound to the cells was determined using a Packard Cobra II Gamma
counter. The specific binding was determined by subtracting
non-specific binding from total binding. All assays were performed
in duplicate. The binding data was analyzed using the computer
program, Graph Pad Prism 2.01.
[0287] These experiments demonstrate that anti-M-CSF antibodies of
the invention inhibit the binding of M-CSF to c-fins receptor
compared to control samples. Further, by using various
concentrations of antibodies, the IC.sub.50 for inhibition of
receptor binding was determined for antibodies 252, 88, 100, 3.8.3,
2.7.3, 1.120.1, 9.14.41, 8.10.3F, 9.7.2IF, 9.14.4, 8.10.3, and
9.7.2 (Receptor Binding Inhibition Assay, Table 3a and Table
3b).
Example VI
Determination of Affinity Constants (K.sub.D) of Anti-M-CSF
Monoclonal Antibodies by BIACORE.TM.
[0288] Affinity measures of purified antibodies were performed by
surface plasmon resonance using the BIACORE.TM. 3000 instrument,
following the manufacturer's protocols.
[0289] For antibodies 3.8.3, 2.7.3 and 1.120.1, the experiments
were performed in a BIACORE.TM. 3000 instrument at 25.degree. C. in
Dulbecco's phosphate buffered saline containing 0.0005% Tween-20.
Protein concentrations were obtained from sedimentation velocity
experiments or by measuring the wavelength of the sample at 280 nm
using theoretical extinction coefficients derived from amino acid
sequences. For experiments measuring the binding of antibody to
immobilized antigens, M-CSF was immobilized on a B1 chip by
standard direct amine coupling procedures. Antibody samples were
prepared at 0.69 .mu.M for 3.8.3, 2.7.3 and 1.120.1. These samples
were diluted 3-fold serially to 8.5 nM or 2.8 nM for roughly a
100-fold range in concentrations. For each concentration, the
samples were injected in duplicate at 5 .mu.l/min flow for 4 min.
The dissociation was monitored for 2000 seconds. The data were fit
globally to a simple 1:1 binding model using BIACORE.TM.
Biaevaluation software. In all cases, this method was used to
obtain k.sub.off and it was found that this data set compared well
to data obtained from global fit of association and dissociation
data.
[0290] For antibodies 252, 88 and 100, the experiments were
performed in a BIACORE.TM. 3000 instrument at 25.degree. C. in
HBS-EP Buffer (0.01M HEPES, pH 7.4, 0.15 M NaCl, 3 mM EDTA, 0.005%
Surfactant P20). For experiments measuring the binding of antibody
to immobilized antigens, a M-CSF was immobilized on a CMS Research
Grade Sensor chip by standard direct amine coupling procedures.
Antibody samples were prepared at 12.5 nM for antibodies 252 and
100 and at 25.0 nM for antibody 88. These samples were two-fold
serially diluted to 0.78 nM for roughly a 15-30 fold range in
concentrations. For each concentration, the samples were injected
in duplicate in random order at 30 .mu.l/min flow for 3 min. The
dissociation was monitored for 300 sec. The data were fit globally
to a simple 1:1 binding model using BIACORE.TM. Biaevaluation
software. In all cases, this method was used to obtain k.sub.off
and it was found that this data set compared well to data obtained
from global fit of association and dissociation data.
[0291] Table 4 shows results for antibodies 252, 88, 100, 3.8.3,
2.7.3 and 1.120.1.
TABLE-US-00006 TABLE 4 252 88 100 3.8.3 2.7.3 1.120.1 K.sub.D (M)
1.33 .times. 10.sup.-11 1.33 .times. 10.sup.-9 2.0 .times.
10.sup.-11 4.0 .times. 10.sup.-10 4.7 .times. 10.sup.-9 5.4 .times.
10.sup.-9 k.sub.off (1/s) 1.03 .times. 10.sup.-6 7.3 .times.
10.sup.-5 1.7 .times. 10.sup.-5
Example VII
Production of 8.10.3 Antibodies from 8.10.3 Hybridoma Cells
[0292] Antibody 8.10.3 was produced in 3 L sparged spinners. The 3
L sparged spinner flask is a glass vessel where cultures are mixed
with an impeller controlled by a magnetic platform. The spinner is
connected to gas lines to provide 5% CO.sub.2 and air. 8.10.3
hybridoma cells were initially thawed into T-25 cell culture
flasks. The cells were progressively expanded until there was a
sufficient number of cells to seed the sparged spinners.
[0293] Two 3 L sparged spinner flasks were seeded with 8.10.3
hybridoma cells in Hybridoma Serum-Free Medium with the additions
noted on Table 5, for the two sparged flasks. The concentrations
for Ultra low IgG serum (Gibco cat#16250-078), L-glutamine (JRH
Biosciences cat#59202-500M), Non-Essential Amino Acids (Gibco
cat#11140-050), Peptone (Difco cat#211693), glucose (In-house stock
prepared from JT Baker cat#1920-07), and Anti-foam C (Sigma cat.#
A-8011) are given at their final concentrations in the media. The
balance of the volume in each reactor is Hybridoma Serum-Free
Medium.
TABLE-US-00007 TABLE 5 Conditions for Growing Hybridoma 8.10.3 in
two 3L sparged spinners. Conditions Spinner 1 Spinner 2 Seeding
density (1 .times. 10.sup.6 cells/ml) 0.16 ml 0.16 ml Hybridoma
Serum-Free Medium (Gibco cat# Balance Balance 12045-076) Ultra low
IgG serum (Gibco cat# 16250-078) 5% 5% L-glutamine (JRH Biosciences
cat# 59202-500M) 8 mmol/L 8 mmol/L Non-Essential Amino Acids (Gibco
cat# 1% 1% 11140-050) Peptone (Difco cat# 211693) 1 g/L 1 g/L 2M
glucose (In-house stock prepared from JT 8 g/L 8 g/L Baker cat#
1920-07) Anti-foam C (Sigma cat.# A-8011) 1 ml/L 1 ml/L
[0294] The cultures were grown for 15 days and were harvested when
the viability was below 20%. Viability was determined by trypan
blue exclusion method with an automated cell counter (Cedex,
Innovatis). Harvesting was accomplished by centrifugation and
subsequent filtration. Clarified supernatant was obtained after
centrifugation for 15 minutes at 7000 rpm and subsequent filtration
with a sterile 0.22 .mu.m 4'' Opticap Millipore filter (cat#
KVSCO4HB3) into a 10 L sterile TC-Tech bag (cat # P/N 12420 Bag
Style CC-10-112420). The filtrate was then purified in the
following example.
Example VIII
Purification of an Anti-M-CSF Antibody
[0295] A Protein A column (Amersham Pharmacia) was prepped by
washing with 3 column volumes of 8M Urea, followed by an
equilibration wash with 20 mM Tris (pH 8). The final filtrate from
Example VII was spiked with 2% v/v of 1M Tris pH 8.3 and 0.02%
NaN.sub.3 before being loaded onto the Protein A column via
gravity-drip mode. After load was complete, the resin was washed
with 5 column volumes of 20 mM Tris (pH 8), followed by 5 column
volumes of the elution buffer (0.1 M Glycine pH 3.0). Any
precipitation was noted, and then a 10% v/v spike of 1M Tris pH 8.3
was added to the eluted antibody. The eluted protein was then
dialyzed into 100 fold the volume amount of eluted material of
dialysis buffer (140 mM NaCl/20 mM Sodium Acetate pH 5.5).
Following dialysis, the antibody was sterile filtered with a 0.22
.mu.m filter and stored until further use.
Example IX
Monkey Treatment and Monocyte Counts
[0296] One male and one female cynomolgus monkey per dosage group
were intravenously administered vehicle or antibody 8.10.3
(produced as describe in Examples VII and VIII) at 0, 0.1, 1, or 5
mg/kg in a dose volume of 3.79 mL/kg over an approximately 5 minute
period. Blood samples for clinical laboratory analysis were
collected at 24 and 72 hours postdose and weekly for 3 weeks. The
monocyte counts were determined by light scatter using an Abbott
Diagnostics Inc. Cell Dyn system (Abbott Park, Ill.).
[0297] A dose-related decrease (.about.25% to 85%) in total
monocytes at all doses (FIGS. 1A and 1B) was observed. Monocyte
counts at the 0.1 and 1 mg/kg appeared to rebound to near control
levels by week 2, while monocyte counts at 5 mg/kg were still
decreased at 3 weeks.
CD14+CD16+ Monocyte Subset Analysis
[0298] Primate whole blood was drawn into Vacutainer tubes
containing sodium heparin. 0.2 ml of each blood sample was added to
a 15 ml conical polypropylene centrifuge tube containing 10 ml of
red blood cell lysis buffer (Sigma), and incubated in a 37.degree.
C. water bath for 15 minutes. The tubes were then centrifuged in a
Sorvall RT7 centrifuge for 5 minutes at 1,200 rpm. The supernatant
was aspirated, the pellet resuspended in 10 ml of 4.degree. C. FACS
buffer (Hanks' Balanced Salt Solution/2% FBS/0.02% sodium azide),
and the tube centrifuged again for 5 minutes at 1,200 rpm. The
supernatant was aspirated and the pellet resuspended in an antibody
cocktail consisting of 80 .mu.l 4.degree. C. FACS buffer, 10 .mu.l
FITC-conjugated anti-human CD14 monoclonal antibody (BD
Biosciences, San Diego, Calif.), 0.5 .mu.l Cy5-PE-conjugated
anti-human CD16 monoclonal antibody (BD Biosciences, San Diego,
Calif.), and 10 .mu.l PE-conjugated anti-human CD89 monoclonal
antibody (BD Biosciences, San Diego, Calif.). The cell suspension
was incubated on ice for 20 minutes, after which 10 ml of 4.degree.
C. FACS buffer was added and the cells centrifuged as before. The
supernatant was aspirated, and the cell pellet resuspended in 400
.mu.l FACS buffer and the cells analyzed on a FACSCaliber flow
cytometer (BD Biosciences, San Jose, Calif.). Data for 30,000 cells
were collected from each sample.
[0299] The monocyte population was identified by a combination of
forward angle light scatter and orthogonal light scatter. Cells
within the monocyte gate were further analyzed for expression of
CD14 and CD16. Two distinct population of monocytes were observed,
one expressing high levels of CD14 with little or no CD16
expression (CD14++CD16-) and the other expressing lower levels of
CD14, but high levels of CD16 (CD14+CD16+), similar to the two
monocyte subsets previously described in human peripheral blood
(Ziegler-Heitbrock H. W., Immunology Today 17:424-428 (1996)). For
each primate tested, the percentage of monocytes within the
CD14+CD16+ subset was determined after each blood draw, on days 1,
3, 7, 14, and 21 after 8.10.3 injection.
[0300] In general, 8.10.3 treatment resulted in a reduction in the
percentage of CD14+CD16+ monocytes (see FIGS. 2A and 2B). Monkeys
not receiving 8.10.3 Antibody demonstrated relatively stable
CD14+CD16+ monocyte levels. CD14+CD16+ monocytes have been termed
"proinflammatory" because they produce higher levels of TNF-.alpha.
and other inflammatory cytokines (Frankenberger, M. T., et al.,
Blood 87:373-377 (1996)). It has also been reported that the
differentiation of monocytes from the conventional
CD14++CD16-phenotype to the proinflammatory phenotype is dependent
on M-CSF (Saleh M. N., et al., Blood 85: 2910-2917 (1995)).
Example X
Monkey Treatment and Monocyte Counts
[0301] Three male cynomolgus monkeys per dosage group were
intravenously administered vehicle (20 mM Sodium acetate, pH 5.5,
140 mM NaCl), purified antibody 8.10.3F, or purified antibody
9.14.41 at 0, 1, or 5 mg/kg in a dose volume of 3.79 mL/kg over an
approximately 5 minute period. The monkeys were 4 to 9 years of age
and weighed 6 to 10 kg. Blood samples for clinical laboratory
analysis were collected at 2, 4, 8, 15, 23, and 29 days. Monocyte
counts were determined by light scatter using an Abbott Diagnostics
Inc. Cell Dyn system (Abbott Park, Ill.).
[0302] A decrease in the percentage change in total monocytes at
all doses of antibody 8.10.3F as compared to pre-test levels of
monocytes (FIGS. 3A and 3B) was observed (see e.g., day 4, 8, 15,
and 23 in FIGS. 3A and 3B).
[0303] All publications and patent applications cited in this
specification are herein incorporated by reference as if each
individual publication or patent application were specifically and
individually indicated to be incorporated by reference. Although
the foregoing invention has been described in some detail by way of
illustration and example for purposes of clarity of understanding,
it will be readily apparent to those of ordinary skill in the art
in light of the teachings of this invention that certain changes
and modifications may be made thereto without departing from the
spirit or scope of the appended claims.
TABLE-US-00008 SEQUENCES SEQ ID NO: 1 252 Heavy Chain [Gamma chain]
nucleotide sequence
atggagttggggctgtgctggattttccttgttgctattataaaaggtgtccagtgtCAGGTGCAGCTGGTG
GAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCC
TGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCC
GCCAGGCTCCAGGGAAGGGGCTGGAGTGGATTTCATACATTAGTGGTA
GTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCAT
CTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCT
GAGAGCCGAGGACACGGCCGTGTATCACTGTGCGAGAGCCCTGGGTGG
GATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTtcca
ccaagggcccatccgtcttccccctggcgccctgctctagaagcacctccgagagcacagcggccctgggctgc-
ctg
gtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgctctgaccagcggcgtgcacacctt-
ccc
agctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcaacttcggcaccc-
agac
ctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagacagttgagcgcaaatgttgtgtcg-
agt
gcccaccgtgcccagcaccacctgtggcaggaccgtcagtcttcctcttccccccaaaacccaaggacaccctc-
atga
tctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccacgaagaccccgaggtccagttcaactgg-
tac
gtggacggcgtggaggtgcataatgccaagacaaagccacgggaggagcagttcaacagcacgttccgtgtggt-
ca
gcgtcctcaccgttgtgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctc-
cca
gcccccatcgagaaaaccatctccaaaaccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc-
cc
gggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtg-
ga
gtgggagagcaatgggcagccggagaacaactacaagaccacacctcccatgctggactccgacggctccttct-
tcc
tctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag-
gct ctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 2
252 Heavy Chain [Gamma chain] protein sequence
melglcwiflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWIR
QAPGKGLEWISYISGSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRAE
DTAVYHCARALGGMDVWGQGTTVTVSSAstkgpsvfplapcsrstsestaalgclvkdyfp
epvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvdktverkccvecpp-
cp
appvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqfnstfrvvsv
ltvvhqdwlngkeykckvsnkglpapiektisktkgqprepqvytlppsreemtknqvsltclvkgfypsdiav-
e
wesngqpennykttppmldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 3 252 Light Chain [Kappa chain] nucleotide sequence
atgagggtccctgctcagctcctggggctcctgctactctggctccgaggtgccagatgtGACATCCAGAT
GACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGTCACC
ATCACTTGCCGGGCAAGTCAGAGCATTAGCGGCTTTTTAAATTGGTATC
AGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTACATCCA
GTTTGCAAAGTGGGGTCCCATTCAGGTTCAGTGGCAGTGGATCTGGGA
CAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAAC
TTATTACTGTCAACAGAGTTACAGTGTCCCATTCACTTTCGGCCCTGGG
ACCAAAGTGGATATCAAACGAactgtggctgcaccatctgtcttcatcttcccgccatctgatgagc
agttgaaatctggaactgctagcgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtgg-
aaggt
ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcc-
tc
agcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcaggg-
cc tgagctcgcccgtcacaaagagatcaacaggggagagtgt SEQ ID NO: 4 252 Light
Chain [Kappa chain] protein sequence
mrvpaqllgllllwlrgarcDIQMTQSPSSLSASVGDRVTITCRASQSISGFLNWYQQK
PGKAPKLLIYATSSLQSGVPFRFSGSGSGTDFTLTISSLQPEDFATYYCQQS
YSVPFTFGPGTKVDIKRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgns
qesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec SEQ ID NO:
5 88 Heavy Chain [Gamma chain] nucleotide sequence
atggaatttgggctgtgctgggttttccttgttgctattttagaaggtgtccagtgtGAGGTGCAGCTGGTG
GAGTCTGGGGGAGGCTTGGTCCAGCCTGGGGGGTCCCTGAGACTCTCC
TGTGCAGCCTCTGGATTCACCTTTAGTAGCTATTGGATGAGCTGGGTCC
GCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTGGCCAACATAAAGCAA
GATGGAAGTGAGAAATACTATGTGGACTCTGTGAAGGGCCGATTCACC
ATCTCCAGAGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGC
CTGAGAGCCGAGGACACGGCTGTGTATTACTGTGCTCCGGGTATAGCA
GCAGCTGGTAGGGCCTACTGGGGCCAGGGAACCCTGGTCACCGTCTCC
TCAGCTtccaccaagggcccatccgtcttccccctggcgccctgctctagaagcacctccgagagcacagcggc
cctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgctctgaccagcg-
gcg
tgcacaccttcccagctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagc-
aacttc
ggcacccagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagacagttgagcgcaa-
at
gttgtgtcgagtgcccaccgtgcccagcaccacctgtggcaggaccgtcagtatcctatccccccaaaacccaa-
gg
acaccctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccacgaagaccccgaggtc-
ca
gttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccacgggaggagcagttcaacagca-
cg
ttccgtgtggtcagcgtcctcaccgttgtgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctc-
caac
aaaggcctcccagcccccatcgagaaaaccatctccaaaaccaaagggcagccccgagaaccacaggtgtacac-
c
ctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccag-
cg
acatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacacctcccatgctggactcc-
g
acggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgc-
tccg tgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa
SEQ ID NO: 6 88 Heavy Chain [Gamma chain] protein sequence
mefglcwvflvailegvqcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSYWMSWV
RQAPGKGLEWVANIKQDGSEKYYVDSVKGRFTISRDNAKNSLYLQMNSL
RAEDTAVYYCAPGIAAAGRAYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalgcl
vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvdktverkc-
cv
ecppcpappvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqfns
tfrvvsvltvvhqdwlngkeykckvsnkglpapiektisktkgqprepqvytlppsreemtknqvsltclvkgf-
yp
sdiavewesngqpennykttppmldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 7 88 Light Chain [Kappa chain] nucleotide sequence
atgagggtccctgctcagctcctggggctcctgctactctggctccgaggtgccagatgtGACATCCAGAT
GACCCAGTCTCCATCCTCCCTGTCTGCATCTGTTGGAGACAGAGTCACC
ATCACTTGCCGGCCAAGTCAGGACATTAGCAGTTATTTAAATTGGTATC
AGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTGCATCCA
GTTTGCAAAGTGGGGTCCCATTAAGGTTCAGTGGCAGTGGATCTGGGA
CAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGCAAC
TTACTACTGTCAACAGAGTTACAGTACCCCATTCACTTTCGGCCCTGGG
ACCAAAGTGGATATCAAACGAactgtggctgcaccatctgtcttcatcttcccgccatctgatgagc
agttgaaatctggaactgctagcgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtgg-
aaggt
ggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcc-
tc
agcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcaggg-
cc tgagctcgcccgtcacaaagagatcaacaggggagagtgt SEQ ID NO: 8 88 Light
Chain [Kappa chain] protein sequence
mrvpaqllgllllwlrgarcDIQMTQSPSSLSASVGDRVTITCRPSQDISSYLNWYQQK
PGKAPKLLIYAASSLQSGVPLRFSGSGSGTDFTLTISSLQPEDFATYYCQQS
YSTPFTFGPGTKVDIKRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgns
qesvteqdskdstyslsstldskadyekhkvyacevthqglsspvtksfnrgec SEQ ID NO: 9
100 Heavy Chain [Gamma chain] nucleotide sequence
atggagtttgggctccgctggatttttcttgtggctattttaaaaggtgtccagtgtGAGGTGCAGCTGTTG
GAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCC
TGTGCAGCCTCTGGATTCACCTTTAGCAGCTATGCCATGAGCTGGGTCC
GCCAGGCTCCAGGGAAGGGGCTGGAATGGGTCTCAGCTATTAGTGGTC
GTGGTGGTAGGACATACTTCGCAGACTCCGTGAAGGGCCGGTTCACCA
TCTCCAGAGACAATTCCAAGAACACGCTGTATCTGCAAATGAACAGCC
TGAGAGCCGAGGACACGGCCGTATATTTCTGTGCGGTAGAAGGCTATA
GTGGGCGCTACGGATTTTTTGACTACTGGGGCCAGGGAACCCTAGTCAC
CGTCTCCTCAGCCtccaccaagggcccatcggtcttccccctggcgccctgctctagaagcacctccgag
agcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgc-
tct
gaccagcggcgtgcacaccttcccagctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccg-
tgcc
ctccagcaacttcggcacccagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaaga-
ca
gttgagcgcaaatgttgtgtcgagtgcccaccgtgcccagcaccacctgtggcaggaccgtcagtatcctatcc-
ccc
caaaacccaaggacaccctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccacgaa-
ga
ccccgaggtccagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccacgggaggagc-
a
gttcaacagcacgttccgtgtggtcagcgtectcaccgttgtgcaccaggactggctgaacggcaaggagtaca-
agtg
caaggtctccaacaaaggcctcccagcccccatcgagaaaaccatctccaaaaccaaagggcagccccgagaac-
c
acaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag-
gc
ttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacacctcc-
ca
tgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaac-
gtc
ttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaa-
a SEQ ID NO: 10 100 Heavy Chain [Gamma chain] protein sequence
mefglrwiflvailkgvqcEVQLLESGGGLVQPGGSLRLSCAASGFTFSSYAMSWVR
QAPGKGLEWVSAISGRGGRTYFADSVKGRFTISRDNSKNTLYLQMNSLRA
EDTAVYFCAVEGYSGRYGFFDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaal
gclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvdktve-
rkc
cvecppcpappvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqf
nstfrvvsvltvvhqdwlngkeykckvsnkglpapiektisktkgqprepqvytlppsreemtknqvsltclvk-
gf
ypsdiavewesngqpennykttppmldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspg
k SEQ ID NO: 11 100 Light Chain [Kappa chain] nucleotide sequence
atggaagccccagctcagcttctcttcctcctgctactctggctcccagataccactggaGAAATAGTGATG
ACGCAGTCTCCAGCCACCCTGTCTGTGTCTCCAGGGGAAAGAGCCACC
CTCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAACTTAGCCTGGTACC
AGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCCAC
CAGGGCCAGTGGTATCCCAGACAGGATCAGTGGCAGTGGGTCTGGAAC
AGAGTTCACTCTCATCATCAGCAGCCTGCAGTCTGAAGATTTTGCAGTT
TATTACTGTCAGCAGTCTAATAACTGGCCATTCACTTTCGGCCCTGGGA
CCAAAGTGGATATCAAACGAactgtggctgcaccatctgtcttcatcttcccgccatctgatgagca
gttgaaatctggaactgctagcgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagtgga-
aggtg
gataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacagcct-
ca
gcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcagggc-
ct gagctcgcccgtcacaaagagcttcaacaggggagagtgt SEQ ID NO: 12 100 Light
Chain [Kappa chain] protein sequence
meapaqllfllllwlpdttgEIVMTQSPATLSVSPGERATLSCRASQSVSSNLAWYQQ
KPGQAPRLLIYGASTRASGIPDRISGSGSGTEFTLIISSLQSEDFAVYYCQQS
NNWPFTFGPGTKVDIKRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsgn
sqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec SEQ ID NO:
14 3.8.3 Heavy Chain [Gamma chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWFSYISSSGSTIYYADSVKGRFTISRDNAKNSLSLQMNSLRA
EDTAVYYCARGLTGDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalgclvkdyfpe
pvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvdktverkccvecppc-
pa
ppvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqfnstfrvvsvl-
t
vvhqdwlngkeykckvsnkglpapiektisktkgqprepqvytlppsreemtknqvsltclvkgfypsdiavew
esngqpennykttppmldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 16 3.8.3 Light Chain [Kappa chain] protein sequence
mdmrvpaqllgllllwfpgsrcDIQMTQSPSSVSASVGDRVTISCRASQDISGWLAWY
QQKPGKAPKLLISATSSLHSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYC
QQTNSFPFTFGPGTKVDIKRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalq
sgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec SEQ ID
NO: 18 2.7.3 Heavy Chain [Gamma chain[ protein sequence
mefglswvflvallrgcqcQVQLVESGGGVVQPGRSLRLSCAASGFTFSSYGMHWV
RQAPGKGLEWVAFIWYDGSNKYYADSVKGRFTISRDNSKNTLYLQMNSL
RAEDTAVYYCARGYRVYFDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalgcl
vkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrvesky-
gp
pcpscpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfns
tyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgf-
y
psdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 20 2.7.3 Light Chain [Kappa chain] protein sequence
mdmrvpaqllgllllwfpgsrcDIQMTQSPSSVSASVGDRVTITCRASQDISSWLAWY
QRKPGKAPKLQIYAASSLESGVPSRFNGSGSGTDFTLSISSLQPEDFATYYC
QQTNSFPLTFGGGTKVEIKRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnal
qsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec SEQ ID
NO: 22 1.120.1 Heavy Chain [Gamma chain] protein sequence
mewtwsflflvaaatgahsQVQLVQSGAEVKKPGASVKVSCKASGYTFTSYGISWV
RQAPGQGLEWMGWISAYNGNTNYAQKLQDRVTMTTDTSTTTAYMELRS
LRSDDTAVYYCARRAYGANFFDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaa
lgclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvdktv-
erk
ccvecppcpappvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpree
qfnstfrvvsvltvvhqdwlngkeykckvsnkglpapiektisktkgqprepqvytlppsreemtknqvsltcl-
vk
gfypsdiavewesngqpennykttppmldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslsls
pgk SEQ ID NO: 24 1.120.1 Light Chain [Kappa chain] protein
sequence
mvlqtqvfislllwisgaygDIVMTQSPDSLAVSLGERATINCKSSQSILFFSNNKNYL
AWYRQKPGQPPNLLIYWASTRESGVPDRFSGSGSGTDFTLTISSLQAEDVA
VYYCQQYYSSPWTFGQGTKVEIKRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvq
wkvdnalqsgnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec
SEQ ID NO: 25 9.14.41 Heavy Chain [Gamma Chain] nucleotide sequence
atggagtttgggctgagctgggttttccttgttgctattataaaaggtgtCCAGTGTCAGGTGCAGCTG
GTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTC
TCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTATATGAGCTGGA
TCCGCCAGGCTCCAGGGAAGGGACTGGAGTGGGTTTCATACATTAGTA
GTAGTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCA
CCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACA
GCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGGCCTAA
CTGGGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTtcc
accaagggcccatccgtcttccccctggcgccctgctctagaagcacctccgagagcacagcggccctgggctg-
cct
ggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgctctgaccagcggcgtgcacacct-
tcc
cagctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcaacttcggcacc-
caga
cctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagacagttgagcgcaaatgttgtgtc-
gag
tgcccaccgtgcccagcaccacctgtggcaggaccgtcagtcttcctcttccccccaaaacccaaggacaccct-
catg
atctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccacgaagaccccgaggtccagttcaactg-
gta
cgtggacggcgtggaggtgcataatgccaagacaaagccacgggaggagcagttcaacagcacgttccgtgtgg-
tc
agcgtcctcaccgttgtgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcct-
ccc
agcccccatcgagaaaaccatctccaaaaccaaagggcagccccgagaaccacaggtgtacaccctgcccccat-
cc
cgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgt-
gg
agtgggagagcaatgggcagccggagaacaactacaagaccacacctcccatgctggactccgacggctccttc-
ttc
ctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtatctcatgctccgtgatgcatgag-
gc tctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 26
9.14.41 Heavy Chain [Gamma Chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCARGLTGDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalgclvkdyfpe
pvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvdktverkccvecppc-
pa
ppvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqfnstfrvvsvl-
t
vvhqdwlngkeykckvsnkglpapiektisktkgqprepqvytlppsreemtknqvsltclvkgfypsdiavew
esngqpennykttppmldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 27 9.14.4, 9.14.41, 9.14.4-Ser and 9.14.4-G1 Light Chain
[Kappa Chain] nucleotide sequence
atggacatgagggtccccgctcagctcctggggctcctgctactctggctccgaggtgccagatgTGACATCC
AGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTCGGAGACAGAGT
CACCATCACTTGCCGGCCAAGTCAGATCATTAGCAGTTTATTAAATTGG
TATCAGCAGAAACCAGGGAAAGCCCCTAAGCTCCTGATCCATGCTGCA
TCCAGTTTGCAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTG
GGACAGATTTCACTCTCACCATCAGTAGTCTGCAACCTGAAGATTTTGC
AACTTACTACTGTCAACAGAGTTACAGTACCCCATTCACTTTCGGCCCT
GGGACCAAAGTGGATATCAAACGAactgtggctgcaccatctgtatcatcttcccgccatctga
tgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtac-
agtgga
aggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctac-
a
gcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccat-
ca gggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt SEQ ID NO: 28
9.14.4, 9.14.41, 9.14.4-Ser and 9.14.4-G1 Light Chain [Kappa Chain]
protein sequence
mdmrvpaqllgllllwlrgarcDIQMTQSPSSLSASVGDRVTITCRPSQIISSLLNWYQ
QKPGKAPKLLIHAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ
QSYSTPFTFGPGTKVD1KRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkydnalqs
gnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec SEQ ID
NO: 37 9.14.4 Heavy Chain [Gamma Chain] nucleotide sequence
atggagtttgggctgagctgggttttccttgttgctattataaaaggtgtCCAGTGTCAGGTGCAGCTG
GTGGAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTC
TCCTGTGCAGCCTCTGGATTCACCTTCAGTGACTACTATATGAGCTGGA
TCCGCCAGGCTCCAGGGAAGGGACTGGAGTGGGTTTCATACATTAGTA
GTAGTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCA
CCATCTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACA
GCCTGAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGGCCTAA
CTGGGGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTtcc
accaagggcccatccgtatccccctggcgccctgctctagaagcacctccgagagcacagcggccctgggctgc-
ct
ggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgctctgaccagcggcgtgcacacct-
tcc
cagctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacg-
aaga
cctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtccc-
cca
tgcccatcatgcccagcacctgagttcctggggggaccatcagtatcctgttccccccaaaacccaaggacact-
ctca
tgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaac-
tgg
tacgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgt-
gg
tcagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggc-
ctc
ccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgccccc-
at
cccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggatctaccccagcgacatcgccg-
t
ggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctcct-
tc
ttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgca-
tgag gctctgcacaaccactacacacagaagagcctctccctgtctccgggtaaa SEQ ID NO:
38 9.14.4 Heavy Chain [Gamma Chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCARGLTGDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalgclvkdyfpe
pvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcpsc-
pa
peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsv-
l
tvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiave
wesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 54 9.14.4C-Ser Heavy Chain [Gamma chain] protein
sequence mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCARGLTGDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalgclvkdyfpe
pvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppc-
pa
peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsv-
l
tvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiave
wesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 56 9.14.4C-Ser, 9.14.4-CG2 and 9.14.4-CG4 Light Chain
[Kappa chain] protein sequence
mdmrvpaqllgllllwlrgarcDIQMTQSPSSLSASVGDRVTITCRPSQIISSLLNWYQ
QKPGKAPKLLIYAASSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ
QSYSTPFTFGPGTKVDIKRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqs
gnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec SEQ ID
NO: 74 9.14.4-CG2 Heavy Chain [Gamma chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCARGLTGDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalgclvkdyfpe
pvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvdktverkccvecppc-
pa
ppvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqfnstfrvvsvl-
t
vvhqdwlngkeykckvsnkglpapiektisktkgqprepqvytlppsreemtknqvsltclvkgfypsdiavew
esngqpennykttppmldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 78 9.14.4-CG4 Heavy Chain [Gamma chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCARGLTGDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalgclvkdyfpe
pvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcpsc-
pa
peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsv-
l
tvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiave
wesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 82 9.14.4-Ser Heavy Chain [Gamma chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCARGLTGDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalgclvkdyfpe
pvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcppc-
pa
peflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvsv-
l
tvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdiave
wesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslspgk
SEQ ID NO. 101 9.14.4G1 Heavy chain (gamma chain) nucleotide
sequence
atggagtttgggctgagctgggttttccttgttgctattataaaaggtgtccagtgtCAGGTGCAGCTGGTG
GAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCC
TGTGCAGCCTCTGGATTCACCTTCAGTGACTACTATATGAGCTGGATCC
GCCAGGCTCCAGGGAAGGGACTGGAGTGGGTTTCATACATTAGTAGTA
GTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCAT
CTCCAGGGACAACGCCAAGAACTCACTGTATCTGCAAATGAACAGCCT
GAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGAGGCCTAACTGG
GGACTACTGGGGCCAGGGAACCCTGGTCACCGTCTCCTCAGCTtccaccaag
ggcccatcggtatccccctggcaccctcctccaagagcacctctgggggcacageggccctgggctgcctggtc-
aa
ggactacttccccgaaccggtgacggtgtcgtggaactcaggcgccctgaccageggcgtgcacaccttcccgg-
ctg
tectacagtectcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacccagacc-
tacat
ctgcaacgtgaatcacaagcccagcaacaccaaggtggacaagaaagttgagcccaaatcttgtgacaaaactc-
aca
catgcccaccgtgcccagcacctgaactectggggggaccgtcagtatcctatccccccaaaacccaaggacac-
c
ctcatgatctcccggacccctgaggtcacatgcgtggtggtggacgtgagccacgaagaccctgaggtcaagtt-
caa
ctggtacgtggacggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagtacaacagcacgtacc-
g
tgtggtcagcgtectcaccgtectgcaccaggactggctgaatggcaaggagtacaagtgcaaggtctccaaca-
aag
ccctcccagcccccatcgagaaaaccatctccaaagccaaagggcagccccgagaaccacaggtgtacaccctg-
cc
cccatcccgggatgagctgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctatcccagcgaca-
tcg
ccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggc-
t
ccttatcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtga-
tgc atgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaatag SEQ
ID NO 102 9.14.4G1 Heavy chain (gamma chain) protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCARGLTGDYWGQGTLVTVSSAstkgpsvfplapsskstsggtaalgclvkdyfp
epvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkvepkscdktht-
cpp
cpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpreeqynstyrv
vsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvsltclvkgfypsd-
ia
vewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 29 8.10.3 and 8.10.3F Heavy Chain [Gamma chain]
nucleotide sequence
atggagttggggctgtgctgggttttccttgttgctattttagaaggtgtccagtgtGAGGTGCAGCTGGTG
GAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCC
TGTGCAGCCTCTGGATTCACCTTCAGTAGTTTTAGTATGACCTGGGTCC
GCCAGGCTCCAGGAAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTA
GAAGTAGTACCATATCCTACGCAGACTCTGTGAAGGGCCGATTCACCA
TCTCCAGAGACAATGCCAAGAACTCACTGTATCTGCAAATGAACAGCC
TGAGAGACGAGGACACGGCTGTGTATTACTGTGCGAGAGATCCTCTTCT
AGCGGGAGCTACCTTCTTTGACTACTGGGGCCAGGGAACCCTGGTCAC
CGTCTCCTCAGCCtccaccaagggcccatcggtcttccccctggcgccctgctccaggagcacctccgag
agcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgc-
tct
gaccagcggcgtgcacaccttcccagctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccg-
tgcc
ctccagcaacttcggcacccagacctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaaga-
ca
gttgagcgcaaatgttgtgtcgagtgcccaccgtgcccagcaccacctgtggcaggaccgtcagtatcctatcc-
ccc
caaaacccaaggacaccctcatgatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccacgaa-
ga
ccccgaggtccagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagccacgggaggagc-
a
gttcaacagcacgttccgtgtggtcagcgtcctcaccgttgtgcaccaggactggctgaacggcaaggagtaca-
agtg
caaggtctccaacaaaggcctcccagcccccatcgagaaaaccatctccaaaaccaaagggcagccccgagaac-
c
acaggtgtacaccctgcccccatcccgggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaag-
gc
ttctaccccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaagaccacacctcc-
ca
tgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggcagcaggggaac-
gtc
ttctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtctccgggtaa-
a SEQ ID NO: 30 8.10.3 and 8.10.3F Heavy Chain [Gamma chain]
protein sequence
melglcwvflvailegvqcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSFSMTWV
RQAPGKGLEWVSYISSRSSTISYADSVKGRFTISRDNAKNSLYLQMNSLRD
EDTAVYYCARDPLLAGATFFDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalg
clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvdktver-
kcc
vecppcpappvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqfn
stfrvvsvltvvhqdwlngkeykckvsnkglpapiektisktkgqprepqvytlppsreemtknqvsltclvkg-
fy
psdiavewesngqpennykttppmldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 31 8.10.3FG1 and 8.10.3F Light Chain [Kappa chain]
nucleotide sequence
atggaaaccccagcgcagatctatcctcctgctactctggctcccagataccaccggaGAATTTGTGTTG
ACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCC
TCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGTTACTTAGCCTGGTA
CCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCC
AGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGG
ACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGCAG
TGTATTACTGTCAGCAGTATGGTAGCTCACCTCTCACTTTCGGCGGAGG
GACCAAGGTGGAGATCAAACGAactgtggctgcaccatctgtatcatcttcccgccatctgatga
gcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagt-
ggaag
gtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacag-
cc
tcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcag-
gg cctgagctcgcccgtcacaaagagcttcaacaggggagagtgt SEQ ID NO: 32
8.10.3FG1 and 8.10.3F Light Chain [Kappa chain] protein sequence
metpaqllfllllwlpdttgEFVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQ
KPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQ
YGSSPLTFGGGTKVEIKRtvaapsvfifppsdeqlksgtasyvcllnnfypreakvqwkvdnalqsg
nsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspytksfnrgec SEQ ID
NO: 43 8.10.3 and 8.10.3-Ser Light Chain [Kappa chain] nucleotide
sequence
atggaaaccccagcgcagatctatcctcctgctactctggctcccagataccaccggaGAATTTGTGTTG
ACGCAGTCTCCAGGCACCCTGTCTTTGTCTCCAGGGGAAAGAGCCACCC
TCTCCTGCAGGGCCAGTCAGAGTGTTAGCAGCAGTTACTTAGCCTGGTA
CCAGCAGAAACCTGGCCAGGCTCCCAGGCTCCTCATCTATGGTGCATCC
AGCAGGGCCACTGGCATCCCAGACAGGTTCAGTGGCAGTGGGTCTGGG
ACAGACTTCACTCTCACCATCAGCAGACTGGAGCCTGAAGATTTTGTAG
TGTATTACTGTCAGCAGTATGGTAGCTCACCTCTCACTTTCGGCGGAGG
GACCAAGGTGGAGATCAAACGAactgtggctgcaccatctgtatcatcttcccgccatctgatga
gcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtacagt-
ggaag
gtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctacag-
cc
tcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccatcag-
gg cctgagctcgcccgtcacaaagagcttcaacaggggagagtgt SEQ ID NO: 44 8.10.3
and 8.10.3-Ser Light Chain +Kappa chain+ protein sequence
metpaqllfllllwlpdttgEFVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQ
KPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFVVYYCQQ
YGSSPLTFGGGTKVEIKRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqsg
nsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspytksfnrgec SEQ ID
NO: 58 8.10.3C-Ser Heavy Chain [Gamma chain] protein sequence
melglcwvflvailegvqcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSFSMTWV
RQAPGKGLEWVSYISSRSSTISYADSVKGRFTISRDNAKNSLYLQMNSLRD
EDTAVYYCARDPLLAGATFFDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalg
clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrves-
kyg
ppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqf
nstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvk-
gf
ypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslspg-
k SEQ ID NO: 60 8.10.3-CG2, 8.10.3-CG4 and 8.10.3C-Ser Light Chain
[kappa chain] protein sequence
metpaqllfllllwlpdttgEIVLTQSPGTLSLSPGERATLSCRASQSVSSSYLAWYQQ
KPGQAPRLLIYGASSRATGIPDRFSGSGSGTDFTLTISRLEPEDFAVYYCQQ
YGSSPLTFGGGTKVEIKRtvaapsvfifppsdeqlksgtasvvellnnfypreakvqwkvdnalqsg
nsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec SEQ ID
NO: 62 8.10.3-CG2 Heavy Chain [Gamma chain] protein sequence
melglcwvflvailegvqcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSFSMTWV
RQAPGKGLEWVSYISSRSSTISYADSVKGRFTISRDNAKNSLYLQMNSLRD
EDTAVYYCARDPLLAGATFFDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalg
clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvdktver-
kcc
vecppcpappvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqfn
stfrvvsyltvvhqdwlngkeykckvsnkglpapiektisktkgqprepqvytlppsreemtknqvsltclvkg-
fy
psdiavewesngqpennykttppmldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 90 8.10.3-Ser Heavy Chain [Gamma chain] protein sequence
melglcwvflvailegvqcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSFSMTWV
RQAPGKGLEWVSYISSRSSTISYADSVKGRFTISRDNAKNSLYLQMNSLRD
EDTAVYYCARDPLLAGATFFDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalg
clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrves-
kyg
ppcppcpapeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqf
nstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvk-
gf
ypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslspg-
k SEQ ID NO: 94 8.10.3-CG4 Heavy Chain [Gamma chain] protein
sequence melglcwvflvailegvqcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSFSMTWV
RQAPGKGLEWVSYISSRSSTISYADSVKGRFTISRDNAKNSLYLQMNSLRD
EDTAVYYCARDPLLAGATFFDYWGQGTLVTVSSAstkgpsvfplapcsrstsestaalg
clvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrves-
kyg
ppcpscpapeflggpsvflfppkpkddmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqf
nstyrvvsvltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvk-
gf
ypsdiavewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslspg-
k SEQ ID NO: 97 8.10.3FG1 Heavy Chain nucleotide sequence
atggagttggggctgagctgggttttccttgttgctattataaaaggtgtccagtgtGAGGTGCAGCTGGTG
GAGTCTGGGGGAGGCTTGGTACAGCCTGGGGGGTCCCTGAGACTCTCC
TGTGCAGCCTCTGGATTCACCTTCAGTAGTTTTAGTATGACCTGGGTCC
GCCAGGCTCCAGGAAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTA
GAAGTAGTACCATATCCTACGCAGACTCTGTGAAGGGCCGATTCACCA
TCTCCAGAGACAATGCCAAGAACTCACTGTATCTGCAAATGAACAGCC
TGAGAGACGAGGACACGGCTGTGTATTACTGTGCGAGAGATCCTCTTCT
AGCGGGAGCTACCTTCTTTGACTACTGGGGCCAGGGAACCCTGGTCAC
CGTCTCCTCAGCCtccaccaagggcccatcggtatccccctggcaccctcctccaagagcacctctggg
ggcacagcggccctgggctgcctggtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgc-
cc
tgaccagcggcgtgcacaccttcccggctgtcctacagtcctcaggactctactccctcagcagcgtggtgacc-
gtgc
cctccagcagcttgggcacccagacctacatctgcaacgtgaatcacaagcccagcaacaccaaggtggacaag-
aa
agttgagcccaaatcttgtgacaaaactcacacatgcccaccgtgcccagcacctgaactcctggggggaccgt-
cagt
cttcctatccccccaaaacccaaggacaccctcatgatctcccggacccctgaggtcacatgcgtggtggtgga-
cgtg
agccacgaagaccctgaggtcaagttcaactggtacgtggacggcgtggaggtgcataatgccaagacaaagcc-
gc
gggaggagcagtacaacagcacgtaccgtgtggtcagcgtcctcaccgtcctgcaccaggactggctgaatggc-
aa
ggagtacaagtgcaaggtctccaacaaagccctcccagcccccatcgagaaaaccatctccaaagccaaagggc-
ag
ccccgagaaccacaggtgtacaccctgcccccatcccgggatgagctgaccaagaaccaggtcagcctgacctg-
cc
tggtcaaaggatctatcccagcgacatcgccgtggagtgggagagcaatgggcagccggagaacaactacaaga-
c
cacgcctcccgtgctggactccgacggctccttcttcctctacagcaagctcaccgtggacaagagcaggtggc-
agca
ggggaacgtatctcatgctccgtgatgcatgaggctctgcacaaccactacacgcagaagagcctctccctgtc-
tccg ggtaaatag SEQ ID NO: 98 8.10.3FG1 Heavy chain (gamma chain)
protein sequence
melglcwvflvailegvqcEVQLVESGGGLVQPGGSLRLSCAASGFTFSSFSMTWV
RQAPGKGLEWVSYISSRSSTISYADSVKGRFTISRDNAKNSLYLQMNSLRD
EDTAVYYCARDPLLAGATFFDYWGQGTLVTVSSAstkgpsvfplapsskstsggtaal
gclvkdyfpepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtqtyicnvnhkpsntkvdkkve-
pk
scdkthtcppcpapellggpsvflfppkpkdtlmisrtpevtcvvvdvshedpevkfnwyvdgvevhnaktkpr
eeqynstyrvvsvltvlhqdwlngkeykckvsnkalpapiektiskakgqprepqvytlppsrdeltknqvslt-
clv
kgfypsdiavewesngqpennykttppvldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslsl-
s pgk SEQ ID NO: 33 9.7.2IF Heavy Chain [Gamma chain] nucleotide
sequence
atggagtttgggctgagctgggttttccttgttgctattataaaaggtgtccagtgtcAGGTGCAGCTGGTG
GAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCC
TGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCC
GCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTA
GTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCAT
CTCCAGGGACAACGCCAAGAATTCACTGTATCTGCAAATGAACAGCCT
GAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGGCGTATAGGAGG
TATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTtcca
ccaagggcccatccgtcttccccctggcgccctgctctagaagcacctccgagagcacagcggccctgggctgc-
ctg
gtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgctctgaccagcggcgtgcacacctt-
ccc
agctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcaacttcggcaccc-
agac
ctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagacagttgagcgcaaatgttgtgtcg-
agt
gcccaccgtgcccagcaccacctgtggcaggaccgtcagtcttcctcttccccccaaaacccaaggacaccctc-
atga
tctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccacgaagaccccgaggtccagttcaactgg-
tac
gtggacggcgtggaggtgcataatgccaagacaaagccacgggaggagcagttcaacagcacgttccgtgtggt-
ca
gcgtcctcaccgttgtgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcctc-
cca
gcccccatcgagaaaaccatctccaaaaccaaagggcagccccgagaaccacaggtgtacaccctgcccccatc-
cc
gggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggcttctaccccagcgacatcgccgtg-
ga
gtgggagagcaatgggcagccggagaacaactacaagaccacacctcccatgctggactccgacggctccttct-
tcc
tctacagcaagctcaccgtggacaagagcaggtggcagcaggggaacgtcttctcatgctccgtgatgcatgag-
gct ctgcacaaccactacacgcagaagagcctctccctgtctccgggtaaa SEQ ID NO: 34
9.7.2IF Heavy Chain [Gamma Chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCARRIGGMDVWGQGTTVTVSSAstkgpsvfplapcsrstsestaalgclvkdyf
pepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvdktverkccvecp-
pc
pappvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqfnstfrvvs
vltvvhqdwingkeykckvsnkglpapiektisktkgqprepqvytlppsreemtknqvsltclvkgfypsdia-
v
ewesngqpennykttppmldsdgsfflyskltvdksrwqqgnyfscsvmhealhnhytqkslslspgk
SEQ ID NO: 35 9.7.2IF Light Chain [Kappa chain] nucleotide sequence
atggacatgagggtccccgctcagctcctggggctcctgctactctggctccgaggtgccagatgtGACATCC
AGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGT
CACCATCACTTGCCGGGCAAGTCAGAGCATTAGCGGCTTTTTAATTTGG
TATCAGCAGAGACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTACA
TCCAGTTTACAAAGTGGGGTCCCATCAAGGTTCAGTGGCAGTGGATCTG
GGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGC
AACTTACTACTGTCAACAGAGTTACAGTACCCCATTCACTTTCGGCCCT
GGGACCAAAGTGGATATCAAACGAactgtggctgcaccatctgtcttcatcttcccgccatctga
tgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtac-
agtgga
aggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctac-
a
gcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccat-
ca gggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt SEQ ID NO: 36
9.7.2IF Light Chain [Kappa chain] protein sequence
mdmrvpaqllgllllwlrgarcDIQMTQSPSSLSASVGDRVTITCRASQSISGFLIWYQ
QRPGKAPKLLIYATSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ
QSYSTPFTFGPGTKVDIKRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqs
gnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec SEQ ID
NO: 45 9.7.2 Heavy Chain [Gamma chain] nucleotide sequence
atggagtttgggctgagctgggttttccttgttgctattataaaaggtgtccagtgtcAGGTGCAGCTGGTG
GAGTCTGGGGGAGGCTTGGTCAAGCCTGGAGGGTCCCTGAGACTCTCC
TGTGCAGCCTCTGGATTCACCTTCAGTGACTACTACATGAGCTGGATCC
GCCAGGCTCCAGGGAAGGGGCTGGAGTGGGTTTCATACATTAGTAGTA
GTGGTAGTACCATATACTACGCAGACTCTGTGAAGGGCCGATTCACCAT
CTCCAGGGACAACGCCAAGAATTCACTGTATCTGCAAATGAACAGCCT
GAGAGCCGAGGACACGGCCGTGTATTACTGTGCGAGGCGTATAGGAGG
TATGGACGTCTGGGGCCAAGGGACCACGGTCACCGTCTCCTCAGCTtcca
ccaagggcccatccgtatccccctggcgccctgctctagaagcacctccgagagcacagcggccctgggctgcc-
tg
gtcaaggactacttccccgaaccggtgacggtgtcgtggaactcaggcgctctgaccagcggcgtgcacacctt-
ccc
agctgtcctacagtcctcaggactctactccctcagcagcgtggtgaccgtgccctccagcagcttgggcacga-
agac
ctacacctgcaacgtagatcacaagcccagcaacaccaaggtggacaagagagttgagtccaaatatggtcccc-
cat
gcccatcatgcccagcacctgagttcctggggggaccatcagtatcctgttccccccaaaacccaaggacactc-
tcat
gatctcccggacccctgaggtcacgtgcgtggtggtggacgtgagccaggaagaccccgaggtccagttcaact-
ggt
acgtggatggcgtggaggtgcataatgccaagacaaagccgcgggaggagcagttcaacagcacgtaccgtgtg-
gt
cagcgtcctcaccgtcctgcaccaggactggctgaacggcaaggagtacaagtgcaaggtctccaacaaaggcc-
tc
ccgtcctccatcgagaaaaccatctccaaagccaaagggcagccccgagagccacaggtgtacaccctgccccc-
at
cccaggaggagatgaccaagaaccaggtcagcctgacctgcctggtcaaaggatctaccccagcgacatcgccg-
t
ggagtgggagagcaatgggcagccggagaacaactacaagaccacgcctcccgtgctggactccgacggctcct-
tc
ttcctctacagcaggctaaccgtggacaagagcaggtggcaggaggggaatgtcttctcatgctccgtgatgca-
tgag gctctgcacaaccactacacacagaagagcctctccctgtctccgggtaaa SEQ ID NO:
46 9.7.2 Heavy Chain [Gamma Chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCARRIGGMDVWGQGTTVTVSSAstkgpsvfplapcsrstsestaalgclvkdyf
pepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcp-
sc
papeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvv
svltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdi-
a
vewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 47 9.7.2 and 9.7.2-Ser Light Chain [Kappa chain]
nucleotide sequence
atggacatgagggtccccgctcagctcctggggctcctgctactctggctccgaggtgccagatgtGACATCC
AGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGAGACAGAGT
CACCATCACTTGCCGGGCAAGTCAGAGCATTAGCGGCTTTTTAATTTGG
TATCAGCAGAGACCAGGGAAAGCCCCTAAGCTCCTGATCTATGCTACA
TCCAGTTTACAAAGTGGGGTCCCATTAAGGTTCAGTGGCAGTGAATCTG
GGACAGATTTCACTCTCACCATCAGCAGTCTGCAACCTGAAGATTTTGC
AACTTACTACTGTCAACAGAGTTACAGTACCCCATTCACTTTCGGCCCT
GGGACCAAAGTGGATATCAAACGAactgtggctgcaccatctgtatcatcttcccgccatctga
tgagcagttgaaatctggaactgcctctgttgtgtgcctgctgaataacttctatcccagagaggccaaagtac-
agtgga
aggtggataacgccctccaatcgggtaactcccaggagagtgtcacagagcaggacagcaaggacagcacctac-
a
gcctcagcagcaccctgacgctgagcaaagcagactacgagaaacacaaagtctacgcctgcgaagtcacccat-
ca gggcctgagctcgcccgtcacaaagagcttcaacaggggagagtgt SEQ ID NO: 48
9.7.2 and 9.7.2-Ser Light Chain [Kappa chain] protein sequence
mdmrvpaqllgllllwlrgarcDIQMTQSPSSLSASVGDRVTITCRASQSISGFLIWYQ
QRPGKAPKLLIYATSSLQSGVPLRFSGSESGTDFTLTISSLQPEDFATYYCQ
QSYSTPFTFGPGTKVDIKRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqs
gnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec SEQ ID
NO: 50 9.7.2C-Ser Heavy Chain [Gamma chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCAIRIGGMDVWGQGTTVTVSSAstkgpsvfplapcsrstsestaalgclvkdyfp
epvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcpp-
cp
apeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvs
vltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdia-
v
ewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 52 9.7.2C-Ser, 9.7.2-CG2 and 9.7.2-CG4 Light Chain
[Kappa chain] protein sequence
mdmrvpaqllgllllwlrgarcDIQMTQSPSSLSASVGDRVTITCRASQSISGFLIWYQ
QKPGKAPKLLIYATSSLQSGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQ
QSYSTPFTFGPGTKVDIKRtvaapsvfifppsdeqlksgtasvvcllnnfypreakvqwkvdnalqs
gnsqesvteqdskdstyslsstltlskadyekhkvyacevthqglsspvtksfnrgec SEQ ID
NO: 66 9.7.2-CG2 Heavy Chain [Gamma chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCAIRIGGMDVWGQGTTVTVSSAstkgpsvfplapcsrstsestaalgclvkdyfp
epvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssnfgtqtytcnvdhkpsntkvdktverkccvecpp-
cp
appvagpsvflfppkpkdtlmisrtpevtcvvvdvshedpevqfnwyvdgvevhnaktkpreeqfnstfrvvsv
ltvvhqdwlngkeykckvsnkglpapiektisktkgqprepqvytlppsreemtknqvsltclvkgfypsdiav-
e
wesngqpennykttppmldsdgsfflyskltvdksrwqqgnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 70 9.7.2-CG4 Heavy Chain [Gamma chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCARIGGMDVWGQGTTVTVSSAstkgpsvfplapcsrstsestaalgclvkdyfp
epvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcps-
cp
apeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvvs
vltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdia-
v
ewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqkslslspgk
SEQ ID NO: 86 9.7.2-Ser Heavy Chain [Gamma chain] protein sequence
mefglswvflvaiikgvqcQVQLVESGGGLVKPGGSLRLSCAASGFTFSDYYMSWI
RQAPGKGLEWVSYISSSGSTIYYADSVKGRFTISRDNAKNSLYLQMNSLRA
EDTAVYYCARRIGGMDVWGQGTTVTVSSAstkgpsvfplapcsrstsestaalgclvkdyf
pepvtvswnsgaltsgvhtfpavlqssglyslssvvtvpssslgtktytcnvdhkpsntkvdkrveskygppcp-
pc
papeflggpsvflfppkpkdtlmisrtpevtcvvvdvsqedpevqfnwyvdgvevhnaktkpreeqfnstyrvv
svltvlhqdwlngkeykckvsnkglpssiektiskakgqprepqvytlppsqeemtknqvsltclvkgfypsdi-
a
vewesngqpennykttppvldsdgsfflysrltvdksrwqegnvfscsvmhealhnhytqks1slspgk
Key: Signal peptide: underlined lower case CDRs 1,2,3: underlined
UPPERCASE Variable domain: UPPER CASE Constant domain: lower case
Mutations from germline in bold
Sequence CWU 1 SEQUENCE LISTING <160> NUMBER OF SEQ ID
NOS: 117 <210> SEQ ID NO 1 <211> LENGTH: 1383
<212> TYPE: DNA <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 1 atggagttgg ggctgtgctg gattttcctt gttgctatta
taaaaggtgt ccagtgtcag 60 gtgcagctgg tggagtctgg gggaggcttg
gtcaagcctg gagggtccct gagactctcc 120 tgtgcagcct ctggattcac
cttcagtgac tactacatga gctggatccg ccaggctcca 180 gggaaggggc
tggagtggat ttcatacatt agtggtagtg gtagtaccat atactacgca 240
gactctgtga agggccgatt caccatctcc agggacaacg ccaagaactc actgtatctg
300 caaatgaaca gcctgagagc cgaggacacg gccgtgtatc actgtgcgag
agccctgggt 360 gggatggacg tctggggcca agggaccacg gtcaccgtct
cctcagcttc caccaagggc 420 ccatccgtct tccccctggc gccctgctct
agaagcacct ccgagagcac agcggccctg 480 ggctgcctgg tcaaggacta
cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgct 540 ctgaccagcg
gcgtgcacac cttcccagct gtcctacagt cctcaggact ctactccctc 600
agcagcgtgg tgaccgtgcc ctccagcaac ttcggcaccc agacctacac ctgcaacgta
660 gatcacaagc ccagcaacac caaggtggac aagacagttg agcgcaaatg
ttgtgtcgag 720 tgcccaccgt gcccagcacc acctgtggca ggaccgtcag
tcttcctctt ccccccaaaa 780 cccaaggaca ccctcatgat ctcccggacc
cctgaggtca cgtgcgtggt ggtggacgtg 840 agccacgaag accccgaggt
ccagttcaac tggtacgtgg acggcgtgga ggtgcataat 900 gccaagacaa
agccacggga ggagcagttc aacagcacgt tccgtgtggt cagcgtcctc 960
accgttgtgc accaggactg gctgaacggc aaggagtaca agtgcaaggt ctccaacaaa
1020 ggcctcccag cccccatcga gaaaaccatc tccaaaacca aagggcagcc
ccgagaacca 1080 caggtgtaca ccctgccccc atcccgggag gagatgacca
agaaccaggt cagcctgacc 1140 tgcctggtca aaggcttcta ccccagcgac
atcgccgtgg agtgggagag caatgggcag 1200 ccggagaaca actacaagac
cacacctccc atgctggact ccgacggctc cttcttcctc 1260 tacagcaagc
tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc 1320
gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct gtctccgggt
1380 aaa 1383 <210> SEQ ID NO 2 <211> LENGTH: 461
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 2 Met Glu Leu Gly Leu Cys Trp Ile Phe Leu Val
Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val Gln Leu Val Glu
Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser Leu Arg Leu
Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp Tyr Tyr Met
Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp Ile
Ser Tyr Ile Ser Gly Ser Gly Ser Thr Ile Tyr Tyr Ala 65 70 75 80 Asp
Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90
95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val
100 105 110 Tyr His Cys Ala Arg Ala Leu Gly Gly Met Asp Val Trp Gly
Gln Gly 115 120 125 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
Pro Ser Val Phe 130 135 140 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
Glu Ser Thr Ala Ala Leu 145 150 155 160 Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175 Asn Ser Gly Ala Leu
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190 Gln Ser Ser
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 195 200 205 Ser
Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 210 215
220 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu
225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser
Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile
Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val Val Asp Val Ser
His Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp Tyr Val Asp Gly
Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro Arg Glu Glu Gln
Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 305 310 315 320 Thr Val
Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 325 330 335
Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 340
345 350 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro
Ser 355 360 365 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys
Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp
Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn Tyr Lys Thr Thr
Pro Pro Met Leu Asp Ser Asp Gly 405 410 415 Ser Phe Phe Leu Tyr Ser
Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430 Gln Gly Asn Val
Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435 440 445 His Tyr
Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210>
SEQ ID NO 3 <211> LENGTH: 702 <212> TYPE: DNA
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 3
atgagggtcc ctgctcagct cctggggctc ctgctactct ggctccgagg tgccagatgt
60 gacatccaga tgacccagtc tccatcctcc ctgtctgcat ctgtaggaga
cagagtcacc 120 atcacttgcc gggcaagtca gagcattagc ggctttttaa
attggtatca gcagaaacca 180 gggaaagccc ctaagctcct gatctatgct
acatccagtt tgcaaagtgg ggtcccattc 240 aggttcagtg gcagtggatc
tgggacagat ttcactctca ccatcagcag tctgcaacct 300 gaagattttg
caacttatta ctgtcaacag agttacagtg tcccattcac tttcggccct 360
gggaccaaag tggatatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca
420 tctgatgagc agttgaaatc tggaactgct agcgttgtgt gcctgctgaa
taacttctat 480 cccagagagg ccaaagtaca gtggaaggtg gataacgccc
tccaatcggg taactcccag 540 gagagtgtca cagagcagga cagcaaggac
agcacctaca gcctcagcag caccctgacg 600 ctgagcaaag cagactacga
gaaacacaaa gtctacgcct gcgaagtcac ccatcagggc 660 ctgagctcgc
ccgtcacaaa gagcttcaac aggggagagt gt 702 <210> SEQ ID NO 4
<211> LENGTH: 234 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 4 Met Arg Val Pro Ala Gln Leu
Leu Gly Leu Leu Leu Leu Trp Leu Arg 1 5 10 15 Gly Ala Arg Cys Asp
Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser 20 25 30 Ala Ser Val
Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Ser 35 40 45 Ile
Ser Gly Phe Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 50 55
60 Lys Leu Leu Ile Tyr Ala Thr Ser Ser Leu Gln Ser Gly Val Pro Phe
65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr
Ile Ser 85 90 95 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys
Gln Gln Ser Tyr 100 105 110 Ser Val Pro Phe Thr Phe Gly Pro Gly Thr
Lys Val Asp Ile Lys Arg 115 120 125 Thr Val Ala Ala Pro Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln 130 135 140 Leu Lys Ser Gly Thr Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Glu
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 165 170 175 Gly
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 180 185
190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro 210 215 220 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230
<210> SEQ ID NO 5 <211> LENGTH: 1389 <212> TYPE:
DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 5
atggaatttg ggctgtgctg ggttttcctt gttgctattt tagaaggtgt ccagtgtgag
60 gtgcagctgg tggagtctgg gggaggcttg gtccagcctg gggggtccct
gagactctcc 120 tgtgcagcct ctggattcac ctttagtagc tattggatga
gctgggtccg ccaggctcca 180 gggaaggggc tggagtgggt ggccaacata
aagcaagatg gaagtgagaa atactatgtg 240 gactctgtga agggccgatt
caccatctcc agagacaacg ccaagaactc actgtatctg 300 caaatgaaca
gcctgagagc cgaggacacg gctgtgtatt actgtgctcc gggtatagca 360
gcagctggta gggcctactg gggccaggga accctggtca ccgtctcctc agcttccacc
420 aagggcccat ccgtcttccc cctggcgccc tgctctagaa gcacctccga
gagcacagcg 480 gccctgggct gcctggtcaa ggactacttc cccgaaccgg
tgacggtgtc gtggaactca 540 ggcgctctga ccagcggcgt gcacaccttc
ccagctgtcc tacagtcctc aggactctac 600 tccctcagca gcgtggtgac
cgtgccctcc agcaacttcg gcacccagac ctacacctgc 660 aacgtagatc
acaagcccag caacaccaag gtggacaaga cagttgagcg caaatgttgt 720
gtcgagtgcc caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc
780 ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg
cgtggtggtg 840 gacgtgagcc acgaagaccc cgaggtccag ttcaactggt
acgtggacgg cgtggaggtg 900 cataatgcca agacaaagcc acgggaggag
cagttcaaca gcacgttccg tgtggtcagc 960 gtcctcaccg ttgtgcacca
ggactggctg aacggcaagg agtacaagtg caaggtctcc 1020 aacaaaggcc
tcccagcccc catcgagaaa accatctcca aaaccaaagg gcagccccga 1080
gaaccacagg tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc
1140 ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg
ggagagcaat 1200 gggcagccgg agaacaacta caagaccaca cctcccatgc
tggactccga cggctccttc 1260 ttcctctaca gcaagctcac cgtggacaag
agcaggtggc agcaggggaa cgtcttctca 1320 tgctccgtga tgcatgaggc
tctgcacaac cactacacgc agaagagcct ctccctgtct 1380 ccgggtaaa 1389
<210> SEQ ID NO 6 <211> LENGTH: 463 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 6 Met
Glu Phe Gly Leu Cys Trp Val Phe Leu Val Ala Ile Leu Glu Gly 1 5 10
15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe 35 40 45 Ser Ser Tyr Trp Met Ser Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Asn Ile Lys Gln Asp Gly
Ser Glu Lys Tyr Tyr Val 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala
Pro Gly Ile Ala Ala Ala Gly Arg Ala Tyr Trp Gly 115 120 125 Gln Gly
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 130 135 140
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 145
150 155 160 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val 165 170 175 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
Thr Phe Pro Ala 180 185 190 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
Ser Ser Val Val Thr Val 195 200 205 Pro Ser Ser Asn Phe Gly Thr Gln
Thr Tyr Thr Cys Asn Val Asp His 210 215 220 Lys Pro Ser Asn Thr Lys
Val Asp Lys Thr Val Glu Arg Lys Cys Cys 225 230 235 240 Val Glu Cys
Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 245 250 255 Phe
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 260 265
270 Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu
275 280 285 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
Ala Lys 290 295 300 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
Arg Val Val Ser 305 310 315 320 Val Leu Thr Val Val His Gln Asp Trp
Leu Asn Gly Lys Glu Tyr Lys 325 330 335 Cys Lys Val Ser Asn Lys Gly
Leu Pro Ala Pro Ile Glu Lys Thr Ile 340 345 350 Ser Lys Thr Lys Gly
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 355 360 365 Pro Ser Arg
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 370 375 380 Val
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390
395 400 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp
Ser 405 410 415 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
Lys Ser Arg 420 425 430 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
Met His Glu Ala Leu 435 440 445 His Asn His Tyr Thr Gln Lys Ser Leu
Ser Leu Ser Pro Gly Lys 450 455 460 <210> SEQ ID NO 7
<211> LENGTH: 702 <212> TYPE: DNA <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 7 atgagggtcc ctgctcagct
cctggggctc ctgctactct ggctccgagg tgccagatgt 60 gacatccaga
tgacccagtc tccatcctcc ctgtctgcat ctgttggaga cagagtcacc 120
atcacttgcc ggccaagtca ggacattagc agttatttaa attggtatca gcagaaacca
180 gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg
ggtcccatta 240 aggttcagtg gcagtggatc tgggacagat ttcactctca
ccatcagcag tctgcaacct 300 gaagattttg caacttacta ctgtcaacag
agttacagta ccccattcac tttcggccct 360 gggaccaaag tggatatcaa
acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 420 tctgatgagc
agttgaaatc tggaactgct agcgttgtgt gcctgctgaa taacttctat 480
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag
540 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag
caccctgacg 600 ctgagcaaag cagactacga gaaacacaaa gtctacgcct
gcgaagtcac ccatcagggc 660 ctgagctcgc ccgtcacaaa gagcttcaac
aggggagagt gt 702 <210> SEQ ID NO 8 <211> LENGTH: 234
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 8 Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu
Leu Leu Trp Leu Arg 1 5 10 15 Gly Ala Arg Cys Asp Ile Gln Met Thr
Gln Ser Pro Ser Ser Leu Ser 20 25 30 Ala Ser Val Gly Asp Arg Val
Thr Ile Thr Cys Arg Pro Ser Gln Asp 35 40 45 Ile Ser Ser Tyr Leu
Asn Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro 50 55 60 Lys Leu Leu
Ile Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Leu 65 70 75 80 Arg
Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser 85 90
95 Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr
100 105 110 Ser Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile
Lys Arg 115 120 125 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro
Ser Asp Glu Gln 130 135 140 Leu Lys Ser Gly Thr Ala Ser Val Val Cys
Leu Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Glu Ala Lys Val Gln
Trp Lys Val Asp Asn Ala Leu Gln Ser 165 170 175 Gly Asn Ser Gln Glu
Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 180 185 190 Tyr Ser Leu
Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 195 200 205 His
Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 210 215
220 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 <210> SEQ
ID NO 9 <211> LENGTH: 1398 <212> TYPE: DNA <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 9 atggagtttg
ggctccgctg gatttttctt gtggctattt taaaaggtgt ccagtgtgag 60
gtgcagctgt tggagtctgg gggaggcttg gtacagcctg gggggtccct gagactctcc
120 tgtgcagcct ctggattcac ctttagcagc tatgccatga gctgggtccg
ccaggctcca 180 gggaaggggc tggaatgggt ctcagctatt agtggtcgtg
gtggtaggac atacttcgca 240 gactccgtga agggccggtt caccatctcc
agagacaatt ccaagaacac gctgtatctg 300 caaatgaaca gcctgagagc
cgaggacacg gccgtatatt tctgtgcggt agaaggctat 360 agtgggcgct
acggattttt tgactactgg ggccagggaa ccctagtcac cgtctcctca 420
gcctccacca agggcccatc ggtcttcccc ctggcgccct gctctagaag cacctccgag
480 agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt
gacggtgtcg 540 tggaactcag gcgctctgac cagcggcgtg cacaccttcc
cagctgtcct acagtcctca 600 ggactctact ccctcagcag cgtggtgacc
gtgccctcca gcaacttcgg cacccagacc 660 tacacctgca acgtagatca
caagcccagc aacaccaagg tggacaagac agttgagcgc 720 aaatgttgtg
tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 780
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc
840 gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta
cgtggacggc 900 gtggaggtgc ataatgccaa gacaaagcca cgggaggagc
agttcaacag cacgttccgt 960 gtggtcagcg tcctcaccgt tgtgcaccag
gactggctga acggcaagga gtacaagtgc 1020 aaggtctcca acaaaggcct
cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 1080 cagccccgag
aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1140
caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg
1200 gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct
ggactccgac 1260 ggctccttct tcctctacag caagctcacc gtggacaaga
gcaggtggca gcaggggaac 1320 gtcttctcat gctccgtgat gcatgaggct
ctgcacaacc actacacgca gaagagcctc 1380 tccctgtctc cgggtaaa 1398
<210> SEQ ID NO 10 <211> LENGTH: 466 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 10 Met
Glu Phe Gly Leu Arg Trp Ile Phe Leu Val Ala Ile Leu Lys Gly 1 5 10
15 Val Gln Cys Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln
20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe 35 40 45 Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu 50 55 60 Glu Trp Val Ser Ala Ile Ser Gly Arg Gly
Gly Arg Thr Tyr Phe Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Phe Cys Ala
Val Glu Gly Tyr Ser Gly Arg Tyr Gly Phe Phe Asp 115 120 125 Tyr Trp
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145
150 155 160 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Asn Phe
Gly Thr Gln Thr Tyr Thr Cys Asn 210 215 220 Val Asp His Lys Pro Ser
Asn Thr Lys Val Asp Lys Thr Val Glu Arg 225 230 235 240 Lys Cys Cys
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly 245 250 255 Pro
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265
270 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
Val His 290 295 300 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
Ser Thr Phe Arg 305 310 315 320 Val Val Ser Val Leu Thr Val Val His
Gln Asp Trp Leu Asn Gly Lys 325 330 335 Glu Tyr Lys Cys Lys Val Ser
Asn Lys Gly Leu Pro Ala Pro Ile Glu 340 345 350 Lys Thr Ile Ser Lys
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365 Thr Leu Pro
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 370 375 380 Thr
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 385 390
395 400 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
Met 405 410 415 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
Thr Val Asp 420 425 430 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
Cys Ser Val Met His 435 440 445 Glu Ala Leu His Asn His Tyr Thr Gln
Lys Ser Leu Ser Leu Ser Pro 450 455 460 Gly Lys 465 <210> SEQ
ID NO 11 <211> LENGTH: 702 <212> TYPE: DNA <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 11 atggaagccc
cagctcagct tctcttcctc ctgctactct ggctcccaga taccactgga 60
gaaatagtga tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc
120 ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca
gcagaaacct 180 ggccaggctc ccaggctcct catctatggt gcatccacca
gggccagtgg tatcccagac 240 aggatcagtg gcagtgggtc tggaacagag
ttcactctca tcatcagcag cctgcagtct 300 gaagattttg cagtttatta
ctgtcagcag tctaataact ggccattcac tttcggccct 360 gggaccaaag
tggatatcaa acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 420
tctgatgagc agttgaaatc tggaactgct agcgttgtgt gcctgctgaa taacttctat
480 cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg
taactcccag 540 gagagtgtca cagagcagga cagcaaggac agcacctaca
gcctcagcag caccctgacg 600 ctgagcaaag cagactacga gaaacacaaa
gtctacgcct gcgaagtcac ccatcagggc 660 ctgagctcgc ccgtcacaaa
gagcttcaac aggggagagt gt 702 <210> SEQ ID NO 12 <211>
LENGTH: 234 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 12 Met Glu Ala Pro Ala Gln Leu Leu
Phe Leu Leu Leu Leu Trp Leu Pro 1 5 10 15 Asp Thr Thr Gly Glu Ile
Val Met Thr Gln Ser Pro Ala Thr Leu Ser 20 25 30 Val Ser Pro Gly
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser 35 40 45 Val Ser
Ser Asn Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 50 55 60
Arg Leu Leu Ile Tyr Gly Ala Ser Thr Arg Ala Ser Gly Ile Pro Asp 65
70 75 80 Arg Ile Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile
Ile Ser 85 90 95 Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys
Gln Gln Ser Asn 100 105 110 Asn Trp Pro Phe Thr Phe Gly Pro Gly Thr
Lys Val Asp Ile Lys Arg 115 120 125 Thr Val Ala Ala Pro Ser Val Phe
Ile Phe Pro Pro Ser Asp Glu Gln 130 135 140 Leu Lys Ser Gly Thr Ala
Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Glu
Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 165 170 175 Gly
Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 180 185
190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys
195 200 205 His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser
Ser Pro 210 215 220 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230
<210> SEQ ID NO 13 <400> SEQUENCE: 13 000 <210>
SEQ ID NO 14 <211> LENGTH: 460 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 14 Met Glu
Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20
25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
Phe 35 40 45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly
Lys Gly Leu 50 55 60 Glu Trp Phe Ser Tyr Ile Ser Ser Ser Gly Ser
Thr Ile Tyr Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Ser Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg
Gly Leu Thr Gly Asp Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150
155 160 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
Asn 165 170 175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
Val Leu Gln 180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
Thr Val Pro Ser Ser 195 200 205 Asn Phe Gly Thr Gln Thr Tyr Thr Cys
Asn Val Asp His Lys Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Thr
Val Glu Arg Lys Cys Cys Val Glu Cys 225 230 235 240 Pro Pro Cys Pro
Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 245 250 255 Pro Pro
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 260 265 270
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe 275
280 285 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
Pro 290 295 300 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
Val Leu Thr 305 310 315 320 Val Val His Gln Asp Trp Leu Asn Gly Lys
Glu Tyr Lys Cys Lys Val 325 330 335 Ser Asn Lys Gly Leu Pro Ala Pro
Ile Glu Lys Thr Ile Ser Lys Thr 340 345 350 Lys Gly Gln Pro Arg Glu
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 355 360 365 Glu Glu Met Thr
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 370 375 380 Phe Tyr
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 385 390 395
400 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser
405 410 415 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
Gln Gln 420 425 430 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
Leu His Asn His 435 440 445 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
Gly Lys 450 455 460 <210> SEQ ID NO 15 <400> SEQUENCE:
15 000 <210> SEQ ID NO 16 <211> LENGTH: 236 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
16 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15 Phe Pro Gly Ser Arg Cys Asp Ile Gln Met Thr Gln Ser Pro
Ser Ser 20 25 30 Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Ser
Cys Arg Ala Ser 35 40 45 Gln Asp Ile Ser Gly Trp Leu Ala Trp Tyr
Gln Gln Lys Pro Gly Lys 50 55 60 Ala Pro Lys Leu Leu Ile Ser Ala
Thr Ser Ser Leu His Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 100 105 110 Thr Asn
Ser Phe Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130
135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr
Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> SEQ ID NO
17 <400> SEQUENCE: 17 000 <210> SEQ ID NO 18
<211> LENGTH: 463 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 18 Met Glu Phe Gly Leu Ser Trp
Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10 15 Cys Gln Cys Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln 20 25 30 Pro Gly Arg
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Val Ala Phe Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser
Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Tyr Arg Val Tyr
Phe Asp Tyr Trp Gly Gln 115 120 125 Gly Thr Leu Val Thr Val Ser Ser
Ala Ser Thr Lys Gly Pro Ser Val 130 135 140 Phe Pro Leu Ala Pro Cys
Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 145 150 155 160 Leu Gly Cys
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser 165 170 175 Trp
Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val 180 185
190 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
195 200 205 Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
His Lys 210 215 220 Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser
Lys Tyr Gly Pro 225 230 235 240 Pro Cys Pro Ser Cys Pro Ala Pro Glu
Phe Leu Gly Gly Pro Ser Val 245 250 255 Phe Leu Phe Pro Pro Lys Pro
Lys Asp Thr Leu Met Ile Ser Arg Thr 260 265 270 Pro Glu Val Thr Cys
Val Val Val Asp Val Ser Gln Glu Asp Pro Glu 275 280 285 Val Gln Phe
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys 290 295 300 Thr
Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser 305 310
315 320 Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
Lys 325 330 335 Cys Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
Lys Thr Ile 340 345 350 Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln
Val Tyr Thr Leu Pro 355 360 365 Pro Ser Gln Glu Glu Met Thr Lys Asn
Gln Val Ser Leu Thr Cys Leu 370 375 380 Val Lys Gly Phe Tyr Pro Ser
Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390 395 400 Gly Gln Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser 405 410 415 Asp Gly
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg 420 425 430
Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu 435
440 445 His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460 <210> SEQ ID NO 19 <400> SEQUENCE: 19 000
<210> SEQ ID NO 20 <211> LENGTH: 236 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 20 Met
Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10
15 Phe Pro Gly Ser Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30 Val Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser 35 40 45 Gln Asp Ile Ser Ser Trp Leu Ala Trp Tyr Gln Arg
Lys Pro Gly Lys 50 55 60 Ala Pro Lys Leu Gln Ile Tyr Ala Ala Ser
Ser Leu Glu Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Asn Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Ser 85 90 95 Ile Ser Ser Leu Gln Pro
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 100 105 110 Thr Asn Ser Phe
Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile 115 120 125 Lys Arg
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145
150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys
Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser
Phe Asn Arg Gly Glu Cys 225 230 235 <210> SEQ ID NO 21
<400> SEQUENCE: 21 000 <210> SEQ ID NO 22 <211>
LENGTH: 464 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 22 Met Glu Trp Thr Trp Ser Phe Leu
Phe Leu Val Ala Ala Ala Thr Gly 1 5 10 15 Ala His Ser Gln Val Gln
Leu Val Gln Ser Gly Ala Glu Val Lys Lys 20 25 30 Pro Gly Ala Ser
Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe 35 40 45 Thr Ser
Tyr Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu 50 55 60
Glu Trp Met Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala 65
70 75 80 Gln Lys Leu Gln Asp Arg Val Thr Met Thr Thr Asp Thr Ser
Thr Thr 85 90 95 Thr Ala Tyr Met Glu Leu Arg Ser Leu Arg Ser Asp
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Arg Ala Tyr Gly Ala
Asn Phe Phe Asp Tyr Trp 115 120 125 Gly Gln Gly Thr Leu Val Thr Val
Ser Ser Ala Ser Thr Lys Gly Pro 130 135 140 Ser Val Phe Pro Leu Ala
Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr 145 150 155 160 Ala Ala Leu
Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr 165 170 175 Val
Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro 180 185
190 Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr
195 200 205 Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn
Val Asp 210 215 220 His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr Val
Glu Arg Lys Cys 225 230 235 240 Cys Val Glu Cys Pro Pro Cys Pro Ala
Pro Pro Val Ala Gly Pro Ser 245 250 255 Val Phe Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met Ile Ser Arg 260 265 270 Thr Pro Glu Val Thr
Cys Val Val Val Asp Val Ser His Glu Asp Pro 275 280 285 Glu Val Gln
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 290 295 300 Lys
Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val 305 310
315 320 Ser Val Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu
Tyr 325 330 335 Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile
Glu Lys Thr 340 345 350 Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu 355 360 365 Pro Pro Ser Arg Glu Glu Met Thr Lys
Asn Gln Val Ser Leu Thr Cys 370 375 380 Leu Val Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser 385 390 395 400 Asn Gly Gln Pro
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp 405 410 415 Ser Asp
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 420 425 430
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 435
440 445 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
Lys 450 455 460 <210> SEQ ID NO 23 <400> SEQUENCE: 23
000 <210> SEQ ID NO 24 <211> LENGTH: 240 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
24 Met Val Leu Gln Thr Gln Val Phe Ile Ser Leu Leu Leu Trp Ile Ser
1 5 10 15 Gly Ala Tyr Gly Asp Ile Val Met Thr Gln Ser Pro Asp Ser
Leu Ala 20 25 30 Val Ser Leu Gly Glu Arg Ala Thr Ile Asn Cys Lys
Ser Ser Gln Ser 35 40 45 Ile Leu Phe Phe Ser Asn Asn Lys Asn Tyr
Leu Ala Trp Tyr Arg Gln 50 55 60 Lys Pro Gly Gln Pro Pro Asn Leu
Leu Ile Tyr Trp Ala Ser Thr Arg 65 70 75 80 Glu Ser Gly Val Pro Asp
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp 85 90 95 Phe Thr Leu Thr
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr 100 105 110 Tyr Cys
Gln Gln Tyr Tyr Ser Ser Pro Trp Thr Phe Gly Gln Gly Thr 115 120 125
Lys Val Glu Ile Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe 130
135 140 Pro Pro Ser Asp Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val
Cys 145 150 155 160 Leu Leu Asn Asn Phe Tyr Pro Arg Glu Ala Lys Val
Gln Trp Lys Val 165 170 175 Asp Asn Ala Leu Gln Ser Gly Asn Ser Gln
Glu Ser Val Thr Glu Gln 180 185 190 Asp Ser Lys Asp Ser Thr Tyr Ser
Leu Ser Ser Thr Leu Thr Leu Ser 195 200 205 Lys Ala Asp Tyr Glu Lys
His Lys Val Tyr Ala Cys Glu Val Thr His 210 215 220 Gln Gly Leu Ser
Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 240
<210> SEQ ID NO 25 <211> LENGTH: 1380 <212> TYPE:
DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 25
atggagtttg ggctgagctg ggttttcctt gttgctatta taaaaggtgt ccagtgtcag
60 gtgcagctgg tggagtctgg gggaggcttg gtcaagcctg gagggtccct
gagactctcc 120 tgtgcagcct ctggattcac cttcagtgac tactatatga
gctggatccg ccaggctcca 180 gggaagggac tggagtgggt ttcatacatt
agtagtagtg gtagtaccat atactacgca 240 gactctgtga agggccgatt
caccatctcc agggacaacg ccaagaactc actgtatctg 300 caaatgaaca
gcctgagagc cgaggacacg gccgtgtatt actgtgcgag aggcctaact 360
ggggactact ggggccaggg aaccctggtc accgtctcct cagcttccac caagggccca
420 tccgtcttcc ccctggcgcc ctgctctaga agcacctccg agagcacagc
ggccctgggc 480 tgcctggtca aggactactt ccccgaaccg gtgacggtgt
cgtggaactc aggcgctctg 540 accagcggcg tgcacacctt cccagctgtc
ctacagtcct caggactcta ctccctcagc 600 agcgtggtga ccgtgccctc
cagcaacttc ggcacccaga cctacacctg caacgtagat 660 cacaagccca
gcaacaccaa ggtggacaag acagttgagc gcaaatgttg tgtcgagtgc 720
ccaccgtgcc cagcaccacc tgtggcagga ccgtcagtct tcctcttccc cccaaaaccc
780 aaggacaccc tcatgatctc ccggacccct gaggtcacgt gcgtggtggt
ggacgtgagc 840 cacgaagacc ccgaggtcca gttcaactgg tacgtggacg
gcgtggaggt gcataatgcc 900 aagacaaagc cacgggagga gcagttcaac
agcacgttcc gtgtggtcag cgtcctcacc 960 gttgtgcacc aggactggct
gaacggcaag gagtacaagt gcaaggtctc caacaaaggc 1020 ctcccagccc
ccatcgagaa aaccatctcc aaaaccaaag ggcagccccg agaaccacag 1080
gtgtacaccc tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc
1140 ctggtcaaag gcttctaccc cagcgacatc gccgtggagt gggagagcaa
tgggcagccg 1200 gagaacaact acaagaccac acctcccatg ctggactccg
acggctcctt cttcctctac 1260 agcaagctca ccgtggacaa gagcaggtgg
cagcagggga acgtcttctc atgctccgtg 1320 atgcatgagg ctctgcacaa
ccactacacg cagaagagcc tctccctgtc tccgggtaaa 1380 <210> SEQ ID
NO 26 <211> LENGTH: 460 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 26 Met Glu Phe Gly Leu
Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40
45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr
Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Thr
Gly Asp Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys
Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170
175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
Ser Ser 195 200 205 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp
His Lys Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Thr Val Glu Arg
Lys Cys Cys Val Glu Cys 225 230 235 240 Pro Pro Cys Pro Ala Pro Pro
Val Ala Gly Pro Ser Val Phe Leu Phe 245 250 255 Pro Pro Lys Pro Lys
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 260 265 270 Thr Cys Val
Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe 275 280 285 Asn
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 290 295
300 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr
305 310 315 320 Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
Cys Lys Val 325 330 335 Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys
Thr Ile Ser Lys Thr 340 345 350 Lys Gly Gln Pro Arg Glu Pro Gln Val
Tyr Thr Leu Pro Pro Ser Arg 355 360 365 Glu Glu Met Thr Lys Asn Gln
Val Ser Leu Thr Cys Leu Val Lys Gly 370 375 380 Phe Tyr Pro Ser Asp
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 385 390 395 400 Glu Asn
Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 405 410 415
Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 420
425 430 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
His 435 440 445 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450
455 460 <210> SEQ ID NO 27 <211> LENGTH: 708
<212> TYPE: DNA <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 27 atggacatga gggtccccgc tcagctcctg
gggctcctgc tactctggct ccgaggtgcc 60 agatgtgaca tccagatgac
ccagtctcca tcctccctgt ctgcatctgt cggagacaga 120 gtcaccatca
cttgccggcc aagtcagatc attagcagtt tattaaattg gtatcagcag 180
aaaccaggga aagcccctaa gctcctgatc catgctgcat ccagtttgca aagtggggtc
240 ccatcaaggt tcagtggcag tggatctggg acagatttca ctctcaccat
cagtagtctg 300 caacctgaag attttgcaac ttactactgt caacagagtt
acagtacccc attcactttc 360 ggccctggga ccaaagtgga tatcaaacga
actgtggctg caccatctgt cttcatcttc 420 ccgccatctg atgagcagtt
gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480 ttctatccca
gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc
600 ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga
agtcacccat 660 cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt
708 <210> SEQ ID NO 28 <211> LENGTH: 236 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
28 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro
Ser Ser 20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
Cys Arg Pro Ser 35 40 45 Gln Ile Ile Ser Ser Leu Leu Asn Trp Tyr
Gln Gln Lys Pro Gly Lys 50 55 60 Ala Pro Lys Leu Leu Ile His Ala
Ala Ser Ser Leu Gln Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly
Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 100 105 110 Ser Tyr
Ser Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130
135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr
Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> SEQ ID NO
29 <211> LENGTH: 1398 <212> TYPE: DNA <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 29 atggagttgg
ggctgtgctg ggttttcctt gttgctattt tagaaggtgt ccagtgtgag 60
gtgcagctgg tggagtctgg gggaggcttg gtacagcctg gggggtccct gagactctcc
120 tgtgcagcct ctggattcac cttcagtagt tttagtatga cctgggtccg
ccaggctcca 180 ggaaaggggc tggagtgggt ttcatacatt agtagtagaa
gtagtaccat atcctacgca 240 gactctgtga agggccgatt caccatctcc
agagacaatg ccaagaactc actgtatctg 300 caaatgaaca gcctgagaga
cgaggacacg gctgtgtatt actgtgcgag agatcctctt 360 ctagcgggag
ctaccttctt tgactactgg ggccagggaa ccctggtcac cgtctcctca 420
gcctccacca agggcccatc ggtcttcccc ctggcgccct gctccaggag cacctccgag
480 agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt
gacggtgtcg 540 tggaactcag gcgctctgac cagcggcgtg cacaccttcc
cagctgtcct acagtcctca 600 ggactctact ccctcagcag cgtggtgacc
gtgccctcca gcaacttcgg cacccagacc 660 tacacctgca acgtagatca
caagcccagc aacaccaagg tggacaagac agttgagcgc 720 aaatgttgtg
tcgagtgccc accgtgccca gcaccacctg tggcaggacc gtcagtcttc 780
ctcttccccc caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc
840 gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta
cgtggacggc 900 gtggaggtgc ataatgccaa gacaaagcca cgggaggagc
agttcaacag cacgttccgt 960 gtggtcagcg tcctcaccgt tgtgcaccag
gactggctga acggcaagga gtacaagtgc 1020 aaggtctcca acaaaggcct
cccagccccc atcgagaaaa ccatctccaa aaccaaaggg 1080 cagccccgag
aaccacaggt gtacaccctg cccccatccc gggaggagat gaccaagaac 1140
caggtcagcc tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg
1200 gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct
ggactccgac 1260 ggctccttct tcctctacag caagctcacc gtggacaaga
gcaggtggca gcaggggaac 1320 gtcttctcat gctccgtgat gcatgaggct
ctgcacaacc actacacgca gaagagcctc 1380 tccctgtctc cgggtaaa 1398
<210> SEQ ID NO 30 <211> LENGTH: 466 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 30 Met
Glu Leu Gly Leu Cys Trp Val Phe Leu Val Ala Ile Leu Glu Gly 1 5 10
15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe 35 40 45 Ser Ser Phe Ser Met Thr Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Arg Ser
Ser Thr Ile Ser Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met
Asn Ser Leu Arg Asp Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala
Arg Asp Pro Leu Leu Ala Gly Ala Thr Phe Phe Asp 115 120 125 Tyr Trp
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145
150 155 160 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Asn Phe
Gly Thr Gln Thr Tyr Thr Cys Asn 210 215 220 Val Asp His Lys Pro Ser
Asn Thr Lys Val Asp Lys Thr Val Glu Arg 225 230 235 240 Lys Cys Cys
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly 245 250 255 Pro
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265
270 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
Val His 290 295 300 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
Ser Thr Phe Arg 305 310 315 320 Val Val Ser Val Leu Thr Val Val His
Gln Asp Trp Leu Asn Gly Lys 325 330 335 Glu Tyr Lys Cys Lys Val Ser
Asn Lys Gly Leu Pro Ala Pro Ile Glu 340 345 350 Lys Thr Ile Ser Lys
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365 Thr Leu Pro
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 370 375 380 Thr
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 385 390
395 400 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
Met 405 410 415 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
Thr Val Asp 420 425 430 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
Cys Ser Val Met His 435 440 445 Glu Ala Leu His Asn His Tyr Thr Gln
Lys Ser Leu Ser Leu Ser Pro 450 455 460 Gly Lys 465 <210> SEQ
ID NO 31 <211> LENGTH: 705 <212> TYPE: DNA <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 31 atggaaaccc
cagcgcagct tctcttcctc ctgctactct ggctcccaga taccaccgga 60
gaatttgtgt tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc
120 ctctcctgca gggccagtca gagtgttagc agcagttact tagcctggta
ccagcagaaa 180 cctggccagg ctcccaggct cctcatctat ggtgcatcca
gcagggccac tggcatccca 240 gacaggttca gtggcagtgg gtctgggaca
gacttcactc tcaccatcag cagactggag 300 cctgaagatt ttgcagtgta
ttactgtcag cagtatggta gctcacctct cactttcggc 360 ggagggacca
aggtggagat caaacgaact gtggctgcac catctgtctt catcttcccg 420
ccatctgatg agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc
480 tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc
gggtaactcc 540 caggagagtg tcacagagca ggacagcaag gacagcacct
acagcctcag cagcaccctg 600 acgctgagca aagcagacta cgagaaacac
aaagtctacg cctgcgaagt cacccatcag 660 ggcctgagct cgcccgtcac
aaagagcttc aacaggggag agtgt 705 <210> SEQ ID NO 32
<211> LENGTH: 235 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 32 Met Glu Thr Pro Ala Gln Leu
Leu Phe Leu Leu Leu Leu Trp Leu Pro 1 5 10 15 Asp Thr Thr Gly Glu
Phe Val Leu Thr Gln Ser Pro Gly Thr Leu Ser 20 25 30 Leu Ser Pro
Gly Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser 35 40 45 Val
Ser Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala 50 55
60 Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro
65 70 75 80 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile 85 90 95 Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
Cys Gln Gln Tyr 100 105 110 Gly Ser Ser Pro Leu Thr Phe Gly Gly Gly
Thr Lys Val Glu Ile Lys 115 120 125 Arg Thr Val Ala Ala Pro Ser Val
Phe Ile Phe Pro Pro Ser Asp Glu 130 135 140 Gln Leu Lys Ser Gly Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe 145 150 155 160 Tyr Pro Arg
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 165 170 175 Ser
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 180 185
190 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
Ser Ser 210 215 220 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225
230 235 <210> SEQ ID NO 33 <211> LENGTH: 1383
<212> TYPE: DNA <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 33 atggagtttg ggctgagctg ggttttcctt
gttgctatta taaaaggtgt ccagtgtcag 60 gtgcagctgg tggagtctgg
gggaggcttg gtcaagcctg gagggtccct gagactctcc 120 tgtgcagcct
ctggattcac cttcagtgac tactacatga gctggatccg ccaggctcca 180
gggaaggggc tggagtgggt ttcatacatt agtagtagtg gtagtaccat atactacgca
240 gactctgtga agggccgatt caccatctcc agggacaacg ccaagaattc
actgtatctg 300 caaatgaaca gcctgagagc cgaggacacg gccgtgtatt
actgtgcgag gcgtatagga 360 ggtatggacg tctggggcca agggaccacg
gtcaccgtct cctcagcttc caccaagggc 420 ccatccgtct tccccctggc
gccctgctct agaagcacct ccgagagcac agcggccctg 480 ggctgcctgg
tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgct 540
ctgaccagcg gcgtgcacac cttcccagct gtcctacagt cctcaggact ctactccctc
600 agcagcgtgg tgaccgtgcc ctccagcaac ttcggcaccc agacctacac
ctgcaacgta 660 gatcacaagc ccagcaacac caaggtggac aagacagttg
agcgcaaatg ttgtgtcgag 720 tgcccaccgt gcccagcacc acctgtggca
ggaccgtcag tcttcctctt ccccccaaaa 780 cccaaggaca ccctcatgat
ctcccggacc cctgaggtca cgtgcgtggt ggtggacgtg 840 agccacgaag
accccgaggt ccagttcaac tggtacgtgg acggcgtgga ggtgcataat 900
gccaagacaa agccacggga ggagcagttc aacagcacgt tccgtgtggt cagcgtcctc
960 accgttgtgc accaggactg gctgaacggc aaggagtaca agtgcaaggt
ctccaacaaa 1020 ggcctcccag cccccatcga gaaaaccatc tccaaaacca
aagggcagcc ccgagaacca 1080 caggtgtaca ccctgccccc atcccgggag
gagatgacca agaaccaggt cagcctgacc 1140 tgcctggtca aaggcttcta
ccccagcgac atcgccgtgg agtgggagag caatgggcag 1200 ccggagaaca
actacaagac cacacctccc atgctggact ccgacggctc cttcttcctc 1260
tacagcaagc tcaccgtgga caagagcagg tggcagcagg ggaacgtctt ctcatgctcc
1320 gtgatgcatg aggctctgca caaccactac acgcagaaga gcctctccct
gtctccgggt 1380 aaa 1383 <210> SEQ ID NO 34 <211>
LENGTH: 461 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 34 Met Glu Phe Gly Leu Ser Trp Val
Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val Gln
Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp
Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60
Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala 65
70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Arg Ile Gly Gly Met
Asp Val Trp Gly Gln Gly 115 120 125 Thr Thr Val Thr Val Ser Ser Ala
Ser Thr Lys Gly Pro Ser Val Phe 130 135 140 Pro Leu Ala Pro Cys Ser
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 145 150 155 160 Gly Cys Leu
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175 Asn
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185
190 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
195 200 205 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
Lys Pro 210 215 220 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
Cys Cys Val Glu 225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Pro Val
Ala Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp
Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val
Val Asp Val Ser His Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 305 310
315 320 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr
Ile Ser Lys 340 345 350 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
Thr Leu Pro Pro Ser 355 360 365 Arg Glu Glu Met Thr Lys Asn Gln Val
Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile
Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 405 410 415 Ser Phe
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435
440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455
460 <210> SEQ ID NO 35 <211> LENGTH: 708 <212>
TYPE: DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE:
35 atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct
ccgaggtgcc 60 agatgtgaca tccagatgac ccagtctcca tcctccctgt
ctgcatctgt aggagacaga 120 gtcaccatca cttgccgggc aagtcagagc
attagcggct ttttaatttg gtatcagcag 180 agaccaggga aagcccctaa
gctcctgatc tatgctacat ccagtttaca aagtggggtc 240 ccatcaaggt
tcagtggcag tggatctggg acagatttca ctctcaccat cagcagtctg 300
caacctgaag attttgcaac ttactactgt caacagagtt acagtacccc attcactttc
360 ggccctggga ccaaagtgga tatcaaacga actgtggctg caccatctgt
cttcatcttc 420 ccgccatctg atgagcagtt gaaatctgga actgcctctg
ttgtgtgcct gctgaataac 480 ttctatccca gagaggccaa agtacagtgg
aaggtggata acgccctcca atcgggtaac 540 tcccaggaga gtgtcacaga
gcaggacagc aaggacagca cctacagcct cagcagcacc 600 ctgacgctga
gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660
cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 708
<210> SEQ ID NO 36 <211> LENGTH: 236 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 36 Met
Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10
15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser 35 40 45 Gln Ser Ile Ser Gly Phe Leu Ile Trp Tyr Gln Gln
Arg Pro Gly Lys 50 55 60 Ala Pro Lys Leu Leu Ile Tyr Ala Thr Ser
Ser Leu Gln Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 100 105 110 Ser Tyr Ser Thr
Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 115 120 125 Lys Arg
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145
150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys
Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser
Phe Asn Arg Gly Glu Cys 225 230 235 <210> SEQ ID NO 37
<211> LENGTH: 1383 <212> TYPE: DNA <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 37 atggagtttg
ggctgagctg ggttttcctt gttgctatta taaaaggtgt ccagtgtcag 60
gtgcagctgg tggagtctgg gggaggcttg gtcaagcctg gagggtccct gagactctcc
120 tgtgcagcct ctggattcac cttcagtgac tactatatga gctggatccg
ccaggctcca 180 gggaagggac tggagtgggt ttcatacatt agtagtagtg
gtagtaccat atactacgca 240 gactctgtga agggccgatt caccatctcc
agggacaacg ccaagaactc actgtatctg 300 caaatgaaca gcctgagagc
cgaggacacg gccgtgtatt actgtgcgag aggcctaact 360 ggggactact
ggggccaggg aaccctggtc accgtctcct cagcttccac caagggccca 420
tccgtcttcc ccctggcgcc ctgctctaga agcacctccg agagcacagc ggccctgggc
480 tgcctggtca aggactactt ccccgaaccg gtgacggtgt cgtggaactc
aggcgctctg 540 accagcggcg tgcacacctt cccagctgtc ctacagtcct
caggactcta ctccctcagc 600 agcgtggtga ccgtgccctc cagcagcttg
ggcacgaaga cctacacctg caacgtagat 660 cacaagccca gcaacaccaa
ggtggacaag agagttgagt ccaaatatgg tcccccatgc 720 ccatcatgcc
cagcacctga gttcctgggg ggaccatcag tcttcctgtt ccccccaaaa 780
cccaaggaca ctctcatgat ctcccggacc cctgaggtca cgtgcgtggt ggtggacgtg
840 agccaggaag accccgaggt ccagttcaac tggtacgtgg atggcgtgga
ggtgcataat 900 gccaagacaa agccgcggga ggagcagttc aacagcacgt
accgtgtggt cagcgtcctc 960 accgtcctgc accaggactg gctgaacggc
aaggagtaca agtgcaaggt ctccaacaaa 1020 ggcctcccgt cctccatcga
gaaaaccatc tccaaagcca aagggcagcc ccgagagcca 1080 caggtgtaca
ccctgccccc atcccaggag gagatgacca agaaccaggt cagcctgacc 1140
tgcctggtca aaggcttcta ccccagcgac atcgccgtgg agtgggagag caatgggcag
1200 ccggagaaca actacaagac cacgcctccc gtgctggact ccgacggctc
cttcttcctc 1260 tacagcaggc taaccgtgga caagagcagg tggcaggagg
ggaatgtctt ctcatgctcc 1320 gtgatgcatg aggctctgca caaccactac
acacagaaga gcctctccct gtctccgggt 1380 aaa 1383 <210> SEQ ID
NO 38 <211> LENGTH: 461 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 38 Met Glu Phe Gly Leu
Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40
45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr
Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Thr
Gly Asp Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser
Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys
Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys
Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170
175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln
180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro
Ser Ser 195 200 205 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp
His Lys Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Arg Val Glu Ser
Lys Tyr Gly Pro Pro Cys 225 230 235 240 Pro Ser Cys Pro Ala Pro Glu
Phe Leu Gly Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro
Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys
Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 275 280 285 Phe
Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295
300 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu
305 310 315 320 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr
Lys Cys Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu
Lys Thr Ile Ser Lys 340 345 350 Ala Lys Gly Gln Pro Arg Glu Pro Gln
Val Tyr Thr Leu Pro Pro Ser 355 360 365 Gln Glu Glu Met Thr Lys Asn
Gln Val Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser
Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu
Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 405 410 415
Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 420
425 430 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His
Asn 435 440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys
450 455 460 <210> SEQ ID NO 39 <400> SEQUENCE: 39 000
<210> SEQ ID NO 40 <400> SEQUENCE: 40 000 <210>
SEQ ID NO 41 <400> SEQUENCE: 41 000 <210> SEQ ID NO 42
<400> SEQUENCE: 42 000 <210> SEQ ID NO 43 <211>
LENGTH: 705 <212> TYPE: DNA <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 43 atggaaaccc cagcgcagct tctcttcctc
ctgctactct ggctcccaga taccaccgga 60 gaatttgtgt tgacgcagtc
tccaggcacc ctgtctttgt ctccagggga aagagccacc 120 ctctcctgca
gggccagtca gagtgttagc agcagttact tagcctggta ccagcagaaa 180
cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca
240 gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag
cagactggag 300 cctgaagatt ttgtagtgta ttactgtcag cagtatggta
gctcacctct cactttcggc 360 ggagggacca aggtggagat caaacgaact
gtggctgcac catctgtctt catcttcccg 420 ccatctgatg agcagttgaa
atctggaact gcctctgttg tgtgcctgct gaataacttc 480 tatcccagag
aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg
600 acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt
cacccatcag 660 ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt
705 <210> SEQ ID NO 44 <211> LENGTH: 235 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
44 Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15 Asp Thr Thr Gly Glu Phe Val Leu Thr Gln Ser Pro Gly Thr
Leu Ser 20 25 30 Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Ser 35 40 45 Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala 50 55 60 Pro Arg Leu Leu Ile Tyr Gly Ala
Ser Ser Arg Ala Thr Gly Ile Pro 65 70 75 80 Asp Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 85 90 95 Ser Arg Leu Glu
Pro Glu Asp Phe Val Val Tyr Tyr Cys Gln Gln Tyr 100 105 110 Gly Ser
Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 130
135 140 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
Phe 145 150 155 160 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln 165 170 175 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp Ser 180 185 190 Thr Tyr Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr Glu 195 200 205 Lys His Lys Val Tyr Ala
Cys Glu Val Thr His Gln Gly Leu Ser Ser 210 215 220 Pro Val Thr Lys
Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> SEQ ID NO 45
<211> LENGTH: 1386 <212> TYPE: DNA <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 45 atggagtttg
ggctgagctg ggttttcctt gttgctatta taaaaggtgt ccagtgtcag 60
gtgcagctgg tggagtctgg gggaggcttg gtcaagcctg gagggtccct gagactctcc
120 tgtgcagcct ctggattcac cttcagtgac tactacatga gctggatccg
ccaggctcca 180 gggaaggggc tggagtgggt ttcatacatt agtagtagtg
gtagtaccat atactacgca 240 gactctgtga agggccgatt caccatctcc
agggacaacg ccaagaattc actgtatctg 300 caaatgaaca gcctgagagc
cgaggacacg gccgtgtatt actgtgcgag gcgtatagga 360 ggtatggacg
tctggggcca agggaccacg gtcaccgtct cctcagcttc caccaagggc 420
ccatccgtct tccccctggc gccctgctct agaagcacct ccgagagcac agcggccctg
480 ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa
ctcaggcgct 540 ctgaccagcg gcgtgcacac cttcccagct gtcctacagt
cctcaggact ctactccctc 600 agcagcgtgg tgaccgtgcc ctccagcagc
ttgggcacga agacctacac ctgcaacgta 660 gatcacaagc ccagcaacac
caaggtggac aagagagttg agtccaaata tggtccccca 720 tgcccatcat
gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 780
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac
840 gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt
ggaggtgcat 900 aatgccaaga caaagccgcg ggaggagcag ttcaacagca
cgtaccgtgt ggtcagcgtc 960 ctcaccgtcc tgcaccagga ctggctgaac
ggcaaggagt acaagtgcaa ggtctccaac 1020 aaaggcctcc cgtcctccat
cgagaaaacc atctccaaag ccaaagggca gccccgagag 1080 ccacaggtgt
acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 1140
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg
1200 cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg
ctccttcttc 1260 ctctacagca ggctaaccgt ggacaagagc aggtggcagg
aggggaatgt cttctcatgc 1320 tccgtgatgc atgaggctct gcacaaccac
tacacacaga agagcctctc cctgtctccg 1380 ggtaaa 1386 <210> SEQ
ID NO 46 <211> LENGTH: 462 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 46 Met Glu Phe Gly Leu
Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40
45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr
Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Arg Ile Gly
Gly Met Asp Val Trp Gly Gln Gly 115 120 125 Thr Thr Val Thr Val Ser
Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 130 135 140 Pro Leu Ala Pro
Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 145 150 155 160 Gly
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170
175 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu
180 185 190 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val
Pro Ser 195 200 205 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val
Asp His Lys Pro 210 215 220 Ser Asn Thr Lys Val Asp Lys Arg Val Glu
Ser Lys Tyr Gly Pro Pro 225 230 235 240 Cys Pro Ser Cys Pro Ala Pro
Glu Phe Leu Gly Gly Pro Ser Val Phe 245 250 255 Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro 260 265 270 Glu Val Thr
Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 275 280 285 Gln
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 290 295
300 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val
305 310 315 320 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
Tyr Lys Cys 325 330 335 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile
Glu Lys Thr Ile Ser 340 345 350 Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu Pro Pro 355 360 365 Ser Gln Glu Glu Met Thr Lys
Asn Gln Val Ser Leu Thr Cys Leu Val 370 375 380 Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly 385 390 395 400 Gln Pro
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 405 410 415
Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 420
425 430 Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu
His 435 440 445 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
Lys 450 455 460 <210> SEQ ID NO 47 <211> LENGTH: 708
<212> TYPE: DNA <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 47 atggacatga gggtccccgc tcagctcctg
gggctcctgc tactctggct ccgaggtgcc 60 agatgtgaca tccagatgac
ccagtctcca tcctccctgt ctgcatctgt aggagacaga 120 gtcaccatca
cttgccgggc aagtcagagc attagcggct ttttaatttg gtatcagcag 180
agaccaggga aagcccctaa gctcctgatc tatgctacat ccagtttaca aagtggggtc
240 ccattaaggt tcagtggcag tgaatctggg acagatttca ctctcaccat
cagcagtctg 300 caacctgaag attttgcaac ttactactgt caacagagtt
acagtacccc attcactttc 360 ggccctggga ccaaagtgga tatcaaacga
actgtggctg caccatctgt cttcatcttc 420 ccgccatctg atgagcagtt
gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480 ttctatccca
gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac 540
tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct cagcagcacc
600 ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct acgcctgcga
agtcacccat 660 cagggcctga gctcgcccgt cacaaagagc ttcaacaggg gagagtgt
708 <210> SEQ ID NO 48 <211> LENGTH: 236 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
48 Met Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp
1 5 10 15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro
Ser Ser 20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr
Cys Arg Ala Ser 35 40 45 Gln Ser Ile Ser Gly Phe Leu Ile Trp Tyr
Gln Gln Arg Pro Gly Lys 50 55 60 Ala Pro Lys Leu Leu Ile Tyr Ala
Thr Ser Ser Leu Gln Ser Gly Val 65 70 75 80 Pro Leu Arg Phe Ser Gly
Ser Glu Ser Gly Thr Asp Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu
Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 100 105 110 Ser Tyr
Ser Thr Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 115 120 125
Lys Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130
135 140 Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn
Asn 145 150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val
Asp Asn Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr
Glu Gln Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr
Leu Thr Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr
Ala Cys Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr
Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> SEQ ID NO
49 <400> SEQUENCE: 49 000 <210> SEQ ID NO 50
<211> LENGTH: 462 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 50 Met Glu Phe Gly Leu Ser Trp
Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Ile Arg Ile Gly Gly Met
Asp Val Trp Gly Gln Gly 115 120 125 Thr Thr Val Thr Val Ser Ser Ala
Ser Thr Lys Gly Pro Ser Val Phe 130 135 140 Pro Leu Ala Pro Cys Ser
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 145 150 155 160 Gly Cys Leu
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175 Asn
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185
190 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
195 200 205 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
Lys Pro 210 215 220 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
Tyr Gly Pro Pro 225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Glu Phe
Leu Gly Gly Pro Ser Val Phe 245 250 255 Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met Ile Ser Arg Thr Pro 260 265 270 Glu Val Thr Cys Val
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 275 280 285 Gln Phe Asn
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 290 295 300 Lys
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 305 310
315 320 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
Cys 325 330 335 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
Thr Ile Ser 340 345 350 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
Tyr Thr Leu Pro Pro 355 360 365 Ser Gln Glu Glu Met Thr Lys Asn Gln
Val Ser Leu Thr Cys Leu Val 370 375 380 Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu Trp Glu Ser Asn Gly 385 390 395 400 Gln Pro Glu Asn
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 405 410 415 Gly Ser
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 420 425 430
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 435
440 445 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450
455 460 <210> SEQ ID NO 51 <400> SEQUENCE: 51 000
<210> SEQ ID NO 52 <211> LENGTH: 236 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 52 Met
Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10
15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser 35 40 45 Gln Ser Ile Ser Gly Phe Leu Ile Trp Tyr Gln Gln
Lys Pro Gly Lys 50 55 60 Ala Pro Lys Leu Leu Ile Tyr Ala Thr Ser
Ser Leu Gln Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 100 105 110 Ser Tyr Ser Thr
Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 115 120 125 Lys Arg
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145
150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys
Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser
Phe Asn Arg Gly Glu Cys 225 230 235 <210> SEQ ID NO 53
<400> SEQUENCE: 53 000 <210> SEQ ID NO 54 <211>
LENGTH: 461 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 54 Met Glu Phe Gly Leu Ser Trp Val
Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val Gln
Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp
Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60
Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala 65
70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Thr Gly Asp
Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser
Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys Ser Arg
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185
190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
Gly Pro Pro Cys 225 230 235 240 Pro Pro Cys Pro Ala Pro Glu Phe Leu
Gly Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp
Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 305 310
315 320 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
Ile Ser Lys 340 345 350 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
Thr Leu Pro Pro Ser 355 360 365 Gln Glu Glu Met Thr Lys Asn Gln Val
Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile
Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 405 410 415 Ser Phe
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435
440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455
460 <210> SEQ ID NO 55 <400> SEQUENCE: 55 000
<210> SEQ ID NO 56 <211> LENGTH: 236 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 56 Met
Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10
15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
Pro Ser 35 40 45 Gln Ile Ile Ser Ser Leu Leu Asn Trp Tyr Gln Gln
Lys Pro Gly Lys 50 55 60 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser
Ser Leu Gln Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 100 105 110 Ser Tyr Ser Thr
Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 115 120 125 Lys Arg
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145
150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys
Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser
Phe Asn Arg Gly Glu Cys 225 230 235 <210> SEQ ID NO 57
<400> SEQUENCE: 57 000 <210> SEQ ID NO 58 <211>
LENGTH: 467 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 58 Met Glu Leu Gly Leu Cys Trp Val
Phe Leu Val Ala Ile Leu Glu Gly 1 5 10 15 Val Gln Cys Glu Val Gln
Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser
Phe Ser Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60
Glu Trp Val Ser Tyr Ile Ser Ser Arg Ser Ser Thr Ile Ser Tyr Ala 65
70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Pro Leu Leu Ala
Gly Ala Thr Phe Phe Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val
Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145 150 155 160 Ser Thr Ala
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185
190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr
Cys Asn 210 215 220 Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
Arg Val Glu Ser 225 230 235 240 Lys Tyr Gly Pro Pro Cys Pro Pro Cys
Pro Ala Pro Glu Phe Leu Gly 245 250 255 Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp Thr Leu Met 260 265 270 Ile Ser Arg Thr Pro
Glu Val Thr Cys Val Val Val Asp Val Ser Gln 275 280 285 Glu Asp Pro
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 290 295 300 His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 305 310
315 320 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
Gly 325 330 335 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
Ser Ser Ile 340 345 350 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
Arg Glu Pro Gln Val 355 360 365 Tyr Thr Leu Pro Pro Ser Gln Glu Glu
Met Thr Lys Asn Gln Val Ser 370 375 380 Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp Ile Ala Val Glu 385 390 395 400 Trp Glu Ser Asn
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 405 410 415 Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 420 425 430
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 435
440 445 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
Ser 450 455 460 Pro Gly Lys 465 <210> SEQ ID NO 59
<400> SEQUENCE: 59 000 <210> SEQ ID NO 60 <211>
LENGTH: 235 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 60 Met Glu Thr Pro Ala Gln Leu Leu
Phe Leu Leu Leu Leu Trp Leu Pro 1 5 10 15 Asp Thr Thr Gly Glu Ile
Val Leu Thr Gln Ser Pro Gly Thr Leu Ser 20 25 30 Leu Ser Pro Gly
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser 35 40 45 Val Ser
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala 50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro 65
70 75 80 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile 85 90 95 Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
Cys Gln Gln Tyr 100 105 110 Gly Ser Ser Pro Leu Thr Phe Gly Gly Gly
Thr Lys Val Glu Ile Lys 115 120 125 Arg Thr Val Ala Ala Pro Ser Val
Phe Ile Phe Pro Pro Ser Asp Glu 130 135 140 Gln Leu Lys Ser Gly Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe 145 150 155 160 Tyr Pro Arg
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 165 170 175 Ser
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 180 185
190 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
Ser Ser 210 215 220 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225
230 235 <210> SEQ ID NO 61 <400> SEQUENCE: 61 000
<210> SEQ ID NO 62 <211> LENGTH: 466 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 62 Met
Glu Leu Gly Leu Cys Trp Val Phe Leu Val Ala Ile Leu Glu Gly 1 5 10
15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe 35 40 45 Ser Ser Phe Ser Met Thr Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Arg Ser
Ser Thr Ile Ser Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met
Asn Ser Leu Arg Asp Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala
Arg Asp Pro Leu Leu Ala Gly Ala Thr Phe Phe Asp 115 120 125 Tyr Trp
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145
150 155 160 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Asn Phe
Gly Thr Gln Thr Tyr Thr Cys Asn 210 215 220 Val Asp His Lys Pro Ser
Asn Thr Lys Val Asp Lys Thr Val Glu Arg 225 230 235 240 Lys Cys Cys
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly 245 250 255 Pro
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265
270 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
Val His 290 295 300 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
Ser Thr Phe Arg 305 310 315 320 Val Val Ser Val Leu Thr Val Val His
Gln Asp Trp Leu Asn Gly Lys 325 330 335 Glu Tyr Lys Cys Lys Val Ser
Asn Lys Gly Leu Pro Ala Pro Ile Glu 340 345 350 Lys Thr Ile Ser Lys
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365 Thr Leu Pro
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 370 375 380 Thr
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 385 390
395 400 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
Met 405 410 415 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
Thr Val Asp 420 425 430 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
Cys Ser Val Met His 435 440 445 Glu Ala Leu His Asn His Tyr Thr Gln
Lys Ser Leu Ser Leu Ser Pro 450 455 460 Gly Lys 465 <210> SEQ
ID NO 63 <400> SEQUENCE: 63 000 <210> SEQ ID NO 64
<400> SEQUENCE: 64 000 <210> SEQ ID NO 65 <400>
SEQUENCE: 65 000 <210> SEQ ID NO 66 <211> LENGTH: 461
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 66 Met Glu Phe Gly Leu Ser Trp Val Phe Leu
Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val Gln Leu Val
Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser Leu Arg
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp Tyr Tyr
Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp
Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala 65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85
90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
Val 100 105 110 Tyr Tyr Cys Ala Ile Arg Ile Gly Gly Met Asp Val Trp
Gly Gln Gly 115 120 125 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys
Gly Pro Ser Val Phe 130 135 140 Pro Leu Ala Pro Cys Ser Arg Ser Thr
Ser Glu Ser Thr Ala Ala Leu 145 150 155 160 Gly Cys Leu Val Lys Asp
Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175 Asn Ser Gly Ala
Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190 Gln Ser
Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 195 200 205
Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 210
215 220 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val
Glu 225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro
Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val Val Asp Val
Ser His Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro Arg Glu Glu
Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 305 310 315 320 Thr
Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 325 330
335 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys
340 345 350 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
Pro Ser 355 360 365 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro Met Leu Asp Ser Asp Gly 405 410 415 Ser Phe Phe Leu Tyr
Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430 Gln Gly Asn
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435 440 445 His
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460
<210> SEQ ID NO 67 <400> SEQUENCE: 67 000 <210>
SEQ ID NO 68 <400> SEQUENCE: 68 000 <210> SEQ ID NO 69
<400> SEQUENCE: 69 000 <210> SEQ ID NO 70 <211>
LENGTH: 461 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 70 Met Glu Phe Gly Leu Ser Trp Val
Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val Gln
Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp
Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60
Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala 65
70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Ile Gly Gly Met Asp
Val Trp Gly Gln Gly Thr 115 120 125 Thr Val Thr Val Ser Ser Ala Ser
Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys Ser Arg
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185
190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
Gly Pro Pro Cys 225 230 235 240 Pro Ser Cys Pro Ala Pro Glu Phe Leu
Gly Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp
Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 305 310
315 320 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
Ile Ser Lys 340 345 350 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
Thr Leu Pro Pro Ser 355 360 365 Gln Glu Glu Met Thr Lys Asn Gln Val
Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile
Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 405 410 415 Ser Phe
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435
440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455
460 <210> SEQ ID NO 71 <400> SEQUENCE: 71 000
<210> SEQ ID NO 72 <400> SEQUENCE: 72 000 <210>
SEQ ID NO 73 <400> SEQUENCE: 73 000 <210> SEQ ID NO 74
<211> LENGTH: 460 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 74 Met Glu Phe Gly Leu Ser Trp
Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Thr Gly Asp
Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser
Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys Ser Arg
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185
190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys
Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys
Cys Val Glu Cys 225 230 235 240 Pro Pro Cys Pro Ala Pro Pro Val Ala
Gly Pro Ser Val Phe Leu Phe 245 250 255 Pro Pro Lys Pro Lys Asp Thr
Leu Met Ile Ser Arg Thr Pro Glu Val 260 265 270 Thr Cys Val Val Val
Asp Val Ser His Glu Asp Pro Glu Val Gln Phe 275 280 285 Asn Trp Tyr
Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro 290 295 300 Arg
Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr 305 310
315 320 Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys
Val 325 330 335 Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile
Ser Lys Thr 340 345 350 Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr
Leu Pro Pro Ser Arg 355 360 365 Glu Glu Met Thr Lys Asn Gln Val Ser
Leu Thr Cys Leu Val Lys Gly 370 375 380 Phe Tyr Pro Ser Asp Ile Ala
Val Glu Trp Glu Ser Asn Gly Gln Pro 385 390 395 400 Glu Asn Asn Tyr
Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser 405 410 415 Phe Phe
Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln 420 425 430
Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His 435
440 445 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460
<210> SEQ ID NO 75 <400> SEQUENCE: 75 000 <210>
SEQ ID NO 76 <400> SEQUENCE: 76 000 <210> SEQ ID NO 77
<400> SEQUENCE: 77 000 <210> SEQ ID NO 78 <211>
LENGTH: 461 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 78 Met Glu Phe Gly Leu Ser Trp Val
Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val Gln
Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp
Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60
Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala 65
70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Thr Gly Asp
Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser
Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys Ser Arg
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185
190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
Gly Pro Pro Cys 225 230 235 240 Pro Ser Cys Pro Ala Pro Glu Phe Leu
Gly Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp
Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 305 310
315 320 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
Ile Ser Lys 340 345 350 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
Thr Leu Pro Pro Ser 355 360 365 Gln Glu Glu Met Thr Lys Asn Gln Val
Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile
Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 405 410 415 Ser Phe
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435
440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455
460 <210> SEQ ID NO 79 <400> SEQUENCE: 79 000
<210> SEQ ID NO 80 <400> SEQUENCE: 80 000 <210>
SEQ ID NO 81 <400> SEQUENCE: 81 000 <210> SEQ ID NO 82
<211> LENGTH: 461 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 82 Met Glu Phe Gly Leu Ser Trp
Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Thr Gly Asp
Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser
Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys Ser Arg
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185
190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
Gly Pro Pro Cys 225 230 235 240 Pro Pro Cys Pro Ala Pro Glu Phe Leu
Gly Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp
Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 305 310
315 320 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
Ile Ser Lys 340 345 350 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
Thr Leu Pro Pro Ser 355 360 365 Gln Glu Glu Met Thr Lys Asn Gln Val
Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile
Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 405 410 415 Ser Phe
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435
440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455
460 <210> SEQ ID NO 83 <400> SEQUENCE: 83 000
<210> SEQ ID NO 84 <400> SEQUENCE: 84 000 <210>
SEQ ID NO 85 <400> SEQUENCE: 85 000 <210> SEQ ID NO 86
<211> LENGTH: 462 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 86 Met Glu Phe Gly Leu Ser Trp
Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Arg Ile Gly Gly Met
Asp Val Trp Gly Gln Gly 115 120 125 Thr Thr Val Thr Val Ser Ser Ala
Ser Thr Lys Gly Pro Ser Val Phe 130 135 140 Pro Leu Ala Pro Cys Ser
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 145 150 155 160 Gly Cys Leu
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175 Asn
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185
190 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
195 200 205 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
Lys Pro 210 215 220 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
Tyr Gly Pro Pro 225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Glu Phe
Leu Gly Gly Pro Ser Val Phe 245 250 255 Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met Ile Ser Arg Thr Pro 260 265 270 Glu Val Thr Cys Val
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 275 280 285 Gln Phe Asn
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 290 295 300 Lys
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 305 310
315 320 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
Cys 325 330 335 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
Thr Ile Ser 340 345 350 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
Tyr Thr Leu Pro Pro 355 360 365 Ser Gln Glu Glu Met Thr Lys Asn Gln
Val Ser Leu Thr Cys Leu Val 370 375 380 Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu Trp Glu Ser Asn Gly 385 390 395 400 Gln Pro Glu Asn
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 405 410 415 Gly Ser
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 420 425 430
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 435
440 445 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450
455 460 <210> SEQ ID NO 87 <400> SEQUENCE: 87 000
<210> SEQ ID NO 88 <400> SEQUENCE: 88 000 <210>
SEQ ID NO 89 <400> SEQUENCE: 89 000 <210> SEQ ID NO 90
<211> LENGTH: 467 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 90 Met Glu Leu Gly Leu Cys Trp
Val Phe Leu Val Ala Ile Leu Glu Gly 1 5 10 15 Val Gln Cys Glu Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Ser Phe Ser Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Val Ser Tyr Ile Ser Ser Arg Ser Ser Thr Ile Ser Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Pro Leu Leu Ala
Gly Ala Thr Phe Phe Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val
Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145 150 155 160 Ser Thr Ala
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185
190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val
195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr Tyr Thr
Cys Asn 210 215 220 Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys
Arg Val Glu Ser 225 230 235 240 Lys Tyr Gly Pro Pro Cys Pro Pro Cys
Pro Ala Pro Glu Phe Leu Gly 245 250 255 Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp Thr Leu Met 260 265 270 Ile Ser Arg Thr Pro
Glu Val Thr Cys Val Val Val Asp Val Ser Gln 275 280 285 Glu Asp Pro
Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 290 295 300 His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr 305 310
315 320 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn
Gly 325 330 335 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro
Ser Ser Ile 340 345 350 Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
Arg Glu Pro Gln Val 355 360 365 Tyr Thr Leu Pro Pro Ser Gln Glu Glu
Met Thr Lys Asn Gln Val Ser 370 375 380 Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp Ile Ala Val Glu 385 390 395 400 Trp Glu Ser Asn
Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 405 410 415 Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 420 425 430
Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met 435
440 445 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu
Ser 450 455 460 Pro Gly Lys 465 <210> SEQ ID NO 91
<400> SEQUENCE: 91 000 <210> SEQ ID NO 92 <400>
SEQUENCE: 92 000 <210> SEQ ID NO 93 <400> SEQUENCE: 93
000 <210> SEQ ID NO 94 <211> LENGTH: 467 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
94 Met Glu Leu Gly Leu Cys Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe 35 40 45 Ser Ser Phe Ser Met Thr Trp Val Arg Gln
Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser
Arg Ser Ser Thr Ile Ser Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu
Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val 100 105 110 Tyr Tyr
Cys Ala Arg Asp Pro Leu Leu Ala Gly Ala Thr Phe Phe Asp 115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130
135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
Glu 145 150 155 160 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu
Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser
Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser
Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn 210 215 220 Val Asp His Lys
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser 225 230 235 240 Lys
Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly 245 250
255 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
Ser Gln 275 280 285 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
Gly Val Glu Val 290 295 300 His Asn Ala Lys Thr Lys Pro Arg Glu Glu
Gln Phe Asn Ser Thr Tyr 305 310 315 320 Arg Val Val Ser Val Leu Thr
Val Leu His Gln Asp Trp Leu Asn Gly 325 330 335 Lys Glu Tyr Lys Cys
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 340 345 350 Glu Lys Thr
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 355 360 365 Tyr
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 370 375
380 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro 405 410 415 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
Ser Arg Leu Thr Val 420 425 430 Asp Lys Ser Arg Trp Gln Glu Gly Asn
Val Phe Ser Cys Ser Val Met 435 440 445 His Glu Ala Leu His Asn His
Tyr Thr Gln Lys Ser Leu Ser Leu Ser 450 455 460 Pro Gly Lys 465
<210> SEQ ID NO 95 <400> SEQUENCE: 95 000 <210>
SEQ ID NO 96 <400> SEQUENCE: 96 000 <210> SEQ ID NO 97
<211> LENGTH: 1413 <212> TYPE: DNA <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 97 atggagttgg
ggctgagctg ggttttcctt gttgctatta taaaaggtgt ccagtgtgag 60
gtgcagctgg tggagtctgg gggaggcttg gtacagcctg gggggtccct gagactctcc
120 tgtgcagcct ctggattcac cttcagtagt tttagtatga cctgggtccg
ccaggctcca 180 ggaaaggggc tggagtgggt ttcatacatt agtagtagaa
gtagtaccat atcctacgca 240 gactctgtga agggccgatt caccatctcc
agagacaatg ccaagaactc actgtatctg 300 caaatgaaca gcctgagaga
cgaggacacg gctgtgtatt actgtgcgag agatcctctt 360 ctagcgggag
ctaccttctt tgactactgg ggccagggaa ccctggtcac cgtctcctca 420
gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg
480 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt
gacggtgtcg 540 tggaactcag gcgccctgac cagcggcgtg cacaccttcc
cggctgtcct acagtcctca 600 ggactctact ccctcagcag cgtggtgacc
gtgccctcca gcagcttggg cacccagacc 660 tacatctgca acgtgaatca
caagcccagc aacaccaagg tggacaagaa agttgagccc 720 aaatcttgtg
acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 780
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct
840 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa
gttcaactgg 900 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc
cgcgggagga gcagtacaac 960 agcacgtacc gtgtggtcag cgtcctcacc
gtcctgcacc aggactggct gaatggcaag 1020 gagtacaagt gcaaggtctc
caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1080 aaagccaaag
ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1140
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc
1200 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac
gcctcccgtg 1260 ctggactccg acggctcctt cttcctctac agcaagctca
ccgtggacaa gagcaggtgg 1320 cagcagggga acgtcttctc atgctccgtg
atgcatgagg ctctgcacaa ccactacacg 1380 cagaagagcc tctccctgtc
tccgggtaaa tag 1413 <210> SEQ ID NO 98 <211> LENGTH:
470 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 98 Met Glu Leu Gly Leu Cys Trp Val Phe Leu
Val Ala Ile Leu Glu Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val
Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Phe Ser
Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp
Val Ser Tyr Ile Ser Ser Arg Ser Ser Thr Ile Ser Tyr Ala 65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85
90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala
Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Pro Leu Leu Ala Gly Ala Thr
Phe Phe Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro
Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210
215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro
Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330
335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
Leu Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn
Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455
460 Ser Leu Ser Pro Gly Lys 465 470 <210> SEQ ID NO 99
<400> SEQUENCE: 99 000 <210> SEQ ID NO 100 <400>
SEQUENCE: 100 000 <210> SEQ ID NO 101 <211> LENGTH:
1395 <212> TYPE: DNA <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 101 atggagtttg ggctgagctg ggttttcctt
gttgctatta taaaaggtgt ccagtgtcag 60 gtgcagctgg tggagtctgg
gggaggcttg gtcaagcctg gagggtccct gagactctcc 120 tgtgcagcct
ctggattcac cttcagtgac tactatatga gctggatccg ccaggctcca 180
gggaagggac tggagtgggt ttcatacatt agtagtagtg gtagtaccat atactacgca
240 gactctgtga agggccgatt caccatctcc agggacaacg ccaagaactc
actgtatctg 300 caaatgaaca gcctgagagc cgaggacacg gccgtgtatt
actgtgcgag aggcctaact 360 ggggactact ggggccaggg aaccctggtc
accgtctcct cagcttccac caagggccca 420 tcggtcttcc ccctggcacc
ctcctccaag agcacctctg ggggcacagc ggccctgggc 480 tgcctggtca
aggactactt ccccgaaccg gtgacggtgt cgtggaactc aggcgccctg 540
accagcggcg tgcacacctt cccggctgtc ctacagtcct caggactcta ctccctcagc
600 agcgtggtga ccgtgccctc cagcagcttg ggcacccaga cctacatctg
caacgtgaat 660 cacaagccca gcaacaccaa ggtggacaag aaagttgagc
ccaaatcttg tgacaaaact 720 cacacatgcc caccgtgccc agcacctgaa
ctcctggggg gaccgtcagt cttcctcttc 780 cccccaaaac ccaaggacac
cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 840 gtggacgtga
gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 900
gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta ccgtgtggtc
960 agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa
gtgcaaggtc 1020 tccaacaaag ccctcccagc ccccatcgag aaaaccatct
ccaaagccaa agggcagccc 1080 cgagaaccac aggtgtacac cctgccccca
tcccgggatg agctgaccaa gaaccaggtc 1140 agcctgacct gcctggtcaa
aggcttctat cccagcgaca tcgccgtgga gtgggagagc 1200 aatgggcagc
cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1260
ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc
1320 tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag
cctctccctg 1380 tctccgggta aatag 1395 <210> SEQ ID NO 102
<211> LENGTH: 464 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 102 Met Glu Phe Gly Leu Ser Trp
Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Thr Gly Asp
Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser
Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Ser Ser Lys
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185
190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
Cys Asp Lys Thr 225 230 235 240 His Thr Cys Pro Pro Cys Pro Ala Pro
Glu Leu Leu Gly Gly Pro Ser 245 250 255 Val Phe Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met Ile Ser Arg 260 265 270 Thr Pro Glu Val Thr
Cys Val Val Val Asp Val Ser His Glu Asp Pro 275 280 285 Glu Val Lys
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 290 295 300 Lys
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 305 310
315 320 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
Tyr 325 330 335 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu Lys Thr 340 345 350 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu 355 360 365 Pro Pro Ser Arg Asp Glu Leu Thr Lys
Asn Gln Val Ser Leu Thr Cys 370 375 380 Leu Val Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser 385 390 395 400 Asn Gly Gln Pro
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 405 410 415 Ser Asp
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 420 425 430
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 435
440 445 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
Lys 450 455 460 <210> SEQ ID NO 103 <211> LENGTH: 107
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 103 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe 85
90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105
<210> SEQ ID NO 104 <211> LENGTH: 120 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 104
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Tyr Ser Gly
Ser Tyr Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val
Thr Val Ser Ser Ala 115 120 <210> SEQ ID NO 105 <211>
LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 105 Glu Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn
Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65
70 75 80 Leu Gln Met Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys Ala 85 90 95 Arg Gly Ile Ala Ala Ala Gly Tyr Phe Asp Tyr Trp
Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala 115
<210> SEQ ID NO 106 <211> LENGTH: 117 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 106
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Leu Gly
Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val 100 105 110 Thr Val Ser
Ser Ala 115 <210> SEQ ID NO 107 <211> LENGTH: 107
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 107 Glu Ile Val Met Thr Gln Ser Pro Ala Thr
Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser
Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Phe 85
90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105
<210> SEQ ID NO 108 <211> LENGTH: 115 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 108
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Thr Gly
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala
115 <210> SEQ ID NO 109 <211> LENGTH: 108 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
109 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser
Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr
Tyr Cys Gln Gln Ala Asn Ser Phe Pro Phe 85 90 95 Thr Phe Gly Pro
Gly Thr Lys Val Asp Ile Lys Arg 100 105 <210> SEQ ID NO 110
<211> LENGTH: 117 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 110 Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Gly Tyr Ser Tyr Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala 115 <210> SEQ
ID NO 111 <211> LENGTH: 118 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 111 Gln Val Gln Leu
Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala 1 5 10 15 Ser Val
Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr Ser Tyr 20 25 30
Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly Leu Glu Trp Met 35
40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr Asn Tyr Ala Gln Lys
Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr Asp Thr Ser Thr Ser
Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr
Ala Val Tyr Tyr Cys 85 90 95 Ala Asp Tyr Gly Gly Asn Tyr Phe Asp
Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr Val Ser Ser Ala 115
<210> SEQ ID NO 112 <211> LENGTH: 114 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 112
Asp Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala Val Ser Leu Gly 1 5
10 15 Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser Val Leu Tyr
Ser 20 25 30 Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Gln Gln Lys
Pro Gly Gln 35 40 45 Pro Pro Lys Leu Leu Ile Tyr Trp Ala Ser Thr
Arg Glu Ser Gly Val 50 55 60 Pro Asp Arg Phe Ser Gly Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr 65 70 75 80 Ile Ser Ser Leu Gln Ala Glu
Asp Val Ala Val Tyr Tyr Cys Gln Gln 85 90 95 Tyr Tyr Ser Thr Pro
Trp Thr Phe Gly Gln Gly Thr Lys Val Glu Ile 100 105 110 Lys Arg
<210> SEQ ID NO 113 <211> LENGTH: 116 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 113
Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ser Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Ser Ser Thr Ile Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Asp Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ile Val Gly
Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr 100 105 110 Val Ser Ser
Ala 115 <210> SEQ ID NO 114 <211> LENGTH: 109
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 114 Glu Ile Val Leu Thr Gln Ser Pro Gly Thr
Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Ser Ser Ser 20 25 30 Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35 40 45 Ile Tyr Gly Ala
Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe Ser 50 55 60 Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Arg Leu Glu 65 70 75 80
Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Gly Ser Ser Pro 85
90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys Arg 100 105
<210> SEQ ID NO 115 <211> LENGTH: 114 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 115
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Ile Gly Met Asp
Val Trp Gly Gln Gly Thr Thr Val Thr Val Ser 100 105 110 Ser Ala
<210> SEQ ID NO 116 <211> LENGTH: 115 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 116
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Thr Gly
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala
115 <210> SEQ ID NO 117 <211> LENGTH: 108 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
117 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser
Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr
Tyr Cys Gln Gln Ala Asn Ser Phe Pro Leu 85 90 95 Thr Phe Gly Gly
Gly Thr Lys Val Glu Ile Lys Arg 100 105
1 SEQUENCE LISTING <160> NUMBER OF SEQ ID NOS: 117
<210> SEQ ID NO 1 <211> LENGTH: 1383 <212> TYPE:
DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 1
atggagttgg ggctgtgctg gattttcctt gttgctatta taaaaggtgt ccagtgtcag
60 gtgcagctgg tggagtctgg gggaggcttg gtcaagcctg gagggtccct
gagactctcc 120 tgtgcagcct ctggattcac cttcagtgac tactacatga
gctggatccg ccaggctcca 180 gggaaggggc tggagtggat ttcatacatt
agtggtagtg gtagtaccat atactacgca 240 gactctgtga agggccgatt
caccatctcc agggacaacg ccaagaactc actgtatctg 300 caaatgaaca
gcctgagagc cgaggacacg gccgtgtatc actgtgcgag agccctgggt 360
gggatggacg tctggggcca agggaccacg gtcaccgtct cctcagcttc caccaagggc
420 ccatccgtct tccccctggc gccctgctct agaagcacct ccgagagcac
agcggccctg 480 ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg
tgtcgtggaa ctcaggcgct 540 ctgaccagcg gcgtgcacac cttcccagct
gtcctacagt cctcaggact ctactccctc 600 agcagcgtgg tgaccgtgcc
ctccagcaac ttcggcaccc agacctacac ctgcaacgta 660 gatcacaagc
ccagcaacac caaggtggac aagacagttg agcgcaaatg ttgtgtcgag 720
tgcccaccgt gcccagcacc acctgtggca ggaccgtcag tcttcctctt ccccccaaaa
780 cccaaggaca ccctcatgat ctcccggacc cctgaggtca cgtgcgtggt
ggtggacgtg 840 agccacgaag accccgaggt ccagttcaac tggtacgtgg
acggcgtgga ggtgcataat 900 gccaagacaa agccacggga ggagcagttc
aacagcacgt tccgtgtggt cagcgtcctc 960 accgttgtgc accaggactg
gctgaacggc aaggagtaca agtgcaaggt ctccaacaaa 1020 ggcctcccag
cccccatcga gaaaaccatc tccaaaacca aagggcagcc ccgagaacca 1080
caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc
1140 tgcctggtca aaggcttcta ccccagcgac atcgccgtgg agtgggagag
caatgggcag 1200 ccggagaaca actacaagac cacacctccc atgctggact
ccgacggctc cttcttcctc 1260 tacagcaagc tcaccgtgga caagagcagg
tggcagcagg ggaacgtctt ctcatgctcc 1320 gtgatgcatg aggctctgca
caaccactac acgcagaaga gcctctccct gtctccgggt 1380 aaa 1383
<210> SEQ ID NO 2 <211> LENGTH: 461 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 2 Met
Glu Leu Gly Leu Cys Trp Ile Phe Leu Val Ala Ile Ile Lys Gly 1 5 10
15 Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe 35 40 45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro
Gly Lys Gly Leu 50 55 60 Glu Trp Ile Ser Tyr Ile Ser Gly Ser Gly
Ser Thr Ile Tyr Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr His Cys Ala
Arg Ala Leu Gly Gly Met Asp Val Trp Gly Gln Gly 115 120 125 Thr Thr
Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 130 135 140
Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 145
150 155 160 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val
Ser Trp 165 170 175 Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe
Pro Ala Val Leu 180 185 190 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser
Val Val Thr Val Pro Ser 195 200 205 Ser Asn Phe Gly Thr Gln Thr Tyr
Thr Cys Asn Val Asp His Lys Pro 210 215 220 Ser Asn Thr Lys Val Asp
Lys Thr Val Glu Arg Lys Cys Cys Val Glu 225 230 235 240 Cys Pro Pro
Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu 245 250 255 Phe
Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265
270 Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln
275 280 285 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys
Thr Lys 290 295 300 Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val
Val Ser Val Leu 305 310 315 320 Thr Val Val His Gln Asp Trp Leu Asn
Gly Lys Glu Tyr Lys Cys Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro
Ala Pro Ile Glu Lys Thr Ile Ser Lys 340 345 350 Thr Lys Gly Gln Pro
Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 355 360 365 Arg Glu Glu
Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly
Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390
395 400 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp
Gly 405 410 415 Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser
Arg Trp Gln 420 425 430 Gln Gly Asn Val Phe Ser Cys Ser Val Met His
Glu Ala Leu His Asn 435 440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu
Ser Pro Gly Lys 450 455 460 <210> SEQ ID NO 3 <211>
LENGTH: 702 <212> TYPE: DNA <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 3 atgagggtcc ctgctcagct cctggggctc
ctgctactct ggctccgagg tgccagatgt 60 gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgtaggaga cagagtcacc 120 atcacttgcc
gggcaagtca gagcattagc ggctttttaa attggtatca gcagaaacca 180
gggaaagccc ctaagctcct gatctatgct acatccagtt tgcaaagtgg ggtcccattc
240 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag
tctgcaacct 300 gaagattttg caacttatta ctgtcaacag agttacagtg
tcccattcac tttcggccct 360 gggaccaaag tggatatcaa acgaactgtg
gctgcaccat ctgtcttcat cttcccgcca 420 tctgatgagc agttgaaatc
tggaactgct agcgttgtgt gcctgctgaa taacttctat 480 cccagagagg
ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg
600 ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac
ccatcagggc 660 ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 702
<210> SEQ ID NO 4 <211> LENGTH: 234 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 4 Met
Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Arg 1 5 10
15 Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser
Gln Ser 35 40 45 Ile Ser Gly Phe Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro 50 55 60 Lys Leu Leu Ile Tyr Ala Thr Ser Ser Leu
Gln Ser Gly Val Pro Phe 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95 Ser Leu Gln Pro Glu Asp
Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr 100 105 110 Ser Val Pro Phe
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 115 120 125 Thr Val
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 145
150 155 160 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser 165 170 175 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr 180 185 190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys 195 200 205 His Lys Val Tyr Ala Cys Glu Val
Thr His Gln Gly Leu Ser Ser Pro 210 215 220 Val Thr Lys Ser Phe Asn
Arg Gly Glu Cys 225 230 <210> SEQ ID NO 5 <211> LENGTH:
1389 <212> TYPE: DNA <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 5 atggaatttg ggctgtgctg ggttttcctt gttgctattt
tagaaggtgt ccagtgtgag 60
gtgcagctgg tggagtctgg gggaggcttg gtccagcctg gggggtccct gagactctcc
120 tgtgcagcct ctggattcac ctttagtagc tattggatga gctgggtccg
ccaggctcca 180 gggaaggggc tggagtgggt ggccaacata aagcaagatg
gaagtgagaa atactatgtg 240 gactctgtga agggccgatt caccatctcc
agagacaacg ccaagaactc actgtatctg 300 caaatgaaca gcctgagagc
cgaggacacg gctgtgtatt actgtgctcc gggtatagca 360 gcagctggta
gggcctactg gggccaggga accctggtca ccgtctcctc agcttccacc 420
aagggcccat ccgtcttccc cctggcgccc tgctctagaa gcacctccga gagcacagcg
480 gccctgggct gcctggtcaa ggactacttc cccgaaccgg tgacggtgtc
gtggaactca 540 ggcgctctga ccagcggcgt gcacaccttc ccagctgtcc
tacagtcctc aggactctac 600 tccctcagca gcgtggtgac cgtgccctcc
agcaacttcg gcacccagac ctacacctgc 660 aacgtagatc acaagcccag
caacaccaag gtggacaaga cagttgagcg caaatgttgt 720 gtcgagtgcc
caccgtgccc agcaccacct gtggcaggac cgtcagtctt cctcttcccc 780
ccaaaaccca aggacaccct catgatctcc cggacccctg aggtcacgtg cgtggtggtg
840 gacgtgagcc acgaagaccc cgaggtccag ttcaactggt acgtggacgg
cgtggaggtg 900 cataatgcca agacaaagcc acgggaggag cagttcaaca
gcacgttccg tgtggtcagc 960 gtcctcaccg ttgtgcacca ggactggctg
aacggcaagg agtacaagtg caaggtctcc 1020 aacaaaggcc tcccagcccc
catcgagaaa accatctcca aaaccaaagg gcagccccga 1080 gaaccacagg
tgtacaccct gcccccatcc cgggaggaga tgaccaagaa ccaggtcagc 1140
ctgacctgcc tggtcaaagg cttctacccc agcgacatcg ccgtggagtg ggagagcaat
1200 gggcagccgg agaacaacta caagaccaca cctcccatgc tggactccga
cggctccttc 1260 ttcctctaca gcaagctcac cgtggacaag agcaggtggc
agcaggggaa cgtcttctca 1320 tgctccgtga tgcatgaggc tctgcacaac
cactacacgc agaagagcct ctccctgtct 1380 ccgggtaaa 1389 <210>
SEQ ID NO 6 <211> LENGTH: 463 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 6 Met Glu
Phe Gly Leu Cys Trp Val Phe Leu Val Ala Ile Leu Glu Gly 1 5 10 15
Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20
25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
Phe 35 40 45 Ser Ser Tyr Trp Met Ser Trp Val Arg Gln Ala Pro Gly
Lys Gly Leu 50 55 60 Glu Trp Val Ala Asn Ile Lys Gln Asp Gly Ser
Glu Lys Tyr Tyr Val 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Pro
Gly Ile Ala Ala Ala Gly Arg Ala Tyr Trp Gly 115 120 125 Gln Gly Thr
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser 130 135 140 Val
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala 145 150
155 160 Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
Val 165 170 175 Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
Phe Pro Ala 180 185 190 Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
Ser Val Val Thr Val 195 200 205 Pro Ser Ser Asn Phe Gly Thr Gln Thr
Tyr Thr Cys Asn Val Asp His 210 215 220 Lys Pro Ser Asn Thr Lys Val
Asp Lys Thr Val Glu Arg Lys Cys Cys 225 230 235 240 Val Glu Cys Pro
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val 245 250 255 Phe Leu
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 260 265 270
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu 275
280 285 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
Lys 290 295 300 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
Val Val Ser 305 310 315 320 Val Leu Thr Val Val His Gln Asp Trp Leu
Asn Gly Lys Glu Tyr Lys 325 330 335 Cys Lys Val Ser Asn Lys Gly Leu
Pro Ala Pro Ile Glu Lys Thr Ile 340 345 350 Ser Lys Thr Lys Gly Gln
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 355 360 365 Pro Ser Arg Glu
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 370 375 380 Val Lys
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390 395
400 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
405 410 415 Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
Ser Arg 420 425 430 Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
His Glu Ala Leu 435 440 445 His Asn His Tyr Thr Gln Lys Ser Leu Ser
Leu Ser Pro Gly Lys 450 455 460 <210> SEQ ID NO 7 <211>
LENGTH: 702 <212> TYPE: DNA <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 7 atgagggtcc ctgctcagct cctggggctc
ctgctactct ggctccgagg tgccagatgt 60 gacatccaga tgacccagtc
tccatcctcc ctgtctgcat ctgttggaga cagagtcacc 120 atcacttgcc
ggccaagtca ggacattagc agttatttaa attggtatca gcagaaacca 180
gggaaagccc ctaagctcct gatctatgct gcatccagtt tgcaaagtgg ggtcccatta
240 aggttcagtg gcagtggatc tgggacagat ttcactctca ccatcagcag
tctgcaacct 300 gaagattttg caacttacta ctgtcaacag agttacagta
ccccattcac tttcggccct 360 gggaccaaag tggatatcaa acgaactgtg
gctgcaccat ctgtcttcat cttcccgcca 420 tctgatgagc agttgaaatc
tggaactgct agcgttgtgt gcctgctgaa taacttctat 480 cccagagagg
ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag 540
gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag caccctgacg
600 ctgagcaaag cagactacga gaaacacaaa gtctacgcct gcgaagtcac
ccatcagggc 660 ctgagctcgc ccgtcacaaa gagcttcaac aggggagagt gt 702
<210> SEQ ID NO 8 <211> LENGTH: 234 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 8 Met
Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp Leu Arg 1 5 10
15 Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Leu Ser
20 25 30 Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Pro Ser
Gln Asp 35 40 45 Ile Ser Ser Tyr Leu Asn Trp Tyr Gln Gln Lys Pro
Gly Lys Ala Pro 50 55 60 Lys Leu Leu Ile Tyr Ala Ala Ser Ser Leu
Gln Ser Gly Val Pro Leu 65 70 75 80 Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp Phe Thr Leu Thr Ile Ser 85 90 95 Ser Leu Gln Pro Glu Asp
Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr 100 105 110 Ser Thr Pro Phe
Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys Arg 115 120 125 Thr Val
Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu Gln 130 135 140
Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn Phe Tyr 145
150 155 160 Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu
Gln Ser 165 170 175 Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser
Lys Asp Ser Thr 180 185 190 Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
Lys Ala Asp Tyr Glu Lys 195 200 205 His Lys Val Tyr Ala Cys Glu Val
Thr His Gln Gly Leu Ser Ser Pro 210 215 220 Val Thr Lys Ser Phe Asn
Arg Gly Glu Cys 225 230 <210> SEQ ID NO 9 <211> LENGTH:
1398 <212> TYPE: DNA <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 9 atggagtttg ggctccgctg gatttttctt gtggctattt
taaaaggtgt ccagtgtgag 60 gtgcagctgt tggagtctgg gggaggcttg
gtacagcctg gggggtccct gagactctcc 120 tgtgcagcct ctggattcac
ctttagcagc tatgccatga gctgggtccg ccaggctcca 180 gggaaggggc
tggaatgggt ctcagctatt agtggtcgtg gtggtaggac atacttcgca 240
gactccgtga agggccggtt caccatctcc agagacaatt ccaagaacac gctgtatctg
300 caaatgaaca gcctgagagc cgaggacacg gccgtatatt tctgtgcggt
agaaggctat 360 agtgggcgct acggattttt tgactactgg ggccagggaa
ccctagtcac cgtctcctca 420 gcctccacca agggcccatc ggtcttcccc
ctggcgccct gctctagaag cacctccgag 480
agcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg
540 tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct
acagtcctca 600 ggactctact ccctcagcag cgtggtgacc gtgccctcca
gcaacttcgg cacccagacc 660 tacacctgca acgtagatca caagcccagc
aacaccaagg tggacaagac agttgagcgc 720 aaatgttgtg tcgagtgccc
accgtgccca gcaccacctg tggcaggacc gtcagtcttc 780 ctcttccccc
caaaacccaa ggacaccctc atgatctccc ggacccctga ggtcacgtgc 840
gtggtggtgg acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc
900 gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag
cacgttccgt 960 gtggtcagcg tcctcaccgt tgtgcaccag gactggctga
acggcaagga gtacaagtgc 1020 aaggtctcca acaaaggcct cccagccccc
atcgagaaaa ccatctccaa aaccaaaggg 1080 cagccccgag aaccacaggt
gtacaccctg cccccatccc gggaggagat gaccaagaac 1140 caggtcagcc
tgacctgcct ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 1200
gagagcaatg ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac
1260 ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca
gcaggggaac 1320 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc
actacacgca gaagagcctc 1380 tccctgtctc cgggtaaa 1398 <210> SEQ
ID NO 10 <211> LENGTH: 466 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 10 Met Glu Phe Gly Leu
Arg Trp Ile Phe Leu Val Ala Ile Leu Lys Gly 1 5 10 15 Val Gln Cys
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40
45 Ser Ser Tyr Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60 Glu Trp Val Ser Ala Ile Ser Gly Arg Gly Gly Arg Thr Tyr
Phe Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val 100 105 110 Tyr Phe Cys Ala Val Glu Gly Tyr
Ser Gly Arg Tyr Gly Phe Phe Asp 115 120 125 Tyr Trp Gly Gln Gly Thr
Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145 150 155 160 Ser
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170
175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
Ser Val 195 200 205 Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr
Tyr Thr Cys Asn 210 215 220 Val Asp His Lys Pro Ser Asn Thr Lys Val
Asp Lys Thr Val Glu Arg 225 230 235 240 Lys Cys Cys Val Glu Cys Pro
Pro Cys Pro Ala Pro Pro Val Ala Gly 245 250 255 Pro Ser Val Phe Leu
Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265 270 Ser Arg Thr
Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 275 280 285 Asp
Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 290 295
300 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
305 310 315 320 Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu
Asn Gly Lys 325 330 335 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu
Pro Ala Pro Ile Glu 340 345 350 Lys Thr Ile Ser Lys Thr Lys Gly Gln
Pro Arg Glu Pro Gln Val Tyr 355 360 365 Thr Leu Pro Pro Ser Arg Glu
Glu Met Thr Lys Asn Gln Val Ser Leu 370 375 380 Thr Cys Leu Val Lys
Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 385 390 395 400 Glu Ser
Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met 405 410 415
Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp 420
425 430 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met
His 435 440 445 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser
Leu Ser Pro 450 455 460 Gly Lys 465 <210> SEQ ID NO 11
<211> LENGTH: 702 <212> TYPE: DNA <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 11 atggaagccc cagctcagct
tctcttcctc ctgctactct ggctcccaga taccactgga 60 gaaatagtga
tgacgcagtc tccagccacc ctgtctgtgt ctccagggga aagagccacc 120
ctctcctgca gggccagtca gagtgttagc agcaacttag cctggtacca gcagaaacct
180 ggccaggctc ccaggctcct catctatggt gcatccacca gggccagtgg
tatcccagac 240 aggatcagtg gcagtgggtc tggaacagag ttcactctca
tcatcagcag cctgcagtct 300 gaagattttg cagtttatta ctgtcagcag
tctaataact ggccattcac tttcggccct 360 gggaccaaag tggatatcaa
acgaactgtg gctgcaccat ctgtcttcat cttcccgcca 420 tctgatgagc
agttgaaatc tggaactgct agcgttgtgt gcctgctgaa taacttctat 480
cccagagagg ccaaagtaca gtggaaggtg gataacgccc tccaatcggg taactcccag
540 gagagtgtca cagagcagga cagcaaggac agcacctaca gcctcagcag
caccctgacg 600 ctgagcaaag cagactacga gaaacacaaa gtctacgcct
gcgaagtcac ccatcagggc 660 ctgagctcgc ccgtcacaaa gagcttcaac
aggggagagt gt 702 <210> SEQ ID NO 12 <211> LENGTH: 234
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 12 Met Glu Ala Pro Ala Gln Leu Leu Phe Leu
Leu Leu Leu Trp Leu Pro 1 5 10 15 Asp Thr Thr Gly Glu Ile Val Met
Thr Gln Ser Pro Ala Thr Leu Ser 20 25 30 Val Ser Pro Gly Glu Arg
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser 35 40 45 Val Ser Ser Asn
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro 50 55 60 Arg Leu
Leu Ile Tyr Gly Ala Ser Thr Arg Ala Ser Gly Ile Pro Asp 65 70 75 80
Arg Ile Ser Gly Ser Gly Ser Gly Thr Glu Phe Thr Leu Ile Ile Ser 85
90 95 Ser Leu Gln Ser Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Ser
Asn 100 105 110 Asn Trp Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp
Ile Lys Arg 115 120 125 Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro
Pro Ser Asp Glu Gln 130 135 140 Leu Lys Ser Gly Thr Ala Ser Val Val
Cys Leu Leu Asn Asn Phe Tyr 145 150 155 160 Pro Arg Glu Ala Lys Val
Gln Trp Lys Val Asp Asn Ala Leu Gln Ser 165 170 175 Gly Asn Ser Gln
Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser Thr 180 185 190 Tyr Ser
Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu Lys 195 200 205
His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser Pro 210
215 220 Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 <210>
SEQ ID NO 13 <400> SEQUENCE: 13 000 <210> SEQ ID NO 14
<211> LENGTH: 460 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 14 Met Glu Phe Gly Leu Ser Trp
Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Phe Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Ser Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110
Tyr Tyr Cys Ala Arg Gly Leu Thr Gly Asp Tyr Trp Gly Gln Gly Thr 115
120 125 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe
Pro 130 135 140 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala
Ala Leu Gly 145 150 155 160 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro
Val Thr Val Ser Trp Asn 165 170 175 Ser Gly Ala Leu Thr Ser Gly Val
His Thr Phe Pro Ala Val Leu Gln 180 185 190 Ser Ser Gly Leu Tyr Ser
Leu Ser Ser Val Val Thr Val Pro Ser Ser 195 200 205 Asn Phe Gly Thr
Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 210 215 220 Asn Thr
Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 225 230 235
240 Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe
245 250 255 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
Glu Val 260 265 270 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro
Glu Val Gln Phe 275 280 285 Asn Trp Tyr Val Asp Gly Val Glu Val His
Asn Ala Lys Thr Lys Pro 290 295 300 Arg Glu Glu Gln Phe Asn Ser Thr
Phe Arg Val Val Ser Val Leu Thr 305 310 315 320 Val Val His Gln Asp
Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val 325 330 335 Ser Asn Lys
Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 340 345 350 Lys
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 355 360
365 Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly
370 375 380 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
Gln Pro 385 390 395 400 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu
Asp Ser Asp Gly Ser 405 410 415 Phe Phe Leu Tyr Ser Lys Leu Thr Val
Asp Lys Ser Arg Trp Gln Gln 420 425 430 Gly Asn Val Phe Ser Cys Ser
Val Met His Glu Ala Leu His Asn His 435 440 445 Tyr Thr Gln Lys Ser
Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> SEQ ID NO 15
<400> SEQUENCE: 15 000 <210> SEQ ID NO 16 <211>
LENGTH: 236 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 16 Met Asp Met Arg Val Pro Ala Gln
Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Phe Pro Gly Ser Arg Cys
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Val Ser Ala Ser
Val Gly Asp Arg Val Thr Ile Ser Cys Arg Ala Ser 35 40 45 Gln Asp
Ile Ser Gly Trp Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60
Ala Pro Lys Leu Leu Ile Ser Ala Thr Ser Ser Leu His Ser Gly Val 65
70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
Tyr Cys Gln Gln 100 105 110 Thr Asn Ser Phe Pro Phe Thr Phe Gly Pro
Gly Thr Lys Val Asp Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro Ser
Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly
Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185
190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235 <210> SEQ ID NO 17 <400> SEQUENCE: 17 000
<210> SEQ ID NO 18 <211> LENGTH: 463 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 18 Met
Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Leu Leu Arg Gly 1 5 10
15 Cys Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Val Val Gln
20 25 30 Pro Gly Arg Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe 35 40 45 Ser Ser Tyr Gly Met His Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu 50 55 60 Glu Trp Val Ala Phe Ile Trp Tyr Asp Gly
Ser Asn Lys Tyr Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ser Lys Asn 85 90 95 Thr Leu Tyr Leu Gln Met
Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala
Arg Gly Tyr Arg Val Tyr Phe Asp Tyr Trp Gly Gln 115 120 125 Gly Thr
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val 130 135 140
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala 145
150 155 160 Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
Val Ser 165 170 175 Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
Phe Pro Ala Val 180 185 190 Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
Ser Val Val Thr Val Pro 195 200 205 Ser Ser Ser Leu Gly Thr Lys Thr
Tyr Thr Cys Asn Val Asp His Lys 210 215 220 Pro Ser Asn Thr Lys Val
Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro 225 230 235 240 Pro Cys Pro
Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val 245 250 255 Phe
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr 260 265
270 Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu
275 280 285 Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn
Ala Lys 290 295 300 Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
Arg Val Val Ser 305 310 315 320 Val Leu Thr Val Leu His Gln Asp Trp
Leu Asn Gly Lys Glu Tyr Lys 325 330 335 Cys Lys Val Ser Asn Lys Gly
Leu Pro Ser Ser Ile Glu Lys Thr Ile 340 345 350 Ser Lys Ala Lys Gly
Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro 355 360 365 Pro Ser Gln
Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu 370 375 380 Val
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn 385 390
395 400 Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp
Ser 405 410 415 Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp
Lys Ser Arg 420 425 430 Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
Met His Glu Ala Leu 435 440 445 His Asn His Tyr Thr Gln Lys Ser Leu
Ser Leu Ser Pro Gly Lys 450 455 460 <210> SEQ ID NO 19
<400> SEQUENCE: 19 000 <210> SEQ ID NO 20 <211>
LENGTH: 236 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 20 Met Asp Met Arg Val Pro Ala Gln
Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Phe Pro Gly Ser Arg Cys
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Val Ser Ala Ser
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 35 40 45
Gln Asp Ile Ser Ser Trp Leu Ala Trp Tyr Gln Arg Lys Pro Gly Lys 50
55 60 Ala Pro Lys Leu Gln Ile Tyr Ala Ala Ser Ser Leu Glu Ser Gly
Val 65 70 75 80 Pro Ser Arg Phe Asn Gly Ser Gly Ser Gly Thr Asp Phe
Thr Leu Ser 85 90 95 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr
Tyr Tyr Cys Gln Gln 100 105 110 Thr Asn Ser Phe Pro Leu Thr Phe Gly
Gly Gly Thr Lys Val Glu Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro
Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser
Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr
Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175
Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180
185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp
Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln
Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu
Cys 225 230 235 <210> SEQ ID NO 21 <400> SEQUENCE: 21
000 <210> SEQ ID NO 22 <211> LENGTH: 464 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
22 Met Glu Trp Thr Trp Ser Phe Leu Phe Leu Val Ala Ala Ala Thr Gly
1 5 10 15 Ala His Ser Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val
Lys Lys 20 25 30 Pro Gly Ala Ser Val Lys Val Ser Cys Lys Ala Ser
Gly Tyr Thr Phe 35 40 45 Thr Ser Tyr Gly Ile Ser Trp Val Arg Gln
Ala Pro Gly Gln Gly Leu 50 55 60 Glu Trp Met Gly Trp Ile Ser Ala
Tyr Asn Gly Asn Thr Asn Tyr Ala 65 70 75 80 Gln Lys Leu Gln Asp Arg
Val Thr Met Thr Thr Asp Thr Ser Thr Thr 85 90 95 Thr Ala Tyr Met
Glu Leu Arg Ser Leu Arg Ser Asp Asp Thr Ala Val 100 105 110 Tyr Tyr
Cys Ala Arg Arg Ala Tyr Gly Ala Asn Phe Phe Asp Tyr Trp 115 120 125
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro 130
135 140 Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser
Thr 145 150 155 160 Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
Glu Pro Val Thr 165 170 175 Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
Gly Val His Thr Phe Pro 180 185 190 Ala Val Leu Gln Ser Ser Gly Leu
Tyr Ser Leu Ser Ser Val Val Thr 195 200 205 Val Pro Ser Ser Asn Phe
Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp 210 215 220 His Lys Pro Ser
Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys 225 230 235 240 Cys
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser 245 250
255 Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg
260 265 270 Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
Asp Pro 275 280 285 Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
Val His Asn Ala 290 295 300 Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
Ser Thr Phe Arg Val Val 305 310 315 320 Ser Val Leu Thr Val Val His
Gln Asp Trp Leu Asn Gly Lys Glu Tyr 325 330 335 Lys Cys Lys Val Ser
Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr 340 345 350 Ile Ser Lys
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu 355 360 365 Pro
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys 370 375
380 Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser
385 390 395 400 Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
Met Leu Asp 405 410 415 Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
Thr Val Asp Lys Ser 420 425 430 Arg Trp Gln Gln Gly Asn Val Phe Ser
Cys Ser Val Met His Glu Ala 435 440 445 Leu His Asn His Tyr Thr Gln
Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> SEQ ID
NO 23 <400> SEQUENCE: 23 000 <210> SEQ ID NO 24
<211> LENGTH: 240 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 24 Met Val Leu Gln Thr Gln Val
Phe Ile Ser Leu Leu Leu Trp Ile Ser 1 5 10 15 Gly Ala Tyr Gly Asp
Ile Val Met Thr Gln Ser Pro Asp Ser Leu Ala 20 25 30 Val Ser Leu
Gly Glu Arg Ala Thr Ile Asn Cys Lys Ser Ser Gln Ser 35 40 45 Ile
Leu Phe Phe Ser Asn Asn Lys Asn Tyr Leu Ala Trp Tyr Arg Gln 50 55
60 Lys Pro Gly Gln Pro Pro Asn Leu Leu Ile Tyr Trp Ala Ser Thr Arg
65 70 75 80 Glu Ser Gly Val Pro Asp Arg Phe Ser Gly Ser Gly Ser Gly
Thr Asp 85 90 95 Phe Thr Leu Thr Ile Ser Ser Leu Gln Ala Glu Asp
Val Ala Val Tyr 100 105 110 Tyr Cys Gln Gln Tyr Tyr Ser Ser Pro Trp
Thr Phe Gly Gln Gly Thr 115 120 125 Lys Val Glu Ile Lys Arg Thr Val
Ala Ala Pro Ser Val Phe Ile Phe 130 135 140 Pro Pro Ser Asp Glu Gln
Leu Lys Ser Gly Thr Ala Ser Val Val Cys 145 150 155 160 Leu Leu Asn
Asn Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val 165 170 175 Asp
Asn Ala Leu Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln 180 185
190 Asp Ser Lys Asp Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser
195 200 205 Lys Ala Asp Tyr Glu Lys His Lys Val Tyr Ala Cys Glu Val
Thr His 210 215 220 Gln Gly Leu Ser Ser Pro Val Thr Lys Ser Phe Asn
Arg Gly Glu Cys 225 230 235 240 <210> SEQ ID NO 25
<211> LENGTH: 1380 <212> TYPE: DNA <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 25 atggagtttg
ggctgagctg ggttttcctt gttgctatta taaaaggtgt ccagtgtcag 60
gtgcagctgg tggagtctgg gggaggcttg gtcaagcctg gagggtccct gagactctcc
120 tgtgcagcct ctggattcac cttcagtgac tactatatga gctggatccg
ccaggctcca 180 gggaagggac tggagtgggt ttcatacatt agtagtagtg
gtagtaccat atactacgca 240 gactctgtga agggccgatt caccatctcc
agggacaacg ccaagaactc actgtatctg 300 caaatgaaca gcctgagagc
cgaggacacg gccgtgtatt actgtgcgag aggcctaact 360 ggggactact
ggggccaggg aaccctggtc accgtctcct cagcttccac caagggccca 420
tccgtcttcc ccctggcgcc ctgctctaga agcacctccg agagcacagc ggccctgggc
480 tgcctggtca aggactactt ccccgaaccg gtgacggtgt cgtggaactc
aggcgctctg 540 accagcggcg tgcacacctt cccagctgtc ctacagtcct
caggactcta ctccctcagc 600 agcgtggtga ccgtgccctc cagcaacttc
ggcacccaga cctacacctg caacgtagat 660 cacaagccca gcaacaccaa
ggtggacaag acagttgagc gcaaatgttg tgtcgagtgc 720 ccaccgtgcc
cagcaccacc tgtggcagga ccgtcagtct tcctcttccc cccaaaaccc 780
aaggacaccc tcatgatctc ccggacccct gaggtcacgt gcgtggtggt ggacgtgagc
840 cacgaagacc ccgaggtcca gttcaactgg tacgtggacg gcgtggaggt
gcataatgcc 900 aagacaaagc cacgggagga gcagttcaac agcacgttcc
gtgtggtcag cgtcctcacc 960 gttgtgcacc aggactggct gaacggcaag
gagtacaagt gcaaggtctc caacaaaggc 1020 ctcccagccc ccatcgagaa
aaccatctcc aaaaccaaag ggcagccccg agaaccacag 1080 gtgtacaccc
tgcccccatc ccgggaggag atgaccaaga accaggtcag cctgacctgc 1140
ctggtcaaag gcttctaccc cagcgacatc gccgtggagt gggagagcaa tgggcagccg
1200 gagaacaact acaagaccac acctcccatg ctggactccg acggctcctt
cttcctctac 1260 agcaagctca ccgtggacaa gagcaggtgg cagcagggga
acgtcttctc atgctccgtg 1320
atgcatgagg ctctgcacaa ccactacacg cagaagagcc tctccctgtc tccgggtaaa
1380 <210> SEQ ID NO 26 <211> LENGTH: 460 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
26 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly
1 5 10 15 Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Lys 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe 35 40 45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln
Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser
Ser Gly Ser Thr Ile Tyr Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr
Cys Ala Arg Gly Leu Thr Gly Asp Tyr Trp Gly Gln Gly Thr 115 120 125
Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 130
135 140 Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu
Gly 145 150 155 160 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr
Val Ser Trp Asn 165 170 175 Ser Gly Ala Leu Thr Ser Gly Val His Thr
Phe Pro Ala Val Leu Gln 180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser
Ser Val Val Thr Val Pro Ser Ser 195 200 205 Asn Phe Gly Thr Gln Thr
Tyr Thr Cys Asn Val Asp His Lys Pro Ser 210 215 220 Asn Thr Lys Val
Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys 225 230 235 240 Pro
Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 245 250
255 Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val
260 265 270 Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val
Gln Phe 275 280 285 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala
Lys Thr Lys Pro 290 295 300 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg
Val Val Ser Val Leu Thr 305 310 315 320 Val Val His Gln Asp Trp Leu
Asn Gly Lys Glu Tyr Lys Cys Lys Val 325 330 335 Ser Asn Lys Gly Leu
Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr 340 345 350 Lys Gly Gln
Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 355 360 365 Glu
Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 370 375
380 Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro
385 390 395 400 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser
Asp Gly Ser 405 410 415 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys
Ser Arg Trp Gln Gln 420 425 430 Gly Asn Val Phe Ser Cys Ser Val Met
His Glu Ala Leu His Asn His 435 440 445 Tyr Thr Gln Lys Ser Leu Ser
Leu Ser Pro Gly Lys 450 455 460 <210> SEQ ID NO 27
<211> LENGTH: 708 <212> TYPE: DNA <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 27 atggacatga gggtccccgc
tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60 agatgtgaca
tccagatgac ccagtctcca tcctccctgt ctgcatctgt cggagacaga 120
gtcaccatca cttgccggcc aagtcagatc attagcagtt tattaaattg gtatcagcag
180 aaaccaggga aagcccctaa gctcctgatc catgctgcat ccagtttgca
aagtggggtc 240 ccatcaaggt tcagtggcag tggatctggg acagatttca
ctctcaccat cagtagtctg 300 caacctgaag attttgcaac ttactactgt
caacagagtt acagtacccc attcactttc 360 ggccctggga ccaaagtgga
tatcaaacga actgtggctg caccatctgt cttcatcttc 420 ccgccatctg
atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac 480
ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca atcgggtaac
540 tcccaggaga gtgtcacaga gcaggacagc aaggacagca cctacagcct
cagcagcacc 600 ctgacgctga gcaaagcaga ctacgagaaa cacaaagtct
acgcctgcga agtcacccat 660 cagggcctga gctcgcccgt cacaaagagc
ttcaacaggg gagagtgt 708 <210> SEQ ID NO 28 <211>
LENGTH: 236 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 28 Met Asp Met Arg Val Pro Ala Gln
Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg Cys
Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala Ser
Val Gly Asp Arg Val Thr Ile Thr Cys Arg Pro Ser 35 40 45 Gln Ile
Ile Ser Ser Leu Leu Asn Trp Tyr Gln Gln Lys Pro Gly Lys 50 55 60
Ala Pro Lys Leu Leu Ile His Ala Ala Ser Ser Leu Gln Ser Gly Val 65
70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
Tyr Cys Gln Gln 100 105 110 Ser Tyr Ser Thr Pro Phe Thr Phe Gly Pro
Gly Thr Lys Val Asp Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro Ser
Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly
Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185
190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235 <210> SEQ ID NO 29 <211> LENGTH: 1398
<212> TYPE: DNA <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 29 atggagttgg ggctgtgctg ggttttcctt
gttgctattt tagaaggtgt ccagtgtgag 60 gtgcagctgg tggagtctgg
gggaggcttg gtacagcctg gggggtccct gagactctcc 120 tgtgcagcct
ctggattcac cttcagtagt tttagtatga cctgggtccg ccaggctcca 180
ggaaaggggc tggagtgggt ttcatacatt agtagtagaa gtagtaccat atcctacgca
240 gactctgtga agggccgatt caccatctcc agagacaatg ccaagaactc
actgtatctg 300 caaatgaaca gcctgagaga cgaggacacg gctgtgtatt
actgtgcgag agatcctctt 360 ctagcgggag ctaccttctt tgactactgg
ggccagggaa ccctggtcac cgtctcctca 420 gcctccacca agggcccatc
ggtcttcccc ctggcgccct gctccaggag cacctccgag 480 agcacagcgg
ccctgggctg cctggtcaag gactacttcc ccgaaccggt gacggtgtcg 540
tggaactcag gcgctctgac cagcggcgtg cacaccttcc cagctgtcct acagtcctca
600 ggactctact ccctcagcag cgtggtgacc gtgccctcca gcaacttcgg
cacccagacc 660 tacacctgca acgtagatca caagcccagc aacaccaagg
tggacaagac agttgagcgc 720 aaatgttgtg tcgagtgccc accgtgccca
gcaccacctg tggcaggacc gtcagtcttc 780 ctcttccccc caaaacccaa
ggacaccctc atgatctccc ggacccctga ggtcacgtgc 840 gtggtggtgg
acgtgagcca cgaagacccc gaggtccagt tcaactggta cgtggacggc 900
gtggaggtgc ataatgccaa gacaaagcca cgggaggagc agttcaacag cacgttccgt
960 gtggtcagcg tcctcaccgt tgtgcaccag gactggctga acggcaagga
gtacaagtgc 1020 aaggtctcca acaaaggcct cccagccccc atcgagaaaa
ccatctccaa aaccaaaggg 1080 cagccccgag aaccacaggt gtacaccctg
cccccatccc gggaggagat gaccaagaac 1140 caggtcagcc tgacctgcct
ggtcaaaggc ttctacccca gcgacatcgc cgtggagtgg 1200 gagagcaatg
ggcagccgga gaacaactac aagaccacac ctcccatgct ggactccgac 1260
ggctccttct tcctctacag caagctcacc gtggacaaga gcaggtggca gcaggggaac
1320 gtcttctcat gctccgtgat gcatgaggct ctgcacaacc actacacgca
gaagagcctc 1380 tccctgtctc cgggtaaa 1398 <210> SEQ ID NO 30
<211> LENGTH: 466 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 30 Met Glu Leu Gly Leu Cys Trp
Val Phe Leu Val Ala Ile Leu Glu Gly 1 5 10 15 Val Gln Cys Glu Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30
Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35
40 45 Ser Ser Phe Ser Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly
Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Arg Ser Ser Thr Ile
Ser Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg
Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu
Arg Asp Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Pro
Leu Leu Ala Gly Ala Thr Phe Phe Asp 115 120 125 Tyr Trp Gly Gln Gly
Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser
Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145 150 155 160
Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165
170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His
Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu
Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln
Thr Tyr Thr Cys Asn 210 215 220 Val Asp His Lys Pro Ser Asn Thr Lys
Val Asp Lys Thr Val Glu Arg 225 230 235 240 Lys Cys Cys Val Glu Cys
Pro Pro Cys Pro Ala Pro Pro Val Ala Gly 245 250 255 Pro Ser Val Phe
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265 270 Ser Arg
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu 275 280 285
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His 290
295 300 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Phe
Arg 305 310 315 320 Val Val Ser Val Leu Thr Val Val His Gln Asp Trp
Leu Asn Gly Lys 325 330 335 Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
Leu Pro Ala Pro Ile Glu 340 345 350 Lys Thr Ile Ser Lys Thr Lys Gly
Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365 Thr Leu Pro Pro Ser Arg
Glu Glu Met Thr Lys Asn Gln Val Ser Leu 370 375 380 Thr Cys Leu Val
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 385 390 395 400 Glu
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met 405 410
415 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp
420 425 430 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val
Met His 435 440 445 Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
Ser Leu Ser Pro 450 455 460 Gly Lys 465 <210> SEQ ID NO 31
<211> LENGTH: 705 <212> TYPE: DNA <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 31 atggaaaccc cagcgcagct
tctcttcctc ctgctactct ggctcccaga taccaccgga 60 gaatttgtgt
tgacgcagtc tccaggcacc ctgtctttgt ctccagggga aagagccacc 120
ctctcctgca gggccagtca gagtgttagc agcagttact tagcctggta ccagcagaaa
180 cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac
tggcatccca 240 gacaggttca gtggcagtgg gtctgggaca gacttcactc
tcaccatcag cagactggag 300 cctgaagatt ttgcagtgta ttactgtcag
cagtatggta gctcacctct cactttcggc 360 ggagggacca aggtggagat
caaacgaact gtggctgcac catctgtctt catcttcccg 420 ccatctgatg
agcagttgaa atctggaact gcctctgttg tgtgcctgct gaataacttc 480
tatcccagag aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc
540 caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag
cagcaccctg 600 acgctgagca aagcagacta cgagaaacac aaagtctacg
cctgcgaagt cacccatcag 660 ggcctgagct cgcccgtcac aaagagcttc
aacaggggag agtgt 705 <210> SEQ ID NO 32 <211> LENGTH:
235 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 32 Met Glu Thr Pro Ala Gln Leu Leu Phe Leu
Leu Leu Leu Trp Leu Pro 1 5 10 15 Asp Thr Thr Gly Glu Phe Val Leu
Thr Gln Ser Pro Gly Thr Leu Ser 20 25 30 Leu Ser Pro Gly Glu Arg
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser 35 40 45 Val Ser Ser Ser
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala 50 55 60 Pro Arg
Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro 65 70 75 80
Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 85
90 95 Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
Tyr 100 105 110 Gly Ser Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Val
Glu Ile Lys 115 120 125 Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe
Pro Pro Ser Asp Glu 130 135 140 Gln Leu Lys Ser Gly Thr Ala Ser Val
Val Cys Leu Leu Asn Asn Phe 145 150 155 160 Tyr Pro Arg Glu Ala Lys
Val Gln Trp Lys Val Asp Asn Ala Leu Gln 165 170 175 Ser Gly Asn Ser
Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 180 185 190 Thr Tyr
Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu 195 200 205
Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu Ser Ser 210
215 220 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225 230 235
<210> SEQ ID NO 33 <211> LENGTH: 1383 <212> TYPE:
DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 33
atggagtttg ggctgagctg ggttttcctt gttgctatta taaaaggtgt ccagtgtcag
60 gtgcagctgg tggagtctgg gggaggcttg gtcaagcctg gagggtccct
gagactctcc 120 tgtgcagcct ctggattcac cttcagtgac tactacatga
gctggatccg ccaggctcca 180 gggaaggggc tggagtgggt ttcatacatt
agtagtagtg gtagtaccat atactacgca 240 gactctgtga agggccgatt
caccatctcc agggacaacg ccaagaattc actgtatctg 300 caaatgaaca
gcctgagagc cgaggacacg gccgtgtatt actgtgcgag gcgtatagga 360
ggtatggacg tctggggcca agggaccacg gtcaccgtct cctcagcttc caccaagggc
420 ccatccgtct tccccctggc gccctgctct agaagcacct ccgagagcac
agcggccctg 480 ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg
tgtcgtggaa ctcaggcgct 540 ctgaccagcg gcgtgcacac cttcccagct
gtcctacagt cctcaggact ctactccctc 600 agcagcgtgg tgaccgtgcc
ctccagcaac ttcggcaccc agacctacac ctgcaacgta 660 gatcacaagc
ccagcaacac caaggtggac aagacagttg agcgcaaatg ttgtgtcgag 720
tgcccaccgt gcccagcacc acctgtggca ggaccgtcag tcttcctctt ccccccaaaa
780 cccaaggaca ccctcatgat ctcccggacc cctgaggtca cgtgcgtggt
ggtggacgtg 840 agccacgaag accccgaggt ccagttcaac tggtacgtgg
acggcgtgga ggtgcataat 900 gccaagacaa agccacggga ggagcagttc
aacagcacgt tccgtgtggt cagcgtcctc 960 accgttgtgc accaggactg
gctgaacggc aaggagtaca agtgcaaggt ctccaacaaa 1020 ggcctcccag
cccccatcga gaaaaccatc tccaaaacca aagggcagcc ccgagaacca 1080
caggtgtaca ccctgccccc atcccgggag gagatgacca agaaccaggt cagcctgacc
1140 tgcctggtca aaggcttcta ccccagcgac atcgccgtgg agtgggagag
caatgggcag 1200 ccggagaaca actacaagac cacacctccc atgctggact
ccgacggctc cttcttcctc 1260 tacagcaagc tcaccgtgga caagagcagg
tggcagcagg ggaacgtctt ctcatgctcc 1320 gtgatgcatg aggctctgca
caaccactac acgcagaaga gcctctccct gtctccgggt 1380 aaa 1383
<210> SEQ ID NO 34 <211> LENGTH: 461 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 34 Met
Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10
15 Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe 35 40 45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro
Gly Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly
Ser Thr Ile Tyr Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95
Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100
105 110 Tyr Tyr Cys Ala Arg Arg Ile Gly Gly Met Asp Val Trp Gly Gln
Gly 115 120 125 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro
Ser Val Phe 130 135 140 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu
Ser Thr Ala Ala Leu 145 150 155 160 Gly Cys Leu Val Lys Asp Tyr Phe
Pro Glu Pro Val Thr Val Ser Trp 165 170 175 Asn Ser Gly Ala Leu Thr
Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190 Gln Ser Ser Gly
Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 195 200 205 Ser Asn
Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro 210 215 220
Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu 225
230 235 240 Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val
Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser
Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val Val Asp Val Ser His
Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp Tyr Val Asp Gly Val
Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro Arg Glu Glu Gln Phe
Asn Ser Thr Phe Arg Val Val Ser Val Leu 305 310 315 320 Thr Val Val
His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 325 330 335 Val
Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys 340 345
350 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser
355 360 365 Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu
Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu
Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn Tyr Lys Thr Thr Pro
Pro Met Leu Asp Ser Asp Gly 405 410 415 Ser Phe Phe Leu Tyr Ser Lys
Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430 Gln Gly Asn Val Phe
Ser Cys Ser Val Met His Glu Ala Leu His Asn 435 440 445 His Tyr Thr
Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460 <210> SEQ
ID NO 35 <211> LENGTH: 708 <212> TYPE: DNA <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 35 atggacatga
gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc 60
agatgtgaca tccagatgac ccagtctcca tcctccctgt ctgcatctgt aggagacaga
120 gtcaccatca cttgccgggc aagtcagagc attagcggct ttttaatttg
gtatcagcag 180 agaccaggga aagcccctaa gctcctgatc tatgctacat
ccagtttaca aagtggggtc 240 ccatcaaggt tcagtggcag tggatctggg
acagatttca ctctcaccat cagcagtctg 300 caacctgaag attttgcaac
ttactactgt caacagagtt acagtacccc attcactttc 360 ggccctggga
ccaaagtgga tatcaaacga actgtggctg caccatctgt cttcatcttc 420
ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct gctgaataac
480 ttctatccca gagaggccaa agtacagtgg aaggtggata acgccctcca
atcgggtaac 540 tcccaggaga gtgtcacaga gcaggacagc aaggacagca
cctacagcct cagcagcacc 600 ctgacgctga gcaaagcaga ctacgagaaa
cacaaagtct acgcctgcga agtcacccat 660 cagggcctga gctcgcccgt
cacaaagagc ttcaacaggg gagagtgt 708 <210> SEQ ID NO 36
<211> LENGTH: 236 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 36 Met Asp Met Arg Val Pro Ala
Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly Ala Arg
Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu Ser Ala
Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 35 40 45 Gln
Ser Ile Ser Gly Phe Leu Ile Trp Tyr Gln Gln Arg Pro Gly Lys 50 55
60 Ala Pro Lys Leu Leu Ile Tyr Ala Thr Ser Ser Leu Gln Ser Gly Val
65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr
Tyr Cys Gln Gln 100 105 110 Ser Tyr Ser Thr Pro Phe Thr Phe Gly Pro
Gly Thr Lys Val Asp Ile 115 120 125 Lys Arg Thr Val Ala Ala Pro Ser
Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys Ser Gly
Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe Tyr Pro
Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170 175 Gln
Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp 180 185
190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr
195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly
Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys
225 230 235 <210> SEQ ID NO 37 <211> LENGTH: 1383
<212> TYPE: DNA <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 37 atggagtttg ggctgagctg ggttttcctt
gttgctatta taaaaggtgt ccagtgtcag 60 gtgcagctgg tggagtctgg
gggaggcttg gtcaagcctg gagggtccct gagactctcc 120 tgtgcagcct
ctggattcac cttcagtgac tactatatga gctggatccg ccaggctcca 180
gggaagggac tggagtgggt ttcatacatt agtagtagtg gtagtaccat atactacgca
240 gactctgtga agggccgatt caccatctcc agggacaacg ccaagaactc
actgtatctg 300 caaatgaaca gcctgagagc cgaggacacg gccgtgtatt
actgtgcgag aggcctaact 360 ggggactact ggggccaggg aaccctggtc
accgtctcct cagcttccac caagggccca 420 tccgtcttcc ccctggcgcc
ctgctctaga agcacctccg agagcacagc ggccctgggc 480 tgcctggtca
aggactactt ccccgaaccg gtgacggtgt cgtggaactc aggcgctctg 540
accagcggcg tgcacacctt cccagctgtc ctacagtcct caggactcta ctccctcagc
600 agcgtggtga ccgtgccctc cagcagcttg ggcacgaaga cctacacctg
caacgtagat 660 cacaagccca gcaacaccaa ggtggacaag agagttgagt
ccaaatatgg tcccccatgc 720 ccatcatgcc cagcacctga gttcctgggg
ggaccatcag tcttcctgtt ccccccaaaa 780 cccaaggaca ctctcatgat
ctcccggacc cctgaggtca cgtgcgtggt ggtggacgtg 840 agccaggaag
accccgaggt ccagttcaac tggtacgtgg atggcgtgga ggtgcataat 900
gccaagacaa agccgcggga ggagcagttc aacagcacgt accgtgtggt cagcgtcctc
960 accgtcctgc accaggactg gctgaacggc aaggagtaca agtgcaaggt
ctccaacaaa 1020 ggcctcccgt cctccatcga gaaaaccatc tccaaagcca
aagggcagcc ccgagagcca 1080 caggtgtaca ccctgccccc atcccaggag
gagatgacca agaaccaggt cagcctgacc 1140 tgcctggtca aaggcttcta
ccccagcgac atcgccgtgg agtgggagag caatgggcag 1200 ccggagaaca
actacaagac cacgcctccc gtgctggact ccgacggctc cttcttcctc 1260
tacagcaggc taaccgtgga caagagcagg tggcaggagg ggaatgtctt ctcatgctcc
1320 gtgatgcatg aggctctgca caaccactac acacagaaga gcctctccct
gtctccgggt 1380 aaa 1383 <210> SEQ ID NO 38 <211>
LENGTH: 461 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 38 Met Glu Phe Gly Leu Ser Trp Val
Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val Gln
Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp
Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60
Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala 65
70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Thr Gly Asp
Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser
Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys Ser Arg
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180
185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
Ser 195 200 205 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
Lys Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
Tyr Gly Pro Pro Cys 225 230 235 240 Pro Ser Cys Pro Ala Pro Glu Phe
Leu Gly Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 305
310 315 320 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
Cys Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
Thr Ile Ser Lys 340 345 350 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
Tyr Thr Leu Pro Pro Ser 355 360 365 Gln Glu Glu Met Thr Lys Asn Gln
Val Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 405 410 415 Ser
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425
430 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn
435 440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450
455 460 <210> SEQ ID NO 39 <400> SEQUENCE: 39 000
<210> SEQ ID NO 40 <400> SEQUENCE: 40 000 <210>
SEQ ID NO 41 <400> SEQUENCE: 41 000 <210> SEQ ID NO 42
<400> SEQUENCE: 42 000 <210> SEQ ID NO 43 <211>
LENGTH: 705 <212> TYPE: DNA <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 43 atggaaaccc cagcgcagct tctcttcctc
ctgctactct ggctcccaga taccaccgga 60 gaatttgtgt tgacgcagtc
tccaggcacc ctgtctttgt ctccagggga aagagccacc 120 ctctcctgca
gggccagtca gagtgttagc agcagttact tagcctggta ccagcagaaa 180
cctggccagg ctcccaggct cctcatctat ggtgcatcca gcagggccac tggcatccca
240 gacaggttca gtggcagtgg gtctgggaca gacttcactc tcaccatcag
cagactggag 300 cctgaagatt ttgtagtgta ttactgtcag cagtatggta
gctcacctct cactttcggc 360 ggagggacca aggtggagat caaacgaact
gtggctgcac catctgtctt catcttcccg 420 ccatctgatg agcagttgaa
atctggaact gcctctgttg tgtgcctgct gaataacttc 480 tatcccagag
aggccaaagt acagtggaag gtggataacg ccctccaatc gggtaactcc 540
caggagagtg tcacagagca ggacagcaag gacagcacct acagcctcag cagcaccctg
600 acgctgagca aagcagacta cgagaaacac aaagtctacg cctgcgaagt
cacccatcag 660 ggcctgagct cgcccgtcac aaagagcttc aacaggggag agtgt
705 <210> SEQ ID NO 44 <211> LENGTH: 235 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
44 Met Glu Thr Pro Ala Gln Leu Leu Phe Leu Leu Leu Leu Trp Leu Pro
1 5 10 15 Asp Thr Thr Gly Glu Phe Val Leu Thr Gln Ser Pro Gly Thr
Leu Ser 20 25 30 Leu Ser Pro Gly Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Ser 35 40 45 Val Ser Ser Ser Tyr Leu Ala Trp Tyr Gln
Gln Lys Pro Gly Gln Ala 50 55 60 Pro Arg Leu Leu Ile Tyr Gly Ala
Ser Ser Arg Ala Thr Gly Ile Pro 65 70 75 80 Asp Arg Phe Ser Gly Ser
Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile 85 90 95 Ser Arg Leu Glu
Pro Glu Asp Phe Val Val Tyr Tyr Cys Gln Gln Tyr 100 105 110 Gly Ser
Ser Pro Leu Thr Phe Gly Gly Gly Thr Lys Val Glu Ile Lys 115 120 125
Arg Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp Glu 130
135 140 Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn
Phe 145 150 155 160 Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp
Asn Ala Leu Gln 165 170 175 Ser Gly Asn Ser Gln Glu Ser Val Thr Glu
Gln Asp Ser Lys Asp Ser 180 185 190 Thr Tyr Ser Leu Ser Ser Thr Leu
Thr Leu Ser Lys Ala Asp Tyr Glu 195 200 205 Lys His Lys Val Tyr Ala
Cys Glu Val Thr His Gln Gly Leu Ser Ser 210 215 220 Pro Val Thr Lys
Ser Phe Asn Arg Gly Glu Cys 225 230 235 <210> SEQ ID NO 45
<211> LENGTH: 1386 <212> TYPE: DNA <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 45 atggagtttg
ggctgagctg ggttttcctt gttgctatta taaaaggtgt ccagtgtcag 60
gtgcagctgg tggagtctgg gggaggcttg gtcaagcctg gagggtccct gagactctcc
120 tgtgcagcct ctggattcac cttcagtgac tactacatga gctggatccg
ccaggctcca 180 gggaaggggc tggagtgggt ttcatacatt agtagtagtg
gtagtaccat atactacgca 240 gactctgtga agggccgatt caccatctcc
agggacaacg ccaagaattc actgtatctg 300 caaatgaaca gcctgagagc
cgaggacacg gccgtgtatt actgtgcgag gcgtatagga 360 ggtatggacg
tctggggcca agggaccacg gtcaccgtct cctcagcttc caccaagggc 420
ccatccgtct tccccctggc gccctgctct agaagcacct ccgagagcac agcggccctg
480 ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa
ctcaggcgct 540 ctgaccagcg gcgtgcacac cttcccagct gtcctacagt
cctcaggact ctactccctc 600 agcagcgtgg tgaccgtgcc ctccagcagc
ttgggcacga agacctacac ctgcaacgta 660 gatcacaagc ccagcaacac
caaggtggac aagagagttg agtccaaata tggtccccca 720 tgcccatcat
gcccagcacc tgagttcctg gggggaccat cagtcttcct gttcccccca 780
aaacccaagg acactctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac
840 gtgagccagg aagaccccga ggtccagttc aactggtacg tggatggcgt
ggaggtgcat 900 aatgccaaga caaagccgcg ggaggagcag ttcaacagca
cgtaccgtgt ggtcagcgtc 960 ctcaccgtcc tgcaccagga ctggctgaac
ggcaaggagt acaagtgcaa ggtctccaac 1020 aaaggcctcc cgtcctccat
cgagaaaacc atctccaaag ccaaagggca gccccgagag 1080 ccacaggtgt
acaccctgcc cccatcccag gaggagatga ccaagaacca ggtcagcctg 1140
acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg
1200 cagccggaga acaactacaa gaccacgcct cccgtgctgg actccgacgg
ctccttcttc 1260 ctctacagca ggctaaccgt ggacaagagc aggtggcagg
aggggaatgt cttctcatgc 1320 tccgtgatgc atgaggctct gcacaaccac
tacacacaga agagcctctc cctgtctccg 1380 ggtaaa 1386 <210> SEQ
ID NO 46 <211> LENGTH: 462 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 46 Met Glu Phe Gly Leu
Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro
Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40
45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr
Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val
100 105 110 Tyr Tyr Cys Ala Arg Arg Ile Gly Gly Met Asp Val Trp Gly
Gln Gly 115 120 125 Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly
Pro Ser Val Phe 130 135 140 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
Glu Ser Thr Ala Ala Leu 145 150 155 160 Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175 Asn Ser Gly Ala Leu
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185 190 Gln Ser Ser
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser 195 200 205 Ser
Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro 210 215
220 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
225 230 235 240 Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
Ser Val Phe 245 250 255 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg Thr Pro 260 265 270 Glu Val Thr Cys Val Val Val Asp Val
Ser Gln Glu Asp Pro Glu Val 275 280 285 Gln Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala Lys Thr 290 295 300 Lys Pro Arg Glu Glu
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 305 310 315 320 Leu Thr
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys 325 330 335
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 340
345 350 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
Pro 355 360 365 Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
Cys Leu Val 370 375 380 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
Trp Glu Ser Asn Gly 385 390 395 400 Gln Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro Val Leu Asp Ser Asp 405 410 415 Gly Ser Phe Phe Leu Tyr
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 420 425 430 Gln Glu Gly Asn
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 435 440 445 Asn His
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460
<210> SEQ ID NO 47 <211> LENGTH: 708 <212> TYPE:
DNA <213> ORGANISM: Homo sapiens <400> SEQUENCE: 47
atggacatga gggtccccgc tcagctcctg gggctcctgc tactctggct ccgaggtgcc
60 agatgtgaca tccagatgac ccagtctcca tcctccctgt ctgcatctgt
aggagacaga 120 gtcaccatca cttgccgggc aagtcagagc attagcggct
ttttaatttg gtatcagcag 180 agaccaggga aagcccctaa gctcctgatc
tatgctacat ccagtttaca aagtggggtc 240 ccattaaggt tcagtggcag
tgaatctggg acagatttca ctctcaccat cagcagtctg 300 caacctgaag
attttgcaac ttactactgt caacagagtt acagtacccc attcactttc 360
ggccctggga ccaaagtgga tatcaaacga actgtggctg caccatctgt cttcatcttc
420 ccgccatctg atgagcagtt gaaatctgga actgcctctg ttgtgtgcct
gctgaataac 480 ttctatccca gagaggccaa agtacagtgg aaggtggata
acgccctcca atcgggtaac 540 tcccaggaga gtgtcacaga gcaggacagc
aaggacagca cctacagcct cagcagcacc 600 ctgacgctga gcaaagcaga
ctacgagaaa cacaaagtct acgcctgcga agtcacccat 660 cagggcctga
gctcgcccgt cacaaagagc ttcaacaggg gagagtgt 708 <210> SEQ ID NO
48 <211> LENGTH: 236 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 48 Met Asp Met Arg Val
Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15 Leu Arg Gly
Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20 25 30 Leu
Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala Ser 35 40
45 Gln Ser Ile Ser Gly Phe Leu Ile Trp Tyr Gln Gln Arg Pro Gly Lys
50 55 60 Ala Pro Lys Leu Leu Ile Tyr Ala Thr Ser Ser Leu Gln Ser
Gly Val 65 70 75 80 Pro Leu Arg Phe Ser Gly Ser Glu Ser Gly Thr Asp
Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala
Thr Tyr Tyr Cys Gln Gln 100 105 110 Ser Tyr Ser Thr Pro Phe Thr Phe
Gly Pro Gly Thr Lys Val Asp Ile 115 120 125 Lys Arg Thr Val Ala Ala
Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu Gln Leu Lys
Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150 155 160 Phe
Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu 165 170
175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp
180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala
Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu Val Thr His
Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe Asn Arg Gly
Glu Cys 225 230 235 <210> SEQ ID NO 49 <400> SEQUENCE:
49 000 <210> SEQ ID NO 50 <211> LENGTH: 462 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
50 Met Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly
1 5 10 15 Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Lys 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe 35 40 45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln
Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser
Ser Gly Ser Thr Ile Tyr Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu
Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr
Cys Ala Ile Arg Ile Gly Gly Met Asp Val Trp Gly Gln Gly 115 120 125
Thr Thr Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe 130
135 140 Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala
Leu 145 150 155 160 Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val
Thr Val Ser Trp 165 170 175 Asn Ser Gly Ala Leu Thr Ser Gly Val His
Thr Phe Pro Ala Val Leu 180 185 190 Gln Ser Ser Gly Leu Tyr Ser Leu
Ser Ser Val Val Thr Val Pro Ser 195 200 205 Ser Ser Leu Gly Thr Lys
Thr Tyr Thr Cys Asn Val Asp His Lys Pro 210 215 220 Ser Asn Thr Lys
Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro 225 230 235 240 Cys
Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe 245 250
255 Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro
260 265 270 Glu Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro
Glu Val 275 280 285 Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val His
Asn Ala Lys Thr 290 295 300 Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr
Tyr Arg Val Val Ser Val 305 310 315 320 Leu Thr Val Leu His Gln Asp
Trp Leu Asn Gly Lys Glu Tyr Lys Cys 325 330 335 Lys Val Ser Asn Lys
Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser 340 345 350 Lys Ala Lys
Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro 355 360 365 Ser
Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val 370 375
380 Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly
385 390 395 400 Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu
Asp Ser Asp 405 410 415 Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val
Asp Lys Ser Arg Trp 420 425 430 Gln Glu Gly Asn Val Phe Ser Cys Ser
Val Met His Glu Ala Leu His 435 440 445
Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460
<210> SEQ ID NO 51 <400> SEQUENCE: 51 000 <210>
SEQ ID NO 52 <211> LENGTH: 236 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 52 Met Asp
Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10 15
Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser 20
25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg Ala
Ser 35 40 45 Gln Ser Ile Ser Gly Phe Leu Ile Trp Tyr Gln Gln Lys
Pro Gly Lys 50 55 60 Ala Pro Lys Leu Leu Ile Tyr Ala Thr Ser Ser
Leu Gln Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly Ser
Gly Thr Asp Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro Glu
Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 100 105 110 Ser Tyr Ser Thr Pro
Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 115 120 125 Lys Arg Thr
Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140 Glu
Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145 150
155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala
Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp
Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu
Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys Glu
Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser Phe
Asn Arg Gly Glu Cys 225 230 235 <210> SEQ ID NO 53
<400> SEQUENCE: 53 000 <210> SEQ ID NO 54 <211>
LENGTH: 461 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 54 Met Glu Phe Gly Leu Ser Trp Val
Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val Gln
Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp
Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60
Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala 65
70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Thr Gly Asp
Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser
Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys Ser Arg
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185
190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
Gly Pro Pro Cys 225 230 235 240 Pro Pro Cys Pro Ala Pro Glu Phe Leu
Gly Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp
Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 305 310
315 320 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
Ile Ser Lys 340 345 350 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
Thr Leu Pro Pro Ser 355 360 365 Gln Glu Glu Met Thr Lys Asn Gln Val
Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile
Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 405 410 415 Ser Phe
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435
440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455
460 <210> SEQ ID NO 55 <400> SEQUENCE: 55 000
<210> SEQ ID NO 56 <211> LENGTH: 236 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 56 Met
Asp Met Arg Val Pro Ala Gln Leu Leu Gly Leu Leu Leu Leu Trp 1 5 10
15 Leu Arg Gly Ala Arg Cys Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
20 25 30 Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Arg
Pro Ser 35 40 45 Gln Ile Ile Ser Ser Leu Leu Asn Trp Tyr Gln Gln
Lys Pro Gly Lys 50 55 60 Ala Pro Lys Leu Leu Ile Tyr Ala Ala Ser
Ser Leu Gln Ser Gly Val 65 70 75 80 Pro Ser Arg Phe Ser Gly Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr 85 90 95 Ile Ser Ser Leu Gln Pro
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln 100 105 110 Ser Tyr Ser Thr
Pro Phe Thr Phe Gly Pro Gly Thr Lys Val Asp Ile 115 120 125 Lys Arg
Thr Val Ala Ala Pro Ser Val Phe Ile Phe Pro Pro Ser Asp 130 135 140
Glu Gln Leu Lys Ser Gly Thr Ala Ser Val Val Cys Leu Leu Asn Asn 145
150 155 160 Phe Tyr Pro Arg Glu Ala Lys Val Gln Trp Lys Val Asp Asn
Ala Leu 165 170 175 Gln Ser Gly Asn Ser Gln Glu Ser Val Thr Glu Gln
Asp Ser Lys Asp 180 185 190 Ser Thr Tyr Ser Leu Ser Ser Thr Leu Thr
Leu Ser Lys Ala Asp Tyr 195 200 205 Glu Lys His Lys Val Tyr Ala Cys
Glu Val Thr His Gln Gly Leu Ser 210 215 220 Ser Pro Val Thr Lys Ser
Phe Asn Arg Gly Glu Cys 225 230 235 <210> SEQ ID NO 57
<400> SEQUENCE: 57 000 <210> SEQ ID NO 58 <211>
LENGTH: 467 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 58 Met Glu Leu Gly Leu Cys Trp Val
Phe Leu Val Ala Ile Leu Glu Gly 1 5 10 15 Val Gln Cys Glu Val Gln
Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser
Phe Ser Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Arg Ser Ser Thr Ile Ser
Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg
Asp Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Pro Leu
Leu Ala Gly Ala Thr Phe Phe Asp 115 120 125 Tyr Trp Gly Gln Gly Thr
Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val
Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145 150 155 160 Ser
Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170
175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
Tyr Thr Cys Asn 210 215 220 Val Asp His Lys Pro Ser Asn Thr Lys Val
Asp Lys Arg Val Glu Ser 225 230 235 240 Lys Tyr Gly Pro Pro Cys Pro
Pro Cys Pro Ala Pro Glu Phe Leu Gly 245 250 255 Gly Pro Ser Val Phe
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 260 265 270 Ile Ser Arg
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 275 280 285 Glu
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 290 295
300 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
305 310 315 320 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
Leu Asn Gly 325 330 335 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
Leu Pro Ser Ser Ile 340 345 350 Glu Lys Thr Ile Ser Lys Ala Lys Gly
Gln Pro Arg Glu Pro Gln Val 355 360 365 Tyr Thr Leu Pro Pro Ser Gln
Glu Glu Met Thr Lys Asn Gln Val Ser 370 375 380 Leu Thr Cys Leu Val
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 385 390 395 400 Trp Glu
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 420
425 430 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
Met 435 440 445 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
Ser Leu Ser 450 455 460 Pro Gly Lys 465 <210> SEQ ID NO 59
<400> SEQUENCE: 59 000 <210> SEQ ID NO 60 <211>
LENGTH: 235 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 60 Met Glu Thr Pro Ala Gln Leu Leu
Phe Leu Leu Leu Leu Trp Leu Pro 1 5 10 15 Asp Thr Thr Gly Glu Ile
Val Leu Thr Gln Ser Pro Gly Thr Leu Ser 20 25 30 Leu Ser Pro Gly
Glu Arg Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser 35 40 45 Val Ser
Ser Ser Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala 50 55 60
Pro Arg Leu Leu Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro 65
70 75 80 Asp Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu
Thr Ile 85 90 95 Ser Arg Leu Glu Pro Glu Asp Phe Ala Val Tyr Tyr
Cys Gln Gln Tyr 100 105 110 Gly Ser Ser Pro Leu Thr Phe Gly Gly Gly
Thr Lys Val Glu Ile Lys 115 120 125 Arg Thr Val Ala Ala Pro Ser Val
Phe Ile Phe Pro Pro Ser Asp Glu 130 135 140 Gln Leu Lys Ser Gly Thr
Ala Ser Val Val Cys Leu Leu Asn Asn Phe 145 150 155 160 Tyr Pro Arg
Glu Ala Lys Val Gln Trp Lys Val Asp Asn Ala Leu Gln 165 170 175 Ser
Gly Asn Ser Gln Glu Ser Val Thr Glu Gln Asp Ser Lys Asp Ser 180 185
190 Thr Tyr Ser Leu Ser Ser Thr Leu Thr Leu Ser Lys Ala Asp Tyr Glu
195 200 205 Lys His Lys Val Tyr Ala Cys Glu Val Thr His Gln Gly Leu
Ser Ser 210 215 220 Pro Val Thr Lys Ser Phe Asn Arg Gly Glu Cys 225
230 235 <210> SEQ ID NO 61 <400> SEQUENCE: 61 000
<210> SEQ ID NO 62 <211> LENGTH: 466 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 62 Met
Glu Leu Gly Leu Cys Trp Val Phe Leu Val Ala Ile Leu Glu Gly 1 5 10
15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln
20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe 35 40 45 Ser Ser Phe Ser Met Thr Trp Val Arg Gln Ala Pro
Gly Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Arg Ser
Ser Thr Ile Ser Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr
Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met
Asn Ser Leu Arg Asp Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala
Arg Asp Pro Leu Leu Ala Gly Ala Thr Phe Phe Asp 115 120 125 Tyr Trp
Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130 135 140
Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145
150 155 160 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro
Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser
Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu
Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser Asn Phe
Gly Thr Gln Thr Tyr Thr Cys Asn 210 215 220 Val Asp His Lys Pro Ser
Asn Thr Lys Val Asp Lys Thr Val Glu Arg 225 230 235 240 Lys Cys Cys
Val Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala Gly 245 250 255 Pro
Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met Ile 260 265
270 Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser His Glu
275 280 285 Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu
Val His 290 295 300 Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn
Ser Thr Phe Arg 305 310 315 320 Val Val Ser Val Leu Thr Val Val His
Gln Asp Trp Leu Asn Gly Lys 325 330 335 Glu Tyr Lys Cys Lys Val Ser
Asn Lys Gly Leu Pro Ala Pro Ile Glu 340 345 350 Lys Thr Ile Ser Lys
Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr 355 360 365 Thr Leu Pro
Pro Ser Arg Glu Glu Met Thr Lys Asn Gln Val Ser Leu 370 375 380 Thr
Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu Trp 385 390
395 400 Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro
Met 405 410 415 Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu
Thr Val Asp 420 425 430 Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser
Cys Ser Val Met His 435 440 445 Glu Ala Leu His Asn His Tyr Thr Gln
Lys Ser Leu Ser Leu Ser Pro 450 455 460 Gly Lys 465 <210> SEQ
ID NO 63 <400> SEQUENCE: 63 000
<210> SEQ ID NO 64 <400> SEQUENCE: 64 000 <210>
SEQ ID NO 65 <400> SEQUENCE: 65 000 <210> SEQ ID NO 66
<211> LENGTH: 461 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 66 Met Glu Phe Gly Leu Ser Trp
Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Ile Arg Ile Gly Gly Met
Asp Val Trp Gly Gln Gly 115 120 125 Thr Thr Val Thr Val Ser Ser Ala
Ser Thr Lys Gly Pro Ser Val Phe 130 135 140 Pro Leu Ala Pro Cys Ser
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 145 150 155 160 Gly Cys Leu
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175 Asn
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185
190 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
195 200 205 Ser Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His
Lys Pro 210 215 220 Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys
Cys Cys Val Glu 225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Pro Val
Ala Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp
Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val
Val Asp Val Ser His Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro
Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu 305 310
315 320 Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr
Ile Ser Lys 340 345 350 Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
Thr Leu Pro Pro Ser 355 360 365 Arg Glu Glu Met Thr Lys Asn Gln Val
Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile
Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly 405 410 415 Ser Phe
Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430
Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435
440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455
460 <210> SEQ ID NO 67 <400> SEQUENCE: 67 000
<210> SEQ ID NO 68 <400> SEQUENCE: 68 000 <210>
SEQ ID NO 69 <400> SEQUENCE: 69 000 <210> SEQ ID NO 70
<211> LENGTH: 461 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 70 Met Glu Phe Gly Leu Ser Trp
Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Ile Gly Gly Met Asp
Val Trp Gly Gln Gly Thr 115 120 125 Thr Val Thr Val Ser Ser Ala Ser
Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys Ser Arg
Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185
190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205 Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys
Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr
Gly Pro Pro Cys 225 230 235 240 Pro Ser Cys Pro Ala Pro Glu Phe Leu
Gly Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp
Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val
Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp
Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro
Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 305 310
315 320 Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys
Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr
Ile Ser Lys 340 345 350 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr
Thr Leu Pro Pro Ser 355 360 365 Gln Glu Glu Met Thr Lys Asn Gln Val
Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile
Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn
Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly 405 410 415 Ser Phe
Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430
Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435
440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455
460 <210> SEQ ID NO 71 <400> SEQUENCE: 71 000
<210> SEQ ID NO 72 <400> SEQUENCE: 72 000 <210>
SEQ ID NO 73 <400> SEQUENCE: 73 000 <210> SEQ ID NO 74
<211> LENGTH: 460 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 74 Met Glu
Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20
25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
Phe 35 40 45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly
Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser
Thr Ile Tyr Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg
Gly Leu Thr Gly Asp Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150
155 160 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
Asn 165 170 175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
Val Leu Gln 180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
Thr Val Pro Ser Ser 195 200 205 Asn Phe Gly Thr Gln Thr Tyr Thr Cys
Asn Val Asp His Lys Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Thr
Val Glu Arg Lys Cys Cys Val Glu Cys 225 230 235 240 Pro Pro Cys Pro
Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe 245 250 255 Pro Pro
Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val 260 265 270
Thr Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe 275
280 285 Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys
Pro 290 295 300 Arg Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser
Val Leu Thr 305 310 315 320 Val Val His Gln Asp Trp Leu Asn Gly Lys
Glu Tyr Lys Cys Lys Val 325 330 335 Ser Asn Lys Gly Leu Pro Ala Pro
Ile Glu Lys Thr Ile Ser Lys Thr 340 345 350 Lys Gly Gln Pro Arg Glu
Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg 355 360 365 Glu Glu Met Thr
Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly 370 375 380 Phe Tyr
Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro 385 390 395
400 Glu Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser
405 410 415 Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp
Gln Gln 420 425 430 Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala
Leu His Asn His 435 440 445 Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro
Gly Lys 450 455 460 <210> SEQ ID NO 75 <400> SEQUENCE:
75 000 <210> SEQ ID NO 76 <400> SEQUENCE: 76 000
<210> SEQ ID NO 77 <400> SEQUENCE: 77 000 <210>
SEQ ID NO 78 <211> LENGTH: 461 <212> TYPE: PRT
<213> ORGANISM: Homo sapiens <400> SEQUENCE: 78 Met Glu
Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15
Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20
25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr
Phe 35 40 45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly
Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser
Thr Ile Tyr Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile
Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn
Ser Leu Arg Ala Glu Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg
Gly Leu Thr Gly Asp Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr
Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu
Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly 145 150
155 160 Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp
Asn 165 170 175 Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala
Val Leu Gln 180 185 190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val
Thr Val Pro Ser Ser 195 200 205 Ser Leu Gly Thr Lys Thr Tyr Thr Cys
Asn Val Asp His Lys Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Arg
Val Glu Ser Lys Tyr Gly Pro Pro Cys 225 230 235 240 Pro Ser Cys Pro
Ala Pro Glu Phe Leu Gly Gly Pro Ser Val Phe Leu 245 250 255 Phe Pro
Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu 260 265 270
Val Thr Cys Val Val Val Asp Val Ser Gln Glu Asp Pro Glu Val Gln 275
280 285 Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr
Lys 290 295 300 Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val
Ser Val Leu 305 310 315 320 Thr Val Leu His Gln Asp Trp Leu Asn Gly
Lys Glu Tyr Lys Cys Lys 325 330 335 Val Ser Asn Lys Gly Leu Pro Ser
Ser Ile Glu Lys Thr Ile Ser Lys 340 345 350 Ala Lys Gly Gln Pro Arg
Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser 355 360 365 Gln Glu Glu Met
Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys 370 375 380 Gly Phe
Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln 385 390 395
400 Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp Gly
405 410 415 Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg
Trp Gln 420 425 430 Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu
Ala Leu His Asn 435 440 445 His Tyr Thr Gln Lys Ser Leu Ser Leu Ser
Pro Gly Lys 450 455 460 <210> SEQ ID NO 79 <400>
SEQUENCE: 79 000 <210> SEQ ID NO 80 <400> SEQUENCE: 80
000 <210> SEQ ID NO 81 <400> SEQUENCE: 81 000
<210> SEQ ID NO 82 <211> LENGTH: 461 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 82 Met
Glu Phe Gly Leu Ser Trp Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10
15 Val Gln Cys Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys
20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe
Thr Phe 35 40 45 Ser Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro
Gly Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly
Ser Thr Ile Tyr Tyr Ala 65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85
90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala
Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Thr Gly Asp Tyr Trp Gly
Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser Thr Lys Gly
Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Cys Ser Arg Ser Thr Ser
Glu Ser Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser Gly Ala Leu
Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185 190 Ser Ser
Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser 195 200 205
Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser 210
215 220 Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys Tyr Gly Pro Pro
Cys 225 230 235 240 Pro Pro Cys Pro Ala Pro Glu Phe Leu Gly Gly Pro
Ser Val Phe Leu 245 250 255 Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
Ile Ser Arg Thr Pro Glu 260 265 270 Val Thr Cys Val Val Val Asp Val
Ser Gln Glu Asp Pro Glu Val Gln 275 280 285 Phe Asn Trp Tyr Val Asp
Gly Val Glu Val His Asn Ala Lys Thr Lys 290 295 300 Pro Arg Glu Glu
Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val Leu 305 310 315 320 Thr
Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys 325 330
335 Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys Thr Ile Ser Lys
340 345 350 Ala Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro
Pro Ser 355 360 365 Gln Glu Glu Met Thr Lys Asn Gln Val Ser Leu Thr
Cys Leu Val Lys 370 375 380 Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
Trp Glu Ser Asn Gly Gln 385 390 395 400 Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro Val Leu Asp Ser Asp Gly 405 410 415 Ser Phe Phe Leu Tyr
Ser Arg Leu Thr Val Asp Lys Ser Arg Trp Gln 420 425 430 Glu Gly Asn
Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn 435 440 445 His
Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450 455 460
<210> SEQ ID NO 83 <400> SEQUENCE: 83 000 <210>
SEQ ID NO 84 <400> SEQUENCE: 84 000 <210> SEQ ID NO 85
<400> SEQUENCE: 85 000 <210> SEQ ID NO 86 <211>
LENGTH: 462 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 86 Met Glu Phe Gly Leu Ser Trp Val
Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val Gln
Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly Ser
Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Asp
Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60
Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala 65
70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Arg Ile Gly Gly Met
Asp Val Trp Gly Gln Gly 115 120 125 Thr Thr Val Thr Val Ser Ser Ala
Ser Thr Lys Gly Pro Ser Val Phe 130 135 140 Pro Leu Ala Pro Cys Ser
Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu 145 150 155 160 Gly Cys Leu
Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp 165 170 175 Asn
Ser Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu 180 185
190 Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser
195 200 205 Ser Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn Val Asp His
Lys Pro 210 215 220 Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser Lys
Tyr Gly Pro Pro 225 230 235 240 Cys Pro Pro Cys Pro Ala Pro Glu Phe
Leu Gly Gly Pro Ser Val Phe 245 250 255 Leu Phe Pro Pro Lys Pro Lys
Asp Thr Leu Met Ile Ser Arg Thr Pro 260 265 270 Glu Val Thr Cys Val
Val Val Asp Val Ser Gln Glu Asp Pro Glu Val 275 280 285 Gln Phe Asn
Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr 290 295 300 Lys
Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr Arg Val Val Ser Val 305 310
315 320 Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys
Cys 325 330 335 Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile Glu Lys
Thr Ile Ser 340 345 350 Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val
Tyr Thr Leu Pro Pro 355 360 365 Ser Gln Glu Glu Met Thr Lys Asn Gln
Val Ser Leu Thr Cys Leu Val 370 375 380 Lys Gly Phe Tyr Pro Ser Asp
Ile Ala Val Glu Trp Glu Ser Asn Gly 385 390 395 400 Gln Pro Glu Asn
Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp Ser Asp 405 410 415 Gly Ser
Phe Phe Leu Tyr Ser Arg Leu Thr Val Asp Lys Ser Arg Trp 420 425 430
Gln Glu Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His 435
440 445 Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys 450
455 460 <210> SEQ ID NO 87 <400> SEQUENCE: 87 000
<210> SEQ ID NO 88 <400> SEQUENCE: 88 000 <210>
SEQ ID NO 89 <400> SEQUENCE: 89 000 <210> SEQ ID NO 90
<211> LENGTH: 467 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 90 Met Glu Leu Gly Leu Cys Trp
Val Phe Leu Val Ala Ile Leu Glu Gly 1 5 10 15 Val Gln Cys Glu Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Ser Phe Ser Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Val Ser Tyr Ile Ser Ser Arg Ser Ser Thr Ile Ser Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Pro Leu Leu Ala
Gly Ala Thr Phe Phe Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val
Thr Val Ser Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro
Leu Ala Pro Cys Ser Arg Ser Thr Ser Glu 145 150 155 160 Ser Thr Ala
Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val
Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr
180 185 190 Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser
Ser Val 195 200 205 Val Thr Val Pro Ser Ser Ser Leu Gly Thr Lys Thr
Tyr Thr Cys Asn 210 215 220 Val Asp His Lys Pro Ser Asn Thr Lys Val
Asp Lys Arg Val Glu Ser 225 230 235 240 Lys Tyr Gly Pro Pro Cys Pro
Pro Cys Pro Ala Pro Glu Phe Leu Gly 245 250 255 Gly Pro Ser Val Phe
Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met 260 265 270 Ile Ser Arg
Thr Pro Glu Val Thr Cys Val Val Val Asp Val Ser Gln 275 280 285 Glu
Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val Glu Val 290 295
300 His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser Thr Tyr
305 310 315 320 Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp
Leu Asn Gly 325 330 335 Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly
Leu Pro Ser Ser Ile 340 345 350 Glu Lys Thr Ile Ser Lys Ala Lys Gly
Gln Pro Arg Glu Pro Gln Val 355 360 365 Tyr Thr Leu Pro Pro Ser Gln
Glu Glu Met Thr Lys Asn Gln Val Ser 370 375 380 Leu Thr Cys Leu Val
Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu 385 390 395 400 Trp Glu
Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr Pro Pro 405 410 415
Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Arg Leu Thr Val 420
425 430 Asp Lys Ser Arg Trp Gln Glu Gly Asn Val Phe Ser Cys Ser Val
Met 435 440 445 His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu
Ser Leu Ser 450 455 460 Pro Gly Lys 465 <210> SEQ ID NO 91
<400> SEQUENCE: 91 000 <210> SEQ ID NO 92 <400>
SEQUENCE: 92 000 <210> SEQ ID NO 93 <400> SEQUENCE: 93
000 <210> SEQ ID NO 94 <211> LENGTH: 467 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
94 Met Glu Leu Gly Leu Cys Trp Val Phe Leu Val Ala Ile Leu Glu Gly
1 5 10 15 Val Gln Cys Glu Val Gln Leu Val Glu Ser Gly Gly Gly Leu
Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg Leu Ser Cys Ala Ala Ser
Gly Phe Thr Phe 35 40 45 Ser Ser Phe Ser Met Thr Trp Val Arg Gln
Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp Val Ser Tyr Ile Ser Ser
Arg Ser Ser Thr Ile Ser Tyr Ala 65 70 75 80 Asp Ser Val Lys Gly Arg
Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85 90 95 Ser Leu Tyr Leu
Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val 100 105 110 Tyr Tyr
Cys Ala Arg Asp Pro Leu Leu Ala Gly Ala Thr Phe Phe Asp 115 120 125
Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala Ser Thr Lys 130
135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser Thr Ser
Glu 145 150 155 160 Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr
Phe Pro Glu Pro 165 170 175 Val Thr Val Ser Trp Asn Ser Gly Ala Leu
Thr Ser Gly Val His Thr 180 185 190 Phe Pro Ala Val Leu Gln Ser Ser
Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205 Val Thr Val Pro Ser Ser
Ser Leu Gly Thr Lys Thr Tyr Thr Cys Asn 210 215 220 Val Asp His Lys
Pro Ser Asn Thr Lys Val Asp Lys Arg Val Glu Ser 225 230 235 240 Lys
Tyr Gly Pro Pro Cys Pro Ser Cys Pro Ala Pro Glu Phe Leu Gly 245 250
255 Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr Leu Met
260 265 270 Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val
Ser Gln 275 280 285 Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp
Gly Val Glu Val 290 295 300 His Asn Ala Lys Thr Lys Pro Arg Glu Glu
Gln Phe Asn Ser Thr Tyr 305 310 315 320 Arg Val Val Ser Val Leu Thr
Val Leu His Gln Asp Trp Leu Asn Gly 325 330 335 Lys Glu Tyr Lys Cys
Lys Val Ser Asn Lys Gly Leu Pro Ser Ser Ile 340 345 350 Glu Lys Thr
Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro Gln Val 355 360 365 Tyr
Thr Leu Pro Pro Ser Gln Glu Glu Met Thr Lys Asn Gln Val Ser 370 375
380 Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala Val Glu
385 390 395 400 Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr
Thr Pro Pro 405 410 415 Val Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr
Ser Arg Leu Thr Val 420 425 430 Asp Lys Ser Arg Trp Gln Glu Gly Asn
Val Phe Ser Cys Ser Val Met 435 440 445 His Glu Ala Leu His Asn His
Tyr Thr Gln Lys Ser Leu Ser Leu Ser 450 455 460 Pro Gly Lys 465
<210> SEQ ID NO 95 <400> SEQUENCE: 95 000 <210>
SEQ ID NO 96 <400> SEQUENCE: 96 000 <210> SEQ ID NO 97
<211> LENGTH: 1413 <212> TYPE: DNA <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 97 atggagttgg
ggctgagctg ggttttcctt gttgctatta taaaaggtgt ccagtgtgag 60
gtgcagctgg tggagtctgg gggaggcttg gtacagcctg gggggtccct gagactctcc
120 tgtgcagcct ctggattcac cttcagtagt tttagtatga cctgggtccg
ccaggctcca 180 ggaaaggggc tggagtgggt ttcatacatt agtagtagaa
gtagtaccat atcctacgca 240 gactctgtga agggccgatt caccatctcc
agagacaatg ccaagaactc actgtatctg 300 caaatgaaca gcctgagaga
cgaggacacg gctgtgtatt actgtgcgag agatcctctt 360 ctagcgggag
ctaccttctt tgactactgg ggccagggaa ccctggtcac cgtctcctca 420
gcctccacca agggcccatc ggtcttcccc ctggcaccct cctccaagag cacctctggg
480 ggcacagcgg ccctgggctg cctggtcaag gactacttcc ccgaaccggt
gacggtgtcg 540 tggaactcag gcgccctgac cagcggcgtg cacaccttcc
cggctgtcct acagtcctca 600 ggactctact ccctcagcag cgtggtgacc
gtgccctcca gcagcttggg cacccagacc 660 tacatctgca acgtgaatca
caagcccagc aacaccaagg tggacaagaa agttgagccc 720 aaatcttgtg
acaaaactca cacatgccca ccgtgcccag cacctgaact cctgggggga 780
ccgtcagtct tcctcttccc cccaaaaccc aaggacaccc tcatgatctc ccggacccct
840 gaggtcacat gcgtggtggt ggacgtgagc cacgaagacc ctgaggtcaa
gttcaactgg 900 tacgtggacg gcgtggaggt gcataatgcc aagacaaagc
cgcgggagga gcagtacaac 960 agcacgtacc gtgtggtcag cgtcctcacc
gtcctgcacc aggactggct gaatggcaag 1020 gagtacaagt gcaaggtctc
caacaaagcc ctcccagccc ccatcgagaa aaccatctcc 1080 aaagccaaag
ggcagccccg agaaccacag gtgtacaccc tgcccccatc ccgggatgag 1140
ctgaccaaga accaggtcag cctgacctgc ctggtcaaag gcttctatcc cagcgacatc
1200 gccgtggagt gggagagcaa tgggcagccg gagaacaact acaagaccac
gcctcccgtg 1260 ctggactccg acggctcctt cttcctctac agcaagctca
ccgtggacaa gagcaggtgg 1320 cagcagggga acgtcttctc atgctccgtg
atgcatgagg ctctgcacaa ccactacacg 1380 cagaagagcc tctccctgtc
tccgggtaaa tag 1413 <210> SEQ ID NO 98 <211> LENGTH:
470 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 98 Met Glu Leu Gly Leu Cys Trp Val Phe Leu
Val Ala Ile Leu Glu Gly 1 5 10 15 Val Gln Cys Glu Val Gln Leu Val
Glu Ser Gly Gly Gly Leu Val Gln 20 25 30 Pro Gly Gly Ser Leu Arg
Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser Ser Phe Ser
Met Thr Trp Val Arg Gln Ala Pro Gly Lys Gly Leu 50 55 60 Glu Trp
Val Ser Tyr Ile Ser Ser Arg Ser Ser Thr Ile Ser Tyr Ala 65 70 75 80
Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn 85
90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala
Val 100 105 110 Tyr Tyr Cys Ala Arg Asp Pro Leu Leu Ala Gly Ala Thr
Phe Phe Asp 115 120 125 Tyr Trp Gly Gln Gly Thr Leu Val Thr Val Ser
Ser Ala Ser Thr Lys 130 135 140 Gly Pro Ser Val Phe Pro Leu Ala Pro
Ser Ser Lys Ser Thr Ser Gly 145 150 155 160 Gly Thr Ala Ala Leu Gly
Cys Leu Val Lys Asp Tyr Phe Pro Glu Pro 165 170 175 Val Thr Val Ser
Trp Asn Ser Gly Ala Leu Thr Ser Gly Val His Thr 180 185 190 Phe Pro
Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val 195 200 205
Val Thr Val Pro Ser Ser Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn 210
215 220 Val Asn His Lys Pro Ser Asn Thr Lys Val Asp Lys Lys Val Glu
Pro 225 230 235 240 Lys Ser Cys Asp Lys Thr His Thr Cys Pro Pro Cys
Pro Ala Pro Glu 245 250 255 Leu Leu Gly Gly Pro Ser Val Phe Leu Phe
Pro Pro Lys Pro Lys Asp 260 265 270 Thr Leu Met Ile Ser Arg Thr Pro
Glu Val Thr Cys Val Val Val Asp 275 280 285 Val Ser His Glu Asp Pro
Glu Val Lys Phe Asn Trp Tyr Val Asp Gly 290 295 300 Val Glu Val His
Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Tyr Asn 305 310 315 320 Ser
Thr Tyr Arg Val Val Ser Val Leu Thr Val Leu His Gln Asp Trp 325 330
335 Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Ala Leu Pro
340 345 350 Ala Pro Ile Glu Lys Thr Ile Ser Lys Ala Lys Gly Gln Pro
Arg Glu 355 360 365 Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Asp Glu
Leu Thr Lys Asn 370 375 380 Gln Val Ser Leu Thr Cys Leu Val Lys Gly
Phe Tyr Pro Ser Asp Ile 385 390 395 400 Ala Val Glu Trp Glu Ser Asn
Gly Gln Pro Glu Asn Asn Tyr Lys Thr 405 410 415 Thr Pro Pro Val Leu
Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys 420 425 430 Leu Thr Val
Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys 435 440 445 Ser
Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu 450 455
460 Ser Leu Ser Pro Gly Lys 465 470 <210> SEQ ID NO 99
<400> SEQUENCE: 99 000 <210> SEQ ID NO 100 <400>
SEQUENCE: 100 000 <210> SEQ ID NO 101 <211> LENGTH:
1395 <212> TYPE: DNA <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 101 atggagtttg ggctgagctg ggttttcctt
gttgctatta taaaaggtgt ccagtgtcag 60 gtgcagctgg tggagtctgg
gggaggcttg gtcaagcctg gagggtccct gagactctcc 120 tgtgcagcct
ctggattcac cttcagtgac tactatatga gctggatccg ccaggctcca 180
gggaagggac tggagtgggt ttcatacatt agtagtagtg gtagtaccat atactacgca
240 gactctgtga agggccgatt caccatctcc agggacaacg ccaagaactc
actgtatctg 300 caaatgaaca gcctgagagc cgaggacacg gccgtgtatt
actgtgcgag aggcctaact 360 ggggactact ggggccaggg aaccctggtc
accgtctcct cagcttccac caagggccca 420 tcggtcttcc ccctggcacc
ctcctccaag agcacctctg ggggcacagc ggccctgggc 480 tgcctggtca
aggactactt ccccgaaccg gtgacggtgt cgtggaactc aggcgccctg 540
accagcggcg tgcacacctt cccggctgtc ctacagtcct caggactcta ctccctcagc
600 agcgtggtga ccgtgccctc cagcagcttg ggcacccaga cctacatctg
caacgtgaat 660 cacaagccca gcaacaccaa ggtggacaag aaagttgagc
ccaaatcttg tgacaaaact 720 cacacatgcc caccgtgccc agcacctgaa
ctcctggggg gaccgtcagt cttcctcttc 780 cccccaaaac ccaaggacac
cctcatgatc tcccggaccc ctgaggtcac atgcgtggtg 840 gtggacgtga
gccacgaaga ccctgaggtc aagttcaact ggtacgtgga cggcgtggag 900
gtgcataatg ccaagacaaa gccgcgggag gagcagtaca acagcacgta ccgtgtggtc
960 agcgtcctca ccgtcctgca ccaggactgg ctgaatggca aggagtacaa
gtgcaaggtc 1020 tccaacaaag ccctcccagc ccccatcgag aaaaccatct
ccaaagccaa agggcagccc 1080 cgagaaccac aggtgtacac cctgccccca
tcccgggatg agctgaccaa gaaccaggtc 1140 agcctgacct gcctggtcaa
aggcttctat cccagcgaca tcgccgtgga gtgggagagc 1200 aatgggcagc
cggagaacaa ctacaagacc acgcctcccg tgctggactc cgacggctcc 1260
ttcttcctct acagcaagct caccgtggac aagagcaggt ggcagcaggg gaacgtcttc
1320 tcatgctccg tgatgcatga ggctctgcac aaccactaca cgcagaagag
cctctccctg 1380 tctccgggta aatag 1395 <210> SEQ ID NO 102
<211> LENGTH: 464 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 102 Met Glu Phe Gly Leu Ser Trp
Val Phe Leu Val Ala Ile Ile Lys Gly 1 5 10 15 Val Gln Cys Gln Val
Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys 20 25 30 Pro Gly Gly
Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe 35 40 45 Ser
Asp Tyr Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu 50 55
60 Glu Trp Val Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala
65 70 75 80 Asp Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala
Lys Asn 85 90 95 Ser Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu
Asp Thr Ala Val 100 105 110 Tyr Tyr Cys Ala Arg Gly Leu Thr Gly Asp
Tyr Trp Gly Gln Gly Thr 115 120 125 Leu Val Thr Val Ser Ser Ala Ser
Thr Lys Gly Pro Ser Val Phe Pro 130 135 140 Leu Ala Pro Ser Ser Lys
Ser Thr Ser Gly Gly Thr Ala Ala Leu Gly 145 150 155 160 Cys Leu Val
Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn 165 170 175 Ser
Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln 180 185
190 Ser Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser
195 200 205 Ser Leu Gly Thr Gln Thr Tyr Ile Cys Asn Val Asn His Lys
Pro Ser 210 215 220 Asn Thr Lys Val Asp Lys Lys Val Glu Pro Lys Ser
Cys Asp Lys Thr 225 230 235 240 His Thr Cys Pro Pro Cys Pro Ala Pro
Glu Leu Leu Gly Gly Pro Ser 245 250 255 Val Phe Leu Phe Pro Pro Lys
Pro Lys Asp Thr Leu Met Ile Ser Arg 260 265 270 Thr Pro Glu Val Thr
Cys Val Val Val Asp Val Ser His Glu Asp Pro 275 280 285 Glu Val Lys
Phe Asn Trp Tyr Val Asp Gly Val Glu Val His Asn Ala 290 295 300 Lys
Thr Lys Pro Arg Glu Glu Gln Tyr Asn Ser Thr Tyr Arg Val Val 305 310
315 320 Ser Val Leu Thr Val Leu His Gln Asp Trp Leu Asn Gly Lys Glu
Tyr 325 330 335 Lys Cys Lys Val Ser Asn Lys Ala Leu Pro Ala Pro Ile
Glu Lys Thr 340 345 350 Ile Ser Lys Ala Lys Gly Gln Pro Arg Glu Pro
Gln Val Tyr Thr Leu 355 360 365 Pro Pro Ser Arg Asp Glu Leu Thr Lys
Asn Gln Val Ser Leu Thr Cys 370 375 380 Leu Val Lys Gly Phe Tyr Pro
Ser Asp Ile Ala Val Glu Trp Glu Ser 385 390 395 400 Asn Gly Gln Pro
Glu Asn Asn Tyr Lys Thr Thr Pro Pro Val Leu Asp 405 410 415 Ser Asp
Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser 420 425
430
Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser Val Met His Glu Ala 435
440 445 Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly
Lys 450 455 460 <210> SEQ ID NO 103 <211> LENGTH: 107
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 103 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser
Leu Ser Ala Ser Val Gly 1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg
Ala Ser Gln Ser Ile Ser Ser Tyr 20 25 30 Leu Asn Trp Tyr Gln Gln
Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser
Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80
Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ser Tyr Ser Thr Pro Phe 85
90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105
<210> SEQ ID NO 104 <211> LENGTH: 120 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 104
Glu Val Gln Leu Leu Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser
Tyr 20 25 30 Ala Met Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Ala Ile Ser Gly Ser Gly Gly Ser Thr Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ser Lys Asn Thr Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Lys Tyr Ser Gly
Ser Tyr Tyr Tyr Phe Asp Tyr Trp Gly Gln Gly 100 105 110 Thr Leu Val
Thr Val Ser Ser Ala 115 120 <210> SEQ ID NO 105 <211>
LENGTH: 119 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 105 Glu Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Trp Met Ser Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala Asn
Ile Lys Gln Asp Gly Ser Glu Lys Tyr Tyr Val Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65
70 75 80 Leu Gln Met Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr
Cys Ala 85 90 95 Arg Gly Ile Ala Ala Ala Gly Tyr Phe Asp Tyr Trp
Gly Gln Gly Thr 100 105 110 Leu Val Thr Val Ser Ser Ala 115
<210> SEQ ID NO 106 <211> LENGTH: 117 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 106
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Ala Leu Gly
Gly Met Asp Val Trp Gly Gln Gly Thr Thr Val 100 105 110 Thr Val Ser
Ser Ala 115 <210> SEQ ID NO 107 <211> LENGTH: 107
<212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 107 Glu Ile Val Met Thr Gln Ser Pro Ala Thr
Leu Ser Val Ser Pro Gly 1 5 10 15 Glu Arg Ala Thr Leu Ser Cys Arg
Ala Ser Gln Ser Val Ser Ser Asn 20 25 30 Leu Ala Trp Tyr Gln Gln
Lys Pro Gly Gln Ala Pro Arg Leu Leu Ile 35 40 45 Tyr Gly Ala Ser
Thr Arg Ala Thr Gly Ile Pro Ala Arg Phe Ser Gly 50 55 60 Ser Gly
Ser Gly Thr Glu Phe Thr Leu Thr Ile Ser Ser Leu Gln Ser 65 70 75 80
Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln Tyr Asn Asn Trp Pro Phe 85
90 95 Thr Phe Gly Pro Gly Thr Lys Val Asp Ile Lys 100 105
<210> SEQ ID NO 108 <211> LENGTH: 115 <212> TYPE:
PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE: 108
Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5
10 15 Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp
Tyr 20 25 30 Tyr Met Ser Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu
Glu Trp Val 35 40 45 Ser Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr
Tyr Ala Asp Ser Val 50 55 60 Lys Gly Arg Phe Thr Ile Ser Arg Asp
Asn Ala Lys Asn Ser Leu Tyr 65 70 75 80 Leu Gln Met Asn Ser Leu Arg
Ala Glu Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Arg Leu Thr Gly
Asp Tyr Trp Gly Gln Gly Thr Leu Val Thr Val 100 105 110 Ser Ser Ala
115 <210> SEQ ID NO 109 <211> LENGTH: 108 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
109 Asp Ile Gln Met Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly
1 5 10 15 Asp Arg Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser
Ser Trp 20 25 30 Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro
Lys Leu Leu Ile 35 40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val
Pro Ser Arg Phe Ser Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr
Leu Thr Ile Ser Ser Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr
Tyr Cys Gln Gln Ala Asn Ser Phe Pro Phe 85 90 95 Thr Phe Gly Pro
Gly Thr Lys Val Asp Ile Lys Arg 100 105 <210> SEQ ID NO 110
<211> LENGTH: 117 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 110 Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Val Val Gln Pro Gly Arg 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Gly Met His
Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ala
Val Ile Trp Tyr Asp Gly Ser Asn Lys Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Gly Tyr Ser Tyr Phe Asp Tyr Trp Gly Gln
Gly Thr Leu Val 100 105 110 Thr Val Ser Ser Ala
115 <210> SEQ ID NO 111 <211> LENGTH: 118 <212>
TYPE: PRT <213> ORGANISM: Homo sapiens <400> SEQUENCE:
111 Gln Val Gln Leu Val Gln Ser Gly Ala Glu Val Lys Lys Pro Gly Ala
1 5 10 15 Ser Val Lys Val Ser Cys Lys Ala Ser Gly Tyr Thr Phe Thr
Ser Tyr 20 25 30 Gly Ile Ser Trp Val Arg Gln Ala Pro Gly Gln Gly
Leu Glu Trp Met 35 40 45 Gly Trp Ile Ser Ala Tyr Asn Gly Asn Thr
Asn Tyr Ala Gln Lys Leu 50 55 60 Gln Gly Arg Val Thr Met Thr Thr
Asp Thr Ser Thr Ser Thr Ala Tyr 65 70 75 80 Met Glu Leu Arg Ser Leu
Arg Ser Asp Asp Thr Ala Val Tyr Tyr Cys 85 90 95 Ala Asp Tyr Gly
Gly Asn Tyr Phe Asp Tyr Trp Gly Gln Gly Thr Leu 100 105 110 Val Thr
Val Ser Ser Ala 115 <210> SEQ ID NO 112 <211> LENGTH:
114 <212> TYPE: PRT <213> ORGANISM: Homo sapiens
<400> SEQUENCE: 112 Asp Ile Val Met Thr Gln Ser Pro Asp Ser
Leu Ala Val Ser Leu Gly 1 5 10 15 Glu Arg Ala Thr Ile Asn Cys Lys
Ser Ser Gln Ser Val Leu Tyr Ser 20 25 30 Ser Asn Asn Lys Asn Tyr
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln 35 40 45 Pro Pro Lys Leu
Leu Ile Tyr Trp Ala Ser Thr Arg Glu Ser Gly Val 50 55 60 Pro Asp
Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr 65 70 75 80
Ile Ser Ser Leu Gln Ala Glu Asp Val Ala Val Tyr Tyr Cys Gln Gln 85
90 95 Tyr Tyr Ser Thr Pro Trp Thr Phe Gly Gln Gly Thr Lys Val Glu
Ile 100 105 110 Lys Arg <210> SEQ ID NO 113 <211>
LENGTH: 116 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 113 Glu Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Gln Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr 20 25 30 Ser Met Asn Trp
Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr
Ile Ser Ser Ser Ser Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65
70 75 80 Leu Gln Met Asn Ser Leu Arg Asp Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Ile Val Gly Phe Asp Tyr Trp Gly Gln Gly
Thr Leu Val Thr 100 105 110 Val Ser Ser Ala 115 <210> SEQ ID
NO 114 <211> LENGTH: 109 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 114 Glu Ile Val Leu
Thr Gln Ser Pro Gly Thr Leu Ser Leu Ser Pro Gly 1 5 10 15 Glu Arg
Ala Thr Leu Ser Cys Arg Ala Ser Gln Ser Val Ser Ser Ser 20 25 30
Tyr Leu Ala Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Arg Leu Leu 35
40 45 Ile Tyr Gly Ala Ser Ser Arg Ala Thr Gly Ile Pro Asp Arg Phe
Ser 50 55 60 Gly Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser
Arg Leu Glu 65 70 75 80 Pro Glu Asp Phe Ala Val Tyr Tyr Cys Gln Gln
Tyr Gly Ser Ser Pro 85 90 95 Leu Thr Phe Gly Gly Gly Thr Lys Val
Glu Ile Lys Arg 100 105 <210> SEQ ID NO 115 <211>
LENGTH: 114 <212> TYPE: PRT <213> ORGANISM: Homo
sapiens <400> SEQUENCE: 115 Gln Val Gln Leu Val Glu Ser Gly
Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser Cys
Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser Trp
Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser Tyr
Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55 60
Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr 65
70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Ile Gly Met Asp Val Trp Gly Gln Gly Thr Thr
Val Thr Val Ser 100 105 110 Ser Ala <210> SEQ ID NO 116
<211> LENGTH: 115 <212> TYPE: PRT <213> ORGANISM:
Homo sapiens <400> SEQUENCE: 116 Gln Val Gln Leu Val Glu Ser
Gly Gly Gly Leu Val Lys Pro Gly Gly 1 5 10 15 Ser Leu Arg Leu Ser
Cys Ala Ala Ser Gly Phe Thr Phe Ser Asp Tyr 20 25 30 Tyr Met Ser
Trp Ile Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val 35 40 45 Ser
Tyr Ile Ser Ser Ser Gly Ser Thr Ile Tyr Tyr Ala Asp Ser Val 50 55
60 Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ala Lys Asn Ser Leu Tyr
65 70 75 80 Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr
Tyr Cys 85 90 95 Ala Arg Leu Thr Gly Asp Tyr Trp Gly Gln Gly Thr
Leu Val Thr Val 100 105 110 Ser Ser Ala 115 <210> SEQ ID NO
117 <211> LENGTH: 108 <212> TYPE: PRT <213>
ORGANISM: Homo sapiens <400> SEQUENCE: 117 Asp Ile Gln Met
Thr Gln Ser Pro Ser Ser Val Ser Ala Ser Val Gly 1 5 10 15 Asp Arg
Val Thr Ile Thr Cys Arg Ala Ser Gln Gly Ile Ser Ser Trp 20 25 30
Leu Ala Trp Tyr Gln Gln Lys Pro Gly Lys Ala Pro Lys Leu Leu Ile 35
40 45 Tyr Ala Ala Ser Ser Leu Gln Ser Gly Val Pro Ser Arg Phe Ser
Gly 50 55 60 Ser Gly Ser Gly Thr Asp Phe Thr Leu Thr Ile Ser Ser
Leu Gln Pro 65 70 75 80 Glu Asp Phe Ala Thr Tyr Tyr Cys Gln Gln Ala
Asn Ser Phe Pro Leu 85 90 95 Thr Phe Gly Gly Gly Thr Lys Val Glu
Ile Lys Arg 100 105
* * * * *