RU2789033C2 - Use of antibodies to sclerostin for treating osteogenesis imperfecta - Google Patents

Abstract

FIELD: biotechnology.

SUBSTANCE: invention relates to the use of the anti-sclerostin antibody in the treatment of osteogenesis imperfecta (OI) in a human patient. Use involves administering to a human patient a therapeutically effective amount of a sclerostin antibody, where OI is a type I OI, a type III OI or a type IV OI, wherein the human patient has one or more mutations in the COL1A1 and/or COL1A2 genes, wherein the sclerostin antibody is administered in dose of 2–50 mg per 1 kg of the human patient’s body weight on a monthly, bi-monthly or quarterly basis.

EFFECT: invention is effective for treating osteogenesis imperfecta.

19 cl, 8 dwg, 3 tbl, 2 ex

Description

FIELD OF TECHNOLOGY TO WHICH THE INVENTION RELATES

[0001] This invention relates to antibodies and their use as pharmaceutical compositions, more specifically, to the use of antibodies to sclerostin in the treatment of osteogenesis imperfecta (imperfect bone formation).

SEQUENCE LIST

[0002] This application contains a sequence listing that is electronically presented in ASCII format using EFS-Web and is incorporated herein in its entirety by reference. The specified ASCII copy, created on December 1, 2016, is named P069492US SeqListing.txt and is 153 kilobytes in size.

BACKGROUND OF THE INVENTION

[0003] Osteogenesis imperfecta (OI)) is a rare genetic connective tissue disease characterized by bone fragility and reduced bone mass. OI includes a group of hereditary disorders that are mainly, but not always, due to mutations in the genes encoding type I collagen. About 85% of cases are associated with mutations in one or two genes encoding type I collagen (COL1A1 and COL1A2). Clinically, OI is characterized by brittle bones that often break without injury. In addition, patients with OI often have weak muscles, hearing loss, fatigue, excessive joint mobility, bone curvature, scoliosis, blue sclera, dentinogenesis imperfecta, and short stature.

[0004] The clinical classification system subdivides OI into types I-V. Patients with type I OI usually suffer from a moderate non-deforming disease that is often associated with a premature stop codon in COL1A1. This defect results in a reduced rate of production of type I collagen and less collagen in the bones. Type II OI patients usually die in the perinatal period as a result of respiratory failure due to multiple severe fractures that involve the rib cage. Type III and IV OIs are often associated with a glycine substitution in COL1A1 and COL1A2, which is a quantitative defect that prevents the three polypeptide chains of type I collagen from properly coiling into a normal triple alpha helix structure. Type III OI represents the most severe form of OI in those affected children who survive infancy, and patients with type IV OI are characterized by mild to moderate bone deformity. Type V OI is rare

[0005] There is still a need for therapeutic methods and agents for the treatment of OI.

SUMMARY OF THE INVENTION

[0006] The inventors have unexpectedly found that human patients with osteogenesis imperfecta (OI) can be successfully treated with an anti-sclerostin antibody, as shown in the examples, which confirm that an anti-sclerostin antibody can both accelerate bone formation and reduce bone resorption in patients with O.I. We have found high affinity, neutralization of a complete human anti-sclerostin monoclonal antibody (generally referred to as "anti-sclerostin human monoclonal antibody") and its in vitro and in vivo activity and have described this in our US Pat. Nos. 7,879,322, 8,246,953 and incorporated into this application by reference.

[0007] In one aspect, the present invention provides a method of treating a patient suffering from osteogenesis imperfecta, comprising administering to the patient a therapeutically effective amount of an anti-sclerostin antibody. In one embodiment, the present invention provides a method for promoting bone formation and reducing bone resorption in a patient with osteogenesis imperfecta by administering to the patient a therapeutically effective amount of an anti-sclerostin antibody. In another aspect, the invention provides an anti-sclerostin antibody for use in the treatment of osteogenesis imperfecta. In one embodiment, the anti-sclerostin antibody accelerates bone formation and/or reduces bone resorption. The following options apply to both of these aspects. In one embodiment, the anti-sclerostin antibody comprises: a) at least one immunoglobulin heavy chain (VH) variable domain, which sequentially contains the hypervariable regions CDR1 in the heavy chain variable region, CDR2 in the heavy chain variable region, and CDR3 in the heavy chain variable region, wherein said heavy chain variable region CDR1 comprises the amino acid sequence shown in SEQ ID NO: 4, said heavy chain variable region CDR2 comprises the amino acid sequence shown in SEQ ID NO: 15, and said heavy chain variable region CDR3 comprises the amino acid sequence presented in SEQ ID NO: 26; and b) at least one immunoglobulin (VL) light chain variable domain that comprises, in sequence, the hypervariable regions CDR1 in the variable light chain, CDR2 in the variable light chain, and CDR3 in the variable light chain, wherein said CDR1 in the variable light chain contains the amino acid sequence shown in SEQ ID NO: 37, said CDR2 in the light chain variable region contains the amino acid sequence shown in SEQ ID NO: 48, and said CDR3 in the light chain variable region contains the amino acid sequence shown in SEQ ID NO: 59 In another embodiment, the anti-sclerostin antibody comprises at least one or more complementarity determining regions (CDRs) selected from the group consisting of: (a) a heavy chain variable region CDR1 comprising the amino acid sequence represented by SEQ ID NO: 4; (b) a heavy chain variable region CDR2 comprising the amino acid sequence shown in SEQ ID NO: 15; (c) a heavy chain variable region CDR3 containing the amino acid sequence shown in SEQ ID NO: 26; (d) a light chain variable region CDR1 comprising the amino acid sequence shown in SEQ ID NO: 37; (e) a light chain variable region CDR2 comprising the amino acid sequence shown in SEQ ID NO: 48; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 59. In one embodiment, the anti-sclerostin antibody comprises at least a heavy chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO: 26. In one embodiment, the anti-sclerostin antibody comprises all six of the CDRs mentioned above.

[0008] In another embodiment, the anti-sclerostin antibody comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence shown in SEQ ID NO: 4; (b) a heavy chain variable region CDR2 containing the amino acid sequence shown in SEQ ID NO: 15; (c) a heavy chain variable region CDR3 containing the amino acid sequence shown in SEQ ID NO:26; (d) a light chain variable region CDR1 containing the amino acid sequence shown in SEQ ID NO: 37; (e) a light chain variable region CDR2 containing the amino acid sequence shown in SEQ ID NO: 48; and (f) a light chain variable region CDR3 comprising the amino acid sequence set forth in SEQ ID NO:59; or an anti-sclerostin antibody that binds to the same epitope as an anti-sclerostin antibody comprises: (a) a heavy chain variable region CDR1 comprising the amino acid sequence shown in SEQ ID NO: 4; (b) a heavy chain variable region CDR2 containing the amino acid sequence shown in SEQ ID NO: 15; (c) a heavy chain variable region CDR3 containing the amino acid sequence shown in SEQ ID NO: 26; (d) a light chain variable region CDR1 containing the amino acid sequence shown in SEQ ID NO: 37; (e) a light chain variable region CDR2 containing the amino acid sequence shown in SEQ ID NO: 48; and (f) a light chain variable region CDR3 comprising the amino acid sequence shown in SEQ ID NO: 59. In a related embodiment, an anti-sclerostin antibody binds to the same epitope as an anti-sclerostin antibody comprising a VL polypeptide sequence having the amino acid sequences, set forth in SEQ ID NO: 81, and a VH polypeptide sequence having the amino acid sequences set forth in SEQ ID NO: 70. In another embodiment, an anti-sclerostin antibody binds to the same epitope as an anti-sclerostin antibody comprising the entire light chain amino acid sequence, having the amino acid sequence set forth in SEQ ID NO: 125 and the complete heavy chain amino acid sequence having the amino acid sequence set forth in SEQ ID NO: 114. In one embodiment, the anti-sclerostin antibody binds to the same epitope as the anti-sclerostin antibody, containing full th light chain amino acid sequence having the amino acid sequence set forth in SEQ ID NO: 173 and the complete heavy chain amino acid sequence set forth in SEQ ID NO: 172.

In one embodiment, the anti-sclerostin antibody binds to an epitope in the region of the following human sclerostin sequences:

CGPARLLPNAIGRGKWWRPSGPDFRC ("loop 2 epitope"; SEQ ID NO: 174) and/or DVSEYCRELHFTR SAKPVTELVCSGQCGPAR WWRPSGPDFRCIPDRYR LVASCKCKRLTR ("T20.6 epitope" SEQ ID NO: 175). Thus, in one embodiment, an anti-sclerostin antibody of the invention binds to epitope loop 2/in the epitope loop 2 region. In another embodiment, an anti-sclerostin antibody of the invention binds to a T20.6 epitope/in the region of the T20.6 epitope. Anti-sclerostin antibodies that bind to the loop 2 epitope/in the loop 2 epitope region and regions of the T20.6 epitope are known in the art - see, for example, WO 00/32773, WO 2005/003158, WO 2005/014650 , WO 2006/119107, WO 2006/119062, WO 2009/039175 and WO 2008/061013. The 'Ab-A', 'Ab-B', 'Ab-C', 'Ab-D' and Ab-1 antibodies described in WO 2006/119062 are expressly incorporated herein by reference, including six CDRs, variable the heavy and light chain sequences, as well as the complete heavy and light chain sequences of these antibodies. In one embodiment, an anti-sclerostin antibody of the invention binds to the same epitope as an anti-sclerostin antibody comprising a VL polypeptide sequence having the amino acid sequences set forth in SEQ ID NO: 176 and a VH polypeptide sequence having the amino acid sequences set forth in SEQ ID NO: 176. NO: 177. In another embodiment, an anti-sclerostin antibody of the invention binds to the same epitope as Ab-A, Ab-B, Ab-C or Ab-D antibodies described in WO 2006/119062.

[0009] In one embodiment, the anti-sclerostin antibody is selected from blososumab.

[0010] In another embodiment, the anti-sclerostin antibody comprises a VH region that is at least 90 (e.g., at least 95, 98, or 99, or 100%) identical to the amino acid sequence shown in SEQ ID NO: 70. According to yet another in an embodiment, the anti-sclerostin antibody comprises a VL region that is at least 90 (e.g., at least 95, 98, or 99, or 100%) identical to the amino acid sequence shown in SEQ ID NO: 81. In another embodiment, the anti-sclerostin antibody comprises a VH region at least 90 (e.g., at least 95, 98, or 99, or 100%) identical to the amino acid sequence shown in SEQ ID NO: 70 and a VL region at least 90 (e.g., by at least 95, 98, or 99 or 100%) of the amino acid sequence represented by SEQ ID NO: 81. In another embodiment, the anti-sclerostin antibody contains a VH region that is at least 90 (e.g., at least 95, 98, and or 99 or 100%) of the amino acid sequence shown in SEQ ID NO: 81 and a VL region at least 90 (e.g., at least 95, 98, or 99 or 100%) identical to the amino acid sequence shown in SEQ ID NO: 81. In yet another embodiment, the anti-sclerostin antibody comprises a heavy chain that is at least 90 (e.g., at least 95, 98, or 99 or 100) percent identical to the amino acid sequence shown in SEQ ID NO: 114 or 172 , and/or at least 90 (e.g., at least 95, 98, or 99, or 100) percent identical to a light chain having the amino acid sequence shown in SEQ ID NO: 125 or 173. In one embodiment, the sclerostin antibody comprises a heavy chain having the amino acid sequence shown in SEQ ID NO: 172 and a light chain having the amino acid sequence shown in SEQ ID NO: 173.

[0011] In one embodiment, a therapeutically effective amount of an anti-sclerostin antibody is about 1-50 mg of said antibody per kg of the patient's body weight.

[0012] Another aspect of the invention relates to a pharmaceutical composition for accelerating bone formation and reducing bone resorption in a patient with osteogenesis imperfecta. In some embodiments, the composition comprises an anti-sclerostin antibody comprising: a) at least one immunoglobulin heavy chain (VH) variable domain that sequentially contains the hypervariable regions CDR1 in the heavy chain variable region, CDR2 in the heavy chain variable region, and CDR3 in the variable region of the heavy chain, and the specified CDR1 in the variable region of the heavy chain contains the amino acid sequence shown in SEQ ID NO: 4, the specified CDR2 in the variable region of the heavy chain contains the amino acid sequence shown in SEQ ID NO: 15, and the specified CDR3 in the variable region the heavy chain region contains the amino acid sequence shown in SEQ ID NO: 26; and b) at least one immunoglobulin light chain (VL) variable domain that comprises, in sequence, the hypervariable regions CDR1 in the variable light chain, CDR2 in the variable light chain, and CDR3 in the variable light chain, wherein said CDR1 in the variable light chain contains the amino acid sequence shown in SEQ ID NO: 37, said CDR2 in the light chain variable region contains the amino acid sequence shown in SEQ ID NO: 48, and said CDR3 in the light chain variable region contains the amino acid sequence shown in SEQ ID NO: 59.

[0013] In another embodiment, the anti-sclerostin antibody in the pharmaceutical composition comprises a VH that is at least 95 percent identical to the amino acid sequence shown in SEQ ID NO: 70. In another embodiment, the anti-sclerostin antibody contains a VL that is at least 95 percent identical the amino acid sequence shown in SEQ ID NO: 81.

[0014] In yet another embodiment, the anti-sclerostin antibody comprises a VH that is at least 95 percent identical to the amino acid sequence shown in SEQ ID NO: 70 and a VL that is at least 95 percent identical to the amino acid sequence shown in SEQ ID NO: 81 In another embodiment, the anti-sclerostin antibody comprises a VH having the amino acid sequence shown in SEQ ID NO: 70 and a VL having the amino acid sequence shown in SEQ ID NO: 81. In another embodiment, the anti-sclerostin antibody comprises a heavy chain having an amino acid sequence as set forth in SEQ ID NO: 114 or 172 and/or a light chain having an amino acid sequence as set forth in SEQ ID NO: 125 or 173.

[0015] In one aspect, the invention provides a pharmaceutical composition comprising an anti-sclerostin antibody described herein. According to one option, the pharmaceutical composition can be used in the methods/applications described in this application

BRIEF DESCRIPTION OF THE FIGURES

[0016] Figure 1 is a table showing the results of the one-sample t-test method in the analysis of biomarkers of bone metabolism.

[0017] Figure 2 is a table showing the results of the two-sample t-test method in the analysis of biomarkers of bone metabolism.

[0018] Figure 3 is a graph showing the ratios of geometric mean versus turn-on time (plus or minus SD) for PINP.

[0019] Figure 4 is a graph showing the ratios of geometric mean versus turn-on time (plus or minus SD) for PICP.

[0020] Figure 5 is a graph showing the ratios of geometric mean versus turn-on time (plus or minus SD) for BSAP.

[0021] Figure 6 is a graph showing the ratios of geometric mean versus turn-on time (plus or minus SD) for the OS.

[0022] Figure 7 is a graph showing the Bayesian posterior probability of relationship versus turn-on time for BMD of the lumbar spine (data measured by DXA).

[0023] Figure 8 is a graph showing the ratios of geometric mean versus turn-on (plus or minus SD) for CTX-1.

IMPLEMENTATION OF THE INVENTION

[0024] The present invention is based on unexpected and surprising data indicating that human patients with osteogenesis imperfecta (OI) can be successfully treated with an anti-sclerostin antibody. The use of an anti-sclerostin antibody in humans with OI accelerates bone formation and reduces bone resorption as shown in the examples.

[0025] For reference, sclerostin is a naturally occurring protein that is encoded by the SOST gene in humans. Sclerostin is a secreted C-terminal cysteine knot glycoprotein (CTCK) similar in sequence to the DAN (Differentiated Screening Selective Aberrant Genes in Neuroblastoma) family of proteins, antagonists of bone morphogenetic protein (BMP) activity.

[0026] As shown for the first time by the present inventors, inhibition of sclerostin by anti-sclerostin antibodies actively promotes bone formation and bone density and provides a beneficial effect in the treatment of OI in humans. Unlike known anabolic drug treatments using GH (growth hormone) or PTH (parathyroid hormone), which accelerate bone remodeling, anti-sclerostin antibody treatment has the advantage of promoting bone formation while inhibiting bone resorption in patients with OI. Therefore, the clinical use of anti-sclerostin antibodies includes the treatment of osteogenesis imperfecta in humans, where bone formation is a beneficial therapeutic effect in a disease characterized by a significant lack of bone matrix.

[0027] In fact, this invention is directed to methods of using anti-sclerostin antibodies in the treatment of OI, as well as compositions containing anti-sclerostin antibodies for use in the treatment of OI. According to one aspect, the present invention relates to the treatment of osteogenesis imperfecta types I, III or IV. Accordingly, the invention provides antibodies to sclerostin and pharmaceutical compositions containing said antibodies for use in the treatment of OI, preferably OI types I, III or IV. In one embodiment, an anti-sclerostin antibody of the invention is an anti-sclerostin monoclonal antibody. In one embodiment, an anti-sclerostin antibody of the invention is a human or humanized anti-sclerostin monoclonal antibody. Alternatively, the antibody may be, for example, a chimeric antibody.

[0028] The methods and uses of the anti-sclerostin antibody of the present invention are unexpected and surprising because treatment of patients with OI with this antibody results in both increased bone formation and decreased bone resorption.

[0029] For a better understanding of the present invention, some definitions are first given. Additional definitions are given in the text of the detailed description.

[0030] The term "comprising" encompasses the term "comprising" as well as "consisting of", for example, a composition "comprising" X may consist solely of X or may include something additional, for example, may include X +Y.

[0031] The term "about" in relation to the numerical value of x means, for example, x ± 10%.

[0032] The term "sclerostin" refers to human sclerostin, the sequence of which is shown in SEQ ID NO: 155. Recombinant human sclerostin can be purchased from R&D Systems (Minneapolis, Minn., USA; 2006 cat# 1406-ST-025). In addition, recombinant murine sclerostin/SOST is commercially available from R&D Systems (Minneapolis, Minn., USA; 2006 cat# 1589-ST-025). US Patent Nos. 6,395,511 and 6,803,453 and US Published Applications 20040009535 and 20050106683 refer to anti-sclerostin antibodies in general.

[0033] The term "antibody" as used in this application encompasses full-length antibodies and any antigen-binding fragment (ie, "antigen-binding site") or single-stranded variants thereof. A naturally occurring "antibody" is a glycoprotein containing at least two heavy (H) chains and two light (L) chains linked by disulfide bridges. Each heavy chain consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains, CH1, CH2 and CH3. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of a single domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability called complementarity determining regions (CDRs), which are interspersed with regions that are more conserved and called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged in the direction from amino to carboxyl in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, FR4. The variable regions of the heavy and light chains contain a binding domain that interacts with an antigen. Antibody constant regions can mediate immunoglobulin binding to host tissues or factors, including various cells of the immune system (eg, effector cells) and the first component (C1q) of the classical complement system. In one embodiment, reference to an antibody in this application includes isolated, monoclonal, human, and humanized antibodies.

[0034] The term "antigen-binding site" of an antibody (or simply "part" of an antibody) as used herein refers to a full-length antibody or one or more antibody fragments that retain the ability to specifically bind to an antigen (for example, in the case of sclerostin). It has been found that the antigen-binding function of an antibody can be performed using fragments of a full length antibody. Examples of binding fragments encompassed by the term "antigen binding site" of an antibody include the Fab fragment, a monovalent fragment consisting of the VL, VH, CL, and CH1 domains; F(ab) ₂ fragment, bivalent fragment, consisting of two Fab fragments connected by a disulfide bridge in the hinge region; Fd fragment consisting of VH and CH1 domains; Fv fragment, consisting of the VL and VH domains of one antibody arm; dAb fragment (Ward et al., 1989 Nature 341:544-546), which consists of a VH domain and a complementarity determined region (CDR).

[0035] In addition, although the two domains of the Fv fragment, VL and VH, are encoded by different genes, they can be connected using recombinant methods using a synthetic linker that allows them to form a single protein chain in which the pair of VL and VH combines to form monovalent molecules (known as single-stranded Fv fragment (scFv); see, for example, Bird et al., 1988 Science 242:423-426; and Huston et al., 1988 Proc. Natl. Acad. Sci. 85 :5879-5883). It is assumed that such single-chain antibodies also fall under the concept of "antigen-binding site" antibodies. These antibody fragments can be obtained using conventional methods known to the person skilled in the art, and these fragments are screened for utility similar to the use of intact antibodies.

[0036] The term "isolated antibody" as used herein refers to an antibody that is substantially free of other antibodies having a different antigenic specificity (e.g., an isolated antibody that specifically binds sclerostin is substantially free of other antibodies that specifically bind to antigens other than sclerostin). An isolated antibody that specifically binds to sclerostin may, however, be cross-reacted with other antigens, such as sclerostin molecules from other species. Moreover, the isolated antibody may be substantially free of other cellular material and/or chemicals. In one embodiment, reference to an antibody in this application means an isolated antibody.

[0037] The terms "monoclonal antibody" or "monoclonal antibody composition" as used in the context of this invention refer to the preparation of antibody molecules of a single molecular composition. A monoclonal antibody composition has the same binding specificity and affinity for a particular epitope.

[0038] The term "human antibody" as used in the context of this application is intended to include antibodies carrying variable regions in which both the framework regions and the CDR regions are derived from sequences of human origin. In addition, if the antibody contains a constant region, that constant region is also derived from human sequences, e.g., human germline sequences or from mutant versions of human germline sequences, or an antibody containing consensus framework sequences derived from analysis of human framework sequences, such as described in Knappik, et al. (2000. J. Mol. Biol. 296, 57-86).

[0039] Human antibodies may include amino acid residues that are not encoded by human sequences (eg, as a result of mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo). However, as used herein, the term "human antibody" is not intended to refer to antibodies in which CDR sequences derived from the germline of other mammalian species, such as the mouse, have been "grafted" onto (grafted into) human framework sequences.

[0040] The term "human monoclonal antibody" refers to antibodies exhibiting the same binding specificity that have variable regions in which both the framework regions and the CDR regions are derived from human sequences. In one embodiment, human monoclonal antibodies are generated by a hybridoma that includes a B cell derived from a transgenic non-human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.

[0041] The term "recombinant human antibody" as used herein includes all human antibodies that are produced, expressed, generated, or isolated by recombination techniques, such as antibodies isolated from an animal (e.g., mouse), e.g., an antibody that is transgenic or transchromosomal with respect to the genes of a human immunoglobulin or a hybridoma derived from it, an antibody isolated from a host cell transformed to express a human antibody, for example, using a transfectome, an antibody isolated from a library of recombinant combinatorial human antibodies, and an antibody, obtained, expressed, created, or isolated by any other means, which includes splicing all or part of the human immunoglobulin gene sequences with other DNA sequences. Such recombinant human antibodies have variable regions in which framework regions and CDR regions are derived from human germline immunoglobulin sequences. However, in some embodiments, such recombinant human antibodies may be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, may be subjected to somatic mutagenesis in vivo) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, although bred, are related to human germline VH and VL sequences may not occur naturally in the in vivo human germline antibody population.

[0042] In one embodiment, and as used herein, "an antibody that binds to sclerostin" (eg, an anti-sclerostin antibody) means that it specifically binds to a sclerostin polypeptide. The expression "specifically binds to a sclerostin polypeptide" is intended to refer to an antibody that binds to a sclerostin polypeptide with a K _D value of 1×10 ^-8 M or less, 1×10 ^-9 M or less, or 1×10 ^-10 M or less. The designation "K _D ", used in this application, refers to the dissociation constant, which is obtained from the ratio of Kd to K _a (ie, K _d /K _a ) and is expressed as a molar concentration (M). The K _D values for antibodies can be determined using methods well known in the art. The method for determining the K _D of an antibody is carried out using the surface plasmon resonance phenomenon or a biosensor system such as the Biacore® system.

[0043] Standard assay methods for evaluating the binding ability of anti-sclerostin antibodies of various species are known in the art, including, for example, ELISAs, Western blots, and RIAs (radioimmunoassay). Suitable methods of analysis are described in detail in the application WO 2009/047356. The binding kinetics (eg, affinity) of antibodies can also be assessed using standard assay methods known in the art, such as the Biacore assay. Assay methods for evaluating the effect of antibodies on the functional properties of sclerostin (eg, receptor binding, preventing or attenuating osteolysis) are described in detail in WO 2009/047356.

[0044] In the context of this application, the percent identity of two sequences is a function of the number of identical positions divided by the number of compared sequences (i.e., % identity = # identical positions / total number of positions × 100), taking into account the number of gaps (breaks) and length each gap that needs to be introduced to optimally align the two sequences. Comparing sequences and determining percent identity between two sequences can be accomplished using a mathematical algorithm as described in the non-limiting examples below.

[0045] Percent identity between two amino acid sequences can be determined using the Myers and Miller algorithm (E. Meyers and W. Miller (Comput. Appl. Biosci., 4:11-17, 1988)), which was included in the ALIGN program ( version 2.0) using a PAM 120 weighted residue table, a gap length penalty of 12, and a gap penalty of 4. In addition, percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J . Mol, Biol. 48:444-453, 1970)), which was included in the GAP program in the GCG software package (available at http://www.gcg.com), using either the 62 matrix or the PAM matrix 250, and gap weights of 16, 14, 12, 10, 8, 6, or 4, and length weights of 1, 2, 3, 4, 5, or 6.

[0046] Additionally or alternatively, the sequence of the proteins according to the present invention can also be used as a "search (query) sequence" for searches in public databases, for example, to identify related sequences. Such searches can be performed using the XBLAST program (version 2.0) described in Altschul, et al., 1990 J. Mol. Biol. 215:403-10. BLAST protein searches can be performed with the XBLAST program, score=50, wordlength=3, to obtain amino acid sequences homologous to antibody molecules of the invention. Gapped BLAST can be used to obtain a gapped alignment for comparison purposes, as described in Altschul et al., 1997 Nucleic Acids Res. 25(17): 3389-3402. When using the BLAST and Gapped BLAST programs, default parameter values from the respective programs (eg, XBLAST and NBLAST) are used. See http:www.ncbi.nhn.nih.gov.

[0047] Various aspects of the invention are further described in detail in the following subsections.

Methods of treatment and use of antibodies to sclerostin in the treatment of QI

[0048] According to one aspect, the invention is directed to methods for treating patients with OI with anti-sclerostin antibodies or using anti-sclerostin antibodies in the treatment of OI. Treatment with anti-sclerostin antibodies can both accelerate bone formation and decrease bone resorption in patients with OI. In one aspect, the present invention provides an anti-sclerostin antibody for use in the treatment of OI. Suitable antibodies to sclerostin for use in the treatment of OI are described in this application.

[0049] In some embodiments, the invention relates to a method for increasing bone formation and decreasing bone resorption in a patient with OI, and the method comprises administering to the patient a therapeutically effective amount of an anti-sclerostin antibody. In one embodiment, treating a patient with OI with an anti-sclerostin antibody of the invention increases bone formation and/or reduces bone resorption in said patient with OI.

[0050] In one embodiment, the amino acid sequences of the anti-sclerostin VH antibody are shown in SEQ ID NOs: 69-77. The amino acid sequences of the VL anti-sclerostin antibody are shown in SEQ ID NOs: 80-88, respectively. The corresponding heavy chain amino acid sequences of the full-length anti-sclerostin antibodies are shown in SEQ ID NOs: 113-121. The corresponding light chain amino acid sequences of the full-length anti-sclerostin antibodies are shown in SEQ ID NOs: 124-132, respectively. In another embodiment, the anti-sclerostin antibody comprises amino acids that have been mutated but are still at least 60 percent, 70 percent, 80 percent, 90 percent, or 95 percent or more sequence identical in the CDR regions, with the CDR regions shown in the sequences described above. In yet another embodiment, the anti-sclerostin antibody comprises mutated amino acid sequences in which no more than 1, 2, 3, 4, or 5 amino acids are mutated in the CDR regions when compared to the CDR regions shown in the sequence described above.

[0051] In some embodiments, the nucleotide sequences of the variable region of the parent anti-sclerostin antibody heavy chain are shown in SEQ ID NOs 89-90. The nucleotide sequences of the variable region of the parent anti-sclerostin antibody heavy chain are shown in SEQ ID NOs 100-101. Full length light chain nucleotide sequences optimized for expression in a mammalian cell are shown in SEQ ID NOs 146-154. Full length heavy chain nucleotide sequences optimized for expression in a mammalian cell are shown in SEQ ID NOs 135-143. Full length light chain amino acid sequences encoded by optimized light chain nucleotide sequences are shown in SEQ ID NOs 124-132. Full length heavy chain amino acid sequences encoded by optimized heavy chain nucleotide sequences are shown in SEQ ID NOs 113-121. In other embodiments, the anti-sclerostin antibody comprises amino acids or nucleic acids that have been mutated but are still at least 60 percent, 70 percent, 80 percent, 90 percent, or 95 percent or more identical to the sequences described above. In some embodiments, the anti-sclerostin antibody comprises mutant amino acid sequences in which no more than 1, 2, 3, 4, or 5 amino acids have been mutated in the variable regions as compared to the variable regions shown in the sequence described above, while retaining substantially the same the most therapeutic activity.

[0052] In other embodiments, the full length light chain VH, VL sequences and full length heavy chain sequences (nucleotide sequences and amino acid sequences) described above can be "matched". Binding of sclerostin to such "matched" antibodies can be determined using the binding assay methods described above and in the Examples (eg, ELISAs). When such strands are matched and combined, the VH sequence in a particular VH/VL pair must be replaced with a structurally similar VH sequence. Similarly, the full-length heavy chain sequence of a particular full-length heavy chain/full-length light chain pair must be replaced with a structurally similar full-length heavy chain sequence. Similarly, the VL sequence in a particular VH/VL pair must be replaced by a structurally similar VL sequence. Similarly, the full-length light chain sequence of a particular full-length heavy chain/full-length light chain pair must be replaced with a structurally similar full-length light chain sequence. In one aspect, the invention provides an isolated monoclonal antibody, or antigen-binding site thereof, comprising a heavy chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 69-77; and a light chain variable region comprising an amino acid sequence selected from the group consisting of SEQ ID NOs: 80-88; moreover, this antibody specifically binds to sclerostin.

[0053] In some embodiments, the anti-sclerostin antibody is (i) an isolated monoclonal antibody having a full length heavy chain comprising an amino acid sequence that has been optimized for expression in a mammalian cell selected from the group consisting of SEQ ID NOs: 113-121; and a full length light chain containing an amino acid sequence that has been optimized for expression in a mammalian cell selected from the group consisting of SEQ ID NOs: 124-132; or (ii) a functional protein containing its antigen-binding fragment.

[0054] In other embodiments, the anti-sclerostin antibody is (i) an isolated monoclonal antibody having a full length heavy chain comprising an amino acid sequence that has been optimized for expression in a mammalian cell selected from the group consisting of SEQ ID NOs: 135-143; and a full-length light chain containing an amino acid sequence that has been optimized for expression in a mammalian cell selected from the group consisting of SEQ ID NOs: 146-154; or (ii) a functional protein containing its antigen-binding fragment.

[0055] In yet another aspect, the anti-sclerostin antibody comprises CDR1s, CDR2s, and CDR3s of the antibody heavy chain and light chain, or combinations thereof. The amino acid sequences of the CDR1s VH antibodies are shown in SEQ ID NOs: 1-11. The amino acid sequences of the CDR2s VH antibodies are shown in SEQ ID NOs: 12-22. The amino acid sequences of the CDR3s VH antibodies are shown in SEQ ID NOs: 23-33. The amino acid sequences of the CDR1s VL antibodies are shown in SEQ ID NOs: 34-44. The amino acid sequences of the CDR2s VL antibodies are shown in SEQ ID NOs: 45-55. The amino acid sequences of the CDR3s VL antibodies are shown in SEQ ID NOs: 56-66. Sequence numbering in CDR regions is given according to the Kabat system (Kabat, E. A., et al., 1991 Sequences of Proteins of Immunological Interest, Fifth Edition, U.S. Department of Health and Human Services, NIH Publication No. 91-3242).

[0056] In some embodiment, the anti-sclerostin antibody is generated after the CDR1, 2 and 3 VH sequences and the CDR1, 2 and 3 VL sequences are "matched" (ie, CDRs from different antibodies can be mixed and matched). Binding of sclerostin to such "matched" antibodies can be determined using the binding assay methods described above and in the Examples (eg, ELISAs). When the VH CDR sequences are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from the particular VH sequence must be replaced with structurally similar CDR sequence(s). Similarly, when VL CDRs are mixed and matched, the CDR1, CDR2 and/or CDR3 sequence from a particular VL sequence must be replaced with structurally similar CDR sequence(s). One of ordinary skill in the art will readily recognize that new VH and VL sequences can be created by replacing one or more of the VH and/or VL variable region CDR sequences with structurally similar sequences from the CDR sequences described herein for monoclonal antibodies according to invention.

[0057] For example, an anti-sclerostin antibody may have a CDR1 in the heavy chain variable region containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 1-11; CDR2 in the variable region of the heavy chain, containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 12-22; CDR3 in the variable region of the heavy chain, containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 23-33; CDR1 in the variable region of the light chain, containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 34-44; CDR2 in the variable region of the light chain, containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 45-55; and a CDR3 in the variable region of the light chain containing an amino acid sequence selected from the group consisting of SEQ ID NOs: 56-66; moreover, this antibody specifically binds to sclerostin.

[0058] In some embodiment, the anti-sclerostin antibody comprises: CDR1 of SEQ ID NO: 3 heavy chain variable region; CDR2 of SEQ ID NO: 14 heavy chain variable region; CDR3 of SEQ ID NO: 25 heavy chain variable region; CDR1 of SEQ ID NO: 36 light chain variable region; CDR2 of SEQ ID NO: 47 light chain variable region; and CDR3 of SEQ ID NO: 58 light chain variable region.

[0059] In some embodiment, the anti-sclerostin antibody comprises: CDR1 of SEQ ID NO: 4 heavy chain variable region; CDR2 of SEQ ID NO: 15 heavy chain variable region; CDR3 of SEQ ID NO: 26 heavy chain variable region; CDR1 of SEQ ID NO: 37 light chain variable region; CDR2 of SEQ ID NO: 48 light chain variable region; and CDR3 of SEQ ID NO: 59 of the light chain variable region.

[0060] In some embodiment, the anti-sclerostin antibody comprises: CDR1 of SEQ ID NO: 5 of the heavy chain variable region; CDR2 of SEQ ID NO: 16 heavy chain variable region; CDR3 of SEQ ID NO: 27 heavy chain variable region; CDR1 of SEQ ID NO: 38 light chain variable region; CDR2 of SEQ ID NO: 49 light chain variable region; and CDR3 of SEQ ID NO: 60 of the light chain variable region.

[0061] In some embodiment, the anti-sclerostin antibody comprises: CDR1 of SEQ ID NO: 6 of the heavy chain variable region; CDR2 of SEQ ID NO: 17 heavy chain variable region; CDR3 of SEQ ID NO: 28 heavy chain variable region; CDR1 of SEQ ID NO: 39 light chain variable region; CDR2 of SEQ ID NO: 50 light chain variable region; and CDR3 of SEQ ID NO: 61 light chain variable region.

[0062] In some embodiment, the anti-sclerostin antibody comprises: CDR1 of SEQ ID NO: 7 of the heavy chain variable region; CDR2 of SEQ ID NO: 18 heavy chain variable region; CDR3 of SEQ ID NO: 29 heavy chain variable region; CDR1 of SEQ ID NO: 40 light chain variable region; CDR2 of SEQ ID NO: 51 light chain variable region; and CDR3 of SEQ ID NO: 62 light chain variable region.

[0063] In some embodiment, the anti-sclerostin antibody comprises: CDR1 of SEQ ID NO: 8 heavy chain variable region; CDR2 of SEQ ID NO: 19 heavy chain variable region; CDR3 of SEQ ID NO: 30 heavy chain variable region; CDR1 of SEQ ID NO: 41 light chain variable region; CDR2 of SEQ ID NO: 52 light chain variable region; and CDR3 of SEQ ID NO: 63 light chain variable region.

[0064] In some embodiment, the anti-sclerostin antibody comprises: CDR1 of SEQ ID NO: 9 of the heavy chain variable region; CDR2 of SEQ ID NO: 20 heavy chain variable region; CDR3 of SEQ ID NO: 31 heavy chain variable regions; CDR1 of SEQ ID NO: 42 light chain variable region; CDR2 of SEQ ID NO: 53 light chain variable region; and CDR3 of SEQ ID NO: 64 light chain variable region.

[0065] In some embodiment, the anti-sclerostin antibody comprises: CDR1 of SEQ ID NO: 10 of the heavy chain variable region; CDR2 of SEQ ID NO: 21 heavy chain variable regions; CDR3 of SEQ ID NO: 32 heavy chain variable region; CDR1 of SEQ ID NO: 43 light chain variable region; CDR2 of SEQ ID NO: 54 light chain variable region; and CDR3 of SEQ ID NO: 65 of the light chain variable region.

[0066] In some embodiment, the anti-sclerostin antibody comprises: CDR1 of SEQ ID NO: 11 of the heavy chain variable region; CDR2 of SEQ ID NO: 22 heavy chain variable region; CDR3 of SEQ ID NO: 33 heavy chain variable region; CDR1 of SEQ ID NO: 44 light chain variable region; CDR2 of SEQ ID NO: 55 light chain variable region; and CDR3 of SEQ ID NO: 66 of the light chain variable region.

[0067] In some embodiment, the anti-sclerostin antibody comprises: an amino acid sequence of a VH polypeptide that is at least 95 percent identical to the amino acid sequence shown in SEQ ID NO: 70.

[0068] In some embodiment, the anti-sclerostin antibody comprises: an amino acid sequence of a VL polypeptide that is at least 95 percent identical to the amino acid sequence shown in SEQ ID NO: 81.

[0069] In some embodiment, the anti-sclerostin antibody comprises: a VH polypeptide amino acid sequence that is at least 95 percent identical to the amino acid sequence shown in SEQ ID NO: 70 and a VL polypeptide amino acid sequence that is at least 95 percent amino acid identical. the sequence shown in SEQ ID NO: 81.

[0070] In some embodiment, the anti-sclerostin antibody comprises: the amino acid sequence of the VH polypeptide set forth in SEQ ID NO: 70 and the amino acid sequence of the VL polypeptide set forth in SEQ ID NO: 81.

[0071] In some embodiment, the anti-sclerostin antibody comprises: the polypeptide heavy chain amino acid sequence set forth in SEQ ID NO: 114 or 172 and the polypeptide light chain amino acid sequence set forth in SEQ ID NO: 125 or 173.

[0072] In a preferred embodiment, the anti-sclerostin antibody is BPS804, which is a human anti-sclerostin monoclonal antibody. BPS804 includes the following CDRs: CDR1 region of SEQ ID NO: 4 of the heavy chain variable region; plot CDR2 from SEQ ID NO: 15 variable region of the heavy chain; plot CDR3 from SEQ ID NO: 26 variable region of the heavy chain; plot CDR1 of SEQ ID NO: 37 variable region of the light chain; plot CDR2 from SEQ ID NO: 48 variable region of the light chain; and the CDR3 region of SEQ ID NO: 59 of the light chain variable region. The VH and VL sequences of BPS804 comprise: the amino acid sequence of the VH polypeptide shown in SEQ ID NO: 70 and the amino acid sequence of the VL polypeptide shown in SEQ ID NO: 81. The heavy and light chain sequences of the BPS804 antibody contain: the amino acid sequence of the heavy chain polypeptide shown in in SEQ ID NO: 172, and the amino acid sequence of the light chain polypeptide shown in SEQ ID NO: 173.

[0073] Additional characteristics of the anti-sclerostin antibodies of the present invention, such as BPS804, are described in WO 2009/047356, the description, discussion and data of which are incorporated herein by reference. For example, by way of example only, antibodies of the invention may exhibit at least one of the following functional characteristics: an antibody blocks the inhibitory effect of sclerostin as assessed by a cellular Wnt signaling assay, an antibody blocks the inhibitory effect of sclerostin as assessed by a cellular assay mineralization, the antibody blocks the inhibitory effect of sclerostin as measured by Smad1 phosphorylation cell assay, the antibody inhibits the binding of sclerostin to LRP-6, and the antibody accelerates bone formation and increases bone density and mass. As noted above, these properties are described in detail in WO 2009/047356.

[0074] With respect to an antibody that "blocks the inhibitory effect of sclerostin as assessed by a cellular wnt signaling assay", it is meant to refer to an antibody that restores wnt-induced signaling in the presence of sclerostin as assessed by a cellular (reporter) signaling assay. SuperTopFlash (STF) assay that has IC50 values of less than 1 mM, 100 nM, 20 nM, 10 nM, or less. WO 2009/047356 describes said wnt STF assay.

[0075] With respect to an antibody that "blocks inhibitory sclerostin as assessed by cellular mineralization assay", it is understood that this term refers to an antibody that restores BMP2-induced mineralization in the presence of sclerostin as assessed by cellular analysis, which is characterized by IC50 values less than 1 mM, 500 nM, 100 nM, 10 nM, 1 nM or less.

[0076] With respect to an antibody that "blocks the inhibitory effect of sclerostin as assessed by a cellular assay of Smad1 phosphorylation", it is meant to refer to an antibody that restores BMP6-induced Smad1 phosphorylation in the presence of sclerostin as assessed by a cellular assay, which is characterized IC50 values less than 1 mM, 500 nM, 100 nM, 10 nM, 1 nM or less.

[0077] With respect to an antibody that "inhibits the binding of sclerostin to LRP-6", it is understood that this term refers to an antibody that inhibits the binding of sclerostin to LRP-6, which has IC50 values of less than 1 mM, 500 nM, 100 nM, 10 nM, 5 nM, 3 nM, 1 nM or less.

[0078] In relation to an antibody that "accelerates bone formation and increases its density and mass", it is understood that this term refers to an antibody that has the ability to enhance bone formation, increase its mass and density at a level characteristic of intermittent therapy with an interval of one day, using a high anabolic dose of PTH, such as intermittent therapy with a dose of 100 mcg/kg hPTH.

[0079] In one embodiment, the anti-sclerostin antibody of the invention accelerates bone formation and/or reduces bone resorption.

Dosing regimen

[0080] Dosage regimens are adjusted to provide the optimal desired response (eg, therapeutic response). For example, a single bolus may be administered, several separate doses may be administered over a period of time, or the dose may be proportionally reduced or increased, according to the needs of the therapeutic situation. It is most advantageous to formulate compositions for parenteral administration in the form of unit dosage forms of the drug for ease of administration and uniformity of doses. Unit dosage form of the drug in this application refers to physically discrete units suitable for the introduction of unit doses of subjects undergoing treatment; each unit contains a predetermined amount of the active compound calculated to produce the desired therapeutic effect in combination with the required pharmaceutical carrier. The specifics of the unit dosage forms of the invention are determined by and directly dependent on the individual characteristics of the active compound and the particular therapeutic effect to be achieved, and are determined by the limitations known in the art of making such an active compound associated with the treatment of sensitive individuals. In one embodiment, the unit dosage form of the invention is 10-5000 mg of an anti-sclerostin antibody, or 10-4000 mg, 10-3000 mg, 10-2000 mg, 10-1000 mg, 10-500 mg, 10-400 mg, mg, 10-200 mg, 10-150 mg, 10-100 mg, 10-80 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-35 mg, 10-30 mg, 10-25 mg, 10-20 mg, or 10-15 mg. In one embodiment, the unit dosage form is 150 mg of an anti-sclerostin antibody. In another embodiment, the unit dosage form is 210 mg of an anti-sclerostin antibody.

[0081] In one embodiment, the anti-sclerostin antibody in unit dosage form is in a lyophilized state and may have a powdery consistency. In another embodiment, the anti-sclerostin antibody in unit dosage form is in the form of a solution. In one embodiment, the unit dosage form of the invention is contained in a container, such as a vial. In another embodiment, the container is a syringe.

[0082] In addition to the active substance (ie, the anti-sclerostin antibody), the unit dosage form may contain one or more additional substances and/or excipients. In one embodiment, the unit dosage form contains one or more of the following: sucrose, arginine hydrochloride, L-histidine, polysorbate 80, hydrochloric acid, and water for injection (wfi).

[0083] In one aspect, the invention provides a kit comprising an anti-sclerostin antibody of the invention, or a pharmaceutical composition of the invention, or a lyophilisate of the invention, or a unit dosage form of the invention. The kit may also optionally contain instructions in the form of, for example, a patient information leaflet, instructions for reconstituting the lyophilisate, and/or instructions for administration. In one embodiment, the kit includes a syringe containing one or more therapeutically effective doses of an anti-sclerostin antibody. The anti-sclerostin antibody in the syringe may be in liquid or lyophilized form. The kit may also contain a lyophilisate reconstitution solution and/or an infusion solution (eg 5% dextrose in sterile water).

[0084] When administering an anti-sclerostin antibody, the dose ranges from about 1 milligram of said antibody per kilogram of patient weight (hereinafter referred to as "mg/kg" in this application) to 50 mg/kg, typically from about 1 to 30 mg/kg, and more often from about 1 to 20 mg/kg For example, the dose may be about 5 mg/kg of weight, about 10 mg/kg of weight, about 20 mg/kg of weight, or range from about 5-20 mg/kg.

[0085] According to another aspect of the invention, the anti-sclerostin antibody is administered at a dose of 1-50 mg per kg of patient weight, eg 2-50, 3-50, 5-50, 8-50 mg/kg.

[0086] In one embodiment, the anti-sclerostin antibody is administered at a dose of 2-50 mg per kg of patient weight, eg 2-45, 2-40, 2-35, 2-30 mg/kg.

[0087] In one embodiment, the anti-sclerostin antibody is administered at a dose of 3-50 mg per kg of patient weight, eg 3-45, 3-40, 3-35, 3-30 mg/kg.

[0088] In one embodiment, the anti-sclerostin antibody is administered at a dose of 5-50 mg per kg of patient weight, eg 5-45, 5-40, 5-35, 5-30 mg/kg.

[0089] In one embodiment, the anti-sclerostin antibody is administered at a dose of 8-50 mg per kg of patient weight, eg 8-45, 8-40, 8-35, 8-30 mg/kg.

[0090] In one embodiment, the anti-sclerostin antibody is administered at a dose of 10-50 mg per kg of patient weight, eg 10-45, 10-40, 10-35, 10-30 mg/kg.

[0091] In one embodiment, the anti-sclerostin antibody is administered at a dose of 11-50 mg per kg of patient weight, eg, 11-45, 11-40, 11-35, 11-30 mg/kg.

[0092] In one embodiment, the anti-sclerostin antibody is administered at a dose of 12-50 mg per kg of patient weight, eg 12-45, 12-40, 12-35, 12-30 mg/kg.

[0093] In one embodiment, the anti-sclerostin antibody is administered at a dose of 15-50 mg per kg of patient weight, eg 15-45, 15-40, 15-35, 15-30 mg/kg.

[0094] In one embodiment, the anti-sclerostin antibody is administered at a dose of 18-50 mg per kg of patient weight, eg 18-45, 18-40, 18-35, 18-30 mg/kg.

[0095] In one embodiment, the anti-sclerostin antibody is administered at a dose of 20-50 mg per kg of patient weight, eg 20-45, 20-40, 20-35, 20-30 mg/kg.

[0096] In one embodiment, the anti-sclerostin antibody is administered at a dose of 5-20 mg per kg of patient weight, eg 8-20, 10-20, 12-20, 15-20 mg/kg.

[0097] In one embodiment, the anti-sclerostin antibody is administered at a dose of 10 mg per kg of patient weight, or 1, 2, 3, 4, 5, 6, 7, 8, 9 mg/kg.

[0098] In one embodiment, the anti-sclerostin antibody is administered at a dose of 20 mg per kg of patient weight, or 11, 12, 13, 14, 15, 17, 18, 19 mg/kg.

[0099] In one embodiment, the anti-sclerostin antibody is administered at a dose of 30 mg per kg of patient weight, or 21, 22, 23, 24, 25, 26, 27, 28, 29 mg/kg.

[00100] In one embodiment, the anti-sclerostin antibody is administered at a dose of 10 mg per kg of patient weight. In a related embodiment, the anti-sclerostin antibody is administered at a dose of 8-12 mg/kg or 8-15 mg/kg.

[00101] In one embodiment, the anti-sclerostin antibody is administered at a dose of 20 mg per kg of patient weight. In a related embodiment, the anti-sclerostin antibody is administered at a dose of 8-22 mg/kg or 15-25 mg/kg.

[00102] According to another aspect of the invention, the anti-sclerostin antibody is administered at a dose of 10-5000 g. In one embodiment, the anti-sclerostin antibody is administered at a dose of 10-4000 mg, 10-3000 mg, mg, 10-400 mg, 10-300 mg, 10-200 mg, 10-150 mg, 10-100 mg, 10-80 mg, 10-60 mg, 10-50 mg, 10-40 mg, 10-35 mg, 10-30 mg, 10-25 mg, 10-20 mg or 10-15 mg. In one embodiment, the anti-sclerostin antibody is administered at a dose of 10-3500 mg. In one embodiment, the anti-sclerostin antibody is administered at a dose of 10-3000 mg. In one embodiment, the anti-sclerostin antibody is administered at a dose of 10-2000 mg. In one embodiment, the anti-sclerostin antibody is administered at a dose of 10-1500 mg. In one embodiment, the anti-sclerostin antibody is administered at a dose of 10-1000 mg.

[00103] An exemplary dosing regimen provides for the administration of multiple doses, which may be the same or different doses, comprising, for example, about 5-20 mg/kg, with a schedule of once a week, once every two weeks, once every three weeks , once every four weeks, once a month or monthly, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months (that is, once every two months), once every three months (that is, quarterly), once every three to six months, every six months or annually. In some embodiments, multiple doses may be 2-20 doses, more commonly 2-10 doses, and more commonly 3-5 doses, and even more often 3 doses in a dosing regimen of once a week, once every two weeks, once every three weeks, once every four weeks, once a month or monthly, once every five weeks, once every six weeks, once every seven weeks, once every eight weeks, once every two months (that is, once every two months), once every three months, once every three to six months, every six months or annually.

[00104] According to another aspect of the invention, the anti-sclerostin antibody may be administered to the patient on a daily, weekly, biweekly, monthly, bimonthly, quarterly, or yearly basis.

[00105] In one embodiment, the anti-sclerostin antibody is administered to the patient on a weekly basis. According to another variant, the introduction is carried out every 2, 3, 4, 5, 6 or 7 weeks.

[00106] In one embodiment, the anti-sclerostin antibody is administered to the patient on a monthly basis. According to another variant, the introduction is carried out every 2, 3, 4, 5 or 6 months.

[00107] In one embodiment, the anti-sclerostin antibody is administered to the patient every three months (ie, on a quarterly basis). For more frequent use, weekly or daily administration, an administration schedule that allows patients to self-administer the antibody, is preferred. For example, subcutaneous, topical, or oral administration facilitates self-administration of the anti-sclerostin antibody and eliminates physician/hospital visits for treatment.

[00108] Another exemplary treatment regimen involves the administration of multiple doses, which may be the same or different doses, for example, about 5-20 mg/kg, until the patient's goal of treatment is provided or achieved. The goal of treatment is achieved or achieved after the introduction of a certain number of doses. The goal of treatment may be complete normalization of bone mineral density, partial normalization of bone mineral density, or reduced incidence of bone fractures, increased levels of bone formation markers, or decreased levels of bone resorption markers. Thus, in one embodiment, the invention provides an anti-sclerostin antibody for use in the treatment of OI, wherein the anti-sclerostin antibody reduces the number of fractures in a patient/patient population compared to a control patient/patient population. Preferably, the anti-sclerostin antibody reduces fractures by at least 10, 20, 30, 35, 40, 50, 60, 70, 80, or 90 percent. In one embodiment, the anti-sclerostin antibody reduces fractures by at least 30 percent. In one embodiment, fractures are defined as peripheral fractures or vertebral fractures (including all major, minor, and clinical forms of vertebral fractures; fractures detectable only by examination without clinical symptoms are not included) confirmed by radiological examination(s). In one embodiment, the number of fractures refers to a population of patients. The patient population and the control patient population preferably contain a number of patients that allows a statistically significant comparison to be made.

[00109] According to one aspect of the invention, the treatment regimen comprises a first dosage regimen, optionally accompanied by a second dosage regimen. The dosage regimen includes the doses to be administered and the frequency of administration. They may be selected from any of the above doses and frequency of administration and may vary according to the clinical requirements of the patient. The magnitude of the doses and frequency of administration described above are expressly covered by this aspect of the invention.

[00110] For example, according to one variant, the first dosage regimen provides for the introduction of 1-50 mg per kg of patient weight, or 2-50 mg/kg, or 3-50 mg/kg, or 5-50 mg/kg, or 8-50 mg/kg, or 3-30 mg/kg, 5-30 mg/kg, or 8-30 mg/kg, or 10-30 mg/kg, or 12-30 mg/kg, or 15-30 mg/kg , or 12-25 mg/kg, or 15-25 mg/kg, on a monthly basis. In another exemplary embodiment, the first dosage regimen is 10-5000 mg administered on a monthly basis.

[00111] According to one embodiment, the first dosing regimen provides for the introduction of a dose of 1-50 mg per kg of the patient's weight monthly.

[00112] According to one embodiment, the first dosing regimen provides for the introduction of a dose of 2-50 mg per kg of the patient's weight monthly.

[00113] According to one embodiment, the first dosing regimen provides for the introduction of a dose of 2-30 mg per kg of the patient's weight monthly.

[00114] In one embodiment, the first dosing regimen is administered at a dose of 3-50 mg per kg of patient weight monthly.

[00115] According to one embodiment, the first dosing regimen provides for the introduction of a dose of 3-30 mg per kg of the patient's weight monthly.

[00116] According to one embodiment, the first dosing regimen provides for the introduction of a dose of 5-30 mg per kg of the patient's weight monthly.

[00117] In one embodiment, the first dosing regimen is administered at a dose of 5-25 mg per kg of patient weight monthly.

[00118] According to one embodiment, the first dosing regimen provides for the introduction of a dose of 12-25 mg per kg of the patient's weight monthly.

[00119] According to one embodiment, the first dosing regimen provides for the introduction of a dose of 20 mg per kg of the patient's weight monthly.

[00120] In another exemplary embodiment, the first dosing regimen is 1-50 mg per kg of patient weight, or 2-50 mg/kg, or 3-50 mg/kg, or 5-50 mg/kg, or 8- 50 mg/kg or 8-30 mg/kg or 10-30 mg/kg or 12-30 mg/kg or 15-30 mg/kg or 12-25 mg/kg or 15-25 mg /kg quarterly. In another exemplary embodiment, the first dosing regimen is administered at a dose of 10-5000 mg quarterly.

[00121] According to one embodiment, the first dosing regimen provides for the introduction of a dose of 2-30 mg per kg of the patient's weight once a quarter.

[00122] According to one embodiment, the first dosing regimen provides for the introduction of a dose of 3-30 mg per kg of the patient's weight once a quarter.

[00123] According to one variant, the first dosing regimen provides for the introduction of a dose of 5-30 mg per kg of the patient's weight once a quarter.

[00124] According to one variant, the first dosing regimen provides for the introduction of a dose of 5-25 mg per kg of the patient's weight once a quarter.

[00125] According to one embodiment, the first dosing regimen provides for the introduction of a dose of 12-25 mg per kg of the patient's weight once a quarter.

[00126] According to one variant, the first dosing regimen provides for the introduction of a dose of 20 mg per kg of the patient's weight once a quarter.

[00127] In one embodiment, and by way of example only, the second dosage regimen is 1-50 mg per kg of patient weight, or 2-50 mg/kg, or 3-50 mg/kg, or 5-50 mg/kg. kg, or 8-50 mg/kg, or 3-30 mg/kg, or 5-30 mg/kg, or 8-30 mg/kg, or 10-30 mg/kg, or 12-30 mg/kg, or 12-25 mg/kg, or 15-30 mg/kg, or 15-25 mg/kg, per kg of patient's weight monthly. In another exemplary embodiment, the second dosing regimen is 10-5000 mg administered monthly.

[00128] In one embodiment, the second dosing regimen is administered at a dose of 1-50 mg per kg of patient weight monthly.

[00129] In one embodiment, the second dosing regimen is administered at a dose of 2-50 mg per kg of patient weight monthly.

[00130] In one embodiment, the second dosing regimen is administered at a dose of 2-30 mg per kg of patient weight monthly.

[00131] In one embodiment, the second dosing regimen is administered at a dose of 3-50 mg per kg of patient weight monthly.

[00132] In one embodiment, the second dosing regimen is administered at a dose of 3-30 mg per kg of patient weight monthly.

[00133] In one embodiment, the second dosing regimen is administered at a dose of 5-30 mg per kg of patient weight monthly.

[00134] According to one embodiment, the second dosing regimen provides for the introduction of a dose of 5-25 mg per kg of the patient's weight monthly.

[00135] According to one embodiment, the second dosing regimen provides for the introduction of a dose of 12-25 mg per kg of the patient's weight monthly.

[00136] According to one embodiment, the second dosing regimen provides for the introduction of a dose of 20 mg per kg of the patient's weight monthly.

[00137] According to another variant, the second dosing regimen provides for the introduction of a dose of 1-50 mg per kg of patient weight, or 2-50 mg/kg, or 3-50 mg/kg, or 5-50 mg/kg, or 8-50 mg/kg, or 3-30 mg/kg, 5-30 mg/kg, or 8-30 mg/kg, or 10-30 mg/kg, or 12-30 mg/kg, or 12-25 mg/kg , or 15-30 mg/kg, or 15-25 mg/kg every two months. In another exemplary embodiment, the second dosing regimen is 10-5000 mg administered every two months.

[00138] In one embodiment, the second dosing regimen is administered at a dose of 1-50 mg per kg of patient weight every two months.

[00139] In one embodiment, the second dosing regimen is administered at a dose of 2-50 mg per kg of patient weight every two months.

[00140] In one embodiment, the second dosing regimen is administered at a dose of 2-30 mg per kg of the patient's weight every two months.

[00141] In one embodiment, the second dosing regimen is administered at a dose of 3-50 mg per kg of patient weight every two months.

[00142] In one embodiment, the second dosing regimen is administered at a dose of 3-30 mg per kg of patient weight every two months.

[00143] In one embodiment, the second dosing regimen is administered at a dose of 5-30 mg per kg of the patient's weight every two months.

[00144] In one embodiment, the second dosing regimen is administered at a dose of 5-25 mg per kg of patient weight every two months.

[00145] In one embodiment, the second dosing regimen comprises

administration at a dose of 12-25 mg per kg of the patient's weight every two months.

[00146] In one embodiment, the second dosing regimen is administered at a dose of 20 mg per kg of the patient's weight every two months.

[00147] In another exemplary embodiment, the second dosing regimen is 1-50 mg per kg of patient weight, or 2-50 mg/kg, 3-50 mg/kg, or 5-50 mg/kg, or 8-50 mg/kg or 8-30 mg/kg or 10-30 mg/kg or 12-30 mg/kg or 12-25 mg/kg or 15-30 mg/kg or 15-25 mg/kg kg once a quarter. In another exemplary embodiment, the second dosing regimen is administered at a dose of 10-5000 mg quarterly.

[00148] In one embodiment, the second dosing regimen is administered at a dose of 2-30 mg per kg of the patient's body weight quarterly.

[00149] In one embodiment, the second dosing regimen is administered at a dose of 3-30 mg per kg of the patient's body weight quarterly.

[00150] In one embodiment, the second dosing regimen is administered at a dose of 5-30 mg per kg of the patient's body weight quarterly.

[00151] In one embodiment, the second dosing regimen is administered at a dose of 5-25 mg per kg of the patient's body weight quarterly.

[00152] In one embodiment, the second dosing regimen is administered at a dose of 12-25 mg per kg of the patient's body weight quarterly.

[00153] According to one embodiment, the second dosing regimen provides for the introduction of a dose of 20 mg per kg of the patient's weight once a quarter.

[00154] In a similar embodiment, the first dosing regimen is administered at a dose of 20 mg per kg of patient weight monthly, and the second dosage regimen is administered at a dose of 20 mg per kg of patient weight every two months or quarterly.

[00155] The duration of the first and second dosing regimens can be varied according to the clinical needs of the patient. Thus, the first dosing regimen is carried out for one period of time, and the second dosing regimen is carried out for another period of time.

[00156] For example, the duration of the first and second periods may be 1 month, 6 months, 12 months, or some other period of time.

[00157] In one embodiment, the anti-sclerostin antibody may be initially administered to the patient monthly for 1 year, followed by bimonthly or quarterly administration for at least 1 year (eg, for 2 or more years).

[00158] So, according to one variant, the first dosing regimen may include the introduction of a dose of 20 mg per kg of the weight of a sick person monthly for 1 year, and the second dosing regimen may include the introduction of a dose of 20 mg per kg of the weight of a sick person once every two months or quarterly for at least 1 year (eg, for 2 or more years).

[00159] Periods of drug withdrawal, i.e. periods during which anti-sclerostin antibody is not administered are also considered in the present invention, depending on the clinical needs of the patient. Thus, in one embodiment, anti-sclerostin antibody treatment is interrupted for one or more (eg, 2, 3, 4, 5, 6, 8, 10, 12 or more) months, or even one or more years.

[00160] Methods for measuring targets are known in the art. For example, bone mineral density can be measured by dual energy x-ray absorptiometry (DXA, DERA), single energy x-ray absorptiometry (SXA, OERA), quantitative computed tomography (CT, CT), and ultrasound. DXA is an x-ray method that has become the standard method for measuring bone mineral density in the prior art. Although this method can be used to measure any part of the skeleton, clinical tests are usually performed in the region of the lumbosacral spine and hip bone. Portable DXA instruments have been developed that measure the heel (calcaneus), forearm (radius and ulna), or toe (phalanges), and DXA can also be used to perform body composition analysis. As a consequence, it has become standard practice to correlate results with "normal" values using T-scores, which compare individual results with results in a youth population matched by race and sex. Alternatively, Z-scores involve comparing individual scores with those of an age-matched population that is also matched for race and sex. So, for example, a 60-year-old woman with a Z-score of 1 (1 SD below the average for the elderly) could have a T-score of 2.5 (2.5 SD below the average for the youth control group).

[00161] Another exemplary treatment regimen involves the administration of multiple doses, which may be the same dosage or different dosages, starting from about 5-20 mg/kg, for long-term use without a specific time frame before stopping the administration. This may be the treatment regimen to be followed when a dose is required to maintain symptom relief for a long time.

[00162] In other embodiments, the sclerostin antibody regimen includes three doses at the same dosage, for example, at a dosage of 5 mg/kg of body weight, 10 mg/kg of body weight, or 20 mg/kg of body weight, using intravenous administration, sequentially with an interval of 1 -3 weeks, preferably 2 weeks between two consecutive doses. In other embodiments, the anti-sclerostin antibody schedule includes three doses at three different dosages, for example, the first at a dosage of 5 mg/kg of body weight, then 10 mg/kg of body weight, and finally 20 mg/kg of body weight via intravenous administration sequentially with an interval of 1 -3 weeks, preferably 2 weeks, between two consecutive doses. In other embodiments, the anti-sclerostin antibody regimen includes three doses at three different dosages, for example, the first at a dosage of 20 mg/kg of body weight, then 10 mg/kg of body weight, and finally 5 mg/kg of body weight via intravenous administration sequentially with an interval of 1 -3 weeks, preferably 2 weeks between two consecutive doses.

[00163] In some embodiments, the anti-sclerostin antibody and one or more monoclonal antibodies with different binding specificities are administered simultaneously or sequentially, in which case the dosage of each antibody administered is within the indicated range. In one embodiment, the one or more additional monoclonal antibodies are also anti-sclerostin antibodies. The antibody is usually administered multiple times. The frequency of administration of unit doses may be, for example, weekly, monthly, every two months (ie every two months), every three months or annually. The frequency may also be irregular as measured by the levels of antibody to the target antigen in the patient's blood. In some methods, the dose is adjusted to achieve a plasma antibody concentration of about 1-1000 µg/ml and, in some methods, about 25-300 µg/ml. In some embodiments, the dose of an anti-sclerostin antibody of the invention is adjusted to achieve a plasma antibody concentration of about 1-1000 µg/mL and, in some methods, about 25-300 µg/mL.

[00164] Alternatively, in some embodiments, the anti-sclerostin antibody can be administered to OI patients in a sustained release dosage form, in which case less frequent administration is required. The dose and frequency of administration vary depending on the half-life of the antibody in the patient's body. Typically, human antibodies have the longest half-life, followed by humanized antibodies, chimeric antibodies, and non-human antibodies. The dose and frequency of administration may vary depending on whether the treatment is prophylactic or therapeutic. When used for prophylaxis, a relatively low dose is administered at relatively infrequent intervals over an extended period of time. Some patients continue to receive treatment for the rest of their lives. In the case of therapeutic use, a relatively high dose is sometimes required at relatively short intervals until the progression of the disease slows down or stops, or until the patient experiences partial or complete relief of the symptoms of the disease. After that, the patient can be transferred to a preventive treatment regimen.

[00165] In some embodiments, the actual dose levels of the anti-sclerostin antibody can be varied so as to obtain an amount of the anti-sclerostin antibody that is effective to achieve the desired therapeutic effect for a particular patient with OI, while the particular composition and the particular route of administration are not toxic to patient. The selected dose level will depend on various pharmacokinetic factors, including the activity of the specific compositions of the present invention used, the route of administration, the time of administration, the rate of excretion of the particular anti-sclerostin antibody used, the duration of treatment, other drugs, compounds and/or materials used in combination with specific compositions used, age, sex, body weight, pathological condition, general condition of the patient, medical history of the patient being treated, and similar factors well known in the medical field.

[00166] A "therapeutically effective amount" of an anti-sclerostin antibody may result in a reduction in the severity of symptoms of the disease, an increase in the frequency and duration of periods of asymptomatic disease, or the prevention of dysfunction or disability due to the disease.

[00167] The anti-sclerostin antibody composition can be administered by one or more routes of administration using one or more of a variety of methods known in the art. As will be apparent to those skilled in the art, the route and/or mode of administration will vary depending on the desired results. Routes of administration of the antibodies of the invention include intravenous, intramuscular, intradermal, intraperitoneal, subcutaneous, spinal, or other parenteral routes of administration, for example, by injection or infusion. According to one variant, the administration is carried out by intravenous route. According to one variant, the administration is carried out intravenously by infusion. In one embodiment, administration is carried out subcutaneously. The expression "parenteral administration" in this context means methods of administration other than enteral and topical administration, usually by injection, and includes, but is not limited to, intravenous, intramuscular, intraarterial, intrathecal, intraarticular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal , subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrasternal injection and infusion.

[00168] Alternatively, the anti-sclerostin antibody can be administered by a non-parenteral route, eg, topical, epidermal, or transmucosal route, eg, intranasally, orally, vaginally, rectally, sublingually, or topically.

The anti-sclerostin antibody can be formulated with carriers that can prevent the compound from being released rapidly, for example, controlled release formulations can be provided, including delivery systems such as implants, transdermal patches, and microencapsulated formulations. Biodegradable polymers can be used, for example, ethylene-vinyl acetate, polyanhydrides, polyglycolic acid, collagen, polyorthoesters, and polylactic acid. Many methods for preparing such formulations are patented or well known to those skilled in the art. See, for example, Sustained and Controlled Release Drug Delivery Systems, J. R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.

Patient group

[00169] In one embodiment, the methods and uses described herein are for the treatment of osteogenesis imperfecta using the anti-sclerostin antibodies of the present disclosure. OIs are categorized according to genetics and disease severity, and according to the Van Dijk and Sillence classification (2014 publications, Am. J. Med. Genet. Part A 164A:1470-1481 and Van Dijk and Sillence, 2014, Am. J. Med. Genet. Part A 167A:1178; which are incorporated herein by reference in their entirety) it can be classified as Type I OI, Type II OI, Type III OI, Type IV OI, or Type V OI. evaluation/diagnosis, biochemical analysis, as well as molecular genetic testing and is common to a person skilled in the art. This description uses the terminology/classification of OI proposed by Van Dijk and Sillence, as indicated above.

К. et al. (2016) описал b методы секвенирования следующего поколения (Sci. Rep.6, 28417). Эти ссылочные материалы включены в настоящее изобретение посредством отсылки.[00170] In 80%-90% of people with OI, this disease is caused by mutations in the COL1A1 and COL1A2 genes (17q21.33 and 7q22.3, respectively), encoding the alpha1 and alpha 2 collagen type-I chains. A comprehensive database describing over 1000 known mutations along with genotype-phenotype correlation has been published (https://oi.gene.le.ac.uk/home.php; accessed 12 December 2016). Mutations in other genes such as CRTAP, LEPRE1 or PPIB are also known. Molecular genetic tests for mutations in, inter alia, the COL1A1 and COL1A2 genes are known and are routine procedures for those skilled in the art. For example, Korkko et al. (1998) describe PCR amplification of the COL1A1 and COL1A2 genes followed by conformation sensitive gel electrophoresis (CSGE) scanning for mutations (Am. J. Hum. Genet. 62:98-110, 1998). Van Dijk et al. (2010) describe the detection of COL1A1 mutation by multiplex ligase-dependent probe amplification (MLPA) (Genet Med 12(11):736-741). Later

K. et al. (2016) described next generation sequencing methods (Sci. Rep.6, 28417). These reference materials are incorporated into the present invention by reference.

[00171] In one embodiment, the methods and uses described herein are for the treatment of patients who are deficient in type I collagen, such as OI types I-IV. As a result, the normal structure of the bone, consisting of collagen fibrils and hydroxyapatite crystals, changes, which causes bone fragility. In one embodiment, the methods and uses of this invention are for the treatment of human patients with OI characterized by one or more mutations in COL1A1 and/or COL1A2.

[00172] In one embodiment, the methods and uses described herein are for the treatment of Type I, III, and/or IV OI. In one embodiment, type I, III, and IV OIs are confirmed by DNA testing, i. detection of COL1A1/COL1A2 mutations. Thus, in one embodiment, the methods and uses of the present invention are for the treatment of type I, III and/or IV OI characterized by one or more mutations in COL1A1 and/or COL1A2.

[00173] In some embodiments, the methods and uses of the anti-sclerostin antibody are for the treatment of mild to moderate OI. In other embodiments of the methods and use of the anti-sclerostin antibody, the patient being treated has type I OI, type II OI, type III OI, or type IV OI. In still other embodiments of the methods and uses of the anti-sclerostin antibody, OI patients are adult patients 18 years of age or older. In still other embodiments of the methods and uses of the anti-sclerostin antibody, OI patients are pediatric patients. Pediatric patients as defined in this application encompasses children aged 0-17 years, for example, aged 2-17 years, 3-17 years, 4-17 years or 5-17 years. The term patients in this context refers to sick people.

Pharmaceutical compositions

[00174] In another aspect, the present invention provides a pharmaceutical composition for promoting bone formation and for reducing bone resorption in a patient suffering from osteogenesis imperfecta, the composition comprising an anti-sclerostin antibody as described above. The pharmaceutical composition may be formulated with a pharmaceutically acceptable carrier. In one aspect, the invention provides a pharmaceutical composition comprising an anti-sclerostin antibody disclosed herein. In one embodiment, a pharmaceutical composition comprising an anti-sclerostin antibody is for use in the treatment of OI.

[00175] As used herein, a "pharmaceutically acceptable carrier" includes any solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like, which are physiologically compatible. The carrier must be suitable for intravenous, intramuscular, subcutaneous, parenteral, intraspinal, or epidermal administration (eg, by injection or infusion). Depending on the route of administration, the anti-sclerostin antibody may be coated with a substance to protect the compound from acids and other natural conditions that may inactivate the compound.

[00176] These compositions may also contain adjuvants, such as preservatives, wetting agents, emulsifiers, and dispersing agents. The presence of microorganisms can be prevented both by sterilization methods and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol, sorbic acid, etc. It is also desirable to include isotonic agents such as sugars, sodium chloride, and the like in the compositions. In addition, prolonged absorption of the injectable dosage form can be achieved by the inclusion of agents that delay absorption, such as aluminum monostearate and gelatin.

[00177] Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous manufacture of sterile injectable solutions or dispersions. The use of such media and agents for pharmaceutically active substances is known in the art. The use of any standard media or agents in the pharmaceutical compositions of the invention is contemplated, unless they are incompatible with the active compound. Additional active agents may also be included in the compositions.

[00178] Therapeutic compositions generally must be sterile and stable under the conditions of manufacture and storage.

[00179] Sterile injectable solutions can be prepared by incorporating the active compound in the desired amount in a suitable solvent with one or a combination of the ingredients listed above, if necessary, followed by microfiltration sterilization. Typically, dispersions are prepared by incorporating the active compound into a sterile vehicle which contains the basic dispersion medium and the necessary other ingredients listed above. In the case of sterile powders for making sterile injectable solutions, the manufacturing methods are vacuum drying and freeze-drying (lyophilization) which yield a powder of the active ingredient plus any additional ingredient of interest from a pre-sterilized filtered solution thereof. Thus, in one embodiment, an anti-sclerostin antibody of the invention/pharmaceutical composition of the invention is prepared as a powder lyophilisate. In a related embodiment, the lyophilisate is reconstituted prior to administration. Suitable recovery fluids include water for injection (wfi, water for injection).

[00180] The amount of active ingredient that can be mixed with the carrier material to obtain a unit dosage form varies depending on the subject being treated and the particular route of administration. The amount of active ingredient that can be mixed with the carrier material to form a unit dosage form is usually that amount of the composition that provides a therapeutic effect. Typically, on a 100-point (percentage) scale, this amount ranges from about 0.01 percent to about ninety-five percent of the active ingredient, from about 0.1 percent to about 70 percent, or from about 1 percent to about 30 percent of the active ingredient in combination with a pharmaceutical active carrier.

[00181] The pharmaceutical compositions of the invention and the antibodies of the invention may also be used in combination therapy, i. in combination with other active agents. For example, combination therapy may include an anti-sclerostin antibody of the present invention in combination with at least one other anti-inflammatory or anti-osteoporosis agent. Examples of therapeutic agents that can be used in combination therapy include bisphosphonates (such as alendronate, risedronate sodium, ibandronic acid, zoledronic acid, olpadronate, neridronate, skelid, bonephos), parathyroid hormone (such as teriparatide (recombinant), injection)), calcilytics, calcimimetics (eg cinacalcet), statins, anabolic steroids, lanthanum and strontium salts and sodium fluoride. Thus, in one embodiment, the anti-sclerostin antibodies of the invention may be administered in combination with one or more agents selected from the group consisting of: calcitonin or an analog or derivative thereof, e.g. salmon, eel or human calcitonin, calcilytics, calcimimetics (e.g. ), steroid hormone, eg estrogen, partial estrogen agonist or estrogen-progestogen combinations, SERM (Selective Estrogen Receptor Modulator), eg raloxifene, lasofoxifene, bazedoxifene, arzoxifene, FC1271, Tibolone (Livial®), SARM (Selective Androgen Receptor Modulator ), a RANKL antibody (such as denosumab), a cathepsin K inhibitor, vitamin D or an analogue thereof, or PTH, a PTH fragment or a PTH derivative, such as PTH (1-84) (such as Preos™ (parathyroid hormone 1-84)), PTH(1-34) (such as Forteo™ (teriparatide (recombinant), injection)), PTH(1-36), PTH(1-38), PTH(1-31)NH2, or PTS 893. According to another antibody variant according to the invention can be applied to combinations with other modern osteoporosis treatments, including bisphosphonates (eg, Fosamax™ (alendronate), Actonel™ (risedronate sodium), Bonviva™ (ibandronic acid), Zometa™ (zoledronic acid), Aclasta™/Reclast™ (zoledronic acid) , olpadronate, neridronate, skelid, bonefos), statins, anabolic steroids, lanthanum and strontium salts and sodium fluoride.

[00182] In one embodiment, the antibodies of the invention may be administered in combination with an LRP4 modulating agent, i. with an agent that modulates the expression or activity of LRP4, for example, an antibody that neutralizes LRP4.

[00183] In one embodiment, the antibodies of the invention may be administered in combination with an LRP5 modulating agent, i. with an agent that modulates the expression or activity of LRP5, for example, an antibody that neutralizes LRP5.

[00184] In another embodiment, the antibodies of the invention may be administered in combination with a DKK1 modulating agent, i. an agent that disrupts or neutralizes Dkk-1-mediated antagonism of signal transduction from Wnt proteins, for example, with a DKK1 neutralizing antibody.

[00185] In one embodiment, the antibodies of the invention may be administered in combination with a bisphosphonate, eg, alendronate, risedronate, risedronate sodium, ibandronic acid, zoledronic acid, olpadronate, neridronate, skelid, bonephos.

[0186] In one embodiment, antibodies of the invention may be administered in combination with (i) zoledronic acid, (ii) anti-DKK1 antibody, (iii) alendronate, (iv) anti-LRP4 antibody, (v) hPTH, and/or (vi) p and parathyroid hormone leasing agents (calcilytics).

[00187] Other agents that can be administered in combination with the anti-sclerostin antibodies of the invention include vitamin D and/or calcium. In one embodiment, vitamin D and/or calcium is administered if the patient is deficient in vitamin D and/or calcium.

[00188] According to one variant, the antibodies of the invention are administered together with another agent (eg, with the above agents), sequentially (ie, one after the other), or simultaneously. In one embodiment, the anti-sclerostin antibody is administered according to the above doses and frequency of administration. Suitable doses for combination therapy may vary according to the clinical needs of the patient.

[00189] the Compositions are preferably prepared at physiological pH values.

[00190] Therapeutic compositions can be administered using medical devices known in the art. For example, in one embodiment, the therapeutic composition of the invention may be administered using a needleless hypodermic injector such as those described in US Pat. Nos. 5,399,163; 5,383,851; 5,312,335; 5,064,413; 4,941,880; 4,790,824 or 4,596,556. Examples of well-known implants and modules useful in the present invention include: US Patent No. 4,487,603, which provides an implantable microinfusion pump for drug dosing at a controlled rate; US patent No. 4,486,194, which presents a therapeutic device for the introduction of drugs through the skin; US Pat. No. 4,447,233, which provides an infusion pump for administering a drug at a precise infusion rate; US patent No. 4,447,224, which provides an implantable infusion system with a flow controller for continuous drug delivery; US patent No. 4,439,196, which shows an osmotic system for drug delivery containing multi-chamber compartments; and US Pat. No. 4,475,196, which provides an osmotic drug delivery system. These patents are incorporated into the present invention by reference. Many other such implants, delivery systems and modules are known to those skilled in the art. In one embodiment, the therapeutic composition of the invention may be administered via a syringe.

[00191] In some embodiments, the antibodies of the invention can be formulated to provide adequate distribution in vivo.

[00192] In one aspect, the invention provides for the use of an anti-sclerostin antibody for the manufacture of a medicament for the treatment of osteogenesis imperfecta. All other aspects/variants of the present description are equally applicable to this particular aspect of the invention.

[00193] In another aspect of the invention, an anti-sclerostin antibody is provided for use in the treatment of osteogenesis imperfecta. All other aspects/variants of the present description are equally applicable to this particular aspect of the invention.

[00194] In one aspect of the invention, an anti-sclerostin antibody is provided for use in a clinical study of osteogenesis imperfecta, comprising comparing the number of bone fractures that occurred in the population participating in the clinical study at an intermediate reference time point during the period of the clinical study, with the number of fractures expected in a specified intermediate reference point in time for a specified population participating in a clinical trial.

[00195] According to a related aspect of the invention, a method is provided for conducting a clinical study of osteogenesis imperfecta using an antibody to sclerostin, comprising comparing the number of bone fractures that occurred in the population participating in the clinical study, at an intermediate control point in time during the period of the clinical study, with the number of fractures, expected at a specified intermediate reference time for a specified population. According to one variant of the above aspects, this aspect may also include the recruitment of additional patients in the clinical study population if the number of fractures in the clinical study population in the intermediate control period is lower than the expected number of fractures for said clinical study population. research. In another embodiment, the clinical trial time is reduced if the number of fractures in the clinical trial population in the intermediate reference time period is higher than the expected number of fractures for the specified clinical trial population. The clinical trial population includes patients receiving anti-sclerostin antibody and a control group of patients receiving placebo. The advantage of these aspects of the / options is that it becomes possible to change the time of the clinical study during the study in the clinic, this ultimately makes the clinical study more efficient and less costly, which is also positive for the patient. The expected number of fractures can be calculated from a baseline fracture rate that can be determined from statistical data and/or from data obtained from the clinical trial population before the start of the clinical trial. In one embodiment, the anti-sclerostin antibody is an anti-sclerostin antibody as defined herein. The intermediate reference time may vary and may be selected according to when a statistically significant comparison can be made. Clinical study time begins with the administration of anti-sclerostin antibody or placebo and ends as soon as the last dose of anti-sclerostin antibody/placebo has been administered and relevant data has been collected.

[00196] BPS804 H-strand sequence (SEQ ID NO: 172):

[00197] BPS804 L chain sequence (SEQ ID NO: 173):

METHODS FOR CARRYING OUT THE INVENTION

Example 1

[00198] This example describes a clinical study evaluating the use of antibodies to sclerostin in the treatment of adults with OI. Patients were treated with three consecutive, individually escalated, doses of anti-sclerostin antibody BPS804 administered as intravenous infusions with an interval of 2 weeks between doses. An undercooked control group was also included in the study to monitor and follow the natural progression of OI disease in relation to changes in bone biomarker profiles. This study was a randomized, open-label, individual dose escalation study with an untreated control group of 14 adult patients with moderate OI. Patients were randomly assigned to the treatment group or the control group in a 2:1 ratio.

[00199] Patients were administered anti-sclerostin antibody every two weeks with dose escalation: Week 1: 5 mg/kg, Week 3: 10 mg/kg, and Week 5: 20 mg/kg. The treatment period was followed by a follow-up period of approximately 3.6 months. Patients randomly assigned to the non-treatment control group at screening were admitted to the study site at week 7, Day 43 of the study, and at the end of the study.

[00200] A description of study BPS804 formulation is provided in Table 1. BPS804 infusion solution was infused at a flow rate of about 2 ml/min until the desired dose was delivered.

[00201] Biomarkers of bone metabolism, including N-terminal procollagen I propeptide (PLNP), C-terminal procollagen I propeptide (PICP), bone-specific alkaline phosphatase (BSAP), osteocalcin (OC), and bone mineral density (BMD) ( measured by DXA) were analyzed at study entry, day 43, and day 141.

[00202] Of the 14 patients included in the study, nine patients were exposed to an antibody to sclerostin. The overall mean age of patients was slightly higher in the anti-sclerostin group (30.7 years) compared to the control group (27.4 years). The overall average weight and height of the two groups were very similar. A summary of patient personal data is presented in Table 2. Overall median z-score values for the lumbosacral spine were comparatively lower in the anti-sclerostin group. A comparison of the number of years spent on bisphosphonates cannot be made between groups, taking into account the relative number of patients in each group. See Table 3.

[00203] The results of the analysis of bone metabolism biomarkers for the study are shown in Figure 1. Geometric mean ratios for PINP, PICP, B SAP, and OS on Day 43 were 1.84, 1.53, 1.59, and 1.44 with P-values <0.001, 0.003,< 0.001 and 0.012 in BPS804 group. The geometric mean ratio for BMD on Day 141 was 1.04 with a P-value of 0.038.

[00204] Bayesian analysis of change from baseline for PINP, PICP, and B SAP showed a posterior probability of about 90% or greater for an increase of at least 70% (PINP) or 30% (PICP, BSAP). Bayesian analysis for BMD had a 98% posterior probability for an increase in BMD, and 87% for an increase of at least 2%. See Figure 3, Figure 4, Figure 5, Figure 6 and Figure 7 for detailed results for PINP, PICP, BSAP, OS and BMD, respectively.

[00205] The results obtained for geometric mean values for CTX-1 from Day 8 to Day 43 showed a decrease in CTX-1 levels, which, together with the results obtained for biomarkers of bone formation, confirms the anabolic effect on bones. Figure 8 details the results compared to baseline data at entry into the study. On Day 43, the ratio from baseline in the BPS804 group was 56% of baseline at study entry, hence a 44% reduction. Concentration levels rose steadily from Day 50 to Day 85 with minimal declines on Days 113 and 141.

[00206] Comparison of ratios with corresponding ratios in the control group was carried out using a scheduled one-tailed t-test for duplicated samples, and a P value of less than 0.1 in this comparison was considered to be evidence of efficacy. Based on a dual sample t-test analysis, P values of <0.001, 0.014, 0.006, and 0.015 for PINP, PICP, BSAP, and OS, respectively, were obtained, which confirmed efficacy. The P-value for comparison of BMD in the therapeutic group is 0.1, this is also a fact confirming that the increase is greater under the action of the antibody than in the control group. See Figure 2. These analyzes confirmed an increased increase in results for all three biomarkers and for BMD in the sclerostin antibody treated group compared to the control group.

[00207] Following the administration of anti-sclerostin antibody, median PINP, PICP, BSAP activity and OS levels were increased on Day 43 by 84%, 53%, 59% and 44%, respectively, while in the untreated control group, the corresponding biomarkers remained unchanged or moderately decreased. In addition, after the introduction of antibodies to sclerostin, the level of CTX-1 decreased by 44% on Day 43 from the start of the study. An increase in bone formation biomarkers (PINP, PICP, BSAP, and OS) and a decrease in bone resorption biomarker (CTX-1) were consistent with an observed ~4% increase in BMD in the lumbosacral spine on Day 141 in the anti- sclerostin, thereby confirming the first clinical evidence of an anabolic effect on bone of an anti-sclerostin antibody in patients with osteogenesis imperfecta.

[00208] In addition, the study showed that the anti-sclerostin antibody was safe and well tolerated by adult patients with OI. The most common AEs were headache, influenza, arthralgia, and fatigue. None of the described AEs were considered to be related to the investigational drug. There was one SAE (Goiter), mild, described in one patient in the control group. This AE was considered serious due to hospitalization. SAE was eliminated before the end of the study. The AEs showed no signs of target organ toxicity. Three fractures were reported during the study (Study 5103 - Day 47, Study 5109 - Day 4, Study 5113 - Day 4). Also, there were no clinically significant data on violations of hematological, biochemical parameters, urinalysis results, ECG, or vital signs that threaten patient safety.

[00209] According to the results of a clinical study using an osteoanabolic drug such as BPS804, bone formation or anabolic activity in relation to bones can be stimulated in patients with OI. An increase in BMD results in an increase in bone quality, which leads to a reduction in the rate and risk of fractures. Genotyping may be required to identify or predict patients with OI who would benefit most from this therapeutic strategy.

Example 2

[00210] A pharmacokinetic (PK) model, as well as a pharmacokinetic (PK) and pharmacodynamic (PD) (PK-PD) model, for the circulating effects of sclerostin following BPS804 administration was developed for BPS804 based on a combination of clinical study results and publicly available data for other anti-sclerostin antibodies. The PK-PD model was linked to an existing systemic pharmacology model to evaluate putative dosing regimens for BPS804. Simulation models were used to provide guidance for dose selection and dosing interval over 1-2 years of treatment for typical OI patients. These included situations with different aspects of dosing, in the first year (for example, comparing dose size and QM (i.e., monthly) versus Q3M (i.e., quarterly) dosing), as well as recommendations for subsequent years (for example, switching from QM to Q3M dosing).

[00211] Results:

[00212] The results showed that BPS804 dosing regimens approaching maximal (>75%) sclerostin inhibition provide a near maximal objective response in circulating sclerostin, bone remodeling markers (BTM) and lumbosacral bone mineral density (BMD) . In order to demonstrate this, regimens were modelled: different doses from 0.1 mg/kg to 20 mg/kg with QM (ie, monthly) and Q3M (ie, quarterly) intervals over two years. The results were evaluated under the condition of the overall effect of BPS804 on sclerostin and inhibition from relative to maximum. Thus, a dosage of 20 mg/kg QM gave a near-maximal sclerostin response. The maximum level of inhibition was achieved with both the monthly and quarterly dosing regimens, similarly, both the QM and Q3M 20 mg/kg dosing regimens achieved the maximum level of inhibition.

[00213] The simulation results also showed that the BPS804 dosing regimen at 20 mg/kg QM provided a similar or slightly greater increase in BMD over 12 months compared to the Q3M dosing regimen due to longer sustained inhibition of sclerostin by BPS804.

[00214] After treatment with BPS804 on a 20 mg/kg QM regimen for one year, almost the same maximum peak response of sclerostin can also be achieved with a quarterly dose of 20 mg/kg. This possible change in dosing regimen after one year of drug use may reflect the new observed steady state of the bone remodeling system after one year of sclerostin-inhibiting treatment. Therefore, less frequent dosing after the first year of drug administration may allow the increase in BMD achieved after the first year of treatment to be maintained.

[00215] Thus, the simulation results show that a BPS804 20 mg/kg QM dosing regimen can provide close to maximal sclerostin inhibition, which can translate into a maximal BMD response. In addition, prolonging dosing intervals to longer durations (eg, switching to every two months (Q2M) or Q3M after one year of QM) may be beneficial if changes in bone remodeling markers are observed after the first year of treatment. .

[00216] The patents and publications listed in the present invention describe general knowledge in the art. In the event of any conflict between the opposing material and this description, the description shall govern. In describing embodiments of the present application, specific terminology is used for complete clarity. However, it is not intended that the invention be limited to the specific terminology thus chosen. Nothing in this description should be construed as limiting the scope of the present invention. All examples presented are exemplary and non-limiting. In view of the foregoing principles, those skilled in the art will appreciate that the embodiments described above may be modified and varied within the scope of the invention. Therefore, it is to be understood that, within the scope of the claims and their equivalents, the invention may be practiced otherwise than as specifically described.

--->

Sequence listing

<110> MEREO BIOPHARMA 3 LIMITED

<120> APPLICATION OF ANTIBODIES TO SCLEROSTIN FOR THE TREATMENT OF OSTEOGENESIS IMPERFECT

<130> P069492-US

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Gly Phe Thr Phe Arg Ser His Trp Leu Ser

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Gly Phe Thr Phe Ser Ser Tyr Val Met Asn

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Gly Phe Thr Phe Arg Ser His Trp Leu Ser

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Gly Phe Thr Phe Arg Ser His Trp Leu Ser

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Gly Phe Thr Phe Arg Ser His Trp Leu Ser

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Gly Phe Thr Phe Arg Ser His Trp Leu Ser

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Gly Phe Thr Phe Arg Ser His Trp Leu Ser

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Gly Phe Thr Phe Arg Ser His Trp Leu Ser

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<213> Homo sapiens

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Gly Phe Thr Phe Arg Ser His Trp Leu Ser

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Gly Phe Thr Phe Arg Ser His Trp Leu Ser

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<213> Homo sapiens

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Trp Val Ser Phe Ile Ser Gly Asp Ser Ser Asn Thr Tyr Tyr Ala Asp

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Ser Val Lys Gly

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Trp Val Ser Asn Ile Asn Tyr Asp Gly Ser Ser Thr Tyr Tyr Ala Asp

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Ser Val Lys Gly

20

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Trp Val Ser Phe Ile Ser Gly Asp Ser Ser Asn Thr Tyr Tyr Ala Asp

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Ser Val Lys Gly

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Trp Val Ser Asn Ile Asn Tyr Asp Gly Ser Ser Thr Tyr Tyr Ala Asp

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Ser Val Lys Gly

20

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Trp Val Ser Val Thr Gly Val His Gly Asp Thr Tyr Tyr Ala Asp Ser

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Val Lys Gly

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Trp Val Ser Val Ile Gly Asn Trp Gly Asp Thr Tyr Tyr Ala Asp Ser

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Val Lys Gly

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Trp Val Ser Val Thr Thr His Gln Gly Tyr Thr Tyr Tyr Ala Asp Ser

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Val Lys Gly

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Trp Val Ser Ala Thr Asn Arg Tyr Gly Tyr Thr Tyr Tyr Ala Asp Ser

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Val Lys Gly

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<213> Homo sapiens

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Trp Val Ser Asn Ile Asn Tyr Asp Gly Ser Ser Thr Tyr Tyr Ala Asp

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Ser Val Lys Gly

20

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Trp Val Ser Val Ile Thr Pro Tyr Gly Asp Thr Tyr Tyr Ala Asp Ser

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Val Lys Gly

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Trp Val Ser Val Ile Thr Pro Tyr Gly Asp Thr Tyr Tyr Ala Asp Ser

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Val Lys Gly

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<213> Homo sapiens

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Thr Phe Met His Gly His Leu Gly Gly Gly Leu Ser Met Asp Phe

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<212> PROTEIN

<213> Homo sapiens

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Asp Thr Tyr Leu His Phe Asp Tyr

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<213> Homo sapiens

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Thr Phe Met His Gly His Leu Gly Gly Gly Leu Ser Met Asp Phe

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<212> PROTEIN

<213> Homo sapiens

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Asp Thr Tyr Leu His Phe Asp Tyr

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<213> Homo sapiens

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Asp Thr Tyr Leu His Phe Asp Tyr

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Asp Thr Tyr Leu His Phe Asp Tyr

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<213> Homo sapiens

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Asp Thr Tyr Leu His Phe Asp Tyr

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<213> Homo sapiens

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Asp Thr Tyr Leu His Phe Asp Tyr

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Asp Thr Tyr Leu His Phe Asp Tyr

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Asp Thr Tyr Leu His Phe Asp Tyr

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<213> Homo sapiens

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Asp Thr Tyr Leu His Phe Asp Tyr

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<213> Homo sapiens

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Ser Gly Asp Asn Ile Gly Ser Phe Tyr Val His

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<213> Homo sapiens

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Trp Val Ser Asn Ile Asn Tyr Asp Gly Ser Ser Thr Tyr Tyr Ala Asp

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Ser Val Lys Gly

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<213> Homo sapiens

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Ser Gly Asp Asn Ile Gly Ser Phe Tyr Val His

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Thr Gly Thr Ser Ser Asp Val Gly Asp Ile Asn Asp Val Ser

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<213> Homo sapiens

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Thr Gly Thr Ser Ser Asp Val Gly Asp Ile Asn Asp Val Ser

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<213> Homo sapiens

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Thr Gly Thr Ser Ser Asp Val Gly Asp Ile Asn Asp Val Ser

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<213> Homo sapiens

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Thr Gly Thr Ser Ser Asp Val Gly Asp Ile Asn Asp Val Ser

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<213> Homo sapiens

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Thr Gly Thr Ser Ser Asp Val Gly Asp Ile Asn Asp Val Ser

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<213> Homo sapiens

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Thr Gly Thr Ser Ser Asp Val Gly Asp Ile Asn Asp Val Ser

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<213> Homo sapiens

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Thr Gly Thr Ser Ser Asp Val Gly Asp Ile Asn Asp Val Ser

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<213> Homo sapiens

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Thr Gly Thr Ser Ser Asp Val Gly Asp Ile Asn Asp Val Ser

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<211> 11

<212> PROTEIN

<213> Homo sapiens

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Leu Val Ile Tyr Asp Asp Asn Asn Arg Pro Ser

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<212> PROTEIN

<213> Homo sapiens

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Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser

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<211> 11

<212> PROTEIN

<213> Homo sapiens

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Leu Val Ile Tyr Asp Asp Asn Asn Arg Pro Ser

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<211> 11

<212> PROTEIN

<213> Homo sapiens

<400> 48

Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser

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<211> 11

<212> PROTEIN

<213> Homo sapiens

<400> 49

Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser

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<210> 50

<211> 11

<212> PROTEIN

<213> Homo sapiens

<400> 50

Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser

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<210> 51

<211> 11

<212> PROTEIN

<213> Homo sapiens

<400> 51

Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser

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<210> 52

<211> 11

<212> PROTEIN

<213> Homo sapiens

<400> 52

Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser

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<210> 53

<211> 11

<212> PROTEIN

<213> Homo sapiens

<400> 53

Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser

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<210> 54

<211> 11

<212> PROTEIN

<213> Homo sapiens

<400> 54

Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser

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<210> 55

<211> 11

<212> PROTEIN

<213> Homo sapiens

<400> 55

Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser

1 5 10

<210> 56

<211> 10

<212> PROTEIN

<213> Homo sapiens

<400> 56

Gly Ser Trp Ala Gly Ser Ser Gly Ser Tyr

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<210> 57

<211> 10

<212> PROTEIN

<213> Homo sapiens

<400> 57

Ser Ser Tyr Gly Glu Ser Leu Thr Ser Tyr

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<210> 58

<211> 10

<212> PROTEIN

<213> Homo sapiens

<400> 58

Ala Ser Trp Thr Gly Val Glu Pro Asp Tyr

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<212> PROTEIN

<213> Homo sapiens

<400> 59

Gln Ser Tyr Ala Gly Ser Tyr Leu Ser Glu

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<210> 60

<211> 10

<212> PROTEIN

<213> Homo sapiens

<400> 60

Ser Ser Tyr Gly Glu Ser Leu Thr Ser Tyr

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<210> 61

<211> 10

<212> PROTEIN

<213> Homo sapiens

<400> 61

Ser Ser Tyr Gly Glu Ser Leu Thr Ser Tyr

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<210> 62

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<212> PROTEIN

<213> Homo sapiens

<400> 62

Ser Ser Tyr Gly Glu Ser Leu Thr Ser Tyr

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<210> 63

<211> 10

<212> PROTEIN

<213> Homo sapiens

<400> 63

Ser Ser Tyr Gly Glu Ser Leu Thr Ser Tyr

1 5 10

<210> 64

<211> 10

<212> PROTEIN

<213> Homo sapiens

<400> 64

Ser Thr Tyr Asp Gly Pro Gly Leu Ser Glu

1 5 10

<210> 65

<211> 10

<212> PROTEIN

<213> Homo sapiens

<400> 65

Ser Ser Tyr Gly Glu Ser Leu Thr Ser Tyr

1 5 10

<210> 66

<211> 10

<212> PROTEIN

<213> Homo sapiens

<400> 66

Ser Ser Tyr Gly Glu Ser Leu Thr Ser Tyr

1 5 10

<210> 67

<211> 124

<212> PROTEIN

<213> Homo sapiens

<400> 67

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Val Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

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Ser Phe Ile Ser Gly Asp Ser Ser Asn Thr Tyr Tyr Ala Asp Ser Val

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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

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Ala Arg Thr Phe Met His Gly His Leu Gly Gly Gly Leu Ser Met Asp

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Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 68

<211> 117

<212> PROTEIN

<213> Homo sapiens

<400> 68

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His

20 25 30

Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

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Ser Asn Ile Asn Tyr Asp Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val

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Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

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Ala Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly Thr Leu

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Val Thr Val Ser Ser

115

<210> 69

<211> 124

<212> PROTEIN

<213> Homo sapiens

<400> 69

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Ser Ser Tyr

20 25 30

Val Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Glu Trp Val

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Ser Phe Ile Ser Gly Asp Ser Ser Asn Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Thr Phe Met His Gly His Leu Gly Gly Gly Leu Ser Met Asp

100 105 110

Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser

115 120

<210> 70

<211> 117

<212> PROTEIN

<213> Homo sapiens

<400> 70

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His

20 25 30

Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Asn Ile Asn Tyr Asp Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 71

<211> 116

<212> PROTEIN

<213> Homo sapiens

<400> 71

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His

20 25 30

Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Thr Gly Val His Gly Asp Thr Tyr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

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Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 72

<211> 116

<212> PROTEIN

<213> Homo sapiens

<400> 72

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

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Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His

20 25 30

Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Gly Asn Trp Gly Asp Thr Tyr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

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Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

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Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 73

<211> 116

<212> PROTEIN

<213> Homo sapiens

<400> 73

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His

20 25 30

Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Thr Thr His Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

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Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 74

<211> 116

<212> PROTEIN

<213> Homo sapiens

<400> 74

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His

20 25 30

Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Ala Thr Asn Arg Tyr Gly Tyr Thr Tyr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

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Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 75

<211> 117

<212> PROTEIN

<213> Homo sapiens

<400> 75

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His

20 25 30

Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

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Ser Asn Ile Asn Tyr Asp Gly Ser 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

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Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

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Ala Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser

115

<210> 76

<211> 116

<212> PROTEIN

<213> Homo sapiens

<400> 76

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His

20 25 30

Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Thr Pro Tyr Gly Asp Thr Tyr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 77

<211> 116

<212> PROTEIN

<213> Homo sapiens

<400> 77

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His

20 25 30

Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Val Ile Thr Pro Tyr Gly Asp Thr Tyr Tyr Ala Asp Ser Val Lys

50 55 60

Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr Leu

65 70 75 80

Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys Ala

85 90 95

Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly Thr Leu Val

100 105 110

Thr Val Ser Ser

115

<210> 78

<211> 110

<212> PROTEIN

<213> Homo sapiens

<400> 78

Asp Ile Glu Leu Thr Gln Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Ile Gly Ser Phe Tyr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Ala Gly Ser Ser Gly Ser

85 90 95

Tyr Val Phe Gly Gly Arg Thr Lys Leu Thr Val Leu Gly Gln

100 105 110

<210> 79

<211> 113

<212> PROTEIN

<213> Homo sapiens

<400> 79

Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Ile

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Glu Ser

85 90 95

Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly

100 105 110

Gln

<210> 80

<211> 110

<212> PROTEIN

<213> Homo sapiens

<400> 80

Asp Ile Glu Leu Thr Gln Pro Ser Val Ser Val Ala Pro Gly Gln

1 5 10 15

Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Ile Gly Ser Phe Tyr Val

20 25 30

His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val Leu Val Ile Tyr

35 40 45

Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Glu Arg Phe Ser Gly Ser

50 55 60

Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly Thr Gln Ala Glu

65 70 75 80

Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Thr Gly Val Glu Pro Asp

85 90 95

Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly Gln

100 105 110

<210> 81

<211> 113

<212> PROTEIN

<213> Homo sapiens

<400> 81

Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Ile

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Ala Gly Ser

85 90 95

Tyr Leu Ser Glu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly

100 105 110

Gln

<210> 82

<211> 113

<212> PROTEIN

<213> Homo sapiens

<400> 82

Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Ile

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Glu Ser

85 90 95

Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly

100 105 110

Gln

<210> 83

<211> 113

<212> PROTEIN

<213> Homo sapiens

<400> 83

Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Ile

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Glu Ser

85 90 95

Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly

100 105 110

Gln

<210> 84

<211> 113

<212> PROTEIN

<213> Homo sapiens

<400> 84

Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Ile

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Glu Ser

85 90 95

Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly

100 105 110

Gln

<210> 85

<211> 113

<212> PROTEIN

<213> Homo sapiens

<400> 85

Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Ile

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Glu Ser

85 90 95

Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly

100 105 110

Gln

<210> 86

<211> 113

<212> PROTEIN

<213> Homo sapiens

<400> 86

Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Ile

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Thr Tyr Asp Gly Pro

85 90 95

Gly Leu Ser Glu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly

100 105 110

Gln

<210> 87

<211> 113

<212> PROTEIN

<213> Homo sapiens

<400> 87

Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Ile

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser Tyr Gly Glu Ser

85 90 95

Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly

100 105 110

Gln

<210> 88

<211> 113

<212> PROTEIN

<213> Homo sapiens

<400> 88

Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Ile

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Thr Tyr Asp Gly Pro

85 90 95

Gly Leu Ser Glu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly

100 105 110

Gln

<210> 89

<211> 372

<212> DNA

<213> Homo sapiens

<400> 89

caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60

agctgcgcgg cctccggatt taccttttct tcttatgtta tgaattgggt gcgccaagcc 120

cctgggaagg gtctcgagtg ggtgagcttt atctctggtg attctagcaa tacctattat 180

gcggatagcg tgaaaggccg ttttaccatt tcacgtgata attcgaaaaa caccctgtat 240

ctgcaaatga acagcctgcg tgcggaagat acggccgtgt attattgcgc gcgtactttt 300

atgcatggtc atcttggtgg tggtctttct atggattttt ggggccaagg caccctggtg 360

acggttagct ca 372

<210> 90

<211> 351

<212> DNA

<213> Homo sapiens

<400> 90

caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60

agctgcgcgg cctccggatt tacctttcgt tctcattggc ttttcttgggt gcgccaagcc 120

cctgggaagg gtctcgagtg ggtgagcaat atcaattatg atggtagctc tacctattat 180

gcggatagcg tgaaaggccg ttttaccatt tcacgtgata attcgaaaaa caccctgtat 240

ctgcaaatga acagcctgcg tgcggaagat acggccgtgt attattgcgc gcgtgatact 300

tatcttcatt ttgattattg gggccaaggc accctggtga cggttagctc a 351

<210> 91

<211> 372

<212> DNA

<213> Homo sapiens

<400> 91

caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60

agctgcgcgg cctccggatt taccttttct tcttatgtta tgaattgggt gcgccaagcc 120

cctgggaagg gtctcgagtg ggtgagcttt atctctggtg attctagcaa tacctattat 180

gcggatagcg tgaaaggccg ttttaccatt tcacgtgata attcgaaaaa caccctgtat 240

ctgcaaatga acagcctgcg tgcggaagat acggccgtgt attattgcgc gcgtactttt 300

atgcatggtc atcttggtgg tggtctttct atggattttt ggggccaagg caccctggtg 360

acggttagct ca 372

<210> 92

<211> 351

<212> DNA

<213> Homo sapiens

<400> 92

caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60

agctgcgcgg cctccggatt tacctttcgt tctcattggc ttttcttgggt gcgccaagcc 120

cctgggaagg gtctcgagtg ggtgagcaat atcaattatg atggtagctc tacctattat 180

gcggatagcg tgaaaggccg ttttaccatt tcacgtgata attcgaaaaa caccctgtat 240

ctgcaaatga acagcctgcg tgcggaagat acggccgtgt attattgcgc gcgtgatact 300

tatcttcatt ttgattattg gggccaaggc accctggtga cggttagctc a 351

<210> 93

<211> 348

<212> DNA

<213> Homo sapiens

<400> 93

caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60

agctgcgcgg cctccggatt tacctttcgt tctcattggc ttttcttgggt gcgccaagcc 120

cctgggaagg gtctcgagtg ggtgagcgtt actggtgttc atggtgatac ttattatgct 180

gattctgtta agggtcgttt taccattttca cgtgataatt cgaaaaacac cctgtatctg 240

caaatgaaca gcctgcgtgc ggaagatacg gccgtgtatt attgcgcgcg tgatacttat 300

cttcattttg attattgggg ccaaggcacc ctggtgacgg ttagctca 348

<210> 94

<211> 348

<212> DNA

<213> Homo sapiens

<400> 94

caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60

agctgcgcgg cctccggatt tacctttcgt tctcattggc ttttcttgggt gcgccaagcc 120

cctgggaagg gtctcgagtg ggtgagcgtt attggtaatt ggggtgatac ttattatgct 180

gattctgtta agggtcgttt taccattttca cgtgataatt cgaaaaacac cctgtatctg 240

caaatgaaca gcctgcgtgc ggaagatacg gccgtgtatt attgcgcgcg tgatacttat 300

cttcattttg attattgggg ccaaggcacc ctggtgacgg ttagctca 348

<210> 95

<211> 348

<212> DNA

<213> Homo sapiens

<400> 95

caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60

agctgcgcgg cctccggatt tacctttcgt tctcattggc ttttcttgggt gcgccaagcc 120

cctgggaagg gtctcgagtg ggtgagcgtt actactcatc agggttatac ttattatgct 180

gattctgtta agggtcgttt taccattttca cgtgataatt cgaaaaacac cctgtatctg 240

caaatgaaca gcctgcgtgc ggaagatacg gccgtgtatt attgcgcgcg tgatacttat 300

cttcattttg attattgggg ccaaggcacc ctggtgacgg ttagctca 348

<210> 96

<211> 348

<212> DNA

<213> Homo sapiens

<400> 96

caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60

agctgcgcgg cctccggatt tacctttcgt tctcattggc ttttcttgggt gcgccaagcc 120

cctgggaagg gtctcgagtg ggtgagcgct actaatcgtt atggttatac ttattatgct 180

gattctgtta agggtcgttt taccattttca cgtgataatt cgaaaaacac cctgtatctg 240

caaatgaaca gcctgcgtgc ggaagatacg gccgtgtatt attgcgcgcg tgatacttat 300

cttcattttg attattgggg ccaaggcacc ctggtgacgg ttagctca 348

<210> 97

<211> 351

<212> DNA

<213> Homo sapiens

<400> 97

caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60

agctgcgcgg cctccggatt tacctttcgt tctcattggc ttttcttgggt gcgccaagcc 120

cctgggaagg gtctcgagtg ggtgagcaat atcaattatg atggtagctc tacctattat 180

gcggatagcg tgaaaggccg ttttaccatt tcacgtgata attcgaaaaa caccctgtat 240

ctgcaaatga acagcctgcg tgcggaagat acggccgtgt attattgcgc gcgtgatact 300

tatcttcatt ttgattattg gggccaaggc accctggtga cggttagctc a 351

<210> 98

<211> 348

<212> DNA

<213> Homo sapiens

<400> 98

caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60

agctgcgcgg cctccggatt tacctttcgt tctcattggc ttttcttgggt gcgccaagcc 120

cctgggaagg gtctcgagtg ggtgagcgtt attactcctt atggtgatac ttattatgct 180

gattctgtta agggtcgttt taccattttca cgtgataatt cgaaaaacac cctgtatctg 240

caaatgaaca gcctgcgtgc ggaagatacg gccgtgtatt attgcgcgcg tgatacttat 300

cttcattttg attattgggg ccaaggcacc ctggtgacgg ttagctca 348

<210> 99

<211> 348

<212> DNA

<213> Homo sapiens

<400> 99

caggtgcaat tggtggaaag cggcggcggc ctggtgcaac cgggcggcag cctgcgtctg 60

agctgcgcgg cctccggatt tacctttcgt tctcattggc ttttcttgggt gcgccaagcc 120

cctgggaagg gtctcgagtg ggtgagcgtt attactcctt atggtgatac ttattatgct 180

gattctgtta agggtcgttt taccattttca cgtgataatt cgaaaaacac cctgtatctg 240

caaatgaaca gcctgcgtgc ggaagatacg gccgtgtatt attgcgcgcg tgatacttat 300

cttcattttg attattgggg ccaaggcacc ctggtgacgg ttagctca 348

<210> 100

<211> 330

<212> DNA

<213> Homo sapiens

<400> 100

gatatcgaac tgacccagcc gccttcagtg agcgttgcac caggtcagac cgcgcgtatc 60

tcgtgtagcg gcgataatat tggttctttt tatgttcatt ggtaccagca gaaacccgggg 120

caggcgccag ttcttgtgat ttatgatgat aataatcgtc cctcaggcat ccgggaacgc 180

tttagcggat ccaacagcgg caacaccgcg accctgacca ttagcggcac tcaggcggaa 240

gacgaagcgg attattattg cggttcttgg gctggttctt ctggttctta tgtgtttggc 300

ggccgcacga agttaaccgt tcttggccag 330

<210> 101

<211> 339

<212> DNA

<213> Homo sapiens

<400> 101

gatatcgcac tgacccagcc agcttcagtg agcggctcac caggtcagag cattaccatc 60

tcgtgtacgg gtactagcag cgatgttggt gatattaatg atgtgtcttg gtaccagcag 120

catcccggga aggcgccgaa acttatgatt tatgatgtta ataatcgtcc ctcaggcgtg 180

agcaaccgtt ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg 240

caagcggaag acgaagcgga ttattattgc tcttcttatg gtgagtctct tacttcttat 300

gtgtttggcg gcggcacgaa gttaaccgtt cttggccag 339

<210> 102

<211> 330

<212> DNA

<213> Homo sapiens

<400> 102

gatatcgaac tgacccagcc gccttcagtg agcgttgcac caggtcagac cgcgcgtatc 60

tcgtgtagcg gcgataatat tggttctttt tatgttcatt ggtaccagca gaaacccgggg 120

caggcgccag ttcttgtgat ttatgatgat aataatcgtc cctcaggcat ccgggaacgc 180

tttagcggat ccaacagcgg caacaccgcg accctgacca ttagcggcac tcaggcggaa 240

gacgaagcgg attattattg cgcttcttgg actggtgttg agcctgatta tgtgtttggc 300

ggcggcacga agttaaccgt tcttggccag 330

<210> 103

<211> 339

<212> DNA

<213> Homo sapiens

<400> 103

gatatcgcac tgacccagcc agcttcagtg agcggctcac caggtcagag cattaccatc 60

tcgtgtacgg gtactagcag cgatgttggt gatattaatg atgtgtcttg gtaccagcag 120

catcccggga aggcgccgaa acttatgatt tatgatgtta ataatcgtcc ctcaggcgtg 180

agcaaccgtt ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg 240

caagcggaag acgaagcgga ttattattgc cagtcttatg ctggttctta tctttctgag 300

gtgtttggcg gcggcacgaa gttaaccgtt cttggccag 339

<210> 104

<211> 339

<212> DNA

<213> Homo sapiens

<400> 104

gatatcgcac tgacccagcc agcttcagtg agcggctcac caggtcagag cattaccatc 60

tcgtgtacgg gtactagcag cgatgttggt gatattaatg atgtgtcttg gtaccagcag 120

catcccggga aggcgccgaa acttatgatt tatgatgtta ataatcgtcc ctcaggcgtg 180

agcaaccgtt ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg 240

caagcggaag acgaagcgga ttattattgc tcttcttatg gtgagtctct tacttcttat 300

gtgtttggcg gcggcacgaa gttaaccgtt cttggccag 339

<210> 105

<211> 339

<212> DNA

<213> Homo sapiens

<400> 105

gatatcgcac tgacccagcc agcttcagtg agcggctcac caggtcagag cattaccatc 60

tcgtgtacgg gtactagcag cgatgttggt gatattaatg atgtgtcttg gtaccagcag 120

catcccggga aggcgccgaa acttatgatt tatgatgtta ataatcgtcc ctcaggcgtg 180

agcaaccgtt ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg 240

caagcggaag acgaagcgga ttattattgc tcttcttatg gtgagtctct tacttcttat 300

gtgtttggcg gcggcacgaa gttaaccgtt cttggccag 339

<210> 106

<211> 339

<212> DNA

<213> Homo sapiens

<400> 106

gatatcgcac tgacccagcc agcttcagtg agcggctcac caggtcagag cattaccatc 60

tcgtgtacgg gtactagcag cgatgttggt gatattaatg atgtgtcttg gtaccagcag 120

catcccggga aggcgccgaa acttatgatt tatgatgtta ataatcgtcc ctcaggcgtg 180

agcaaccgtt ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg 240

caagcggaag acgaagcgga ttattattgc tcttcttatg gtgagtctct tacttcttat 300

gtgtttggcg gcggcacgaa gttaaccgtt cttggccag 339

<210> 107

<211> 339

<212> DNA

<213> Homo sapiens

<400> 107

gatatcgcac tgacccagcc agcttcagtg agcggctcac caggtcagag cattaccatc 60

tcgtgtacgg gtactagcag cgatgttggt gatattaatg atgtgtcttg gtaccagcag 120

catcccggga aggcgccgaa acttatgatt tatgatgtta ataatcgtcc ctcaggcgtg 180

agcaaccgtt ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg 240

caagcggaag acgaagcgga ttattattgc tcttcttatg gtgagtctct tacttcttat 300

gtgtttggcg gcggcacgaa gttaaccgtt cttggccag 339

<210> 108

<211> 339

<212> DNA

<213> Homo sapiens

<400> 108

gatatcgcac tgacccagcc agcttcagtg agcggctcac caggtcagag cattaccatc 60

tcgtgtacgg gtactagcag cgatgttggt gatattaatg atgtgtcttg gtaccagcag 120

catcccggga aggcgccgaa acttatgatt tatgatgtta ataatcgtcc ctcaggcgtg 180

agcaaccgtt ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg 240

caagcggaag acgaagcgga ttattattgc tctacttatg atggtcctgg tctttctgag 300

gtgtttggcg gcggcacgaa gttaaccgtt cttggccag 339

<210> 109

<211> 339

<212> DNA

<213> Homo sapiens

<400> 109

gatatcgcac tgacccagcc agcttcagtg agcggctcac caggtcagag cattaccatc 60

tcgtgtacgg gtactagcag cgatgttggt gatattaatg atgtgtcttg gtaccagcag 120

catcccggga aggcgccgaa acttatgatt tatgatgtta ataatcgtcc ctcaggcgtg 180

agcaaccgtt ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg 240

caagcggaag acgaagcgga ttattattgc tcttcttatg gtgagtctct tacttcttat 300

gtgtttggcg gcggcacgaa gttaaccgtt cttggccag 339

<210> 110

<211> 339

<212> DNA

<213> Homo sapiens

<400> 110

gatatcgcac tgacccagcc agcttcagtg agcggctcac caggtcagag cattaccatc 60

tcgtgtacgg gtactagcag cgatgttggt gatattaatg atgtgtcttg gtaccagcag 120

catcccggga aggcgccgaa acttatgatt tatgatgtta ataatcgtcc ctcaggcgtg 180

agcaaccgtt ttagcggatc caaaagcggc aacaccgcga gcctgaccat tagcggcctg 240

caagcggaag acgaagcgga ttattattgc tctacttatg atggtcctgg tctttctgag 300

gtgtttggcg gcggcacgaa gttaaccgtt cttggccag 339

<210> 111

<211> 469

<212> PROTEIN

<213> Homo sapiens

<400> 111

Met Ala Trp Val Trp Thr Leu Pro Phe Leu Met Ala Ala Ala Gln Ser

1 5 10 15

Val Gln Ala Gln 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 Val Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ser Phe Ile Ser Gly Asp Ser Ser Asn Thr 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 Thr Phe Met His Gly His Leu Gly Gly Gly Leu

115 120 125

Ser Met Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

130 135 140

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser

145 150 155 160

Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe

165 170 175

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly

180 185 190

Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu

195 200 205

Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr

210 215 220

Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr

225 230 235 240

Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser

305 310 315 320

Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala

340 345 350

Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

370 375 380

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro Gly Lys

465

<210> 112

<211> 462

<212> PROTEIN

<213> Homo sapiens

<400> 112

Met Ala Trp Val Trp Thr Leu Pro Phe Leu Met Ala Ala Ala Gln Ser

1 5 10 15

Val Gln Ala Gln 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

Arg Ser His Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ser Asn Ile Asn Tyr Asp Gly Ser Ser Thr 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 Asp Thr Tyr Leu His 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 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys

210 215 220

Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val

225 230 235 240

Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 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 His 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 Phe Arg Val Val Ser Val

305 310 315 320

Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

Ser Arg 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 Met Leu Asp Ser Asp

405 410 415

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

Gln Gln 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> 113

<211> 469

<212> PROTEIN

<213> Homo sapiens

<400> 113

Met Ala Trp Val Trp Thr Leu Pro Phe Leu Met Ala Ala Ala Gln Ser

1 5 10 15

Val Gln Ala Gln 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 Val Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ser Phe Ile Ser Gly Asp Ser Ser Asn Thr 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 Thr Phe Met His Gly His Leu Gly Gly Gly Leu

115 120 125

Ser Met Asp Phe Trp Gly Gln Gly Thr Leu Val Thr Val Ser Ser Ala

130 135 140

Ser Thr Lys Gly Pro Ser Val Phe Pro Leu Ala Pro Cys Ser Arg Ser

145 150 155 160

Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys Leu Val Lys Asp Tyr Phe

165 170 175

Pro Glu Pro Val Thr Val Ser Trp Asn Ser Gly Ala Leu Thr Ser Gly

180 185 190

Val His Thr Phe Pro Ala Val Leu Gln Ser Ser Gly Leu Tyr Ser Leu

195 200 205

Ser Ser Val Val Thr Val Pro Ser Ser Asn Phe Gly Thr Gln Thr Tyr

210 215 220

Thr Cys Asn Val Asp His Lys Pro Ser Asn Thr Lys Val Asp Lys Thr

225 230 235 240

Val Glu Arg Lys Cys Cys Val Glu Cys Pro Pro Cys Pro Ala Pro Pro

245 250 255

Val Ala Gly Pro Ser Val Phe Leu Phe Pro Pro Lys Pro Lys Asp Thr

260 265 270

Leu Met Ile Ser Arg Thr Pro Glu Val Thr Cys Val Val Val Asp Val

275 280 285

Ser His Glu Asp Pro Glu Val Gln Phe Asn Trp Tyr Val Asp Gly Val

290 295 300

Glu Val His Asn Ala Lys Thr Lys Pro Arg Glu Glu Gln Phe Asn Ser

305 310 315 320

Thr Phe Arg Val Val Ser Val Leu Thr Val Val His Gln Asp Trp Leu

325 330 335

Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser Asn Lys Gly Leu Pro Ala

340 345 350

Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys Gly Gln Pro Arg Glu Pro

355 360 365

Gln Val Tyr Thr Leu Pro Ser Arg Glu Glu Met Thr Lys Asn Gln

370 375 380

Val Ser Leu Thr Cys Leu Val Lys Gly Phe Tyr Pro Ser Asp Ile Ala

385 390 395 400

Val Glu Trp Glu Ser Asn Gly Gln Pro Glu Asn Asn Tyr Lys Thr Thr

405 410 415

Pro Pro Met Leu Asp Ser Asp Gly Ser Phe Phe Leu Tyr Ser Lys Leu

420 425 430

Thr Val Asp Lys Ser Arg Trp Gln Gln Gly Asn Val Phe Ser Cys Ser

435 440 445

Val Met His Glu Ala Leu His Asn His Tyr Thr Gln Lys Ser Leu Ser

450 455 460

Leu Ser Pro Gly Lys

465

<210> 114

<211> 462

<212> PROTEIN

<213> Homo sapiens

<400> 114

Met Ala Trp Val Trp Thr Leu Pro Phe Leu Met Ala Ala Ala Gln Ser

1 5 10 15

Val Gln Ala Gln 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

Arg Ser His Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ser Asn Ile Asn Tyr Asp Gly Ser Ser Thr 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 Asp Thr Tyr Leu His 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 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys

210 215 220

Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val

225 230 235 240

Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 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 His 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 Phe Arg Val Val Ser Val

305 310 315 320

Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

Ser Arg 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 Met Leu Asp Ser Asp

405 410 415

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

Gln Gln 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> 115

<211> 461

<212> PROTEIN

<213> Homo sapiens

<400> 115

Met Ala Trp Val Trp Thr Leu Pro Phe Leu Met Ala Ala Ala Gln Ser

1 5 10 15

Val Gln Ala Gln 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

Arg Ser His Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ser Val Thr Gly Val His Gly Asp Thr Tyr Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

85 90 95

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

100 105 110

Tyr Cys Ala Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly

115 120 125

Thr Leu 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 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> 116

<211> 461

<212> PROTEIN

<213> Homo sapiens

<400> 116

Met Ala Trp Val Trp Thr Leu Pro Phe Leu Met Ala Ala Ala Gln Ser

1 5 10 15

Val Gln Ala Gln 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

Arg Ser His Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ser Val Ile Gly Asn Trp Gly Asp Thr Tyr Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

85 90 95

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

100 105 110

Tyr Cys Ala Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly

115 120 125

Thr Leu 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 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> 117

<211> 461

<212> PROTEIN

<213> Homo sapiens

<400> 117

Met Ala Trp Val Trp Thr Leu Pro Phe Leu Met Ala Ala Ala Gln Ser

1 5 10 15

Val Gln Ala Gln 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

Arg Ser His Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ser Val Thr Thr His Gln Gly Tyr Thr Tyr Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

85 90 95

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

100 105 110

Tyr Cys Ala Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly

115 120 125

Thr Leu 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 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> 118

<211> 465

<212> PROTEIN

<213> Homo sapiens

<400> 118

Met Lys His Leu Trp Phe Phe Leu Leu Leu Val Ala Ala Pro Arg Trp

1 5 10 15

Val Leu Ser Gln 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

Arg Ser His Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ser Ala Thr Asn Arg Tyr Gly Tyr Thr Tyr Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

85 90 95

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

100 105 110

Tyr Cys Ala Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly

115 120 125

Thr Leu Val Thr Val Ser Ser Ala Lys Thr Thr Ala Pro Ser Val Tyr

130 135 140

Pro Leu Ala Pro Val Cys Gly Asp Thr Thr Gly Ser Ser Val Thr Leu

145 150 155 160

Gly Cys Leu Val Lys Gly Tyr Phe Pro Glu Pro Val Thr Leu Thr Trp

165 170 175

Asn Ser Gly Ser Leu Ser Ser Gly Val His Thr Phe Pro Ala Val Leu

180 185 190

Gln Ser Asp Leu Tyr Thr Leu Ser Ser Ser Val Thr Val Thr Ser Ser

195 200 205

Thr Trp Pro Ser Gln Ser Ile Thr Cys Asn Val Ala His Pro Ala Ser

210 215 220

Ser Thr Lys Val Asp Lys Lys Ile Glu Pro Arg Gly Pro Thr Ile Lys

225 230 235 240

Pro Cys Pro Pro Cys Lys Cys Pro Ala Pro Asn Leu Leu Gly Gly Pro

245 250 255

Ser Val Phe Ile Phe Pro Pro Lys Ile Lys Asp Val Leu Met Ile Ser

260 265 270

Leu Ser Pro Ile Val Thr Cys Val Val Val Asp Val Ser Glu Asp Asp

275 280 285

Pro Asp Val Gln Ile Ser Trp Phe Val Asn Asn Val Glu Val His Thr

290 295 300

Ala Gln Thr Gln Thr His Arg Glu Asp Tyr Asn Ser Thr Leu Arg Val

305 310 315 320

Val Ser Ala Leu Pro Ile Gln His Gln Asp Trp Met Ser Gly Lys Glu

325 330 335

Phe Lys Cys Lys Val Asn Asn Lys Asp Leu Pro Ala Pro Ile Glu Arg

340 345 350

Thr Ile Ser Lys Pro Lys Gly Ser Val Arg Ala Pro Gln Val Tyr Val

355 360 365

Leu Pro Pro Pro Glu Glu Glu Met Thr Lys Lys Gln Val Thr Leu Thr

370 375 380

Cys Met Val Thr Asp Phe Met Pro Glu Asp Ile Tyr Val Glu Trp Thr

385 390 395 400

Asn Asn Gly Lys Thr Glu Leu Asn Tyr Lys Asn Thr Glu Pro Val Leu

405 410 415

Asp Ser Asp Gly Ser Tyr Phe Met Tyr Ser Lys Leu Arg Val Glu Lys

420 425 430

Lys Asn Trp Val Glu Arg Asn Ser Tyr Ser Cys Ser Val Val His Glu

435 440 445

Gly Leu His Asn His Thr Thr Lys Ser Phe Ser Arg Thr Pro Gly

450 455 460

Lys

465

<210> 119

<211> 462

<212> PROTEIN

<213> Homo sapiens

<400> 119

Met Ala Trp Val Trp Thr Leu Pro Phe Leu Met Ala Ala Ala Gln Ser

1 5 10 15

Val Gln Ala Gln 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

Arg Ser His Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ser Asn Ile Asn Tyr Asp Gly Ser Ser Thr 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 Asp Thr Tyr Leu His 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 Asn Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys

210 215 220

Pro Ser Asn Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val

225 230 235 240

Glu Cys Pro Pro Cys Pro Ala Pro Pro Val Ala 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 His 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 Phe Arg Val Val Ser Val

305 310 315 320

Leu Thr Val Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys

325 330 335

Lys Val Ser Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser

340 345 350

Lys Thr Lys Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro

355 360 365

Ser Arg 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 Met Leu Asp Ser Asp

405 410 415

Gly Ser Phe Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp

420 425 430

Gln Gln 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> 120

<211> 461

<212> PROTEIN

<213> Homo sapiens

<400> 120

Met Ala Trp Val Trp Thr Leu Pro Phe Leu Met Ala Ala Ala Gln Ser

1 5 10 15

Val Gln Ala Gln 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

Arg Ser His Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ser Val Ile Thr Pro Tyr Gly Asp Thr Tyr Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

85 90 95

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

100 105 110

Tyr Cys Ala Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly

115 120 125

Thr Leu 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 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> 121

<211> 461

<212> PROTEIN

<213> Homo sapiens

<400> 121

Met Ala Trp Val Trp Thr Leu Pro Phe Leu Met Ala Ala Ala Gln Ser

1 5 10 15

Val Gln Ala Gln 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

Arg Ser His Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Ser Val Ile Thr Pro Tyr Gly Asp Thr Tyr Tyr Ala Asp

65 70 75 80

Ser Val Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

85 90 95

Leu Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr

100 105 110

Tyr Cys Ala Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly

115 120 125

Thr Leu 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 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> 122

<211> 130

<212> PROTEIN

<213> Homo sapiens

<400> 122

Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr

1 5 10 15

Gly Thr Arg Cys Asp Ile Glu Leu Thr Gln Pro Pro Ser Val Ser Val

20 25 30

Ala Pro Gly Gln Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Ile Gly

35 40 45

Ser Phe Tyr Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val

50 55 60

Leu Val Ile Tyr Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Glu Arg

65 70 75 80

Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly

85 90 95

Thr Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gly Ser Trp Ala Gly

100 105 110

Ser Ser Gly Ser Tyr Val Phe Gly Gly Arg Thr Lys Leu Thr Val Leu

115 120 125

Gly Gln

130

<210> 123

<211> 237

<212> PROTEIN

<213> Homo sapiens

<400> 123

Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr

1 5 10 15

Gly Thr Arg Cys Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly

20 25 30

Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp

35 40 45

Val Gly Asp Ile Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys

50 55 60

Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val

65 70 75 80

Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr

85 90 95

Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser

100 105 110

Tyr Gly Glu Ser Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu

115 120 125

Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro

130 135 140

Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu

145 150 155 160

Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp

165 170 175

Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln

180 185 190

Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu

195 200 205

Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly

210 215 220

Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

225 230 235

<210> 124

<211> 234

<212> PROTEIN

<213> Homo sapiens

<400> 124

Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr

1 5 10 15

Gly Thr Arg Cys Asp Ile Glu Leu Thr Gln Pro Pro Ser Val Ser Val

20 25 30

Ala Pro Gly Gln Thr Ala Arg Ile Ser Cys Ser Gly Asp Asn Ile Gly

35 40 45

Ser Phe Tyr Val His Trp Tyr Gln Gln Lys Pro Gly Gln Ala Pro Val

50 55 60

Leu Val Ile Tyr Asp Asp Asn Asn Arg Pro Ser Gly Ile Pro Glu Arg

65 70 75 80

Phe Ser Gly Ser Asn Ser Gly Asn Thr Ala Thr Leu Thr Ile Ser Gly

85 90 95

Thr Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ala Ser Trp Thr Gly

100 105 110

Val Glu Pro Asp Tyr Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu

115 120 125

Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser

130 135 140

Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp

145 150 155 160

Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro

165 170 175

Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn

180 185 190

Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys

195 200 205

Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val

210 215 220

Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

225 230

<210> 125

<211> 237

<212> PROTEIN

<213> Homo sapiens

<400> 125

Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr

1 5 10 15

Gly Thr Arg Cys Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly

20 25 30

Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp

35 40 45

Val Gly Asp Ile Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys

50 55 60

Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val

65 70 75 80

Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr

85 90 95

Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser

100 105 110

Tyr Ala Gly Ser Tyr Leu Ser Glu Val Phe Gly Gly Gly Thr Lys Leu

115 120 125

Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro

130 135 140

Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu

145 150 155 160

Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp

165 170 175

Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln

180 185 190

Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu

195 200 205

Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly

210 215 220

Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

225 230 235

<210> 126

<211> 237

<212> PROTEIN

<213> Homo sapiens

<400> 126

Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr

1 5 10 15

Gly Thr Arg Cys Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly

20 25 30

Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp

35 40 45

Val Gly Asp Ile Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys

50 55 60

Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val

65 70 75 80

Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr

85 90 95

Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser

100 105 110

Tyr Gly Glu Ser Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu

115 120 125

Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro

130 135 140

Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu

145 150 155 160

Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp

165 170 175

Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln

180 185 190

Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu

195 200 205

Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly

210 215 220

Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

225 230 235

<210> 127

<211> 237

<212> PROTEIN

<213> Homo sapiens

<400> 127

Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr

1 5 10 15

Gly Thr Arg Cys Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly

20 25 30

Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp

35 40 45

Val Gly Asp Ile Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys

50 55 60

Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val

65 70 75 80

Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr

85 90 95

Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser

100 105 110

Tyr Gly Glu Ser Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu

115 120 125

Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro

130 135 140

Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu

145 150 155 160

Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp

165 170 175

Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln

180 185 190

Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu

195 200 205

Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly

210 215 220

Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

225 230 235

<210> 128

<211> 237

<212> PROTEIN

<213> Homo sapiens

<400> 128

Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr

1 5 10 15

Gly Thr Arg Cys Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly

20 25 30

Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp

35 40 45

Val Gly Asp Ile Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys

50 55 60

Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val

65 70 75 80

Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr

85 90 95

Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser

100 105 110

Tyr Gly Glu Ser Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu

115 120 125

Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro

130 135 140

Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu

145 150 155 160

Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp

165 170 175

Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln

180 185 190

Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu

195 200 205

Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly

210 215 220

Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

225 230 235

<210> 129

<211> 237

<212> PROTEIN

<213> Homo sapiens

<400> 129

Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr

1 5 10 15

Gly Thr Arg Cys Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly

20 25 30

Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp

35 40 45

Val Gly Asp Ile Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys

50 55 60

Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val

65 70 75 80

Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr

85 90 95

Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser

100 105 110

Tyr Gly Glu Ser Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu

115 120 125

Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro

130 135 140

Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu

145 150 155 160

Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp

165 170 175

Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln

180 185 190

Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu

195 200 205

Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly

210 215 220

Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

225 230 235

<210> 130

<211> 237

<212> PROTEIN

<213> Homo sapiens

<400> 130

Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr

1 5 10 15

Gly Thr Arg Cys Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly

20 25 30

Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp

35 40 45

Val Gly Asp Ile Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys

50 55 60

Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val

65 70 75 80

Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr

85 90 95

Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Thr

100 105 110

Tyr Asp Gly Pro Gly Leu Ser Glu Val Phe Gly Gly Gly Thr Lys Leu

115 120 125

Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro

130 135 140

Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu

145 150 155 160

Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp

165 170 175

Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln

180 185 190

Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu

195 200 205

Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly

210 215 220

Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

225 230 235

<210> 131

<211> 237

<212> PROTEIN

<213> Homo sapiens

<400> 131

Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr

1 5 10 15

Gly Thr Arg Cys Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly

20 25 30

Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp

35 40 45

Val Gly Asp Ile Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys

50 55 60

Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val

65 70 75 80

Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr

85 90 95

Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Ser

100 105 110

Tyr Gly Glu Ser Leu Thr Ser Tyr Val Phe Gly Gly Gly Thr Lys Leu

115 120 125

Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro

130 135 140

Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu

145 150 155 160

Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp

165 170 175

Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln

180 185 190

Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu

195 200 205

Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly

210 215 220

Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

225 230 235

<210> 132

<211> 237

<212> PROTEIN

<213> Homo sapiens

<400> 132

Met Ser Val Leu Thr Gln Val Leu Ala Leu Leu Leu Leu Trp Leu Thr

1 5 10 15

Gly Thr Arg Cys Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly

20 25 30

Ser Pro Gly Gln Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp

35 40 45

Val Gly Asp Ile Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys

50 55 60

Ala Pro Lys Leu Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val

65 70 75 80

Ser Asn Arg Phe Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr

85 90 95

Ile Ser Gly Leu Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Ser Thr

100 105 110

Tyr Asp Gly Pro Gly Leu Ser Glu Val Phe Gly Gly Gly Thr Lys Leu

115 120 125

Thr Val Leu Gly Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro

130 135 140

Pro Ser Ser Glu Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu

145 150 155 160

Ile Ser Asp Phe Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp

165 170 175

Ser Ser Pro Val Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln

180 185 190

Ser Asn Asn Lys Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu

195 200 205

Gln Trp Lys Ser His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly

210 215 220

Ser Thr Val Glu Lys Thr Val Ala Pro Thr Glu Cys Ser

225 230 235

<210> 133

<211> 1410

<212> DNA

<213> Homo sapiens

<400> 133

atggcttggg tgtggacctt gccattcctg atggcagctg cccaaagcgt gcaggcccag 60

gtgcagctgg tcgagtctgg cggcggactg gtgcagcctg gcggcagcct gagactgagc 120

tgcgccgcca gcggcttcac cttcagcagc tacgtgatga actgggtgcg gcaggcccct 180

ggcaagggcc tggagtgggt gtccttcatc agcggcgaca gcagcaacac ctactacgcc 240

gacagcgtga agggccggtt caccatcagc cgggacaaca gcaagaacac cctgtacctg 300

cagatgaaca gcctgcgggc cgaggacacc gccgtgtact actgcgcccg gaccttcatg 360

cacggccacc tgggcggagg actgagcatg gatttctggg gccagggcac cctggtcacc 420

gtctcctcag cttccaccaa gggcccatcc gtcttccccc tggcgccctg ctccaggagc 480

acctccgaga gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 540

acggtgtcgt ggaactcagg cgctctgacc agcggcgtgc acaccttccc agctgtccta 600

cagtcctcag gactctactc cctcagcagc gtggtgacag tgccctccag caacttcggc 660

acccagacct acacctgcaa cgtagatcac aagcccagca acaccaaggt ggacaagaca 720

gttgagcgca aatgttgtgt cgagtgccca ccgtgcccag caccacctgt ggcaggaccg 780

tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 840

gtcacgtgcg tggtggtgga cgtgagccac gaagaccccg aggtccagtt caactggtac 900

gtggacggcg tggaggtgca taatgccaag acaaagccac gggaggagca gttcaacagc 960

acgttccgtg tggtcagcgt cctcaccgtt gtgcaccagg actggctgaa cggcaaggag 1020

tacaagtgca aggtctccaa caaaggcctc ccagccccca tcgagaaaac catctccaaa 1080

accaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1140

accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1200

gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacacc tcccatgctg 1260

gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1320

cagggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1380

aagagcctct ccctgtctcc gggtaaatga 1410

<210> 134

<211> 1389

<212> DNA

<213> Homo sapiens

<400> 134

atggcttggg tgtggacctt gccattcctg atggcagctg cccaaggtgt ccaggcccag 60

gtgcagctgg tcgagagcgg cggagggctg gtgcagcctg gcggcagcct gagactgagc 120

tgcgccgcca gcggcttcac cttcagaagc cactggctgt cctgggtgcg gcaggcccct 180

ggcaagggcc tggaatgggt gtccaacatc aactacgacg gcagcagcac ctactacgcc 240

gacagcgtga agggccggtt caccatcagc cgggacaaca gcaagaacac cctgtacctg 300

cagatgaaca gcctgcgggc cgaggacacc gccgtgtact actgcgccag ggacacctac 360

ctgcacttcg actactgggg ccagggcacc ctggtcaccg tctcctcagc ttccaccaag 420

ggcccatccg tcttccccct ggcgccctgc tccaggagca cctccgagag cacagcggcc 480

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 540

gctctgacca gcggcgtgca caccttccca gctgtcctac agtcctcagg actctactcc 600

ctcagcagcg tggtgacagt gccctccagc aacttcggca cccagaccta cacctgcaac 660

gtagatcaca agcccagcaa caccaaggtg gacaagcag ttgagcgcaa atgttgtgtc 720

gagtgcccac cgtgcccagc accacctgtg gcaggaccgt cagtcttcct cttcccccca 780

aaacccaagg acaccctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 840

gtgagccacg aagaccccga ggtccagttc aactggtacg tggacggcgt ggaggtgcat 900

aatgccaaga caaagccacg ggaggagcag ttcaacagca cgttccgtgt ggtcagcgtc 960

ctcaccgttg tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 1020

aaaggcctcc cagcccccat cgagaaaacc atctccaaaa ccaaagggca gccccgagaa 1080

ccacaggtgt acaccctgcc cccatcccgg gaggagatga ccaagaacca ggtcagcctg 1140

acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 1200

cagccggaga acaactacaa gaccacacct cccatgctgg actccgacgg ctccttcttc 1260

ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1320

tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1380

ggtaaatga 1389

<210> 135

<211> 1410

<212> DNA

<213> Homo sapiens

<400> 135

atggcttggg tgtggacctt gccattcctg atggcagctg cccaaagcgt gcaggcccag 60

gtgcagctgg tcgagtctgg cggcggactg gtgcagcctg gcggcagcct gagactgagc 120

tgcgccgcca gcggcttcac cttcagcagc tacgtgatga actgggtgcg gcaggcccct 180

ggcaagggcc tggagtgggt gtccttcatc agcggcgaca gcagcaacac ctactacgcc 240

gacagcgtga agggccggtt caccatcagc cgggacaaca gcaagaacac cctgtacctg 300

cagatgaaca gcctgcgggc cgaggacacc gccgtgtact actgcgcccg gaccttcatg 360

cacggccacc tgggcggagg actgagcatg gatttctggg gccagggcac cctggtcacc 420

gtctcctcag cttccaccaa gggcccatcc gtcttccccc tggcgccctg ctccaggagc 480

acctccgaga gcacagcggc cctgggctgc ctggtcaagg actacttccc cgaaccggtg 540

acggtgtcgt ggaactcagg cgctctgacc agcggcgtgc acaccttccc agctgtccta 600

cagtcctcag gactctactc cctcagcagc gtggtgacag tgccctccag caacttcggc 660

acccagacct acacctgcaa cgtagatcac aagcccagca acaccaaggt ggacaagaca 720

gttgagcgca aatgttgtgt cgagtgccca ccgtgcccag caccacctgt ggcaggaccg 780

tcagtcttcc tcttcccccc aaaacccaag gacaccctca tgatctcccg gacccctgag 840

gtcacgtgcg tggtggtgga cgtgagccac gaagaccccg aggtccagtt caactggtac 900

gtggacggcg tggaggtgca taatgccaag acaaagccac gggaggagca gttcaacagc 960

acgttccgtg tggtcagcgt cctcaccgtt gtgcaccagg actggctgaa cggcaaggag 1020

tacaagtgca aggtctccaa caaaggcctc ccagccccca tcgagaaaac catctccaaa 1080

accaaagggc agccccgaga accacaggtg tacaccctgc ccccatcccg ggaggagatg 1140

accaagaacc aggtcagcct gacctgcctg gtcaaaggct tctaccccag cgacatcgcc 1200

gtggagtggg agagcaatgg gcagccggag aacaactaca agaccacacc tcccatgctg 1260

gactccgacg gctccttctt cctctacagc aagctcaccg tggacaagag caggtggcag 1320

cagggggaacg tcttctcatg ctccgtgatg catgaggctc tgcacaacca ctacacgcag 1380

aagagcctct ccctgtctcc gggtaaatga 1410

<210> 136

<211> 1389

<212> DNA

<213> Homo sapiens

<400> 136

atggcttggg tgtggacctt gccattcctg atggcagctg cccaaggtgt ccaggcccag 60

gtgcagctgg tcgagagcgg cggagggctg gtgcagcctg gcggcagcct gagactgagc 120

tgcgccgcca gcggcttcac cttcagaagc cactggctgt cctgggtgcg gcaggcccct 180

ggcaagggcc tggaatgggt gtccaacatc aactacgacg gcagcagcac ctactacgcc 240

gacagcgtga agggccggtt caccatcagc cgggacaaca gcaagaacac cctgtacctg 300

cagatgaaca gcctgcgggc cgaggacacc gccgtgtact actgcgccag ggacacctac 360

ctgcacttcg actactgggg ccagggcacc ctggtcaccg tctcctcagc ttccaccaag 420

ggcccatccg tcttccccct ggcgccctgc tccaggagca cctccgagag cacagcggcc 480

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 540

gctctgacca gcggcgtgca caccttccca gctgtcctac agtcctcagg actctactcc 600

ctcagcagcg tggtgacagt gccctccagc aacttcggca cccagaccta cacctgcaac 660

gtagatcaca agcccagcaa caccaaggtg gacaagcag ttgagcgcaa atgttgtgtc 720

gagtgcccac cgtgcccagc accacctgtg gcaggaccgt cagtcttcct cttcccccca 780

aaacccaagg acaccctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 840

gtgagccacg aagaccccga ggtccagttc aactggtacg tggacggcgt ggaggtgcat 900

aatgccaaga caaagccacg ggaggagcag ttcaacagca cgttccgtgt ggtcagcgtc 960

ctcaccgttg tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 1020

aaaggcctcc cagcccccat cgagaaaacc atctccaaaa ccaaagggca gccccgagaa 1080

ccacaggtgt acaccctgcc cccatcccgg gaggagatga ccaagaacca ggtcagcctg 1140

acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 1200

cagccggaga acaactacaa gaccacacct cccatgctgg actccgacgg ctccttcttc 1260

ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1320

tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1380

ggtaaatga 1389

<210> 137

<211> 1386

<212> DNA

<213> Homo sapiens

<400> 137

atggcttggg tgtggacctt gccattcctg atggcagctg cccaaagtgt ccaggcccag 60

gtgcagctgg tcgagagcgg cggagggctg gtgcagcctg gcggcagcct gagactgagc 120

tgcgccgcca gcggcttcac cttcagaagc cactggctgt cctgggtgcg gcaggcccct 180

ggcaagggcc tggaatgggt gtccgtgacc ggcgtgcacg gcgacaccta ctacgccgac 240

agcgtgaagg gccggttcac catcagccgg gacaacagca agaacaccct gtacctgcag 300

atgaacagcc tgcgggccga ggacaccgcc gtgtactact gcgccaggga cacctacctg 360

cacttcgact actggggcca gggcaccctg gtcaccgtct cctcagcttc caccaagggc 420

ccatccgtct tccccctggc gccctgctcc aggagcacct ccgagagcac agcggccctg 480

ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgct 540

ctgaccagcg gcgtgcacac cttcccagct gtcctacagt cctcaggact ctactccctc 600

agcagcgtgg tgacagtgcc ctccagcaac ttcggcaccc agacctacac ctgcaacgta 660

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

aaatga 1386

<210> 138

<211> 1386

<212> DNA

<213> Homo sapiens

<400> 138

atggcttggg tgtggacctt gccattcctg atggcagctg cccaaagtgt ccaggcccag 60

gtgcagctgg tcgagagcgg cggagggctg gtgcagcctg gcggcagcct gagactgagc 120

tgcgccgcca gcggcttcac cttcagaagc cactggctgt cctgggtgcg gcaggcccct 180

ggcaagggcc tggaatgggt gtccgtgatc ggcaactggg gcgacaccta ctacgccgac 240

agcgtgaagg gccggttcac catcagccgg gacaacagca agaacaccct gtacctgcag 300

atgaacagcc tgcgggccga ggacaccgcc gtgtactact gcgccaggga cacctacctg 360

cacttcgact actggggcca gggcaccctg gtcaccgtct cctcagcttc caccaagggc 420

ccatccgtct tccccctggc gccctgctcc aggagcacct ccgagagcac agcggccctg 480

ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgct 540

ctgaccagcg gcgtgcacac cttcccagct gtcctacagt cctcaggact ctactccctc 600

agcagcgtgg tgacagtgcc ctccagcaac ttcggcaccc agacctacac ctgcaacgta 660

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

aaatga 1386

<210> 139

<211> 1386

<212> DNA

<213> Homo sapiens

<400> 139

atggcttggg tgtggacctt gccattcctg atggcagctg cccaaagtgt ccaggcccag 60

gtgcagctgg tcgagagcgg cggagggctg gtgcagcctg gcggcagcct gagactgagc 120

tgcgccgcca gcggcttcac cttcagaagc cactggctgt cctgggtgcg gcaggcccct 180

ggcaagggcc tggaatgggt gtccgtgacc acccaccagg gctacaccta ctacgccgac 240

agcgtgaagg gccggttcac catcagccgg gacaacagca agaacaccct gtacctgcag 300

atgaacagcc tgcgggccga ggacaccgcc gtgtactact gcgccaggga cacctacctg 360

cacttcgact actggggcca gggcaccctg gtcaccgtct cctcagcttc caccaagggc 420

ccatccgtct tccccctggc gccctgctcc aggagcacct ccgagagcac agcggccctg 480

ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgct 540

ctgaccagcg gcgtgcacac cttcccagct gtcctacagt cctcaggact ctactccctc 600

agcagcgtgg tgacagtgcc ctccagcaac ttcggcaccc agacctacac ctgcaacgta 660

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

aaatga 1386

<210> 140

<211> 1386

<212> DNA

<213> Homo sapiens

<400> 140

atggcttggg tgtggacctt gccattcctg atggcagctg cccaaagtgt ccaggcccag 60

gtgcagctgg tcgagagcgg cggagggctg gtgcagcctg gcggcagcct gagactgagc 120

tgcgccgcca gcggcttcac cttcagaagc cactggctgt cctgggtgcg gcaggcccct 180

ggcaagggcc tggaatgggt gtccgccacc aacagatacg gctacaccta ctacgccgac 240

agcgtgaagg gccggttcac catcagccgg gacaacagca agaacaccct gtacctgcag 300

atgaacagcc tgcgggccga ggacaccgcc gtgtactact gcgccaggga cacctacctg 360

cacttcgact actggggcca gggcaccctg gtcaccgtct cctcagcttc caccaagggc 420

ccatccgtct tccccctggc gccctgctcc aggagcacct ccgagagcac agcggccctg 480

ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgct 540

ctgaccagcg gcgtgcacac cttcccagct gtcctacagt cctcaggact ctactccctc 600

agcagcgtgg tgacagtgcc ctccagcaac ttcggcaccc agacctacac ctgcaacgta 660

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

aaatga 1386

<210> 141

<211> 1389

<212> DNA

<213> Homo sapiens

<400> 141

atggcttggg tgtggacctt gccattcctg atggcagctg cccaaggtgt ccaggcccag 60

gtgcagctgg tcgagagcgg cggagggctg gtgcagcctg gcggcagcct gagactgagc 120

tgcgccgcca gcggcttcac cttcagaagc cactggctgt cctgggtgcg gcaggcccct 180

ggcaagggcc tggaatgggt gtccaacatc aactacgacg gcagcagcac ctactacgcc 240

gacagcgtga agggccggtt caccatcagc cgggacaaca gcaagaacac cctgtacctg 300

cagatgaaca gcctgcgggc cgaggacacc gccgtgtact actgcgccag ggacacctac 360

ctgcacttcg actactgggg ccagggcacc ctggtcaccg tctcctcagc ttccaccaag 420

ggcccatccg tcttccccct ggcgccctgc tccaggagca cctccgagag cacagcggcc 480

ctgggctgcc tggtcaagga ctacttcccc gaaccggtga cggtgtcgtg gaactcaggc 540

gctctgacca gcggcgtgca caccttccca gctgtcctac agtcctcagg actctactcc 600

ctcagcagcg tggtgacagt gccctccagc aacttcggca cccagaccta cacctgcaac 660

gtagatcaca agcccagcaa caccaaggtg gacaagcag ttgagcgcaa atgttgtgtc 720

gagtgcccac cgtgcccagc accacctgtg gcaggaccgt cagtcttcct cttcccccca 780

aaacccaagg acaccctcat gatctcccgg acccctgagg tcacgtgcgt ggtggtggac 840

gtgagccacg aagaccccga ggtccagttc aactggtacg tggacggcgt ggaggtgcat 900

aatgccaaga caaagccacg ggaggagcag ttcaacagca cgttccgtgt ggtcagcgtc 960

ctcaccgttg tgcaccagga ctggctgaac ggcaaggagt acaagtgcaa ggtctccaac 1020

aaaggcctcc cagcccccat cgagaaaacc atctccaaaa ccaaagggca gccccgagaa 1080

ccacaggtgt acaccctgcc cccatcccgg gaggagatga ccaagaacca ggtcagcctg 1140

acctgcctgg tcaaaggctt ctaccccagc gacatcgccg tggagtggga gagcaatggg 1200

cagccggaga acaactacaa gaccacacct cccatgctgg actccgacgg ctccttcttc 1260

ctctacagca agctcaccgt ggacaagagc aggtggcagc aggggaacgt cttctcatgc 1320

tccgtgatgc atgaggctct gcacaaccac tacacgcaga agagcctctc cctgtctccg 1380

ggtaaatga 1389

<210> 142

<211> 1386

<212> DNA

<213> Homo sapiens

<400> 142

atggcttggg tgtggacctt gccattcctg atggcagctg cccaaagtgt ccaggcccag 60

gtgcagctgg tcgagagcgg cggagggctg gtgcagcctg gcggcagcct gagactgagc 120

tgcgccgcca gcggcttcac cttcagaagc cactggctgt cctgggtgcg gcaggcccct 180

ggcaagggcc tggaatgggt gtccgtgatc accccctacg gcgacaccta ctacgccgac 240

agcgtgaagg gccggttcac catcagccgg gacaacagca agaacaccct gtacctgcag 300

atgaacagcc tgcgggccga ggacaccgcc gtgtactact gcgccaggga cacctacctg 360

cacttcgact actggggcca gggcaccctg gtcaccgtct cctcagcttc caccaagggc 420

ccatccgtct tccccctggc gccctgctcc aggagcacct ccgagagcac agcggccctg 480

ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgct 540

ctgaccagcg gcgtgcacac cttcccagct gtcctacagt cctcaggact ctactccctc 600

agcagcgtgg tgacagtgcc ctccagcaac ttcggcaccc agacctacac ctgcaacgta 660

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

aaatga 1386

<210> 143

<211> 1386

<212> DNA

<213> Homo sapiens

<400> 143

atggcttggg tgtggacctt gccattcctg atggcagctg cccaaagtgt ccaggcccag 60

gtgcagctgg tcgagagcgg cggagggctg gtgcagcctg gcggcagcct gagactgagc 120

tgcgccgcca gcggcttcac cttcagaagc cactggctgt cctgggtgcg gcaggcccct 180

ggcaagggcc tggaatgggt gtccgtgatc accccctacg gcgacaccta ctacgccgac 240

agcgtgaagg gccggttcac catcagccgg gacaacagca agaacaccct gtacctgcag 300

atgaacagcc tgcgggccga ggacaccgcc gtgtactact gcgccaggga cacctacctg 360

cacttcgact actggggcca gggcaccctg gtcaccgtct cctcagcttc caccaagggc 420

ccatccgtct tccccctggc gccctgctcc aggagcacct ccgagagcac agcggccctg 480

ggctgcctgg tcaaggacta cttccccgaa ccggtgacgg tgtcgtggaa ctcaggcgct 540

ctgaccagcg gcgtgcacac cttcccagct gtcctacagt cctcaggact ctactccctc 600

agcagcgtgg tgacagtgcc ctccagcaac ttcggcaccc agacctacac ctgcaacgta 660

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

aaatga 1386

<210> 144

<211> 393

<212> DNA

<213> Homo sapiens

<400> 144

atgaaaaaga cagctatcgc gattgcagtg gcactggctg gtttcgctac cgtagcgcag 60

gccgatatcg aactgaccca gccgccttca gtgagcgttg caccaggtca gaccgcgcgt 120

atctcgtgta gcggcgataa tattggttct ttttatgttc attggtacca gcagaaaccc 180

gggcaggcgc cagttcttgt gatttatgat gataataatc gtccctcagg catcccggaa 240

cgctttagcg gatccaacag cggcaacacc gcgaccctga ccattagcgg cactcaggcg 300

360

ggcggccgca cgaagttaac cgttcttggc cag 393

<210> 145

<211> 714

<212> DNA

<213> Homo sapiens

<400> 145

atgagtgtgc tcactcaggt cctggcgttg ctgctgctgt ggcttacagg tacgcgttgc 60

gacatcgccc tgacccagcc cgccagcgtg agcggcagcc ctggccagag catcaccatc 120

agctgcaccg gcaccagcag cgacgtgggc gacatcaacg acgtgagctg gtatcagcag 180

caccccggca aggcccccaa gctgatgatc tacgacgtga acaaccggcc cagcggcgtg 240

agcaaccggt tcagcggcag caagagcggc aacaccgcca gcctgaccat cagcggcctc 300

caggccgagg acgaggccga ctactactgc agcagctacg gcgagagcct gaccagctac 360

gtgtttggcg gcggaaccaa gcttaccgtc ctaggtcagc ccaaggctgc cccctcggtc 420

actctgttcc cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 480

ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 540

aaggcgggag tggagacaac cacaccctcc aaacaaagca acaacaagta cgcggccagc 600

agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag ctgccaggtc 660

acgcatgaag ggagcaccgt ggaaaagaca gtggccccta cagaatgttc atag 714

<210> 146

<211> 705

<212> DNA

<213> Homo sapiens

<400> 146

atgagtgtgc tcactcaggt cctggcgttg ctgctgctgt ggcttacagg tacgcgttgc 60

gacatcgagc tgacccagcc ccccagcgtg agcgtggccc ctggccagac cgcccggatc 120

agctgcagcg gcgacaacat cggcagcttc tacgtgcact ggtatcagca gaagcccggc 180

caggcccccg tgctggtgat ctacgacgac aacaaccggc ccagcggcat ccccgagcgg 240

ttcagcggca gcaacagcgg caacaccgcc accctgacca tcagcggcac ccaggccgag 300

gacgaggccg actactactg cgccagctgg accggcgtgg agcccgacta cgtgtttggc 360

ggcggaacaa agcttaccgt cctaggtcag cccaaggctg ccccctcggt cactctgttc 420

ccgccctcct ctgaggagct tcaagccaac aaggccacac tggtgtgtct cataagtgac 480

ttctacccgg gagccgtgac agtggcctgg aaggcagata gcagccccgt caaggcggga 540

gtggagacaa ccacaccctc caaacaaagc aacaacaagt acgcggccag cagctatctg 600

agcctgacgc ctgagcagtg gaagtcccac agaagctaca gctgccaggt cacgcatgaa 660

gggagcaccg tggaaaagac agtggcccct acagaatgtt catag 705

<210> 147

<211> 714

<212> DNA

<213> Homo sapiens

<400> 147

atgagtgtgc tcactcaggt cctggcgttg ctgctgctgt ggcttacagg tacgcgttgc 60

gacatcgccc tgacccagcc cgccagcgtg agcggcagcc ctggccagag catcaccatc 120

agctgcaccg gcaccagcag cgacgtgggc gacatcaacg acgtgagctg gtatcagcag 180

caccccggca aggcccccaa gctgatgatc tacgacgtga acaaccggcc cagcggcgtg 240

agcaaccggt tcagcggcag caagagcggc aacaccgcca gcctgaccat cagcggcctc 300

caggccgagg acgaggccga ctactactgc cagagctacg ccggcagcta cctgagcgag 360

gtgttcggcg gagggaccaa gcttaccgtc ctaggtcagc ccaaggctgc cccctcggtc 420

actctgttcc cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 480

ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 540

aaggcgggag tggagacaac cacaccctcc aaacaaagca acaacaagta cgcggccagc 600

agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag ctgccaggtc 660

acgcatgaag ggagcaccgt ggaaaagaca gtggccccta cagaatgttc atag 714

<210> 148

<211> 714

<212> DNA

<213> Homo sapiens

<400> 148

atgagtgtgc tcactcaggt cctggcgttg ctgctgctgt ggcttacagg tacgcgttgc 60

gacatcgccc tgacccagcc cgccagcgtg agcggcagcc ctggccagag catcaccatc 120

agctgcaccg gcaccagcag cgacgtgggc gacatcaacg acgtgagctg gtatcagcag 180

caccccggca aggcccccaa gctgatgatc tacgacgtga acaaccggcc cagcggcgtg 240

agcaaccggt tcagcggcag caagagcggc aacaccgcca gcctgaccat cagcggcctc 300

caggccgagg acgaggccga ctactactgc agcagctacg gcgagagcct gaccagctac 360

gtgtttggcg gcggaaccaa gcttaccgtc ctaggtcagc ccaaggctgc cccctcggtc 420

actctgttcc cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 480

ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 540

aaggcgggag tggagacaac cacaccctcc aaacaaagca acaacaagta cgcggccagc 600

agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag ctgccaggtc 660

acgcatgaag ggagcaccgt ggaaaagaca gtggccccta cagaatgttc atag 714

<210> 149

<211> 714

<212> DNA

<213> Homo sapiens

<400> 149

atgagtgtgc tcactcaggt cctggcgttg ctgctgctgt ggcttacagg tacgcgttgc 60

gacatcgccc tgacccagcc cgccagcgtg agcggcagcc ctggccagag catcaccatc 120

agctgcaccg gcaccagcag cgacgtgggc gacatcaacg acgtgagctg gtatcagcag 180

caccccggca aggcccccaa gctgatgatc tacgacgtga acaaccggcc cagcggcgtg 240

agcaaccggt tcagcggcag caagagcggc aacaccgcca gcctgaccat cagcggcctc 300

caggccgagg acgaggccga ctactactgc agcagctacg gcgagagcct gaccagctac 360

gtgtttggcg gcggaaccaa gcttaccgtc ctaggtcagc ccaaggctgc cccctcggtc 420

actctgttcc cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 480

ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 540

aaggcgggag tggagacaac cacaccctcc aaacaaagca acaacaagta cgcggccagc 600

agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag ctgccaggtc 660

acgcatgaag ggagcaccgt ggaaaagaca gtggccccta cagaatgttc atag 714

<210> 150

<211> 714

<212> DNA

<213> Homo sapiens

<400> 150

atgagtgtgc tcactcaggt cctggcgttg ctgctgctgt ggcttacagg tacgcgttgc 60

gacatcgccc tgacccagcc cgccagcgtg agcggcagcc ctggccagag catcaccatc 120

agctgcaccg gcaccagcag cgacgtgggc gacatcaacg acgtgagctg gtatcagcag 180

caccccggca aggcccccaa gctgatgatc tacgacgtga acaaccggcc cagcggcgtg 240

agcaaccggt tcagcggcag caagagcggc aacaccgcca gcctgaccat cagcggcctc 300

caggccgagg acgaggccga ctactactgc agcagctacg gcgagagcct gaccagctac 360

gtgtttggcg gcggaaccaa gcttaccgtc ctaggtcagc ccaaggctgc cccctcggtc 420

actctgttcc cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 480

ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 540

aaggcgggag tggagacaac cacaccctcc aaacaaagca acaacaagta cgcggccagc 600

agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag ctgccaggtc 660

acgcatgaag ggagcaccgt ggaaaagaca gtggccccta cagaatgttc atag 714

<210> 151

<211> 714

<212> DNA

<213> Homo sapiens

<400> 151

atgagtgtgc tcactcaggt cctggcgttg ctgctgctgt ggcttacagg tacgcgttgc 60

gacatcgccc tgacccagcc cgccagcgtg agcggcagcc ctggccagag catcaccatc 120

agctgcaccg gcaccagcag cgacgtgggc gacatcaacg acgtgagctg gtatcagcag 180

caccccggca aggcccccaa gctgatgatc tacgacgtga acaaccggcc cagcggcgtg 240

agcaaccggt tcagcggcag caagagcggc aacaccgcca gcctgaccat cagcggcctc 300

caggccgagg acgaggccga ctactactgc agcagctacg gcgagagcct gaccagctac 360

gtgtttggcg gcggaaccaa gcttaccgtc ctaggtcagc ccaaggctgc cccctcggtc 420

actctgttcc cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 480

ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 540

aaggcgggag tggagacaac cacaccctcc aaacaaagca acaacaagta cgcggccagc 600

agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag ctgccaggtc 660

acgcatgaag ggagcaccgt ggaaaagaca gtggccccta cagaatgttc atag 714

<210> 152

<211> 714

<212> DNA

<213> Homo sapiens

<400> 152

atgagtgtgc tcactcaggt cctggcgttg ctgctgctgt ggcttacagg tacgcgttgc 60

gacatcgccc tgacccagcc cgccagcgtg agcggcagcc ctggccagag catcaccatc 120

agctgcaccg gcaccagcag cgacgtgggc gacatcaacg acgtgagctg gtatcagcag 180

caccccggca aggcccccaa gctgatgatc tacgacgtga acaaccggcc cagcggcgtg 240

agcaaccggt tcagcggcag caagagcggc aacaccgcca gcctgaccat cagcggcctc 300

caggccgagg acgaggccga ctactactgc agcacctacg acggccctgg cctgagcgag 360

gtgttcggcg gagggaccaa gcttaccgtc ctaggtcagc ccaaggctgc cccctcggtc 420

actctgttcc cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 480

ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 540

aaggcgggag tggagacaac cacaccctcc aaacaaagca acaacaagta cgcggccagc 600

agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag ctgccaggtc 660

acgcatgaag ggagcaccgt ggaaaagaca gtggccccta cagaatgttc atag 714

<210> 153

<211> 714

<212> DNA

<213> Homo sapiens

<400> 153

atgagtgtgc tcactcaggt cctggcgttg ctgctgctgt ggcttacagg tacgcgttgc 60

gacatcgccc tgacccagcc cgccagcgtg agcggcagcc ctggccagag catcaccatc 120

agctgcaccg gcaccagcag cgacgtgggc gacatcaacg acgtgagctg gtatcagcag 180

caccccggca aggcccccaa gctgatgatc tacgacgtga acaaccggcc cagcggcgtg 240

agcaaccggt tcagcggcag caagagcggc aacaccgcca gcctgaccat cagcggcctc 300

caggccgagg acgaggccga ctactactgc agcacctacg acggccctgg cctgagcgag 360

gtgttcggcg gagggaccaa gcttaccgtc ctaggtcagc ccaaggctgc cccctcggtc 420

actctgttcc cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 480

ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 540

aaggcgggag tggagacaac cacaccctcc aaacaaagca acaacaagta cgcggccagc 600

agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag ctgccaggtc 660

acgcatgaag ggagcaccgt ggaaaagaca gtggccccta cagaatgttc atag 714

<210> 154

<211> 714

<212> DNA

<213> Homo sapiens

<400> 154

atgagtgtgc tcactcaggt cctggcgttg ctgctgctgt ggcttacagg tacgcgttgc 60

gacatcgccc tgacccagcc cgccagcgtg agcggcagcc ctggccagag catcaccatc 120

agctgcaccg gcaccagcag cgacgtgggc gacatcaacg acgtgagctg gtatcagcag 180

caccccggca aggcccccaa gctgatgatc tacgacgtga acaaccggcc cagcggcgtg 240

agcaaccggt tcagcggcag caagagcggc aacaccgcca gcctgaccat cagcggcctc 300

caggccgagg acgaggccga ctactactgc agcacctacg acggccctgg cctgagcgag 360

gtgttcggcg gagggaccaa gcttaccgtc ctaggtcagc ccaaggctgc cccctcggtc 420

actctgttcc cgccctcctc tgaggagctt caagccaaca aggccacact ggtgtgtctc 480

ataagtgact tctacccggg agccgtgaca gtggcctgga aggcagatag cagccccgtc 540

aaggcgggag tggagacaac cacaccctcc aaacaaagca acaacaagta cgcggccagc 600

agctatctga gcctgacgcc tgagcagtgg aagtcccaca gaagctacag ctgccaggtc 660

acgcatgaag ggagcaccgt ggaaaagaca gtggccccta cagaatgttc atag 714

<210> 155

<211> 213

<212> PROTEIN

<213> Homo sapiens

<400> 155

Met Gln Leu Pro Leu Ala Leu Cys Leu Val Cys Leu Leu Val His Thr

1 5 10 15

Ala Phe Arg Val Val Glu Gly Gln Gly Trp Gln Ala Phe Lys Asn Asp

20 25 30

Ala Thr Glu Ile Ile Pro Glu Leu Gly Glu Tyr Pro Glu Pro Pro Pro

35 40 45

Glu Leu Glu Asn Asn Lys Thr Met Asn Arg Ala Glu Asn Gly Gly Arg

50 55 60

Pro Pro His His Pro Phe Glu Thr Lys Asp Val Ser Glu Tyr Ser Cys

65 70 75 80

Arg Glu Leu His Phe Thr Arg Tyr Val Thr Asp Gly Pro Cys Arg Ser

85 90 95

Ala Lys Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro Ala

100 105 110

Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg Pro Ser

115 120 125

Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg Ala Gln Arg Val

130 135 140

Gln Leu Leu Cys Pro Gly Gly Glu Ala Pro Arg Ala Arg Lys Val Arg

145 150 155 160

Leu Val Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg Phe His Asn Gln

165 170 175

Ser Glu Leu Lys Asp Phe Gly Thr Glu Ala Ala Arg Pro Gln Lys Gly

180 185 190

Arg Lys Pro Arg Pro Arg Ala Arg Ser Ala Lys Ala Asn Gln Ala Glu

195 200 205

Leu Glu Asn Ala Tyr

210

<210> 156

<211> 14

<212> PROTEIN

<213> Homo sapiens

<400> 156

Ala Arg Leu Leu Asn Ala Ile Gly Arg Gly Lys Trp Trp Arg

1 5 10

<210> 157

<211> 15

<212> PROTEIN

<213> Homo sapiens

<400> 157

Arg Leu Val Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg Phe His

1 5 10 15

<210> 158

<211> 13

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 158

Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly

1 5 10

<210> 159

<211> 19

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 159

Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly Gly Gly Gly Ser Gly

1 5 10 15

Gly Gly Gly

<210> 160

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 160

taaattatca taaagtccta a 21

<210> 161

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 161

aggactttat gataatttat t 21

<210> 162

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 162

atagtggtta aataactcca g 21

<210> 163

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 163

ggagttattt aaccactatt t 21

<210> 164

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 164

taaattctcg tgatgtgcca t 21

<210> 165

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 165

ggcacatcac gagaatttat t 21

<210> 166

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 166

tttcttatag cacagctggt t 21

<210> 167

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 167

ccagctgtgc tataagaaat t 21

<210> 168

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 168

tagacctttc catccacgct g 21

<210> 169

<211> 21

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 169

gcgtggatgg aaaggtctat t 21

<210> 170

<211> 29

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 170

atgcagctcc cactggccct gtgtcttgt 29

<210> 171

<211> 30

<212> DNA

<213> Artificial sequence

<220>

<223> Artificial sequence

<400> 171

aatcaggccg agctggagaa cgcctactag 30

<210> 172

<211> 443

<212> PROTEIN

<213> Homo sapiens

<400> 172

Gln Val Gln Leu Val Glu Ser Gly Gly Gly Leu Val Gln Pro Gly Gly

1 5 10 15

Ser Leu Arg Leu Ser Cys Ala Ala Ser Gly Phe Thr Phe Arg Ser His

20 25 30

Trp Leu Ser Trp Val Arg Gln Ala Pro Gly Lys Gly Leu Glu Trp Val

35 40 45

Ser Asn Ile Asn Tyr Asp Gly Ser Ser Thr Tyr Tyr Ala Asp Ser Val

50 55 60

Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr Leu Tyr

65 70 75 80

Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Val Tyr Tyr Cys

85 90 95

Ala Arg Asp Thr Tyr Leu His Phe Asp Tyr Trp Gly Gln Gly Thr Leu

100 105 110

Val Thr Val Ser Ser Ala Ser Thr Lys Gly Pro Ser Val Phe Pro Leu

115 120 125

Ala Pro Cys Ser Arg Ser Thr Ser Glu Ser Thr Ala Ala Leu Gly Cys

130 135 140

Leu Val Lys Asp Tyr Phe Pro Glu Pro Val Thr Val Ser Trp Asn Ser

145 150 155 160

Gly Ala Leu Thr Ser Gly Val His Thr Phe Pro Ala Val Leu Gln Ser

165 170 175

Ser Gly Leu Tyr Ser Leu Ser Ser Val Val Thr Val Pro Ser Ser Asn

180 185 190

Phe Gly Thr Gln Thr Tyr Thr Cys Asn Val Asp His Lys Pro Ser Asn

195 200 205

Thr Lys Val Asp Lys Thr Val Glu Arg Lys Cys Cys Val Glu Cys Pro

210 215 220

Pro Cys Pro Ala Pro Pro Val Ala Gly Pro Ser Val Phe Leu Phe Pro

225 230 235 240

Pro Lys Pro Lys Asp Thr Leu Met Ile Ser Arg Thr Pro Glu Val Thr

245 250 255

Cys Val Val Val Asp Val Ser His Glu Asp Pro Glu Val Gln Phe Asn

260 265 270

Trp Tyr Val Asp Gly Val Glu Val His Asn Ala Lys Thr Lys Pro Arg

275 280 285

Glu Glu Gln Phe Asn Ser Thr Phe Arg Val Val Ser Val Leu Thr Val

290 295 300

Val His Gln Asp Trp Leu Asn Gly Lys Glu Tyr Lys Cys Lys Val Ser

305 310 315 320

Asn Lys Gly Leu Pro Ala Pro Ile Glu Lys Thr Ile Ser Lys Thr Lys

325 330 335

Gly Gln Pro Arg Glu Pro Gln Val Tyr Thr Leu Pro Pro Ser Arg Glu

340 345 350

Glu Met Thr Lys Asn Gln Val Ser Leu Thr Cys Leu Val Lys Gly Phe

355 360 365

Tyr Pro Ser Asp Ile Ala Val Glu Trp Glu Ser Asn Gly Gln Pro Glu

370 375 380

Asn Asn Tyr Lys Thr Thr Pro Pro Met Leu Asp Ser Asp Gly Ser Phe

385 390 395 400

Phe Leu Tyr Ser Lys Leu Thr Val Asp Lys Ser Arg Trp Gln Gln Gly

405 410 415

Asn Val Phe Ser Cys Ser Val Met His Glu Ala Leu His Asn His Tyr

420 425 430

Thr Gln Lys Ser Leu Ser Leu Ser Pro Gly Lys

435 440

<210> 173

<211> 217

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Homo sapiens

<400> 173

Asp Ile Ala Leu Thr Gln Pro Ala Ser Val Ser Gly Ser Pro Gly Gln

1 5 10 15

Ser Ile Thr Ile Ser Cys Thr Gly Thr Ser Ser Asp Val Gly Asp Ile

20 25 30

Asn Asp Val Ser Trp Tyr Gln Gln His Pro Gly Lys Ala Pro Lys Leu

35 40 45

Met Ile Tyr Asp Val Asn Asn Arg Pro Ser Gly Val Ser Asn Arg Phe

50 55 60

Ser Gly Ser Lys Ser Gly Asn Thr Ala Ser Leu Thr Ile Ser Gly Leu

65 70 75 80

Gln Ala Glu Asp Glu Ala Asp Tyr Tyr Cys Gln Ser Tyr Ala Gly Ser

85 90 95

Tyr Leu Ser Glu Val Phe Gly Gly Gly Thr Lys Leu Thr Val Leu Gly

100 105 110

Gln Pro Lys Ala Ala Pro Ser Val Thr Leu Phe Pro Pro Ser Ser Glu

115 120 125

Glu Leu Gln Ala Asn Lys Ala Thr Leu Val Cys Leu Ile Ser Asp Phe

130 135 140

Tyr Pro Gly Ala Val Thr Val Ala Trp Lys Ala Asp Ser Ser Pro Val

145 150 155 160

Lys Ala Gly Val Glu Thr Thr Thr Pro Ser Lys Gln Ser Asn Asn Lys

165 170 175

Tyr Ala Ala Ser Ser Tyr Leu Ser Leu Thr Pro Glu Gln Trp Lys Ser

180 185 190

His Arg Ser Tyr Ser Cys Gln Val Thr His Glu Gly Ser Thr Val Glu

195 200 205

Lys Thr Val Ala Pro Thr Glu Cys Ser

210 215

<210> 174

<211> 26

<212> PROTEIN

<213> Homo sapiens

<400> 174

Cys Gly Pro Ala Arg Leu Leu Pro Asn Ala Ile Gly Arg Gly Lys Trp

1 5 10 15

Trp Arg Pro Ser Gly Pro Asp Phe Arg Cys

20 25

<210> 175

<211> 60

<212> PROTEIN

<213> Homo sapiens

<400> 175

Asp Val Ser Glu Tyr Cys Arg Glu Leu His Phe Thr Arg Ser Ala Lys

1 5 10 15

Pro Val Thr Glu Leu Val Cys Ser Gly Gln Cys Gly Pro Ala Arg Trp

20 25 30

Trp Arg Pro Ser Gly Pro Asp Phe Arg Cys Ile Pro Asp Arg Tyr Arg

35 40 45

Leu Val Ala Ser Cys Lys Cys Lys Arg Leu Thr Arg

50 55 60

<210> 176

<211> 133

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic peptide

<220>

<221> MISC_FEATURE

<223> Humanized antibody sequence

<400> 176

Met Asp Thr Arg Ala Pro Thr Gln Leu Leu Gly Leu Leu Leu Leu Trp

1 5 10 15

Leu Pro Gly Ala Thr Phe Ala Gln Val Leu Thr Gln Ser Pro Ser Ser

20 25 30

Leu Ser Ala Ser Val Gly Asp Arg Val Thr Ile Thr Cys Gln Ser Ser

35 40 45

Gln Ser Val Tyr Asp Asn Asn Trp Leu Ala Trp Tyr Gln Gln Lys Pro

50 55 60

Gly Lys Ala Pro Lys Leu Leu Ile Tyr Asp Ala Ser Asp Leu Ala Ser

65 70 75 80

Gly Val Pro Ser Arg Phe Ser Gly Ser Gly Ser Gly Thr Asp Phe Thr

85 90 95

Leu Thr Ile Ser Ser Leu Gln Pro Glu Asp Phe Ala Thr Tyr Tyr Cys

100 105 110

Gln Gly Ala Tyr Asn Asp Val Ile Tyr Ala Phe Gly Gln Gly Thr Lys

115 120 125

Val Glu Ile Lys Arg

130

<210> 177

<211> 131

<212> PROTEIN

<213> Artificial sequence

<220>

<223> Synthetic peptide

<220>

<221> MISC_FEATURE

<223> Humanized antibody sequence

<400> 177

Met Glu Thr Gly Leu Arg Trp Leu Leu Leu Val Ala Val Leu Lys Gly

1 5 10 15

Val His 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 Ser Leu

35 40 45

Ser Ser Tyr Trp Met Asn Trp Val Arg Gln Ala Pro Gly Lys Gly Leu

50 55 60

Glu Trp Val Gly Thr Ile Asp Ser Gly Gly Arg Thr Asp Tyr Ala Ser

65 70 75 80

Trp Ala Lys Gly Arg Phe Thr Ile Ser Arg Asp Asn Ser Lys Asn Thr

85 90 95

Met Tyr Leu Gln Met Asn Ser Leu Arg Ala Glu Asp Thr Ala Arg Tyr

100 105 110

Tyr Cys Ala Arg Asn Trp Asn Leu Trp Gly Gln Gly Thr Leu Val Thr

115 120 125

Val Ser Ser

130

<---

Claims (32)

1. The use of an anti-sclerostin antibody in the treatment of osteogenesis imperfecta (OI) in a human patient, comprising administering to the human patient a therapeutically effective amount of an anti-sclerostin antibody, wherein the OI is type I OI, type III OI, or type IV OI, wherein the patient is human has one or more mutations in the COL1A1 and/or COL1A2 genes, where the antibody to sclerostin is administered at a dose of 2-50 mg per 1 kg of body weight of the human patient monthly, bimonthly or quarterly, and the antibody to sclerostin contains: (a) a heavy chain variable region CDR1 region comprising the amino acid sequence shown in SEQ ID NO: 4; (b) a heavy chain variable region CDR2 region comprising the amino acid sequence shown in SEQ ID NO: 15; (c) a heavy chain variable region CDR3 region comprising the amino acid sequence shown in SEQ ID NO: 26; (d) a light chain variable region CDR1 region comprising the amino acid sequence shown in SEQ ID NO: 37; (e) a light chain variable region CDR2 region comprising the amino acid sequence shown in SEQ ID NO: 48; and (f) a light chain variable region CDR3 region containing the amino acid sequence shown in SEQ ID NO: 59. 2. The use of an anti-sclerostin antibody according to claim 1, wherein the anti-sclerostin antibody contains: a) a VH polypeptide sequence at least 90 percent identical to the amino acid sequences shown as SEQ ID NO: 70; and/or b) a VL polypeptide sequence at least 90 percent identical to the amino acid sequences shown as SEQ ID NO: 81. 3. The use of an anti-sclerostin antibody according to any one of the preceding claims, wherein the anti-sclerostin antibody comprises: a) a full-length heavy chain sequence at least 90 percent identical to the amino acid sequence shown as SEQ ID NO: 172; and/or b) a full length light chain sequence at least 90 percent identical to the amino acid sequence shown as SEQ ID NO: 173. 4. The use of an anti-sclerostin antibody according to any one of the preceding claims, wherein the anti-sclerostin antibody comprises a VL polypeptide sequence comprising the amino acid sequence shown as SEQ ID NO: 81 and a VH polypeptide sequence containing the amino acid sequence shown as SEQ ID NO: 70. 5. The use of an anti-sclerostin antibody according to any one of the preceding claims, wherein the anti-sclerostin antibody comprises a full length light chain sequence comprising the amino acid sequence set forth in SEQ ID NO: 173 and a full length heavy chain sequence comprising the amino acid sequence set forth as SEQ ID NO: 172. 6. The use of an anti-sclerostin antibody according to any one of the preceding claims, wherein the anti-sclerostin antibody is administered at a dose of 2-40 mg per kg body weight of the human patient. 7. The use of antibodies to sclerotin according to any one of paragraphs. 1-5 wherein the anti-sclerostin antibody is administered at a dose of 8-45 mg/kg body weight of the human patient. 8. The use of an anti-sclerostin antibody according to any of the preceding claims, wherein the anti-sclerostin antibody is administered at a dose of 8-30 mg/kg body weight of the human patient. 9. The use of an anti-sclerostin antibody according to any one of the preceding claims, wherein the anti-sclerostin antibody is administered at a dose of 5-20 mg/kg body weight of the human patient. 10. The use of antibodies to sclerotin according to any one of paragraphs. 1-10 wherein the anti-sclerostin antibody is administered to a human patient on a monthly basis. 11. The use of antibodies to sclerotin according to any one of paragraphs. 1-10 wherein the anti-sclerostin antibody is administered to the human patient quarterly. 12. The use of antibodies to sclerostin according to any one of paragraphs. 1-11, wherein the treatment regimen includes a first treatment regimen, optionally followed by a second treatment regimen. 13. The use of an antibody to sclerostin according to claim 12, in which: (a) the first dosage regimen is administering at a dose of 2-50 mg per 1 kg of body weight of a human patient monthly, for example the first dosage regimen is administering at a dose of 20 mg per 1 kg of body weight of a human patient monthly; (b) the second dosing regimen is administering at a dose of 2-50 mg per 1 kg of body weight of a human patient every two months or quarterly, for example, the second dosage regimen is administering at a dose of 20 mg per 1 kg of body weight of a human patient every two monthly or quarterly, and/or (c) the first dosage regimen is administering at a dose of 20 mg per 1 kg of body weight of a human patient monthly and the second dosage regimen is administering at a dose of 20 mg per 1 kg of body weight of a human patient bimonthly or quarterly. 14. The use of antibodies to sclerostin according to any one of paragraphs. 1-13 wherein the anti-sclerostin antibody is administered intravenously. 15. The use of antibodies to sclerostin according to any one of paragraphs. 1-13 wherein the anti-sclerostin antibody is administered subcutaneously. 16. The use of antibodies to sclerostin according to any one of paragraphs. 1-13, comprising administering an additional therapeutic agent such as a bisphosphonate, parathyroid hormone, calcilytics, calcimimetics (eg, cinacalcet), statins, anabolic steroids, lanthanum and strontium salts, and/or sodium fluoride. 17. The use of an anti-sclerostin antibody according to any one of the preceding claims, wherein the antibody is part of a pharmaceutical composition. 18. The use of antibodies to sclerostin according to any one of paragraphs. 1-16, where the patient is an adult patient. 19. The use of antibodies to sclerostin according to any one of paragraphs. 1-17, where the patient is a pediatric patient.

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