AU2012216589A1 - Sclerostin epitopes - Google Patents

Abstract

Compositions and methods relating to epitopes of sclerostin protein, and sclerostin binding agents, such as antibodies capable of binding to sclerostin, are provided. WO 2006/119062 PCTIUS2006/016345 00) Loop 3 LoopU2

Description

A ustralian Patents Act 1990- Regulation 3.2 ORIGINAL COMPLETE SPECIFICATION STANDARD PATENT Invention Title ""Sclerostin epitopes" The following statement is a full description of this invention, including the best method of performing it known to us:- C\NRPonbl\DCCTL.Um57S95_I DOC-31/'/2al2 SCLEROSTIN EPITOPES This application is a divisional application of Australian Application No. 2006242476 the specification and drawings of which as originally filed are incorporated herein in 5 their entirety by reference. TECHNICAL FIELD The present invention relates generally to epitopes of sclerostin protein. including human sclerostin protein, and binding agents (such as antibodies) capable of binding to 10 sclerostin or fragments thereof. BACKGROUND OF THE INVENTION Two or three distinct phases of changes to bone mass occur over the life of an individual (see Riggs, West .J. Med. 154:63-77 (1991)). The first phase occurs in both men and women 15 and proceeds to attainment of a peak bone mass. This first phase is achieved through linear growth of the endochondral growth plates and radial growth due to a rate of periosteal apposition. The second phase begins around age 30 for trabecular bone (flat bones such as the vertebrae and pelvis) and about age 40 for cortical bone (e.g., long bones found in the limbs) and continues to Old age. This phase is characterized by slow bone loss and occurs in both men and women. In women, 20 a third phase of bone loss also occurs, most likely due to postmenopausal estrogen deficiencies. During this phase alone, women may lose an additional bone mass from the cortical bone and from the trabecular compartment (see Riggs, supra). Loss of bone mineral content can be caused by a wide variety of conditions and may result in significant medical problems. For example, osteoporosis is a debilitating disease in 25 humans and is characterized by marked decreases in skeletal bone mass and mineral density, structural deterioration of bone, including degradation of bone microarchitecture and corresponding increases in bone fragility (i.e., decreases in bone strength), and susceptibility to fracture in afflicted individuals. Osteoporosis in humans is generally preceded by clinical osteopenia (bone mineral density that is greater than one standard deviation but less than 2.5 standard deviations below 30 the mean value for young adult bone), a condition found in approximately 25 million people in the United States. Another 7-8 million patients in the United States have been diagnosed with clinical osteoporosis (defined as bone mineral content greater than 2.5 standard deviations below that of mature young adult bone). The frequency of osteoporosis in the human population increases with age. Among Caucasians, osteoporosis is predominant in women who, in the United States, comprise C \NRPornhDCC\TLD[\45 7 XS9_ I DOC-.1/0I/2102 80% of the osteoporosis patient pool. The increased fragility and susceptibility to fracture of skeletal bone in the aged is aggravated by the greater risk of accidental falls in this population. Fractured hips, wrists, and vertebrae are among the most common injuries associated with osteoporosis. I-lip fractures in 5 1A WO 2006/119062 PCT/US2006/016345 particular are extremely uncomfortable and expensive for the patient, and for women, correlate with high rates of mortality and morbidity. Although osteoporosis has been regarded as an increase in the risk of fracture due to decreased bone mass, few of the presently available treatments for skeletal disorders can 5 increase the bone density of adults, and most of the presently available treatments work primarily by inhibiting further bone resorption rather than stimulating new bone formation. Estrogen is now being prescribed to retard bone loss. However, some controversy exists over whether patients gain any long-term benefit and whether estrogen has any effect on patients over 75 years old. Moreover, use of estrogen is believed to increase the risk of breast and 10 endometrial cancer. Calcitonin, osteocalcin with vitamin K, or high doses of dietary calcium, with or without vitamin D, have also been suggested for postmenopausal women. High doses of calcium, however, often have undesired gastrointestinal side effects, and serum and urinary calcium levels must be continuously monitored (e.g., Khosla and Riggs, Mayo Clin. Proc. 70:978982, 1995). 15 Other current therapeutic approaches to osteoporosis include bisphosphonates (e.g., Fosamaxm, Actonell", Bonviva

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, Zometarm, olpadronate, neridronate, skelid, bonefos), parathyroid hormone, calcilytics, calcimimetics (e.g., cinacalcet), statins, anabolic steroids, lanthanum and strontium salts, and sodium fluoride. Such therapeutics, however, are often associated with undesirable side effects (see Khosla and Riggs, supra). 20 Sclerostin, the product of the SOST gene, is absent in sclerosteosis, a skeletal disease characterized by bone overgrowth and strong dense bones (Brunkow et al., Am. J. Hum. Genet., 68:577-589, 2001; Balemans et al., Hum. Mol. Genet., 10:537-543, 2001). The amino acid sequence of human sclerostin is reported by Brunkow et al. ibid and is disclosed herein as SEQ ID NO:1. 25 BRIEF SUMMARY OF THE INVENTION Disclosed herein are compositions and methods that can be used to increase at least one of bone formation, bone mineral density, bone mineral content, bone mass, bone 30 quality and bone strength, and that therefore may be used to treat a wide variety of conditions in which an increase in at least one of bone formation, bone mineral density, bone mineral content, bone mass, bone quality and bone strength is desirable. The present invention also offers other related advantages described herein. SEA 1803910lv 60117-223 2 WO 2006/119062 PCTIUS2006/016345 The invention relates to regions (epitopes) of human sclerostin recognized by the binding agents disclosed herein, methods of using these epitopes, and methods of making such epitopes. The invention also relates to epitopes specific to the region of sclerostin 5 identified as Loop 2, and binding agents which specifically bind to that region. The invention also relates to epitopes specific to the cystine-knot region of sclerostin, and binding agents such as antibodies specifically binding to that region. The invention relates to binding agents, such as antibodies, that specifically bind to sclerostin. The binding agents can be characterized by their ability to cross-block the binding 10 of at least one antibody disclosed herein to sclerostin and/or to be cross-blocked from binding sclerostin by at least one antibody disclosed herein. The antibodies and other binding agents can also be characterized by their binding pattern to human sclerostin peptides in a "human sclerostin peptide epitope competition binding assay" as disclosed herein. The invention relates to binding agents, such as antibodies, that can increase at 15 least one of bone formation, bone mineral density, bone mineral content, bone mass, bone quality and bone strength in a mammal. The invention relates to binding agents, such as antibodies, that can block the inhibitory effect of sclerostin in a cell based mineralization assay. The invention further relates to polypeptide constructs comprising two, three, or 20 four polypeptide fragments linked by at least one disulfide bond, representing a core region of the cystine-knot of sclerostin, and antibodies capable of specifically binding thereto. The invention relates to methods of obtaining epitopes suitable for use as immunogens for generating, in mammals, binding agents, such as antibodies capable of binding specifically to sclerostin; in certain embodiments the binding agents generated are capable of 25 neutralizing sclerostin activity in vivo. The invention relates to a composition for eliciting an antibody specific for sclerostin when the composition is administered to an animal, the composition comprising a polypeptide having the amino acid sequence of SEQ ID NO:6, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, or SEQ ID NO:69. 30 The invention also relates to a composition for eliciting an antibody specific for sclerostin when the composition is administered to an animal, the composition comprising at least one polypeptide consisting essentially of the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5; the composition may comprise at least two or at least three of the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID SEA 180391 lvI 60117-223 3 WO 2006/119062 PCT/US2006/016345 NO:5, and the composition may comprise all four of the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5. The invention further relates to a composition for eliciting an antibody specific for sclerostin when the composition is administered to an animal, the composition comprising a 5 polypeptide having the amino acid sequences of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5, wherein SEQ ID NO:2 and 4 are joined by a disulfide bond at amino acid positions 57 and 111 with reference to SEQ ID NO:1, and SEQ ID NO:3 and 5 arejoined by at least one of (a) a disulfide bond at amino acid positions 82 and 142 with reference to SEQ ID NO: 1, and (b) a disulfide bond at amino acid positions 86 and 144 with reference to SEQ ID 10 NO: 1; the polypeptide may retain the tertiary structure of the corresponding polypeptide region of human sclerostin of SEQ IID NO: 1. The invention also relates to polypeptide T20.6 consisting essentially of a multiply truncated human sclerostin protein of SEQ ID NO: 1, wherein amino acids 1-50, 65-72, 91-100, 118-137, and 150-190 of SEQ ID NO:1 are absent from the polypeptide; this 15 polypeptide may be obtained by cryptic digestion of human sclerostin, and the protein may be isolated by HPLC fractionation. The invention further relates to immunogenic portion T20.6 of human sclerostin comprising amino acids 51-64, 73-90, 101-117, and 138-149 of SEQ ID NO:1, wherein the immunogenic portion comprises at least one of: 20 (a) a disulfide bond between amino acids 57 and 111; (b) a disulfide bond between amino acids 82 and 142; and (c) a disulfide bond between amino acids 86 and 144; the immunogenic portion may have at least two of these disulfide bonds; and the immunogenic portion may have all three disulfide bonds. 25 The invention further relates to an immunogenic portion T20.6 derivative of human sclerostin comprising amino acids 57-64, 73-86, 111-117, and 138-144 of SEQ ID NO:1, wherein the immunogenic portion comprises at least one of: (a) a disulfide bond between amino acids 57 and 111; (b) a disulfide bond between amino acids 82 and 142; and 30 (c) a disulfide bond between amino acids 86 and 144; the immunogenic portion may have at least two of these disulfide bonds; and the immunogenic portion may have all three disulfide bonds. SEA 180391 lvi 60117-223 4 WO 2006/119062 PCT/US2006/016345 The invention yet further relates to a polypeptide consisting essentially of a human sclerostin protein of SEQ ID NO: 1 truncated at the C-terminal and N-terminal ends, wherein amino acids 1-85 and 112-190 of SEQ ID NO: 1 are absent from the polypeptide. The invention also relates to an immunogenic portion of human sclerostin, 5 comprising amino acids 86-111 of SEQ ID NO: 1; the immunogenic portion may consist essentially of contiguous amino acids CGPARLLPNAIGRGKWWRPSGPDFRC (SEQ ID NO:6). The invention further relates to an immunogenic portion of rat sclerostin, comprising amino acids 92-109 of SEQ ID NO:98; the immunogenic portion may consist 10 essentially of contiguous amino acids PNAIGRVKWWRPNGPDFR (SEQ ID NO:96). The invention still further relates to an immunogenic portion of rat sclerostin, comprising amino acids 99-120 of SEQ ID NO:98; the immunogenic portion may consist essentially of contiguous amino acids KWWRPNGPDFRCIPDRYRAQRV (SEQ ID NO:97). The invention relates to a method of producing an immunogenic portion of 15 human sclerostin, comprising the steps of: (a) treating human sclerostin to achieve complete tryptic digestion; (b) collecting the tryptic digest sample having average molecular weight of 7,122.0 Daltons (theoretical mass 7121.5 Daltons) or retention time of about 20.6 minutes as determined by elution from a reverse-phase HPLC column 20 with linear gradient from 0.05% trifluoroacetic acid to 90% acetonitrile in 0.05% TFA at a flow rate of 0.2ml/min; and (c) purifying the immunogenic portion. The invention relates to a method of generating an antibody capable of specifically binding to sclerostin, comprising: 25 (a) immunizing an animal with a composition comprising a polypeptide of SEQ ID NO:6, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:96, or SEQ ID NO:97; (b) collecting sera from the animal; and 30 (c) isolating from the sera an antibody capable of specifically binding to sclerostin. The invention also relates to a method of generating an antibody capable of specifically binding to sclerostin, the method comprising: SEA 1803911vl 60117-223 5 WO 2006/119062 PCTIUS2006/016345 (a) immunizing an animal with a composition comprising polypeptide T20.6 or a derivative of T20.6; (b) collecting sera from the animal; and (c) isolating from the sera an antibody capable of specifically binding to 5 sclerostin. The invention further relates to a method of detecting an anti-sclerostin antibody in a biological sample, comprising the steps of (a) contacting the biological sample with a polypeptide consisting essentially of SEQ ID NO:6, SEQ ID NO:63, SEQ ID NO:64, SEQ ID NO:65, SEQ ID 10 NO:66, SEQ ID NO:67, SEQ ID NO:68, SEQ ID NO:69, SEQ ID NO:96, or SEQ ID NO:97 under conditions allowing a complex to form between the antibody and the polypeptide; and (b) detecting the presence or absence of the complex, wherein the presence of the complex indicates that the biological sample contains an anti 15 sclerostin antibody. The invention also relates to a method of detecting an anti-sclerostin antibody in a biological sample, comprising the steps. of (a) contacting the biological sample with polypeptide T20.6 or a derivative of T20.6 under conditions allowing a complex to form between the antibody and 20 the polypeptide; and (b) detecting the presence or absence of the complex, wherein the presence of the complex indicates that the biological sample contains an anti sclerostin antibody. The invention further relates to a sclerostin binding agent, such as an antibody, 25 that cross-blocks the binding of at least one of antibodies Ab-A, Ab-B, Ab-C, or Ab-D to a sclerostin protein. The sclerostin binding agent may also be cross-blocked from binding to sclerostin by at least one of antibodies Ab-A, Ab-B, Ab-C, or Ab-D. The isolated antibody, or an antigen-binding fragment thereof, may be a polyclonal antibody, a monoclonal antibody, a humanized antibody, a human antibody, a chimeric antibody or the like. 30 The invention further relates to a sclerostin binding agent, such as an antibody, that is cross-blocked from binding to sclerostin by at least one of antibodies Ab-A, Ab-B, Ab-C, or Ab-D. The isolated antibody, or an antigen-binding fragment thereof, may be a polyclonal antibody, a monoclonal antibody, a humanized antibody, a human antibody, a chimeric antibody or the like. SEA 1803911v1 60117-223 6 WO 2006/119062 PCT/US2006/016345 The invention further relates to a sclerostin binding agent, such as an isolated antibody, that cross-blocks the binding of at least one of antibodies 1-24 (Ab-1 to Ab-24) to a sclerostin protein. The sclerostin binding agent may also be cross-blocked from binding to sclerostin by at least one of antibodies 1-24 (Ab-1 to Ab-24). The isolated antibody, or an 5 antigen-binding fragment thereof, may be a polyclonal antibody, a monoclonal antibody, a humanized antibody, a human antibody, or a chimeric antibody. The invention further relates to a sclerostin binding agent, such as an isolated antibody, that is cross-blocked from binding to sclerostin by at least one of antibodies 1-24 (Ab 1 to Ab-24); the isolated antibody, or an antigen-binding fragment thereof, may be a polyclonal 10 antibody, a monoclonal antibody, a humanized antibody, a human antibody, or a chimeric antibody. The invention further relates to a binding agent, such as an isolated antibody that exhibits a similar binding pattern to human sclerostin peptides in a "human sclerostin peptide epitope competition binding assay" as that exhibited by at least one of the antibodies Ab-A, Ab 15 B, Ab-C or Ab-D; the isolated antibody, or an antigen-binding fragment thereof, may be a polyclonal antibody, a monoclonal antibody, a humanized antibody, a human antibody, or a chimeric antibody. The invention still further relates to a method for treating a bone disorder associated with at least one of low bone formation, low bone mineral density, low bone mineral 20 content, low bone mass, low bone quality and low bone strength in a mammalian subject which comprises providing to a subject in need of such treatment an amount of an anti-sclerostin binding agent sufficient to increase at least one of bone formation, bone mineral density, bone mineral content, bone mass, bone quality and bone strength wherein the anti-sclerostin binding agent comprises an antibody, or sclerostin-binding fragment thereof. 25 The invention also relates to an isolated sclerostin polypeptide or fragments thereof, wherein the polypeptide contains 6 conserved cysteine residues and the fragments thereof comprise from 7 to 14 amino acids of SEQ ID NO:2; 8 to 17 amino acids of SEQ ID NO:3; 8 to 18 residues of SEQ ID NO:4; and 6 to 12 residues of SEQ ID NO:5, and the polypeptide or fragments thereof are stabilized by disulfide bonds between SEQ ID NO:2 and 4, 30 and between SEQ ID NO:3 and 5; the polypeptide or fragments may comprise 10-14 amino acids of SEQ ID NO:2; 14 to 17 amino acids of SEQ ID NO:3; 13 to 18 amino acids of SEQ ID NO:4;, and 8 to 12 residues of SEQ ID NO:5; and the polypeptide or fragments may comprise SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4, and SEQ ID NO:5. Provided herein are antibodies that specifically bind to human sclerostin. The SEA 180391v1 60117-223 WO 2006/119062 PCT/US2006/016345 antibodies are characterized by their ability to cross-block the binding of at least one antibody disclosed herein to human sclerostin and/or to be cross-blocked from binding human sclerostin by at least one antibody disclosed herein. Also provided is an isolated antibody, or an antigen-binding fragment thereof, 5 that can increase at least one of bone formation, bone mineral density, bone mineral content, bone mass, bone quality and bone strength in a mammal. Also provided in an isolated antibody, or an antigen-binding fragment thereof, that can block the inhibitory effect of sclerostin in a cell based mineralization assay. Also provided is a binding agent, such as an antibody, that specifically binds to 10 human sclerostin and has at least one CDR sequence selected from SEQ ID NOs: 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 78, 79, 80, 81, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116,237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264,265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 15 277, 278, 279, 280, 281, 282, 283,284, 285, 286, 287, 288, 289, 290, 291, 292, 293, 294, 295, 296, 297, 298, 351, 352, 353, 358, 359, and 360, and variants thereof, wherein the antibody or antigen-binding fragment thereof neutralizes sclerostin. Also provided is a binding agent, such as an antibody, that specifically binds to human sclerostin and has at least one CDR sequence selected from SEQ ID NOs:39, 40, 41, 42, 20 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 78, 79, 80, 81, 99, 100, 101, 102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 237, 238, 239, 240, 241, 242, 243, 244, 245, 246, 247, 248, 249, 250, 251, 252, 253, 254, 255, 256, 257, 258, 259, 260, 261, 262, 263, 264, 265, 266, 267, 268, 269, 270, 271, 272, 273, 274, 275, 276, 277, 278, 279, 280, 281, 282, 283, 284, 285, 286, 287, 288, 289, 290,291,292, 293, 294, 295, 25 296, 297, 298, 351, 352, 353, 358, 359, and 360, and variants thereof. Also provided are regions of human sclerostin which are important for the in vivo activity of the protein. These and other aspects of the present invention will become apparent upon reference to the following detailed description and attached drawings. All references disclosed 30 herein are hereby incorporated by reference in their entireties as if each was incorporated individually. SEA 1803911v 60117-223 8 WO 2006/119062 PCT/US2006/016345 BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 depicts the amino acid sequences of the mature form (signal peptides cleaved off) of the light chain (Figure IA) (SEQ ID NO:23) and heavy chain (Figure 1B) (SEQ ID NO:27) for the anti-human sclerostin and anti-mouse sclerostin antibody Ab-A. 5 Figure 2 depicts the amino acid sequences of the mature form (signal peptides cleaved off) of the light chain (Figure 2A) (SEQ ID NO:3 1) and heavy chain (Figure 2B) (SEQ ID NO:35) for the anti-human sclerostin and anti-mouse sclerostin antibody Ab-B. Figure 3 depicts the amino acid sequences of the mature form (signal peptides cleaved off) of the light chain (Figure 3A) (SEQ ID NO: 15) and heavy chain (Figure 3B) (SEQ 10 ID NO:19) for the anti-human sclerostin and anti-mouse sclerostin antibody Ab-C. Figure 4 depicts the amino acid sequences of the mature form (signal peptides cleaved off) of the light chain (Figure 4A) (SEQ ID NO:7) and heavy chain (Figure 4B) (SEQ ID NO: 11) for the anti-human sclerostin and anti-mouse sclerostin antibody Ab-D. Figure 5 depicts bone mineral density in mice measured at two skeletal sites 15 (lumbar vertebrae and tibial metaphysis) after 3 weeks of treatment with vehicle, PTH (1-34), Ab-A or Ab-B. Figure 6 shows bone mineral density in mice measured at two skeletal sites (lumbar vertebrae and tibial metaphysis) after 2 weeks of treatment with vehicle, PTH (1-34) or Ab-C. 20 Figure 7 depicts bone mineral density in mice measured at two skeletal sites (lumbar vertebrae and tibial metaphysis) after 3 weeks of treatment with vehicle or Ab-D., Figure 8 depicts the amino acid sequence of the mature form (signal peptide cleaved off) of human sclerostin (SEQ ID NO: 1). Also depicted is the nucleotide sequence of the human sclerostin coding region that encodes the mature form of human sclerostin. The eight 25 cysteines are numbered Cl through C8. The cystine-knot is formed by three disulfide bonds (Cl-C5; C3-C7; C4-C8). C2 and C6 also form a disulfide bond, however this disulfide is not part of the cystine-knot. Figure 9 depicts a schematic of the basic structure of human sclerostin. There is an N-terminal arm (from the first Q to Cl) and a C-terminal arm (from C8 to the terminal Y). In 30 between these arms there is the cystine-knot structure (formed by three disulfides: Cl-C5; C3 C7; C4-C8) and three loops which are designated Loop1, Loop 2 and Loop 3. The distal regions of Loop I and Loop 3 are linked by the C2-C6 disulfide. Potential trypsin cleavage sites are indicated (arginine=R and lysine=K). Some of the potential AspN cleavage sites are indicated (only aspartic acid (D) residues are shown). SEA 180391lv 60117-223 9 WO 2006/119062 PCTfUS2006/016345 Figure 10 depicts the HPLC peptide maps of human sclerostin after digestion with either trypsin or AspN. The human sclerostin peptides generated by trypsin digestion are indicated (T19.2, 120, 120.6 and T21-22) as are the human sclerostin peptides generated by AspN digestion (AspN14.6, AspN18.6 and AspN22.7-23.5). 5 Figure 11 depicts sequence and mass information for the isolated human sclerostin disulfide linked peptides generated by trypsin digestion. Seq. pos. = sequence position. Obs. = observed. Observed mass was determined by ESI-LC-MS analysis. Figure 12 depicts sequence and mass information for the isolated human sclerostin peptides generated by AspN digestion. The AspN22.7-23.5 peptide contains the 4 10 disulfide bonds. Seq. pos. = sequence position. Obs. = observed. Observed mass was determined by ESI-LC-MS analysis. Figure 13 shows a linear schematic of four human sclerostin peptides (T19.2, T20, T20.6 and T21-22) generated by trypsin digestion. Figure 14 shows a linear schematic of five human sclerostin peptides (AspN14.6, 15 AspN18.6 and AspN22.7-23.5) generated by AspN digestion. The AspN14.6 HPLC peak is composed of three peptides not linked by any disulfide bonds. Figure 15 shows the resonance unit (Ru) signal from the Biacore-based "human sclerostin peptide epitope competition binding assay." Relative Mab binding to various human sclerostin-peptides (in solution) versus Mab binding to intact mature form human sclerostin 20 (immobilized on Biacore chip) was assessed. Data shown is for Ab-A. Human sclerostin. peptides used were T19.2, T20, T20.6, T21-22, AspN14.6, AspN18.6 and AspN22.7-23.5. Figure 16 shows the resonance unit (Ru) signal from the Biacore-based "human sclerostin peptide epitope competition binding assay." Relative Mab binding to various human sclerostin-peptides (in solution) versus Mab binding to intact mature form human sclerostin 25 (immobilized on Biacore chip) was assessed. Data shown is for Ab-B. Human sclerostin peptides used were T19.2, 120, T20.6, T21-22, AspN14.6, AspN18.6 and AspN22.7-23.5. Figure 17 shows the resonance unit (Ru) signal from the Biacore-based "human sclerostin peptide epitope competition binding assay." Relative Mab binding to various human sclerostin-peptides (in solution) versus Mab binding to intact mature form human sclerostin 30 (immobilized on Biacore chip) was assessed. Data shown is for Ab-C. Human sclerostin peptides used were T19.2, T20, T20.6, T21-22, AspN14.6, AspN18.6 and AspN22.7-23.5. Figure 18 shows the resonance unit (Ru) signal from Biacore-based "human sclerostin peptide epitope competition binding assay." Relative Mab binding to various human sclerostin-peptides (in solution) versus Mab binding to intact mature form human sclerostin SEA ISO391YI 60117-223 10 WO 2006/119062 PCT/US2006/016345 (immobilized on Biacore chip) was assessed. Data shown is for Ab-D. Human sclerostin peptides used were T19.2, T20, T20.6, T21-22, AspN14.6, AspN18.6 and AspN22.7-23.5. Figure 19 shows two Mab binding epitopes of human sclerostin. Figure 19A shows sequence of the Loop 2 epitope for binding of Ab-A and Ab-B to human sclerostin (SEQ 5 ID NO:6). Figure 19B shows sequence, disulfide bonding and schematic of the T20.6 epitope for binding of Ab-C and Ab-D to human sclerostin (SEQ ID NO:2-5). Figure 20 depicts the HPLC peptide maps of human sclerostin after digestion with trypsin. Figure 20A shows digestion of the human sclerostin Ab-D complex. Figure 20B shows digestion of human sclerostin alone. The T19.2, o20, T20.6 and T21-22 peptide peaks 10 are indicated. Figure 21 shows the sequence, disulfide bonding and schematic of the "T20.6 derivative I (cystine-knot + 4 arms)" epitope for binding of Ab-D to human sclerostin. (SEQ ID NO:70-73). Figure 22 shows results from the MC3T3-El-BF osteoblast cell line 15 mineralization assay used for identifying anti-sclerostin neutralizing Mabs. Mouse sclerostin (Sc1) was used at 1 pg/ml. Monoclonal antibodies were used at 10 and 5 ptg/ml. Extent of mineralization (various types of insoluble calcium phosphate) was quantitated by measuring calcium. Figure 23 depicts results from the MC3T3-El-BF osteoblast cell line 20 mineralization assay used for identifying anti-sclerostin neutralizing Mabs. Human sclerostin (Scl) was used at 1 pg/ml. Monoclonal antibodies were used at 8 and 4 pg/mI. Extent of mineralization (various types of insoluble calcium phosphate) was quantitated by measuring calcium. Figure 24 shows results from the MC3T3-EI-BF osteoblast cell line 25 mineralization assay used for identifying anti-sclerostin neutralizing Mabs. Human sclerostin (Scl) was used at 1 pg/ml. Monoclonal antibodies were used at 10 pg/mI. Extent of mineralization (various types of insoluble calcium phosphate) was quantitated by measuring calcium. Figure 25 depicts results from an inflammation-induced bone loss SCID mouse 30 model. Ab-A treatment protected mice from inflammation-related bone loss associated with colitis when measured as total bone mineral density (Figure 25A), vertebral bone density (Figure 25B), and femur bone density (Figure 25C). SEA 1803911vl 60117-223 11 WO 2006/119062 PCT/US2006/016345 DETAILED DESCRIPTION The present invention relates to regions of the human sclerostin protein that contain epitopes recognized by antibodies that also bind to full-length sclerostin, and methods of 5 making and using these epitopes. The invention also provides binding agents (such as antibodies) that specifically bind to sclerostin or portions of sclerostin, and methods for using such binding agents. The binding agents are useful to block or impair binding of human sclerostin to one or more ligand. Recombinant human sclerostin/SOST is commercially available from R&D 10 Systems (Minneapolis, MN, USA; 2006 cat# 1406-ST-025). Additionally, recombinant mouse sclerostin/SOST is commercially available from R&D Systems (Minneapolis, MN, USA; 2006 cat# 1589-ST-025). Research grade sclerostin binding monoclonal antibodies are commercially available from R&D Systems (Minneapolis, MN, USA; mouse monoclonal: 2006 cat# MAB1406; rat monoclonal: 2006 cat# MAB1589). U.S. Patent Nos. 6,395,511 and 6,803,453, 15 and U.S. Patent Publications 20040009535 and 20050106683 refer to anti-sclerostin antibodies generally. As used herein, the term human sclerostin is intended to include the protein of SEQ ID NO: 1 and allelic variants thereof. Sclerostin can be purified from 293T host cells that have been transfected by a gene encoding sclerostin by elution of filtered supernatant of host cell 20 culture fluid using a Heparin HP column, using a salt gradient. The preparation and further purification using cation exchange chromatography are described in Examples 1 and 2. Binding agents of the invention are preferably antibodies, as defined herein. The term "antibody" refers to an intact antibody, or a binding fragment thereof. An antibody may comprise a complete antibody molecule (including polyclonal, monoclonal, chimeric, 25 humanized, or human versions having full length heavy and/or light chains), or comprise an antigen binding fragment thereof. Antibody fragments include F(ab')2, Fab, Fab', Fv, Fc, and Fd fragments, and can be incorporated into single domain antibodies, single-chain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NAR and bis-scFv (See e.g.,, Hollinger and Hudson, 2005, Nature Biotechnology, 23, 9, 1126-1136). Antibody 30 polypeptides are also disclosed in U. S. Patent No. 6,703,199, including fibronectin polypeptide monobodies. Other antibody polypeptides are disclosed in U.S. Patent Publication 2005/0238646, which are single-chain polypeptides. Antigen binding fragments derived from an antibody can be obtained, for example, by proteolytic hydrolysis of the antibody, for example, pepsin or papain digestion of SEA 103911v1 60117-223 12 WO 2006/119062 PCT/US2006/016345 whole antibodies according to conventional methods. By way of example, antibody fragments can be produced by enzymatic cleavage of antibodies with pepsin to provide a 5S fragment termed F(ab') 2 . This fragment can be further cleaved using a thiol reducing agent to produce 3.5S Fab' monovalent fragments. Optionally, the cleavage reaction can be performed using a 5 blocking group for the sulfhydryl groups that result from cleavage of disulfide linkages. As an alternative, an enzymatic cleavage using papain produces two monovalent Fab fragments and an Fc fragment directly. These methods are described, for example, by Goldenberg, U.S. Patent No. 4,331,647, Nisonoff et al., Arch. Biochem. Biophys. 89:230, 1960; Porter, Biochem. J. 73:119, 1959; Edelman et al., in Methods in Enzymology 1:422 (Academic Press 1967); and by 10 Andrews, S.M. and Titus, J.A. in Current Protocols in Immunology (Coligan J.E., et al., eds), John Wiley & Sons, New York (2003). pages 2.8.1-2.8.10 and 2.10A.1-2.10A.5. Other methods for cleaving antibodies, such as separating heavy chains to form monovalent light-heavy chain fragments (Fd), further cleaving of fragments, or other enzymatic, chemical, or genetic techniques may also be used, so long as the fragments bind to the antigen that is recognized by 15 the intact antibody. An antibody fragment may also be any synthetic or genetically engineered protein. For example, antibody fragments include isolated fragments consisting of the light chain variable region, "Fv" fragments consisting of the variable regions of the heavy and light chains, recombinant single chain polypeptide molecules in which light and heavy variable 20 regions are connected by a peptide linker (scFv proteins). Another form of an antibody fragment is a peptide comprising one or more complementarity determining regions (CDRs) of an antibody. CDRs (also termed "minimal recognition units", or "hypervariable region") can be obtained by constructing polynucleotides that encode the CDR of interest. Such polynucleotides are prepared, for example, by using the 25 polymerase chain reaction to synthesize the variable region using mRNA of antibody-producing cells as a template (see, for example, Larrick et al., Methods: A Companion to Methods in Enzymology 2:106, 1991; Courtenay-Luck, "Genetic Manipulation of Monoclonal Antibodies," in Monoclonal Antibodies: Production, Engineering and Clinical Application, Ritter et al. (eds.), page 166 (Cambridge University Press 1995); and Ward et al., "Genetic Manipulation 30 and Expression of Antibodies," in Monoclonal Antibodies: Principles and Applications, Birch et al., (eds.), page 137 (Wiley-Liss, Inc. 1995)). Thus, in one embodiment, the binding agent comprises at least one CDR as described herein. The binding agent may comprise at least two, three, four, five or six CDR's as described herein. The binding agent further may comprise at least one variable region domain of SEA 1803911vl 60117-223 13 WO 2006/119062 PCT/US2006/016345 an antibody described herein. The variable region domain may be of any size or amino acid composition and will generally comprise at least one CDR sequence responsible for binding to human sclerostin, for example CDR-H1, CDR-H2, CDR-H3 and/or the light chain CDRs specifically described herein and which is adjacent to or in frame with one or more framework 5 sequences. In general terms, the variable (V) region domain may be any suitable arrangement of immunoglobulin heavy (V) and/or light (VL) chain variable domains. Thus, for example, the V region domain may be monomeric and be a VH or VL domain, which is capable of independently binding human sclerostin with an affinity at least equal to 1 x 1 0 7 M or less as describedbelow. Alternatively, the V region domain may be dimeric and contain VH-VH, VH-VL, or VL-VL, 10 dimers. The V region dimer comprises at least one VH and at least one VL chain that may be non-covalently associated (hereinafter referred to as Fv). If desired, the chains may be covalently coupled either directly, for example via a disulfide bond between the two variable domains, or through a linker, for example a peptide linker, to form a single chain Fv (scFv). The variable region domain may be any naturally occurring variable domain or an 15 engineered version thereof. By engineered version is meant a variable region domain that has been created using recombinant DNA engineering techniques. Such engineered versions include those created, for example, from a specific antibody variable region by insertions, deletions, or changes in or to the amino acid sequences of the specific antibody. Particular examples include engineered variable region domains containing at least one CDR and optionally one or more 20 framework amino acids from a first antibody and the remainder of the variable region domain from a second antibody. The variable region domain may be covalently attached at a C-terminal amino acid to at least one other antibody domain or a fragment thereof. Thus, for example, a VH domain that is present in the variable region domain may be linked to an immunoglobulin CHi 25 domain, or a fragment thereof. Similarly a VL domain may be linked to a CK domain or a fragment thereof. In this way, for example, the antibody may be a Fab fragment wherein the antigen binding domain contains associated VH and VL domains covalently linked at their C-termini to a CHI and CK domain, respectively. The CHi domain may be extended with further amino acids, for example to provide a hinge region or a portion of a hinge region domain 30 as found in a Fab' fragment, or to provide further domains, such as antibody CH2 and CH3 domains. As described herein, binding agents comprise at least one of these CDRs. For example, one or more CDR may be incorporated into known antibody framework regions (IgG1, IgG2, etc.), or conjugated to a suitable vehicle to enhance the half-life thereof. Suitable vehicles SEA 1803911 vi 60117.223 14 WO 2006/119062 PCT/US2006/016345 include, but are not limited to Fc, polyethylene glycol (PEG), albumin, transferrin, and the like. These and other suitable vehicles are known in the art. Such conjugated CDR peptides may be in monomeric, dimeric, tetrameric, or other form. In one embodiment, one or more water soluble polymer is bonded at one or more specific position, for example at the amino terminus, 5 of a binding agent In certain preferred embodiments, a binding agent comprises one or more water soluble polymer attachments, including, but not limited to, polyethylene glycol, polyoxyethylene glycol, or polypropylene glycol. See, e.g., U.S. Pat. Nos. 4,640,835, 4,496,689, 4,301,144, 4,670,417, 4,791,192 and 4,179,337. In certain embodiments, a derivative binding agent 10 comprises one or more of monomethoxy-polyethylene glycol, dextran, cellulose, or other carbohydrate based polymers, poly-(N-vinyl pyrrolidone)-polyethylene glycol, propylene glycol homopolymers, a polypropylene oxide/ethylene oxide co-polymer, polyoxyethylated polyols (e.g., glycerol) and polyvinyl alcohol, as well as mixtures of such polymers. In certain embodiments, one or more water-soluble polymer is randomly attached to one or more side 15 chains. In certain embodiments, PEG can act to improve the therapeutic capacity for a binding agent, such as an antibody. Certain such methods are discussed, for example, in U.S. Pat. No. 6,133,426, which is hereby incorporated by reference for any purpose. It will be appreciated that a binding agent of the present invention may have at least one amino acid substitution, providing that the binding agent retains binding specificity. 20 Therefore, modifications to the binding agent structures are encompassed within the scope of the invention. These may include amino acid substitutions, which may be conservative or non conservative, that do not destroy the sclerostin binding capability of a binding agent. Conservative amino acid substitutions may encompass non-naturally occurring amino acid residues, which are typically incorporated by chemical peptide synthesis rather than by synthesis 25 in biological systems. These include peptidomimetics and other reversed or inverted forms of amino acid moieties. A conservative amino acid substitution may also involve a substitution of a native amino acid residue with a normative residue such that there is little or no effect on the polarity or charge of the amino acid residue at that position. Non-conservative substitutions may involve the exchange of a member of one 30 class of amino acids or amino acid mimetics for a member from another class with different physical properties (e.g. size, polarity, hydrophobicity, charge). Such substituted residues may be introduced into regions of the human antibody that are homologous with non-human antibodies, or into the non-homologous regions of the molecule. Moreover, one skilled in the art may generate test variants containing a single SEA 180391vi 60117M 15 WO 2006/119062 PCT/US2006/016345 amino acid substitution at each desired amino acid residue. The variants can then be screened using activity assays known to those skilled in the art. Such variants could be used to gather information about suitable variants. For example, if one discovered that a change to a particular amino acid residue resulted in destroyed, undesirably reduced, or unsuitable activity, variants 5 with such a change may be avoided. In other words, based on information gathered from such routine experiments, one skilled in the art can readily determine the amino acids where further substitutions should be avoided either alone or in combination with other mutations. A skilled artisan will be able to determine suitable variants of the polypeptide as set forth herein using well-known techniques. In certain embodiments, one skilled in the art 10 may identify suitable areas of the molecule that may be changed without destroying activity by targeting regions not believed to be important for activity. In certain embodiments, one can identify residues and portions of the molecules that are conserved among similar polypeptides. In certain embodiments, even areas that may be important for biological activity or for structure may be subject to conservative amino acid substitutions without destroying the biological 15 activity or without adversely affecting the polypeptide structure. Additionally, one skilled in the art can review structure-function studies identifying residues in similar polypeptides that are important for activity or structure. In view of such a comparison, one can predict the importance of amino acid residues in a protein that correspond to amino acid residues which are important for activity or structure in similar: 20 proteins. One skilled in the art may opt for chemically similar amino acid substitutions for such predicted important amino acid residues. One skilled in the art can also analyze the three-dimensional structure and amino acid sequence in relation to that structure in similar polypeptides. In view of such information, one skilled in the art may predict the alignment of amino acid residues of an antibody with 25 respect to its three dimensional structure. In certain embodiments, one skilled in the art may choose not to make radical changes to amino acid residues predicted to be on the surface of the protein, since such residues may be involved in important interactions with other molecules. A number of scientific publications have been devoted to the prediction of secondary structure. See Moult J., Curr. Op. in Biotech., 7(4):422-427 (1996), Chou et al., 30 Biochemistry, 13(2):222-245 (1974); Chou et al., Biochemistry, 113(2):211-222 (1974); Chou et al., Adv. Enzymol. Relat. Areas Mol. Biol., 47:45-148 (1978); Chou et al., Ann. Rev. Biochem., 47:251-276 and Chou et al., Biophys. J., 26:367-3 84 (1979). Moreover, computer programs are currently available to assist with predicting secondary structure. One method of predicting secondary structure is based upon homology modeling. For example, two polypeptides or SEA 1803911vl 60117-223 16 WO 2006/119062 PCT/US2006/016345 proteins which have a sequence identity of greater than 30%, or similarity greater than 40% often have similar structural topologies. The recent growth of the protein structural database (PDB) has provided enhanced predictability of secondary structure, including the potential number of folds within a polypeptide's or protein's structure. See Holm et al., Nucl. Acid. Res., 5 27(1):244-247 (1999). It has been suggested (Brenner et al., Curr. Op. Struct. Biol., 7(3):369 376 (1997)) that there are a limited number of folds in a given polypeptide or protein and that once a critical number of structures have been resolved, structural prediction will become dramatically more accurate. Additional methods of predicting secondary structure include "threading" (Jones, 10 D., Curr. Opin. Struct. Biol., 7(3):377-87 (1997); Sippl et al., Structure, 4(1):15-19 (1996)), "profile analysis" (Bowie et al., Science, 253:164-170 (1991); Gribskov et al., Meth. Enzym., 183:146-159 (1990); Gribskov et al., Proc. Nat. Acad. Sci., 84(13):4355-4358 (1987)), and "evolutionary linkage" (See Holm, supra (1999), and Brenner, supra (1997)). In certain embodiments, variants of binding agents include glycosylation variants 15 wherein the number and/or type of glycosylation site has been altered compared to the amino acid sequences of a parent polypeptide. In certain embodiments, variants comprise a greater or a lesser number of N-linked glycosylation sites than the native protein. An N-linked glycosylation site is characterized by the sequence: Asn-X-Ser or Asn-X-Thr, wherein the amino acid residue designated as X may be any amino acid residue except proline. The substitution of amino acid 20 residues to create this sequence provides a potential new site for the addition of an N-linked carbohydrate chain. Alternatively, substitutions which eliminate this sequence will remove an existing N-linked carbohydrate chain. Also provided is a rearrangement of N-linked carbohydrate chains wherein one or more N-linked glycosylation sites (typically those that are naturally occurring) are eliminated and one or more new N-linked sites are created. Additional 25 preferred antibody variants include cysteine variants wherein one or more cysteine residues are deleted from or substituted for another amino acid (e.g., serine) as compared to the parent amino acid sequence. Cysteine variants may be useful when antibodies must be refolded into a biologically active conformation such as after the isolation of insoluble inclusion bodies. Cysteine variants generally have fewer cysteine residues than the native protein, and typically 30 have an even number to minimize interactions resulting from unpaired cysteines. Desired amino acid substitutions (whether conservative or non-conservative) can be determined by those skilled in the art at the time such substitutions are desired. In certain embodiments, amino acid substitutions can be used to identify important residues of antibodies to sclerostin, or to increase or decrease the affinity of the antibodies to sclerostin described SEA 1803911vl 60117-22 17 WO 2006/119062 PCTfUS2006/016345 herein. According to certain embodiments, preferred amino acid substitutions are those which: (1) reduce susceptibility to proteolysis, (2) reduce susceptibility to oxidation, (3) alter binding affinity for forming protein complexes, (4) alter binding affinities, and/or (4) confer or 5 modify other physiochemical or functional properties on such polypeptides. According to certain embodiments, single or multiple amino acid substitutions (in certain embodiments, conservative amino acid substitutions) may be made in the naturally-occurring sequence (in certain embodiments, in the portion of the polypeptide outside the domain(s) forming intermolecular contacts). In certain embodiments, a conservative amino acid substitution 10 typically may not substantially change the structural characteristics of the parent sequence (e.g., a replacement amino acid should not tend to break a helix that occurs in the parent sequence, or disrupt other types of secondary structure that characterizes the parent sequence). Examples of art-recognized polypeptide secondary and tertiary structures are described in Proteins, Structures and Molecular Principles (Creighton, Ed., W. H. Freeman and Company, New York (1984)); 15 Introduction to Protein Structure (C. Branden and J. Tooze, eds., Garland Publishing, New York, N.Y. (1991)); and Thornton et al. Nature 354:105 (1991), which are each incorporated herein by reference. In certain embodiments, binding agents of the invention may be chemically 20 bonded with polymers, lipids, or other moieties. The binding agents may comprise at least one of the CDRs described herein incorporated into a biocompatible framework structure. In one example, the biocompatible framework structure comprises a polypeptide or portion thereof that is sufficient to form a conformationally stable structural support, or framework, or scaffold, which is able to display 25 one or more sequences of amino acids that bind to an antigen (e.g., CDRs, a variable region, etc.) in a localized surface region. Such structures can be a naturally occurring polypeptide or polypeptide "fold" (a structural motif), or can have one or more modifications, such as additions, deletions or substitutions of amino acids, relative to a naturally occurring polypeptide or fold. These scaffolds can be derived from a polypeptide of any species (or of more than one species), 30 such as a human, other mammal, other vertebrate, invertebrate, plant, bacteria or virus. Typically the biocompatible framework structures are based on protein scaffolds or skeletons other than immunoglobulin domains. For example, those based on fibronectin, ankyrin, lipocalin, neocarzinostain, cytochrome b, CP I zinc finger, PST1, coiled coil, LACI-D 1, SEA 1803911vl 60117-223 18 WO 2006/119062 PCT/US2006/016345 Z domain and tendramisat domains may be used (See e.g.,, Nygren and Uhlen, 1997, Current Opinion in Structural Biology, 7,463-469). In preferred embodiments, it will be appreciated that the binding agents of the invention include the humanized antibodies described herein. Humanized antibodies such as 5 those described herein can be produced using techniques known to those skilled in the art (Zhang, W., et al., Molecular Immunology. 42(12):1445-1451, 2005; Hwang W. et al., Methods. 36(1):35-42, 2005; Dall'Acqua WF, et al., Methods 36(1):43-60, 2005; and Clark, M., Immunology Today. 21(8):397-402, 2000). Additionally, one skilled in the art will recognize that suitable binding agents 10 include portions of these antibodies, such as one or more of CDR-Hl, CDR-H2, CDR-H3, CDR LI, CDR-L2 and CDR-L3 as specifically disclosed herein. At least one of the regions of CDR Hi, CDR-H2, CDR-H3, CDR-Ll, CDR-L2 and CDR-L3 may have at least one amino acid substitution, provided that the binding agent retains the binding specificity of the non-substituted CDR. The non-CDR portion of the binding agent may be a non-protein molecule, wherein the 15 binding agent cross-blocks the binding of an antibody disclosed herein to sclerostin and/or neutralizes sclerostin. The non-CDR portion of the binding agent may be a non-protein molecule in which the binding agent exhibits a similar binding pattern to human sclerostin peptides in a "human sclerostin peptide epitope competition binding assay" as that exhibited by at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab 20 7, Ab-8, Ab-9, Ab-10, Ab-1 1, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab 20, Ab-21, Ab-22, Ab-23, and Ab-24, and/or neutralizes sclerostin. The non-CDR portion of the binding agent may be composed of amino acids, wherein the binding agent is a recombinant binding protein or a synthetic peptide, and the recombinant binding protein cross-blocks the binding of an antibody disclosed herein to sclerostin and/or neutralizes sclerostin. The non 25 CDR portion of the binding agent may be composed of amino acids, wherein the binding agent is a recombinant binding protein, and the recombinant binding protein exhibits a similar binding pattern to human sclerostin peptides in the human sclerostin peptide epitope competition binding assay (described hereinbelow) as that exhibited by at least one of the antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, 30 Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24, and/or neutralizes sclerostin. Where an antibody comprises one or more of CDR-H1, CDR-H2, CDR-H3, CDR-Ll, CDR-L2 and CDR-L3 as described above, it may be obtained by expression from a host cell containing DNA coding for these sequences. A DNA coding for each CDR sequence SEA 1803911vl 60117-2Z 19 WO 2006/119062 PCT/US2006/016345 may be determined on the basis of the amino acid sequence of the CDR and synthesized together with any desired antibody variable region framework and constant region DNA sequences using oligonucleotide synthesis techniques, site-directed mutagenesis and polymerase chain reaction (PCR) techniques as appropriate. DNA coding for variable region frameworks and constant 5 regions is widely available to those skilled in the art from genetic sequences databases such as GenBank@. Each of the above-mentioned CDRs will be typically located in a variable region framework at positions 31-35 (CDR-HL), 50-65 (CDR-H2) and 95-102 (CDR-H3) of the heavy chain and positions 24-34 (CDR-L1), 50-56 (CDR-L2) and 89-97 (CDR-L3) of the light chain according to the Kabat numbering system (Kabat et al., 1987 in Sequences ofProteins of 10 Immunological Interest, U.S. Department of Health and Human Services, NIH, USA). Once synthesized, the DNA encoding an antibody of the invention or fragment thereof may be propagated and expressed according to any of a variety of well-known procedures for nucleic acid excision, ligation, transformation, and transfection using any number of known expression vectors. Thus, in certain embodiments expression of an antibody fragment 15 may be preferred in a prokaryotic host, such as Escherichia coli (see, e.g., Pluckthun et al., 1989 Methods Enzymol. 178:497-515). In certain other embodiments, expression of the antibody or a fragment thereof may be preferred in a eukaryotic host cell, including yeast (e.g., Saccharomyces cerevisiae, Schizosaccharomyces pombe, and Pichia pastoris), animal cells (including mammalian cells) or plant cells. Examples of suitable animal cells include, but are 20 not limited to, myeloma (such as a mouse NSO line), COS, CHO, or hybridoma cells. Examples of plant cells include tobacco, corn, soybean, and rice cells. One or more replicable expression vectors containing DNA encoding an antibody variable and/or constant region may be prepared and used to transform an appropriate cell line, for example, a non-producing myeloma cell line, such as a mouse NSO line or a bacteria, such 25 as E. coli, in which production of the antibody will occur. In order to obtain efficient transcription and translation, the DNA sequence in each vector should include appropriate regulatory sequences, particularly a promoter and leader sequence operatively linked to the variable domain sequence. Particular methods for producing antibodies in this way are generally well-known and routinely used. For example, basic molecular biology procedures are described 30 by Maniatis et al. (Molecular Cloning, A Laboratory Manual, 2nd ed., Cold Spring Harbor Laboratory, New York, 1989; see also Maniatis et al, 3rd ed., Cold Spring Harbor Laboratory, New York, (2001)). DNA sequencing can be performed as described in Sanger et al. (PNAS 74:5463, (1977)) and the Amersham International plc sequencing handbook, and site directed mutagenesis can be carried out according to methods known in the art (Kramer et al., Nucleic SEA 180391M 60117-223 20 WO 2006/119062 PCT/US2006/016345 Acids Res. 12:9441, (1984); Kunkel Proc. Nati. Acad. Sci. USA 82:488-92 (1985); Kunkel et al., Methods in Enzymol. 154:367-82 (1987); the Anglian Biotechnology Ltd handbook). Additionally, numerous publications describe techniques suitable for the preparation of antibodies by manipulation of DNA, creation of expression vectors, and transformation and 5 culture of appropriate cells (Mountain A and Adair, J R in Biotechnology and Genetic Engineering Reviews (ed. Tombs, M P, 10, Chapter 1, 1992, Intercept, Andover, UK); "Current Protocols in Molecular Biology", 1999, F.M. Ausubel (ed.), Wiley Interscience, New York). Where it is desired to improve the affinity of antibodies according to the invention containing one or more of the above-mentioned CDRs can be obtained by a number of 10 affinity maturation protocols including maintaining the CDRs (Yang et al., J. Mol. Biol., 254, 392-403, 1995), chain shuffling (Marks et al., Bio/Technology, 10, 779-783, 1992), use of mutation strains of E. coli. (Low et al., J. Mol. Biol., 250, 350-368, 1996), DNA shuffling (Patten et al., Curr. Opin. Biotechnol., 8, 724-733, 1997), phage display (Thompson et al., J. Mol. Biol., 256, 7-88, 1996) and sexual PCR (Crameri, et al., Nature, 391, 288-291, 1998). All 15 of these methods of affinity maturation are discussed by Vaughan et al. (Nature Biotechnology, 16, 535-539, 1998). Other antibodies according to the invention may be obtained by conventional immunization and cell fusion procedures as described herein and known in the art. Monoclonal antibodies of the invention may be generated using a variety of known techniques. In general, 20 monoclonal antibodies that bind to specific antigens may be obtained by methods known to those skilled in the art (see, for example, Kohler et al., Nature 256:495, 1975; Coligan et al. (eds.), Current Protocols in Immunology, 1:2.5.12.6.7 (John Wiley & Sons 1991); U.S. Patent Nos. RE 32,011, 4,902,614, 4,543,439, and 4,411,993; MonoclonalAntibodies, Hybridomas: A New Dimension in Biological Analyses, Plenum Press, Kennett, McKearn, and Bechtol (eds.) 25 (1980); and Antibodies: A Laboratory Manual, Harlow and Lane (eds.), Cold Spring Harbor Laboratory Press (1988); Picksley et al., "Production of monoclonal antibodies against proteins expressed in E. coli," in DNA Cloning 2: Expression Systems, 2nd Edition, Glover et al. (eds.), page 93 (Oxford University Press 1995)). Antibody fragments may be derived therefrom using any suitable standard technique such as proteolytic digestion, or optionally, by proteolytic 30 digestion (for example, using papain or pepsin) followed by mild reduction of disulfide bonds and alkylation. Alternatively, such fragments may also be generated by recombinant genetic engineering techniques as described herein. Monoclonal antibodies can be obtained by injecting an animal, for example, a rat, hamster, a rabbit, or preferably a mouse, including for example a transgenic or a knock-out, as SEA 1so391uvi 60117-223 21 WO 2006/119062 PCTIUS2006/016345 known in the art, with an immunogen comprising human sclerostin of SEQ ID NO:1, or a fragment thereof, according to methods known in the art and described herein. The presence of specific antibody production may be monitored after the initial injection and/or after a booster injection by obtaining a serum sample and detecting the presence of an antibody that binds to 5 human sclerostin or peptide using any one of several immunodetection methods known in the art and described herein. From animals producing the desired antibodies, lymphoid cells, most commonly cells from the spleen or lymph node, are removed to obtain B-lymphocytes. The B lymphocytes are then fused with a drug-sensitized myeloma cell fusion partner, preferably one that is syngeneic with the immunized animal and that optionally has other desirable properties 10 (e.g., inability to express endogenous Ig gene products, e.g., P3X63 - Ag 8.653 (ATCC No. CRL 1580); NSO, SP20) to produce hybridomas, which are immortal eukaryotic cell lines. The lymphoid (e.g., spleen) cells and the myeloma cells may be combined for a few minutes with a membrane fusion-promoting agent, such as polyethylene glycol or a nonionic detergent, and then plated at low density on a selective medium that supports the growth of hybridoma cells but 15 not unfused myeloma cells. A preferred selection media is HAT (hypoxanthine, aminopterin, thymidine). After a sufficient time, usually about one to two weeks, colonies of cells are observed. Single colonies are isolated, and antibodies produced by the cells may be tested for binding activity to human sclerostin, using any one of a variety of immunoassays known in the art and described herein. The hybridomas are cloned (e.g., by limited dilution cloning or by soft 20 agar plaque isolation) and positive clones that produce an antibody specific to sclerostin are selected and cultured. The monoclonal antibodies from the hybridoma cultures may be isolated from the supernatants of hybridoma cultures. An alternative method for production of a murine monoclonal antibody is to inject the hybridoma cells into the peritoneal cavity of a syngeneic mouse, for example, a mouse that has been treated (e.g., pristane-primed) to promote formation 25 of ascites fluid containing the monoclonal antibody. Monoclonal antibodies can be isolated and purified by a variety of well-established techniques. Such isolation techniques include affinity chromatography with Protein-A Sepharose, size-exclusion chromatography, and ion-exchange chromatography (see, for example, Coligan at pages 2.7.1-2.7.12 and pages 2.9.1-2.9.3; Baines et al., "Purification of Immunoglobulin G (IgG)," in Methods in Molecular Biology, Vol. 10, 30 pages 79-104 (The Humana Press, Inc. 1992)). Monoclonal antibodies may be purified by affinity chromatography using an appropriate ligand selected based on particular properties of the antibody (e.g., heavy or light chain isotype, binding specificity, etc.). Examples of a suitable ligand, immobilized on a solid support, include Protein A, Protein G, an anticonstant region SEA 1803911vl 60117-23 22 WO 2006/119062 PCT/US2006/016345 (light chain or heavy chain) antibody, an anti-idiotype antibody, and a TGF-beta binding protein, or fragment or variant thereof. An antibody of the present invention may also be a human monoclonal antibody. Human monoclonal antibodies may be generated by any number of techniques with which those 5 having ordinary skill in the art will be familiar. Such methods include, but are not limited to, Epstein Barr Virus (EBV) transformation of human peripheral blood cells (e.g., containing B lymphocytes), in vitro immunization of human B cells, fusion of spleen cells from immunized transgenic mice carrying inserted human immunoglobulin genes, isolation from human immunoglobulin V region phage libraries, or other procedures as known in the art and based on 10 the disclosure herein. For example, human monoclonal antibodies may be obtained from transgenic mice that have been engineered to produce specific human antibodies in response to antigenic challenge. Methods for obtaining human antibodies from transgenic mice are described, for example, by Green et al., Nature Genet. 7:13, 1994; Lonberg et al., Nature 368:856, 1994; Taylor et al., nt. Immun. 6:579, 1994; U.S. Patent No. 5,877,397; Bruggemann 15 et al., 1997 Curr. Opin. Biotechnol. 8:455-58; Jakobovits et al., 1995 Ann. N. Y Acad Sci. 764:525-35. In this technique, elements of the human heavy and light chain locus are introduced into strains of mice derived from embryonic stem cell lines that contain targeted disruptions of the endogenous heavy chain and light chain loci (see also Bruggemann et al., Curr. Opin. Biotechnol. 8:455-58 (1997)). For example, human immunoglobulin transgenes may be 20 mini-gene constructs, or transloci on yeast artificial chromosomes, which undergo B cell-specific DNA rearrangement and hypermutation in the mouse lymphoid tissue. Human monoclonal antibodies may be obtained by immunizing the transgenic mice, which may then produce human antibodies specific for sclerostin. Lymphoid cells of the immunized transgenic mice can be used to produce human antibody-secreting hybridomas according to the methods 25 described herein. Polyclonal sera containing human antibodies may also be obtained from the blood of the immunized animals. Another method for generating human antibodies of the invention includes immortalizing human peripheral blood cells by EBV transformation. See, e.g., U.S. Patent No. 4,464,456. Such an immortalized B cell line (or lymphoblastoid cell line) producing a 30 monoclonal antibody that specifically binds to sclerostin can be identified by immunodetection methods as provided herein, for example, an ELISA, and then isolated by standard cloning techniques. The stability of the lymphoblastoid cell line producing an anti-sclerostin antibody may be improved by fusing the transformed cell line with a murine myeloma to produce a mouse-human hybrid cell line according to methods known in the art (see, e.g., Glasky et al., SEA 1803911vl 60117-223 23 WO 2006/119062 PCT/US2006/016345 Hybridoma 8:377-89 (1989)). Still another method to generate human monoclonal antibodies is in vitro immunization, which includes priming human splenic B cells with human sclerostin, followed by fusion of primed B cells with a heterohybrid fusion partner. See, e.g., Boerner et al., 1991 J Immunol. 147:86-95. 5 In certain embodiments, a B cell that is producing an anti-human sclerostin antibody is selected and the light chain and heavy chain variable regions are cloned from the B cell according to molecular biology techniques known in the art (WO 92/02551; US patent 5,627,052; Babcook et al., Proc. Nat!. Acad. Sci. USA 93:7843-48 (1996)) and described herein. B cells from an immunized animal may be isolated from the spleen, lymph node, or peripheral 10 blood sample by selecting a cell that is producing an antibody that specifically binds to sclerostin. B cells may also be isolated from humans, for example, from a peripheral blood sample. Methods for detecting single B cells that are producing an antibody with the desired specificity are well known in the art, for example, by plaque formation, fluorescence-activated cell sorting, in vitro stimulation followed by detection of specific antibody, and the like. 15 Methods for selection of specific antibody-producing B cells include, for example, preparing a single cell suspension of B cells in soft agar that contains human sclerostin. Binding of the specific antibody produced by the B cell to the antigen results in the formation of a complex, which may be visible as an immunoprecipitate. After the B cells producing the desired antibody are selected, the specific antibody genes may be cloned by isolating and amplifying DNA or 20 mRNA according to methods known in the art and described herein. An additional method for obtaining antibodies of the invention is by phage display. See, e.g., Winter et al., 1994 Annu. Rev.. Immunol. 12:433-55; Burton et al., 1994 Adv. Immunol. 57:191-280. Human or murine immunoglobulin variable region gene combinatorial libraries may be created in phage vectors that can be screened to select Ig fragments (Fab, Fv, 25 sFv, or multimers thereof) that bind specifically to TGF-beta binding protein or variant or fragment thereof. See, e.g., U.S. Patent No. 5,223,409; Huse et al., 1989 Science 246:1275-81; Sastry et al., Proc. Nat!. Acad Sci. USA 86:5728-32 (1989); Alting-Mees et al., Strategies in Molecular Biology 3:1-9 (1990); Kang et al., 1991 Proc. Nat. Acad Sci. USA 88:4363-66; Hoogenboom et al., 1992 J. Molec. Biol. 227:381-388; Schlebusch et al., 1997 Hybridoma 30 16:47-52 and references cited therein. For example, a library containing a plurality of polynucleotide sequences encoding Ig variable region fragments may be inserted into the genome of a filamentous bacteriophage, such as M13 or a variant thereof, in frame with the sequence encoding a phage coat protein. A fusion protein may be a fusion of the coat protein with the light chain variable region domain and/or with the heavy chain variable region domain. SEA 1803911vl 60117-223 24 WO 2006/119062 PCT/US2006/016345 According to certain embodiments, immunoglobulin Fab fragments may also be displayed on a phage particle (see, e.g., U.S. Patent No. 5,698,426). Heavy and light chain immunoglobulin cDNA expression libraries may also be prepared in lambda phage, for example, using MmmunoZapm(H) and MmmunoZapm(L) 5 vectors (Stratagene, La Jolla, California). Briefly, mRNA is isolated from a B cell population, and used to create heavy and light chain immunoglobulin cDNA expression libraries in the MmmunoZap(H) and MmmunoZap(L) vectors. These vectors may be screened individually or co-expressed to form Fab fragments or antibodies (see Huse et al., supra; see also Sastry et al., supra). Positive plaques may subsequently be converted to a non-lytic plasmid that allows high 10 level expression of monoclonal antibody fragments from E. coli. In one embodiment, in a hybridoma the variable regions of a gene expressing a monoclonal antibody of interest are amplified using nucleotide primers. These primers may be synthesized by one of ordinary skill in the art, or may be purchased from commercially available sources. (See, e.g., Stratagene (La Jolla, California), which sells primers for mouse and human 15 variable regions including, among others, primers for Va, VHb, VHr, VHd, CHI, VL and CL regions.) These primers may be used to amplify heavy or light chain variable regions, which may then be inserted into vectors such as ImmunoZAPMH or ImmunoZAP"ML (Stratagene), respectively. These vectors may then be introduced into E. coli, yeast, or mammalian-based systems for expression. Large amounts of a single-chain protein containing a fusion of the VH 20 and VL domains may be produced using these methods (see Bird et al., Science 242:423-426, 1988). Once cells producing antibodies according to the invention have been obtained using any of the above-described immunization and other techniques, the specific antibody genes may be cloned by isolating and amplifying DNA or mRNA therefrom according to 25 standard procedures as described herein. The antibodies produced therefrom may be sequenced and the CDRs identified and the DNA coding for the CDRs may be manipulated as described previously to generate other antibodies according to the invention. Preferably the binding agents specifically bind to sclerostin. As with all binding agents and binding assays, one of skill in this art recognizes that the various moieties to which a 30 binding agent should not detectably bind in order to be therapeutically effective and suitable would be exhaustive and impractical to list. Therefore, for a binding agent disclosed herein, the term "specifically binds" refers to the ability of a binding agent to bind to sclerostin, preferably human sclerostin, with greater affinity than it binds to an unrelated control protein. Preferably the control protein is hen egg white lysozyme. Preferably the binding agents bind to sclerostin SEA 1803911v 60117-zM 25 WO 2006/119062 PCT/US2006/016345 with an affinity that is at least, 50, 100, 250, 500, 1000, or 10,000 times greater than the affinity for a control protein. A binding agent may have a binding affinity for human sclerostin of less than or equal to 1 x 10-7M less than or equal to 1 x 10- 8 M, less than or equal to 1 x 10~M, less than or equal to 1 x 10-'M, less than or equal to 1 x 10-"M, or less than or equal to 1 x 10~ 2 M. 5 Affinity may be determined by an affinity ELISA assay. In certain embodiments, affinity may be determined by a BlAcore assay. In certain embodiments, affinity may be determined by a kinetic method. In certain embodiments, affinity may be determined by an equilibrium/solution method. Such methods are described in further detail herein or known in the art. 10 Sclerostin binding agents of the present invention preferably modulate sclerostin function in the cell-based assay described herein and/or the in vivo assay described herein and/or bind to one or more of the epitopes described herein and/or cross-block the binding of one of the antibodies described in this application and/or are cross-blocked from binding sclerostin by one of the antibodies described in this application. Accordingly such binding agents can be 15 identified using the assays described herein. In certain embodiments, binding agents are generated by first identifying antibodies that bind to one more of the epitopes provided herein and/or neutralize in the cell based and/or in vivo assays described herein and/or cross-block the antibodies described in this application and/or are cross-blocked from binding sclerostin by one of the antibodies described 20 in this application. The CDR regions from these antibodies are then used to insert into appropriate biocompatible frameworks to generate sclerostin binding agents. The non-CDR portion of the binding agent may be composed of amino acids, or may be a non-protein molecule. The assays described herein allow the characterization of binding agents. Preferably the binding agents of the present invention are antibodies as defined herein. 25 It will be understood by one skilled in the art that some proteins, such as antibodies, may undergo a variety of posttranslational modifications. The type and extent of these modifications often depends on the host cell line used to express the protein as well as the culture conditions. Such modifications may include variations in glycosylation, methionine oxidation, diketopiperizine formation, aspartate isomerization and asparagine deamidation. A 30 frequent modification is the loss of a carboxy-terminal basic residue (such as lysine or arginine) due to the action of carboxypeptidases (as described in Harris, RJ. Journal of Chromatography 705:129-134, 1995). SEA 1s03911vi 60117-23 26 WO 2006/119062 PCT/US2006/016345 Antibodies referred to as Ab-A, Ab-B, Ab-C, Ab-D and Ab-1 are described below. "HC" refers to the heavy chain and "LC" refers to the light chain. For some antibodies below, the CDRs are box shaded and the constant (C) regions are shown in bold italics. 5 Ab-D Antibody D (also referred to herein as Ab-D and Mab-D) is a mouse antibody which exhibits high affinity binding to sclerostin. The BIAcore binding pattern of Ab-D is shown in Figure 18. The amino acid sequence of the mature form (signal peptide removed) of Ab-D 10 light chain: 1 DVQMIQSPSS LSASLGDIVT MTCQAghdT~SN&ofWFQQKP GKAPKLLIYO 51 SiSNEDGVPS RFSGSRYGTD FTLTISSLED EDLATYFCLqHSY.L -YTFGG 101 GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFYPDINVKWKI 151 DGSERQNGVL NSWTDQDSKD STYSMSSTLTLTEDEYERJNSYTCFATHKT 15 201 STSPIVKSFN RNEC (SEQ ID NO:7) Nucleic acid sequence encoding the mature form (signal peptide removed) of Ab D LC is as follows: 1 GATGTCCAGA TGATTCAGTC TCCATCCTCC CTGTCTGCAT CTTTGGGAGA 20 51 CATAGTCACC ATGACTTGCC AGGCAAGTCA GGGCACTAGC ATTAATTTAA 101 ACTGGTITCA GCAAAAACCA GGGAAGGCTC CTAAGCTCCT GATCTATGGT 151 TCAAGCAACT TGGAAGATGG GGTCCCATCA AGGTTCAGTG GCAGTAGATA 201 TGGGACAGAT TTCACTCTCA CCATCAGCAG CCTGGAGGAT GAAGATCTGG 251 CAACTFAT CTGTCTACAA CATAGTTATC TCCCGTACAC GITCGGAGGG 25 301 GGGACCAAGC TGGAAATAAA ACGGGCTGAT GCTGCACCAA CTGTATCCAT 351 CTTCCCACCA TCCAGTGAGC AGTIAACATC TGGAGGTGCC TCAGTCGTGT 401 GCTTCTTGAA CAACTFCTAC CCCAAAGACA TCAATGTCAA GTGGAAGATT 451 GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA CTGATCAGGA 501 CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG TTGACCAAGG 30 551 ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC TCACAAGACA 601 TCAACTTCAC CCATJGTCAA GAGCTTCAAC AGGAATGAGT GTTAG (SEQ ID NO:8) The amino acid sequence of Ab-D LC including signal peptide is as follows: 35 1 MNTRAPAEFL GFLLLWFLGA RCDVQMIQSP SSLSASLGDI VTMTCQASQG 51 TSINLNWFQQ KPGKAPKLLI YGSSNLEDGV PSRFSGSRYG TDFTLTSSL 101 EDEDLATYFC LQHSYLPYTF GGGTKLEIKR ADAAPTVSIF PPSSEQLTSG 151 GASVVCFLNN FYPKDINVKW KIDGSERQNG VLNSWTDQDS KDSTYSMSST 201 LTLTKDEYER HNSYTCEATH KTSTSPIVKS FNRNEC (SEQ ID NO:9) 40 Nucleic acid sequence of Ab-D LC including signal peptide encoding sequence: 1 ATGAACACGA GGGCCCCTGC TGAGTTCCTT GGGTTCCTGT TGCTCTGGTr 51 TTTAGGTGCC AGATGTGATG TCCAGATGAT TCAGTCTCCA TCCTCCCTGT 101 CTGCATCTTT GGGAGACATA GTCACCATGA CTTGCCAGGC AAGTCAGGGC SEA 1803911vl 60117-223 27 WO 2006/119062 PCT/US2006/016345 151 ACTAGCATTA ATTTAAACTG GTTCAGCAA AAACCAGGGA AGGCTCCTAA 201 GCTCCTGATC TATGGTTCAA GCAACTTGGA AGATGGGGTC CCATCAAGGT 251 TCAGTGGCAG TAGATATGGG ACAGATITCA CTCTCACCAT CAGCAGCCTG 301 GAGGATGAAG ATCTGGCAAC TrATTFTCTGT CTACAACATA GTfATCTCCC 5 351 GTACACGTTC GGAGGGGGGA CCAAGCTGGA AATAAAACGG GCTGATGCTG 401 CACCAACTGT ATCCATCTfC CCACCATCCA GTGAGCAGTT AACATCTGGA 451 GGTGCCTCAG TCGTGTGCTT CTTGAACAAC TTCTACCCCA AAGACATCAA 501 TGTCAAGTGG AAGATTGATG GCAGTGAACG ACAAAATGGC GTCCTGAACA 551 GTTGGACTGA TCAGGACAGC AAAGACAGCA CCTACAGCAT GAGCAGCACC 10 601 CTCACGTTGA CCAAGGACGA GTATGAACGA CATAACAGCT ATACCTGTGA 651 GGCCACTCAC AAGACATCAA CTTCACCCAT TGTCAAGAGC TTCAACAGGA 701 ATGAGTGTTA G (SEQ ID NO:10) The amino acid sequence of the mature form (signal peptide removed) of Ab-D 15 HC heavy chain is as follows: 1 EVQLQQSGPE LVTPGASVKI SCKASGYTFT -I J1WVKQS HGKSLEWIGl, 51 iPYSQEB'ifNQiF TATL TVDKSSSIAY MEIRGLTSED SAVYYCARqD 101 YDASPJAYWG QGTLVTVSAA KTTPPSVYPL APGSAAQTNS MVTLGCLVKG 151 YFPEPVTVTWNSGSLSSGVH TFPAVLQSDL YTLSSSVTVP SSTWPSETVT 20 201 CNVARPASSTKVDKUVPRD CGCKPCICTVPEVSSVFIFP PEPKDVLTIT 251 LTPKVTCVVVDISEDDPEVQ FSWFVDDVEVHTAQTQPREE QFNSTFRSVS 301 ELPMHQDWL NGKEFKCRVN SPAFPAPIEK TISKTKGRPKAPQVYTIPPP 351 EEQMAKDKVS LTCMITDFFP EDITVEWQWN GQPAENYKNT QPIMDTDGSY 401 FIYSELNVQK SNWEA GNTFT CSVLHEGLHN HHTEKSLSHS PGK (SEQ ID NO:11) 25 The nucleic acid sequence encoding the mature form (signal peptide removed) of Ab-D HC is: 1 GAGGTCCAGC TGCAACAGTC TGGACCTGAA CTGGTGACGC CTGGGGCTTC 51 AGTGAAGATA TCTTGTAAGG CTTCTGGATA CACATTCACT GACCACTACA 30 101 TGAGCTGGGT GAAGCAGAGT CATGGAAAAA GCCTTGAGTG GATTGGAGAT 151 ATTAATCCCT ATrCTGGTGA AACTACCTAC AACCAGAAGT TCAAGGGCAC 201 GGCCACATTG ACTGTAGACA AGTCTTCCAG TATAGCCTAC ATGGAGATCC 251 GCGGCCTGAC ATCTGAGGAC TCTGCAGTCT ATrACTGTGC AAGAGATGAT 301 TACGACGCCT CTCCGTTTGC TTACTGGGG3C CAAGGGACTC TGGTCACTGT 35 351 CTCTGCAGCC AAAACGACAC CCCCATCTGT CTATCCACTG GCCCCTGGAT 401 CTGCTGCCCA AACTAACTCC ATGGTGACCC TGGGATGCCT GGTCAAGGGC 451 TATITCCCTG AGCCAGTGAC AGTGACCTGG AACTCTGGAT CCCTGTCCAG 501 CGGTGTGCAC ACCTTCCCAG CTGTCCTGCA GTCTGACCTC TACACTCTGA 551 GCAGCTCAGT GACTGTCCCC TCCAGCACCT GGCCCAGCGA GACCGTCACC 40 601 TGCAACGTTG CCCACCCGGC CAGCAGCACC AAGGTGGACA AGAAAATrGT 651 GCCCAGGGAT TGTGGITGTA AGCCTTGCAT ATGTACAGTC CCAGAAGTAT 701 CATCTGTCTT CATCTTCCCC CCAAAGCCCA AGGATGTGCT CACCATTACT 751 CTGACTCCTA AGGTCACGTG TGTTGTGGTA GACATCAGCA AGGATGATCC 801 CGAGGTCCAG TFCAGCTGGT TTGTAGATGA TGTGGAGGTG CACACAGCTC 45 851 AGACGCAACC CCGGGAGGAG CAGTTCAACA GCACTTFCCG CTCAGTCAGT 901 GAACTTCCCA TCATGCACCA GGACTGGCTC AATGGCAAGG AGTTCAAATG 951 CAGGGTCAAC AGTCCAGCTT TCCCTGCCCC CATCGAGAAA ACCATCTCCA 1001 AAACCAAAGG CAGACCGAAG GCTCCACAGG TGTACACCAT TCCACCTCCC 1051 AAGGAGCAGA TGGCCAAGGA TAAAGTCAGT CTGACCTGCA TGATAACAGA SEA 1803911vl 60117-2 28 WO 2006/119062 PCT/US2006/016345 1101 CTTCTTCCCT GAAGACATrA CTGTGGAGTG GCAGTGOAAT GGGCAGCCAG 1151 CGGAGAACTA CAAGAACACT CAGCCCATCA TGGACACAGA TGGCTCTTAC 1201 TTCATCTACA GCAAGCTCAA TGTGCAGAAG AGCAACTGGG AGGCAGGAAA 1251 TACTTTCACC TGCTCTGTGT TACATGAGGG CCTGCACAAC CACCATACTG 5 1301 AGAAGAGCCT CTCCCACTCT CCTGGTAAAT GA (SEQ ID NO:12) The amino acid sequence of Ab-D HC including signal peptide is: 1 MRCRWIFLFL LSGTAGVLSE VQLQQSGPEL VTPGASVKIS CKASGYTFTD 51 HYMSWVKQSH GKSLEWIGDI NPYSGETTYN QKFKGTATLT VDKSSSIAYM 10 101 EIRGLTSEDS AVYYCARDDY DASPFAYWGQ GTLVTVSAAK TTPPSVYPLA 151 PGSAAQTNSM VTLGCLVKGY FPEPVTVTWN SGSLSSGVHT FPAVLQSDLY 201 TLSSSVTVPS STWPSETVTC NVAHPASSTK VDKKIVPRDC GCKPCICTVP 251 EVSSVFIFPP KPKDVLTITL TPKVTCVVVD ISKDDPEVQF SWFVDDVEVH 301 TAQTQPREEQ FNSTFRSVSE LPIMHQDWLN GKEFKCRVNS PAFPAPIEKT 15 351 ISKTKGRPKA PQVYTIPPPK EQMAKDKVSL TCMITDFFPE DITVEWQWNG 401 QPAENYKNTQ PIMDTDGSYF IYSKLNVQKS NWEAGNTFTC SVLHEGLHNH 451 HTEKSLSHSP GK (SEQ ID NO:13) The nucleic acid sequence of Ab-D HC including signal peptide encoding 20 sequence is: 1 ATGAGATGCA GGTGGATCTT TCTCTTTCTC CTGTCAGGAA CTGCAGGTGT 51 CCTCTCTGAG GTCCAGCTGC AACAGTCTGG ACCTGAACTG GTGACGCCTG 101 GGGCTTCAGT GAAGATATCT TGTAAGGCTT CTGGATACAC ATTCACTGAC 151 CACTACATGA GCTGGGTGAA GCAGAGTCAT GGAAAAAGCC TTGAGTGGAT 25 201 TGGAGATATT AATCCCTATT CTGGTGAAAC TACCTACAAC CAGAAGTTCA 251 AGGGCACGGC CACATTGACT GTAGACAAGT CTTCCAGTAT AGCCTACATG 301 GAGATCCGCG GCCTGACATC TGAGGACTCT GCAGTCTAT1 ACTGTGCAAG 351 AGATGATTAC GACGCCTCTC CGTITGCTTA CTGGGGCCAA GGGACTCTGG 401 TCACTGTCTC TGCAGCCAAA ACGACACCCC CATCTGTCTA TCCACTGGCC 30 451 CCTGGATCTG CTGCCCAAAC TAACTCCATG GTGACCCTGG GATGCCTGGT 501 CAAGGGCTAT TTCCCTGAGC CAGTGACAGT GACCTGGAAC TCTGGATCCC 551 TGTCCAGCGG TGTGCACACC TrCCCAGCTG TCCTGCAGTC TGACCTCTAC 601 ACTCTGAGCA GCTCAGTGAC TGTCCCCTCC AGCACCTGGC CCAGCGAGAC 651 CGTCACCTGC AACGTTGCCC ACCCGGCCAG CAGCACCAAG GTGGACAAGA 35 701 AAATTGTGCC CAGGGATTGT GGTTGTAAGC CTTGCATATG TACAGTCCCA 751 GAAGTATCAT CTGTCTTCAT CTTCCCCCCA AAGCCCAAGG ATGTGCTCAC 801 CATTACTCTG ACTCCTAAGG TCACGTGTGT TGTGGTAGAC ATCAGCAAGG 851 ATGATCCCGA GGTCCAGTTC AGCTGGTTTG TAGATGATGT GGAGGTGCAC 901 ACAGCTCAGA CGCAACCCCG GGAGGAGCAG TICAACAGCA CTTTCCGCTC 40 951 AGTCAGTGAA CTTCCCATCA TGCACCAGGA CTGGCTCAAT GGCAAGGAGT 1001 TCAAATGCAG GGTCAACAGT CCAGCTTTCC CTGCCCCCAT CGAGAAAACC 1051 ATCTCCAAAA CCAAAGGCAG ACCGAAGGCT CCACAGGTGT ACACCATTCC 1101 ACCTCCCAAG GAGCAGATGG CCAAGGATAA AGTCAGTCTG ACCTGCATGA 1151 TAACAGACTr CTTCCCTGAA GACATTACTG TGGAGTGGCA GTGGAATGGG 45 1201 CAGCCAGCGG AGAACTACAA GAACACTCAG CCCATCATGG ACACAGATGG 1251 CTCTTACTTC ATCTACAGCA AGCTCAATGT GCAGAAGAGC AACTGGGAGG 1301 CAGGAAATAC TTTCACCTGC TCTGTGTTAC ATGAGGGCCT GCACAACCAC 1351 CATACTGAGA AGAGCCTCTC CCACTCTCCT GGTAAATGA (SEQ ID NO:14) SEA 1803911v 60117-223 29 WO 2006/119062 PCT/US2006/016345 The CDR (complementarity determining region) sequences in the variable region of the heavy chain of Ab-D are as follows: CDR-H1: DHYMS (SEQ ID NO:39) CDR-H2: DINPYSGETTYNQKFKG (SEQ ID NO:40) 5 CDR-H3: DDYDASPFAY (SEQ ID NO:41) The light chain variable region CDR sequences of Ab-D are: CDR-L1: QASQGTSINLN (SEQ ID NO:42) CDR-L2: GSSNLED (SEQ ID NO:43) CDR-L3: LQHSYLPYT (SEQ ID NO:44) 10 Ab-C Antibody C (also referred to herein as Ab-C and Mab-C) is a mouse antibody which exhibits high affinity binding to sclerostin. The BlAcore binding pattern of Ab-C is shown in Figure 17. The amino acid sequence of the mature form (signal peptide removed) of 15 Ab-C Light Chain is as follows: 1 DIVLTQSPAS LTVSLGLRAT ISC4SKSDYDGDSYMNIWY QQKPGQPPKL 51 LIYWASTLAS GIPARFSGNG SGTDFTLNIH PVEEEDAVTY YCQSN]5W 101 IFGGGT KLEI KRADAAPTVS IFPPSSEQL T SGGASVVCFL NNFYPKDINV 151 KWKIDGSERQ NG VLNSWTDQ DSKDSTYSMS STLTLTKDEY ERHNSYTCEA 20 201 THKTSTSPIV KSFNRNEC (SEQ ID NO:15) The nucleic acid sequence encoding the mature form (signal peptide removed) of Ab-C LC is: 1 GACATTGTGC TGACCCAATC TCCAGCTTCT TTGACTGTGT CTCTAGGCCT 25 51 GAGGGCCACC ATCTCCTGCA AGGCCAGCCA AAGTGTTGAT TATGATGGTG 101 ATAGITATAT GAACTGGTAC CAGCAGAAAC CAGGACAGCC ACCCAAACTC 151 CTCATCTATG CTGCATCCAA TCTAGAATCT GGGATCCCAG CCAGGITAG 201 TGGCAATGGG TCTGGGACAG ACTTCACCCT CAACATCCAT CCTGTGGAGG 251 AGGAGGATGC TGTAACCTAT TACTGTCAAC AAAGTAATGA GGATCCGTGG 30 301 ACGTTCGGTG GAGGCACCAA GCTGGAAATC AAACGGGCTG ATGCTGCACC 351 AACTGTATCC ATCTTCCCAC CATCCAGTGA GCAGTTAACA TCTGGAGGTG 401 CCTCAGTCGT GTGCTTCTTG AACAACTTCT ACCCCAAAGA CATCAATGTC 451 AAGTGGAAGA TTGATGGCAG TGAACGACAA AATGGCGTCC TGAACAGTTG 501 GACTGATCAG GACAGCAAAG ACAGCACCTA CAGCATGAGC AGCACCCTCA 35 551 CGTrGACCAA GGACGAGTAT GAACGACATA ACAGCTATAC CTGTGAGGCC 601 ACTCACAAGA CATCAACTTC ACCCATTGTC AAGAGCTTCA ACAGGAATGA 651 GTGTTAG (SEQ ID NO:16) The amino acid sequence of Ab-C LC including signal peptide is: 40 1 METDTILLWV LLLWVPGSTG DIVLTQSPAS LTVSLGLRAT ISCKASQSVD 51 YDGDSYMNWY QQKPGQPPKL LIYAASNLES GIPARFSGNG SGTDFTLNIH 101 PVEEEDAVTY YCQQSNEDPW TFGGGTKLEI KRADAAPTVS IFPPSSEQLT SEA 1803911v1 60117-23 30 WO 2006/119062 PCTIUS2006/016345 151 SGGASVVCFL NNFYPKDINV KWKIDGSERQ NGVLNSWTDQ DSKDSTYSMS 201 STLTLTKDEY ERHNSYTCEA THKTSTSPIV KSFNRNEC (SEQ ID NO:17) The nucleic acid sequence of Ab-C LC including signal peptide encoding 5 sequence is: 1 ATGGAGACAG ACACAATCCT GCTATGGGTG CTGCTGCTCT GGGTTCCAGG 51 CTCCACTGGT GACATTGTGC TGACCCAATC TCCAGCITCT TTGACTGTGT 101 CTCTAGGCCT GAGGGCCACC ATCTCCTGCA AGGCCAGCCA AAGTGTTGAT 151 TATGATGGTG ATAGTTATAT GAACTGGTAC CAGCAGAAAC CAGGACAGCC 10 201 ACCCAAACTC CTCATCTATG CTGCATCCAA TCTAGAATCT GGGATCCCAG 251 CCAGGTTTAG TGGCAATGGG TCTGGGACAG ACTTCACCCT CAACATCCAT 301 CCTGTGGAGG AGGAGGATGC TGTAACCTAT TACTGTCAAC AAAGTAATGA 351 GGATCCGTGG ACGTTCGGTG GAGGCACCAA QCTGGAAATC AAACGGGCTG 401 ATGCTGCACC AACTGTATCC ATCTTCCCAC CATCCAGTGA GCAGTTAACA 15 451 TCTGGAGGTG CCTCAGTCGT GTGCTTCTTG AACAACTTCT ACCCCAAAGA 501 CATCAATGTC AAGTGGAAGA TrGATGGCAG TGAACGACAA AATGGCGTCC 551 TGAACAGTTG GACTGATCAG GACAGCAAAG ACAGCACCTA CAGCATGAGC 601 AGCACCCTCA CGITGACCAA GGACGAGTAT GAACGACATA ACAGCTATAC 651 CTGTGAGGCC ACTCACAAGA CATCAACTTC ACCCATTGTC AAGAGCTTCA 20 701 ACAGGAATGA GTGTTAG (SEQ ID NO:18) Ab-C Heavy Chain The amino acid sequence of the mature form (signal peptide removed) of Ab-C HC is: 25 1 EVQLQQSGPE LVKPGTSVKM SCKASGYTFT lYMNWVKQS HGKSLEWIGO 51 3t fNGNili-9lidlkATL TVDKSSSTAY MQLNSLTSDD SAVYYCARNfl 10 1FYYI6GRV P P MDjWGQGTS VTVSSAKTTP PSVYPL4PGS AAQTNSMVTL 151 GCLVKGYFPE PVTVTWNSGS LSSGVHTFPA VLQSDLYTLS SSVTVPSSTW 201 PSETVTCNVA HPASSTKVDK KVPRDCGCK PCICTVPEVS SVFIFPPKPK 30 251 DVLTITLTPK VTCVVVDISKDDPEVQFSWF VDDVEVHTAQ TQPREEQFNS 301 TFRSVSELPI MHQDWLNGEE FKCRVNSAA F PAPIEKTISK TKGRPKAPQV 351 YTIPPPKEQMAKDKVSLTCMITDFFPEDIT VEWQWNGQPA ENYENTQPJM 401 DTDGSYFIYS KLNVQKSNWE AGNTFTCSVL HEGLHNHHTE KSLSHSPGK (SEQ ID NO:19) 35 The nucleic acid sequence encoding the mature form (signal peptide removed) of Ab-C HC is as follows: 1 GAGGTCCAGC TGCAACAATC TGGACCTGAG CTGGTGAAGC CTGGGACTTC 51 AGTGAAGATG TCCTGTAAGG CTTCTGGATA CACATCACT GACTGCTACA 40 101 TGAACTGGGT GAAGCAGAGC CATGGGAAGA GCCTIGAATG GATTGGAGAT 151 ATTAATCCTT TCAACGGTGG TACTACCTAC AACCAGAAGT TCAAGGGCAA 201 GGCCACATTG ACTGTAGACA AATCCTCCAG CACAGCCTAC ATGCAGCTCA 251 ACAGCCTGAC ATCTGACGAC TCTGCAGTCT ATTACTGTGC AAGATCCCAT 301 TATTACTTCG ATGGTAGAGT CCCTTGGGAT GCTATGGACT ACTGGGGTCA 45 351 AGGAACCTCA GTCACCGTCT CCTCAGCCAA AACGACACCC CCATCTGTCT 401 ATCCACTGGC CCCTGGATCT GCTGCCCAAA CTAACTCCAT GGTGACCCTG 451 GGATGCCTGG TCAAGGGCTA TTTCCCTGAG CCAGTGACAG TGACCTGGAA SEA 1803911v 60117-223 31 WO 2006/119062 PCT/US2006/016345 501 CTCTGGATCC CTGTCCAGCG GTGTGCACAC CTTCCCAGCT GTCCTGCAGT 551 CTGACCTCTA CACTCTGAGC AGCTCAGTGA CTGTCCCCTC CAGCACCTGG 601 CCCAGCGAGA CCGTCACCTG CAACGITGCC CACCCGGCCA GCAGCACCAA 651 GGTGGACAAG AAAAITGTGC CCAGGGATTG TGGTTGTAAG CCTTGCATAT 5 701 GTACAGTCCC AGAAGTATCA TCTGTCTTCA TCTTCCCCCC AAAGCCCAAG 751 GATGTGCTCA CCATTACTCT GACTCCTAAG GTCACGTGTG TTGTGGTAGA 801 CATCAGCAAG GATGATCCCG AGGTCCAGTr CAGCTGGTIT GTAGATGATG 851 TGGAGGTGCA CACAGCTCAG ACGCAACCCC GGGAGGAGCA GTTCAACAGC 901 ACYTTCCGCT CAGTCAGTGA ACTTCCCATC ATGCACCAGG ACTGGCTCAA 10 951 TGGCAAGGAG TICAAATGCA GGGTCAACAG TGCAGCTTTC CCTGCCCCCA 1001 TCGAGAAAAC CATCTCCAAA ACCAAAGGCA GACCGAAGGC TCCACAGGTG 1051 TACACCATTC CACCTCCCAA GAGCAGATG GCCAAGGATA AAGTCAGTCT 1101 GACCTGCATG ATAACAGACT TCTTCCCTGA AGACATTACT GTGGAGTGGC 1151 AGTGGAATGG GCAGCCAGCG GAGAACTACA AGAACACTCA GCCCATCATG 15 1201 GACACAQATG GCTCTTACTT CATCTACAGC AAGCTCAATG TGCAGAAGAG 1251 CAACTGGGAG GCAGGAAATA CTITCACCTG CTCTGTGTTA CATGAGGGCC 1301 TGCACAACCA CCATACTGAG AAGAGCCTCT CCCACTCTCC TGGTAAATGA (SEQ ID NO:20) 20 The amino acid sequence of Ab-C HC including signal peptide is: 1 MGWNWIFLFL LSGTAGVYSE VQLQQSGPEL VKPGTSVKMS CKASGYTFTD 51 CYMNWVKQSH GKSLEWIGDI NPFNGGTYN QKFKGKATLT VDKSSSTAYM 101 QLNSLTSDDS AVYYCARSHY YFDGRVPWDA MDYWGQGTSV TVSSAKTMPP 151 SVYPLAPGSA AQTNSMVTLG CLVKGYFPEP VTVTWNSGSL SSGVHTFPAV 25 201 LQSDLYTLSS SVTVPSSTWP SETVTCNVAH PASSTKVDKK IVPRDCGCKP 251 CICTVPEVSS VFIFPPKPKD VLTITLTPKV TCVVVDISKD DPEVQFSWFV 301 DDVEVHTAQT QPREEQFNST FRSVSELPIM HQDWLNGKEF KCRVNSAAFP 351 APIEKTISKT KGRPKAPQVY TIPPPKEQMA KDKVSLTCMI TDFFPEDITV 401 EWQWNGQPAE NYKNTQPIMD TDGSYFIYSK LNVQKSNWEA GNTFTCSVLH 30 451 EGLHNHHTEK SLSHSPGK (SEQ ID NO:21) The nucleic acid sequence of Ab-C HC including signal peptide encoding sequence is: 1 ATGGGATGGA ACTGGATCTT TCTCTTCCTC TTGTCAGGAA CTGCAGGTGT 35 51 CTACTCTGAG GTCCAGCTGC AACAATCTGG ACCTGAGCTG GTGAAGCCTG 101 GGACTCAGT GAAGATGTCC TGTAAGGCTT CTGGATACAC ATTCACTGAC 151 TGCTACATGA ACTGGGTGAA GCAGAGCCAT GGGAAGAGCC TTGAATGGAT 201 TGGAGATATT AATCCTTTCA ACGGTGGTAC TACCTACAAC CAGAAGTTCA 251 AGGGCAAGGC CACATTGACT GTAGACAAAT CCTCCAGCAC AGCCTACATG 40 301 CAGCTCAACA GCCTGACATC TGACGACTCT GCAGTCTATT ACTGTGCAAG 351 ATCCCATrAT TACTTCGATG GTAGAGTCCC TTGGGATGCT ATGGACTACT 401 GGGGTCAAGG AACCTCAGTC ACCGTCTCCT CAGCCAAAAC GACACCCCCA 451 TCTGTCTATC CACTGGCCCC TGGATCTGCT GCCCAAACTA ACTCCATGGT 501 GACCCTGGGA TGCCTGGTCA AGGGCTATTT CCCTGAGCCA GTGACAGTGA 45 551 CCTGGAACTC TGGATCCCTG TCCAGCGGTG TGCACACCTT CCCAGCTGTC 601 CTGCAGTCTG ACCTCTACAC TCTGAGCAGC TCAGTGACTG TCCCCTCCAG 651 CACCTGGCCC AGCGAGACCG TCACCTGCAA CGTTGCCCAC CCGGCCAGCA 701 GCACCAAGGT GGACAAGAAA ATTGTGCCCA GGGATTGTGG TTGTAAGCCT 751 TGCATATGTA CAGTCCCAGA AGTATCATCT GTCTTCATCT TCCCCCCAAA 50 801 GCCCAAGGAT GTGCTCACCA TTACTCTGAC TCCTAAGGTC ACGTGTGTTG SEA 1803911vi 60117-nm 32 WO 2006/119062 PCTIUS2006/016345 851 TGGTAGACAT CAGCAAGGAT GATCCCGAGG TCCAGTTCAG CTGGTTTGTA 901 GATGATGTGG AGGTGCACAC AGCTCAGACG CAACCCCGGG AGGAGCAGTr 951 CAACAGCACT TTCCGCTCAG TCAGTGAACT TCCCATCATG CACCAGGACT 1001 GGCTCAATGG CAAGGAGTTC AAATGCAGGG TCAACAGTGC AGCYTfCCCT 5 1051 GCCCCCATCG AGAAAACCAT CTCCAAAACC AAAGGCAGAC CGAAGGCTCC 1101 ACAGGTGTAC ACCATTCCAC CTCCCAAGGA GCAGATGGCC AAGGATAAAG 1151 TCAGTCTGAC CTGCATGATA ACAGACTrCT TCCCTGAAGA CATTACTGTG 1201 GAGTGGCAGT GGAATGGGCA GCCAGCGGAG AACTACAAGA ACACTCAGCC 1251 CATCATGGAC ACAGATGGCT CTFACTTCAT CTACAGCAAG CTCAATGTGC 10 1301 AGAAGAGCAA CTGGGAGGCA GGAAATACTT TCACCTGCTC TGTGTTACAT 1351 GAGGGCCTGC ACAACCACCA TACTGAGAAG AGCCTCTCCC ACTCTCCTGG 1401 TAAATGA (SEQ ID NO:22) The CDR (complementarity determining region) sequences in the variable region 15 of the heavy chain of Ab-C are as follows: CDR-H1: DCYMN (SEQ ID NO:45) CDR-H2: DINPFNGGTTYNQKFKG (SEQ ID NO:46) CDR-H3: SHYYFDGRVPWDAMDY (SEQ ID NO:47) The light chain variable region CDR sequences of Ab-C are: 20 CDR-L1: KASQSVDYDGDSYMN (SEQ ID NO:48) CDR-L2: AASNLES (SEQ ID NO:49) CDR-L3: QQSNEDPWT (SEQ ID NO:50) Ab-A 25 Antibody A (also referred to herein as Ab-A and Mab-A) is a rabbit-mouse chimeric antibody which exhibits high affinity binding to sclerostin. The BIAcore binding pattern of Ab-A is shown in Figure 15. Ab-A Light Chain 30 The amino acid sequence of the mature form (signal peptide removed) of Ab-A LC: 1 AQVLTQTPAS VSAAVGGTVT INCQSSiY WFQQ KPGPPLLI 51 Y'DtASGV PSRFSGSGSG TQFTLTISGV QCADAATYYC QGAYNDVWA 35 101 FGGTEVVK R TDAAPTVSI FPPSSEQLTS GGASVVCFLNNFYPKDINVK 151 WKJDGSERQNGVLNSWTDQD SKDSTYSMSS TLTLTKDEYE RHNSYTCEAT 201 HKTSTSPIVKSFNRNEC (SEQ ID NO:23) The nucleic acid sequence encoding the mature form (signal peptide removed) of 40 Ab-A LC: 1 GCGCAAGTGC TGACCCAGAC TCCAGCCTCC GTGTCTGCAG CTGTGGGAGG SEA 1803911v 60117-22 33 WO 2006/119062 PCT/US2006/016345 51 CACAGTCACC ATCAATTGCC AGTCCAGTCA GAGTGTTTAT GATAACAACT 101 GGTTAGCCTG GTTrCAGCAG AAACCAGGGC AGCCTCCCAA GCTCCTGATT 151 TATGATGCAT CCGATCTGGC ATCTGGGGTC CCATCGCGGT TCAGTGGCAG 201 TGGATCTGGG ACACAGTTCA CTCTCACCAT CAGCGGCGTG CAGTGTGCCG 5 251 ATGCTGCCAC TTACTACTGT CAAGGCGCTT ATAATGATGT TATITATGCT 301 TTCGGCGGAG GGACCGAGGT GGTGGTCAAA CGTACGGATG CTGCACCAAC 351 TGTATCCATC TTCCCACCAT CCAGTGAGCA GTfAACATCT GGAGGTGCCT 401 CAGTCGTGTG CTrCTTGAAC AACTTCTACC CCAAAGACAT CAATGTCAAG 451 TGGAAGATrG ATGGCAGTGA ACGACAAAAT GGCGTCCTGA ACAGTTGGAC 10 501 TGATCAGGAC AGCAAAGACA GCACCTACAG CATGAGCAGC ACCCTCACGT 551 TGACCAAGGA CGAGTATGAA CGACATAACA GCTATACCTG TGAGGCCACT 601 CACAAGACAT CAACTCACC CATTGTCAAG AGCTTCAACA GGAATGAGTG 651 TTAG (SEQ ID NO:24) 15 The amino acid sequence of Ab-A LC including signal peptide is: 1 MDTRAPTQLL GLLLLWLPGA TFAQVLTQTP ASVSAAVGGT VTINCQSSQS 51 VYDNNWLAWF QQKPGQPPKL L1YDASDLAS GVPSRFSGSG SGTQFTLTIS 101 GVQCADAATY YCQGAYNDVI YAFGGGTEVV VKRTDAAPTV SIFPPSSEQL 151 TSGGASVVCF LNNFYPKDIN VKWKIDGSER QNGVLNSWTD QDSKDSTYSM 20 201 SSTLTLTKDE YERHNSYTCE ATHKTSTSPI VKSFNRNEC (SEQ ID NO:25) The nucleic acid sequence of Ab-A LC including signal peptide encoding sequence is: 1 ATGGACACGA GGGCCCCCAC TCAGCTGCTG GGGCTCCTGC TGCTCTGGCT 25 51 CCCAGGTGCC ACATITGCGC AAGTGCTGAC CCAGACTCCA GCCTCCGTGT 101 CTGCAGCTGT GGGAGGCACA GTCACCATCA ATTGCCAGTC CAGTCAGAGT 151 GTLTATGATA ACAACTGGTT AGCCTGGTIT CAGCAGAAAC CAGGGCAGCC 201 TCCCAAGCTC CTGAYfTATG ATGCATCCGA TCTGGCATCT GGGGTCCCAT 251 CGCGGTTCAG TGGCAGTGGA TCTGGGACAC AGTTCACTCT CACCATCAGC 30 301 GGCGTGCAGT GTGCCGATGC TGCCACTTAC TACTGTCAAG GCGCTTATAA 351 TGATGTTATT TATGCTfTCG GCGGAGGGAC CGAGGTGGTG GTCAAACGTA 401 CGGATGCTGC ACCAACTGTA TCCATCTTCC CACCATCCAG TGAGCAGTTA 451 ACATCTGGAG GTGCCTCAGT CGTGTGCTTC TTGAACAACT TCTACCCCAA 501 AGACATCAAT GTCAAGTGGA AGATTGATGG CAGTGAACGA CAAAATGGCG 35 551 TCCTGAACAG TTGGACTGAT CAGGACAGCA AAGACAGCAC CTACAGCATG 601 AGCAGCACCC TCACGTfGAC CAAGGACGAG TATGAACGAC ATAACAGCTA 651 TACCTGTGAG GCCACTCACA AGACATCAAC TTCACCCATr GTCAAGAGCT 701 TCAACAGGAA TGAGTGTTAG (SEQ ID NO:26) 40 The amino acid sequence of the mature form (signal peptide removed) of Ab-A HC is: 1 QSLEESGGRL VTPGTPLTLT CTASGFSLSS YiliWVRQAP GEGLEWIGt 51 USGGffiYAS WAkGRFTISR TSTMDLKMT SLTTGDTARY FCAR~W--W G 101 QGT iTV 5ASTKGPS VYPL APGSA AQTNS MVTLGCLVKG YFPEPVTVTW 45 151 NSGSLSSGVH TFPA VLQSDL YTLSSSVTVP SSTWPSETVT CNVAHPASST 201 KVDEKIVPRD CGCKPCICTV PEVSSVFIFP PKPKD VLTIT LTPKVTCVVV 251 DISKDDPEVQ FSWFVDDVEV HTAQTQPREE QFNSTFRSVS ELPIMHQDWL 301 NGKE FKCR VN SAA FPAPIEK TISKTKGRPK APQ VYTIPPP KEQMAKDKVS 351 LTCMhTDFFP EDITVE WQ WN GQPAENYKNT QPIMNTNGSY FVYSKLNVQK SEA 1803911v1 60117-2M 34 WO 2006/119062 PCT/US2006/016345 401 SNWE AGNTFT CSVLHEGLHNHHTEKSLSHS PGK(SEQ ID NO:27) The nucleic acid sequence encoding the mature form (signal peptide removed) of Ab-A HC: 5 1 CAGTCGCTGG AGGAGTCCGG GGGTCGCCTG GTCACGCCTG GGACACCCCT 51 GACACTCACC TGCACAGCCT CTGGATTCTC CCTCAGTAGT TATTGGATGA 101 ACTGGGTCCG CCAGGCTCCA GGGGAGGGGC TGGAATGGAT CGGAACCATT 151 GATTCTGGTG GTAGGACGGA CTACGCGAGC TGGGCAAAAG GCCGATTCAC 201 CATCTCCAGA ACCTCGACTA CGATGGATCT GAAAATGACC AGTCTGACGA 10 251 CCGGGACAC GGCCCGTTAT TTCTGTGCCA GAAATTGGAA CTTGTGGGGC 301 CAAGGCACCC TCGTCACCGT CTCGAGCGCT TCTACAAAGG GCCCATCTGT 351 CTATCCACTG GCCCCTGGAT CTGCTGCCCA AACTAACTCC ATGGTGACCC 401 TGGGATGCCT GGTCAAGGGC TATTTCCCTG AGCCAGTGAC AGTGACCTGG 451 AACTCTGGAT CCCTGTCCAG CGGTGTGCAC ACCTTCCCAG CTGTCCTGCA 15 501 GTCTGACCTC TACACTCTGA GCAGCTCAGT GACTGTCCCC TCCAGCACCT 551 GGCCCAGCGA GACCGTCACC TGCAACGTTG CCCACCCGGC CAGCAGCACC 601 AAGGTGGACA AGAAAATTGT GCCCAGGGAT TGTGGTTGTA AGCCTTGCAT 651 ATGTACAGTC CCAGAAGTAT CATCTGTCTT CATCTTCCCC CCAAAGCCCA 701 AGGATGTGCT CACCATIACT CTGACTCCTA AGGTCACGTG TGTTGTGGTA 20 751 GACATCAGCA AGGATGATCC CGAGGTCCAG TTCAGCTGGT TTGTAGATGA 801 TGTGGAGGTG CACACAGCTC AGACGCAACC CCGGGAGGAG CAGTTCAACA 851 GCACTTTCCG CTCAGTCAGT GAACTTCCCA TCATGCACCA GGACTGGCTC 901 AATGGCAAGG AGTTCAAATG CAGGGTCAAC AGTGCAGCTf TCCCTGCCCC 951 CATCGAGAAA ACCATCTCCA AAACCAAAGG CAGACCGAAG GCTCCACAGG 25 1001 TGTACACCAT TCCACCTCCC AAGGAGCAGA TGGCCAAGGA TAAAGTCAGT 1051 CTGACCTGCA TGATAACAGA CTTCIfCCCT GAAGACATTA CTGTGGAGTG 1101 GCAGTGGAAT GGGCAGCCAG CGGAGAACTA CAAGAACACT CAGCCCATCA 1151 TGGACACAGA TGGCTCTTAC TTCGTCTACA GCAAGCTCAA TGTGCAGAAG 1201 AGCAACTGGG AGGCAGGAAA TACTTFCACC TGCTCTGTGT TACATGAGGG 30 1251 CCTGCACAAC CACCATACTG AGAAGAGCCT CTCCCACTCT CCTGGTAAAT 1301 GA (SEQ ID NO:28) The amino acid sequence of the Ab-A HC including signal peptide is: 1 METGLRWLLL VAVLKGVHCQ SLEESGGRLV TPGTPLTLTC TASGFSLSSY 35 51 WMNWVRQAPG EGLEWIGTID SGGRTDYASW AKGRFTISRT STEMDLKMTS 101 LTTGDTARYF CARNWNLWGQ GTLVTVSSAS TKGPSVYPLA PGSAAQTNSM 151 VTLGCLVKGY FPEPVTVTWN SGSLSSGVHT FPAVLQSDLY TLSSSVTVPS 201 STWPSETVTC NVAHPASSTK VDKKIVPRDC GCKPCICTVP EVSSVFIFPP 251 KPKDVLTITL TPKVTCVVVD ISKDDPEVQF SWFVDDVEVH TAQTQPREEQ 40 301 FNSTFRSVSE LPIMHQDWLN GKEFKCRVNS AAFPAPIEKT ISKTKGRPKA 351 PQVYTIPPPK EQMAKDKVSL TCMITDFFPE DITVEWQWNG QPAENYKNTQ 401 PIMNTNGSYF VYSKLNVQKS NWEAGNTFTC SVLHEGLHNH HTEKSLSHSP 451 GK (SEQ ID NO:29) 45 The nucleic acid sequence of Ab-A HC including signal peptide encoding sequence: 1 ATGGAGACTG GGCTGCGCTG GCTTCTCCTG GTCGCTGTGC TCAAAGGTGT 51 CCACTGTCAG TCGCTGGAGG AGTCCGGGGG TCGCCTGGTC ACGCCTGGGA 101 CACCCCTGAC ACTCACCTGC ACAGCCTCTG GATTCTCCCT CAGTAGTTAT SEA 180391 lvI 60117-22 35 WO 2006/119062 PCTIUS2006/016345 151 TGGATGAACT GGGTCCGCCA GGCTCCAGGG GAGGGGCTGG AATGGATCGG 201 AACCATIGAT TCTGGTGGTA GGACGGACTA CGCGAGCTGG GCAAAAGGCC 251 GATTCACCAT CTCCAGAACC TCGACTACGA TGGATCTGAA AATGACCAGT 301 CTGACGACCG GGGACACGGC CCGTTATTTC TGTGCCAGAA ATTGGAACTT 5 351 GTGGGGCCAA GGCACCCTCG TCACCGTCTC GAGCGCTTCT ACAAAGGGCC 401 CATCTGTCTA TCCACTGGCC CCTGGATCTG CTGCCCAAAC TAACTCCATG 451 GTGACCCTGG GATGCCTGGT CAAGGGCTAT TTCCCTGAGC CAGTGACAGT 501 GACCTGGAAC TCTGGATCCC TGTCCAGCGG TGTGCACACC TTCCCAGCTG 551 TCCTGCAGTC TGACCTCTAC ACTCTGAGCA GCTCAGTGAC TGTCCCCTCC 10 601 AGCACCTGGC CCAGCGAGAC CGTCACCTGC AACGTTGCCC ACCCGGCCAG 651 CAGCACCAAG GTGGACAAGA AAATTGTGCC CAGGGATTGT GGTrGTAAGC 701 CTTGCATATG TACAGTCCCA GAAGTATCAT CTGTCTTCAT CTTCCCCCCA 751 AAGCCCAAGG ATGTGCTCAC CATTACTCTG ACTCCTAAGG TCACGTGTGT 801 TGTGGTAGAC ATCAGCAAGG ATGATCCCGA GGTCCAGITC AGCTGGTTTG 15 851 TAGATGATGT GGAGGTGCAC ACAGCTCAGA CGCAACCCCG GGAGGAGCAG 901 TTCAACAGCA CTITCCGCTC AGTCAGTGAA CTTCCCATCA TGCACCAGGA 951 CTGGCTCAAT GGCAAGGAGT TCAAATGCAG GGTCAACAGT GCAGCTJTCC 1001 CTGCCCCCAT CGAGAAAACC ATCTCCAAAA CCAAAGGCAG ACCGAAGGCT 1051 CCACAGGTGT ACACCATTCC ACCTCCCAAG GAGCAGATGG CCAAGGATAA 20 1101 AGTCAGTCTG ACCTGCATGA TAACAGACTf CTTCCCTGAA GACATTACTG 1151 TGGAGTGGCA GTGGAATGGG CAGCCAGCGG AGAACTACAA GAACACTCAG 1201 CCCATCATGG ACACAGATGG CTCTTACTTC GTCTACAGCA AGCTCAATGT 1251 GCAGAAGAGC AACTGGGAGG CAGGAAATAC TTTCACCTGC TCTGTGTTAC 1301 ATGAGGGCCT GCACAACCAC CATACTGAGA AGAGCCTCTC CCACTCTCCT 25 1351 GGTAAATGA (SEQ ID NO:30) The CDR (complementarity determining region) sequences in the variable region of the heavy chain of Ab-A are as follows: 30 CDR-H1: SYWMN (SEQ ID NO:51) CDR-H2: TIDSGGRTDYASWAKG (SEQ ID NO:52) CDR-H3: NWNL (SEQ ID NO:53) The light chain variable region CDR sequences of Ab-A are: CDR-L1: QSSQSVYDNNWLA (SEQ ID NO:54) 35 CDR-L2: DASDLAS (SEQ ID NO:55) CDR-L3: QGAYNDVIYA (SEQ ID NO:56) -Ab-A was humanized, and is referred to as Antibody 1 (also referred to herein as Ab-1), having the following sequences: 40 The nucleic acid sequence of the Ab- 1 LC variable region including signal peptide encoding sequence is ATGGACACGAGGGCCCCCACTCAGCTGCTGGGGCTCCTGCTGCTCTGGCTCCCAGGT 45 GCCACATTrGCTCAAGTTCTGACCCAGAGTCCAAGCAGTCTCTCCCCAGCGTAGGC SEA 1803911yI 60117-223 36 WO 2006/119062 PCT/US2006/016345 GATCGTGTGACTATTACCTGTCAATCTAGTCAGAGCGTGTATGATAACAATTGGCTG GCGTGGTACCAGCAAAAACCGGGCAAAGCCCCGAAGCTGCTCATCTATGACGCGTC CGATCTGGCTAGCGGTGTGCCAAGCCGTITCAGTGGCAGTGGCAGCGGTACTGACT TrACCCTCACAATITCGTCTCTCCAGCCGGAAGATTTCGCCACTTACTATrGTCAAG 5 GTGCTrACAACGATGTGATTATGCCTTCGGTCAGGGCACTAAAGTAGAAATCAAA CGT (SEQ ID NO:74) The amino acid sequence of Ab-1 LC variable region including signal peptide is: 10 MDTRAPTOLLGLLLLWLPGATFAQVLTQSPSSLSASVGDRVTITC-5$Q5YiNINWL WYQQKPGKAPKLLIYDSDGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQGAYN DYVAFGQGTKVEIKR (SEQ ID NO:75) 15 The nucleic acid sequence of Ab-1 HC variable region including signal peptide encoding sequence is: ATGGAGACTGGGCTGCGCTGGCTTCTCCTGGTCGCTGTGCTCAAAGGTGTCCACTGT GAGGTGCAGCTGTTGGAGTCTGGAGGCGGGCTTGTCCAGCCTGGAGGGAGCCTGCG 20 TCTCTCTTGTGCAGCAAGCGGCTTCAGCTTATCCTCTTACTGGATGAATTGGGTGCG GCAGGCACCTGGGAAGGGCCTGGAGTGGGTGGGCACCATTGATTCCGGAGGCCGTA CAGACTACGCGTCTTGGGCAAAGGGCCGTTTCACCATTTCCCGCGACAACTCCAAA AATACCATGTACCTCCAGATGAACTCTCTCCGCGCAGAGGACACAGCACGTTATTA CTGTGCACGCAACTGGAATCTGTGGGGTCAAGGTACTCTTGTAACAGTCTCGAGC 25 (SEQ ID NO:76) Amino acid sequence of Ab-1 HC variable region including signal peptide METGLRWLLLVAVLKGVHCEVQLLESGGGLVQPGGSLRLSCAASGFSLSKYWMNWVR 30 QAPGKGLEWVGTEDa S fXdRF TISRDNSKNTMYLQMNSLRAEDTARYYC A4IWMWGQGTLVTVSS (SEQ IDNO:77) The CDR (complementarity determining region) sequences in the variable region of the heavy chain of Ab-1 are as follows: 35 CDR-H1: SYWMN (SEQ ID NO:51) CDR-H2: TIDSGGRTDYASWAKG (SEQ ID NO:52) CDR-H3: NWNL (SEQ ID NO:53) The light chain variable region CDR sequences of Ab-1 are: CDR-L1: QSSQSVYDNNWLA (SEQ ID NO:54) 40 CDR-L2: DASDLAS (SEQ ID NO:55) CDR-L3: QGAYNDVIYA (SEQ ID NO:56) Ab-B SEA 180391M 60117-23 37 WO 2006/119062 PCT/US2006/016345 Antibody B (also referred to herein as Ab-B and Mab-B) is a mouse antibody which exhibits high affinity binding to sclerostin. The BIAcore binding pattern of Ab-B is shown in Figure 16. 5 Ab-B Light Chain The amino acid sequence of the mature form (signal peptide removed) of the Ab B LC is: 1 QIVLTQSPTI VSASPGEKVT LICOASSSYS FVo3FQQKPG TSPKRWIYON 10 51 SNILFdGVPAR FSGGGSGTSH SLTISRMEAE DAATYYCQQR.STY PTFGAG 101 TkiJLKRADA APTVSIFPPS SEQLTSGGAS VVCFLNNFYP KDINVKWKID 151 GSERQNGVLN SWTDQDSKDS TYSMSSTLTL TKDEYERHNS YTCEATRKTS 201 TSPIVKSFR NEC(SEQ ID NO:31) 15 The nucleic acid sequence encoding the mature form (signal peptide removed) of Ab-B LC is: 1 CAAATTGTTC TCACCCAGTC TCCAACAATC GTGTCTGCAT CTCCAGGGGA 51 GAAGGTCACC CTAATCTGCA GTGCCAGTTC AAGTGTAAGT TTCGTGGACT 101 GGTTCCAGCA GAAGCCAGGC ACTTCTCCCA AACGCTGGAT TTACAGAACA 20 151 TCCAACCTGG GTTTTGGAGT CCCTGCTCGC TTCAGTGGCG GTGGATCTGG 201 GACCTCTCAC TCTCTCACAA TCAGCCGAAT GGAGGCTGAA GATGCTGCCA 251 CTTATTACTG CCAGCAAAGG AGTACTTACC CACCCACGTT CGGTGCTGGG 301 ACCAAGCTGG AACTGAAACG GGCTGATGCT GCACCAACTG TATCCATCTT 351 CCCACCATCC AGTGAGCAGT TAACATCTGG AGGTGCCTCA GTCGTGTGCT 25 401 TCTTGAACAA CTTCTACCCC AAAGACATCA ATGTCAAGTG GAAGATTGAT 451 GGCAGTGAAC GACAAAATGG CGTCCTGAAC AGTTGGACTG ATCAGGACAG 501 CAAAGACAGC ACCTACAGCA TGAGCAGCAC CCTCACGTTG ACCAAGGACG 551 AGTATGAACG ACATAACAGC TATACCTGTG AGGCCACTCA CAAGACATCA 601 ACTTCACCCA TTGTCAAGAG CTTCAACAGG AATGAGTGTT AG(SEQIDNO:32) 30 The amino acid sequence of Ab-B LC including signal peptide is: 1 MHFQVQIFSF LLISASVIVS RGQIVLTQSP TIVSASPGEK VTLICSASSS 51 VSFVDWFQQK PGTSPKRWIY RTSNLGFGVP ARFSGGGSGT SHSLTISRME 101 AEDAATYYCQ QRSTYPPTFG AGTKLELKRA DAAPTVSIFP PSSEQLTSGG 35 151 ASVVCFLNNF YPKDINVKWK IDGSERQNGV LNSWTDQDSK DSTYSMSSTL 201 TLTKDEYERH NSYTCEATHK TSTSPIVKSF NRNEC(SEQIDNO:33) The nucleic acid sequence of Ab-B LC including signal peptide encoding sequence is: 40 1 ATGCATTTTC AAGTGCAGAT TTTCAGCTTC CTGCTAATCA GTGCCTCAGT 51 CATAGTGTCC AGAGGGCAAA TTGTTCTCAC CCAGTCTCCA ACAATCGTGT 101 CTGCATCTCC AGGGGAGAAG GTCACCCTAA TCTGCAGTGC CAGTTCAAGT 151 GTAAGTTTCG TGGACTGGTT CCAGCAGAAG CCAGGCACTT CTCCCAAACG 201 CTGGATTTAC AGAACATCCA ACCTGGGTTT TGGAGTCCCT GCTCGCTTCA 45 251 GTGGCGGTGG ATCTGGGACC TCTCACTCTC TCACAATCAG CCGAATGGAG 301 GCTGAAGATG CTGCCACTTA TTACTGCCAG CAAAGGAGTA CTTACCCACC SEA 180391vi 60117-22 38 WO 2006/119062 PCTIUS2006/016345 351 CACGTTCGGT GCTGGGACCA AGCTGGAACT GAAACGGGCT GATGCTGCAC 401 CAACTGTATC CATCTTCCCA CCATCCAGTG AGCAGTTAAC ATCTGGAGGT 451 GCCTCAGTCG TGTGCTTCTT GAACAACTTC TACCCCAAAG ACATCAATGT 501 CAAGTGGAAG ATTGATGGCA GTGAACGACA AAATGGCGTC CTGAACAGTT 5 551 GGACTGATCA GGACAGCAAA GACAGCACCT ACAGCATGAG CAGCACCCTC 601 ACGTTGACCA AGGACGAGTA TGAACGACAT AACAGCTATA CCTGTGAGGC 651 CACTCACAAG ACATCAACTT CACCCATTGT CAAGAGCTTC AACAGGAATG 701 AGTGTTAG (SEQ ID NO:34) 10 Ab-B Heavy Chain The amino acid sequence of the mature form (signal peptide removed) of Ab-B HC: 1 QVTLKESGPG ILQPSQTLSL TCSFSGFSLS SGDVdWIR HPSGKNLEWL 15 51 AHiNWWDVK9 YNPVI5'*RLT ISKDTSNSQV FLKIANVDTA DTATYYCARI 101 NDFDYDEEYY' AMDilWGQGTS VIVSSAKTTP PSVYPLAPGS AAQTNSMVTL 151 GCLVKGYFPE PVTVTWNSGS LSSGVHTFPA VLQSDLYTLS SSVTVPSSTW 201 PSETVTCNVA HPASSTKVDK KIVPRDCGCK PCICTVPEVS SVFIFPPKPK 251 DVLTITLTPK VTCVVVDISK DDPEVQFSWF VDDVEVHTAQ TQPREQFNS 20 301 TFRSVSELPI M1QDWLNGKE FKCRVNSAAF PAPETISK TKGRPKAPQV 351 YTIPPPKEQM AKDKVSLTC4 ITDEFPEDIT VEWQWNGQPA ENYKNTQPIM 401 DTDGSYEVYS KLNVQKSNWE AGNTFTCSVL REGLHNHHTE KSLSHSPGK(SEQ ID NO:35) 25 The nucleic acid sequence encoding the mature form (signal peptide removed) of Ab-B HC: 1 CAGGTTACTC TGAAAGAGTC TGGCCCTGGG ATATTGCAGC CCTCCCAGAC 51 CCTCAGTCTG ACTTGTTCTT TCTCTGGGTT TTCACTGAGC ACTTCTGGTA 101 TGGGTGTAGG CTGGATTCGT CACCCATCAG GGAAGAATCT GGAGTGGCTG 30 151 GCACACATTT GGTGGGATGA TGTCAAGCGC TATAACCCAG TCCTGAAGAG 201 CCGACTGACT ATCTCCAAGG ATACCTCCAA CAGCCAGGTA TTCCTCAAGA 251 TCGCCAATGT GGACACTGCA GATACTGCCA CATACTACTG TGCTCGAATA 301 GAGGACTTTG ATTACGACGA GGAGTATTAT GCTATGGACT ACTGGGGTCA 351 AGGAACCTCA GTCATCGTCT CCTCAGCCAA AACGACACCC CCATCTGTCT 35 401 ATCCACTGGC CCCTGGATCT GCTGCCCAAA CTAACTCCAT GGTGACCCTG 451 GGATGCCTGG TCAAGGGCTA TTTCCCTGAG CCAGTGACAG TGACCTGGAA 501 CTCTGGATCC CTGTCCAGCG GTGTGCACAC CTTCCCAGCT GTCCTGCAGT 551 CTGACCTCTA CACTCTGAGC AGCTCAGTGA CTGTCCCCTC CAGCACCTGG 601 CCCAGCGAGA CCGTCACCTG CAACGTTGCC CACCCGGCCA GCAGCACCAA 40 651 GGTGGACAAG AAAATTGTGC CCAGGGATTG TGGTTGTAAG CCTTGCATAT 701 GTACAGTCCC AGAAGTATCA TCTGTCTTCA TCTTCCCCCC AAAGCCCAAG 751 GATGTGCTCA CCATTACTCT GACTCCTAAG GTCACGTGTG TTGTGGTAGA 801 CATCAGCAAG GATGATCCCG AGGTCCAGTT CAGCTGGTTT GTAGATGATG 851 TGGAGGTGCA CACAGCTCAG ACGCAACCCC GGGAGGAGCA GTTCAACAGC 45 901 ACTTTCCGCT CAGTCAGTGA ACTTCCCATC ATGCACCAGG ACTGGCTCAA 951 TGGCAAGGAG TTCAAATGCA GGGTCAACAG TGCAGCTTTC CCTGCCCCCA 1001 TCGAGAAAAC CATCTCCAAA ACCAAAGGCA GACCGAAGGC TCCACAGGTG 1051 TACACCATTC CACCTCCCAA GGAGCAGATG GCCAAGGATA AAGTCAGTCT 1101 GACCTGCATG ATAACAGACT TCTTCCCTGA AGACATTACT GTGGAGTGGC 50 1151 AGTGGAATGG GCAGCCAGCG GAGAACTACA AGAACACTCA GCCCATCATG SEA 1803911 y 60117-223 39 WO 2006/119062 PCTIUS2006/016345 1201 GACACAGATG GCTCTTACTT CGTCTACAGC AAGCTCAATG TGCAGAAGAG 1251 CAACTGGGAG GCAGGAAATA CTTTCACCTG CTCTGTGTTA CATGAGGGCC 1301 TGCACAACCA CCATACTGAG AAGAGCCTCT CCCACTCTCC TGGTAAATGA (SEQ ID NO:36) 5 The amino acid sequence of Ab-B HC including signal peptide: 1 MGRLTSSFLL LIVPAYVLSQ VTLKESGPGI LQPSQTLSLT CSFSGFSLST 51 SGMGVGWIRH PSGKNLEWLA HIWWDDVKRY NPVLKSRLTI SKDTSNSQVF 101 LKIANVDTAD TATYYCARIE DFDYDEEYYA MDYWGQGTSV IVSSAKTTPP 10 151 SVYPLAPGSA AQTNSMVTLG CLVKGYFPEP VTVTWNSGSL SSGVHTFPAV 201 LQSDLYTLSS SVTVPSSTWP SETVTCNVAH PASSTKVDKK IVPRDCGCKP 251 CICTVPEVSS VFIFPPKPKD VLTITLTPKV TCVVVDISKD DPEVQFSWFV 301 DDVEVHTAQT QPREEQFNST FRSVSELPIM HQDWLNGKEF KCRVNSAAFP 351 APIEKTISKT KGRPKAPQVY TIPPPKEQMA KDKVSLTCMI TDFFPEDITV 15 401 EWQWNGQPAE NYKNTQPIMD TDGSYFVYSK LNVQKSNWEA GNTFTCSVLH 451 EGLHNHHTEK SLSHSPGK (SEQ ID NO:37) The nucleic acid sequence of Ab-B HC including signal peptide encoding sequence: 20 1 ATGGGCAGGC TTACTTCTTC ATTCCTGCTA CTGATTGTCC CTGCATATGT 51 CCTGTCCCAG GTTACTCTGA AAGAGTCTGG CCCTGGGATA TTGCAGCCCT 101 CCCAGACCCT CAGTCTGACT TGTTCTTTCT CTGGGTTTTC ACTGAGCACT 151 TCTGGTATGG GTGTAGGCTG GATTCGTCAC CCATCAGGGA AGAATCTGGA 201 GTGGCTGGCA CACATTTGGT GGGATGATGT CAAGCGCTAT AACCCAGTCC 25 251 TGAAGAGCCG ACTGACTATC TCCAAGGATA CCTCCAACAG CCAGGTATTC 301 CTCAAGATCG CCAATGTGGA CACTGCAGAT ACTGCCACAT ACTACTGTGC 351 TCGAATAGAG GACTTTGATT ACGACGAGGA GTATTATGCT ATGGACTACT 401 GGGGTCAAGG AACCTCAGTC ATCGTCTCCT CAGCCAAAAC GACACCCCCA 451 TCTGTCTATC CACTGGCCCC TGGATCTGCT GCCCAAACTA ACTCCATGGT 30 501 GACCCTGGGA TGCCTGGTCA AGGGCTATTT CCCTGAGCCA GTGACAGTGA 551 CCTGGAACTC TGGATCCCTG TCCAGCGGTG TGCACACCTT CCCAGCTGTC 601 CTGCAGTCTG ACCTCTACAC TCTGAGCAGC TCAGTGACTG TCCCCTCCAG 651 CACCTGGCCC AGCGAGACCG TCACCTGCAA CGTTGCCCAC CCGGCCAGCA 701 GCACCAAGGT GGACAAGAAA ATTGTGCCCA GGGATTGTGG TTGTAAGCCT 35 751 TGCATATGTA CAGTCCCAGA AGTATCATCT GTCTTCATCT TCCCCCCAAA 801 GCCCAAGGAT GTGCTCACCA TTACTCTGAC TCCTAAGGTC ACGTGTGTTG 851 TGGTAGACAT CAGCAAGGAT GATCCCGAGG TCCAGTTCAG CTGGTTTGTA 901 GATGATGTGG AGGTGCACAC AGCTCAGACG CAACCCCGGG AGGAGCAGTT 951 CAACAGCACT TTCCGCTCAG TCAGTGAACT TCCCATCATG CACCAGGACT 40 1001 GGCTCAATGG CAAGGAGTTC AAATGCAGGG TCAACAGTGC AGCTTTCCCT 1051 GCCCCCATCG AGAAAACCAT CTCCAAAACC AAAGGCAGAC CGAAGGCTCC 1101 ACAGGTGTAC ACCATTCCAC CTCCCAAGGA GCAGATGGCC AAGGATAAAG 1151 TCAGTCTGAC CTGCATGATA ACAGACTTCT TCCCTGAAGA CATTACTGTG 1201 GAGTGGCAGT GGAATGGGCA GCCAGCGGAG AACTACAAGA ACACTCAGCC 45 1251 CATCATGGAC ACAGATGGCT CTTACTTCGT CTACAGCAAG CTCAATGTGC 1301 AGAAGAGCAA CTGGGAGGCA GGAAATACTT TCACCTGCTC TGTGTTACAT 1351 GAGGGCCTGC ACAACCACCA TACTGAGAAG AGCCTCTCCC ACTCTCCTGG 1401 TAAATGA(SEQID NO:3 8 ) SEA 1803911vl 60117-223 40 WO 2006/119062 PCT/US2006/016345 The CDR (complementarity determining region) sequences in the variable region of the heavy chain of Ab-B are as follows: CDR-H1: TSGMGVG (SEQ ID NO:57) CDR-H2: HIWWDDVKRYNPVLKS (SEQ ID NO:58) 5 CDR-H3: EDFDYDEEYYAMDY (SEQ ID NO:59) The light chain variable region CDR sequences of Ab-B are: CDR-L1: SASSSVSFVD (SEQ ID NO:60) CDR-L2: RTSNLGF (SEQ ID NO:61) CDR-L3: QQRSTYPPT (SEQ ID NO:62) 10 Antibodies disclosed herein bind to regions of human sclerostin which are important for the in vivo activity of the protein. Binding of an antibody to sclerostin can be correlated with increases in, for example, the bone mineral density achieved by use of the antibody in vivo such as described in Examples 5 and 9 (mice) and Example 12 (monkey). Increases in at least one of bone formation, bone mineral content, bone mass, bone quality and 15 bone strength can also be achieved by use of the antibody in vivo such as described in Examples 5 and 9 (mice) and Example 12 (monkey). Since the binding of an antibody to sclerostin is primarily determined by its CDR sequences, an antibody for practicing the invention may be generated with all or some of the disclosed CDR sequences in an appropriate framework, wherein the antibody retains the ability to bind specifically to sclerostin, and can be expected to 20 achieve increases in, for example, bone mineral density. Such antibodies are useful in the treatment of human or animal conditions that are caused by, associated with, or result in at least one of low bone formation, low bone mineral density, low bone mineral content, low bone mass, low bone quality and low bone strength. Methods of constructing and expressing antibodies and fragments thereof comprising CDR's of the present invention are known to those of skill in the 25 art. The present invention therefore relates in one embodiment to an isolated antibody, including Ab-A, or an antigen binding fragment thereof, which specifically binds to sclerostin and wherein the variable domain of the heavy chain comprises at least one CDR having the sequences given in SEQ ID NO:51 for CDR-H1l, SEQ ID NO:52 for CDR-112 and 30 SEQ ID NO:53 for CDR-H3. The antibody or antigen binding fragment thereof may comprise a heavy chain variable domain in which the CDRs consist of at least one of the peptides of SEQ ID NO:51 for CDR-H1, SEQ ID NO:52 for CDR-H2 and SEQ ID NO:53 for CDR-H3. When in antibodies of the invention a light chain is present the light chain may be any suitable complementary chain and may in particular be selected from a light chain wherein SEA 1803911v 60117-223 41 WO 2006/119062 PCTIUS2006/016345 the variable domain comprises at least one CDR having the sequences given in SEQ ID NO:54 for CDR-L1, SEQ ID NO:55 for CDR-L2 and SEQ ID NO:56 for CDR-L3. The antibody or antigen binding fragment thereof may comprise a light chain variable domain in which the CDRs consist of at least one of the peptides of SEQ ID NO:54 for CDR-Ll, SEQ ID NO:55 for 5 CDR-L2 and SEQ ID NO:56 for CDR-L3. The present invention further relates to an isolated antibody, including Ab-B, or an antigen binding fragment hereof, which specifically binds to sclerostin and wherein the variable domain of the heavy chain comprises at least one CDR having the sequences given in SEQ ID NO:57 for CDR-Hl, SEQ ID NO:58 for CDR-H2 and SEQ ID NO:59 for CDR-H3. 10 The antibody or antigen binding fragment thereof may comprise a heavy chain variable domain in which the CDRs consist of at least one of the peptides of SEQ ID NO:57 for CDR-H1, SEQ ID NO:58 for CDR-H2 and SEQ ID NO:59 for CDR-H3. When in antibodies of the invention a light chain is present the light chain may be any suitable complementary chain and may in particular be selected from a light chain wherein 15 the variable domain comprises at least one CDR having the sequences given in SEQ ID NO:60 for CDR-L1, SEQ ID NO:61 for CDR-L2 and SEQ ID NO:62 for CDR-L3. The antibody or antigen binding fragment thereof may comprise a light chain variable domain in which the CDRs consist of at least one of the peptides of SEQ ID NO:60 for CDR-L1, SEQ ID NO:61 for CDR-L2 and SEQ ID NO:62 for CDR-L3. 20 The present invention still further relates to an isolated antibody, including Ab-C, or an antigen binding fragment hereof, which specifically binds to sclerostin and wherein the variable domain of the heavy chain comprises at least one CDR having the sequences given in SEQ ID NO:45 for CDR-Hl, SEQ ID NO:46 for CDR-H2 and SEQ ID NO:47 for CDR-H3. The antibody or antigen binding fragment thereof may comprise a heavy chain variable domain 25 in which the CDRs consist of at least one of the peptides of SEQ ID NO:45 for CDR-H1, SEQ ID NO:46 for CDR-H2 and SEQ ID NO:47 for CDR-H3. When in antibodies of the invention a light chain is present the light chain may be any suitable complementary chain and may in particular be selected from a light chain wherein the variable domain comprises at least one CDR having the sequences given in SEQ ID NO:48 30 for CDR-Ll, SEQ ID NO:49 for CDR-L2 and SEQ ID NO:50 for CDR-L3. The antibody or antigen binding fragment thereof may comprise a light chain variable domain in which the CDRs consist of at least one of the peptides of SEQ ID NO:48 for CDR-L1, SEQ ID NO:49 for CDR-L2 and SEQ ID NO:50 for CDR-L3. SEA 1803911vi 60117-223 42 WO 2006/119062 PCT/US2006/016345 The present mvention also relates to an isolated antibody, including Ab-D, or an antigen binding fragment hereof, which specifically binds to sclerostin and wherein the variable domain of the heavy chain comprises at least one CDR having the sequences given in SEQ ID NO:39 for CDR-H1, SEQ ID NO:40 for CDR-H2 and SEQ ID NO:41 for CDR-H3. The 5 antibody or antigen binding fragment thereof may comprise a heavy chain variable domain in which the CDRs consist of at least one of the peptides of SEQ ID NO:39 for CDR-H1, SEQ ID NO:40 for CDR-H2 and SEQ ID NO:41 for CDR-H3. When in antibodies of the invention a light chain is present the light chain may be any suitable complementary chain and may in particular be selected from a light chain wherein 10 the variable domain comprises at least one CDR having the sequences given in SEQ ID NO:42 for CDR-L1, SEQ IID NO:43 for CDR-L2 and SEQ ID NO:44 for CDR-L3. The antibody or antigen binding fragment thereof may comprise a light chain variable domain in which the CDRs consist of at least one of the peptides of SEQ ID NO:42 for CDR-Ll, SEQ ID NO:43 for CDR-L2 and SEQ ID NO:44 for CDR-L3. 15 Additional anti-sclerostin antibodies are described below. For some of the amino acid sequences the complementarity-determining regions (CDRs) are boxed-shaded and the constant regions are in bold-italics. 20 Ab-2 The sequences of the Antibody 2 (also referred to as Ab-2) LC and HC are as follows: Ab-2 Light Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-2 LC: 1 QIVLSQSPAI LSTSPGEKVT MTC 5fYM WYQQKPG SSPKPWYAT 25 51 SNLASGVPVR FSGSGSGTSY SLTITRVEAE DAATYYCDQW S6QTiFGAG 101 TKLELKRADA APTVSIFPPS SEQLTSGGAS VVCFLNNFYP EDINVKWK1D 151 GSERQNGVLNSWTDQDSKDS TYSMSSTLTL TKDEYERHNS YTCEATHKTS 201 TSPIVKSFNR NEC (SEQ ID NO: 117) 30 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-2 LC: 1 CAAATTGTTC TCTCCCAGTC TCCAGCAATC CTGTCTACAT CTCCAGGGGA 51 GAAGGTCACA ATGACTTGCA GGGCCAGCTC AAGTGTATAT TACATGCACT 101 GGTACCAGCA GAAGCCAGGA TCCTCCCCCA AACCCTGGAT TTATGCCACA 35 151 TCCAACCTGO CTTCTGGAGT CCCTGTTCGC TTCAGTGGCA GTGQGTCTGG 201 GACCTCTTAC TCTCTCACAA TCACCAGAGT GGAGGCTGAA GATGCTGCCA 251 CTTATTACTG CCAGCAGTGG AGTAGTGACC CACTCACGTT CGGTGCTGGG SEA 1803911v 60117-223 43 WO 2006/119062 PCT/US2006/016345 301 ACCAAGCTGG AGCTGAAACG GGCTGATGCT GCACCAACTG TATCCATCTT 351 CCCACCATCC AGTGAGCAGT TAACATCTGG AGGTGCCTCA GTCGTGTGCT 401 TCTTGAACAA CTTCTACCCC AAAGACATCA ATGTCAAGTG GAAGATTGAT 451 GGCAGTGAAC GACAAAATGG CGTCCTGAAC AGTTGGACTG ATCAGGACAG 5 501 CAAAGACAGC ACCTACAGCA TGAGCAGCAC CCTCACGIfG ACCAAGGACG 551 AGTATGAACG ACATAACAGC TATACCTGTG AGGCCACTCA CAAGACATCA 601 ACTTCACCCA TTGTCAAGAG CTTCAACAGG AATGAGTGTT AG (SEQ ID NO:118) 10 Amino acid sequence of the Ab-2 LC including signal peptide: 1 MDFQVQIFSF LLISASVIMS RGQIVLSQSP AILSTSPGEK VTMTCRASSS 51 VYYMIHWYQQK PGSSPKPWIY ATSNLASGVP VRFSGSGSGT SYSLTITRVE 101 AEDAATYYCQ QWSSDPLTFG AGTKLELKRA DAAPTVSIFP PSSEQLTSGG 151 ASVVCFLNNF YPKDINVKWK IDGSERQNGV LNSWTDQDSK DSTYSMSSTL 15 201 TLTKDEYERH NSYTCEATEK TSTSPIVKSF NRNEC (SEQ ID NO: 119) Nucleic acid sequence of the Ab-2 LC including signal peptide encoding sequence: 1 ATGGATTITC AAGTGCAGAT TTTCAGCTfC CTGCTAATCA GTGCTTCAGT 20 51 CATTATGTCC AGGGGACAAA TrGTTCTCTC CCAGTCTCCA GCAATCCTGT 101 CTACATCTCC AGGGGAGAAG GTCACAATGA CTTGCAGGGC CAGCTCAAGT 151 GTATATTACA TGCACTGGTA CCAGCAGAAG CCAGGATCCT CCCCCAAACC 201 CTGGATTTAT GCCACATCCA ACCTGGCTTC TGGAGTCCCT GTTCGCTrCA 251 GTGGCAGTGG GTCTGGGACC TCTTACTCTC TCACAATCAC CAGAGTGGAG 25 301 GCTGAAGATG CTGCCACTTA T[ACTGCCAG CAGTGGAGTA GTGACCCACT 351 CACGTfCGGT GCTGGGACCA AGCTGGAGCT GAAACGGGCT GATGCTGCAC 401 CAACTGTATC CATCTTCCCA CCATCCAGTG AGCAGTTAAC ATCTGGAGGT 451 GCCTCAGTCG TGTGCTTCTT GAACAACTTC TACCCCAAAG ACATCAATGT 501 CAAGTGGAAG ATTGATGGCA GTGAACGACA AAATGGCGTC CTGAACAGTT 30 551 GGACTGATCA GGACAGCAAA GACAGCACCT ACAGCATGAG CAGCACCCTC 601 ACGTTGACCA AGGACGAGTA TGAACGACAT AACAGCTATA CCTGTGAGGC 651 CACTCACAAG ACATCAACTT CACCCATTGT CAAGAGCTrC AACAGGAATG 701 AGTGTTAG (SEQ ID NO:120) 35 Ab-2 Heavy Chain Amino acid sequence of the mature form (signal peptide removed) of the Ab-2 HC: 1 EVQVQQSGPE LVKPGASVKL SCTASGFNIK V WVKQR PEQGLEWIG 51 ED EpYk-FQKAM TADTSSNTAY LQLRSLTSED TAIYYCERl 101 (YDo PY WGQGTLVTVS AAKTTPPSVYPLAPGSAAQTNSMVTLGCLV 40 151 KGYFPEPVTV TWNSGSLSSG VHTFPA VLQS DLYTLSSSVT VPSSTWPSET 201 VTCNVAHPAS STKVDKKVP RDCGCKPCIC TVPEVSSVFI FPPKPKDVLT 251 ITLTPKVTCV VVDISKDDPE VQFSWFVDDVEVHTAQTQPR EEQFNSTFRS 301 VSELPIMHQD WLNGKEFKCR VNSAAFPAPI EKTISKTKGR PKAPQVYTLP 351 PPKEQMAKDK VSLTCMITDF FPEDITVEWQ WNGQPAENYK NTQPIMDTDG 45 401 SYFIYSKLNV QKSNWEAGNT FTCSVLBEGL BNHHTEKSLS HSPGK (SEQ ID NO:121) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-2 HC: SEA 1803911vi 60117-223 44 WO 2006/119062 PCTIUS2006/016345 1 GAGGITCAGG TGCAGCAGTC TGGGCCAGAA CTTGTGAAGC CAGGGGCCTC 51 AGTCAAGTTG TCCTGCACAG CTTCTGGCTT CAACATTAAA GACTACTITA 101 TACACTGGGT GAAGCAGAGG CCTGAACAGG GCCTGGAGTG GATTGGAAGG 151 CTTGATCCTG AGGATGGTGA AAGTGATTAT GCCCCGAAGT TCCAGGACAA 5 201 GGCCATTATG ACAGCAGACA CATCATCCAA CACAGCCTAT CTTCAGCTCA 251 GAAGCCTGAC ATCTGAGGAC ACTGCCATCT ATTATTGTGA GAGAGAGGAC 301 TACGATGGTA CCTACACCTT TTTCCT[AC TGGGGCCAAG GGACTCTGGT 351 CACTGTCTCT GCAGCCAAAA CGACACCCCC ATCTGTCTAT CCACTGGCCC 401 CTGGATCTGC TGCCCAAACT AACTCCATGG TGACCCTGGG ATGCCTGGTC 10 451 AAGGGCTATT TCCCTGAGCC AGTGACAGTG ACCTGGAACT CTGGATCCCT 501 GTCCAGCGGT GTGCACACCT TCCCAGCTGT CCTGCAGTCT GACCTCTACA 551 CTCTGAGCAG CTCAGTGACT GTCCCCTCCA GCACCTGGCC CAGCGAGACC 601 GTCACCTGCA ACGTrGCCCA CCCGGCCAGC AGCACCAAGG TGGACAAGAA 651 AATTGTGCCC AGGGATTGTG GTTGTAAGCC TTGCATATGT ACAGTCCCAG 15 701 AAGTATCATC TGTCTTCATC TTCCCCCCAA AGCCCAAGGA TGTGCTCACC 751 ATrACTCTGA CTCCTAAGGT CACGTGTGTT GTGGTAGACA TCAGCAAGGA 801 TGATCCCGAG GTCCAGTTCA GCTGGTTTGT AGATGATGTG GAGGTGCACA 851 CAGCTCAGAC GCAACCCCGG GAGGAGCAGT TCAACAGCAC TCCGCTCA 901 GTCAGTGAAC TICCCATCAT GCACCAGGAC TGGCTCAATG GCAAGGAGTT 20 951 CAAATGCAGG GTCAACAGTG CAGCTITCCC TGCCCCCATC GAGAAAACCA 1001 TCTCCAAAAC CAAAGGCAGA CCGAAGGCTC CACAGGTGTA CACCATTCCA 1051 CCTCCCAAGG AGCAGATGGC CAAGGATAAA GTCAGTCTGA CCTGCATGAT 1101 AACAGACTTC TrCCCTGAAG ACATTACTGT GGAGTGGCAG TGGAATGGGC 1151 AGCCAGCGGA GAACTACAAG AACACTCAGC CCATCATGGA CACAGATGGC 25 1201 TCTTACTTCA TCTACAGCAA GCTCAATGTG CAGAAGAGCA ACTGGGAGGC 1251 AGGAAATACT TTCACCTGCT CTGTGTTACA TGAGGGCCTG CACAACCACC 1301 ATACTGAGAA GAGCCTCTCC CACTCTCCTG GTAAATGA (SEQ ID NO: 122) Amino acid sequence of the Ab-2 HC including signal peptide: 30 1 MKCSWVIFFL MAVVTGVNSE VQVQQSGPEL VKPGASVKLS CTASGFNIKD 51 YFIHWVKQRP EQGLEWIGRL DPEDGESDYA PKFQDKAIMT ADTSSNTAYL 101 QLRSLTSEDT AIYYCEREDY DGTYTFFPYW GQGTLVTVSA AKTTPPSVYP 151 LAPGSAAQTN SMVTLGCLVK GYFPEPVTVT WNSGSLSSGV HTFPAVLQSD 201 LYTLSSSVTV PSSTWPSETV TCNVAHPASS TKVDKKIVPR DCGCKPCICT 35 251 VPEVSSVFIF PPKPKDVLTI TLTPKVTCVV VDISKDDPEV QFSWFVDDVE 301 VHTAQTQPRE EQFNSTFRSV SELPIMHQDW LNGKEFKCRV NSAAFPAPIE 351 KTISKTKGRP KAPQVYTIPP PKEQMAKDKV SLTCMITDFF PEDITVEWQW 401 NGQPAENYKN TQPIMDTDGS YFIYSKLNVQ KSNWEAGNTF TCSVLBEGLH 451 NHHTEKSLSH SPGK (SEQ ID NO:123) 40 Nucleic acid sequence of the Ab-2 HC including signal peptide encoding sequence: 1 ATGAAATGCA GCTGGGTCAT CTTCTTCCTG ATGGCAGTGG TTACAGGGGT 51 CAATTCAGAG GTrCAGGTGC AGCAGTCTGG GCCAGAACTr GTGAAGCCAG 101 GGGCCTCAGT CAAGTTGTCC TGCACAGCTT CTGGCTTCAA CATTAAAGAC 45 151 TACTATAC ACTGGGTGAA GCAGAGGCCT GAACAGGGCC TGGAGTGGAT 201 TGGAAGGCTT GATCCTGAGG ATGGTGAAAG TGATTATGCC CCGAAGTTCC 251 AGGACAAGGC CATTATGACA GCAGACACAT CATCCAACAC AGCCTATCTT 301 CAGCTCAGAA GCCTGACATC TGAGGACACT GCCATCTATT ATTGTGAGAG 351 AGAGGACTAC GATGGTACCT ACACCTTIT TCCTTACTGG GGCCAAGGGA 50 401 CTCTGGTCAC TGTCTCTGCA GCCAAAACGA CACCCCCATC TGTCTATCCA 451 CTGGCCCCTG GATCTGCTGC CCAAACTAAC TCCATGGTGA CCCTGGGATG SEA 1803911v1 60117-n 45 WO 2006/119062 PCT/US2006/016345 501 CCTGGTCAAG GGCTATITCC CTGAGCCAGT GACAGTGACC TGGAACTCTG 551 GATCCCTGTC CAGCGGTGTG CACACCTfCC CAGCTGTCCT GCAGTCTGAC 601 CTCTACACTC TGAGCAGCTC AGTGACTGTC CCCTCCAGCA CCTGGCCCAG 651 CGAGACCGTC ACCTGCAACG TTGCCCACCC GGCCAGCAGC ACCAAGGTGG 5 701 ACAAGAAAAT TGTGCCCAGG GATTGTGGTT GTAAGCCYrG CATATGTACA 751 GTCCCAGAAG TATCATCTGT CTTCATCTUC CCCCCAAAGC CCAAGGATGT 801 GCTCACCAT[ ACTCTGACTC CTAAGGTCAC GTGTGTrGTG GTAGACATCA 851 GCAAGGATGA TCCCGAGGTC CAGTTCAGCT GGTTGTAGA TGATGTGGAG 901 GTGCACACAG CTCAGACGCA ACCCCGGGAG GAGCAGTTCA ACAGCACTTT 10 951 CCGCTCAGTC AGTGAACTTC CCATCATGCA CCAGGACTGG CTCAATGGCA 1001 AGGAGTTCAA ATGCAGGGTC AACAGTGCAG CTLFCCCTGC CCCCATCGAG 1051 AAAACCATCT CCAAAACCAA AGGCAGACCG AAGGCTCCAC AGGTGTACAC 1101 CATTCCACCT CCCAAGGAGC AGATGGCCAA GGATAAAGTC AGTCTGACCT 1151 GCATGATAAC AGACTTCTC CCTGAAGACA TTACTGTGGA GTGGCAGTGG 15 1201 AATGGGCAGC CAGCGGAGAA CTACAAGAAC ACTCAGCCCA TCATGGACAC 1251 AGATGGCTCT TACTTCATCT ACAGCAAGCT CAATGTGCAG AAGAGCAACT 1301 GGGAGGCAGG AAATACFTTC ACCTGCTCTG TGTTACATGA GGGCCTGCAC 1351 AACCACCATA CTGAGAAGAG CCTCTCCCAC TCTCCTGGTA AATGA (SEQ ID NO:124) 20 Ab-3 The sequences of the Antibody 3 (also referred to herein as Ab-3) LC and HC are as follows: Ab-3 Light Chain 25 Amino acid sequence of the mature form (signal peptide removed) of the Ab-3 LC: 1 EIVLTQSPAL MAASPGEKVT ITcSV 5N7BI)WQQK SDTSPKPWIY 51 _T,_GVP VRFSGSGSGT SYSLTISSME AEDAATYYC'QQYSSYL TFG 101 AGTKLELRIRA DAAPTVSIFP PSSEQLTSGG ASVVCFLNNF YPKDINVKWK 151 LDGSERQNGVLNSWTDQDSKDSTYSMSSTL TLTKDEYERUHNSYTCEA THK 30 201 TSTSPIVKSF NRNEC (SEQ ID NO: 125 ) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-3 LC: I GAAATTGTGC TCACCCAGTC TCCAGCACTC ATGGCTGCAT CTCCGGGGGA 51 GAAGGTCACC ATCACCTGCA GTGTCAGTTC AACTATAAGT TCCAACCACT 35 101 TGCACTGGTT CCAGCAGAAG TCAGACACCT CCCCCAAACC CTGGATAT 151 GGCACATCCA ACCTGGCTTC TGGAGTCCCT GTTCGCTfCA GTGGCAGTGG 201 ATCTGGGACC TCTIATTCTC TCACAATCAG CAGCATGGAG GCTGAGGATG 251 CTGCCACTTA TrACTGTCAA CAGTGGAGTA GTrACCCACT CACGTrCGGC 301 GCTGGGACCA AGCTGGAGCT GAGACGGGCT GATGCTGCAC CAACTGTATC 40 351 CATCTTCCCA CCATCCAGTG AGCAGTTAAC ATCTGGAGGT GCCTCAGTCG 401 TGTGCTTCTr GAACAACTTC TACCCCAAAG ACATCAATGT CAAGTGGAAG 451 ATTGATGGCA GTGAACGACA AAATGGCGTC CTGAACAGTT GGACTGATCA 501 GGACAGCAAA GACAGCACCT ACAGCATGAG CAGCACCCTC ACGTFGACCA 551 AGGACGAGTA TGAACGACAT AACAGCTATA CCTGTGAGGC CACTCACAAG 45 601 ACATCAACTT CACCCATTGT CAAGAGCTrC AACAGGAATG AGTGTfAG (SEQ ID NO:126) Amino acid sequence of the Ab-3 LC including signal peptide: SEA 180391v1 60117-223 46 WO 2006/119062 PCTIUS2006/016345 1 MDFHVQIFSF MLISVTVILS SGEIVLTQSP ALMAASPGEK VTITCSVSST 51 ISSNHLHWFQ QKSDTSPKPW IYGTSNLASG VPVRFSGSGS GTSYSLTISS 101 MEAEDAATYY CQQWSSYPLT FGAGTKLELR RADAAPTVSI FPPSSEQLTS 151 GGASVVCFLN NFYPKDINVK WKIDGSERQN GVLNSWTDQD SKDSTYSMSS 5 201 TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC (SEQ ID NO:127) Nucleic acid sequence of the Ab-3 LC including signal peptide encoding sequence: 1 ATGGATITTC ATGTGCAGAT TITCAGCTTC ATGCTAATCA GTGTCACAGT 51 CATITTGTCC AGTGGAGAAA TTGTGCTCAC CCAGTCTCCA GCACTCATGG 10 101 CTGCATCTCC GGGGGAGAAG GTCACCATCA CCTGCAGTGT CAGTTCAACT 151 ATAAGT[CCA ACCACTTGCA CTGGTTCCAG CAGAAGTCAG ACACCTCCCC 201 CAAACCCTGG ATITATGGCA CATCCAACCT GGCTTCTGGA GTCCCTGTfC 251 GCTTCAGTGG CAGTGGATCT GGGACCTCTT ATTCTCTCAC AATCAGCAGC 301 ATGGAGGCTG AGGATGCTGC CACTrATTAC TGTCAACAGT GGAGTAGTTA 15 351 CCCACTCACG TrCGGCGCTG GGACCAAGCT GGAGCTGAGA CGGGCTGATG 401 CTGCACCAAC TGTATCCATC TTCCCACCAT CCAGTGAGCA GTTAACATCT 451 GGAGGTGCCT CAGTCGTGTG CTfCTHGAAC AACTTCTACC CCAAAGACAT 501 CAATGTCAAG TGGAAGATTG ATGGCAGTGA ACGACAAAAT GGCGTCCTGA 551 ACAGTTGGAC TGATCAGGAC AGCAAAGACA GCACCTACAG CATGAGCAGC 20 601 ACCCTCACGT TGACCAAGGA CGAGTATGAA CGACATAACA GCTATACCTG 651 TGAGGCCACT CACAAGACAT CAACTTCACC CATTGTCAAG AGCTTCAACA 701 GGAATGAGTG TTAG (SEQ ID NO:128) Ab-3 Heavy Chain 25 Amino acid sequence of the mature form (signal peptide removed) of the Ab-3 HC: 1 EVQLQQSGAE LVRPGALVKL SCTASDFNIK DPWI1VMRQR PEQGLDWIGA 51 DP FGITL.YDPKFIKATL TTDTSSNTAY LQLSGLTSET TAVYYCSR4_ 101 D 1YVMyFbDWG AGTT ITVSSAKTTP PSVYPLAPGSAAQTNSMVTL 151 GY VKGYFPE PijYTWNSGS LSSGVHTFPA VLQSDLYTLS SSVTVPSSTW 30 201 PSE TVTCNVA RPASSTKVDK KTVPRDCGCK PCICTVPEVS SVFIFPPKPK 251 DVLTITLTPK VTCVVVDISKDDPEVQFSWF VDDVEVHTAQ TQPREEQFNS ' 301 TFRSVSELPIMHQDWLNGKE FKCRVNSAAFPAPIEKTISK TKGRPKAPQV 351 YT1PPPEEQMAKDKVSLTCMITDFFPEDIT VEWQWNGQPA ENYKNTQPIM 401 DTDGSYFIYS KXLNVQKSNWE AGNTFTCSVL HEGLNRHTE KSLSHSPGK (SEQ 35 ID NO:129) 'Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-3 HC: 1 GAGGTTCAGC TGCAGCAGTC TGGGGCTGAA CTTGTGAGGC CAGGGGCCTT 51 AGTCAAGTfG TCCTGCACAG CTTCTGACTT CAACATrAAA GACTTCTATC 40 101 TACACTGGAT GAGGCAGCGG CCTGAACAGG GCCTGGACTG GATTGGAAGG 151 ATTGATCCTG AGAATGGTGA TACTTTATAT GACCCGAAGT TCCAGGACAA 201 GGCCACTCTT ACAACAGACA CATCCTCCAA CACAGCCTAC CTGCAGCTCA 251 GCGGCCTGAC ATCTGAGACC ACTGCCGTCT ATTACTGTC TAGAGAGGCG 301 GATATITCC ACGATGGTAC CTCCTACTGG TACTTCGATG TCTGGGGCGC 45 351 AGGGACCACA ATCACCGTCT CCTCAGCCAA AACGACACCC CCATCTGTCT 401 ATCCACTGGC CCCTGGATCT GCTGCCCAAA CTAACTCCAT GGTGACCCTG 451 GGATGCCTGQ TCAAGGGCTA TTTCCCTGAG CCAGTGACAG TGACCTGGAA 501 CTCTGGATCC CTGTCCAGCG GTGTGCACAC CTTCCCAGCT GTCCTGCAGT 551 CTGACCTCTA CACTCTGAGC AGCTCAGTGA CTGTCCCCTC CAGCACCTGG SEA 1803911vi 60117-23 47 WO 2006/119062 PCT/US2006/016345 601 CCCAGCGAuA ccuci ACCTG CAACGTrGCC CACCCGGCCA GCAGCACCAA 651 GGTGGACAAG AAAATTGTGC CCAGGGATTG TGGTTGTAAG CCTTGCATAT 701 GTACAGTCCC AGAAGTATCA TCTGTCTTCA TCTTCCCCCC AAAGCCCAAG 751 GATGTGCTCA CCATTACTCT GACTCCTAAG GTCACGTGTG TTGTGGTAGA 5 801 CATCAGCAAG GATGATCCCG AGGTCCAGTT CAGCTGGTIT GTAGATGATG 851 TGGAGGTGCA CACAGCTCAG ACGCAACCCC GGGAGGAGCA GTTCAACAGC 901 ACTITCCGCT CAGTCAGTGA ACTTCCCATC ATGCACCAGG ACTGGCTCAA 951 TGGCAAGGAG TTCAAATGCA GGGTCAACAG TGCAGCTITC CCTGCCCCCA 1001 TCGAGAAAAC CATCTCCAAA ACCAAAGGCA GACCGAAGGC TCCACAGGTG 10 1051 TACACCATTC CACCTCCCAA GGAGCAGATG GCCAAGGATA AAGTCAGTCT 1101 GACCTGCATG ATAACAGACT TCTfCCCTGA AGACATTACT GTGGAGTGGC 1151 AGTGGAATGG GCAGCCAGCG GAGAACTACA AGAACACTCA GCCCATCATG 1201 GACACAGATG GCTCTTACTT CATCTACAGC AAGCTCAATG TGCAGAAGAG 1251 CAACTGGGAG GCAGGAAATA CTTfCACCTG CTCTGTGTTA CATGAGGGCC 15 1301 TGCACAACCA CCATACTGAG AAGAGCCTCT CCCACTCTCC TGGTAAATGA (SEQ ID NO:130) Amino acid sequence of the Ab-3 HC including signal peptide: 1 MKCSWVIFFL MAVVTGVNSE VQLQQSGAEL VRPGALVKLS CTASDFNIKD 20 51 FYLHWMRQRP EQGLDWIGRI DPENGDTLYD PKFQDKATLT TDTSSNTAYL 101 QLSGLTSETr AVYYCSREAD YFHDGTSYWY FDVWGAGTTI TVSSAKTPP 151 SVYPLAPGSA AQTNSMVTLG CLVKGYFPEP VTVTWNSGSL SSGVHTFPAV 201 LQSDLYTLSS SVTVPSSTWP SETVTCNVAH PASSTKVDKK IVPRDCGCKP 251 CICTVPEVSS VFIFPPKPKD VLTITTPKV TCVVVDISKD DPEVQFSWFV 25 301 DDVEVHTAQT QPREEQFNST FRSVSELPIM HQDWLNGKEF KCRVNSAAFP 351 APIEKTISKT KGRPKAPQVY TIPPPKEQMA KDKVSLTCMI TDFFPEDITV 401 EWQWNGQPAE NYKNTQPIMD TDGSYFIYSK LNVQKSNWEA GNTFTCSVLH 451 EGLHNHHTEK SLSHSPGK (SEQ ID NO:131) 30 Nucleic acid sequence of the Ab-3 HC including signal peptide encoding sequence: 1 ATGAAATGCA GCTGGGTCAT CTTCTTCCTG ATGGCAGTGG TFACAGGGGT 51 CAATTCAGAG GTTCAGCTGC AGCAGTCTGG GGCTGAACTT GTGAGGCCAG 101 GGGCCTTAGT CAAGTfGTCC TGCACAGCTT CTGACTTCAA CATTAAAGAC 151 TFCTATCTAC ACTGGATGAG GCAGCGGCCT GAACAGGGCC TGGACTGGAT 35 201 TGGAAGGATT GATCCTGAGA ATGGTGATAC TITATATGAC CCGAAGTTCC 251 AGGACAAGGC CACTCTrACA ACAGACACAT CCTCCAACAC AGCCTACCTG 301 CAGCTCAGCG GCCTGACATC TGAGACCACT GCCGTCTATT ACTGTITTAG 351 AGAGGCGGAT TATITCCACG ATGGTACCTC CTACTGGTAC TrCGATGTCT 401 GGGGCGCAGG GACCACAATC ACCGTCTCCT CAGCCAAAAC GACACCCCCA 40 451 TCTGTCTATC CACTGGCCCC TGGATCTGCT GCCCAAACTA ACTCCATGGT 501 GACCCTGGGA TGCCTGGTCA AGGGCTATIT CCCTGAGCCA GTGACAGTGA 551 CCTGGAACTC TGGATCCCTG TCCAGCGGTG TGCACACCTT CCCAGCTGTC 601 CTGCAGTCTG ACCTCTACAC TCTGAGCAGC TCAGTGACTG TCCCCTCCAG 651 CACCTGGCCC AGCGAGACCG TCACCTGCAA CGTrGCCCAC CCGGCCAGCA 45 701 GCACCAAGGT GGACAAGAAA ATTGTGCCCA GGGATTGTGG TrGTAAGCCT 751 TGCATATGTA CAGTCCCAGA AGTATCATCT GTCTTCATCT TCCCCCCAAA 801 GCCCAAGGAT GTGCTCACCA TTACTCTGAC TCCTAAGGTC ACGTGTGTTG 851 TGGTAGACAT CAGCAAGGAT GATCCCGAGG TCCAGTTCAG CTGGTITGTA 901 GATGATGTGG AGGTGCACAC AGCTCAGACG CAACCCCGGG AGGAGCAGTT 50 951 CAACAGCACT TCCGCTCAG TCAGTGAACT TCCCATCATG CACCAGGACT SEA 1803911vI 60117-223 48 WO 2006/119062 PCT/US2006/016345 1001 GGCTCAATGG CAAGGAGTTC AAATGCAGGG TCAACAGTGC AGCTITCCCT 1051 GCCCCCATCG AGAAAACCAT CTCCAAAACC AAAGGCAGAC CGAAGGCTCC 1101 ACAGGTGTAC ACCATTCCAC CTCCCAAGGA GCAGATGGCC AAGGATAAAG 1151 TCAGTCTGAC CTGCATGATA ACAGACTTCT TCCCTGAAGA CATTACTGTG 5 1201 GAGTGGCAGT GGAATGGGCA GCCAGCGGAG AACTACAAGA ACACTCAGCC 1251 CATCATGGAC ACAGATGGCT CTTACTTCAT CTACAGCAAG CTCAATGTGC 1301 AGAAGAGCAA CTGGGAGGCA GGAAATACTT TCACCTGCTC TGTGTTACAT 1351 GAGGGCCTGC ACAACCACCA TACTGAGAAG AGCCTCTCCC ACTCTCCTGG 1401 TAAATGA (SEQ ID NO:132) 10 Ab-4 The sequences of the Antibody 4 (also referred to herein as Ab-4) LC and HC. are as follows: Ab-4 Light Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-4 LC: 15 1 DIQMTQITSS LSASLGDRVS ISCS5(I-NYNW aYQQKP DGTFKLLIFY 51 TSRLtGVPS RFSGSGSGTD YSLTIYNLEQ EDFATYFCrQQf)bThPYTFGG .10 1GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PDNVKWKI 151 DGSERQNGVL NSWTDQDSKD STYSMSSTLTLTKDEYERHN SYTCEA TRKT 201 STSPIVKSFNRNEC (SEQ ID NO:133) 20 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-4 LC: 1 GATATCCAGA TGACACAGAT TACATCCTCC CTGTCTGCCT CTCTGGGAGA 51 CAGGGTCTCC ATCAGTTGCA GGGCAAGTCA AGACATTAGC AATTATTTAA 101 ACTGGTATCA GCAGAAACCA GATGGAACTT TTAAACTCCT TATCTTCTAC 25 151 ACATCAAGAT TACTCTCAGG AGTCCCATCA AGGTrCAGTG GCAGTGGGTC 201 TGGAACAGAT TATTCTCTCA CCATTACAA CCTGGAGCAA GAAGATITG 251 CCACTTACT TTGCCAACAG GGAGATACGC TTCCGTACAC T1TCGGAGGG 301 GGGACCAAGC TGGAAATAAA ACGGGCTGAT GCTGCACCAA CTGTATCCAT 351 CTFCCCACCA TCCAGTGAGC AGTTAACATC TGGAGGTGCC TCAGTCGTGT 30 401 GCTTCTTGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA GTGGAAGATr 451 GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA CTGATCAGGA 501 CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG TTGACCAAGG 551 ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC TCACAAGACA 601 TCAACTTCAC CCATTGTCAA GAGCTFCAAC AGGAATGAGT GTTAG (SEQ ID 35 NO:134) Amino acid sequence of the Ab-4 LC including signal peptide: 1 MMSSAQFLGL LLLCFQGTRC DIQMTQITSS LSASLGDRVS ISCRASQDIS 51 NYLNWYQQKP DGTFKLLIFY TSRLLSGVPS RFSGSGSGTD YSLTIYNLEQ 40 101 EDFATYFCQQ GDTLPYTFGG GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA 151 SVVCFLNNFY PKDINVKWKI DGSERQNGVL NSWTDQDSKD STYSMSSTLT 201 LTKDEYERHN SYTCEATHKT STSPIVKSFN RNEC (SEQ ID NO:135) Nucleic acid sequence of the Ab-4 LC including signal peptide encoding sequence: 45 1 ATGATGTCCT CTGCTCAGTT CCTTGGTCTC CTGTFGCTCT GITTCAAGG 51 TACCAGATGT GATATCCAGA TGACACAGAT TACATCCTCC CTGTCTGCCT SEA 1803911vI 60117-223 49 WO 2006/119062 PCT/US2006/016345 -101 CTCTGGUAGA CAUUufCTCC ATCAGTTGCA GGGCAAGTCA AGACATTAGC 151 AATTATITAA ACTGGTATCA GCAGAAACCA GATGGAACTf TTAAACTCCT 201 TATCTTCTAC ACATCAAGAT TACTCTCAGG AGTCCCATCA AGOTTCAGTG 251 GCAGTGGGTC TGGAACAGAT TATfCTCTCA CCATITACAA CCTGGAGCAA 5 301 GAAGATTG CCACTTACTT TTGCCAACAG GGAGATACGC TTCCGTACAC 351 TITCGGAGGG GGGACCAAGC TGGAAATAAA ACGGGCTGAT GCTGCACCAA 401 CTGTATCCAT CTTCCCACCA TCCAGTGAGC AGTTAACATC TGGAGGTGCC 451 TCAGTCGTGT GCTrCTTGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA 501 GTGGAAGATT GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA 10 551 CTGATCAGGA CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG 601 TTGACCAAGG ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC 651 TCACAAGACA TCAACTTCAC CCATTGTCAA GAGCTTCAAC AGGAATGAGT 701 GTrAG (SEQ ID NO:136) 15 Ab-4 Heavy Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-4 HC: 1 EVQLQQSGPE LMKPGASVKM SCKASGYTFT IY4N"IWVVKQN QGKTLEWIGE 51 PNSGGY INQ4 M*ATL TVDKSSTTAY MELRSLTSED SAVYYCARLG 101 Y1by)IY F"DFGZGTTVT VSSAKTTPPS VYPLAPGSAA QTNSMVTLGC 20 151 LVKGYFPEPV TVTWNSGSLSSGVHTFPAVL QSDLYTLSSSVTVPSSTWPS 201 ETVTCNVARP ASSTKVDEU VPRDCGCKPC ICTVPEVSSVFIFPPEPKDV 251 LTITLTPKVT CVVVDISKDD PEVQFSWFVD DVEVHTAQTQ PREEQFNSTF 301 RSVSELP1MH QDWLNGKEFK CRVNSAA FPA PIEKTISKTK GRPKAPQVYT 351 IPPPKEQMAKDKVSLTCM1TDFFPEDITVE WQWNGQPAEN YKNTQPIMDT 25 401 DGSYFIYSEL NVQKSNWE 4G NTFTCSVLIIE GLHNHIHTEKS LSHSPGK (SEQ ID NO:137) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-4 HC: 1 GAGGTCCAAC TGCAACAGTC TGGACCTGAA CTAATGAAGC CTGGGGCTTC 30 51 AGTGAAGATG TCCTGCAAGG CTTCTGGATA TACATTCACT GACTACAACA 101 TGCACTGGGT GAAGCAGAAC CAAGGAAAGA CCCTAGAGTG GATAGGAGAA 151 ATTAATCCTA ACAGTGGTGG TGCTGGCTAC AACCAGAAGT TCAAGGGCAA 201 GGCCACATTG ACTGTAGACA AGTCCTCCAC CACAGCCTAC ATGGAGCTCC 251 GCAGCCTGAC ATCTGAGGAC TCTGCAGTCT ATrACTGTGC AAGATTGGGC 35 301 TACGATGATA TCTACGACGA CTGGTACTTC GATGTCTGGG GCGCAGGGAC 351 CACGGTCACC GTCTCCTCAG CCAAAACGAC ACCCCCATCT GTCTATCCAC 401 TGGCCCCTGG ATCTGCTGCC CAAACTAACT CCATGGTGAC CCTGGGATGC 451 CTGGTCAAGG GCTATTCCC TGAGCCAGTG ACAGTGACCT GGAACTCTGG 501 ATCCCTGTCC AGCGGTGTGC ACACCTTCCC AGCTGTCCTG CAGTCTGACC 40 551 TCTACACTCT GAGCAGCTCA GTGACTGTCC CCTCCAGCAC CTGGCCCAGC 601 GAGACCGTCA CCTGCAACGT TGCCCACCCG GCCAGCAGCA CCAAGGTGGA 651 CAAGAAAATF GTGCCCAGGG ATrGTGGTFG TAAGCCTTGC ATATGTACAG 701 TCCCAGAAGT ATCATCTGTC TTCATCTTCC CCCCAAAGCC CAAGGATGTG 751 CTCACCATfA CTCTGACTCC TAAGGTCACG TGTGTTGTGG TAGACATCAG 45 801 CAAGGATGAT CCCGAGGTCC AGTTCAGCTG GTTGTAGAT GATGTGGAGG 851 TGCACACAGC TCAGACGCAA CCCCGGGAGG AGCAGTTCAA CAGCACTITC 901 CGCTCAGTCA GTGAACTTCC CATCATGCAC CAGGACTGGC TCAATGGCAA 951 GGAGTTCAAA TGCAGGGTCA ACAGTGCAGC TTrCCCTGCC CCCATCGAGA 1001 AAACCATCTC CAAAACCAAA GGCAGACCGA AGGCTCCACA GGTGTACACC SEA 180391v 60117-223 50 WO 2006/119062 PCTIUS2006/016345 t XffdtCCTUCCAAGGAGCA GATGGCCAAG GATAAAGTCA GTCTGACCTG 1101 CATGATAACA GACTCTTCC CTGAAGACAT TACTGTGGAG TGGCAGTGGA 1151 ATGGGCAGCC AGCGGAGAAC TACAAGAACA CTCAGCCCAT CATGGACACA 1201 GATOGCTCT ACTTCATCTA CAGCAAGCTC AATGTGCAGA AGAGCAACTG 5 1251 GGAGGCAGGA AATACTTTCA CCTGCTCTGT GTTACATGAG GGCCTGCACA 1301 ACCACCATAC TGAGAAGAGC CTCTCCCACT CTCCTGGTAA ATGA (SEQ ID NO: 138) Amino acid sequence of the Ab-4 HC including signal peptide: 10 1 MGWSWTFLFL LSGTAGVLSE VQLQQSGPEL MKPGASVKMS CKASGYTFTD 51 YNMHWVKQNQ GKTLEWIGEI NPNSGGAGYN QKFKGKATLT VDKSSTTAYM 101 ELRSLTSEDS AVYYCARLGY DDIYDDWYFD VWGAGTrVTV SSAKTTPPSV 151 YPLAPGSAAQ TNSMVTLGCL VKGYFPEPVT VTWNSGSLSS GVHTFPAVLQ 201 SDLYTLSSSV TVPSSTWPSE TVTCNVAHPA SSTKVDKKIV PRDCGCKPCI 15 251 CTVPEVSSVF IFPPKPKDVL TITLTPKVTC VVVDISKDDP EVQFSWFVDD 301 VEVHTAQTQP REEQFNSTFR SVSELPIMHQ DWLNGKEFKC RVNSAAFPAP 351 IEKTISKTKG RPKAPQVYTI PPPKEQMAKD KVSLTCMITD FFPEDITVEW 401 QWNGQPAENY KNTQPIvIDTD GSYFlYSKLN VQKSNWEAGN TFTCSVLHEG 451 LHNHHTEKSL SHSPGK (SEQ ID NO:139) 20 Nucleic acid sequence of the Ab-4 HC including signal peptide encoding sequence: 1 ATGGGATGGA GCTGGACCTT TCTCTTCCTC CTGTCAGGAA CTGCAGGTGT 51 CCTCTCTGAG GTCCAACTGC AACAGTCTGG ACCTGAACTA ATGAAGCCTC 101 GGGCTTCAGT GAAGATGTCC TGCAAGGCTF CTGGATATAC ATTCACTGAC 25 151 TACAACATGC ACTGGGTGAA GCAGAACCAA GGAAAGACCC TAGAGTGGAT 201 AGGAGAAAT AATCCTAACA GTGGTGGTGC TGGCTACAAC CAGAAGTTCA 251 AGGGCAAGGC CACATTGACT GTAGACAAGT CCTCCACCAC AGCCTACATG 301 GAGCTCCGCA GCCTGACATC TGAGGACTCT GCAGTCTATT ACTGTGCAAG 351 ATTGGGCTAC GATGATATCT ACGACGACTG GTACTrCGAT GTCTGGGGCG 30 401 CAGGGACCAC GGTCACCGTC TCCTCAGCCA AAACGACACC CCCATCTGTC 451 TATCCACTGG CCCCTGGATC TGCTGCCCAA ACTAACTCCA TGGTGACCCT 501 GGGATGCCTG GTCAAGGGCT ATTTCCCTGA GCCAGTGACA GTGACCTGGA 551 ACTCTGGATC CCTGTCCAGC GGTGTGCACA CCTTCCCAGC TGTCCTGCAG 601 TCTGACCTCT ACACTCTGAG CAGCTCAGTG ACTGTCCCCT CCAGCACCTG 35 651 GCCCAGCGAG ACCGTCACCT GCAACGTIGC CCACCCGGCC AGCAGCACCA 701 AGGTGGACAA GAAAATTGTG CCCAGGGAT GTGGTTGTAA GCCTTGCATA 751 TGTACAGTCC CAGAAGTATC ATCTGTCTTC ATCTTCCCCC CAAAGCCCAA 801 GGATGTGCTC ACCATTACTC TGACTCCTAA GGTCACGTGT GTTGTGGTAG 851 ACATCAGCAA GGATGATCCC GAGGTCCAGT TCAGCTGGTf TGTAGATGAT 40 901 GTGGAGGTGC ACACAGCTCA GACGCAACCC CGGGAGGAGC AGTTCAACAG 951 CACTITCCGC TCAGTCAGTG AACTTCCCAT CATGCACCAG GACTGGCTCA 1001 ATGGCAAGGA GTrCAAATGC AGGGTCAACA GTGCAGCTTT CCCTGCCCCC 1051 ATCGAGAAAA CCATCTCCAA AACCAAAGGC AGACCGAAGG CTCCACAGGT 1101 GTACACCATr CCACCTCCCA AGGAGCAGAT GGCCAAGGAT AAAGTCAGTC 45 1151 TGACCTGCAT GATAACAGAC TTCTTCCCTG AAGACATrAC TGTGGAGTGG 1201 CAGTGGAATG GGCAGCCAGC GGAGAACTAC AAGAACACTC AGCCCATCAT 1251 GGACACAGAT GGCTCTTACT TCATCTACAG CAAGCTCAAT GTGCAGAAGA 1301 GCAACTGGGA GGCAGGAAAT ACTITCACCT GCTCTGTQTT ACATGAGGGC 1351 CTGCACAACC ACCATACTGA GAAGAGCCTC TCCCACTCTC CTGGTAAATG SEA1803911v160117-2Z 51 WO 2006/119062 PCT/US2006/016345 Wi X (SEQ'IlO: 140) Ab-4 was humanized to generate Ab-5. Ab-5 5 The sequences of the Antibody 5 (also referred to herein as Ab-5) LC and HC are as follows: Ab-5 Light Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-5 LC: 1 DIQMTQSPSS LSASVGDRVT ITC AS~QijiS WLTWYQQKP GKAPKLLIYY 51 T 5R'LGVPS RFSGSGSGTD FfLTISSLQP EDFATYYCQQ GDTLPYTFGG 10 10 1GTKVEIKRTVAAPSVFIFPP SDEQLKSGTA SVVCLLNNFYPREAKVQWKV 151 DNALQSGNSQ ESVTEQDSKD STYSLSSTLTLSKADYEKHK VYACEVTHQG 201 LSSPVTKSFNRGEC (SEQ ID NO:141) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-5 LC: 15 1 GACATCCAGA TGACCCAGTC TCCATCCTCC CTCTCCGCAT CCGTAGGCGA 51 CCGCGTAACC ATAACATGTA GAGCATCTCA AGATATITCC AACTATTTGA 101 ATTGGTACCA ACAAAAACCC GGCAAAGCAC CTAAACTCCT CATACTAT 151 ACATCAAGAC TCCTCTCCGG CGTrCCATCA CGATTCTCAG GCTCCGGCTC 201 CGGCACAGAT TTCACACTCA CTATTTCCTC CCTCCAACCA GAAGATTG 20 251 CAACCTATTA CTGTCAACAA GGCGATACAC TCCCATACAC ATTCGGCGGC 301 GGCACAAAAG TTGAAATTAA ACGTACGGTG GCTGCACCAT CTGTCTTCAT 351 CTTCCCGCCA TCTGATGAGC AGTTGAAATC TGGAACTGCC TCTGTTGTGT 401 GCCTGCTGAA TAACTTCTAT CCCAGAGAGG CCAAAGTACA GTGGAAGGTG 451 GATAACGCCC TCCAATCGGG TAACTCCCAG GAGAGTGTCA CAGAGCAGGA 25 501 CAGCAAGGAC AGCACCTACA GCCTCAGCAG CACCCTGACG CTGAGCAAAG 551 CAGACTACGA GAAACACAAA GTCTACGCCT GCGAAGTCAC CCATCAGGGC 601 CTGAGCTCGC CCGTCACAAA GAGCTTCAAC AGGGGAGAGT GT (SEQ ID NO:142) 30 Amino acid sequence of the Ab-5 LC including signal peptide: 1 MDMRVPAQLL GLLLLWLRGA RCDIQMTQSP SSLSASVGDR VTITCRASQD 51 ISNYLNWYQQ KPGKAPKLLI YYTSRLLSGV PSRFSGSGSG TDFTLTISSL 101 QPEDFATYYC QQGDTLPYTF GGGTKVEIKR TVAAPSVFIF PPSDEQLKSG 151 TASVVCLLNN FYPREAKVQW KVDNALQSGN SQESVTEQDS KDSTYSLSST 35 201 LTLSKADYEK HKVYACEVTH QGLSSPVTKS FNRGEC (SEQ ID NO:143) Nucleic acid sequence of the Ab-5 LC including signal peptide encoding sequence: 1 ATGGACATGA GGGTCCCCGC TCAGCTCCTG GGGCTCCTGC TACTCTGGCT 51 CCGAGGTGCC AGATGTGACA TCCAGATGAC CCAGTCTCCA TCCTCCCTCT 40 101 CCGCATCCGT AGGCGACCGC GTAACCATAA CATQTAGAGC ATCTCAAGAT 151 ATTCCAACT ATTTGAATTG GTACCAACAA AAACCCGGCA AAGCACCTAA 201 ACTCCTCATT TACTATACAT CAAGACTCCT CTCCGGCGTT CCATCACGAT 251 TCTCAGGCTC CGGCTCCGGC ACAGATTTCA CACTCACTAT TTCCTCCCTC 301 CAACCAGAAG AT1TTGCAAC CTATrACTGT CAACAAGGCG ATACACTCCC 45 351 ATACACATTC GGCGGCGGCA CAAAAGTTGA AATTAAACGT ACGGTGGCTG 401 CACCATCTGT CTrCATCTTC CCGCCATCTG ATGAGCAGTT GAAATCTGGA 451 ACTGCCTCTG TTGTGTGCCT GCTGAATAAC TTCTATCCCA GAGAGGCCAA SEA 1803911v 60117-22 52 WO 2006/119062 PCT/US2006/016345 51 Af'AOA'5fGd~ATGGATA ACGCCCTCCA ATCGGGTAAC TCCCAGGAGA 551 GTGTCACAGA GCAGGACAGC AAGGACAGCA CCTACAGCCT CAGCAGCACC 601 CTGACGCTGA GCAAAGCAGA CTACGAGAAA CACAAAGTCT ACGCCTGCGA 651 AGTCACCCAT CAGGGCCTGA GCTCGCCCGT CACAAAGAGC TTCAACAGGG 5 701 GAGAGTGT (SEQ ID NO:14 4 ) Ab-5 Heavy Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-5 HC: 1 EVQLVQSGAE VKKPGASVKV SCKASGYTFT pYrgIvWVRQA PGQGLEWMGE 10 51 NPNSGGAGi NQKIFKRVTM TMTSTSTAY MELRSLRSDD TAVYYCARL 101 DDIYDWMY DVWGQGTTVT VSSASTKGPS VFPLAPCSRS TSESTAALGC 151 L VDYFPEPV TVSWNSGALT SG VHTFPA VL QSSGLYSLSS VVTVPSSNFG 201 TQTFT CNVDH EPSNTKVDKT VERKCCVECP PCPAPP VAGP SVFLFPPKPK 251 DTLMAISRTPE VTCVVVDVSHEDPEVQFNWY VDqVEVHNAK TEPREEQFNS 15 301 TFRVVSVLTV VHQDWLNGKE YKCKVSNKGL PAPEKTISK TKGQPREPQV 351 YTLPPSREEM TENQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPML 401 DSDGSFFL YS KLTVDKSR WQ QGNVFSCSVM HEALHNHYTQ KSLSLSPGK (SEQ ID NO:145) 20 Amino acid sequence of the mature form (signal peptide removed) of the Ab-5 HC without carboxy-terminal lysine: I EVQLVQSGAE VKKPGASVKV SCKASGYTFT DYiVi11lpVRQA PGQGLEWMG5 51 IN$ SdtIdaYNQkFiKRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARLG 101 YDDIYJ DFrDV WGQGTfVT VSSASTKGPS VFPLAPCSRS TSESTAALGC 25 151 LVEDYFPEPVT VSWNSGALT SGVHTFPAVL QSSGLYSLSS VVTVPSSNFG 201 TQTYTCNVDH EPSNTKVDKT VERKCCVECP PCPAPPVAGP SVFLFPPEPK 251 DTLMISRTPE VTCVVVDVSH EDPEVQFNWY VDGVEVHNAK TEPREEQFNS 301 TFRVVSVLTV VHQDWLNGKE YKCKVSNKGL PAPIEKTISK TKGQPREPQV 351 YTLPPSREEM TENQVSLTCL VKGFYPSDIA VEWESNGQPE NNYKTTPPML 30 401 DSDGSFFL YS KLTVDKSR WQ Q GNVFSCS VM HEALHNHYTQ KSLSLSPG (SEQ ID NO:392) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-5 HC: 1 GAGGTGCAGC TGGTGCAGAG CGGCGCCGAG GTAAAAAAAC CAGGAGCAAG 35 51 CGTTAAAGTT TCYrGTAAAG CAAGCGGATA TACATITACA GATTACAACA 101 TGCATTGGGT AAGACAAGCG CCAGGACAAG GATTGGAATG GATGGGCGAA 151 ATAACCCTA ATAGTGGAGG AGCAGGCTAC AATCAAAAAT TCAAAGGGAG 20.1 AGTTACAATG ACAACAGACA CAAGCACTTC AACAGCATAT ATGGAACTGC 251 GATCACTTAG AAGCGACGAT ACAGCTGTAT ACTATTGCGC ACGACTGGG 40 301 TATGATGATA TATATGATGA CTGGTATITC GATGTTGGG GCCAGGGAAC 351 AACAGTrACC GTCTCTAGTG CCTCCACCAA GGGCCCATCG GTCTICCCCC 401 TGGCGCCCTG CTCCAGGAGC ACCTCCGAGA GCACAGCGGC CCTGGGCTGC 451 CTGGTCAAGG ACTACTCCC CGAACCGGTG ACGGTGTCGT GGAACTCAGG 501 CGCTCTGACC AGCGGCGTGC ACACCTTCCC AGCTGTCCTA CAGTCCTCAG 45 551 GACTCTACTC CCTCAGCAGC GTGGTGACCG TGCCCTCCAG CAACTTCGGC 601 ACCCAGACCT ACACCTGCAA CGTAGATCAC AAGCCCAGCA ACACCAAGOT 651 GGACAAGACA GTTGAGCGCA AATGTTGTGT CGAGTGCCCA CCGTGCCCAG 701 CACCACCTGT GGCAGGACCG TCAGTCTTCC TCTTCCCCCC AAAACCCAAG SEA 1803911v 60117-223 53 WO 2006/119062 PCT/US2006/016345 Y751GXdACdfA~TATCTCCCG GACCCCTGAG GTCACGTGCG TGGTGGTGGA 801 CGTGAGCCAC GAAGACCCCG AGGTCCAG1T CAACTGGTAC GTGGACGGCG 851 TGGAGGTGCA TAATGCCAAG ACAAAGCCAC GGGAGGAOCA GTTCAACAGC 901 ACGTfCCGTG TGGTCAGCGT CCTCACCGTr GTGCACCAGG ACTGGCTGAA 5 951 CGGCAAGGAG TACAAGTGCA AGGTCTCCAA CAAAGGCCTC CCAGCCCCCA 1001 TCGAGAAAAC CATCTCCAAA ACCAAAGGGC AGCCCCGAGA ACCACAGGTG 1051 TACACCCTGC CCCCATCCCG GGAGGAGATG ACCAAGAACC AGGTCAGCCT 1101 GACCTGCCTG GTCAAAGGCT TCTACCCCAG CGACATCGCC GTGGAGTGGG 1151 AGAGCAATGG GCAGCCGGAG AACAACTACA AGACCACACC TCCCATGCTG 10 1201 GACTCCGACG GCTCCTTCTr CCTCTACAGC AAGCTCACCG TGGACAAGAG 1251 CAGGTGGCAG CAGGGGAACG TCTTCTCATG CTCCGTGATG CATGAGGCTC 1301 TGCACAACCA CTACACGCAG AAGAGCCTCT CCCTGTCTCC GGGTAAA (SEQ D) NO:146) 15 Amino acid sequence of the Ab-5 HC including signal peptide: 1 MDWTWRILFL VAAATGAHSE VQLVQSGAEV KKPGASVKVS CKASGYTFTD 51 YNMHWVRQAP GQGLEWMGEI NPNSGGAGYN QKFKGRVTMT TDTSTSTAYM 101 ELRSLRSDDT AVYYCARLGY DDIYDDWYFD VWGQGTTVT SSASTKGPSV 151 FPLAPCSRST SESTAALGCL VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ 20 201 SSGLYSLSSV VTVPSSNFGT QTYTCNVDHK PSNTKVDKTV ERKCCVECPP 251 CPAPPVAGPS VFLFPPKPKD TLMISRTPEV TCVVVDVSHE DPEVQFNWYV 301 DGVEVHNAKT KPREEQFNST FRVVSVLTVV HQDWLNGKEY KCKVSNKGLP 351 APIEKTISKT KGQPREPQVY TLPPSREEMT KNQVSLTCLV KGFYPSDIAV 401 EWESNGQPEN NYKT'PPMLD SDGSFFLYSK LTVDKSRWQQ GNVFSCSVMH 25 451 EALHNHYTQK SLSLSPGK (SEQ ID NO: 147) Nucleic acid sequence of the Ab-5 HC including signal peptide encoding sequence: 1 ATGGACTGGA CCTGGAGGAT CCTCTTCTTG GTGGCAGCAG CCACAGGAGC 51 CCACTCCGAG GTGCAGCTGG TGCAGAGCGG CGCCGAGGTA AAAAAACCAG 30 101 GAGCAAGCGT TAAAGTTTCT TGTAAAGCAA GCGGATATAC ATTACAGAT 151 TACAACATGC ATTGGGTAAG ACAAGCGCCA GGACAAGGAT TGGAATGGAT 201 GGGCGAAATT AACCCTAATA GTGGAGGAGC AGGCTACAAT CAAAAATTCA 251 AAGGGAGAGT TACAATGACA ACAGACACAA GCACTTCAAC AGCATATATG 301 GAACTGCGAT CACTFAGAAG CGACGATACA GCTGTATACT ATTGCGCACG 35 351 ACTTGGGTAT GATGATATAT ATGATGACTG GTATMTCGAT GTITGGGGCC 401 AGGGAACAAC AGTTACCGTC TCTAGTGCCT CCACCAAGGG CCCATCGGTC 451 TrCCCCCTGG CGCCCTGCTC CAGGAGCACC TCCGAGAGCA CAGCGGCCCT 501 GGGCTGCCTG GTCAAGGACT ACTTCCCCGA ACCGGTGACG GTGTCGTGGA 551 ACTCAGGCGC TCTGACCAGC GGCGTGCACA CCTrCCCAGC TGTCCTACAG 40 601 TCCTCAGGAC TCTACTCCCT CAGCAGCGTG GTGACCGTGC CCTCCAGCAA 651 CTrCGGCACC CAGACCTACA CCTGCAACGT AGATCACAAG CCCAGCAACA 701 CCAAGGTGGA CAAGACAGTT GAGCGCAAAT GTTGTGTCGA GTGCCCACCG 751 TGCCCAGCAC CACCTGTGGC AGGACCGTCA GTCTTCCTCT TCCCCCCAAA 801 ACCCAAGGAC ACCCTCATGA TCTCCCGGAC CCCTGAGGTC ACGTGCGTGG 45 851 TGGTGGACGT GAGCCACGAA GACCCCGAGG TCCAGTTCAA CTGGTACGTG 901 GACGGCGTGG AGGTGCATAA TGCCAAGACA AAGCCACGGG AGGAGCAGTf 951 CAACAGCACG TrCCGTGTGG TCAGCGTCCT CACCGTrGTG CACCAGGACT 1001 GGCTGAACGO CAAGGAGTAC AAGTGCAAGG TCTCCAACAA AGGCCTCCCA 1051 GCCCCCATCG AGAAAACCAT CTCCAAAACC AAAGGGCAGC CCCGAGAACC SEA 1803911v 60117-2Z 54 WO 2006/119062 PCT/US2006/016345 111 ACAGGTGTAC ACCCTGCCCC CATCCCGGGA GGAGATGACC AAGAACCAGG 1151 TCAGCCTGAC CTGCCTGGTC AAAGGCTTCT ACCCCAGCGA CATCGCCGTG 1201 GAGTGGAGA GCAATGGGCA GCCGGAGAAC AACTACAAGA CCACACCTCC 1251 CATGCTGGAC TCCGACGGCT CCTTCTTCCT CTACAGCAAG CTCACCGTGG 5 1301 ACAAGAGCAG GTGGCAGCAG GGGAACGTCT TCTCATGCTC CGTGATGCAT 1351 GAGGCTCTGC ACAACCACTA CACGCAGAAG AGCCTCTCCC TGTCTCCGGG 1401 TAAA (SEQ ID NO:148) Ab-5 Variable domains: 10 Ab-5 light chain variable domain amino acid sequence (without signal sequence): 1 DIQMTQSPSS LSASVGDRVT ITClSQDISNYI2WYQQKP GKAPKLLIYY 51 1TSIRLT4GVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ Gq1TIPYMFGG 15 101 GTKVEIK (SEQ ID NO:376) Ab-5 light chain variable domain DNA sequence (without signal sequence): 20 1 GACATCCAGA TGACCCAGTC TCCATCCTCC CTCTCCGCAT CCGTAGGCGA 51 CCGCGTAACC ATAACATGTA GAGCATCTCA AGATATTTCC AACTAT1TGA 101 ATTGGTACCA ACAAAAACCC GGCAAAGCAC CTAAACTCCT CATACTAT 151 ACATCAAGAC TCCTCTCCGG CGTTCCATCA CGATTCTCAG GCTCCGGCTC 201 CGGCACAGAT TTCACACTCA CTATTTCCTC CCTCCAACCA GAAGATTTTG 25 251 CAACCTATTA CTGTCAACAA GGCGATACAC TCCCATACAC ATTCGGCGGC 301 GGCACAAAAG TTGAAATUAA A (SEQ ID NO:377) Ab-5 heavy chain variable domain amino acid sequence (without signal sequence): 30 1 EVQLVQSGAE VKKPGASVKV SCKASGYTFT kYNIMVVRQA PGQGLEWMGE 51 J1 AG6 if fRVTM TTDTSTSTAY MELRSLRSDD TAVYYCARLG 101 YDJp1YDDWXF DVWGQGTTVT VSS (SEQ ID NO:378) 35 Ab-5 heavy chain variable domain DNA sequence (without signal sequence): 1 GAGGTGCAGC TGQTGCAGAG CGTGCGCCGAG GTAAAAAAAC CAGGAGCAAG 51 CGTTAAAGTT TCTTGTAAAG CAAGCGGATA TACATTTACA GATTACAACA 101 TGCATTGGGT AAGACAAGCG CCAGGACAAG GATGGAATG GATGGGCGAA 40 151 ATTAACCCTA ATAGTGGAGG AGCAGGCTAC AATCAAAAAT TCAAAGGGAG 201 AGTTACAATG ACAACAGACA CAAGCACTTC AACAGCATAT ATGGAACTGC 251 GATCACTTAG AAGCGACGAT ACAGCTGTAT ACTATTGCGC ACGACTTGGG 301 TATGATOATA TATATGATGA CTGGTATTTC GATGTITGGG GCCAGGGAAC 351 AACAGTTACC GTCTCTAGT (SEQ ID NO:379) 45 The CDR (complementarity determining region) sequences in the variable region of the heavy chain of Ab-5 are as follows: SEA 1803911v 60117-223 55 WO 2006/119062 PCT/US2006/016345 CDR-H1: DYNMII (SEQ I) NO:245) CDR-H2: EINPNSGGAGYNQKFKG (SEQ ID NO:246) CDR-H3: LGYDDIYDDWYFDV (SEQ ID NO:247) The light chain variable region CDR sequences of Ab-5 are: 5 CDR-L1: RASQDISNYLN (SEQ ID NO:78) CDR-L2: YTSRLLS (SEQ ID NO:79) CDR-L3: QQGDTLPYT (SEQ ID NO:80) 10 Ab-6 The sequences of the Antibody 6 (also referred to herein as Ab-6) LC and HC are as follows: Ab-6 Light Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-6 LC: 1 DIQMTQTSS LSASLGDRVT ISCA-SQDiTJ WFQQKP DGTLKLLIF. 15 51 'Rii5'GVPS RFSGSGSGTD YSLTISNLEQ EDIATYFCQ~j iXfYTFGG 101 GTKLEIRRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDINVEWE 151DGSERQNGVL NSWTDQDSKD STYSMSSTLTLTKDEYERHNSYTCEATHKT 201 STSPIVKSFN RNEC (SEQ ID NO:149) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-6 LC: 20 1 GATATCCAGA TGACACAGAC TACATCCTCC CTGTCTGCCT CTCTGGGAGA 51 CAGAGTCACC ATCAGTGCA GGGCAAGTCA GGACATTAGC AATTATTTAA 101 ACTGGTT'CA GCAGAAACCA GATGGAACTC TTAAACTCCT GATCTTCTAC 151 ACATCAAGAT TACACTCAGG AGTrCCATCA AGGTTCAGTG GCAGTGGGTC 201 TGGAACAGAT TATTCTCTCA CCATTAGCAA CCTGGAGCAA QAAGATATTG 25 251 CCACTTACTF TTGCCAACAG GGTGATACGC TITCCGTACAC GTTCGGGGGG 301 GGGACCAAGC TGGAAATAAG ACGGGCTGAT GCTGCACCAA CTGTATCCAT 351 CTTCCCACCA TCCAGTGAGC AGTrAACATC TGGAGGTGCC TCAGTCGTGT 401 GCTTCTTGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA GTGGAAGATT 451 GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA CTGATCAGGA 30 501 CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG TTGACCAAGG 551 ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC TCACAAGACA 601 TCAACTTCAC CCATTGTCAA GAGCTTCAAC AGGAATGAGT GTTAG (SEQ ID NO:150) 35 Amino acid sequence of the Ab-6 LC including signal peptide: .1 MMSSAQFLGL LLLCFQGTRC DIQMTQTTSS LSASLGDRVT ISCRASQDIS 51 NYLNWFQQKP DGTLKLLIFY TSRLHSGVPS RFSGSGSGTD YSLTISNLEQ 101 EDIATYFCQQ GDTLPYTFGG GTKLEIRRAD AAPTVSIFPP SSEQLTSGGA 151 SVVCFLNNFY PKDINVKWKI DGSERQNGVL NSWTDQDSKD STYSMSSTLT 40 201 LTKDEYERHN SYTCEATHKT STSPIVKSFN RNEC (SEQ ID NO: 151) SEA 180391 60117-223 56 WO 2006/119062 PCTIUS2006/016345 Nucleic acid sequence of the Ab-6 LC including signal peptide encoding sequence: 1 ATGATGTCCT CTGCTCAGTr CCTTGGTCTC CTGTTGCTCT GITTTCAAGG 51 TACCAGATGT GATATCCAGA TGACACAGAC TACATCCTCC CTGTCTGCCT 101 CTCTGGGAGA CAGAGTCACC ATCAGTTGCA GGGCAAGTCA GGACATTAGC 5 151 AATTATrTAA ACTGGTITCA GCAGAAACCA GATGGAACTC TTAAACTCCT 201 GATCTTCTAC ACATCAAGAT TACACTCAGG AGTTCCATCA AGGTFCAGTG 251 GCAGTGGGTC TGQAACAGAT TATTCTCTCA CCATTAGCAA CCTGGAGCAA 301 GAAGATATTO CCACTTACTT TTGCCAACAG GGTGATACGC TTCCGTACAC 351 GTrCGGGGGG GGGACCAAGC TGG1AAATAAG ACGGGCTGAT GCTGCACCAA 10 401 CTGTATCCAT CTTCCCACCA TCCAGTGAGC AGTTAACATC TGGAGGTGCC 451 TCAGTCGTGT GCTICTTGAA CAAC~fCTAC CCCAAAGACA TCAATGTCAA 501 GTGGAAGATT GATGG7CAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA 551 CTGATCAGGA CAGCAAAGAC AGCACCTACA GCATGAGCAQ CACCCTCACG 601 TTGACCAAGG ACGAGTATGA ACGACATAAC AGCTATACCT OTGAIGCCAC 15 651 TCACAAGACA TCAACTTCAC CCATJGTCAA GAGCTICAAC AGGAATGAGT 701 GTTAG (SEQ ID NO:152) Ab-6 Heavy Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-6 HC: 20 1 EVQLQQSGPE LMKPGASVKM SCKASGYTFT g)YtI VKQN QGKSLEWIGt 51 fSGSCTY N~KFKGMATL TVDKSSSTAY MELRSLTSED SAVYYCARLV 101 SWIY D'WGAGTrVT VSSAKTTPPS VYPL APGSA A QTNSMVTLGC 151 L VKGYFPEPV TVTWNSGSLS SG VHTFPA VL QSDL YTLSSS VTVPSSTWPS 201 ETVTCNVAHPASSTKVDKKI VPRDCGCKPC ICTVPEVSSV FIFPPKPKDV 25 251 LTJTLTPKVT CVVVDISKDD PEVQFSWFVD DVEVHTAQTQ PREEQFNSTF 301 RSVSELPIMH QDWLNGKEFK CRVNSAAFPA PEKTISKTK GRPKAPQVYT 351 1PPPKEQMAK DKVSLTCHT DFFPEDITVE WQ WNGQPAEN YKNTQPIMDT 401 DGSYFIYSKL NVQKSNWEAG NTFTCSVLHE GLHNHTEKS LSHSPGK (SEQ ID NO:153) 30 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-6 HC: 1 GAGGTCCAGC TGCAACAGTC TGGACCTGAA CTAATGAAGC CTGGGGCTTC 51 AGTGAAGATG TCCTGCAAGG CTTCTGGATA CACATTCACT GACTACAACA 101 TGCACTGGGT GAAACAGAAC CAAGGAAAGA GCCTAGAGTG GATAGGAGAA 35 151 ATrAATCCTA ACAGTGGTGG TAGTGGCTAC AACCAAAAGT TCAAAGGCAA 201 GGCCACATTG ACTGTAGACA AGTCTFCCAG CACAGCCTAC ATGGAGCTCC 251 GCAGCCTGAC ATCTGAGGAC TCTGCAGTCT ATTACTGTGC AAGATrGGTC 301 TACGATGGCA GCTACGAGGA CTGGTACTTC GATGTCTGGG GCGCAGGGAC 351 CACGGTCACC GTCTCCTCAG CCAAAACGAC ACCCCCATCT GTCTATCCAC 40 401 TGGCCCCTGG ATCTGCTGCC CAAACTAACT CCATGGTGAC CCTGGGATGC 451 CTGGTCAAGG GCTATITCCC TGAGCCAGTG ACAGTGACCT GGAACTCTGG 501 ATCCCTGTCC AGCGGTGTGC ACACCTTCCC AGCTGTCCTG CAGTCTGACC 551 TCTACACTCT GAGCAGCTCA GTGACTGTCC CCTCCAGCAC CTGGCCCAGC 601 GAQACCGTCA CCTGCAACGT TGCCCACCCG GCCAGCAGCA CCAAGOTGGA 45 651 CAAGAAAATT GTGCCCAGGG ATTOiTGGTTG TAAGCCTTGC ATATGTACAG 701 TCCCAGAAGT ATCATCTGTC TTCATCTrCC CCCCAAAGCC CAAGGATQTG 751 CTCACCATTA CTCTGACTCC TAAGGTCACG TGTGTTGTGG TAGACATCAG 801 CAAGGATGAT CCCGAGGTCC AGTTCAGCTG GTTTGTAGAT GATGTGGAGG 851 TGCACACAGC TCAGACGCAA CCCCGGGAGG AGCAGTTCAA CAGCACTTTC SEA 1803911.1 60117-n3 57 WO 2006/119062 PCT/US2006/016345 OI UbfCNAA YGAACTTCC CATCATGCAC CAGGACTGGC TCAATGGCAA 951 GGAGTTCAAA TGCAGGGTCA ACAGTGCAGC TTTCCCTGCC CCCATCGAQA 1001 AAACCATCTC CAAAACCAAA GGCAGACCGA AGGCTCCACA GGTGTACACC 1051 AITCCACCTC CCAAGGAGCA GATGGCCAAG GATAAAGTCA GTCTGACCTG 5 1101 CATGATAACA GACTTCTTCC CTGAAGACAT TACTGTGGAG TGGCAGTGGA 1151 ATGGGCAGCC AQCGGAGAAC TACAAGAACA CTCAGCCCAT CATGGACACA 1201 GATGGCTCTT ACITCATCTA CAGCAAGCTC AATGTGCAGA AGAGCAACTG 1251 GGAGGCAGGA AATACTTTCA CCTGCTCTGT GTTACATGAG GGCCTGCACA 1301 ACCACCATAC TGAGAAGAGC CTCTCCCACT CTCCTGGTAA ATGA (SEQ ID 10 NO:154) Amino acid sequence of the Ab-6 HC including signal peptide: 1 MGWSWTFLFL LSGTAGVLSE VQLQQSGPEL MKPGASVKMS CKASGYTFTD 51 YNMHWVKQNQ GKSLEWIGEI NPNSGGSGYN QKFKGKATLT VDKSSSTAYM 15 101 ELRSLTSEDS AVYYCARLVY DGSYEDWYFD VWGAGTTVTV SSAKTTPPSV 151 YPLAPGSAAQ TNSMVTLGCL VKGYFPEPVT VTWNSGSLSS GVHTFPAVLQ 201 SDLYTLSSSV TVPSSTWPSE TVTCNVAHPA SSTKVDKKIV PRDCGCKPCI 251 CTVPEVSSVF IFPPKPKDVL TITLTPKVTC VVVDISKDDP EVQFSWFVDD 301 VEVHTAQTQP REEQFNSTFR SVSELPIMHQ DWLNGKEFKC RVNSAAFPAP 20 351 IEKTISKTKG RPKAPQVYTI PPPKEQMAKD KVSLTCMITD FFPEDITVEW 401 QWNGQPAENY KNTQPIMDTD GSYFIYSKLN VQKSNWEAGN TFTCSVLHEG 451 LHNHTEKSL SHSPGK (SEQ ID NO:155) Nucleic acid sequence of the Ab-6 HC including signal peptide encoding sequence: 25 1 ATGGGATGGA GCTGGACCTT TCTCTTCCTC CTGTCAGGAA CTGCAGGTGT 51 CCTCTCTGAG GTCCAGCTGC AACAGTCTGG ACCTGAACTA ATGAAGCCTG 101 GGGCTTCAGT GAAGATGTCC TGCAAGGCTF CTGGATACAC ATTCACTGAC 151 TACAACATGC ACTGGGTGAA ACAGAACCAA GGAAAGAGCC TAGAGTGGAT 201 AGGAGAAATT AATCCTAACA GTGGTGGTAG TGGCTACAAC CAAAAGTTCA 30 251 AAGGCAAGGC CACATrGACT GTAGACAAGT CTTCCAGCAC AGCCTACATG 301 GAGCTCCGCA GCCTGACATC TGAGGACTCT GCAGTCTATT ACTGTGCAAG 351 ATTGGTCTAC GATGGCAGCT ACGAGGACTG GTACTTCGAT QTCTGGGGCO 401 CAGGGACCAC GGTCACCGTC TCCTCAGCCA AAACGACACC CCCATCTGTC 451 TATCCACTGG CCCCTGGATC TGCTGCCCAA ACTAACTCCA TGGTGACCCT 35 501 GGGATGCCTG GTCAAGGGCT ATITCCCTGA GCCAGTGACA GTGACCTGGA 551 ACTCTGGATC CCTGTCCAGC GGTGTGCACA CCTTCCCAGC TGTCCTGCAG 601 TCTGACCTCT ACACTCTGAG CAGCTCAGTG ACTGTCCCCT CCAGCACCTG 651 GCCCAGCGAG ACCGTCACCT GCAACGTTGC CCACCCGGCC AGCAGCACCA 701 AGGTGGACAA GAAAATTGTG CCCAGGGATT GTGGTTGTAA GCCTfGCATA 40 751 TGTACAGTCC CAGAAGTATC ATCTGTCTTC ATCTTCCCCC CAAAGCCCAA 801 GGATGTGCTC ACCATTACTC TGACTCCTAA GGTCACGTGT GTfGTGGTAG 851 ACATCAGCAA GGATGATCCC GAGGTCCAGT TCAGCTGGTT TGTAGATGAT 901 GTGGAGGTGC ACACAGCTCA GACGCAACCC CGGGAGGAGC AGTTCAACAG 951 CACTITCCGC TCAGTCAGTG AACTTCCCAT CATGCACCAG GACTGGCTCA 45 1001 ATGGCAAGGA GTTCAAATOC AGGGTCAACA GTGCAGCTTT CCCTGCCCCC 1051 ATCGAGAAAA CCATCTCCAA AACCAAAGGC AGACCGAAGG CTCCACAGGT 1101 GTACACCAT[ CCACCTCCCA AGGAGCAGAT GGCCAAGGAT AAAGTCAGTC 1151 TGACCTGCAT GATAACAOAC TTCTTCCCTQ AAGACATTAC TGTGGAGTGG 1201 CAGTGGAATG GGCAGCCAGC GGAGAACTAC AAGAACACTC AGCCCATCAT SEA 1803911v1 60117-M 58 WO 2006/119062 PCT/US2006/016345 1251'5C4CX(A1 (GCTCTTACT TCATCTACAG CAAGCTCAAT GTGCAGAAGA 1301 GCAACTGGGA GGCAGGAAAT AC1TTCACCT GCTCTGTGTT ACATGAGGGC 1351 CTGCACAACC ACCATACTGA GAAGAGCCTC TCCCACTCTC CTGGTAAATG 1401 A (SEQ IDNO:156) 5 The sequences of the Antibody 7 (also referred to herein as Ab-7) LC and HC are as follows: Ab-7 Ligbt Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-7 LC: 10 1 DIQMTQTTSS LSASLGDRVT ICCPS QnLIWYQQKP DGTFKLLIYY 51 fTSRLI GVPS RFSGSGSGTD YSLTISNLEQ EDIATYFCQQ GDLPMFGG 101 GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PEDINVEWK 151 DGSERQNGVL NSW TDQDSKD STYSMSSTLTLTEDEYERHN SYTCE A TIAT 201 STSPIVKSFN RNEC (SEQ ID NO:157) 15 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-7 LC: 1 GATATCCAGA TGACACAGAC TACATCCTCC CTGTCTGCCT CTCTGGGAGA 51 CAGAGTCACC ATCTGTTGCA GGGCAAGTCA GGTCATTACC AATTAT1TAT 101 ACTGGTATCA GCAGAAACCA GATGGAACTT TTAAACTCCT GATCTACTAC 20 151 ACATCAAGAT TACACTCAGG AGTCCCATCA AGGTTCAGTG GCAGTGGGTC 201 TGGAACAGAT TATTCTCTCA CCATTAGCAA CCTGGAACAG GAAGATATTG 251 CCACTTACTT TTGCCAACAG GGTGATACGC TTCCGTACAC GTTCGGAGGG 301 GGGACCAAGC TGGAAATAAA ACGGGCTGAT GCTGCACCAA CTGTATCCAT 351 CTTCCCACCA TCCAGTGAGC AGTTAACATC TGGAGGTGCC TCAGTCGTGT 25 401 GCTTCTTGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA GTGGAAGAT 451 GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA CTGATCAGGA 501 CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG TGACCAAGG 551 ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC TCACAAGACA 601 TCAACTTCAC CCATTGTCAA GAGCTTCAAC AGGAATGAGT GT (SEQ ID 30 NO:158) Amino acid sequence of the Ab-7 LC including signal peptide: 1 MMSSAQFLGL LLLCFQGTRC DIQMTQTTSS LSASLGDRVT ICCRASQVIT 51 NYLYWYQQKP DGTFKLUYY TSRLHSGVPS RFSGSGSGTD YSLTISNLEQ 35 101 EDIATYFCQQ-GDTLPYTFGG GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA 151 SVVCFLNNFY PKDINVKWKI DGSERQNGVL NSWTDQDSKD STYSMSSTLT 201 LTKDEYERHN SYTCEATHKT STSPIVKSFN RNEC (SEQ ID NO:159) Nucleic acid sequence of the Ab-7 LC including signal peptide encoding sequence: 40 1 ATGATGTCCT CTGCTCAGTT CCTTGGTCTC CTGTTGCTCT GFTCAAGG 51 TACCAGATGT GATATCCAGA TGACACAGAC TACATCCTCC CTGTCTGCCT 101 CTCTGGGAGA CAGAGTCACC ATCTGTTGCA GGGCAAGTCA GGTCATTACC 151 AATTATTAT ACTGGTATCA GCAGAAACCA GATGGAACTT TTAAACTCCT 201 GATCTACTAC ACATCAAGAT TACACTCAGG AGTCCCATCA AGGTTCAGTG 45 251 GCAGTGGGTC TGGAACAGAT TAITCTCTCA CCATTAGCAA CCTGGAACAG 301 GAAGATATfG CCACTTACTr TTGCCAACAG GGTGATACGC TTCCGTACAC SEA 1803911vi 60117-223 59 WO 2006/119062 PCTIUS2006/016345 351 GTCfGfA~5GodGGACCAAGC TGGAAATAAA ACGGGCTGAT GCTGCACCAA 401 CTGTATCCAT CTTCCCACCA TCCAGTGAGC AGTTAACATC TGGAGGTGCC 451 TCAGTCGTGT GCTlCTTGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA 501 GTGGAAGATT GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA 5 551 CTGATCAGGA CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG 601 T1GACCAAGG ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC 651 TCACAAGACA TCAACTTCAC CCATTGTCAA GAGCTTCAAC AGGAATGAGT 701 GT (SEQ ID NO:160) 10 Ab-7 Heavy Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-7 HC: 1 EVQLQQSGPE LMKPGASVKM SCKASGYTFT YiNth "WMKQN QGKSLEWIG5 51 INPTSOGAGY NQQFKGKATL TVDKSSRTAY MELRSLTSED SAVYYCARL 10 1'&YGNYEDWYF DVWGAGTrVT VSSAKTTPPS VYPLAPGSAA QTNSMVTLGC 15 151 LVKGYFPEP TVTIWNSGSLS SGVHTFPAVL QSDLYTLSSS VTVPSSTWPS 201 ETVTCNVAHP ASSTKVDEKI VPRDCGCEPC ICTVPEVSSV FIFPPKPEDV 251 LTITLTPKVT CVVVDISKDD PEVQFSWFVD DVEVHTAQTQ PREEQFNSTF 301 RSVSELPM H QDWNGfEFK CRVNSAAFPA PLEKTISKTK GRPKAPQVYT 351 1PPPEEQMAK DKVSLTCMIT DFFPEDITVE WQWNGQPAEN YENTQPIMDT 20 401 DGSYFIYSEL NVQKSNWEAG NTFTCSVLHE GLIHNHHTEKS LSHSPGK (SEQ ID NO:161) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-7 HC: 1 GAGGTCCAGC TGCAACAGTC TGGACCTGAA CTAATGAAGC CTGGGGCTTC 25 51 AGTGAAGATG TCCTGCAAGG2 CTTCTGGATA CACATTCACT GACTACAACA 101 TGCACTGOAT GAAGCAGAAC CAAGGAAAGA GCCTAGAATG GATAGGAGAA 151 AT'AATCCTA ACAGTGGTGG TGCTGGCTAC AACCAGCAGT TCAAAGGCAA 201 GGCCACATI'G ACTGTAGACA AGTCCTCCAG GACAGCCTAC ATGGAGCTCC 251 GCAGCCTGAC ATCTGAGGAC TCTGCAGTCT ATTACTGTGC AAGATTGGGC 30 301 TACGTTGTA AT'ACGAGGA CTGGTACTTC GATGTCTGGGi GCGCAGGGAC 351 CACGGTCACC GTCTCCTCAG CCAAAACGAC ACCCCCATCT GTCTATCCAC 401 TGGCCCCTGG ATCTGCTGCC CAAACTAACT CCATGGTGAC CCTGGGATGC 451 CTGGTCAAGG GCTAflTCCC TQAGCCAGTG ACAGTGACCT cGGAACTCTGG 501 ATCCCTGTCC AGCGGTGTGC ACACCTI'CCC AGCTGTCCTG CAGTCTGACC 35 551 TCTACACTCT GAGCAGCTCA GTGACTGTCC CCTCCAGCAC CTGGCCCAGC 601 GAGACCGTCA CCTGCAACGT TGCCCACCCG GCCAGCAGCA CCAAGGTGGA 651 CAAGAAAATT GTGCCCAGGG ATTGTGGTrG TAAGCCTTGC ATATGTACAG 701 TCCCAGAAGT ATCATCTQTC TTCATCTCC CCCCAAAGCC CAAGGATGTG 751 CTCACCATTA CTCTGACTCC TAAGGTCACG TGTGTTGTGG TAGACATCAG 40 801 CAAGGATGAT CCCGAGGTCC AGTCAGCTG GCTTGTAGAT GATGTOGACG 851 TGCACACAGC TCAGACGCAA CCCCGGGAGG AGCAGTrCAA CAGCACTITC 901 CGCTCAGTCA GTGAACTfCC CATCATGCAC CAGGACTGGC TCAATGGCAA 951 GGAGTFCAAA TGCAGGGTCA ACAGTGCAGC TTCCCTGCC CCCATCGAGA 1001 AAACCATCTC CAAAACCAAA GGCAGACCQA AGGCTCCACA GGTGTACACC 45 1051 ATTCCACCTC CCAAGGAGCA GATGGCCAAG GATAAAGTCA GTCTGACCTG 1101 CATGATAACA GACTTCTTCC CTGAAGACAT TACTGTGGAG TGQCAGTGGA 1151 ATGGGCAGCC AGCGGAGAAC TACAAGAACA CTCAGCCCAT CATGGACACA 1201 GATGGCTCTT ACTTCATCTA CAGCAAGCTC AATGTGCAGA AGAGCAACTG 1251 GGAGGCAGGA AATACTITCA CCTGCTCTGT OTTACATGAG GGCCTGCACA SEA 1803911v 60117-n3 60 WO 2006/119062 PCT/US2006/016345 1301 A&dATArA"t -fdAGAAGAGC CTCTCCCACT CTCCTGGTAA A (SEQ ID NO:162) Amino acid sequence of the Ab-7 HC including signal peptide: 5 1 MGWSWTFLFL LSGTAGVLSE VQLQQSGPEL MKPGASVKMS CKASGYTFTD 51 YNMHWMKQNQ QKSLEWIGEI NPNSGGAGYN QQFKGKATLT VDKSSRTAYM 101 ELRSLTSEDS AVYYCARLGY VGNYEDWYFD VWGAGTIVTV SSAKTTPPSV 151 YPLAPGSAAQ TNSMVTLGCL VKGYFPEPVT VTWNSGSLSS GVHTFPAVLQ 201 SDLYTLSSSV TVPSSTWPSE TVTCNVAHPA SSTKVDKKIV PRDCGCKPCI 10 251 CTVPEVSSVF IFPPKPKDVL TITLTPKVTC VVVDISKDDP EVQFSWFVDD 301 VEVHTAQTQP REEQFNSTFR SVSELPIMHQ DWLNGKEFKC RVNSAAFPAP 351 IEKTISKTKG RPKAPQVYTI PPPKEQMAKD KVSLTCMITD FFPEDITVEW 401 QWNGQPAENY KNTQPIMDTD GSYFIYSKLN VQKSNWEAGN TFTCSVLHEG 451 LHNHHTEKSL SHSPGK (SEQ ID NO:163) 15 Nucleic acid sequence of the Ab-7 HC including signal peptide encoding sequence: 1 ATGGGATGGA GCTGGACCTT TCTCYTCCTC CTGTCAGGAA CTGCAGGTGT 51 CCTCTCTGAG GTCCAGCTGC AACAGTCTGG ACCTGAACTA ATGAAGCCTG 101 GGGCTTCAGT GAAGATGTCC TGCAAGGCTT CTGGATACAC ATTCACTGAC 20 151 TACAACATGC ACTGGATGAA GCAGAACCAA GGAAAGAGCC TAGAATGGAT 201 AGGAGAAATT AATCCTAACA GTGGTGGTGC TGGCTACAAC CAGCAGTrCA 251 AAGGCAAGGC CACATTGACT GTAGACAAGT CCTCCAGGAC AGCCTACATG 301 GAGCTCCGCA GCCTGACATC TGAGGACTCT GCAGTCTATT ACTGTGCAAG 351 ATTGGGCTAC GTTGGTAATT ACGAGGACTG GTACTrCGAT GTCTGGGGCG 25 401 CAGCGGACCAC GGTCACCGTC TCCTCAGCCA AAACGACACC CCCATCTGTC 451 TATCCACTGG CCCCTGGATC TGCTGCCCAA ACTAACTCCA TGGTGACCCT 501 GGGATGCCTG GTCAAGGGCT ATCCCTGA GCCAGTGACA GTGACCTGGA 551 ACTCTGGATC CCTGTCCAGC GGTGTGCACA CCTTCCCAGC TGTCCTGCAG 601 TCTGACCTCT ACACTCTGAG CAGCTCAGTG ACTGTCCCCT CCAGCACCTG 30 651 GCCCAGCGAG ACCGTCACCT GCAACGTTGC CCACCCGGCC AGCAGCACCA 701 AGGTGGACAA GAAAATTGTG CCCAGGGATT GTGGTTOTAA GCCTTGCATA 751 TGTACAGTCC CAGAAGTATC ATCTGTCTTC ATCTTCCCCC CAAAGCCCAA 801 GGATGTGCTC ACCATTACTC TGACTCCTAA GGTCACGTGT GTTGTGGTAG 851 ACATCAGCAA GGATGATCCC GAGOiTCCAGT TCAGCTGQTT TGTAGATQAT 35 901 GTGQAGGTGC ACACAGCTCA GACGCAACCC CGGGAGGAGC AGTTCAACAG 951 CACTICCGC TCAGTCAGTG AACTTCCCAT CATGCACCAG GACTGGCTCA 1001 ATGGCAAGGA GTTCAAATGC AGGGTCAACA GTGCAGCTIT CCCTGCCCCC 1051 ATCGAGAAAA CCATCTCCAA AACCAAAGGC AQACCGAAGG CTCCACAGGT 1101 GTACACCAT CCACCTCCCA AGGAGCAGAT GGCCAAGGAT AAAGTCAGTC 40 1151 TGACCTGCAT GATAACAGAC TTCTTCCCTG AAGACATTAC TGTGGAGTGG 1201 CAGTGGAATG GGCAGCCAGC GGAGAACTAC AAGAACACTC AGCCCATCAT 1251 GGACACAGAT GGCTCTTACT TCATCTACAG CAAGCTCAAT GTGCAGAAGA 1301 GCAACTGGGA GGCAGGAAAT ACTTTCACCT GCTCTGTGTT ACATGAGGGC 1351 CTGCACAACC ACCATACTGA GAAGAGCCTC TCCCACTCTC CTGGTAAA 45 (SEQ ID NO:164) Ab-8 The sequences of the Antibody 8 (also referred to herein as Ab-8) LC and HC are as follows: SEA 1803911v 60117-223 61 WO 2006/119062 PCT/US2006/016345 Ab-8 Light Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-8 LC: 1 DIQMTQTTSS LSASLGDRVS ISCASQDIS NYINWYQQKP DGTFKLLIFX. 51 riSRLLSGVPS RFSGSGSGTD YSLT1YNLEQ EDFATYFC'QQGDTLYIG 5 101 GTKLEIKRAD AAPTVSIFPP SSEQL7SGGA SVVCFLNNFY PKDNVWEKI 151 DGSERQNGVL NSWTDQDSKD STYSMSSTLT LTKDEYER HN SYTCEA THKT 201 STSPIVKSFN RNEC (SEQ ID NO:165) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-8 LC: 10 1 GATATCCAGA TGACACAGAC TACATCCTCC CTGTCTGCCT CTCTGGGAGA 51 CAGGGTCTCC ATCAGTTGCA GGGCAAGTCA AGACATTAGC AATTATITAA 101 ACTGGTATCA GCAGAAACCA GATGGAACTT TTAAACTCCT TATCTTCTAC 151 ACATCAAGAT TACTCTCAGG AGTCCCATCA AGGTTCAGTG GCAGTGOTC 201 TGGAACAGAT TATTCTCTCA CCATITACAA CCTGGAGCAA GAAGATTTTG 15 251 CCACTTACTF TTGCCAACAG GGAGATACGC TTCCGTACAC TTCGGAGGG 301 GGGACCAAAC TGGAAATAAA ACGGGCTGAT GCTGCACCAA CTGTATCCAT 351 CTTCCCACCA TCCAGTGAGC AGTIFAACATC TGGAGGTGCC TCAGTCGTGT 401 GCTTCTTGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA GTGGAAGATT 451 GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTrGGA CTGATCAGGA 20 501 CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG TTGACCAAGG 551 ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC TCACAAGACA 601 TCAACTLCAC CCATTGTCAA GAGCTTCAAC AGGAATGAGT GTTAG (SEQ ID NO: 166) 25 Amino acid sequence of the Ab-8 LC including signal peptide: 1 MMSSAQFLGL LLLCFQGTRC DIQMTQTTSS LSASLGDRVS ISCRASQDIS 51 NYLNWYQQKP DGTFKLLIFY TSRLLSGVPS RFSGSGSGTD YSLTIYNLEQ 101 EDFATYFCQQ GDTLPYTFGG OTKLEIKRAD AAPTVSIFPP SSEQLTSGGA 151 SVVCFLNNFY PKDINVKWKI DGSERQNGVL NSWTDQDSKD STYSMSSTLT 30 201 LTKDEYERHN SYTCEATHKT STSPIVKSFN RNEC (SEQ ID NO:167) Nucleic acid sequence of the Ab-8 LC including signal peptide encoding sequence: 1 ATGATGTCCT CTGCTCAGTI CCTrGGTCTC CTGThGCTCT GTIFCAAGG 51 TACCAGATGT GATATCCAGA TGACACAGAC TACATCCTCC CTGTCTGCCT 35 101 CTCTGGGAGA CAGGGTCTCC ATCAGTTGCA GGGCAAGTCA AGACATTAGC 151 AATTATTTAA ACTGGTATCA GCAGAAACCA GATGGAACTT TTAAACTCCT 201 TATCTTCTAC ACATCAAGAT TACTCTCAGG AGTCCCATCA AGGTTCAGTG 251 GCAGTGGGTC TGGAACAGAT TATrCTCTCA CCATITACAA CCTGGAGCAA 301 GAAGATITG CCACTTACTT TTGCCAACAG GGAGATACGC TTCCGTACAC 40 351 TTTCGGAGGG GGGACCAAAC TGGAAATAAA ACGGGCTGAT GCTGCACCAA 401 CTGTATCCAT CTFCCCACCA TCCAGTGAGC AGTTAACATC TGGAGGTGCC 451 TCAGTCGTGT GCTTCTTGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA 501 GTGGAAGATT GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA 551 CTGATCAGGA CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG 45 601 TTGACCAAGG ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC 651 TCACAAGACA TCAACTTCAC CCATTGTCAA GAGCTTCAAC AGGAATGAGT 701 GT TAG (SEQ ID NO:168) SEA 180391nv1 60117-223 62 WO 2006/119062 PCTIUS2006/016345 Ab-8 Heavy thain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-8 HC: 1 EVQLQQSGPE LMKPGASVKM SCKASGYTFT DYNMIWVKQN QGKTLDWIGE 51 ONPNSGGAGY NQKFKQKATL TVDKSSTTAY MELRSLTSED SAVYYCARG 5 101 LYDDIYDDWY F DVWGAGTIVT VSSAKTTPPS VYPLAPGSAA QTNSMVTLGC 151 L VKGYFPEPV TVTWNSGSLS SG VHTFPA VL QSDLYTLSSS VTVPSSTWPS 201 ETVTCNVARPASSTKVDKI VPRDCGCEPC ICTVPEVSSVFLFPPKPEDV 251 LTITLTPKVT CVVVDISKDD PEVQFSWFVD DVEVHTAQTQ PREEQFNSTF 301 RSVSELPIMH QDWLNGEEFK CR VNSAAFPA PIEKTISKTK GRPKAPQVYT 10 351 IPPPKEQMAKDKVSLTCMTDFFPEDITVE WQWNGQPAEN YKNTQPIMDT 401 DGSYFIYSKL NVQKSNWEA G NTFTCSVLHE GLHNHHTEKS LSHSPGK (SEQ ID NO:169) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-8 HC: 15 1 GAGGTCCAAC TGCAACAGTC TGGACCTGAA CTAATGAAGC CTGGGGCTTC 51 AQTGAAGATG TCCTGCAAGG CTTCTGGATA TACATTCACT GACTACAACA 101 TGCACTGGGT GAAGCAGAAC CAAGGAAAGA CCCTAGACTG GATAGGAGAA 151 ATrAATCCTA ACAGTGGTGG TGCTGGCTAC AACCAGAAGT TCAAGGGCAA 201 GGCCACATfG ACTGTAGACA AGTCCTCCAC CACAGCCTAC ATGGAGCTCC 20 251 GCAGCCTGAC ATCTGAGGAC TCTGCAGTCT ATTACTGTGC AAGATGTGGC 301 TACGATGATA TCTACGACGA CTGGTACTTC GATGTCTGGG GCGCAGGGAC 351 CACGGTCACC GTCTCCTCAG CCAAAACGAC ACCCCCATCT GTCTATCCAC 401 TGGCCCCTGG ATCTGCTGCC CAAACTAACT CCATGGTGAC CCTGGGATGC 451 CTGGTCAAGG GCTATTfCCC TGAGCCAQTG ACAGTGACCT GGAACTCTGG 25 501 ATCCCTGTCC AGCGGTGTGC ACACCTTCCC AGCTGTCCTG CAGTCTGACC 551 TCTACACTCT GAGCAGCTCA GTGACTGTCC CCTCCAGCAC CTGGCCCAGC 601 GAGACCGTCA CCTGCAACGT TGCCCACCCG GCCAGCAGCA CCAAGGTGGA 651 CAAGAAAATT GTGCCCAGGG ATTGTGGTrG TAAGCCTTGC ATATGTACAG 701 TCCCAGAAGT ATCATCTGTC TTCATCTCC CCCCAAAGCC CAAGGATOTG 30 751 CTCACCATrA CTCTGACTCC TAAGGTCACG TGTGTFGTGG TAGACATCAG 801 CAAGGATGAT CCCGAGGTCC AGTTCAGCTQ GTTGTAGAT GATGTGGAGGx 851 TGCACACAGC TCAGACGCAA CCCCGGGXAGG AGCAGTCAA CAGCACTMTC 901 CGCTCAGTCA GTGAACTTCC CATCATGCAC CAGGACTGGC TCAATGGCAA 951 GGAGTTCAAA TGCAGGGTCA ACAGTGCAGC TTTCCCTGCC CCCATCGAGA 35 1001 AAACCATCTC CAAAACCAAA GGCAGACCGA AGGCTCCACA GGTGTACACC 1051 ATTCCACCTC CCAAGGAGCA GATGGCCAAG GATAAAGTCA GTCTGACCTG 1101 CATGATAACA GACTTCTTCC CTGAAGACAT TACTGTGGAG TGGCAGTGGA 1151 ATGGGCAGCC AGCGGAGAAC TACAAGAACA CTCAGCCCAT CATGGACACA 1201 GATGGCTCTT ACTTCATCTA CAGCAAGCTC AATGTGCAGA AGAGCAACTG 40 1251 GGAGGCAGGA AATACTTTCA CCTGCTCTGT GTTACATGAG GGCCTGCACA 1301 ACCACCATAC TGAGAAGAGC CTCTCCCACT CTCCTGGTAA ATGA (SEQ ID NO:170) Amino acid sequence of the Ab-8 HC including signal peptide: 45 1 MGWSWTFLFL LSGTAGVLSE VQLQQSGPEL MKPGASVKMS CKASGYTFTD 51 YNMHWVKQNQ GKTLDWIGEI NPNSGGAGYN QKFKGKATLT VDKSSTTAYM 101 ELRSLTSEDS AVYYCARLGY DDIYDDWYFD VWGAGTIVTV SSAKTTPPSV 151 YPLAPGSAAQ TNSMVTLGCL VKQYFPEPVT VTWNSGSLSS GVHTFPAVLQ SEA 1803911v 60117-22 63 WO 2006/119062 PCTIUS2006/016345 2(i1 SD USWTWSBTWPSE TVTCNVAHPA SSTKVDKKIV PRGDCGCKPCI 251 CTVPEVSSVF IFPPKPKDVL TITLTPKVTC VVVDISKDDP EVQFSWFVDD 301 VEVHTAQTQP REEQFNSTFR SVSELPIMHQ DWLNGKEFKC RVNSAAFPAP 351 IEKTISKTKG RPKAPQVYTI PPPKEQMAKD KVSLTCMITD FFPEDITVEW 5 401 QWNGQPAENY KNTQPIMDTD GSYFIYSKLN VQKSNWEAGN TFTCSVLHEG 451 LHNHHTEKSL SHSPGK (SEQ ID NO:171) Nucleic acid sequence of the Ab-8 HC including signal peptide encoding sequence: I ATGGGATGGA GCTGGACCTT TCTCT7CCTC CTGTCAGGAA CTGCAGGTGT 10 51 CCTCTCTGAG GTCCAACTGC AACAGTCTGG ACCTGAACTA ATGAAGCCTQ 101 GGGCTTCAGT GAAGATGTCC TGCAAGOCTT CTGGATATAC ATFCACTGAC 151 TACAACATGC ACTGGGTGAA GCAGAACCAA GGAAAGACCC TAGACTGGAT 201 AGGAGAAATT AATCCTAACA GTGGTGGTGC TGGCTACAAC CAGAAGTICA 251 AGGGCAAGGC CACATFGACT GTAGACAAGT CCTCCACCAC AGCCTACATG 15 301 GAGCTCCGCA GCCTGACATC TGAGGACTCT GCAGTCTATT ACTGTGCAAG 351 ATFGGGCTAC GATGATATCT ACGACGACTG GTACTTCGAT GTCTGGGGCG 401 CAGGGACCAC GGTCACCGTC TCCTCAGCCA AAACGACACC CCCATCTGTC 451 TATCCACTGG CCCCTGGATC TGCTGCCCAA ACTAACTCCA TGGTGACCCT 501 GGGATGCCTG GTCAAGGGCT ATTTCCCTGA GCCAGTGACA GTGACCTGGA 20 551 ACTCTGGATC CCTGTCCAGC GGTGTGCACA CCTTCCCAGC TGTCCTGCAG 601 TCTGACCTCT ACACTCTGAG CAGCTCAGTG ACTGTCCCCT CCAGCACCTG 651 GCCCAGCGAG ACCGTCACCT GCAACGTTGC CCACCCGGCC AGCAGCACCA 701 AGGTGGACAA GAAAATTGTG CCCAGGGATT GTGGTTGTAA GCCTTGCATA 751 TGTACAGTCC CAGAAGTATC ATCTGTCTTC ATCTTCCCCC CAAAGCCCAA 25 801 GGATGTGCTC ACCATTACTC TGACTCCTAA GGTCACGTGT GTFGTGGTAG 851 ACATCAGCAA GGATGATCCC GAGGTCCAGT TCAGCTGGTI TGTAGATGAT 901 GTGGAGGTGC ACACAGCTCA GACGCAACCC CGGGAGGAGC AGTTCAACAG 951. CACTITCCGC TCAGTCAGTG AACTTCCCAT CATGCACCAG GACTGGCTCA 1001 ATGGCAAGGA GTCAAATGC AGGGTCAACA GTGCAGCTTr CCCTGCCCCC 30 1051 ATCGAGAAAA CCATCTCCAA AACCAAAGGC AGACCGAAGG CTCCACAGGT 1101 GTACACCATT CCACCTCCCA AGGAGCAGAT GGCCAAGGAT AAAGTCAGTC 1151 TGACCTGCAT GATAACACAC TTCTTCCCTG AAGACATTAC TGTGGAGTGG 1201 CAGTGGAATG GGCAGCCAGC GGAGAACTAC AAGAACACTC AGCCCATCAT 1251 GGACACAGAT GGCTCTTACT TCATCTACAG CAAGCTCAAT GTGCAGAAGA 35 1301 GCAACTGGGA GGCAGGAAAT ACTfTCACCT GCTCTGTGTT ACATGAGGGC 1351 CTGCACAACC ACCATACTGA GAAGAGCCTC TCCCACTCTC CTGGTAAATG 1401 A (SEQ ID NO:172) Ab-9 40 The sequences of the Antibody 9 (also referred to herein as Ab-9) LC and HC are as follows: Ab-9 Light Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-9 LC: 1 DIQMTQITSS LSASLGDRVS ISC ASQnSINYLNWYQQKP DGTFKLLFY 51 SRLFSGVPS RFSGSGSGTD YSLTIYNLEQ EDFATYFCQQGDTLPYFGG 45 101 GTKVEI KR AAPTVSIFPP SSEQLTSGGA SVVCFLNNFY PKDNVKWKI 151 DGSERQNGVL NSWTDQDSKD STYSMSSTLT LTKDEYERHN SYTCEA THKT 201 STSPIVKSFNRNEC (SEQ ID NO:173) SEA 1803911yI 60117-M 64 WO 2006/119062 PCT/US2006/016345 Nucleic acid siquei 6 e encoding the mature form (signal peptide removed) of the Ab-9 LC: 1 GATATCCAGA TGACACAGAT TACATCCTCC CTGTCTGCCT CTCTGGGAGA 51 CAGGGTCTCC ATCAGTTGCA GGGCAAGTCA AQACATTAGC AATTATTTAA 101 ATrGGTATCA GCAGAAACCA GATGGAACTT TrAAACTCCT TATCTTCTAC 5 151 ACATCAAGAT TAITITCAGG AGTCCCATCA AGGTTCAGTG GCAGTGGGTC 201 TGQAACAGAT TATTCTCTCA CCATACAA CCTGGAGCAA GAAGAITTG 251 CCACTTACT TTGCCAACAG GGAGATACGC TrCCGTACAC TTTCGGAGGG 301 GGGACCAAGG TGGAAATAAA ACGGGCTGAT GCTGCACCAA CTGTATCCAT 351 CTICCCACCA TCCAGTGAGC AGTrAACATC TGGAGGTGCC TCAQTCGTGT 10 401 GCTTCTTGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA GTGGAAGATr 451 GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA CTGATCAGGA 501 CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG TrGACCAAGG 551 ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC TCACAAGACA 601 TCAACTTCAC CCATFGTCAA GAGCTTCAAC AGGAATGAGT GT (SEQ ID 15 NO:174) Amino acid sequence of the Ab-9 LC including signal peptide: 1 MMSSAQFLGL LLLCFQGTRC DIQMTQITSS LSASLGDRVS ISCRASQDIS 51 NYLNWYQQKP DGTFKLLIFY TSRLFSGVPS RFSGSGSGTD YSLTIYNLEQ 20 101 EDFATYFCQQ GDTLPYTFGG GTKVEIKRAD AAPTVSIFPP SSEQLTSGGA 151 SVVCFLNNFY PKDINVKWKI DGSERQNGVL NSWTDQDSKD STYSMSSTLT 201 LTKDEYERHN SYTCEATHKT STSPIVKSFN RNEC (SEQ ID NO: 175) Nucleic acid sequence of the Ab-9 LC including signal peptide encoding sequence: 25 1 ATGATGTCCT CTGCTCAGTf CCTrGGTCTC CTGTrGCTCT GTITrCAAGG 51 TACCAGATGT GATATCCAGA TGACACAGAT TACATCCTCC CTGTCTGCCT 101 CTCTGGGAGA CAGGGTCTCC ATCAGTTGCA GGGCAAGTCA AGACATTAGC 151 AATTATITAA~ATrGGTATCA GCAGAAACCA GATGGAACTT TTAAACTCCT 201 TATCTTCTAC ACATCAAGAT TAITTCAGG AGTCCCATCA AGGTTCAGTG 30 251 GCAGTGGGTC TGGAACAGAT TATTCTCTCA CCATFTACAA CCTGGAGCAA 301 GAAGAYTITG CCACTTACTT TTGCCAACAG GGAGATACGC TTCCGTACAC 351 TTrCGGAGGG GGGACCAAGG TGGAAATAAA ACGGGCTGAT GCTGCACCAA 401 CTGTATCCAT CTTCCCACCA TCCAGTGAGC AGTTAACATC TGGAGGTGCC 451 TCAGTCGTGT GCTTCTrGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA 35 501 GTGGAAQATT GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA 551 CTGATCAGGA CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG 601 TTGACCAAGG ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC 651 TCACAAGACA TCAACTTCAC CCATTGTCAA GAGCTTCAAC AGGAATGAGT 701 GT (SEQ ID NO:176) 40 Ab-9 Heavy Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-9 HC: 1 EVQLQQSGPE LMKPOTSVKM SCKASGYTFT )id1 WVKQT QGKTLEWIGE 51 NlSAGiJYNQiKO(KATL TVDKSSTTAY MELRSLTSED SAVYYCAKWi 45 101 YDDIYDDWYF DVWGAGTTVT VSSAKTTAPS VYPLAPVCGD TTGSSVTLGC 151 LVKGYFPEPV TLTWNSGSLS SDVHTFPALL QSGLYTLSSS VTVTTWPSQT 201 ITCNVARPAS STKVDKKIEP RGSPTHKPCP PCPAPNLLQG PSVFIFPPKI 251 KDVLMTSLSP MVTCVVVD VS EDDPD VHVSW FVNNVEVHTA QTQTHREDYN SEA 1803911vi 60117-M3 65 WO 2006/119062 PCT/US2006/016345 "31 W&iJV YIQHQD WMSGK EFKCKVNNVKA IPAPERTIS KPKGPVRAPQ 351 VYVLPPPEEE MTEKQVTLTC MITDFMPEDI YVEWTNNGQTELNYENVTEPV 401 LDSDGSYFMYSKLRVEHEINW VERNSYSCSV VHEGLHNHHT TKSFSRTPGK (SEQ ID NO:177) 5 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-9 HC: 1 GAGGTCCAAC TGCAACAGTC TGGACCTGAA CTAATGAAGC CTGGGACTTC 51 AGTGAAGATG TCCTGCAAGG CTTCTGGATA TACATTQACT GACTACAACA 101 TGCACTGGGT GAAGCAGACC CAAGGAAAGA CCCTAGAQTG GATAGGAGAA 10 151 ATTAATCCTA ACAGTGGTGG TGCTGGCTAC AACCAGAAGT TCAAGGGCAA 201 GGCCACATTG ACTGTAGACA AGTCCTCCAC CACAGCCTAC ATGGAGCTCC 251 GCAGCCTGAC ATCTGAGGAC TCTGCAGTCT ATTACTGTGC AAAATTGG3GC 301 TACGATGATA TCTACGACGA CTGGTATTTC GATGTCTGGG GCOCAGGGAC 351 CACGGTCACC GTCTCCTCAG CCAAAACAAC AGCCCCATCG GTCTATCCAC 15 401 TGGCCCCTGT GTGTGGAGAT ACAACTGGCT CCTCGGTGAC TCTAGGATGC 451 CTGGTCAAGG GTTATTTCCC TGAGCCAGTG ACCTTGACCT GGAACTCTGG 501 ATCCCTGTCC AGTGATGTGC ACACCTTCCC AGCTCTCCTG CAGTCTGGCC 551 TCTACACCCT CAGCAGCTCA GTGACTGTAA CCACCTGGCC CAGCCAGACC 601 ATCACCTGCA ATGTGGCCCA CCCGCAAGC AGCACCAAAG TGGACAAGAA 20 651 AATTGAGCCC AGAGGGTCCC CAACACATAA ACCCTGTCCT CCATGCCCAG 701 CTCCTAACCT CTrGGGTGGA CCATCCGTCT TCATCTTCCC TCCAAAGATC 751 AAGGATGTAC TCATGATCTC CCTGAGCCCC ATGGTCACGT GTGTGGTGGT 801 GGATGTGAGC GAGGATGACC CAGATGTCCA TGTCAGCTGG TTCGTGAACA 851 ACGTGGAAGT ACACACAGCT CAGACACAAA CCCATAGAGA GGATTACAAC 25. 901 AGTACTATCC GGGTGGTCAG TGCCCTCCCC ATCCAGCACC AGGACTGGAT 951 GAOTGGCAAG GAGTTCAAAT GCAAGGTCAA CAACAAAGCC CTCCCAGCGC 1001 CCATCGAGAG AACCATCTCA AAACCCAAAG GGCCAGTAAG AGCTCCACAG 1051 GTATATGTCT TGCCTCCACC AGAAGAAGAG ATOACTAAGA AACAGGTCAC 1101 TCTGACCTGC ATGATCACAG ACTTCATGCC TGAAGACATT TACGTGGAGT 30 1151 GGACCAACAA CGGGCAAACA GAGCTAAACT ACAAGAACAC TGAACCAGTC 1201 CTGGACTCTG ATGGTTCTTA CTTCATGTAC AGCAAGCTGA GAGTGGAAAA 1251 GAAQAACTGG GTGGAAAGAA ATAGCTACTC CTGTTCAQTG GTCCACGAGG 1301 GTCTGCACAA TCACCACACG ACTAAGAGCT TCTCCCGGAC TCCGGGTAAA (SEQ ID NO:178) 35 Amino acid sequence of the Ab-9 HC including signal peptide: 1 MGWSWTFLFL LSGTAGVLSE VQLQQSGPEL MKPGTSVKMS CKASGYTFTD 51 YNMHWVKQTQ GKTLEWIGEI NPNSGQAGYN QKFKGKATLT VDKSSTTAYM 101 ELRSLTSEDS AVYYCAKLGY DDIYDDWYFD VWGAGTTVTV SSAKTTAPSV 40 151 YPLAPVCGDT TGSSVTLGCL VKGYFPEPVT LTWNSGSLSS DVHTFPALLQ 201 SGLYTLSSSV TVTTWPSQTI TCNVAHPASS TKVDKKIEPR GSPTHKPCPP 251 CPAPNLLGGP SVFIFPPKIK DVLMISLSPM VTCVVVDVSE DDPDVHVSWF 301 VNNVEVHTAQ TQTHREDYNS TIRVVSALPI QHQDWMSGKE FKCKVNNKAL 351 PAPIERTISK PKGPVRAPQV YVLPPPEEEM TKKQVTLTCM ITDFMPEDIY 45 401 VEWTNNGQTE LNYKNTEPVL DSDGSYFMYS KLRVEKKNWV ERNSYSCSVV 451 HEGLHNHHTF KSFSRTPGK (SEQ ID NO: 179) Nucleic acid sequence of the Ab-9 HC including signal peptide encoding sequence: 1 ATGGGATGGA GCTGGACCTT TCTCTTCCTC CTOTCAGGAA CTGCAGGTGT 51 CCTCTCTGAG GTCCAACTGC AACAGTCTGG ACCTGAACTA ATGAAGCCTG SEA 1803911vl 60117-223 66 WO 2006/119062 PCTIUS2006/016345 101EGGACYfdAGT GAAGATGTCC TGCAAGGCTT CTGGATATAC ATTCACTGAC 151 TACAACATGC ACTGGGTGAA GCAGACCCAA GGAAAGACCC TAGAGTGGAT 201 AGGAGAAATT AATCCTAACA GTGGTGGTGC TGGCTACAAC CAGAAGTTCA 251 AGGGCAAGGC CACATGACT GTAGACAAGT CCTCCACCAC AGCCTACATG 5 301 GAGCTCCGCA GCCTGACATC TGAGGACTCT GCAGTCTATT ACTGTGCAAA 351 ATTGGGCTAC GATGATATCT ACGACGACTG GTATfTCGAT GTCTGGGGCG 401 CAGGGACCAC GGTCACCGTC TCCTCAGCCA AAACAACAGC CCCATCGGTC 451 TATCCACTGG CCCCTGTGTG TGGAGATACA ACTGGCTCCT CGGTGACTCT 501 AGGATGCCTG GTCAAGGGIT ATITCCCTGA GCCAGTQACC TTGACCTGGA 10 551 ACTCTGGATC CCTGTCCAGT GATGTGCACA CCTTCCCAGC TCTCCTGCAG 601 TCTGGCCTCT ACACCCTCAG CAGCTCAGTG ACTGTAACCA CCTGGCCCAG 651 CCAGACCATC ACCTGCAATG TGGCCCACCC GGCAAGCAGC ACCAAAGTGG 701 ACAAGAAAAT TGAGCCCAGA GGGTCCCCAA CACATAAACC CTGTCCTCCA 751 TGCCCAGCTC CTAACCTCTT GGGTGGACCA TCCGTCTTCA TCTrCCCTCC 15 801 AAAGATCAAG GATGTACTCA TGATCTCCCT GAGCCCCATG GTCACGTGTG 851 TGGTGGTGGA TGTGAGCGAG GATGACCCAG ATGTCCATGT CAGCTGGTTC 901 GTGAACAACG TGGAAGTACA CACAGCTCAG ACACAAACCC ATAGAGAGGA 951 TfACAACAGT ACTATCCGGG TGGTCAGTGC CCTCCCCATC CAGCACCAGG 1001 ACTGGATGAG TGGCAAGGAG TTCAAATGCA AGGTCAACAA CAAAGCCCTC 20 1051 CCAGCGCCCA TCGAGAGAAC CATCTCAAAA CCCAAAGGGC CAGTAAGAGC 1101 TCCACAGGTA TATGTCTTGC CTCCACCAGA AGAAGAGATG ACTAAGAAAC 1151 AGGTCACTCT GACCTGCATG ATCACAGACT TCATGCCTGA AGACATTTAC 1201 GTGGAGTGGA CCAACAACGG GCAAACAGAG CTAAACTACA AGAACACTGA 1251 ACCAGTCCTG GACTCTGATG GTTCTTACTT CATGTACAGC AAGCTGAGAG 25 1301 TGGAAAAGAA GAACTGGGTG GAAAGAAATA GCTACTCCTG TTCAGTGGTC 1351 CACGAGGGTC TGCACAATCA CCACACGACT AAGAGCTTCT CCCGGACTCC 1401 GGGTAAA (SEQ ID NO:180) Ab-lO 30 The sequences of the Antibody 10 (also referred to herein as Ab-10) LC and HC are as follows: Ab-10 Light Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-10 LC: 1 DIQMTQTTSS LSASLGDRVS ISCS01I4S Yli-TWYQQKP DGTFKLLIFY 51 qg-iiGVPS RFSGSGSGTD YSLTIYNLEQ EDFATYFC|1OFGG 35 101 GTKLEKR AAPTVSIFPL SSEQLTSGGA SVVCFLNNFY PEDNVKWET 151 DGSERQNGVL NSWTDQDSKD STYSMSSTLT LTKDEYER HN SYTCEA TRKT 201 STSPIVKSFNRNEC (SEQ ID NO:181) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab- 10 LC: 40 1 GATATCCAGA TGACACAGAC TACATCCTCC CTGTCTGCCT CTCTGGGAGA 51 CAGGGTCTCC ATCAGTTGCA GGGCAAGTCA AGACATTAGC AATTATTTAA 101 ACTGGTATCA GCAGAAACCA GATGGAACTT TTAAACTCCT TATCTCTAC 151 ACATCAAGAT TACTCTCAGG AGTCCCATCA AGGTrCAGTG GCAGTGGGTC 201 TGGAACAGAT TATTCTCTCA CCATTTACAA CCTGGAGCAA GAAGATTTG 45 251 CCACTrACTT TTGCCAACAG GGAGATACGC TFCCGTACAC T1TCGGAGGG 301 GGOACCAAAC TGGAAATAAA ACGGGCTGAT GCTGCACCAA CTGTATCCAT 351 CTTCCCACTA TCCAGTGAGC AGTTAACATC TGGAGGTGCC TCAGTCGTGT 401 GCT[TCTGAA CAACTTCTAC CCCAAAQACA TCAATGTCAA GTGGAAGATT SEA 180391vi 60117-M3 67 WO 2006/119062 PCT/US2006/016345 451 GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA CTGATCAGGA 501 CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG TTGACCAAGG 551 ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC TCACAAGACA 601 TCAACTTCAC CCATrGTCAA GAGCTTCAAC AGGAATGAGT GTTAG (SEQ ID 5 NO:182) Amino acid sequence of the Ab-10 LC including signal peptide: 1 MMSSAQFLGL LLLCFQGTRC DIQMTQTTSS LSASLGDRVS ISCRASQDIS 51 NYLNWYQQKP DGTFKLLIFY TSRLLSGVPS RFSGSGSGTD YSLTIYNLEQ 10 101 EDFATYFCQQ GDTLPYTFGG GTKLEIKRAD AAPTVSIFPL SSEQLTSGGA 151 SVVCFLNNFY PKDINVKWKI DGSERQNGVL NSWTDQDSKD STYSMSSTLT 201 LTKDEYERHN SYTCEATHKT STSPIVKSFN RNEC (SEQ ID NO:183) Nucleic acid sequence of the Ab-10 LC including signal peptide encoding sequence: 15 1 ATGATGTCCT CTGCTCAGTT CCTTGGTCTC CTGTTGCTCT GYTCAAGG 51 TACCAGATGT GATATCCAGA TGACACAGAC TACATCCTCC CTGTCTGCCT 101 CTCTGGGAGA CAGGGTCTCC ATCAGTTGCA GGGCAAGTCA AGACATTAGC 151 AATTATITAA ACTGGTATCA GCAGAAACCA GATGGAACTT TTAAACTCCT 201 TATCTfCTAC ACATCAAGAT TACTCTCAGG AGTCCCATCA AGGTrCAGTG 20 251 QCAGTGGGTC TGGAACAGAT TATrCTCTCA CCATTTACAA CCTGGAGCAA 301 GAAGATITTG CCACTrACTr TTGCCAACAG GGAGATACGC TTCCGTACAC 351 TTFCGGAGGG GGGACCAAAC TGGAAATAAA ACGGGCTGAT GCTGCACCAA 401 CTGTATCCAT CTTCCCACTA TCCAGTGAGC AGTTAACATC TGGAGGTGCC 451 TCAGTCGTGT GCTTCTrGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA 25 501 GTGGAAGATT GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA 551 CTGATCAGGA CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG 601 TTGACCAAGG ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC 651 TCACAAGACA TCAACTCAC CCATTGTCAA GAGCT[CAAC AGGAATGAGT 701 GTIAG (SEQ ID NO: 184) 30 Ab-10 Heavy Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-10 HC: 1 EVQLQQSGPE LMKPGASVKM SCKASGYTFT D WiWVKQN QGKTLEWIG5 51 NQK.1-GXATL TVDKSSTTAY MELRSLTSED SAVYYCARIN 35 101 YDYDD DGGT vT VSSAKTTPPS VYPLAPGSAA QTNSMVTLGC 151 L VZGYFPEPV TVTWNSGSLS SGVHTFPAVL QSDLYTLSSS VTVPSSTWPS 201 ETVTCNVARPASSTKVDEKI VPRDCGCKPC ICTVPEVSSV FIFPPKPKDV 251 LTITLTPKVT CVVVDISKDD PEVQFSWFVD D VEVHTAQTQ PRE EQFNSTF 301 RSVSELPIMH QDWLNGEEFK CRVNSA AFPA PIEKTISKTK GRPKAPQVYT 40 351 1PPPKEQMAK DKVSLTCMT DFFPEDITVE WQWNGQPAEN YEKNTQPIMDT 401 DGSYFIYSKL NVQKSNWEAG NTFTCSVLHE GLRNHHTEKS LSHSPGK (SEQ ID NO:185) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab- 10 HC: 45 1 GAGGTCCAAC TGCAACAGTC TGGACCTGAA CTAATGAAGC CTGGGGCTTC 51 AGTGAAGATG TCCTGCAAGG CTTCTGGATA TACATCACT GACTACAACA 101 TGCACTGGGT GAAGCAGAAC CAAGGAAAGA CCCTAGAATG GATAGGAGAA SEA 1803911v 60117-223 68 WO 2006/119062 PCT/US2006/016345 iiATAAiCCTA ACAGTGGTGG TGCTGGCTAC AACCAGAAGT TCAAGGGCAA 201 GGCCACATrG ACTGTAGACA AGTCCTCCAC CACAGCCTAC ATGGAGCTCC 251 GCAGCCTGAC ATCTQAGGAC TCTGCAGTCT ATTACTGTGC AAGATTGGGC 301 TACGATGATA TCTACGACGA CTGGTACTTC GATGTCTGGG GCGCAGGGAC 5 351 CACGGTCACC GTCTCCTCAG CCAAAACGAC ACCCCCATCT GTCTATCCAC 401 TGGCCCCTGG ATCTGCTGCC CAAACTAACT CCATGGTGAC CCTGGGATGC 451 CTGGTCAAGG GCTATTTCCC TGAGCCAGTG ACAGTGACCT GGAACTCTGG 501 ATCCCTGTCC AGCGGTGTGC ACACCTTCCC AGCTGTCCTG CAGTCTGACC 551 TCTACACTCT GAGCAGCTCA GTGACTGTCC CCTCCAGCAC CTGGCCCAGC 10 601 GAGACCGTCA CCTGCAACGT TGCCCACCCG QCCAGCAGCA CCAAGGTGGA 651 CAAGAAAATT GTGCCCAGGG ATrGTGGITG TAAGCCTfGC ATATGTACAG 701 TCCCAGAAGT ATCATCTGTC TrCATCTTCC CCCCAAAGCC CAAGGATGTG 751 CTCACCATTA CTCTGACTCC TAAGGTCACG TGTGTTGTGG TAGACATCAG 801 CAAGGATQAT CCCQAGGTCC AGTTCAGCTG GTITGTAGAT GATGTGGAGG 15 851 TGCACACAGC TCAGACGCAA CGCCCGGGAGG AGCAGTTCAA CAGCACTTTC 901 CGCTCAGTCA GTGAACTTCC CATCATGCAC CAGGACTGGC TCAATGGCAA 951 GGAGTTCAAA TGCAGGGTCA ACAGTGCAGC TTTCCCTGCC CCCATCGAGA 1001 AAACCATCTC CAAAACCAAA GGCAGACCGA AGGCTCCACA GGTGTACACC 1051 ATTCCACCTC CCAAGGAGCA GATQGCCAAG GATAAAGTCA GTCTGACCTG 20 1101 CATGATAACA GACTTCTTCC CTGAAGACAT TACTGTGGAG TGGCAGTGGA 1151 ATGGCAGCC AGCGGAGAAC TACAAGAACA CTCAGCCCAT CATGGACACA 1201 GATGGCTCTT ACTTCATCTA CAGCAAGCTC AATGTGCAGA AGAGCAACTG 1251 GGAGGCAGGA AATACTITCA CCTGCTCTGT GTTACATGAG GGCCTGCACA 1301 ACCACCATAC TGAGAAGAGC CTCTCCCACT CTCCTGGTAA ATGA (SEQ ID 25 NO:186) Amino acid sequence of the Ab-10 HC including signal peptide: 1 MGWSWTFLFL LSGTAGVLSE VQLQQSGPEL MKPGASVKMS CKASGYTFTD 51 YNMHWVKQNQ GKTLEWIGEI NPNSGGAGYN QKFKGKATLT VDKSSTTAYM 30 101 ELRSLTSEDS AVYYCARLGY DDIYDDWYFD VWGAGTTVTV SSAKTTPPSV 151 YPLAPGSAAQ TNSMVTLGCL VKGYFPEPVT VTWNSGSLSS GVHTFPAVLQ 201 SDLYTLSSSV TVPSSTWPSE TVTCNVAHPA SSTKVDKKIV PRDCGCKPCI 251 CTVPEVSSVF IFPPIPKDVL TITLTPKVTC VVVDISKDDP EVQFSWFVDD 301 VEVHTAQTQP REEQFNSTFR SVSELPIMHQ DWLNGIEFKC RVNSAAFPAP 35 351 IEKTISKTKG RPKAPQVYTI PPPKEQMAKD KVSLTCMITD FFPEDITVEW 401 QWNGQPAENY KNTQPIMDTD GSYFIYSKLN VQKSNWEAGN TFTCSVLHEG 451 LHNHHTEKSL SHSPGK (SEQ ID NO: 187) Nucleic acid sequence of the Ab-10 HC including signal peptide encoding sequence: 40 1 ATGGGATGGA GCTGGACCTT TCTCTTCCTC CTGTCAGGAA CTGCAGGTGT 51 CCTCTCTGAG GTCCAACTGC AACAGTCTGG ACCTGAACTA ATGAAGCCTG 101 GGGCTTCAGT GAAGATGTCC TGCAAGGCTT CTGGATATAC ATTCACTGAC 151 TACAACATGC ACTGGGTGAA GCAGAACCAA GGAAAGACCC TAGAATGGAT 201 AGGAGAAATT AATCCTAACA GTGGTGGTGC TGGCTACAAC CAGAAGTTCA 45 251 AGGGCAAGGC CACATTGACT GTAGACAAGT CCTCCACCAC AGCCTACATQ 301 GAGCTCCGCA GCCTGACATC TGAGGACTCT GCAGTCTATT ACTGTGCAAG 351 ATTGG*GCTAC GATGATATCT ACGACGACTG GTACTTCGAT GTCTGGGGCG 401 CAGGGACCAC GGTCACCGTC TCCTCAGCCA AAACGACACC CCCATCTGTC 451 TATCCACTGG CCCCTGGATC TGCTGCCCAA ACTAACTCCA TGGTGACCCT 50 501 GGGATGCCTG GTCAAGGGCT ATITCCCTGA GCCAGTGACA GTGACCTGGA SEA 1803911v] 60117-23 69 WO 2006/119062 PCT/US2006/016345 551 CYCTGAXC CCTGTCCAGC GGTGTGCACA CC TCCCAGC TGTCCTGCAG 601 TCTGACCTCT ACACTCTGAG CAGCTCAGTG ACTGTCCCCT CCAGCACCTG 651 GCCCAGCGAG ACCGTCACCT GCAACGTTGC CCACCCGGCC AGCAGCACCA 701 AGGTGGACAA QAAAATTGTG CCCAGGGATT GTGGTTGTAA GCCTTGCATA 5 751 TGTACAGTCC CAGAAGTATC ATCTOTCTTC ATCTfCCCCC CAAAGCCCAA 801 GGATGTGCTC ACCATTACTC TGACTCCTAA GGTCACGTGT GTTGTGGTAG 851 ACATCAGCAA GGATGATCCC GAGGTCCAGT TCAGCTGGTF TGTAGATGAT 901 GTGGAGGTOC ACACAGCTCA GACGCAACCC CGGGAGGAGC AGTTCAACAG 951 CACTlTCCGC TCAGTCAGTG AACTTCCCAT CATGCACCAG GACTGGCTCA 10 1001 ATGQCAAGGA GTTCAAATGC AGGGTCAACA GTGCAGCTIT CCCTGCCCCC 1051 ATCGAGAAAA CCATCTCCAA AACCAAAGGC AGACCGAAGG CTCCACAGGT 1101 GTACACCATT CCACCTCCCA AGGAGCAGAT GGCCAAGGAT AAAGTCAGTC 1151 TGACCTGCAT GATAACAGAC TTCTTCCCTG AAGACATTAC TGTGGAGTGG 1201 CAGTGGAATG GCAGCCAGC GGAGAACTAC AAGAACACTC AGCCCATCAT 15 1251 GGACACAGAT GGCTCTTACT TCATCTACAG CAAGCTCAAT GTGCAGAAGA 1301 GCAACTGGA GGCAGGAAAT ACTITCACCT GCTCTGTGTF ACATGAGGGC 1351 CTGCACAACC ACCATACTGA GAAGAGCCTC TCCCACTCTC CTGGTAAATG 1401 A (SEQ ID NO:188) 20 AlI The sequences of the Antibody 11 (also referred to herein as Ab- 11) LC and HC are as follows: Ab-11 Light Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab- 11 LC: 1 Q1VLSQSPAF LSVSPGDKVT MTC SSiYfHiWFQQKPG SSPRSWIYAT 25 51 SNiAGVPGRFSGSGSGTSY SLTISRVEAE DAATYYCQ DPLITFGAG 101 TKLELKRADA APTVSIFPPS SEQL TSGGA S VVCFLNNFYP EDINVKWKID 151 GSERQNGVLNSWTDQDSKDS TYSMSSTLTL TKDEYERHNS YTCEATHKTS 201 TSPIVKSFNR NEC (SEQ ID NO: 189) 30 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab- 11 LC: 1 CAAATTGTFC TCTCCCAGTC TCCAGCATTC CTGTCTGTAT CTCCAGGGGA 51 TAAGGTCACA ATGACTTGCA GGGCCAGCTC AAGTATAAGT TACATACACT 101 GGTCAGCA GAAGCCAGGA TCCTCCCCCA GATCCTGGAT TTATGCCACA 151 TCCAACCTGG CTTCTGGAGT CCCTGGTCGC TTCAGTGGCA GTGGGTCTGG 35 201 GACCTCTrAC TCTCTCACAA TCAGCAGAGT GGAGGCTGAG GATGCTGCCA 251 CTTATTACTG CCAGCAGTGG AGTAGTGACC CACTCACG1T C7GTGCTGGG 301 ACCAAGCTGG AGCTGAAACG GGCTGATGCT GCACCAACTG TATCCATCTT 351 CCCACCATCC AGTGAGCAGT TAACATCTGG AGGTGCCTCA GTCGTGTGCT 401 TCTrGAACAA CTTCTACCCC AAAGACATCA ATGTCAAGTG GAAGATTGAT 40 451 GGCAGTGAAC GACAAAATGG CGTCCTGAAC AGTTGGACTG ATCAGGACAG 501 CAAAGACAGC ACCTACAGCA TGAGCAGCAC CCTCACGTTG ACCAAGGACG 551 AGTATGAACG ACATAACAGC TATACCTGTG AGGCCACTCA CAAGACATCA 601 ACTTCACCCA TTGTCAAGAG CTTCAACAGG AATGAGTGTT AG (SEQ ID NO:190) 45 Amino acid sequence of the Ab- 11 LC including signal peptide: 1 MDFQVQIFSF LLISASVIMS RGQIVLSQSP AFLSVSPGDK VTMTCRASSS SEA 1803911vi 60117-223 70 WO 2006/119062 PCT/US2006/016345 5 ISYIIWQZPUN5PRSW1Y ATSNLASGVP GRFSGSGSGT SYSLTISRVE 101 AEDAATYYCQ QWSSDPLTFG AGTKLELKRA DAAPTVSIFP PSSEQLTSGQ 151 ASVVCFLNNF YPKDINVKWK IDGSERQNGV LNSWTDQDSK DSTYSMSSTL 201 TLTKDEYERH NSYTCEATHK TSTSPIVKSF NRNEC (SEQ ID NO: 191) 5 Nucleic acid sequence of the Ab- 11 LC including signal peptide encoding sequence: 1 ATGGATTTTC AAGTGCAGAT TITCAGCTFC CTQCTAATCA GTGCTTCAGT 51 CATAATGTCC AGAGGACAAA TTGTTCTCTC CCAQTCTCCA GCATTCCTGT 101 CTGTATCTCC AGGGGATAAG QTCACAATGA CTTGCAGGGC CAGCTCAAGT 10 151 ATAAGTrACA TACACTGGTT TCAGCAGAAG CCAGGATCCT CCCCCAGATC 201 CTGGATITAT GCCACATCCA ACCTGGCTfC TGGAGTCCCT GGTCGCTTCA 251 GTGGCAGTGG GTCTGGGACC TCTTACTCTC TCACAATCAG CAGAGTGGAG 301 GCTGAGGATG CTGCCACTA TTACTGCCAG CAGTGGAGTA GTGACCCACT 351 CACGTTCGGT GCTGGGACCA AGCTGGAGCT GAAACGGGCT GATGCTGCAC 15 401 CAACTGTATC CATCTFCCCA CCATCCAGTG AGCAGTTAAC ATCTGGAGGT 451 GCCTCAGTCG TGTGCTfCTT GAACAACTrC TACCCCAAAG ACATCAATGT 501 CAAGTGGAAG ATTGATGGCA GTGAACGACA AAATGGCGTC CTGAACAGTF 551 GGACTGATCA GGACAGCAAA GACAGCACCT ACAGCATGAG CAGCACCCTC 601 ACGTFGACCA AGGACGAGTA TGAACGACAT AACAGCTATA CCTGTGAGGC 20 651 CACTCACAAG ACATCAACTT CACCCATIGT CAAGAGCTTC AACAGGAATG 701 AGTGTLAG (SEQ ID NO: 192) Ab-Il Heavy Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab- 11 HC: 25 1 EVQLQQSGAD LVQPGASVKV SCTASGFDIK 5YWMQR PDQGLEWIGR 51 IPiTDNGETEF APKFPGKATF TTDTSSNTAY LQLRGLTSED TAIYYCGR5 101YDOTXTWSFPYWGQGTLVTVS AAKTTPPSVYPLAPGSAAQTNSMVTLGCLV 151 KGFFPEPVTV TWNSGSLSSG VHTFPA VLQS DLYTLSSSVT VPSSTWPSET 201 VTCNVAHPAS STKVDKKIVP RDCGCEPCIC TVPEVSSVFI FPPKPEDVLT 30 251 1TLTPKVTCV VVDISKDDPE VQFSWFVDDVEVHITAQTQPR EEQFNSTFRS 301 VSELPMHQD WLNGEEFKCR VNSAAFPAPIEKTISKTKGR PKAPQVYTLP 351 PPKEQMAEDK VSLTCM1TDF FPEDITVEWQ WNGQPAENYK NTQPIMDTDG 401 SYFIYSKLNV QKSNWEAGNT FTCSVLHEGL RNHHTEKSLS HSPGK (SEQ ID NO:193) 35 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-1 1 HC: 1 GAAGTTCAGC TGCAACAGTC TGGGGCAGAC CTTGTGCAGC CAGGGGCCTC 51 AGTCAAGGTG TCCTGCACAG CTrCTGGCTT CGACATTAAG GACTACTATA 101 TACACTGGAT GAAACAGAGG CCTGACCAGG GCCTGGAGTG GATTGGAAGG 40 151 GTTGATCCTG ACAATGGTGA GACTGAATT GCCCCGAAGT TCCCGGGCAA 201 GGCCACTIT ACAACAGACA CATCCTCCAA CACAGCCTAC CTACAACTCA 251 GAGGCCTGAC ATCTGAGGAC ACTGCCATCT ATIACTGTGG GAGAGAAGAC 301 TACGATGGTA CCTACACCTG GTTCCTfAT TGGGGCCAAG GGACTCTGGT 351 CACTGTCTCT GCAGCCAAAA CGACACCCCC ATCTGTCTAT CCACTGGCCC 45 401 CTGGATCTGC TGCCCAAACT AACTCCATGG TGACCCTGGG ATGCCTGGTC 451 AAGGGCTATT TCCCTGAGCC AGTGACAGTG ACCTGGAACT CTGGATCCCT 501 GTCCAGCGGT GTGCACACCT TCCCAGCTGT CCTGCAQTCT GACCTCTACA 551 CTCTGAGCAG CTCAGTGACT GTCCCCTCCA GCACCTGGCC CAQCGAGACC SEA 1803911y 60117-23 71 WO 2006/119062 PCTIUS2006/016345 601 GTCACCTGCA ACGTTGCCCA CCCGGCCAGC AQCACCAAGG TGGACAAGAA 651 AATTGTGCCC AGGGATGTG GTTGTAAGCC TTGCATATOT ACAGTCCCAG 701 AAGTATCATC TGTCTTCATC TTCCCCCCAA AGCCCAAGGA TGTGCTCACC 751 ATTACTCTGA CTCCTAAGT CACGTGTGTT GTGGTAGACA TCAGCAAGGA 5 801 TGATCCCGAG GTCCAGTTCA GCTGGTITGT AGATGATGTG GAGGTGCACA 851 CAGCTCAGAC GCAACCCCGG GAGGAGCAGT TCAACAGCAC TTCCGCTCA. 901 GTCAGTGAAC TrCCCATCAT GCACCAGGAC TGGCTCAATG GCAAGGAGTT 951 CAAATGCAGG GTCAACAGTG CAGCTITCCC TGCCCCCATC GAGAAAACCA 1001 TCTCCAAAAC CAAAGGCAGA CCGAAGQCTC CACAGGTGTA CACCATTCCA 10 1051 CCTCCCAAGG AGCAGATGGC CAAGGATAAA GTCAGTCTGA CCTGCATGAT 1101 AACAGACTrC TTCCCTGAAG ACATTACTGT GGAGTGGCAG TGGAATGGGC 1151 AGCCAGCGGA GAACTACAAG AACACTCAGC CCATCATGGA CACAGATGGC 1201 TCTTACTTCA TCTACAGCAA GCTCAATGTG CAGAAGAGCA ACTG3GAGGC 1251 AGGAAATACT TTCACCTGCT CTGTGTTACA TGAGGGCCTG CACAACCACC 15 1301 ATACTGAGAA GAGCCTCTCC CACTCTCCTG GTAAATGA (SEQ ID NO:194) Amino acid sequence of the Ab- 11 HC including signal peptide: 1 MKCSWVIFFL MAVVTGVNSE VQLQQSGADL VQPGASVKVS CTASGFDIKD 51 YYIHWMKQRP DQGLEWIGRV DPDNGETEFA PKFPGKATFT TDTSSNTAYL 20 101 QLRGLTSEDT AIYYCGREDY DQTYTWFPYW GQGTLVTVSA AKTTPPSVYP 151 LAPGSAAQTN SMVTLGCLVK GYFPEPVTVT WNSGSLSSGV HTFPAVLQSD 201 LYTLSSSVTV PSSTWPSETV TCNVAHPASS TKVDKKIVPR DCGCKPCICT 251 VPEVSSVFIF PPKPKDVLTI TLTPKVTCVV VDISKDDPEV QFSWFVDDVE 301 VHTAQTQPRE EQFNSTFRSV SELPIMHQDW LNGKEFKCRV NSAAFPAPIE 25 351 KTISKTKGRP KAPQVYTIPP PKEQMAKDKV SLTCMITDFF PEDITVEWQW 401 NGQPAENYKN TQPIMDTDGS YFIYSKLNVQ KSNWEAGNTF TCSVLHEGLH 451 NHHTEKSLSH SPGK (SEQ ID NO: 195) Nucleic acid sequence of the Ab-1 1 HC including signal peptide encoding sequence: 30 1 ATGAAATGCA GCTGGGTCAT CTTCTTCCTG ATGGCAGTGG TTACAGGGGT 51 CAATTCAGAA GTTCAGCTGC AACAGTCTGG GGCAGACCTIT GTGCAGCCAG 101 GGGCCTCAGT CAAGGTGTCC TGCACAGCTT CTGGCTTCGA CATTAAGGAC 151 TACTATATAC ACTGGATGAA ACAGAGGCCT GACCAGGGCC TGGAGTGGAT 201 TGGAAGG3GT[ GATCCTGACA ATGGTGAGAC TGAATTGCC CCGAAGTTCC 35 251 CGGGCAAGGC CACiTTTACA ACAGACACAT CCTCCAACAC AGCCTACCTA 301 CAACTCAGAG GCCTGACATC TGAGGACACT GCCATCTATT ACTGTGGGAG 351 AGAAGACTAC GATGGTACCT ACACCTGGTT TCCTTATrGG GGCCAAGGQA 401 CTCTGGTCAC TGTCTCTGCA GCCAAAACGA CACCCCCATC TGTCTATCCA 451 CTGG3CCCCTG GATCTGCTGC CCAAACTAAC TCCATGGTGA CCCTGGGATQ 40 501 CCTGGTCAAG GGCTATITCC CTGAGCCAGT GACAGTGACC TGGAACTCTG 551 GATCCCTGTC CAGCGGTGTG CACACCTTCC CAGCTGTCCT GCAGTCTGAC 601 CTCTACACTC TGAGCAGCTC AGTGACTGTC CCCTCCAGCA CCTGGCCCAQ 651 CGAGACCGTC ACCTGCAACG TTGCCCACCC GGCCAGCAGC ACCAAGGTGG 701 ACAAGAAAAT TGTGCCCAGG GATTGTGGTT GTAAGCCTfG CATATGTACA 45 751 GTCCCAGAAG TATCATCTGT CTTCATCTrC CCCCCAAAGC CCAAGGATGT 801 GCTCACCAT ACTCTGACTC CTAAGGTCAC GTOTGTTGTG GTAGACATCA 851 GCAAGGATGA TCCCGAGGTC CAGTTCAGCT GGTITGTAGA TGATGTGGAG 901 GTGCACACAG CTCAGACGCA ACCCCGGGAG GAGCAGTTCA ACAGCACTIT 951 CCGCTCAGTC AQTGAACTTC CCATCATGCA CCAGGACTGG CTCAATGGCA 50 1001 AGGAGTTCAA ATGCAGGGTC AACAGTGCAG CT1TCCCTGC CCCCATCGAG SEA 1803911vl 60117-223 72 WO 2006/119062 PCT/US2006/016345 105f"AXAAACdfCT CCAAAACCAA AGGCAGACCG AAGGCTCCAC AGGTGTACAC 1101 CATTCCACCT CCCAAGGAGC AGATGGCCAA GGATAAAGTC AGTCTGACCT 1151 QCATGATAAC AGACTrCTTC CCTGAAGACA TTACTGTGGA QTGGCAGTGG 1201 AATGGGCAGC CAGCGGAGAA CTACAAGAAC ACTCAGCCCA TCATGGACAC 5 1251 AGATGGCTCT TACT'CATCT ACAGCAAGCT CAATGTGCAG AAGAGCAACT 1301 GGGAGGCAGG AAATACTTTC ACCTGCTCTG TGTTACATGA GGGCCTGCAC 1351 AACCACCATA CTGAGAAGAG CCTCTCCCAC TCTCCTGGTA AATQA (SEQ ID NO:196) 10 Ab-12 The sequences of the Antibody 12 (also referred to herein as Ab-12) LC and HC are as follows: Ab-12 Light Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab- 12 LC: 1 DLQMTQTTSS LSASLGDRVT ISCiQDQI5 1YJIVYQQKP DGTVKLLIFlY 15 51'TiLQGVPS RFSGSGSGTN YSLTITNLEQ DDAATYFCQ(GDTLifFGG 101 GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA SVVCFLNNFYPKDNVKWKI 151 DGSERQNGVL NSWTDQDSKD STYSMSSTLTLTDEYERN SYTCE ATHKT 201 STSPIVKSFNRNEC (SEQ ID NO:197) 20 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-12 LC: I GATCTCCAGA TGACACAGAC TACTTCCTCC CTGTCTGCCT CTCTGGGAGA 51 CAGAGTCACC ATCAGTTGCA GGGCAAGTCA GGACATTAGC AATIATTTAA 101 ACTGGTATCA GCAGAAACCA GATGGAACTG TTAAGCTCCT GATCITCTAC 151 ACATCAACAT TACAGTCAGG AGTCCCATCG A(G9TTCAGTG GCAGTGGGTC 25 201 TGGAACAAAT TATTCTCTCA CCATTACCAA CCTGGAGCAA GATGATGCTG 251 CCACTTACTT TTGCCAACAG GGTGATACGC TTCCGTACAC GTTCGGAGGG 301 GGGACCAAGC TGGAAATAAA ACGGGCTGAT GCTGCACCAA CTGTATCCAT 351 CTTCCCACCA TCCAGTGAGC AGTTAACATC TGGAGGTGCC TCAGTCGTGT 401 GCTTCTGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA GTGGAAGATr 30 451 GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA CTGATCAGGA 501 CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG TFGACCAAGG 551 ACGAGTATGA ACGACATAAC AGCTATACCT GTGAGGCCAC TCACAAGACA 601 TCAACTTCAC CCATTGTCAA GAGCTTCAAC AGGAATGAGT GTTAG (SEQ ID NO:198) 35 Amino acid sequence of the Ab-12 LC including signal peptide: 1 MMSSAQFLGL LLLCFQGSRC DLQMTQTTSS LSASLGDRVT ISCRASQDIS 51 NYLNWYQQKP DGTVKLLIFY TSTLQSGVPS RFSGSGSGTN YSLTITNLEQ 101 DDAATYFCQQ GDTLPYTFGG GTKLEIKRAD AAPTVSIFPP SSEQLTSGGA 40 151 SVVCFLNNFY PKDINVKWKI DGSERQNGVL NSWTDQDSKD STYSMSSTLT 201 LTKDEYERHN SYTCEATHKT STSPIVKSFN RNEC (SEQ ID NO: 199) Nucleic acid sequence of the Ab-12 LC including signal peptide encoding sequence: 1 ATGATGTCCT CTGCTCAGTT CCTTGGTCTC CTGTTGCTCT GTTrCAAGG 45 51 TTCCAGATGT GATCTCCAGA TGACACAGAC TACTFCCTCC CTGTCTGCCT 101 CTCTGGGAGA CAGAGTCACC ATCAGTTGCA GGGCAAGTCA GGACATTAGC SEA 1803911v 60117-22 73 WO 2006/119062 PCTIUS2006/016345 151 AA~TIA~TIAA ACTGGTATCA GCAGAAACCA QATGGAACTG TTAAGCTCCT 201 GATCTTCTAC ACATCAACAT TACAGTCAGG AGTCCCATCG AGGITrCAGTG 251 GCAGTGGGTC TGGAACAAAT TATTCTCTCA CCATTACCAA CCTGGAGCAA 301 GATGATGCTG CCACTTACTF TTGCCAACAG GGTGATACGC TTCCQTACAC 5 351 GTTCGAGGG GGGACCAAGC TGGAAATAAA ACGGGCTGAT GCTGCACCAA 401 CTGTATCCAT CTTCCCACCA TCCAGTGAGC AGTTAACATC TGGAGGTGCC 451 TCAGTCGTGT GCTTCTTGAA CAACTTCTAC CCCAAAGACA TCAATGTCAA 501 GTGGAAGATT GATGGCAGTG AACGACAAAA TGGCGTCCTG AACAGTTGGA 551 CTGATCAGGA CAGCAAAGAC AGCACCTACA GCATGAGCAG CACCCTCACG 10 601 TrGACCAAGG ACGAGTATGA ACGACATAAC AG;CTATACCT GTGAGGCCAC 651 TCACAAGACA TCAACTTCAC CCATTGTCAA GAGCTTCAAC AGGAATGAGT 701 GTTAG (SEQ ID NO:200) Ab-12 Heavy Chain: 15 Amino acid sequence of the mature form (signal peptide removed) of the Ab-12 HC: 1 EVQLQQSGPE LMKPGASVKM SCKASGYTFT DYNj5IWMKQN QGKSLEWIGE 51 NSGGSjyQ&G ATL TVDKSSSTAY MELRSLTSED SAVYYCARW 101 1NY$DVLFDYWGAGTTVTVSSAKTTPPS VYPLAPGSAA QTNSMVTLGC 151 LVKGYFPEPV TVTWNSGSLS SGVHTFPA VL QSDLYTLSSS VTVPSSTWPS 20 201 ETVTCNVAHPASSTKVDIU VPRDCGCEPCICTVPEVSSV FIFPPKPKDV 251 LTITLTPKVT CVVVDISEDD PEVQFSWFVD DVEVHTAQTQ PREEQFNSTF 301 RSVSELPIMH QDWLNGEEFK CRVNSAAFPA PIEKTISKTK GRPKAPQVYT 351 IPPPKEQMAKDKVSL TCMIT DFFPEDITVE WQWNGQPAEN YKNTQPIMDT 401 DGSYFIYSKL NVQKSNWEA G NTFTCSVLHE GLHNHHTEKS LSHSPGK (SEQ ID 25 NO:201) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-12 HC: 1 QAGGTCCAGT TGCAACAGTC TGGACCTGAA CTAATGAAGC CTGGGGCTTC 51 AGTGAAGATG TCCTGCAAGG CTTCTGGATA CACATTCACT GACTACAACA 30 101 TOCACTGGAT GAAGCAGAAC CAAGGAAAGA GCCTAGAGTG GATAGGAGAG 151 ATTAATCCTA ACAGTGGTGG TTCTGGTTAC AACCAGAAGT TCAAAGGCAA 201 GGCCACATTG ACTGTAGACA AGTCCTCCAG CACAGCCTAC ATGGAGCTCC 251 GCAGCCTGAC ATCTGAGGAC TCTGCAGTCT ATTACTGTGC AAGATTGGGC 301 TACTATGGTA ACTACGAGGA CTGGTATITC GATGTCTGGG GCGCAGGGAC 35 351 CACGGTCACC GTCTCCTCTG CCAAAACGAC ACCCCCATCT GTCTATCCAC 401 TGGCCCCTGG ATCTGCTGCC CAAACTAACT CCATGQTGAC CCTGGGATGC 451 CTGGTCAAGG GCTATTTCCC TGAQCCAGTG ACAGTGACCT GGAACTCTGG 501 ATCCCTGTCC AGCGGTGTGC ACACCTTCCC AGCTGTCCTG CAGTCTGACC 551 TCTACACTCT GAGCAGCTCA GTGACTGTCC CCTCCAGCAC CTGGCCCAGC 40 601 GAGACCGTCA CCTGCAACGT TGCCCACCCG GCCAGCAGCA CCAAGGTGGA 651 CAAGAAAATT GTGCCCAGGG ATTGTGGTTG TAAGCCTTGC ATATGTACAQ 701 TCCCAGAAGT ATCATCTGTC TTCATCTTCC CCCCAAAGCC CAAGGATGTG 751 CTCACCATrA CTCTGACTCC TAAGGTCACG TGTGTTGTGG TAGACATCAG 801 CAAGGATGAT CCCGAGGTCC AGTTCAGCTG GTTTGTAGAT QATGTGGAGG 45 851 TGCACACAGC TCAGACOCAA CCCCGGGAGG AGCAGTTCAA CAGCACTTTC 901 CGCTCAGTCA GTGAAC1TCC CATCATGCAC CAGGACTGC TCAATGGCAA 951 GGAGTTCAAA TGCAGGGTCA ACAGTGCAGC TTTCCCTGCC CCCATCGAGA 1001 AAACCATCTC CAAAACCAAA GGCAGACCGA AGGCTCCACA GGTGTACACC 1051 ATTCCACCTC CCAAGGAGCA GATGGCCAAG GATAAAGTCA GTCTQACCTG SEA 180391 lvI 60117-22 74 WO 2006/119062 PCT/US2006/016345 1101 CATGATAACA GACTrCTrCC CTGAAGACAT TACTGTGGAG TGGCAGTGGA 1151 ATGQGCAGCC AGCGGAGAAC TACAAGAACA CTCAGCCCAT CATGGACACA 1201 GATGGCTCTT ACTTCATCTA CAGCAAGCTC AATGTGCAGA AGAGCAACTG 1251 GGAGGCAGGA AATACTTrCA CCTGCTCTGT GTACATGAG GGCCTGCACA 5 1301 ACCACCATAC TGAGAAGAGC CTCTCCCACT CTCCTGGTAA ATGA (SEQ ID NO:202) Amino acid sequence of the Ab-12 HC including signal peptide: 1 MGWSWTFLFL LSGTSGVLSE VQLQQSGPEL MKPGASVKMS CKASGYTFTD 10 51 YNMHWMKQNQ GKSLEWIGEI NPNSGGSGYN QKFKGKATLT VDKSSSTAYM 101 ELRSLTSEDS AVYYCARLGY YGNYEDWYFD VWGAGTrVTV SSAKTTPPSV 151 YPLAPGSAAQ TNSMVTLGCL VKQYFPEPVT VTWNSGSLSS GVHTFPAVLQ 201 SDLYTLSSSV TVPSSTWPSE TVTCNVAHPA SSTKVDKKIV PRDCGCKPCI 251 CTVPEVSSVF IFPPKPKDVL TffLTPKVTC VVVDISKDDP EVQFSWFVDD 15 301 VEVHTAQTQP REEQFNSTFR SVSELPIMHQ DWLNGKEFKC RVNSAAFPAP 351 IEKTISKTKG RPKAPQVYTI PPPKEQMAKD KVSLTCMITD FFPEDITVEW 401 QWNGQPAENY KNTQPIMDTD GSYF1YSKLN VQKSNWEAGN TFTCSVLHEG 451 LHNHHTEKSL SHSPGK (SEQ ID NO:203) 20 Nucleic acid sequence of the Ab-12 HC including signal peptide encoding sequence: 1 ATGGGATGGA GCTGGACCTr TCTCTrCCTC CTGTCAGGAA CTTCGGGTGT 51 CCTCTCTGAG GTCCAGTTGC AACAGTCTGG ACCTGAACTA ATGAAGCCTG 101 GGGCTfCAGT GAAGATGTCC TGCAAGGCT CTGGATACAC ATTCACTGAC 151 TACAACATGC ACTGGATGAA GCAGAACCAA GGAAAGAGCC TAGAGTGGAT 25 201 AGGAGAGATI AATCCTAACA GTGGTGGTfC TGQTTACAAC CAGAAGTTCA 251 AAGGCAAGGC CACATTGACT GTAGACAAGT CCTCCAGCAC AGCCTACATG 301 GAGCTCCQCA GCCTGACATC TGAGGACTCT GCAQTCTAT ACTGTGCAAG 351 ATTGZGCTAC TATGGTAACT ACGAGGACTG GTATTCGAT GTCTGGGGCG 401 CAGGGACCAC GGTCACCGTC TCCTCTGCCA AAACGACACC CCCATCTGTC 30 451 TATCCACTGG CCCCTGGATC TGCTGCCCAA ACTAACTCCA TG3GTGACCCT 501 GGGATGCCTG GTCAAGGGCT ATTrCCCTGA GCCAGTQACA GTGACCTGGA 551 ACTCTGGATC CCTGTCCAGC GGTGTGCACA CCTTCCCAGC TGTCCTGCAG 601 TCTGACCTCT ACACTCTGAG CAGCTCAGTG ACTGTCCCCT CCAGCACCTG 651 GCCCAGCGAQ ACCQTCACCT GCAACGITGC CCACCCGGCC AGCAGCACCA 35 701 AGGTGGACAA GAAAATTGTG CCCAGGGATT GTGGTTGTAA GCCTTGCATA 751 TGTACAGTCC CAGAAGTATC ATCTGTCTTC ATCTTCCCCC CAAAGCCCAA 801 GGATGTGCTC ACCATTACTC TGACTCCTAA GGTCACGTGT GTTGTGGTAG 851 ACATCAGCAA GGATGATCCC GAGGTCCAGT TCAGCTGGTF TGTAGATGAT 901 GTGGAGGTGC ACACAGCTCA GACGCAACCC CGGGAGGAGC AGTTCAACAG 40 951 CACTITCCGC TCAGTCAGTG AACTTCCCAT CATGCACCAG GACTGGCTCA 1001 ATGGCAAGGA GTTCAAATGC AGGGTCAACA GTGCAGCTT CCCTGCCCCC 1051 ATCGAGAAAA CCATCTCCAA AACCAAAGGC AGACCGAAGG CTCCACAGGT 1101 GTACACCATr CCACCTCCCA AGGAGCAGAT GGCCAAGGAT AAAGTCAGTC 1151 TGACCTGCAT GATAACAGAC TTCTTCCCTG AAGACATTAC TGTGGAGTGG 45 1201 CAGTGGAATG GGCAGCCAGC GGAGAACTAC AAGAACACTC AGCCCATCAT 1251 GGACACAGAT GGCTCTTACT TCATCTACAG CAAGCTCAAT GTGCAGAAGA 1301 GCAACTGGGA GGCAGGAAAT ACTTCACCT GCTCTGTGrf ACATGAGGGC 1351 CTGCACAACC ACCATACTGA GAAGAGCCTC TCCCACTCTC CTGGTAAATG 1401 A (SEQ ID NO:204) SEA 1803911vl 60117-22 75 WO 2006/119062 PCTIUS2006/016345 Ab-13 The sequences of the Antibody 13 (also referred to herein as Ab-13) LC and HC are as follows: Ab-13 Light Chain: 5 Amino acid sequence of the mature form (signal peptide removed) of the Ab-13 LC: 1 QIVLTQSPAI MSASPGEKVT MTCRASSSVT 5SYLNWYQQK PGSSPKLWIY 51 BTSNL5SGVP ARFSGSGSGT SYSLTISSVE AEDAATYYCQQYDFFPSTFG 101 GGThkIKRA DAAPTVSIFP PSSEQLTSGG ASVVCFNNF YPKDENVKWK 151 1DGSERQNGVLNSWTDQDSKDSTYSMSSTL TLTKDEYERINSYTCE ATHK 10 201 TSTSPIVKSFNRNEC (SEQ ID NO:205) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-13 LC: 1 CAGAT[GTTC TCACCCAGTC TCCAGCAATC ATGTCTGCAT CTCCAGGGGA 51 GAAGGTCACC ATGACCTGCA GGGCCAGCTC AAGTGTAACT TCCAGTTACT 15 101 TGAACTGGTA CCAGCAGAAG CCAGGATCTT CCCCCAAACT CTGGATAT 151 AGCACATCCA ACCTGGCTTC AGQAGTCCCA GCTCGCTTCA GTGGCAGTGG 201 GTCTGGGACC TCTTACTCTC TCACAATCAG CAGTGTGGAG GCTGAGGATG 251 CTGCCACTIA TTACTGCCAG CAGTATGATT TITrCCCATC GACGITCGGT 301 GGAGGCACCA AGCTGGAAAT CAAGCGGGCT GATGCTGCAC CAACTGTATC 20 351 CATCTTCCCA CCATCCAGTG AGCAGTTAAC ATCTGGAGGT GCCTCAGTCG 401 TGTGCTTCTI GAACAACTTC TACCCCAAAG ACATCAATGT CAAGTGGAAG 451 ATTGATGGCA GTGAACGACA AAATGGCGTC CTGAACAGTT GGACTGATCA 501 GGACAGCAAA GACAGCACCT ACAGCATGAG CAGCACCCTC ACGTTGACCA 551 AGGACGAGTA TGAACGACAT AACAGCTATA CCTGTGAGGC CACTCACAAG 25 601 ACATCAACTT CACCCATCGT CAAGAGCTTC AACAGGAATG AGTGT (SEQ ID NO:206) Amino acid sequence of the Ab-13 LC including signal peptide: 1 MDSQVQIFSF LLISALVKMS RGQIVLTQSP AIMSASPGEK VTMTCRASSS 30 51 VTSSYLNWYQ QKPGSSPKLW 1YSTSNLASG VPARFSGSGS GTSYSLTISS 101 VEAEDAATYY CQQYDFFPST FGGGTKLEIK RADAAPTVSI FPPSSEQLTS 151 GGASVVCFLN NFYPKDINVK WKIDGSERQN GVLNSWTDQD SKDSTYSMSS 201 TLTLTKDEYE RHNSYTCEAT HKTSTSPIVK SFNRNEC (SEQ ID NO:207) 35 Nucleic acid sequence of the Ab-13 LC including signal peptide encoding sequence: 1 ATGGATTCTC AAGTGCAGAT TTTCAGCTTC CTTCTAATCA GTGCCTTAGT 51 CAAAATGTCC AGAGGACAGA TTGTFCTCAC CCAGTCTCCA GCAATCATGT 101 CTGCATCTCC AGGGGAGAAG GTCACCATGA CCTGCAGGGC CAGCTCAAGT 151 GTAACITCCA GTTACTTGAA CTGGTACCAG CAGAAGCCAG GATCTTCCCC 40 201 CAAACTCTGG ATTTATAGCA CATCCAACCT GGCTTCAGGA GTCCCAGCTC 251 GCT7CAGTGG CAGTGGGTCT GGGACCTCTf ACTCTCTCAC AATCAGCAGT 301 GTGGAGGCTG AGGATGCTGC CACTTATTAC TGCCAGCAGT ATGA1TmT 351 CCCATCGACG TTCGGTGGAG GCACCAAGCT GGAAATCAAG CGGGCTGATG 401 CTGCACCAAC TGTATCCATC TTCCCACCAT CCAGTGAGCA GTTAACATCT 45 451 GGAGGTGCCT CAGTCGTGTG CTICTTGAAC AACTTCTACC CCAAAGACAT 501 CAATGTCAAG TGGAAGATTG ATGGCAGTGA ACGACAAAAT GGCGTCCTGA SEA 1803911v1 60117-rn 76 WO 2006/119062 PCT/US2006/016345 SWA' TdXCTETCAGGAC AGCAAAQACA GCACCTACAG CATGAGCAGC 601 ACCCTCACGT TGACCAAGGA CGAGTATGAA CGACATAACA GCTATACCTQ 651 TGAGGCCACT CACAAGACAT CAACTTCACC CATCGTCAAG AGCTTCAACA 701 GGAATGAOTG T (SEQ ID NO:208) 5 Ab-13 Heavy Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-13 HC: 1 EVQLQQSGPE LVKPGASVKM SCKASGYTFT PYMNWVKQS HGESLEWIGO 51 INPYNDD"T1Y INHIC 1TFiGXATL TVDKSSNTAY MQLNSLTSED SAVYYCARET 10 101AVITEMDi WGQGTSVTVS SAKTTPPSVYPLAPGSAAQTNSMVTLGCLV 151 KGYFPEPVTV TWNSGSLSSG VHTFPA VLQS DLYTLSSSVT VPSSTWPSET 201 VTCNVARPASSTKVDKUVPRDCGCKPCICTVPEVSSVFIFPPKPKDVLT 251 ITLTPKVTCV VVDISKDDPE VQFSWFVDDVEVHTAQTQPR EEQFNSTFRS 301 VSELP1MHQD WLNGKEFKCR VNSAAFPAPI EKTISKTKGR PKAPQVYTIP 15 351 PPKEQMAKDK VSLTCMTDFFPEDITVEWQ WNGQPAENYKNTQPBMDTDG 401 SYFIYSKLNV QKSNWEAGNT FTCSvLHEGL HNHHTEKSLS HSPGK (SEQ 1) NO:209) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab- 13 HC: 20 1 GAGGTCCAGC TGCAACAATC TGGACCTGAG CTGGTGAAGC CTGGGGCTTC 51 AGTGAAGATG TCCTGTAAGG CTTCTGGATA CACATTCACT GACTACTACA 101 TGAACTGGGT GAAGCAGAGC CATGGAGAGA GCCTTGAGTG GATFGGAGAT 151 ATTAATCCTT ACAACGATGA TACTACCTAC AACCACAAGT TCAAGGGCAA 201 GGCCACATTG ACTGTAGACA AATCCTCCAA CACAGCCTAC ATGCAGCTCA 25 251 ACAGCCTGAC ATCTGAGGAC TCTGCAGTCT ATTACTGTGC AAGAGAGACG 301 QCCGITATTA CTACGAATGC TATGGACTAC TGGGGTCAAG GAACCTCAGT 351 CACCGTCTCC TCAGCCAAAA CGACACCCCC ATCTGTCTAT CCACTGGCCC 401 CTGGATCTGC TGCCCAAACT AACTCCATGG TGACCCTGGG ATGCCTGGTC 451 AAGGGCTATT TCCCTGAGCC AGTGACAGTG ACCTGGAACT CTGGATCCCT 30 501 GTCCAGCGGT GTGCACACCT TCCCAGCTOT CCTGCAGTCT GACCTCTACA 551 CTCTGAGCAG CTCAGTGACT GTCCCCTCCA GCACCTG3CC CAGCGAGACC 601 GTCACCTGCA ACGTTGCCCA CCCGGCCAGC AGCACCAAGG TGGACAAGAA 651 AATTGTGCCC AGGGATTGTG GTTGTAAGCC TrGCATATGT ACAGTCCCAG 701 AAGTATCATC TGTCTTCATC TrCCCCCCAA AGCCCAAGGA TGTGCTCACC 35 751 ATTACTCTGA CTCCTAAGGT CACGTGTGTT GTGGTAGACA TCAGCAAGGA 801 TGATCCCGAG GTCCAGTTCA GCTOGITrGT AGATGATGTG GAGGTGCACA 851 CAGCTCAGAC GCAACCCCGG GAGGAGCAGT TCAACAGCAC TITCCGCTCA 901 GTCAGTGAAC TTCCCATCAT GCACCAGGAC TGGCTCAATG GCAAGGAGTT 951 CAAATGCAGG GTCAACAGTG CAGCTITCCC TGCCCCCATC GAGAAAACCA 40 1001 TCTCCAAAAC CAAAGGCAGA CCGAAGGCTC CACAGGTGTA CACCATCCA 1051 CCTCCCAAGG AGCAGATGGC CAAGGATAAA GTCAGTCTGA CCTGCATGAT 1101 AACAGACTC TTCCCTGAAG ACATTACTGT GGAGTGG7CAG TGGAATGGGC 1151 AGCCAGCGGA GAACTACAAG AACACTCAGC CCATCATGGA CACAGATGGC 1201 TCTTACTTCA TCTACAGCAA GCTCAATGTG CAGAAGAGCA ACTGGGAGGC 45 1251 AGGAAATACT TTCACCTGCT CTGTGTTACA TGAGGGCCTG CACAACCACC 1301 ATACTGAGAA GAGCCTCTCC CACTCTCCTG GiTAAA (SEQ ID NO:210) SEA 1803911v 60117.23 77 WO 2006/119062 PCT/US2006/016345 Amino acid sequence of the Ab-13 HC including signal peptide: 1 MGWNWIFLFL LSGTAGVYSE VQLQQSGPEL VKPGASVKMS CKASGYTFTD 51 YYMNWVKQSH GESLEWIGDI NPYNDDITYN HKFKOKATLT VDKSSNTAYM 101 QLNSLTSEDS AVYYCARETA VITNAMDYW GQQTSVTVSS AKTTPPSVYP 5 151 LAPGSAAQTN SMVTLGCLVK GYFPEPVTVT WNSGSLSSOV HTFPAVLQSD 201 LYTLSSSVTV PSSTWPSETV TCNVAHPA55 TKVDKKlVPR DCOCKPCICT 251 VPEVSSVFIF PPKPKDVLTI TLTPKVTCVV VDISKDDPEV QFSWFVDDVE 301 VHTAQTQPRE EQFNSTFRSV SELPIMHQDW LNGKEFKCRV NSAAFPAPIE 351 KTISKTKGRP KAPQVYTIPP PKEQMAKDKV SLTCMITDFF PEDITVEWQW 1Q 401 NGQPAENYKN TQPIMDTDGS YFIYSKLNVQ KSNWEAGNTF TCSVLHEGLH 451 NHHTEKSLSH SPGK (SEQ ID NO:21 1) Nucleic acid sequence of the Ab-13 HC including signal peptide encoding sequence: 1 ATGGGATGGA ACTGGATCTT TCTCTTCCTC TrGTCAGGAA CTGCAGGTGT 15 51 CTACTCTGAG GTCCAGCTGC AACAATCTGG ACCTGAGCTG GTGAAGCCTG 101 GGGCTCAGT GAAGATGTCC TGTAAGGCTT CTGGATACAC ATrCACTGAC 151 TACTACATGA ACTGGGTGAA GCAGAGCCAT GGAGAGAGCC TTGAGTGGAT 201 TGGAGATATr AATCCTTACA ACGATGATAC TACCTACAAC CACAAGTTCA 251 AGGGCAAGGC CACATTGACT GTAGACAAAT CCTCCAACAC AGCCTACATG 20 301 CAGCTCAACA GCCTGACATC TGAGGACTCT GCAGTCTATT ACTQTGCAAG 351 AGAGACGGCC GTTATTACTA CGAATGCTAT GGACTACTGG GGTCAAGGAA 401 CCTCAGTCAC CQTCTCCTCA GCCAAAACGA CACCCCCATC TGTCTATCCA 451 CTGGCCCCTG GATCTGCTGC CCAAACTAAC TCCATGGTGA CCCTGGGATG 501 CCTGGTCAAG GGCTATITCC CTGAGCCAGT GACAGTGACC TGGAACTCTG 25 551 GATCCCTGTC CAGCGGTGTG CACACCTTCC CAGCTGTCCT GCAGTCTGAC 601 CTCTACACTC TGAGCAOCTC AGTGACTGTC CCCTCCAGCA CCTGGCCCAG 651 CGAGACCGTC ACCTGCAACG TTGCCCACCC GGCCAGCAGC ACCAAGGTGG 701 ACAAGAAAAT TGTGCCCAGG GATTGTGTF GTAAGCCTTG CATATGTACA 751 GTCCCAGAAG TATCATCTGT CTTCATCTTC CCCCCAAAGC CCAAGGATQT 30 801 GCTCACCATT ACTCTGACTC CTAAGGTCAC GTGTGTTGTG GTAGACATCA 851 GCAAGGATGA TCCCGAGGTC CAGTTCAGCT GGTTGTAGA TGATGTGGAG 901 GTGCACACAG CTCAGACGCA ACCCCGGGAG GAGCAGTTCA ACAGCACTTT. 951 CCGCTCAGTC AGTGAACTTC CCATCATGCA CCAGGACTGG CTCAATGGCA 1001 AGGAGTTCAA ATGCAGGGTC AACAGTGCAG CTTTCCCTGC CCCCATCGAG 35 1051 AAAACCATCT CCAAAACCAA AGGCAGACCG AAGGCTCCAC AGGTGTACAC 1101 CATrCCACCT CCCAAGGAGC AGATGGCCAA GGATAAAOTC AGTCTGACCT 1151 GCATGATAAC AGACTTCTIC CCTGAAGACA TTACTGTGGA GTGGCAGTGG 1201 AATGGGCAGC CAGCGGAGAA CTACAAGAAC ACTCAGCCCA TCATOGACAC 1251 AGATGGCTCT TACTTCATCT ACAGCAAGCT CAATGTGCAG AAGAGCAACT 40 1301 GGGAGGCAGG AAATACTTC ACCTGCTCTG TGTFACATGA GGGCCTGCAC 1351 AACCACCATA CTGAGAAGAG CCTCTCCCAC TCTCCTGGTA AA (SEQ ID NO:212) Ab-13 was humanized to generate Ab-14. 45 The sequences of the Antibody 14 (also referred to herein as Ab-14) LC and HC are as follows: SEA 18O3gIvI 60117-2D 78 WO 2006/119062 PCT/US2006/016345 Ab-14 Light Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-14 LC: 1 DIQLTQSPSF LSASVGDRVT ITCrA55SVT S5YLWYQQK PGKAPKLuY 51 STSNLASGVP SRFSGSGSGT EFTLTISSLQ PEDFATYYCQ QYDFFPSTFG 5 101 GGTKVEIKRT VA APSVFIFP PSDEQLKSGTASVVCLLNNF YPREL4KVQWK 151 VDNALQSGNS QESVTEQDSKDSTYSLSSTL TLSKADYEKHKVYACEVTHQ 201 GLSSPVTKSF NRGEC (SEQ ID NO:213) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-14 LC: 10 1 GACATCCAGC TGACCCAGAG CCCCAGCTIC CTITCCGCAT CCGTTGGTGA 51 CCGAGTAACA ATCACATGCC GCGCCTCATC TTCAGTTACA TCTTCTTATC 101 TTAATTGGTA TCAACAAAAA CCAGGAAAAG CACCTAAACT TCTTATATAC 151 TCTACATCTA ATCTCGCATC AGGAGTTCCC TCTCGATTT CAGGATCTGG 201 ATCAGGCACA GAATTFACAC TTACTATATC ATCACTCCAA CCAGAAGACT 15 251 TCGCCACTTA TTACTGCCAA CAATACGATT ITITICCAAG CACATTCGGA 301 GQAGGTACAA AAGJTAGAAAT CAAGCGTACG GTGGCTGCAC CATCTGTCTT 351 CATCTTCCCG CCATCTGATG AGCAGTTGAA ATCTGGAACT GCCTCTGTTG 401 TGTGCCTGCT GAATAACTTC TATCCCAGAG AGGCCAAAGT ACAGTGGAAG 451 GTGGATAACG CCCTCCAATC GGGTAACTCC CAGGAGAGTG TCACAGAGCA 20 501 GGACAGCAAG GACAGCACCT ACAGCCTCAG CAGCACCCTG ACGCTGAGCA 551 AAGCAGACTA CGAGAAACAC AAAGTCTACG CCTGCGAAGiT CACCCATCAG 601 GGCCTGAGCT CGCCCGTCAC AAAGAGCTTC AACAGGCGAG AGTGT (SEQ ID NO:214) 25 Amino acid sequence of the Ab-14 LC including signal peptide: 1 MDMRVPAQLL GLLLLWLPGA RCDIQLTQSP SFLSASVGDR VTITCRASSS 51 VTSSYLNWYQ QKPGKAPKLL IYSTSNLASG VPSRFSGSGS GTEFTLTISS 101 LQPEDFATYY CQQYDFFPST FGGGTKVEIK RTVAAPSVFI FPPSDEQLKS 151 GTASVVCLLN NFYPREAKVQ WKVDNALQSG NSQESVTEQD SKDSTYSLSS 30 201 TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC (SEQ ID NO:215) Nucleic acid sequence of the Ab-14 LC including signal peptide encoding sequence: 1 ATGGACATGA GGGTCCCCGC TCAGCTCCTG GGGCTCCTGC TACTCTGGCT 51 CCCAGGTGCC AGATGTGACA TCCAGCTGAC CCAGAGCCCC AGCTTCCTTT 35 101 CCGCATCCGT TGGTGACCGA GTAACAATCA CATGCCGCGC CTCATCTTCA 151 GTTACATCTT CTTATCTTAA TTGGTATCAA CAAAAACCAG GAAAAGCACC 201 TAAACTTCTT ATATACTCTA CATCTAATCT CGCATCAGGA GTTCCCTCTC 251 GATTCAGG ATCTGGATCA GGCACAGAAT TfACACTrAC TATATCATCA 301 CTCCAACCAG AAGACTTCGC CACTTATTAC TGCCAACAAT ACGATITIT 40 351 TCCAAGCACA TTCGGAGGAG GTACAAAAGT AGAAATCAAG CGTACGGTGG 401 CTGCACCATC TGTCTTCATC TTCCCGCCAT CTGATGAGCA GITGAAATCT 451 GGAACTGCCT CTGTTGTGTG CCTGCTGAAT AACTfCTATC CCAGAGAGGC 501 CAAAGTACAG TGGAAGGTGG ATAACGCCCT CCAATCGGGT AACTCCCAGG 551 AGAGTGTCAC AGAGCAGGAC AGCAAOGACA GCACCTACAG CCTCAGCAGC 45 601 ACCCTGACGC TGAGCAAAGC AGACTACGAG AAACACAAAG TCTACGCCTG 651 CGAAGTCACC CATCAGQGCC TGAGCTCGCC CGTCACAAAG AGCTTCAACA 701 GGGGAGAGTQ T (SEQ ID NO:216) SEA 1803911vl 60117-22 79 WO 2006/119062 PCT/US2006/016345 Ab-14 Heavy Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-14 HC: 1 EVQLVQSGAE VKKPGASVKV SCKASGYTFT DYYhd@VRQA PGQRLEWMGP 5 51 %NPYNbDiry RiKdiGRVTI TRDTSASTAY MELSSLRSED TAVYYCARET 101 AVITTNAMDY WGQGTTVTVS STKGPSVF PLAPCSRSTS ESTAALGCL V 151 EDYFPEPVTVSWNSGALTSG VHTFPAVLQS SGLYSLSSVV TVPSSNFGTQ 201 TYTCNVDRKP SNTKVDKTVE RKCCVECPPC PAPPVA GPSV FLFPPRPKDT 251 LMSRTPEVT CVVVDVSHED PEVQFNWYVD GVEVEHNAKTKPREEQFNSTF 10 301 RVVSVLTVVH QD WLNGKEYK CKVSNKGLPA PJEKTISKTK GQPREPQVYT 351 LPPSREEMTK NQVSLTCLVK GFYPSDIA VE WESNGQPENN YKTTPPM LDS 401 DGSFFLYSEL TVDKSRWQQG NVFSCSVME ALHNHYTQKS LSLSPGK (SEQ ID NO:217) 15 Amino acid sequence of the mature form (signal peptide removed) of the Ab-14 HC without carboxy-terminal lysine: 1 EVQLVQSGAE VKKPGASVKV SCKASGYTFT yYWVRQA PGQRLEWMG 51 RlPYN DDMTiNFKbiRVTI TRDTSASTAY MELSSLRSED TAVYYCARET 101 AVE IRAMQYVWGQGITVTVS SASTKGPSVFPLAPCSRSTS ESTAALGCL V 20 151 KDYFPEPVTVSWNSGALTSG VHTFPA VLQS SGLYSLSSVV TVPSSNFGTQ 201 TYT CNVDRKP SNTKVDKTVE RKCCVECPPC PAPPVAGPSVFLFPPKPKDT 251 LMSRTPEVT CVVVDVSHIED PEVQFNWYVD GVEVENAKTKPREEQFNSTF 301 RVVSVLTVVH QDWLNGKEYK CKVSNKGLPA PIEKTISKTK GQPREPQVYT 351 LPPSREEMTK NQ VSL CL VK GFYPSDL4VE WESNGQPEN YK7TPPMLDS 25 401 DGSFFLYSKL TVDKSRWQQG NVFSCSVME ALfNHYTQKS LSLSPG (SEQ ID NO:393) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab- 14 HC: 1 GAGGTGCAGC TGGTGCAGAG CGGCGCCGAG GTCAAGAAAC CTGGAGCAAG 51 CGTAAAGGT AGTTGCAAAG CATCTGGATA CACATTACC GACTACTACA 30 101 TGAATTGGGT ACGACAAGCC CCTGGACAAA GACTTGAATG GATGGGAGAC 151 ATTAACCCTF ATAACGACGA CACTACATAC AATCATAAAT TTAAAGGAAG 201 AGTTACAATT ACAAGAGATA CATCCGCATC AACCGCCTAT ATGGAACTTT 251 CCTCATTGAG ATCTGAAGAC ACTGCTGTIT ATTACTGTGC AAGAGAAACT 301 GCCGTTATTA CTACTAACGC TATOGATTAC TGGGGTCAAG GAACCACTGT 35 351 TACCGTCTCT AGTGCCTCCA CCAAGGGCCC ATCGGTCTTC CCCCTGGCGC 401 CCTGCTCCAG GAGCACCTCC GAGAGCACAG CGGCCCTGGG CTGCCTGGTC 451 AAGGACTACT TCCCCGAACC GGTGACGGTG TCGTGGAACT CAGGCGCTCT 501 GACCAGCGGC GTGCACACCT TCCCAGCTGT CCTACAGTCC TCAGGACTCT 551 ACTCCCTCAG CAGCGTGGTG ACCGTGCCCT CCAGCAACTT CGGCACCCAG 40 601 ACCTACACCT GCAACGTAGA TCACAAGCCC AGCAACACCA AGGTGGACAA 651 GACAGTTGAG CGCAAATGTT GTGTCGAGTG CCCACCGTGC CCAGCACCAC 701 CTGTGGCAGG ACCGTCAGTC TTCCTCTTCC CCCCAAAACC CAAGGACACC 751 CTCATGATCT CCCGGACCCC TGAGGTCACG TGCQTGGTGG TGGACGTGAG 801 CCACGAAGAC CCCGAGGTCC AGTTCAACTG GTACGTGGAC GGCGTGGAGG 45 851 TGCATAATGC CAAGACAAAG CCACGGGAGG AGCAGTTCAA CAGCACGTTC 901 CGTGTGGTCA GCGTCCTCAC CGTTGTGCAC CAGGACTGGC TGAACGGCAA 951 GGAGTACAAG TGCAAGGTCT CCAACAAAGG CCTCCCAGCC CCCATCGAGA 1001 AAACCATCTC CAAAACCAAA GGGCAGCCCC GAGAACCACA GGTGTACACC SEA 1803911v1 60117-223 80 WO 2006/119062 PCT/US2006/016345 1051 CTGCCCCCAT CCCGGGAGGA GATGACCAAG AACCAGGTCA GCCTGACCTG 1101 CCTGGTCAAA GGCTrCTACC CCAGCGACAT CGCCGTGGAG TGGGAGAGCA 1151 ATGGGCAGCC GGAGAACAAC TACAAGACCA CACCTCCCAT GCTGGACTCC 1201 GACGGCTCCT TCTTCCTCTA CAGCAAGCTC ACCGTGGACA AGAGCAGQTG 5 1251 GCAGCAGGG AACGTCTTCT CATGCTCCGT GATGCATGAG GCTCTGCACA 1301 ACCACTACAC GCAGAAGAGC CTCTCCCTGT CTCCGGGTAA A (SEQ ID NO:218) Amino acid sequence of the Ab-14 HC including signal peptide: 10 1 MDWTWRILFL VAAATGAHSE VQLVQSGAEV K.KPGASVKVS CKASGYTFTD 51 YYMNWVRQAP GQRLEWMGDI NPYNDD1TYN HKFKGRVTIT RDTSASTAYM 101 ELSSLRSEDT AVYYCARETA VITNAMDYW GQGTrVTVSS ASTKGPSVFP 151 LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSGALTSGV HTFPAVLQSS 201 GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP 15 251 APPVAGPSVF LFPPKPKDTL WISRTPEVTC VVVDVSHEDP EVQFNWYVDG 301 VEVHNAKTKP REEQFNSTFR VVSVLTVVHQ DWLNGKEYKC KVSNKGLPAP 351 IEKTISKTKG QPREPQVYTL PPSREEMTKN QVSLTCLVKG FYPSDIAVEW 401 ESNGQPENNY KTTPPMLDSD GSFFLYSKLT VDKSRWQQGN VFSCSVMHEA 451 LHNHYTQKSL SLSPGK (SEQ ID NO:219) 20 Nucleic acid sequence of the Ab-14 HC including signal peptide encoding sequence: 1 ATGGACTGGA CCTGGAGGAT CCTCTTCTTG GTGGCAGCAG CCACAGGAGC 51 CCACTCCGAG GTGCAGCTGG TGCAGAGCGG CGCCGAGGTC AAGAAACCTG 101 GAGCAAGCGT AAAGGTTAGT TGCAAAGCAT CTGGATACAC ATTTACCGAC 25 151 TACTACATGA ATTGGGTACG ACAAGCCCCT GGACAAAGAC TTGAATGGAT 201 GGGAGACATT AACCCTTATA ACGACOACAC TACATACAAT CATAAATITA 251 AAGGAAGAGT TACAATTACA AGAGATACAT CCGCATCAAC CGCCTATATG 301 GAACTTTCCT CATTGAGATC TGAAGACACT GCTGTTATT ACTGTGCAAG 351 AGAAACTGCC G'TTATTACTA CTAACGCTAT GGATTACTGG GGTCAAGGAA 30 401 CCACTGTTAC CGTCTCTAGT GCCTCCACCA AGGGCCCATC GGTCTrCCCC 451 CTGGCGCCCT GCTCCAGGAG CACCTCCGAG AGCACAGCGG CCCTGGGCTG 501 CCTGGTCAAG GACTACTTCC CCGAACCGGT GACGGTGTCG TQGAACTCAG 551 GCGCTCTGAC CAGCGGCGTG CACACCTCC CAGCTGTCCT ACAGTCCTCA 601 GGACTCTACT CCCTCAGCAG CGTGGTGACC GTGCCCTCCA GCAACTfCGG 35 651 CACCCAGACC TACACCTGCA ACGTAGATCA CAAGCCCAGC AACACCAAGG 701 TGGACAAGAC AQTTGAGCGC AAATGTfGTG TCGAGTGCCC ACCGTGCCCA 751 GCACCACCTQ TGGCAGGACC GTCAGTCTfC CTCTrCCCCC CAAAACCCAA 801 GGACACCCTC ATGATCTCCC GGACCCCTGA GGTCACGTGC GTGGTGGTGG 851 ACGTGAGCCA CGAAGACCCC GAGGTCCAGT TCAACTGGTA CGTGGACGGC 40 901 GTGGAGGTGC ATAATGCCAA GACAAAGCCA CGGGAGGAGC AGTTCAACAG 951 CACGTTCCGT GTGGTCAGCG TCCTCACCGT TGTGCACCAG GACTGGCTGA 1001 ACGGCAAGGA GTACAAGTGC AAGG3TCTCCA ACAAAGGCCT CCCAGCCCCC 1051 ATCGAGAAAA CCATCTCCAA AACCAAAGGG CAGCCCCQAG AACCACAGGT 1101 GTACACCCTG CCCCCATCCC GGGAGGAGAT GACCAAQAAC CAGQTCAGCC 45 1151 TGACCTGCCT GGTCAAAGGC TrCTACCCCA GCGACATCGC CQTGGAGTGG 1201 QAQAGCAATG GGCAGCCGGA GAACAACTAC AAGACCACAC CTCCCATGCT 1251 GGACTCCGAC GGCTCCTTCT TCCTCTACAG CAAGCTCACC GTGGACAAGA 1301 GCAGGTGGCA GCAGGGGAAC GTCTfCTCAT QCTCCGTGAT GCATGAGGCT 1351 CTGCACAACC ACTACACGCA GAAGAGCCTC TCCCTGTCTC CGQGTAAA SEA 1803911v1 60117-223 81 WO 2006/119062 PCT/US2006/016345 (SEQ I) NO:220) The CDR sequences in the variable region of the heavy chain of Ab-14 are: CDR-H1: DYYMN (SEQ ID NO:296) 5 CDR-H2: DINPYNDDTIYNHKFKG (SEQ ID NO:297) CDR-H3: ETAVITTNAMD (SEQ ID NO:298) The light chain variable region CDR sequences of Ab-14 are: CDR-LI: RASSSVTSSYLN (SEQ ID NO:284) CDR-L2: STSNLAS (SEQ ID NO:285) 10 CDR-L3: QQYDFFPST (SEQ ID NO:286) Ab-14 Variable domains: Ab-14 light chain variable domain amino acid sequence (without signal sequence): 15 1 DIQLTQSPSF LSASVGDRVT ITCS .' $Y.fiiN.WYQQK PGKAPKLLIY 51 TjNLANGVP SRFSGSGSGT EFTLTISSLQ PEDFATYYC[Q QYD'FS'IFG 101 GGTKVEIK (SEQ ID NO:380) 20 Ab-14 light chain variable domain DNA sequence (without signal sequence): 1 GACATCCAGC TGACCCAGAG CCCCAGCTC CTTFCCGCAT CCGTGGTGA 51 CCGAGTAACA ATCACATGCC GCGCCTCATC TTCAGTFACA TCTTCTrATC 101 TTAATrGGTA TCAACAAAAA CCAGGAAAAG CACCTAAACT TCTfATATAC 25 151 TCTACATCTA ATCTCGCATC AGG3AGTTCCC TCTCGATTT CAGG3ATCTGG 201 ATCAGGCACA GAATTTACAC TrACTATATC ATCACTCCAA CCAGAAGACT 251 TCGCCACTTA TTACTGCCAA CAATACGATT TITrTCCAAG CACATFCGGA 301 GGAGGTACAA AAGTAGAAAT CAAG (SEQ ID NO:381) 30 Ab-14 heavy chain variable domain amino acid sequence (without signal sequence): 1 EVQLVQSGAE VKKPGASVKV SCKASGYTFT ~~gWVRQA PGQRLEWMG 51 X jPYMDD'TY NigNPRVTI TRDTSASTAY MELSSLRSED TAVYYCARIT 101 fVIfTNM[DY WGQGTTVTVS S (SEQ ID NO:382) 35 Ab-14 heavy chain variable domain DNA sequence (without signal sequence): 1 GAGGTGCAGC TGGTGCAGAG CGGCGCCGAG QTCAAGAAAC CTGGAGCAAG 51 CGTAAAGGTT AGTfGCAAAG CATCTGGATA QACATTTACC GACTACTACA 40 101 TGAATTGGGT ACGACAAQCC CCTGGACAAA GACTTGAATG GATOGGAGAC 151 ATTAACCCTT ATAACOACGA CACTACATAC AATCATAAAT TAAAGGAAG 201 AGTTACAATT ACAAGAGATA CATCCGCATC AACCGCCTAT ATGGAACTMT 251 CCTCATTGAG ATCTGAAGAC ACTGCTGT ATTACTGTGC AAGAGAAACT SEA 1803911v 60117-223 82 WO 2006/119062 PCT/US2006/016345 301 GCCGTTATTA CTACTAACGC TATGGATTAC TOGGGTCAAG GAACCACTGT 351 TACCGTCTCTAGT (SEQ ID NO:383) 5 Ab-3 was humanized to generate Ab-15. Ab-15 The sequences of the Antibody 15 (also referred to herein as Ab-15) LC and HC are as follows: 10 Ab-15 LightChain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-15 LC: 15 1 DIQMTQSPSS LSASVGDRVT ITCSSIS SNHLiWFQQK PGKAPKSLLY 51 OSINA5GVP SRFSGSGSGT DFTLTISSLQ PEDFATYYCW4Y1S!Y TFG 101 GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT ASVVCLLNNF YPREAKVQWK 151 VDNALQSGNS QESVTEQDSK DSTYSLSSTL TLSKADYEKFHKVYACEVTHQ 201 GLSSPVTKSF NRGEC (SEQ ID NO:221) 20 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-15 LC: 1 GACATCCAGA TGACCCAGTC TCCATCCTCC CTCTCAOCAT CCGTAGGCGA 51 TAGAGTTACA ATAACATGCA GCGTATCATC AACTATATCA TCAAATCATC 25 101 TTCATTGGTT CCAACAGAAA CCCGGCAAAG CACCTAAATC ACTTATATAC 151 GGCACATCAA ATCTCGCATC AGGCGTTCCT TCAAGATTTT CAGGCTCTGG 201 CTCAGGCACC GACTTACTC TTACAATATC CTCCCTCCAA CCCGAAGACT 251 TCGCAACCTA TTACTGTCAA CAATGGTCCT CATATCCACT CACATITGGC 301 GGCGGCACAA AAGTAGAAAT TAAACGTACG GTGGCTGCAC CATCTGTCTI 30 351 CATCTTCCCG CCATCTGATG AGCAGTTGAA ATCTGGAACT GCCTCTGTTG 401 TGTGCCTGCT GAATAACTTC TATCCCAGAG AGGCCAAAGT ACAGTGGAAG 451 GTGGATAACG CCCTCCAATC GGGTAACTCC CAGGAQAGTG TCACAGAGCA 501 GGACAGCAAG GACAGCACCT ACAGCCTCAG CAGCACCCTG ACGCTGAGCA 551 AAGCAGACTA CGAGAAACAC AAAGTCTACG CCTGCGAAGT CACCCATCAG 35 601 GCGCCTGAGCT CGCCCGTCAC AAAGAGCTTC AACAGGGGAG AGTGT (SEQ ID NO:222) Amino acid sequence of the Ab- 15 LC including signal peptide: 40 1 MDMRVPAQLL GLLLLWLRGA RCDIQMTQSP SSLSASVGDR VTITCSVSST 51 ISSNHLHWFQ QKPGKAPKSL 1YGTSNLASG VPSRFSGSGS GTDFTLTISS 101 LQPEDFATYY CQQWSSYPLT FGGGTKVEIK RTVAAPSVFI FPPSDEQLKS 151 GTASVVCLLN NFYPREAKVQ WKVDNAJQSG NSQESVTEQD SKDSTYSLSS 45 201 TLTLSKADYE KHKVYACEVT HQGLSSPVTK SFNRGEC (SEQ ID NO:223) Nucleic acid sequence of the Ab- 15 LC including signal peptide encoding sequence: 50 1 ATGGACATGA GGGTCCCCGC TCAGCTCCTG GGGCTCCTGC TACTCTGGCT 51 CCGAGGTGCC AGATGTGACA TCCAGATGAC CCAGTCTCCA TCCTCCCTCT SEA 180391 vI 60117-23 83 WO 2006/119062 PCT/US2006/016345 IOI CAGCATCCGT AGGCGATAGA GITACAATAA CATGCAGCGT ATCATCAACT 151 ATATCATCAA ATCATCTTCA TTGGTTCCAA CAGAAACCCG GCAAAGCACC 201 TAAATCACTT ATATACGGCA CATCAAATCT CGCATCAGOC GTTCCTrCAA 251 GATITCAGG CTCTGGCTCA GGCACCGACT TTACTCTrAC AATATCCTCC 5 301 CTCCAACCCG AAGACTTCGC AACCTATTAC TGTCAACAAT GGTCCTCATA 351 TCCACTCACA TITGGCGGCG GCACAAAAGT AGAAATTAAA CGTACGGTGG 401 CTGCACCATC TGTCTTCATC TTCCCGCCAT CTGATGAGCA GTTGAAATCT 451 GGAACTGCCT CTGTrGTGTG CCTGCTGAAT AACTCTATC CCAGAGAGGC 501 CAAAGTACAQ TGGAAGGTGG ATAACGCCCT CCAATCGGGT AACTCCCAGG 10 551 AGAQTGTCAC AGAGCAGGAC AGCAAGQACA QCACCTACAG CCTCAGCAGC 601 ACCCTGACGC TGAGCAAAGC AGACTACQAG AAACACAAAG TCTACGCCTG 651 CGAAGTCACC CATCAGGGCC TGAGCTCGCC CGTCACAAAG AGCTTCAACA 701 GGGGAGAGTG T (SEQ ID NO:224) 15 Ab-15 Heavy Chain Amino acid sequence of the mature form (signal peptide removed) of Ab-15 HC. 20 1 EVQLVQSGAE VKKPGASVKV SCKASDFNIK O1 YJNWVRQA PGQGLEWIGi 51 InfD-nf diQiDKVTM TTDTSTSTAY MELRSLRSDD TAVYYCAR 1011DYI)$TPSyWYFDVWGRGTLVTVSSASTKGPSVFPLAPCSRSTSESTAAL 151 GCLVKDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSN 25 201 FGTQTYTCNVDHEPSNTKVD KTVERKCCVE CPPCPAPPVA GPSVFLFPPK 251 PEDTLMTSRT PEVTCVVVDVSHEDPEVQFN WYVDGVEVHNAKTKPREEQF 301 NSTFRVVSVL TVVHQDWLNG KEYKCKVSNK GLPAPIEKTJ SKTKGQPREP 351 QVYTLPPSRE EMTKENQVSLT CL VKGFYPSD IA VEWESNGQ PENNYKTTPP 401 MLDSDGSFFL YSKLTVDKSR WQQGNVFSCS VMHE ALHNHY TQKSLSLSPG 30 451 K(SEQ ID NO:225) Amino acid sequence of the mature form (signal peptide removed) of Ab-15 HC without carboxy-terminal lysine: 35 1 EVQLVQSGAE VKKPGASVKV SCKASDFNIK 0biWVRQA PGQGLEWIGK 51 ]) ENDTL:Y 5i-FQDKVTM TTDTSTSTAY MELRSLRSDD TAVYYCARFA 101 flHDG'T SYV (FDVWGRGTL VTVSSASTKG PSVFPLAPCS RSTSESTAAL 151 GCL VDYFPE PVTVSWNSGA LTSGVHTFPA VLQSSGLYSL SSVVTVPSSN 40 201 FGTQTYTCNVDXPSNTKVD KTVERKCCVE CPPCPAPPVA GPSVFLFPPK 251 PEDTLMISRTPEVTCVVVDVSIIEDPEVQFN WYVDGVEVHNAKTEPREEQF 301 NSTFR VVSL TVVHQD WING KEYKCKVSNK GLPAPIEKTI SKTKGQPREP 351 QVYTLPPSRE EMTENQ VSLT CL VKGFYPSD IA VEWESNGQ PENNYK7TPP 401 MLDSDGSFFL YSELTVDKSR WQQGNVFSCS VWMBEALRNHY TQKSLSLSPG 45 451 (SEQ ID NO:394) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-15 HC: 50 1 GAGGTGCAQC TGGTGCAGTC TGGGGCTGAG GTGAAGAAC3C CTGGGGCCTC SEA 180391M 60117-:rn 84 WO 2006/119062 PCT/US2006/016345 51 AGTGAAGGTC TCCTGCAAGG CTTCTGACTT CAACATTAAA GACTTCTATC 101 TACACTGGGT GCQACAGGCC CCTGGACAAG GGCTrGAGTG GATTGGAAGG 151 ATTGATCCTG AGAATGGTGA TACTTTATAT GACCCGAAGT TCCAGGACAA 201 GGTCACCATG ACCACAGACA CGTCCACCAG CACAGCCTAC ATGGAGCTGA 5 251 GGAGCCTGAG ATCTGACGAC ACGGCCGTGT ATTACTGTGC GAGAGAGGCO 301 GATTATITCC ACGATGGTAC CTCCTACTGG TACTTCGATG TCTGQGCCG 351 TGG7CACCCTG GTCACCGTCT CTAGTGCCTC CACCAAGGC CCATCGOTCT 401 TCCCCCTGGC GCCCTGCTCC AGGAGCACCT CCGAGAGCAC AGCGGCCCTG 451 GGCTGCCTGG TCAAGGACTA CTTCCCCGAA CCGGTGACGG TGTCGTGGAA 10 501 CTCAGGCGCT CTGACCAGCG GCGTGCACAC CTTCCCAGCT GTCCTACAGT 551 CCTCAGGACT CTACTCCCTC AGCAGCGTGG TGACCGTGCC CTCCAGCAAC 601 TTCGGCACCC AGACCTACAC CTGCAACGTA GATCACAAGC CCAGCAACAC 651 CAAGGTGGAC AAGACAGTTG AGCGCAAATG TTGTGTCGAG TGCCCACCGT 701 GCCCAGCACC ACCTGTGGCA GGACCGTCAG TCTTCCTCTT CCCCCCAAAA 15 751 CCCAAGGACA CCCTCATGAT CTCCCGGACC CCTGAGQTCA CGTGCGTGGT 801 GGTGGACGTO AGCCACGAAG ACCCCGAGGT CCAGTTCAAC TGGTACGTGG 851 ACGGCGTGGA GGTGCATAAT GCCAAGACAA AGCCACQGGA GGAGCAGTTC 901 AACAGCACGT TCCGTGTGGT CAGCGTCCTC ACCGTTGTGC ACCAGGACTG 951 GCTGAACGGC AAGGAGTACA AGTGCAAGGT CTCCAACAAA GGCCTCCCAG 20 1001 CCCCCATCQA QAAAACCATC TCCAAAACCA AAGGGCAGCC CCGAGAACCA 1051 CAGGTGTACA CCCTGCCCCC ATCCCGGGAG GAGATOACCA AGAACCAGGT 1101 CAGCCTGACC TGCCTGGTCA AAGGCTTCTA CCCCAGCGAC ATCGCCGTGG 1151 AGTGGGAGAG CAATGGGCAG CCGGAGAACA ACTACAAGAC CACACCTCCC 1201 ATGCTGGACT CCGACGGCTC CTrCTFCCTC TACAGCAAGC TCACCGTGGA 25 1251 CAAGAGCAGG TGGCAGCAGG GGAACGTCTT CTCATGCTCC GTGATGCATG 1301 AGGCTCTGCA CAACCACTAC ACGCAGAAGA GCCTCTCCCT QTCTCCGGGT 1351 AAA (SEQ ID NO:226) Amino acid sequence of the Ab-15 HC including signal peptide: 30 1 MDWTWRILFL VAAATGAHSE VQLVQSQAEV KKPGASVKVS CKASDFNIKD 51 FYLHWVRQAP GQGLEWIGRI DPENGDTLYD PKFQDKVTMT TDTSTSTAYM 101 ELRSLRSDDT AVYYCAREAD YFHDGTSYWY FDVWGRGTLV TVSSASTKGP 151 SVFPLAPCSR STSESTAALG CLVKDYFPEP VTVSWNSGAL TSGVHTFPAV 35 201 LQSSGLYSLS SVVTVPSSNF GTQTYTCNVD IKPSNTKVDK TVERKCCVEC 251 PPCPAPPVAG PSVFLFPPKP KDTLMISRTP EVTCVVVDVS HEDPEVQFNW 301 YVDGVEVHNA KTKPREEQFN STFRVVSVLT VVHQDWLNGK EYKCKVSNKG 351 LPAPIEKTIS KTKGQPREPQ VYTLPPSREE MTKNQVSLTC LVKGFYPSDI 401 AVEWESNGQP ENNYKTTPPM LDSDGSFFLY SKLTVDKSRW QQGNVFSCSV 40 451 MHEALHNHYT QKSLSLSPGK (SEQ ID NO:227) Nucleic acid sequence of the Ab-15 HC including signal peptide encoding sequence: 1 ATGGACTGQA CCTGGAGGAT CCTCTTCTTG GTGGCAGCAG CCACAGGAGC 45 51 CCACTCCGAG GTGCAGCTGG TGCAGTCTGG GGCTGAGGTG AAGAAGCCTG 101 GG3GCCTCAGT GAAGGTCTCC TGCAAGGCTf CTGACTTCAA CATIAAAGAC 151 TTCTATCTAC ACTGGGTGCG ACAGGCCCCT GGACAAGGGC TTGQAGTGGAT 201 TQGAAGGATT GATCCTGAGA ATGGTGATAC TTTATATGAC CCGAAGiTTCC 251 AQGACAAGQT CACCATQACC ACAGACACGT CCACCAGCAC AGCCTACATG 50 301 GAQCTGAGQA GCCTGAGATC TGACGACACG GCCGTGTATT ACTGTGCGAG SEA 1803911vi 60117-2 85 WO 2006/119062 PCTIUS2006/016345 351 AQAGGCGWAT TATTTCCACG ATGGTACCTC CTACTGGTAC TTCGATGTCT 401 GGGGCCGTGG CACCCTGGTC ACCGTCTCTA GTGCCTCCAC CAAGGGCCCA 451 TCGGTCTTCC CCCTGGCQCC CTQCTCCAGG AGCACCTCCG AQAGCACAGC 501 GGCCCTGGGC TGCCTGGjTCA AGGACTACT CCCCGAACCG GTGACGGTGT 5 551 CGTOAACTC AGGCGCTCTG ACCAGCGGCG TGCACACCTT CCCAGCTGTC -601 -CTACAGTCCT CAGGACTCTA CTCCCTCAGC AGCGTGGTGA CCGTGCCCTC 651 CAGCAACTTC GGCACCCAGA CCTACACCTG CAACGTAGAT CACAAGCCCA 701 GCAACACCAA GGTGGACAAG ACAQTTGAGC GCAAATGTTG TGTCGAGTGC 751 CCACCGTGCC CAGCACCACC TGTGGCAGGA CCGTCAGTCT TCCTCTTCCC 10 801 CCCAAAACCC AAGGACACCC TCATGATCTC CCGGACCCCT GAGGTCACGT 851 GCGTGGTGGT GGACGTGAGC CACGAAGACC CCGAGGTCCA GTTCAACTGG 901 TACGTGQACG GCGTGGAGGT GCATAATGCC AAGACAAAGC CACGGGAGGA 951 GCAGTITCAAC AGCACGTTCC GTGTGGTCAG CGTCCTCACC GTrGTGCACC 1001 AGGACTGGCT GAACGGCAAG GAGTACAAQT GCAAGGTCTC CAACAAAGGC 15 1051 CTCCCAGCCC CCATCGAGAA AACCATCTCC AAAACCAAAG GGCAGCCCCG 1101 AGAACCACAG GTGTACACCC TGCCCCCATC CCGGGAGGAG ATGACCAAGA 1151 ACCAGGTCAG CCTGACCTGC CTGGTCAAAG GCTTCTACCC CAGCQACATC 1201 GCCGTGGAGT GGGAGAGCAA TGGGCAGCCG GAQAACAACT ACAAGACCAC 1251 ACCTCCCATG CTGGACTCCG ACGGCTCCTT CTTCCTCTAC AGCAAGCTCA 20 1301 CCGTGGACAA GAGCAGGTGG CAGCAGGGGA ACGTCTTCTC ATGCTCCGTG 1351 ATGCATGAGG CTCTGCACAA CCACTACACG CAGAAGAGCC TCTCCCTQTC 1401 TCCGXGGTAAA (SEQ ID NO:228) 25 The CDR sequences in the variable region of the heavy chain of Ab-15 are: CDR-H1: DFYLH (SEQ ID NO:290) CDR-H2: RIDPENGDTLYDPKFQD (SEQ ID NO:291) CDR-H3: EADYFHDGTSYWYFDV (SEQ ID NO:292) The light chain variable region CDR sequences of Ab-15 are: 30 CDR-L1: SVSSTISSNHLH (SEQ ID NO:278) CDR-L2: GTSNLAS (SEQ ID NO:279) CDR-L3: QQWSSYPLT (SEQ ID NO:280) Ab-15 Variable domains: 35 Ab-15 light chain variable domain amino acid sequence (without signal sequence): 1 DIQMfSPSS LSASVGDRVT ITCSYSSTL5 SNIiNFQQK PGKAPKSLIY 51 &iSNLASGVP SRFSGSGSGT DFTLTISSLQ PEDFATYYCQQMSYITFG 40 101 GGTKVEIK (SEQ ID NQ:384) Ab-15 light chain variable domain DNA sequence (without signal sequence): 45 1 QACATCCAGA TGACCCAGTC TCCATCCTCC CTCTCAGCAT CCGTAGGCGA 51 TAGAGTTACA ATAACATGCA GCGTATCATC AACTATATCA TCAAATCATC SEA 1803911vi 60117-22 86 WO 2006/119062 PCTIUS2006/016345 306 fIT&ATGGT CCAACAGAAA CCCGGCAAAG CACCTAAATC ACTTATATAC 151 GGCACATCAA ATCTCGCATC AGGCGTTCCT TCAAGATTIT CAGGCTCTGG 201 CTCAGGCACC GACTTTACTC TTACAATATC CTCCCTCCAA CCCGAAGACT 251 TCGCAACCTA TTACTGTCAA CAATGGTCCT CATATCCACT CACATITGGC 5 301 GGCGGCACAA AAGTAGAAAT TAAA (SEQ ID NO:385) Ab-15 heavy chain variable domain amino acid sequence (without signal sequence): 1 EVQLVQSGAE VKKPGASVKV SCKASDFNIK b)YijWVRQA PGQGLEWG1 10 51 tP5NGbDjThY DPkFQKVTM TTDTSTSTAY MELRSLRSDD TAVYYCARE4 101 YFHDGTSYW YFDVWGRGTL VTVSS (SEQ ID NO:386) Ab-15 heavy chain variable domain DNA sequence (without signal sequence): 15 1 GAGGTGCAGC TG'GTGCAGTC TGGGGCTGAG GTGAAGAAGC CTGGGGCCTC 51 AGTGAAGGTC TCCTGCAAGG CTTCTGACTT CAACATTAAA GACTTCTATC 101 TACACTGGGT GCGACAGGCC CCTGGACAAG GGCTGAGTG QATTXGAAGG 151 ATTGATCCTG AGAATGGTGA TACTTATAT GACCCGAAGT TCCAGGACAA 201 GGTCACCATO ACCACAGACA CGTCCACCAG CACAGCCTAC ATGGAGCTGA 20 251 GGAGCCTGAG ATCTGACQAC ACGGCCGTGT ATTACTGTGC GAGAGAGGCG 301 QATTATTTCC ACGATGGTAC CTCCTACTGG TACTTCGATG TCTGGGGCCG 351 TGGCACCCTG GTCACCGTCT CTAGT (SEQ ID NO:3 87) 25 Ab- 11 was humanized to generate Ab-16. Ab-16 The sequences of the Antibody 16 (also referred to herein as Ab-16) LC and HC are as follows: 30 Ab-16 Light Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab- 16 LC: 35 1 DIQLTQSPSF LSASVGDRVT ITCMnASiS.SI&YIHWYQQKPG KAPKLLIAt 51 $NARGVPSR FSGSGSGTEF TLTISSLQPE DFATYYCQW-iS PilGG.G 101 TKVEKR TVA APS VFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 151 NAL(SGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEEHKV YACEVTHQGL 201 SSPYTKSFNR GEC (SEQ ID NO:229) 40 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab- 16 LC: 1 GACATCCAGT TGACCCAGTC TCCATCCTTC CTGTCTGCAT CTGTAGGAGA 45 51 CAGAGTCACC ATCACTTGCA GGGCCAGCTC AAQTATAAGT TACATACACT 101 GTATCAGCA AAAACCAGGG AAAGCCCCTA AGCTCCTGAT CTATGCCACA 151 TCCAACCTGG CTTCTGGGGT CCCATCAAGO TTCAQCGGCA QTGGATCTOG 201 GACAGAATTC ACTCTCACAA TCAGCAGCCT GCAGCCTGAA GATTGCAA 251 CTTATTACTG TCAGCAQTGG AQTAGTGACC CACTCACGTT CGGCGGAiGG 50 301 ACCAAGxiTGG AGATCAAACG TACGGTGGCT GCACCATCTG TCTTCATCTT 351 CCCGCCATCT GATGAGCAGT TGAAATCTGG AACTGCCTCT GTTGTGTGCC SEA 190391v1 60117-:M 87 WO 2006/119062 PCTIUS2006/016345 401 TGCTGAATAA CTrCTATCCC AGAGAGGCCA AAGTACAQTG GAAGGTGGAT 451 AACGCCCTCC AATCQGGTAA CTCCCAGGAG AGTGTCACAG AGCAGGACAG 501 CAAGACAGC ACCTACAGCC TCAGCAGCAC CCTGACGCTG AGCAAAGCAG 551 ACTACGAGAA ACACAAAGTC TACGCCTGCG AAGTCACCCA TCAGGGCCTG 5 601 AGCTCQCCCG TCACAAAGAG CTTCAACAGG GGAGAGTGT (SEQ ID NO:230) Amino acid sequence of the Ab-16 LC including signal peptide: 10 1 MDMRVPAQLL GLLLLWLPGA RCDIQLTQSP SFLSASVGDR VTITCRASSS 51 ISYIHWYQQK PQKAPKLLIY ATSNLASGVP SRFSGSGSGT EFTLTISSLQ 101 PEDFATYYCQ QWSSDPLTFQ GGTKVEIKRT VAAPSVFIFP PSDEQLKSGT 151 ASVVCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLSSTL 15 201 TLSKADYEKH KVYACEVTHQ GLSSPVTKSF NRGEC (SEQ ID NO:231) Nucleic acid sequence of the Ab-16 LC including signal peptide encoding sequence: 20 1 ATGGACATGA GGGTCCCCGC TCAGCTCCTG GGGCTCCTGC TGCTCTGGCT 51 CCCAGGTGCC AGATGTGACA TCCAGTrGAC CCAGTCTCCA TCCTTCCTGT 101 CTGCATCTGT AGGAGACAGA GTCACCATCA CTTGCAGGGC CAGCTCAAGT 151 ATAAGTTACA TACACTGGTA TCAGCAAAAA CCAGGGAAAG CCCCTAAGCT 201 CCTGATCTAT GCCACATCCA ACCTGGCTTC TGGGGTCCCA TCAAGGTTCA 25 251 GCGGCAGTGG ATCTGGGACA GAATTCACTC TCACAATCAG CAGCCTGCAG 301 CCTGAAGATT TTGCAACTTA TTACTGTCAG CAGTGGAGTA GTGACCCACT 351 CACGTTCGGC GGAGGGACCA AGGTGGAGAT CAAACGTACG GTGGCTGCAC 401 CATCTGTCTT CATCTFCCCG CCATCTGATG AGCAGTTGAA ATCTGGAACT 451 GCCTCTGTTG TGTGCCTGCT GAATAACTrC TATCCCAGAG AGGCCAAAGT 30 501 ACAGTGGAAG GTGGATAACG CCCTCCAATC GGGTAACTCC CAGGAGAGTG 551 TCACAGAGCA GOACAOCAAG GACAGCACCT ACAGCCTCAG CAGCACCCTG 6Q1 ACGCTGAGCA AAGCAGACTA CGAGAAACAC AAAGTCTACG CCTGCGAAGT 651 CACCCATCAG GGCCTGAGCT CGCCCGTCAC AAAGAGCTTC AACAGG3GGAG 701 AGTGT (SEQ ID NO:232) 35 Ab-16 Heavy Chain: 40 Amino acid sequence of the mature form (signal peptide removed) of the Ab-16 HC: 1 EVQLVQSGAE VKKPGASVKV SCKASGFDIKPYY1IWVRQA PGQGLEWIql, 51 WDPnNG3EO F AfCFPGKVTM TIDTSISTAY MELSRLRSDD TAVYYCAREI 101 YDGTYTWFPY ioQGTLVTVS SASTKGPSVF PLAPCSRSTS EST AALGCL V 45 151 KD YFPEPYTV SWNSGALTSG VHTFPA VLQS SGLYSLSSVV TVPSSNFGTQ 201 TYTCNVDHEP SNTKVDKTVE RKCCVECPPC PAPPVAGPSVFLFPPKPKDT 251 LMJSRTPEVT CVVVD VSHED PEVQFNWYVD GVEVNAKTK PREEQFNSTF 301 RVVSVLTVVH QDWLNGKEYK CKVSNKGLPA PIEKTISKTK GQPREPQVYT 351 LPPSREEMTK NQVSLTCLVK GFYPSDJAVE WESNGQPENN YKT TPPMLDS SEA 1803911vl 60117-223 88 WO 2006/119062 PCT/US2006/016345 4011 D GSFFLYSKL~TVDKSR WQQG N VFS CS VMHE ALHNHYTQKS LSLSPGK (SEQ ID NO:233) Amino acid sequence of the mature form (signal peptide removed) of the Ab-16 HC without 5 carboxy-termmnal lysine: 1 EVQLVQSGAE VKKPGASVKV SCKASGFDUXDYYiWVRQA PGQGLEWIGR, 51 VDPD1NGETEFAPKFPGKVTM TTDTSISTAY MELSRLRSDD TAVYYCARED 1013 DOTY1WWFPM VGQGTLVTVS SASTKGPSVF PL4PCSRSTS ESTA ALGCLV 10 151 EDYFPFPiTVSWNSGALTSG VHTFPA VLQS SGLYSLISSVV TVPSSNFGTQ 201 TYTCNVDEKP SNTKVDKTVE RKCCVECPPC PAPPVAGPSV FLFPPKPEDT 251 LWSRTPEVT CVVVD VSH D PEVQFNWYVD GVEVRN4KTK PREEQFNSTF 301 RVVSVLTVVH QPWLVNGEYK CKVSNKGLPA PE KTIS1KTK GQPREPQVYT 351 LPPSREEMTK NQVSL TCZVK GFYPSDIAVE WESNGQPENN YK TPPMLDS 15 401 DGSFFLYSKL TVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPG (SEQ ID NO:395) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab- 16 HC: 1 GAGGTGCAGC TGGTGCAGTC TGGGGCTGAG GTGAAGAAGC CTGGGGCCTC 20 51 AGTGAAGGTC TCCTGCAAGG CTTCTOGQATT CGACATTAAG GACTACTATA 101 TACACTGGGT GCGACAGGCC CCTGGACAAG GGCTTGAGTG GATCGGAAGG 151 GTTGATCCTG ACAATGGTGA GACTGAATIT GCCCCGAAGT TCCCGGGCAA 201 GGTCACCATG ACCACAGACA CGTCCATCAG CACAGCCTAC ATGGAGCTGA 251 GCAGGCTGAG ATCTGACGAC ACGGCCGTGT ATTACTGTGC GAGAGAAGAC 25 301 TACGATGGTA CCTACACCTG GTITCCTTAT TGGGGCCAAG GGACTCTGGT 351 CACCGTCTCT AGTGCCTCCA CCAAGGGCCC ATCGGTCTTC CCCCTGGCGC 401 CCTGCTCCAG GAGCACCTCC GAGAGCACAG CGGCCCTGGG CTGCCTGGTC 451 AAGGACTACT TCCCCGAACC GGTGACGGTG TCGTGGAACT CAGGCGCTCT 501 GACCAGCGGC GTGCACACCT TCCCAGCTGT CCTACAGTCC TCAGOACTCT 30 551 ACTCCCTCAG CAGCGTGGTG ACCGTGCCCT CCAGCAACTT CGGCACCCAG 601 ACCTACACCT GCAACQTAGA TCACAAGCCC AGCAACACCA AGGTOGACAA 651 QACAQTTGAG CGCAAATGTT GTGTCGAGTG CCCACCGTGC CCAGCACCAC 701 CTGTGGCAG ACCQTCAGTC TTCCTCTTCC CCCCAAAACC CAAGGACACC 751 CTCATGATCT CCCGGACCCC TGAQGTCACG TGCGTGOTQG TGQACGTGAG 35 801 CCACQAAGAC CCCGAGQTCC AG1TCAACTG GTACOTGGAC GGCYTGGAGG 851 TGCATAATQC CAAGACAAAG CCACGGQAGG AGCAGTTCAA CAGCACGTTC 901 CGTGTGGTCA GCGTCCTCAC CGTTGTGCAC CAGGACTGGC TGAACGGCAA 951 GGAGTACAAG TGCAAGOTCT CCAACAAAGG CCTCCCAGCC CCCATCGAGA 1001 AAACCATCTC CAAAACCAAA GGGCAGCCCC GAGAACQACA GGTGTACACC 40 1051 CTGCCCCCAT CCCQGGAGGA GATGACCAAG AACCAGOTCA GCCTGACCTG 1101 CCTGGTCAAA GGCTTCTACC CCAGCGACAT CGCCGTGGAG TGGGAGAGCA 1151 ATGGGCAGCC GGAGAACAAC TACAAGACCA CACCTCCCAT GCTGGACTCC 1201 GACGGCTCCT TCTTCCTCTA CAGCAAGCTC ACCGTGGACA AGAGCAGGTG 1251 GCAGCAGGGG AACGTCTTCT CATGCTCCGT GATGCATGAG GCTCTGCACA 45 1301 ACCACTACAC GCAGAAGAGC CTCTCCCTGT CTCCGGGTAA A (SEQ ID NO:234) Amino acid sequence of the Ab- 16 HC including signal peptide: 50 SEA 190391v 60117-2 89 WO 2006/119062 PCT/US2006/016345 1 MDWTWRIUL VAAATGAHSE VQLVQSGAEV KKPGASVKVS CKASGFDIKD 51 YYIHWVRQAP GQGLEWIGRV DPDNGETEFA PKFPQKVTMT TDTSISTAYM 101 ELSRLRSDDT AVYYCAREDY DGTYTWFPYW GQGTLVTVSS ASTKGPSVFP 5 151 LAPCSRSTSE STAALGCLVK DYFPEPVTVS WNSQALTSGV HTFPAVLQSS 201 GLYSLSSVVT VPSSNFGTQT YTCNVDHKPS NTKVDKTVER KCCVECPPCP 251 APPVAGPSVF LFPPKPKPTL MISRTPEVTC VVVDVSBDP EVQFNWYVDG 301 VEVHNAKTKP REEQFNSTFR VVSVLTVVHQ DWLNGKEYKC KVSNKGLPAP 351 IEKTISKTKG QPREPQVYTL PPSREEMTKN QVSLTCLVKG FYPSDIAVEW 10 401 ESNGQPENNY KTTPPMLDSD GSFFLYSKLT VIKSRWQQGN VFSCSVMHEA 451 LHNHYTQKSL SLSPGK (SEQ ID NO:235) Nucleic acid sequence of the Ab-16 HC including signal peptide encoding sequence: 15 1 ATGGACTGGA CCTGGAGGAT CCTCTTCTTG GTGGCAGCAQ CCACAGGAGC 51 CCACTCCGAG GTGCAGCTGG TGCAGTCTGG GGCTGAGGTG AAGAAOCCTG 101 GGGCCTCAGT GAAGGTCTCC TGCAAGGCTT CTGOATTCGA CATTAAGGAC 151 TACTATATAC ACTGGQTGCG ACAGG3CCCCT GGACAAGGGC TTGAGTGGAT 20 201 CGGAAGGGTr GATCCTGACA ATGGTGAGAC TGAATTTGCC CCGAAGTTCC 251 CGGGCAAGGT CACCATGACC ACAGACACGT CCATCAGCAC AGCCTACATG 301 GAGCTGAGCA GGCTGAGATC TGACGACACO GCCGTOTATT ACTGTGCGAG 351 AGAAGACTAC GATGGTACCT ACACCTGGTT TCCTTATTGG GGCCAAGGGA 401 CTCTGOTCAC CGTCTCTAGT GCCTCCACCA AGGGCCCATC GGTCT'CCCC 25 451 CTGGCGCCCT GCTCCAGGAG CACCTCCGAG AGCACAGCGG CCCTGGGCTG 501 CCTGGTCAAG GACTACTrCC CCGAACCGGT GACGGTQTCQ TGGAACTCAG 551 GCGCTCTGAC CAGCGGCGTO CACACCTTCC CAGCTGTCCT ACAGTCCTCA 601 GGACTCTACT CCCTCAGCAG CGTGGTGACC GTGCCCTCCA GCAACTTCGG 651 CACCCAGACC TACACCTGCA ACGTAGATCA CAAGCCCAGC AACACCAAGG 30 701 TGGACAAGAC AGTrGAGCGC AAATOTTGTG TCGAGTGCCC ACCGTGCCCA 751 GCACCACCT TGGCAGGACC GTCAGTCTTC CTCTTCCCCC CAAAACCCAA 801 GGACACCCTC ATGATCTCCC GGACCCCTGA GGTCACGTGC GTGGTGGTGG 851 ACGTGAGCCA CGAAQACCCC GAGGTCCAGT TCAACTGQTA CGTGGACGQC 901 GTGGAGGTGC ATAATGCCAA GACAAAOCCA CGQAGGAGC AGTrCAACAG 35 951 CACGTICCGT GTGGTCAGCG TCCTCACCGT TGTGCACCAG GACTGGCTGA 1001 ACGGCAAGGA GTACAAOTGC AAGGTCTCCA ACAAAGGCCT CCCAGCCCCC 1051 ATCGAGAAAA CCATCTCCAA AACCAAAGGG CAGCCCCGAG AACCACAGGT 1101 GTACACCCTG CCCCQATCCC GGAGGAGAT GACCAAGAAC CAGGTCAGCC 1151 TGACCTGCCT GGTCAAAGGC TTCTACCCCA GCGACATCGC COTQGAGTGG 40 1201 GAGAGCAATG GGCAGCCGGA QAACAACTAC AAGACCACAC CTCCCATGCT 1251 GGACTCCQAC GGCTCCTTCT TCCTCTACAG CAAGCTCACC GTGGACAAGA 1301 GCAGiGTGCKA GCAGGGGAAC GTCTTCTCAT GCTCCGTGAT GCATGAGGCT 1351 CTGCACAACC ACTACACGCA GAAGAGCCTC TCCCTGTCTC CGQGTAAA (SEQ ID NO:236) 45 The CDR sequences in the variable region of the heavy chain of Ab-16 are: CDR-H1: DYYIH (SEQ ID NO:293) CDR-H2: RVDPDNGETEFAPKFPG (SEQ ID NO:294) CDR-H3: EDYDQTYTWFPY (SEQ ID NO:295) SEA 1803911v 60117-223 90 WO 2006/119062 PCT/US2006/016345 The light chain variable region CDR sequences of Ab-16 are: CDR-L1: RASSSISYIH (SEQ ID NO:281) CDR-L2: ATSNLAS (SEQ ID NO:282) CDR-L3: QQWSSDPLT (SEQ ID NO:283) 5 Ab-16 Variable domains: Ab-16 light chain variable domain amino acid sequence (without signal sequence): 10 1 DIQLTQSPSF LSASVGDRVT ITCNASSSI.HyWYQQKPG KAPKLLIYAT 51 SEASGVPSR FSGSGSGTEF TLTISSLQPE DFATYYCQQYTSDiPLTFIGGG 101 TKVEIK(SEQ ID NQ:388) Ab-16 light chain variable domain DNA sequence (without signal sequence): 15 1 GACATCCAGT TGACCCAGTC TCCATCCTTC CTGTCTGCAT CTGTAGGAGA 51 CAGAGTCACC ATCACTTGCA GGGCCAGCTC AAGTATAAGT TACATACACT 101 GGTATCAGCA AAAACCAGGG AAAGCCCCTA AGCTCCTGAT CTATGCCACA 151 TCCAACCTGG CTTCTGGQGT CCCATCAAGG TTCAGCGGCA GTGGATCTGG 20 201 GACAGAATTC ACTCTCACAA TCAGCAGCCT GCAGCCTQAA GA'ITTGCAA 251 CTTATTACTG TCAGCAGTGG AGTAGTGACC CACTCACGTT CGGCGGAGGG 301 ACCAAGGTGG AGATCAAA (SEQ ID NO:389) Ab-16 heavy chain variable domain amino acid sequence (without signal sequence): 25 1 EVQLVQSGAE VKKPGASVKV SCKASGFDIKiYAHWVRQA PGQGLEWIGR. 51 \O'DNqEEF AigFgGKVTM ITDTSISTAY MELSRLRSDD TAVYYCAROD 101 GiTYJ'WgPY WGQGTLVTVS S (SEQ ID NO:390) 30 Ab-16 heavy chain variable domain DNA sequence (without signal sequence): 1 GAGGTGCAGC TGGTGCAGTC TGGGQCTGAG GTGAAGAAGC CTGGGGCCTC 51 AGTMAAGTC TCCTGCAAGG CTTCTGGATT CGACATTAAG QACTACTATA 101 TACACTGGGT GCOACAGGCC CCTGGACAAGj GGCTTGAGTG GATCGGAACG 35 151 GTTGATCCTG ACAATGGTGA GACTGAATIT GCCCCGAAGT TCCCGGGCAA 201 OGTCACCATG ACCACAGACA CGTCCATCAG CACAGCCTAC ATGGAGCTGA 251 GCAGGCTGAG ATCTGACGAC ACGGCCGTGT ATTACTGTGC GAGAGAAGAC 301 TACGATGGTA CCTACACCTG GTTCCTTAT TGGGGCCAAG GGACTCTGGT 351 CACCGTCTCT AGT (SEQ ID NO:391) 40 Additional antibodies are referred to herein as Antibodies 17-22 (also referred to herein as Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, and Ab-22). The Kappa Constant region for all VK regions of Ab-17, Ab-19, and Ab-21 is as follows: TDAAPTVSIFPPSSEQLTSGASVVCFLNNFYPKDINVKWKIDGSRQNGVLNSWTDQD 45 SKDSTYSMSSTLTLTKDEYERHNSYTCEATHKTSTSPIVKSFNRNEC (SEQ ID NO:323) SEA 180391 ly 60117-223 91 WU 2006/119062 PCT/US2006/016345 The lleavy"Constant Region for all VH regions of antibodies 17, 19 and 21 is as follows: AKTTPPSVYPLAPGSAAQTNSMVTLGCLVKGYFPEPVTVTWNSGSLSSGVHTFPAVLQS 5 DLYTLSSSVTVPSSTWPSETVTCNVAIIPASSTKVOKKIVPRDCGCKPCICTVPEVSSVFIF PPKPKDVLTITLTPKVTCVVVDISKDDPEVQFSWFVDDVEVHTAQTQPREEQFNSTFRS VSELPIMHQDWLNGKEFKCRVNSAAFPAPIEKTSKTKGRPKAPQVYTIPPPKQMAKD KVSLTCMITDFFPEDITVEWQWNGQPAENYKNTQPIMDTDGSYFVYSKLNVQKSNWEA GNTFTCSVLHEGLHNHHTEKSLSHSPGK (SEQ ID NO:324) 10 In the following antibody amino acid sequences, the boxed-shaded amino acids represent complement-determining regions (CDRs) and the underlined amino acids represent signal peptide. 15 Ab-17 Amino acid sequence of the Ab-17 LC including signal peptide: MDFOVOIFSFMLISVTVILSSGEIVLTQSPALMAASPGEKVTITC i55NIIWSQQK 20 SGTSPKLW1YNINIMLGVPVRFSGSGSGTSYSLTISSMEAEDAATYYCQ ' F SGTKLELKR (SEQ ID NO:299) Nucleic acid sequence of the Ab-17 LC including signal peptide: 25 ATGGATITTCAGGTGCAGATTTTCAGCTTCATGCTAATCAGTGTCACAGTCATATTG TCCAGTGGAGAAATTGTGCTCACCCAGTCTCCAGCACTCATGOCTGCATCTCCAG3GG GAGAAGGTCACCATCACCTGCAGTGTCAGCTCGAGTATAAGTTCCAGCAACTrACA CTGGTCCCAGCAGAAGTCAGGAACCTCCCCCAAACTCTGGATITATGGCACATCCA ACCTTOCTTCTGGAGTCCCTOTTCGCTTCAGTGGCATGGATCTGGGACCTCTFATTC 30 TCTCACAATCAGCAGCATGGAGGiCTGAAGATOCTGCCACTTATTACTGTCAACAGT GGACTACTACGTATACGT[CGGATCGGGGACCAAGCTGGAGCTGAAACGT (SEQ ID NO:300) Amino acid sequence of the Ab-17 HC including signal peptide: 35 MGWNWIIFFLMAVVTGVNSEVQLRQSGADLVKPGASVKLSCTASGFNIKYEIYYII-WVK QRPEQGLEWIf aDBNETYl GKTITADTSSNTAYLQLRSLTSEDTAIYYCGR SGLDXGDYAVDYWGQGTSVTVSS (SEQ ID NO:301) 40 Nucleic acid sequence of the Ab-17 HC including signal peptide: ATGGGATGGAACTGGATCATCTTCTTCCTGATGGCAGTGGTrACAGGGGTCAATTCA GAGGTGCAGTTGCGGCAGTCTOGGGCAGACCTTGTGAAGCCAGGGCCTCAGTCAA 45 GTTGTCCTGCACAGCTTCTGGCTTCAACATTAAAGACTACTATATACACTGGGTGAA GCAGAGG3CCTGAACAGGGCCTGGAGTGGATJGGAAGGATTGATCCTGATAATGGTG AAAGTACATATGTCCCGAAGTTCCAGGGCAAGGCCACTATAACAGCAGACACATCA TCCAACACAGCCTACCTACAACTCAGAAGCCTGACATCTGAGGACACTGCCATCTA SEA 1803911 vI 60117-223 92 WO 2006/119062 PCT/US2006/016345 TTATTGTGGGAGAGGGGCTCGACTATGGTGAcTACTATGCTOTGACTACTOGG GTCAAGGAACCTCGGTCACAQTCTCGAGC (SEQ ID NO:302) Ab-17 was humanized to generate Ab-18. 5 Ab-18 Amino acid sequence of the Ab-18 LC including signal peptide: 10 MDMRVPAOLLGLLLLWLPGARCDIQLTQSPSFLSASVGDRVTITCYSSISSNLBWYQ QKPGTKAPKLL,'SNAPVPSRFSGSGSGTEFTLTISSLQPEDFATYYCQQ.WTTITIrF GQGTKLEIXR (SEQ ID NO:303) 15 Nucleic acid sequence of the Ab-18 LC including signal peptide: ATGGATATGCGCGTGCCGGCGCAGCTGCTGGGCCTGCTGCTGCTGTGGCTGCCGGG CGCGCGCTCGATATTCAGCTACCCAGACCCGAGCTTTCTGAGCGCGAGCGTGG 20 GCGjATCGCGTGACCATTACCTGCAGCGTGjAGCAGiCAGCATTAGCAGCAGCAACCTG CATTOGTATCAGCAGAAACCGGGCAAAGCGCCGAAACTGCTGATTTATGGCACCAG CAACCTGGCGiAGCGGCGTGCCGAGCCCGCTITAGCGGCAGCGGCAGCGGCACCGjAAT TTACCCTGACCATTAGCAGCCTGCAGCCGGAAGAT 1GCGACCTATTATTCCAGC AGTOGACCACCACCTATACCTTTGGCCAGGGCACCAAACTGGAAATTAAACGT (SEQ 25 ID NO:304) Amino acid sequence of the Ab- 18 HC including signal peptide: 30 MDWTWSILFLVAAPTGAHSEVQLVQSGAEVKKPGASVKVSCKASGFNIKDYIHVVR QAPQGLEWMGNfkIjg -fiI RVMDSTSTAYMEffLRSLRSDDTAVYY CARLdYGgDPWQGTLVTVSS (SEQ ID NO:305) 35 Nucleic acid sequence of the Ab-18 HC including signal peptide: ATGGATGGACCTAGCATTCTGTTTCTGGTGGCGGCGCCGACCGGCGCGCATAG CGAAGTGCAGCTGTCAGAGCGGCGCGGAAGTGAAAAAACCGGGCCGAGCGTO 40 AAAGTGAGCTGCAAAGCACGGCTTTAACATTAAAGATTATTATATTCATTGGGT GCGCCAGGCGCCGGGCCAGGGCCTGGAATGGATGGGCATTGATCCGGATAACG GCGAAAGCACCTATGTGCCGAAATITCAGGGCCGCGTGACCATGACCACCGATACC AGCACCAGCACCGCTATATGGAACTGCGCAGCCTGCGCAGCGATATACCGCGGT GTATTATTGCGCGCGCGAAGGCCTGGATTATGGCGATTATTATGCGGTGGATTATTG 45 GGGCCAGCGCACCCTGGTGACCGTCTCGAGC (SEQ ID NO:306) Ab-18 light chain variable domain amino acid sequence (without signal sequence): DI QLTQ SP SFL SA SV GDRVTIn?5tV s§i55 SNiL- aWY Q QKPGKAPKLLIYG5RT SP 50 RFSGSGSGTEFTLTISSLQPEDFATYYCQQWTI QGTKEIKR(SEQID) NO:368) SEA 1803911v 60117-2Z 93 WO 2006/119062 PCT/US2006/016345 Ab- 18 light chain variable domain DNA sequence (without signal sequence): GATATTCAGCTGACCCAGAGCCCGAGCTCTGAGCGCGAGCGTGGGCGATCCQT GACCATTACCTGCAGCGTGACACAGCATTAGCACAGCA CATTGGOTATC 5 AGCAGAAACCGGGCAAAGCGCCGAAACTGCTGATTATGG0CACCAGCAACCTGO;CG AGCGGCGTGCCAGCCGCTnTAGCGGCAGCGGCAGCGGCACCGAA7TTACCCTGAC CATrAGCAGiCCTGCAGCCGGAAGATTTGCGACCTATTATTGCCAGCAGTGGACCA CCACCTATACCTITGGCCAGGGCACCAAACTGGAAATTAAACGT (SEQ ID NO:3 69) 10 Ab-18 heavy chain variable domain amino acid sequence (without signal sequence): EVQLVQSGAEVKKPGASVKVSCKASGFN1KYiIIWVRQAPGQGLEWMGiDNGE STVPFQdRVTMTDTSTSTAYMELRSLRSDDTAVYYCA1 IYDyYDG QGTLVTVSS (SEQ ID NO:370) 15 Ab-18 heavy chain variable domain DNA sequence (without signal sequence): GAAGTGCAGCTGGTGCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGCGAGCGTGA AAGTGAGCTGCAAAGCGAGCGGCTTAACATTAAAGATrATTATATTCATTGGGTG 20 CGCCAGGCGCCGGGCCAGGGCCTGGAATGATGGGCCGCATTGATCCGGATAACGG CGAAAGCACCTATOTGCCGAAAT1TCAGGGCCGCGTGACCATGACCACCGATACCA GCACCACACCGCGTATATGGAACTGCGCAGCCTGCGCAGCGATGATACCGCGGTG TATTATGGCGCCGCGAAGGCCTGGATTATGGCGATA TT6CGAUAi ATTAUAGG GGCCAGGGCACCCTGGTGACCGTCTCGAGC (SEQ ID NO:3 71) 25 Ab-19 Amino acid sequence of the Ab-19 LC including signal peptide: 30 MMSSAQFLGLLLLCFQGTRCDIQMTQTTSSLSASLGDRVNISCRA$Qg-nf-fNNYQQ PDGTVKLLIYSijiGVPSRFSGiSGSGTDYSLTISNLAQEDIATYFCQQ~IZ~P ,FGGO TKLF,LKR (SEQ ID NO:307) 35 Nucleic acid sequence of the Ab-19 LC including signal peptide: ATGATGTCCTCTGCTCAGTTCCTTGGTCTCCTGTTGCTCTGTCAAGGTACCAGAT 40 GTGATATCCAGATGACACAGACTACATCCTCCCTOTCTGCCTCTCTGGGAGACAGAG TCAACATCAGCTOCAGGGCAAGTCAGGACATTAGCAGTTATTTAAACTGGTATCAG CAGAAACCAGATGAACTGTrAAACTCCTGATCTACTCCACATCAAGATrAAACTC AGGAGTCCCATCAAGGTTCAGTGCAGTGGTCTGGGACAGATfATTCTCTCACTrAT TAGCAACCTGGCACAAGAAGATATTGCCACTTACTGCCAACAGGATATTAAGC 45 ATCCGACGTTCGGTGGAGGCACCAAGTTGGAGCTGAAACGT (SEQ ID NQ:308) Amino acid sequence of the Ab-19 HC including signal peptide: SEA 1803911v1 60117-223 94 WO 2006/119062 PCT/US2006/016345 MEWIWLFLLSGTAGVHSEVQLQSGPELVPGASVMSCKASGFTFT'YIfiWVKQ KPGQGLEWIGYINPYNDDTEYNEKFKGKATLTSDKSSSTAYMDLSSLTSEGSAVYYCA R$IYYYDAPfAYWrGQTLYTVSS (SEQ ID NO:309) 5 Nucleic acid sequence of the Ab-19 HC including signal peptide: ATGGAATGGATCTGGATATITCTCTTCCTCCTGTCAGGAACTGCAGGTGTCCACTCT GAGGTCCAGCTGCQAGCAGTCTGG'ACCTGjAGCTGIGTAAAGCCTGCGGCTTCAGxTGAA 10 GATOjTCCTCAAGG.CTTCTGGGTTCACATTCACTG;ACTACATTATOYCAC'IOGGTGAA GCAGAAGCCTGGGCAGGOCCTTGAGTGGATTGGATATATTAATCCTfACAATGATG ATACTGAATACAATGAGAAGTTCAAAGGCAAGCCACACTOACTTCAGACAAATCC TCCAGCACAGiCCTACATGGATCTCAGCAGiTCTGACCTCTGAGGGCTCTGCGGTCTAT TACTGTGCAAGATCGATITATTACTACGATOCCCCGTTrGCTlACTGGGGCCAAGG 15 ACTCTGGTCACAGTCTCGAGC (SEQ ID NO:3 10) Ab- 19 was humanized to generate Antibody 20 (also referred to herein as Ab-20) and Antibody 23 (also referred to herein as Ab-23). Ab-20 20 IgG4 version Amino acid sequence of the Ab-20 LC including signal peptide: 25 MMSSAQFLGLLLLFOGTRCIQMTQSPSSLSASVGDRVTITC A(QIS'WYQQK pGKAKLLlY5)(193SGVPSRFSGSGSGTDFTLTISSLQPEDFATYYCQQIKTGQG TKVEKR (SEQ ID NO:311) 30 Nucleic acid sequence of the Ab-20 LC including signal peptide: ATGATGTCCTCTGCTCAGTTCCTFGGTCTCCTOTTGCTCTGTCAAGGTACCAGAT GTGATATCCAGATGACCCAGTCTCCATCCTCCCTGTCTCATCTGTAGTGACCGTG 35 TCACCATCACTTGCCGCGCAAGTCAGGATATTAGCAGCTAAAATIGGTATCAGC AGAAACCAGGGAAAGCCCCTAAGCTCCTGATCTATrCTACTTCCCGTTrGAATAGTG GOTCCCATCACGCTrCAGTGGCAGTGGCTCTGGGACAGATTrCACTCTCACCATCA GCAGTCTGCAACCTGAAGATTTGCAACTTACTACTGTCAACAQGATATTAAACACC CTACGTTCGOTCAAGGCACCAAGGTGGAGATCAAACGT (SEQ ID NO:312) 40 Amino acid sequence of the Ab-20 HC including signal peptide: MEWIWLFLLSGTAGVHSEVQLVQSGAEVKKPGSSVKVSCKASGFTTYIWVRQ APGQGLWMCiiYNfEEIKoRVTITADKSTSTAYMELSSLRSEDTAVYYCA 45 R3YYYDAYWQGTLVTVSS (SEQ INO:313) Nucleic acid sequence of the Ab-20 HC including signal peptide: ATGGAATGGATCTGGATATTCTCTrCCTCCTGTCAGGAACTGCAGGTGTCCACTCT SEA 180391v 60117-22 95 WO 2006/119062 PCT/US2006/016345 GAGQTGCAGCTGGTGAGTCTGGGGCTGAGGTGAAGAAGCCTGGGTCCTCGGTGAA GGTCTCCTGCAAGCTTCT(G ACCTTCACCACTATATTATOCACTGGGTGCG TCAGGCCCCTGTCAAGGGCTTGAGTGGATGGGCTATATCAACCCTrATAATGATG ACACCGAATACAACGAGAAGTTCAAGGGCCGTOTCACGATTACCGCGGACAAATCC 5 ACGAGCACAGCCTACATGAGCTGAGCAGCCTGCGCTCTGAGGACACGGCCGTGTA TTACTGTGCGCGTCGATITATTACTACQATGCCCCGTTGCTTACTOGGGCCAAG GACTCTGGTCACAGTCTCGAGC (SEQ ID NO:349) Ab-23 10 IgG2 version Light Chain: 15 Amino acid sequence of the mature form (signal peptide removed) of the Ab-23 LC: 1 DIQMTQSPSS LSASVGDRVT ITC ASSiI$ 5tkW YQQKP GKAPKLLIY9 51 TSBLNSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ'DIIHPl@FGQG 20 101 TKVBIKRTVA APSVFIFPPS DEQLKSGTAS VVCLLNNFYP REAKVQWKVD 151 NALQSGNSQE SVTEQDSKDS TYSLSSTLTL SKADYEEHKV YACEVTHQGL 201 SSPVTKSFNR GEC (SEQ ID NO:341) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-23 LC: 25 1 GACATCCAGA TGACCCAGTC TCCATCCTCC CTGTCTGCAT CTGTAGGTGA 51 CCGTGTCACC ATCACTTGCC GCGCAAGTCA GGATATTAGC AGCTATTAA 101 ATTGGTATCA GCAQAAACCA GGGAAAGCCC CTAAGCTCCT GATCTATTCT 151 ACTTCCCGTT TGAATAGTGG GQTCCCATCA CQCTrCAGTG GCAGTGGCTC 30 201 TGGQACAGAT TTCACTCTCA CCATCAGCAG TCTGCAACCT GAAGATITG 251 CAACTTACTA CTGTCAACAG GATATTAAAC ACCCTACQTT CGGTCAAGGC 301 ACCAAGGTGG AGATCAAACG TACGGTGGCT GCACCATCTQ TCTTCATCTT 351 CCCGCCATCT GATGAGCAGT TGAAATCTGG AACTGCCTCT GTTGTTGCC 401 TGCTGAATAA CTfCTATCCC AQAGAQGCCA AAGTACAGTG GAAGGTGGAT 35 451 AACGCCCTCC AATCGGGTAA CTCCCAGGAG AGTGTCACAG AGCAGGACAG 501 CAAGGACAGC ACCTACAGCC TCAGCAGCAC CCTGACGCTG AQCAAAGCAQ 551 ACTACGAGAA ACACAAAGTC TACGCCTGCQ AAGTCACCCA TCAGGGCCTG 601 AQCTCGCCCG TCACAAAGAG CTrCAACAGG GGAGAGTGT (SEQ ID NO:342) 40 Amino acid sequence of the Ab-23 LC including signal peptide: 1 MDMRVPAQLL GLLLLWLRGA RCDIQMTQSP SSLSASVGDR VTITCRASQD 51 ISSYLNWYQQ KPGKAPKLLI YSTSRLNSGV PSRFSGSGSG TDFTLTISSL 101 QPEDFATYYC QQDIKHPTFG QGTKVEIKRT VAAPSVFIFP PSDEQLKSGT 45 151 ASVVCLLNNF YPREAKVQWK VDNALQSGNS QESVTEQDSK DSTYSLSSTL 201 TLSKADYEKH KVYACEVTHQ QLSSPVTKSF NRGEC (SEQ ID NO:343) Nucleic acid sequence of the Ab-23 LC including signal peptide encoding sequence: 50 1 ATGGACATGA GGGTGCCCGC TCAQCTCCTG GGGCTCCTGC TQCTQTGGCT 51 GAGAGGTGCC AGATQTGACA TCCAGATGAC CCAGTCTCCA TCCTCCCTGT SEA 1803911 601172 - 96 WU IUUM/119M62 Il. IIUbzUU6/UI645 101 CTGCATCTGT AGGTGACCGT QTCACCATCA CTTGCCGCGC AAGTCAGGAT 151 ATTAGCAGCT ATITAAATTG GTATCAGCAG AAACCAGGQA AAQCCCCTAA 201 CCTCCTGATC TATTCTACTr CCCGTITGAA TAGTGGGGTC CCATCACOCT 251 TCAOTQGCAG TQGCTCTGGO ACAGATITCA CTCTCACCAT CAGCAGTCTG 5 301 CAACCTGAAG ATITGCAAC TTACTACTGT CAACAGGATA TTAAACACCC 351 TACGTrCGGT CAAGGCACCA AGGTGGAGAT CAAACGTACG QTGGCTGCAC 401 CATCTOTC-T CATCTTCCCG CCATCTGATG AGCAGTTGAA ATCTGGAACT 451 GCCTCTGTTG TGTGCCTGCT GAATAACTTC TATCCCAGAG AGGCCAAAGT 501 ACAGTGGAAG QTGGATAACQ CCCTCCAATC GGGTAACTCC CAGGjAGAGTG 10 551 TCACAGAGCA GGiACAGCAAG QACAGCACCT ACAGCCTCAQ CAQCACCCTG 601 ACGCTQAGCA AAGCAGACTA CGAGAAACAC AAAGTCTACG CCTGCGAAGT 651 CACCCATCAG GGCCTGAGCT CGCCCGTCAC AAAGAGCTTC AACAGGGGAG 701 AGTGT (SEQ ID NQ:344) 15 Heavy Chain: Amino acid sequence of the mature form (signal peptide removed) of the Ab-23 HC: 1 EVQLVQSGAE VKKPGSSVKV SCKASGFTFT D'f(WVRQA PGQGLEWMGY 20 51 NPYNUDtEMY.NEKRVT[ TADKSTSTAY MELSSLRSED TAVYYCAI* 101 XYcDAPjFW GQGTLVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK 151 DYFPEPVTVS WNSGALTSGVHTFPA VLQSS GLYSLSSVVT VPSSNFGTQT 201 YTCNVDHKPS NTKVDKTVER KCCVECPPCPAPPVAGPSVFLFPPEPEDTL 251 MISRTPEV TC VVVDVSR EDP EVQFNWYVDG VEVNAKTEP REEQFNSTFR 25 301 VVSVLTVVHQ DWLNGKEYKC KVSNKGLPAP IEKTISKTKG QPREPQVYTL 351 PPSREEMTEN Q VSL TCL VKG FYPSDIA VEW ESNGQPENNY KTTPPMLDSD 401 GSFFLYSE LT VDKSRWQQGN VFSCSVMHEA LIINHYTQKSL SLSPGK (SEQ ID NO:345) 30 Amino acid sequence of the mature form (signal peptide removed) of the Ab-23 HC without carboxy-terminal lysine: 1 EVQLVQSGAE VKKPGSSVKV SCKASGFTFT If lWVRQA PGQGLEWMGky 51 VTI TADKSTSTAY MELSSLRSED TAVYYCAR$I 35 101 Y Y WGQGTLVTVSS ASTKGPSVFP LAPCSRSTSE STAALGCLVK 151 DYFPEPVTVS WNSGALTSGVHTFPAVLQ$S GLYSLSSVVT VPSSNFGTQT 201 YTCNVDHKPS NTKVDKTVER KCCVECPPCPAPPVAGPSVFLFPPKPEDTL 251 MISRTPEVTC VVVDVSHEDP EVQFNWYVDG VEVHNAKTKP R EEQFNSTFR 301 VVSVLTVVHIQ DWLNGEEYKCKVSNKGLPAP IETISKTKG QPREPQVYTL 40 351 PPSREEMTEKN QVSLTCLVKG FYPSDIAVEWESNGQPENNYKTTPPMLDSD 401 GSFFLYSELT VDKSRWQQGN VFSCSVM HEA LHNHYTQKSL SLSPG (SEQ ID NO:396) 45 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-23 HC: 1 GAGGTGCAGC TGGTGCAGTC TGGGGCTGAG GTGAAGAAGC CTGGGTCCTC 51 GGTQAAGGTC TCCTGCAAGQ CTTCTGGTIT TACCTTCACC GACTATATTA 101 TGCACTGGGT GCGTCAGGCC CCTGGTCAAG GGCTTQAGTG GATGGGCTAT 50 15 1 ATCAACCCTT ATAATGATGA CACCGAATAC AACGAGAAGT TCAAGGGCCG SEA 180391Hv 60117-2Z 97 WO 2006/119062 PCT/US2006/016345 201 TGTCACGAIT ACCGCGGACA AATCCACGAG CACAGCCTAC ATGGAGCTGA 251 GCAGCCTGCG CTCTGAGGAC ACGGCCGTGT ATTACTGTGC GCGTTCGATT 301 TATTACTACG ATGCCCCQTT TGCTACTGG GGCCAAGGGA CTCTGGTCAC 351 CGTCTCTAGT GCCTCCACCA AGGCCCATC GGTCTTCCCC CTGGCGCCCT 5 401 GCTCCAGGAG CACCTCCGAG AGCACAGCGG CCCTGGGCTG CCTGGTCAAG 451 GACTACTTCC CCQAACCGGT GACGGTGTCG TGGAACTCAG GCGCTCTGAC 501 CAGCGGCGTG CACACCTTCC CAGCTGTCCT ACAGTCCTCA GGACTCTACT 551 CCCTCAGCAG CGTGGTGACC GTGCCCTCCA GCAACTTCGG CACCCAGACC 601 TACACCTGCA ACGTAGATCA CAAGCCCAGC AACACCAAGG TGGACAAGAC 10 651 AGTTGAGCGC AAATGTTGTG TCGAGTGCCC ACCGTGCCCA GCACCACCTG 701 TGGCAGGACC GTCAGTCTTC CTCTTCCCCC CAAAACCCAA GGACACCCTC 751 ATGATCTCCC GQACCCCTGA GGTCACGTGC GTGGTGGTGG ACGTGAGCCA 801 CGAAGACCCC GAGGTCCAGT TCAACTGGTA CGTGGACGGC GTGGAGGTGC 851 ATAATGCCAA GACAAAGCCA CGGAGGAGC AGTTCAACAG CACGTTCCGT 15 901 GTGGTCAGCQ TCCTCACCGT TGTGCACCAG GACTGGCTGA ACGGCAAGGA 951 GTACAAGTGC AAGGTCTCCA ACAAAGGCCT CCCAGCCCCC ATCGAGAAAA 1001 CCATCTCCAA AACCAAAGGG CAGCCCCGAG AACCACAGOT GTACACCCTG 1051 CCCCCATCCC GGGAGGAGAT GACCAAGAAC CAGGTCAGCC TGACCTGCCT 1101 GOTCAAAGGC TrCTACCCCA GCGACATCGC CGTGGAGTGG GAGAGCAATG 20 1151 GGCAGCCGGA GAACAACTAC AAOACCACAC CTCCCATGCT GGACTCCGAC 1201 GGCTCCTTCT TCCTCTACAG CAAGCTCACC GTGGACAAGA GCAGGTGGCA 1251 GCAGGGGAAC GTCTTCTCAT GCTCCGTGAT GCATGAGGCT CTGCACAACC 1301 ACTACACGCA QAAGAGCCTC TCCCTGTCTC CGG7GTAAA (SEQ ID NQ:346) 25 Amino acid sequence of the Ab-23 HC including signal peptide: I MDWTWRILFL VAAATGAHSE VQLVQSGAEV KKPGSSVKVS CKASGFTFTD 51 YIMHWVRQAP GQGLEWMGYI NPYNDDTEYN EKFKGRVTIT ADKSTSTAYM 101 ELSSLRSEDT AVYYCARSIY YYDAPFAYWG QGTLVTVSSA STKGPSVFPL 30 151 APCSRSTSES TAALGCLVKD YFPEPVTVSW NSGALTSGVH TFPAVLQSSG 201 LYSLSSVVTV PSSNFGTQTY TCNVDHKPSN TKVDKTVERK CCVECPPCPA 251 PPVAGPSVFL FPPKPKDTLM ISRTPEVTCV VVDVSHEDPE VQFNWYVDGV 301 EVHNAKTKPR EEQFNSTFRV VSVLTVVHQD WLNGKEYKCK VSNKGLPAPI 351 EKTISKTKGQ PREPQVYTLP PSREMTKNQ VSLTCLVKGF YPSDIAVEWE 35 401 SNGQPENNYK TTPPMLDSDO SFFLYSKLTV DKSRWQQQNV FSCSVMIHEAL 451 HNHYTQKSLS LSPQK (SEQ ID NO:347) Nucleic acid sequence of the Ab-23 HC including signal peptide encoding sequence: 40 1 ATGGACTGGA CCTGGAGGAT CCTCTTCTTG GTGGCAGCAG CCACAGGAGC 51 CCACTCCGAG GTGCAGCTGG TGCAGTCTGG GCTGAGTG AAGAAGCCTG 101 GOTCCTCGGT GAAGGTCTCC TGCAAGGCTT CTGGTTrTAC CTrCACCGAC 151 TATATTATGC ACTGGGTGCG TCAGGCCCCT GGTCAAGGGC TTGAGTOGAT 201 GQGCTATATC AACCCTTATA ATGATGACAC CGAATACAAC GAGAAGTICA 45 251 AGGGCCGTGT CACGATTACC QCQGACAAAT CCACGAGCAC AGCCTACATG 301 GAGCTGAGCA GCCTGCGCTC TGAGGACACG GCCGTGTATT ACTGTGCGCG 351 TrCGA'TTAT TACTACGATG CCCCGTTGC TTACTGGGGC CAAGGGACTC 401 TGGTCACCGT CTCTAGTGCC TCCACCAAGG GCCCATCGGT CTrCCCCCTQ 451 GCGCCCTGCT CCAGQAGCAC CTCCGAGAGC ACAGCGGCCC TGGGCTGCCT 50 501 GGTCAAGGAC TACTTCCCCG AACCGGTGAC GGTGTCGTGG AACTCAGOCG 551 CTCTGACCAG CGGCGTGCAC ACCTTCCCAG CTGTCCTACA GTCCTCAGGA SEA 18039 lvI 60117-23 98 WO 2006/119062 PCT/US2006/016345 60f CTCTACTCCC TCAGCAGCGT GGTGACCGTG CCCTCCAQCA ACTTCGGCAC 651 CCAGACCTAC ACCTGCAACG TAGATCACAA CGCCCAGCAAC ACCAAGOTOG 701 ACAAGACAGT TOAGCGCAAA TGTTGTGTCG AOTGCCCACC GTOCCCAGCA 751 CCACCTGTGG CAGGACCGTC AGTCTTCCTC TTCCCCCCAA AACCCAAGGA 5 801 CACCCTCATG ATCTCCCGGA CCCCTGAGGT CACGTGCGTG GTGGTGGACG 851 TGAGCCACGA AGACCCCGAG GTCCAGTTCA ACTGGTACGT GGACGQCGTG 901 GAGGTGCATA ATGCCAAGAC AAAGCCACGG GAGGAGCAGT TCAACAGCAC 951 GTCCGTGTG GTCAGCGTCC TCACCGTTGT GCACCAGGAC TGGCTGAACG 1001 GCAAGGAGTA CAAGTQCAAG GTCTCCAACA AAGGCCTCCC AGCCCCCATC 10 1051 GAGAAAACCA TCTCCAAAAC CAAAGGCAG CCCCGAGAAC CACAGGTGTA 1101 CACCCTGCCC CCATCCCGGG AGGAGATGAC CAAQAACCAG GTCAGCCTGA 1151 CCTGCCTGGT CAAAGGCT1TC TACCCCAGCG ACATCGCCGT GGAGTGGGAG 1201 AGCAATQGGC AGCCQGAGAA CAACTACAAG ACCACACCTC CCATGCTGGA 1251 CTCCGACGGC TCCTTCTTCC TCTACAGCAA GCTCACCGTG GACAAGAGCA 15 1301 GGTGGCAGCA GGGGAACGTC TTCTCATGCT CCGTQATGCA TGAGGCTCTG 1351 CACAACCACT ACACGCAQAA GAGCCTCTCC CTGTCTCCGG GTAAA (SEQ ID NQ:348) The CDR (complementarity determining region) sequences in the variable region 20 of the heavy chain of Ab-23 are as follows: CDR-H1: DYIMH (SEQ ID NO:269) CDR-H2: YINPYNDDTEYNEKFKG (SEQ ID NO:270) CDR-H3: SIYYYDAPFAY (SEQ ID NO:271) The light chain variable region CDR sequences of Ab-23 are: 25 CDR-L1: RASQDISSYLN (SEQ ID NO:239) CDR-L2: STSRLNS (SEQ ID NO:240) CDR-L3: QQDIKHPT (SEQ ID NO:241) Ab-23 Variable domains: 30 Ab-23 light chain variable domain amino acid sequence (without signal sequence): DIQMTQSPSS LSASVGDRVT ITCRASQDIS SYLNWYQQKP GKAPKLLIYS TSRLNSGVPS RFSGSGSGTD FTLTISSLQP EDFATYYCQQ DIIIPTFGQG 35 TKVEIK (SEQ ID NO:364) Ab-23 light chain variable domain DNA sequence (without signal sequence): GACATCCAGATGACCCAGTCTCCATCCTCCCTGTCTGCATCTGTAGGTGACCGTOTC 40 ACC ATCACTTGCC GCGCAAGTCA GGATATTAGC AGCTATTAAATrGGTATCA GCAGAAACCA GGGAAAGCCC CTAAGCTCCT GATCTATTCTACTrCCCGTT TQAATAGTGG GGTCCCATCA CGCTTCAGTG GCAGTGGCTCTGGGACAGAT TTCACTCTCA CCATCAGCAG TCTGCAACCT QAAGATGCAACTTACTA CTGTCAACAG GATATTAAAC ACCCTACGTT QQGTCAAGQCACCAAGGTGQ 45 AGATCAAA (SEQ ID NO:365) Ab-23 heavy chain variable domain amino acid sequence (without signal sequence): SEA 180391 v 60117-:3 99 WO 2006/119062 PCT(UJS2006/016345 EvQLVQSGAE VKK1GSSVKV SCKASGTFTFT DyTvIVEWVRQA PGTQCLEWVMGYINVYNDIDTEy N-KSFKQRVTI TADKSTSTAY MELSSLRSED TAVyyCA~rSyyyDApFAyW QQGTLVTvSS (SEQ ID NQ:3 66) 5Ab-23 heavy chain variable domain DNA sequence (without signal sequence): GAGrTGCACTGTGCAGTCTGCOGGCGACTGACCTGCTCCGGTA qGTC TCCTGCAAG7G CTrCTGQ'TrT TACCTI'CACC GACTATATATCACT~rGT 10 GCGjTCAGOCC CCTGGTCAAG GJGCTIGACGTG GATGGGCTATATCAACCCT ATAATGATGA CACCGAATAC AACGAGAAGT TCAAGGjGCCQiTGTCACGAUT ACCCGGACA AATCCACGAG CACAGCCTAC ATGT~iAGCTGjAGCAGCCTG CTCTGAGGAC ACGIGCCGTGT ATIACTGTGC GjCGTICGA'ITTACTACG ATQcccCGTI TGC1TACTGG GQCCAAGGGACTCTOjGTCACCQiTCTCTAGT (SEQ W 15 NQ:367) Ab-21 Amino acid sequence of the Ab-21 LC including signal peptide: 20 FGAQTKLELKR, (SEQ ID NQ:3 15) 25 Nucleic acid sequence of the Ab-21 LC including signal peptide: ATGAAGTCACAACCCACTcTTGTATACATGTTGCTGTGG~rGTCTGGTA c 3 AGACATGTGATGACCCAGTCTCACAAAFlCATGTCCACGTCAGTAGGAA 30 ACAQAAACCA.GACAATCTCCTAAACTACTGAmACTGGATCCACCCGCC CTGGAGTCCcTGATCGCACACAGTGATCTGACAGAMCATCCA TTAGCAATQ3TGCATcTGAAGACGGCAGAAICTGTCMACATATAGAC ATCCTCTCACGT-CGGTGGACcATGATGAACGT (SEQ ID NQ:3 16) 35 Amino acid sequence of the Ab-21 HC including signal peptide: YGDP~WTyWGQGTLVTVSS (SEQ ID NO:3 17) 40 Nucleic acid sequence of the Ab-21 HG including signal peptide: AT0 G~cATGGCAAcTGGATcATcHrcTcCTeATCT AGTGGTTACAGG(XTCATC GUTGTCCTGCAAAG~CTCTCATAUGAAACTACTATATCACTCtTA GCAGCTGAACAGGCCTGGAGTGGA A~GATCCTAGAT.O TCCACACAGCTAC TCGTACCTACTCTGAQjGACACT~rCGCA 50 TATTCTCA O CTQGTCACCGTCTCGCA03C (SEQ EDNQ:318) SEA 180391 1vI 60117-223 100 WO 2006/119062 PCT/US2006/016345 Ab-21 was humanized to yield Ab-22. Ab-22 5 Amino acid sequence of the Ab-22 LC including signal peptide: MDMRVPAOLLGLLLLWLRGARCDIQMTQSPSSLSASVGDRVTITCAbVF-rVAW 10 YQQKPGKAPKLLIY~W'lSTRiGVPSRFSGSGSGTDFTLTISSLQPEDFATCQQYSSYP JFGGGTKVEIKR (SEQ ID NO:319) Nucleic acid sequence of the Ab-22 LC including signal peptide: 15 15ATG3GATATGCGCGTGCCGGCGCAGCTGCTGGGCCTGCTOCTGCTGTGGCTGCGCGG .CG;CGCGCTGCGATATCCAGATGACCCAGAGTCCCGAGCAGCCTGAGCGCGiAGCGiTGG GCGATCGCGTGACCATTACCTGAAAGCGACCAGGATGTGTACCGCGGTGGCG TGTATCAGCAGAAACCGCAAAGCGCCGAAACTGCTGAMATTGGGCGAGCAC 20 CCGCCATACCGGCGTGCCGAGTCGC AGGAGCGGCAAGCGGCACCGATTTA CCCTGACCATTAGCAGCCTGCAGCCGGAAGAT GCGACCTATTATTGCCACAGT ATAGCAGCTATCCGCTGACCTGCGGCGGCACCAAAGTGGAAATTAAACGT (SEQ ID NO:320) 25 Amino acid sequence of the Ab-22 HC including signal peptide: MDWTWSIIYLVAAPTGAHSEVLVQSGAEVKKPGASVKVSCKASGWFNIK6YI3'WV RQAPQGLEIG~fFlGNYTW d RVTMTTDTSTSTAYMELRSLRSDD)TAVYYC AYPAUDiP'TYWGQGTLVTVSS (SEQ ID NO:321) 30 Nucleic acid sequence of the Ab-22 HC including signal peptide: ATGGATTGGACCTGGAGCATTCTmTTTCTGGTGGCGGCGCCGACCGGCGCGCATAG CGAAGTGCAGCTOGTGCAGAGCGGCGCGGAAGTGAAAAAACCGG GAGCGTG 35 AAAGTAGCTGCAAAGCGAGCGGCTITAACATrAAAGATTATTATATGCATTGGGT GCGCCAGGCGCCGGGCCAGGGCCTGGAATGGATCGGCCGCATTGATCCGGAAAAC GCGATATTATATGATCCGAAAMCAGGCCGCGTGACCATGACCACCGATACC AGCACCACACCGCTATATGGAACTGCCAGCCTGCGCAGCGATGATACCGCGGT GTATTATTGCGCGTATGATCGGGCGATCCGGCGTGGTTTACCTATTGGGGCCAGGG 40 CACCCTGGTGACCGTCTCGAGC (SEQ ID NO:322) Ab-22 light chain variable domain amino acid sequence (without signal sequence): DIQMTQSPSS LSASVGDRVT ITCKASQDVF TAVAWYQQKP GKAPKLLIYW 45 ASTRHTGVPS RFSGSQSGTD FTLTISSLQP EDFATYYCQQ YSSYPLTFGG GTKVEIKR (SEQ ID NO:336) Ab-22 light chain variable domain DNA sequence (without signal sequence): 50 GATATCCAGATACCCAGAGCCCGCAGCCTGAGGCGAGCGTGGGCGATCGCOT GACCATTACCTGCAAAGCGAGCCAGGATGTTTACCGCGGTGGCGTGGTATCAGC SEA 1803911 v 60117-2n 101 WO 2006/119062 PCT/US2006/016345 AGAAACCGGGCAAAGCGCCOAAACTGCTGATTTATrGGGCGAGCACCCGCCATACC GGCGTGCCGAGTCGCTTrAGCGGCAGCGGCAGCGGCACCGATTACCCTGACCAT TAGCAGCCTGCAGCCGGAAGATTGCGACCTATATTGCCAGCAGTATAGCAGCT ATCCGCTGACCTTFGGCGQGCGGCACCAAAGTGGAAATAAACGT (SEQ ID NO:337) 5 Ab-22 heavy chain variable domain amino acid sequence (without signal sequence): EVQLVQSGAE VKKPGASVKV SCKASGFNIK DYYMHWVRQA PGQGLEWIGRIDPENGDIIY DPKFQGRVTM TTDTSTSTAY MELRSLRSDD 10 TAVYYCAYDAGDPAWFTYWG QGTLVTVSS (SEQ ID NO:338) Ab-22 heavy chain variable domain DNA sequence (without signal sequence): GAAGTGCAGCTGGTGCAGAGCGGCGCGGAAGTGAAAAAACCGGGCGCGAGCGTGA 15 AAGTGAGCTGCAAACGAGCGGCTTAACATTAAAGATrATrATATGCATTGGGTG CGCCAGGCGCCGGCCAGGGCCTGGAATGGATCGGCCGCATrGATCCGGAAAACG GCGATATrATITATGATCCGAAATITCAGGGCCGCGTGACCATGACCACCGATACCA GCACCAGCACCGCGTATATGGAACTGCGCAGCCTGCGCAGCGATGATACCGCGGTG TATTATTGCGCGTATGATGCGGCGATCCGGCTGGTTTACCTATTOGGGCCAGGGC 20 ACCCTGGTGACCGTCTCGAGC (SEQ ID NO:339). For Ab-18, Ab-20, and Ab-22, the light chain human kappa constant region is as follows: TVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQD 25 SKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC* (SEQ ID NQ:325) and the heavy chain human gamma-4 constant region is as follows: ASTKGiPSVFPLAPCSRSTSESTAALGCLVKD)YFPEPVTVSWNSGALTSGVHTFPAVLQSS GLYSLSSVVTVPSSSLGTKTYTCNVDHKPSNTEVDKRVESKYGPPCPPCPAPEFLGGPSV 30 FLFPPKPKDTLMISRTPEVTCVVVDVSQEDPEVQFNWYVDGVEVHNAKTKPREEQFNS TYRVVSVLTVLHQDWLNGKEYKCKVSNKGLPSSIEKTISKAKGQPREPQVYTLPPSQEE MTKNQVSLTCLVKFYPSDIAVEWESNGQPENNYKTTPVLDSDGSFFLYSRLTVDKSR WQEGNVFSCSVMHEALHNHYTQKSLSLSLGK* (SEQ ID NO:326) 35 The hinge region contains the Ser-241-Pro mutation to improve hinge stability (Angal S et al, (1993), Mol Immunol, 30(1), 105-108). 40 Ab-24 The sequences of Antibody 24 (also referred to herein as Ab-24) LC and HC are as follows: Light Chain: 45 Amino acid sequence of the mature form (signal peptide removed) of the Ab-24 LC: 1 DIVLTQSPAS LAVSLGQRAT IAClQ(A UYD~TYMNWY QKPGQPPKL 51 LIYMSNIE EIPARFSGTG SGTDFTLNIH PVEEEDITY YCQS 1 f SEA 180391M 60117-2 102 WO 2006/119062 PCT/US2006/016345 ~11 WG(QTK1 KP$DAAPTVS IFPPSSEQLTSG9ASVVCFL NNFYPKDJNV 151 KWKMGSERQ NGVLNSWTDQ DSKDSTYSMS STLTLTKDEYERBNSYTCEA 201 THKTS TSPIVKSFNRNEC (SEQ 1 NO:350) 5 Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab 24 LC: I GACATIGTGT TGACCCAGTC TCCAGCTTCT ITGGCTGTGT CTCTAGGGCA 51 GAGGGCCACC ATCQCCTQCA AGGCCAGCCA AAGTGTTGAT TATGATGGTA 10 101 CTAGTTATAT GAATrGGTAC CAACAGAAAC CAGGACAGCC ACCCAAACTC 151 CTCATCTATG CTGCATCCAA TCTAGAATCT GAGATCCCAG CCAGGTT1AG 201 TGGCACTGGG TCTGGGACAG ACTTCACCCT CAACATCCAT CCTGTGGAGG 251 AGGAGGATAT CACAACCTAT TACTGTCAGC AAAGTAATGA GGATCCQTrC 301 ACGTTCGGAG GGGG0ACCAA GTTGGAAATA AAACGG3GCTG ATGCTGCACC 15 351 AACTGTATCC ATCTCCCAC CATCCAQTGA GCAGTTAACA TCTGAGGTG 401 CCTCAGTCGT GTGCTTCTTG AACAACTTCT ACCCCAAAGA CATCAATGTC 451 AAGTGGAAGA TTGATGGCAG TGAACGACAA AATGGCGTCC TGAACAGTTG 501 GACTGATCAG GACAGCAAAG ACAGCACCTA CAGCATGAGC AGCACCCTCA 551 CGTTGACCAA GGACGAGTAT GAACGACATA ACAGCTATAC CTGTGAGGCC 20 601 ACTCACAAGA CATCAACTTC ACCCATFQTC AAGAGCTTCA ACAGGAATGA 651 GTGTrAG (SEQ ID NO:354) Amino acid sequence of the Ab-24 LC including signal peptide: 25 1 METDTILLWV LLLWVPGSTG DIVLTQSPAS LAVSLGQRAT IACKASQSVD 51 YDOTSYMNWY QQKPGQPPKL LIYAASNLES EIPARFSGTG SGTDFTLNIH 101 PVEEEDITY YCQQSNEDPF TFGGGTKLEI KRADAAPTVS IFPPSSEQLT 151 SGGASVVCFL NNFYPKDINV KWKIDGSERQ NGVLNSWTDQ DSKDSTYSMS 201 STLTLTKDEY ERHNSYTCEA THKTSTSPIV KSFNRNEC (SEQ ID NO:355) 30 Nucleic acid sequence of the Ab-24 LC including signal peptide encoding sequence: 1 ATGGAGACAG ACACAATCCT GCTATGGGTG CTGCTGCTCT GQGTTCCAGO 51 CTCCACTGGT GACATTGTOT TGACCCAGTC TCCAGCTTCT TTGGCTGTGT 35 101 CTCTAGGGCA GAGGGCCACC ATCQCCTQCA AGCCCCACA AAGTGTCGAT 151 TATGATGGTA CTAGTTATAT GAATTGGTAC CAACAGAAAC CAGGACAGCC 201 ACCCAAACTC CTCATCTATG CTCATCCAA TCTAGAATCT GAGATCCCAG 251 CCAGGTTAG TGGCACTGGG TCTGGGACAG ACTTCACCCT CAACATCCAT 301 CCTGTGGAGG AGQAGGATAT CACAACCTAT TACTGTCAGC AAAGTAATGA 40 351 GGATCCGITC ACGTTCGGAG GGGGACCAA GTFGGAAATA AAACGGGCTG 401 ATQCTGCACC AACTGTATCC ATCTTCCCAC CATCCAGTGA GCAGTTAACA 451 TCTGGAGGTG CCTCAGTCGT GTQCTTCTTG AACAACT=CT ACCCCAAAGA 501 CATCAATGTC AAOTGAAGA TTGATGGCAG TGAACGACAA AATGGCGTCC 551 TGiAACAGTrG GACTGATCAQ GACAGCAAAG ACAGCACCTA CAGCATGAGC 45 601 AGCACCCTCA CGTTGACCAA GGACGAGTAT GAAQGACATA ACAQCTATAC 651 CTGTQAGGCC ACTCACAAGA CATCAACTTC ACCCATTOTC AAGAGCTTCA 701 ACAGGAATQA QTGTTAG (SEQ ID NO:356) Ab-24 Heavy Chain: SEA 1803911v1 60117-2Z 103 WO 2006/119062 PCT/US2006/016345 Amino acid sequence of the mature form (signal peptide removed) of the Ab-24 HC: 1 QVQLQQPGTE LVRPGTSVKL SCKASGYIFT rYWMNWVKQR PGQGLEWIGM 5 51 iPSASEIRL)QKFKNKATL TLDKSSSTAY-MHLS;PTSVD SAVYYCAR'8_G 101 EWGSMDYWGQ GTSVTVSSAK TTPPSVYPLA PGSAAQTNSM VTLGCLVKqY 151 FPEPVTVTWN SGSLSSWVHT FPA VLQSDLY TLSSSVTVPS STWPSETVTC 201 NVARPASSTK VDKUVPRDC GCKPCICTVPEVSSVFIFPPEPEDVLTITL 251 TPKVTCVVVD ISKDDPEVQF SWFVDDVEVH TAQTQPREEQ FNSTFRSVSE 10 301 LPIMHQDWLIN EEFKCRNSAAFPAPEKTISKTKGRPKA PQVYTLPPPK 351 EQMAKDKVSL TCMJTDFFPE DITVEWQWNG QPAENYKINTQ PMDTDGSYF 401 IYSKLNVQKSNWEAGNTFTC SVLHEGLHNHHTEKSLSHSP GK(SEQ ID NO:357) Nucleic acid sequence encoding the mature form (signal peptide removed) of the Ab-24 HC: 15 1 CAGGTCCAAC TACAGCAGCC TGGGACTGAG CTGGTGAGGC CTGGAACTTC 51 AGTGAAGTTG TCCTQTAAGG CTTCTGGCTA CATCTTCACC ACCTACTGGA 101 TGAACTGGGT GAAACAGAGG CCTGGACAAG GCCTTGAGTG GATTOGCATG 151 ATICATCCTT CCGCAAGTGA AATTAGGTTG QATCAGAAAT TCAAGGACAA 20 201 GGCCACATTG ACTCTTGACA AATCCTCCAG CACAGCCTAT ATQCACCTCA 251 GCGGCCCGAC ATCTGTGGAT TCTGCGGTCT ATTACTGTGC AAGATCAGGG 301 GAATQGGGT CTATGGACTA CTGOIGGTCAA GGAACCTCAG TCACCGTCTC 351 CTCAGCCAAA ACGACACCCC CATCTGTCTA TCCACTGGCC CCTGGATCTG 401 CTGCCCAAAC TAACTCCATG GTGACCCTGG GATGCCTGGT CAAGGGCTAT 25 451 TfCCCTGAGC CAGTGACAGT GACCTGGAAC TCTGGATCCC TGTCCAGCGG 501 TGTGCACACC TTCCCAGCTG TCCTGCAGTC TGACCTCTAC ACTCTGAGCA 551 QCTCAGTGAC TGTCCCCTCC AGCACCTGGC CCAGCGAGAC CGTCACCTGC 601 AACGTTGCCC ACCCGGCCAG CAGCACCAAG QTGOACAAQA AAATTGTGCC 651 CAGGGATTGT GTTGTAAGC CTFGCATATG TACAGTCCCA GAAGTATCAT 30 701 CTGTCTrCAT CTTCCCCCCA AAGCCCAAGG ATGTGCTCAC CATTACTCTG 751 ACTCCTAAGG TCACGTGTGT TQTOGTAGAC ATCAGCAAGG ATGATCCCGA 801 GGTCCAGTTC AGCTGGTTTG TAGATGATGT GAGGTGCAC ACAGCTCAGA 851 CGCAACCCCG GGAGGAGCAQ TTCAACAQCA CTTTCCGCTC AQTCAGTGAA 901 CTTCCCATCA TGCACCAGGA CTGGCTCAAT GGCAAGGAGT TCAAATGCAG 35 951 GOTCAACAGT GCAGCTT1CC CTGCCCCCAT CGAGAAAACC ATCTCCAAAA 1001 CCAAAGGCAG ACCGAAGGCT CCACAGGTGT ACACCATTCC ACCTCCCAAG 1051 GAGCAGATGG CCAAGGATAA AGTCAGTCTG ACCTGCATGA TAACAGACTT 1101 CTICCCTGAA GACATTACTG TGGAGTGGCA GTGGAATGGG CAGCCAGCGG 1151 AGAACTACAA GAACACTCAG CCCATCATGG ACACAGATGO CTCTrACTTC 40 1201 ATCTACAGCA AGCTCAATGT GCAGAAGAGC AACTGGGAGG CAGGAAATAC 1251 T1TCACCTGC TCTGTGTTAC ATGAGGGCCT GCACAACCAC CATACTGAGA 1301 AGAGCCTCTC CCACTCTCCT GGTAAATGA (SEQ ID NO:361) 45 Amino acid sequence of the Ab-24 HC including signal peptide: 1 MGWSSIILFL VATATGVHSQ VQLQQPGTEL VRPGTSVKLS CKASGYITT 51 YWMNWVKQRP GQGLEWIGMI HPSASEIRL QKFKDKATLT LKSSSTAYM 101 HLSGPTSVDS AVYYCARSGE WGSMDYWGQG TSVTVSSAKT TPPSVYPLAP SEA 1803911v160117-22 104 WO 2006/119062 PCTIUS2006/016345 151 GSAAQTNSMV TLOiCLVKGYF PEPVTVTWNS GSLSSGVHTF PAVLQSDLYT 201 LSSSVTVPSS TWPSETVTCN VAHPASSTKV DKKIVPRDCQ CKPCICTVPE 251 VSSVFIFPPK PKDVLTITT PKVTCVVVDI SKDDPEVQFS WFVDDVEVHT 301 AQTQPRFEQF NSTFRSVSEL PIMHQDWLNG KEFKCRVNSA AFPAPIEKTI 5 351 SKTKGRPKAP QVYTIPPPKE QMAKDKVSLT CMIITDFFPED ITVEWQWNGQ 401 PAENYKNTQP IMDTDGSYFI YSKLNVQKSN WEAGNTFTCS VLHEGLHNHH 451 TEKSLSHSPG K (SEQ IID NO:362) Nucleic acid sequence of the Ab-24 HC including signal peptide encoding sequence: 10 1 ATGGGATGGA GCTCTATCAT CCTCTTCTTG GTAGCAACAG CTACAGGTGT 51 CCACTCCCAG GTCCAACTAC AGCAGCCTGG GACTGAGCTG GTGAGGCCTG 101 GAACTTCAGT GAAGTTGTCC TGTAAGQCTr CTGGCTACAT CTTCACCACC 151 TACTGGATGA ACTOGGTGAA ACAGAGG3CCT GGACAAGGCC TTGAOTGGAT 15 201 TGGCATGATT CATCCTTCCG CAAGTGAAAT TAGGTTGGAT CAGAAATTCA 251 AGWACAAGGC CACATTGACT QTGACAAAT CCTCCAGCAC AGCCTATATQ 301 CACCTCAGCG GCCCGACATC TGTGGATTCT GCGGTCTATT ACTOTGCAAG 351 ATCAGGGGAA TGGGGGTCTA TGGACTACTG GGGTCAAGGA ACCTCAGTCA 401 CCOTCTCCTC AGCCAAAACG ACACCCCCAT CTGTCTATCC ACTGGCCCCT 20 451 GQATCTGCTG CCCAAACTAA CTCCATGGTG ACCCTGGGAT GCCTGGTCAA 501 QGGCTATTC CCTGAGCCAG TGACAGTGAC CTGAACTCT GGATCCCTGT 551 CCAGCGGTGT GCACACCITC CCAGCTGTCC TQCAGTCTQA CCTCTACACT 601 CTGAGCAGCT CAGTGACTGT CCCCTCCAGC ACCTGGCCCA GCGAGACCGT 651 CACCTGCAAC GTrGCCCACC CGGCCAGCAG CACCAAGGTG GACAAGAAAA 25 701 TTGTGCCCAG GGATTGTGGT TGTAAGCCTf GCATATGTAC AGTCCCAGAA 751 GTATCATCTG TCTTCATCT CCCCCCAAAG CCCAAGGATG TGCTCACCAT 801 TACTCTGACT CCTAAGGTCA CGTGTQTTGT QGTAGACATC AGCAAGGATG 851 ATCCCQAGT CCAGTJCAGC TGGTTGTAG ATGATGTGGA GGTGCACACA 901 GCTCAGACGC AACCCCGGGA GGAGCAGTTC AACAGCACTT TCCGCTCAGT 30 951 CAGTGAACTT CCCATCATGC ACCAQGACTO GCTCAATGGC AAGGAGTTCA 1001 AATGCAGGGT CAACAGTGCA OCTITCCCTG CCCCCATCGA GAAAACCATC 1051 TCCAAAACCA AAGCAGA C GAAGGCTCCA CAGGTOTACA CCATTCCACC 1101 TCCCAAGGAG CAGATGGCCA AGGATAAAGT CAGTCTGACC TGCATGATAA 1151 CAGACTTCTT CCCTGAAGAC ATTACTGTGG AQTQGCAGTG GAATGGGCAG 35 1201 CCAGCGGAGA ACTACAAGAA CACTCAGCCC ATCATGGACA CAGATGQCTC 1251 TrACTTCATC TACAGCAAGC TCAATGTGCA GAAGAGCAAC TGGGAGGCAG 1301 GAAATACTTr CACCTGCTCT GTGTTACATG AGGQCCTOCA CAACCACCAT 1351 ACTOAGAAGA GCCTCTCCCA CTCTCCTGGT AAATGA (SEQ ID NO:363) 40 The CDR sequences in the variable region of the light chain of Ab-24 are as follows: CDR-L1: KASQSVDYDGTSYMN (SEQ ID NO:351) CDR-L2: AASNLES (SEQ ID NO:3 52) 45 CDR-L3: QQSNEDPFT (SEQ IDNO:353) The CDR sequences in the variable region of the heavy chain of Ab-24 are as follows: CDR-H1: TYWMN (SEQ ID NO:358) SEA 180391IvI 60117-223 105 WO 2006/119062 PCTIUS2006/016345 CDR-H2: MIHPSASEIRLDQKFKD (SEQ ID NO:359) CDR-H3: SGEWGSMDY (SEQ ID NO:360) Table 1 below provides the SEQ ID NOs and amino acid sequences of the CDR's 5 of Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-l1, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab 23, and Ab-24. Li, L2, and L3 refer to light chain CDR's 1, 2, and 3, and HI, H2, and H3 refer to heavy chain CDR's 1, 2, and 3 according to the Kabat numbering system (Kabat et al., 1987 in Sequences ofProteins ofImmunological Interest, U.S. Department of Health and Human 10 Services, NIH, USA). SEA 180391 60117-23 106 WO 2006/119062 PCTIUS2006/016345 ______________Table_1 SE9 ED NO IDESCRWHON AMINO ACID SEQUENCE 54 AbM and Ab-1 I DR-L1 Sg DNL 55 Ab-A and Ab-1 CDR-L2 IAD S6 Ab-A iad A& I CDR -L3 51AbA anid A& 1 CDR-Hl Y1 52Ab-A and Ab- 1 CDR-H2 TWSGGRTDYASWAKCG 53 Ab-A and Ab- 1CDR-H3 NWNL 60 X"- CD-I SSSSVSFVD 61Ab-B CDR-L2 RT'SNLGF 62 A"- CDR-13 QQRSTYPPT 57 Ab-B C1DR-H1 TSQ4MGVG 58,- Ab-B CDR-112 IIIWWDDVKRYNPVLKS 59 Ab-B CIDR-H3 'DFD)YDEMYAMDY 48 ACCD-IKASqSVDYDQDSYN 4 9 Ab-C CDR-L2 AASNLES 50 -Ab-C CDR-L3 QQSNEDPWT -45 Ab-C CDR-H1 DCYMN 46 Ab-C CDR-H2 D)INPFNG6TI'YNQKFKG 47' Ab-C CDR-IT3 SIIYYFPbGRVPWDAMDY 42 Ab-D CDR-L1 QjASQGTSIN 43 Ab-D CDR-L2 GSSNLED 44 Ab-D) CDR-U LOMSYPYT 39Ab-D CDR-H11 DHYMS 40 Ab-D CDR-I12 D!NPYSGEfrYqKFKGj 41 Ab-D CDR-113 DDYDASPFAY 275 Ab-2 ICD)R-L1 RASSSVYYYMH 276 Ab-2 CIDR-L2 ATSNLAS 277 Ab-2 CDR-L3 9qmsDPLT 287 A-CRH YI 2889b- DI RL.DPEDGESD)YAPKFQD 289 Ab-2 CDR-43 EFDYDGirTYTFFPY 28 Ab-3 and Ab-15 CDR-L1 SVSSTISSNIJILH 2 .79 Ab ,-3 anddAb-45 (DR-L2 6TSNLAS 280 Ab-3 and Ab-15 CDR-L,3 9QWSSYPLT 290 Ab-3 and Ab-15 CDR-H1 DFYLH 29 .1 Ab-3 and Ab-15 CDR-112 RJIDPENGDTLYI)PKFQD 2f92 Ab-3 and Ab- 15 C DR-H3 -EDYFHDiQTSYWYFQV 78 AM ia Ab-5 CDR-Ll WASQDISNYLN 79 Ab-4 and Ab-5 CDR-L2YTLS 80 AM- and'Ab-5'ClR-13 _Q GDTLPYT 245 AM4 ad Ab-5 CDR-H1 DYNMH 24 AM- and Ab-5 C-H2SGAQNQF 247 AM- and .Ab-5 CDR-113 LGyYD DWYFD)V 81 Ab-6 CDR-L1 RMOIDISNYLN 99 - 6CDR-L2 YTS1WLHS *100 -Ab-6 CDR-L3 QQGDTLPYT 248 Ab-6 CD)R-H1 D)YNMH SEA 180391 1v1 60117-223 107 WO 2006/119062 PCTIUS2006/016345 Table 1I______________ SEQ ) N D~SR1PIONAMINO ACID SEQUENCE 249 Ab-6 CDR-H2 EN4SGGSVNQFK 250 Ab-6 CDR-H3 LVYW~SMEWMFV 101 1-1 WR-L1 RASQTYY 102 AM- CDR-L,2 YTSRL]HS 10 Ab-7 CDR-L3 QQGDThPYT 251l AM- CDR-HI DYNM2H 252 AM- CDR-H-2 EJNFNSOGAGjYNQQFKG 253 AbM CtDR-H3 LGYViGNMEWYFDV i64 Ab-9 CDR-Li R.ASQDISNYLN 105 Ab,-8 CD)R-12 YTSRLLS f'06 Ab-8 CDR-L3 QQGDThPYr 254 Ab-8 CDR-I DYNMH 255 Ab-8 CDR-H2 EWNSGGAGYNqKFKO~ 256 X&:8 CDR-H3 LGYDDIYDVVWYFDV 107 Ab-9 CtDR-L1 RASQDISNYLN, 168 Ab-9 CDR-L2 'YTSRLFS 10 9 Ab-9 OR-L3 QQGIDTLPYT 257 Ab-9 CDR-H1 DYNNE 258 Ab-9 CDR-112 EINPNS GGNKFKG *259 Ab-9 CDR-H3 LGYDD"YDWYFV 110 i Ab-1O CDR-L1 _________________ 111 Ab-1O CDR-L2 m ___i12Ab-1O CDR-L3 QQGDTLPYT 260 Ab-1O CDR-I11 ___________ 261 Ab-l10 CDR-112 M qgGNKG 262 Ab-l10 CDR-R3 bYDD1YDDWYFD)V 281 Ab-i and Ab-16 CDR-L1 _______________ 282 Ab-lI and Ab-16 CDR-L2 SM ' 283 Ab-1i nd A1 46 CDR-L3 QQW98SDPLT '293 Ab-i and Ab-16 Ct)R-H! DYYIH 2-94 Ab-1 1 and Ab-i6 CDR-H2 RvDpDNQjETEFAPKFPG 29 5 Ab- 11 aW A& 16 Cdk-ff EDYDGTYTWFPY 113 Ab-12 GDR-L1* ASQISNYLN i14 Ab-12 CDR-L2 YTSTLs 115 Ab-12 CDR-L3 QQGDTLPYT 263 Ab-12 CDR-fl1 DY1~fMI 264' Ab-i2 CDR-H2 E[NPNSGGSGYNQKFKGy 26 5 Ab-12 CLR-H3 LGWV'GNYEO)WMFV 284 Ab-13 and Ab-'14 CDR-L1 RASSSVTSSYLN 285 Ab- 13 axid Ab -14 CDR-L2 STSNLAS 286 A6-i! and Ab-14 CD)R-L .3 QQYDFFPST 296 A-3 an~d Ab- 14 Uik-li1 DYYMN 297 iAb- 13 aid Ab -14 CDR-H'2 DIN4PYDITYNHFKG 2 98 Ab-1f3 64 Ab-4OCR43 -lbTNM 116 Ab-17 and Ab-18 UDR-LL $VS5S1SS8NLfi 23 .7 Ab- 17 a Ab- 18 CDR-L2 OTSNLAS 238 Ab- 17 and Ab-1 DR-L3___________ '1 CQQ\ -rfT Y SEA 18M391 1v1 60117-2Z3 108 WO 2006/119062 PCT/US2006/016345 Table 1 Stg ID NO DESCRION AMINO ACID SEQUENCE 266 Ab-i7 and Ab-18 DR-i DYYIH 267 A&_17 and Ab-18 CDR-H2 IDPDNGESTYVPKFQG 268 Ab-17 and Ab-18 ZDR--M EGLDYGDYYAVDY 239 Ab-19, Ab-20 and Ab23'CDR-L1 RXSQDI$8YLN 240 Ab-19, Ab-0 and Ab23 CDR-L2 ST$RLNS 241 Ab-19, Ab-20 and Ab-23 CDR-L3 QQDIlKHPT 269 Ab-19, Ab-20 and Ab-23 CDR-H1 DYI1 270 Ab-19, Ab-26 and -D3 MDR-H2 YINPYNODTEYNEKFKG Ab-i9, Ab-20 and Ab-23 CDR-H3 SIYYYDAPFAY 242 Ab-2 andAb-22 CDR-L1 KASQDVFTAVA 243 Ab-21 and Ab-22 CD-L2 WASTRHT 244 Ab-21 and Ab-22 CDR-L3 QY5$YPia 2712 Ab-21 and Ab-22 CDR-H1 DYYMH 273 Ab-21 and Ab-22 Obi-H2 RCIUl'NGDIIYDPKFQG 274 Ab-21 and Ab-22 CDR-H3 DAGDPAWFTY 351 Ab-24 CUR-L1 KASQSVDYDGTSYMN 352 Ab-24 CUR-L2 AASNLES 3'53 Ab-24 CDR-L3 QQSNEOPFT 358 Ab-24'DR-H1 TYWMN 359 Ab-24 CDR-H2 MIHPSASEILDQKFKD 360 A-24 CDR-N3 __ S S Y An oligopeptide or polypeptide is within the scope of the invention if it has an amino acid sequence that is at least 75%, 76%, 77%, 78%, 79%, 80%, 81%, 82%, 83%, 84%, 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% 5 identical to least one of the CDR's of Table 1 above; and/or to a CDR of a sclerostin binding agent that cross-blocks the binding of at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24 to sclerostin, and/or is cross-blocked from binding to sclerostin by at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, 10 Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24; and/or to a CDR of a sclerostin binding agent wherein the binding agent can block the inhibitory effect of sclerostin in a cell based mineralization assay (i.e. a sclerostin neutralizing binding agent); and/or to a CDR of a sclerostin binding agent that binds to a Loop 2 epitope; and/or to a CDR of 15 a sclerostin binding agent that binds to a T20.6 epitope; and/or to a CDR of a sclerostin binding agent that binds to a "T20.6 derivative (cystine-knot + 4 arms)" epitope. Sclerostin binding agent polypeptides and antibodies are within the scope of the invention if they have amino acid sequences that are at least 85%, 86%, 87%, 88%, 89%, 90%, SEA 180391lvi 60117-n3 109 WO 2006/119062 PCT/US2006/016345 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a variable region of at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-l, Ab- 12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab 21, Ab-22, Ab-23, and Ab-24, and cross-block the binding of at least one of antibodies Ab-A, 5 Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24 to sclerostin, and/or are cross-blocked from binding to sclerostin by at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-), Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab- 11, Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab 10 22, Ab-23, and Ab-24; and/or can block the inhibitory effect of sclerostin in a cell based mineralization assay (i.e. a sclerostin neutralizing binding agent); and/or bind to a Loop 2 epitope; and/or bind to a T20.6 epitope; and/or bind to a "T20.6 derivative (cystine-knot + 4 arms)" epitope. Polynucleotides encoding sclerostin binding agents are within the scope of the 15 invention if they have polynucleotide sequences that are at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98% or 99% identical to a polynucleotide encoding a variable region of at least one of antibodies Ab-A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab- 1l, Ab-12, Ab-13, Ab-14, Ab-15, Ab 16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24, and wherein the encoded 20 sclerostin binding agents cross-block the binding of at least one of antibodies Ab-A, Ab-B, Ab C, Ab-L), Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-11, Ab-12, Ab 13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24 to sclerostin, and/or are cross-blocked from binding to sclerostin by at least one of antibodies Ab A, Ab-B, Ab-C, Ab-D, Ab-1, Ab-2, Ab-3, Ab-4, Ab-5, Ab-6, Ab-7, Ab-8, Ab-9, Ab-10, Ab-1 1, 25 Ab-12, Ab-13, Ab-14, Ab-15, Ab-16, Ab-17, Ab-18, Ab-19, Ab-20, Ab-21, Ab-22, Ab-23, and Ab-24; and/or can block the inhibitory effect of sclerostin in a cell based mineralization assay(i. e. a sclerostin neutralizing binding agent); and/or bind to a Loop 2 epitope; and/or bind to a T20.6 epitope; and/or bind to a "T20.6 derivative (cystine-knot+ 4 arms)" epitope. Antibodies according to the invention may have a binding affinity for human 30 sclerostin of less than or equal to 1 x 10-7M, less than or equal to 1 x 10 8 M, less than or equal to 1 x 10-9M, less than or equal to 1 x 104 0 M, less than or equal to 1 x 10-"M, or less than or equal to 1 x 10-2M. The affinity of a binding agent such as an antibody or binding partner, as well as the extent to which a binding agent (such as an antibody) inhibits binding, can be determined by S sA 190391v 60117-223 110 WO 2006/119062 PCTIUS2006/016345 one of ordinary skill in the art using conventional techniques, for example those described by Scatchard et al. (Ann. N.Y Acad Sci. 51:660-672 (1949)) or by surface plasmon resonance (SPR; BlAcore, Biosensor, Piscataway, NJ). For surface plasmon resonance, target molecules are immobilized on a solid phase and exposed to ligands in a mobile phase running along a flow 5 cell. If ligand binding to the immobilized target occurs, the local refractive index changes, leading to a change in SPR angle, which can be monitored in real time by detecting changes in the intensity of the reflected light The rates of change of the SPR signal can be analyzed to yield apparent rate constants for the association and dissociation phases of the binding reaction. The ratio of these values gives the apparent equilibrium constant (affinity) (see, e.g., Wolff et 10 al., Cancer Res. 53:2560-65 (1993)). An antibody according to the present invention may belong to any immunoglobin class, for example IgG, IgE, IgM, IgD, or IgA. It may be obtained from or derived from an animal, for example, fowl (e.g., chicken) and mammals, which includes but is not limited to a mouse, rat, hamster, rabbit, or other rodent, cow, horse, sheep, goat, camel, human, or other 15 primate. 'The antibody may be an internalizing antibody. Production of antibodies is disclosed generally in U.S. Patent Publication No. 2004/0146888 Al. Characterization Assays In the methods described above to generate antibodies according to the invention, 20 including the manipulation of the specific Ab-A, Ab-B, Ab-C, Ab-D, and Antibody 1-24 (Ab-1 to Ab-24) CDRs into new frameworks and/or constant regions, appropriate assays are available to select the desired antibodies or binding agents (i.e. assays for determining binding affinity to sclerostin; cross-blocking assays; Biacore-based "human sclerostin peptide epitope competition binding assay;" MC3T3-El cell based assay; in vivo assays). 25 Evitope Binding Assays Mature form human sclerostin is a 190 amino acid glycoprotein with a cystine-knot structure (Figures 8 and 9). In addition to the cystine-knot structure, the protein is characterized as having three loops designated as Loop 1, Loop 2 and Loop 3. Human sclerostin 30 was subjected to proteolytic digestion to produce fragments. Briefly, using different proteases, including trypsin, aspN, and lysC, fragments with various cleavage sites and sizes were generated. The sequences and mass for various human sclerostin peptides were determined. Antibody protection was evaluated to determine the effect on accessibility for proteolysis, SEA8o391v16017-223 111 WO 2006/119062 PCT/US2006/016345 including clipped site masking and peptide shifting. Finally, a BIAcore-based "'human sclerostin peptide epitope competition assay" was performed. Exposure of sclerostin to trypsin cleavage resulted in a pattern of peptide fragments as summarized in Figure 13. The fragments are referred to as T19.2, 120, 20.6, and 5 121-22. As shown schematically in Figure 19B, the T20.6 epitope is a complex of four separate peptide sequences which are joined by the three disulfide bonds of the cystine-knot region. Two of the peptides are joined by two disulfide bonds. The other two peptides are linked by one disulfide bond that, schematically, bisects the first two polypeptides. The T20.6 epitope that was generated by trypsin digestion retains the 10 cystine-knot structure of the native polypeptide and is recognized by antibodies Ab-C and Ab-D. A derivative of epitope T20.6 consists of the cystine-knot region and amino acids 58-64, 73-8 1, 112-117 and 138-141 in sequence position with reference to SEQ ID NO:1. This derivative epitope is shown in Figure 21. An epitope comprising the cystine-knot region may have one or more amino acids that is present in the T20.6 epitope (Figure 19B) but not present in the T20.6 15 derivative epitope (Figure 21). Another epitope-containing region was identified in the Loop 2 region of human sclerostin (Figure 19A) and is recognized by antibodies Ab-A and Ab-B. A Loop 2 epitope comprises amino acids 86-111 of SEQ ID NO: 1 (C4GPARLLPNAIGRGKWWRPSGPDFRC5, SEQ ID NO:6). Sterically, with reference to full-length sclerostin of SEQ ID NO:1, the Loop 2 20 containing structure is defined at one end by a disulfide bond between cysteine at position 86 (C4) and cysteine at position 144 (C8), and at the other end by a disulfide bond between cysteine at position 111 (C5) and cysteine at position 57 (Cl). The peptides generated by aspN cleavage of human sclerostin are shown in Figure 12. In the Figure, these peptides are designated as AspN14.6, AspN18.6, and AspN22.7 25 23.5, and are also referred to herein as N14.6, N18.6, and N22.7-23.5, respectively. One group of antibodies exhibits a specific pattern of binding to certain epitopes as evidenced by a Biacore-based "human sclerostin peptide epitope competition binding assay." Briefly, the antibody is preincubated with the epitope to be tested, at concentrations that will saturate the epitope-binding sites on the antibody. The antibody is then exposed to sclerostin 30 bound to a chip surface. After the appropriate incubation and washing procedures, a pattern of competitive binding is established. As shown in Figure 18, exemplairy antibody Ab-D bound to sclerostin molecules attached to the surface of the chip. Preincubation of antibody Ab-D with sclerostin decreased the binding of the antibody to the sclerostin on the chip to close to zero. Preincubation with a peptide consisting of epitope T19.2 showed that T19.2 did not compete SEA 1803911vI 60117-23 112 WO 2006/119062 PCT/US2006/016345 with sclerostin for antibody binding. However, preincubation with any one of the epitopes designated T20, T20.6, T21-22, or N22.7-23.5 abolished a large proportion of the binding of antibody to sclerostin on the chip. In contrast, preincubation of the antibody with any one of the epitopes designated T19.2, N14.6 or N18.6 did not abolish the ability of the antibody to bind to 5 sclerostin. A second exemplary antibody with this binding profile (Fig. 17) is Ab-C. Antibody Ab-D therefore is exemplary and representative of a group of antibodies that bind to the epitopes T20, 120.6, T21-22, and N22.7-23.5, and have minimal detectable binding to epitopes T19.2, N14.6 and N18.6, as measured by the ability to block antibody binding to sclerostin. Antibodies having this characteristic binding pattern may or may 10 not share amino acid sequence in one or more regions of the antibody molecule. Antibody similarity is determined functionally such as by the ability to bind to sclerostin following preincubation with each of the epitopes described above. Antibodies that exhibit a binding pattern similar or identical to that of antibody Ab-D are included in the invention. By "similar to" is meant, for example, the antibody will exhibit binding to each of the polypeptides T20, 15 T20.6, T21-22 and N22.7-23.5 whereby this binding will specifically compete out at least 50% of the antibody's binding to sclerostin that would otherwise occur in the absence of preincubation with sclerostin or a sclerostin peptide. The antibody will also exhibit little or no detectable binding to polypeptides T19.2, N14.6 and N18.6, resulting in a reduction of 30% or less of the binding that would occur in the absence of preincubation with sclerostin or a 20 sclerostin peptide. For example, without being bound by a particular mechanism, the antibody binding pattern of Figure 18 suggests that the epitope space to which antibody Ab-D and other antibodies having the epitope binding pattern of Ab-D bind consists of a polypeptide comprising the cystine-knot region of sclerostin. 25 Thus, as disclosed herein and with reference to Figure 19B, an exemplary T20.6 epitope comprises four peptide chains attached via three separate disulfide bonds. Peptide chain SAKPVTELVC3SGQC4GPAR (SEQ ID NO:3) is attached to peptide chain LVASC7KC8KRLTR (SEQ ID NO:5) by disulfide bonds from C3 to C7, and from C4 to C8. Peptide chain DVSEYSC1RELHFTR (SEQ ID NO:2) is attached to peptide chain 30 WWRPSGPDFRC5IPDRYR (SEQ ID NO:4) by a disulfide bond from CI to C5. The polypeptides of SEQ ID NOs:3 and 5 remain associated with the polypeptides of SEQ ID NOs:2 and 4 through a steric construct whereby the Cl-CS bond crosses the plane of the C4-C8 and C3-C7 bonds and is located between them, as illustrated in Figure 19B. SEA 18v3911A 60117-n 113 WO 2006/119062 PCT/US2006/016345 As disclosed herein and with reference to Figure 21, an exemplary derivative epitope of T20.6 comprises four peptide chains attached via three separate disulfide bonds. Peptide chain SAKPVTELVC3SGQC4 (SEQ ID NO:70) is attached to peptide chain LVASC7KCS (SEQ ID NO:71) by disulfide bonds from C3 to C7, and from C4 to C8. Peptide 5 chain ClRELHFTR (SEQ ID NO:72) is attached to peptide chain CSPPRYR (SEQ IID NO:73) by a disulfide bond from C1 to C5. The polypeptides of SEQ ID NOs:70 and 71 remain associated with the polypeptides of SEQ ID NOs:72 and 73 through a steric construct whereby the C1-C5 bond crosses the plane of the C4-C8 and C3-C7 bonds and is located between them, as illustrated in Figure 21. 10 Antibody Ab-A is exemplary and representative of a second group of antibodies that have a characteristic binding pattern to human sclerostin peptides that is distinct from that obtained for antibodies Ab-C and Ab-D. Ab-A and the group of antibodies it represents bind to the N22.7-23.5 epitope and have minimal detectable binding to epitopes T19.2, T20, T20.6, T21-22, N14.6 or N18.6, as measured by the ability to block antibody binding to sclerostin (Fig 15 15). A second exemplary antibody with this binding profile (Fig. 16) is Ab-B. Antibodies having this characteristic binding pattern may or may not share amino acid sequence in one or more regions of the antibody molecule. Antibody similarity is determined functionally such as by the ability to bind to sclerostin following preincubation with each of the epitopes described above. Antibodies that exhibit a binding pattern similar or identical to that of antibody Ab-A are 20 included in the invention. By "similar to" is meant, for example, the antibody will exhibit binding to the N22.7-23.5 polypeptide whereby this binding will specifically compete out at least 50% of the antibody's binding to sclerostin that would otherwise occur in the absence of preincubation with sclerostin or a sclerostin peptide. The antibody will also exhibit little or no detectable binding to polypeptides T19.2, T20, T20.6,121-22, N14.6 and N18.6, resulting in a 25 reduction of 30% or less of the binding that would occur in the absence of preincubation with sclerostin or a sclerostin peptide. For example, without being bound by a particular mechanism, the antibody binding pattern of Figure 15 suggests that the epitope space to which antibody Ab-A and other antibodies having the epitope binding pattern of Ab-A bind consists of a polypeptide comprising 30 the Loop 2 region of sclerostin. Thus, as disclosed herein and with reference to Figure 19A, the Loop 2 region can be described as a linear peptide, but it acquires a tertiary structure when it is present in native sclerostin or a cystine-knot-containing portion of sclerostin in which the native disulfide bond structure is maintained. The linear or tertiary structure of the Loop 2 epitope can affect antibody binding thereto, as discussed in the Examples. A Loop 2 region can comprise SEA 180391v 60117-M 114 WO 2006/119062 PCT/US2006/016345 the following amino acid sequence: C4GPARLLPNAIGRGKWWRPSGPDFRC5 (SEQ ID NO:6). "C4" refers to a cysteine residue located at position 86 with reference to SEQ ID NO: 1. "C5" refers to a cysteine residue located at position 111 with reference to SEQ ID NO: 1. In native sclerostin protein, C4 is linked to a cysteine at position 144 (C8) by a disulfide bond, and 5 C5 is linked to a cysteine at position 57 (Cl) by a disulfide bond. Epitopes derived from the Loop 2 region include CGPARLLPNAIGRGKWWRPS (SEQ ID NO:63); GPARLLPNAIGRGKWWRPSG (SEQ ID NO:64); PARLLPNAIGRGKWWRPSGP (SEQ ID NO:65); ARLLPNAIGRCYKWWRPSGPD (SEQ ID NO:66); RLLPNAIGRGKWWRPSGPDF (SEQ ID NQ:67); LLPNAIGRGKWWPSGPDFR (SEQ ID NO:68); and 10 LPNAIGRGKWWRPSGPDFRC (SEQ IDNO:69) CROSS-BLOCKING ASSAYS The terms "cross-block", "cross-blocked" and "cross-blocking" are used 15 interchangeably herein to mean the ability of an antibody or other binding agent to interfere with the binding of other antibodies or binding agents to sclerostin. The extent to which an antibody or other binding agent is able to interfere with the binding of another to sclerostin, and therefore whether it. can be said to cross-block according to the invention, can be determined using competition binding assays. One particularly suitable 20 quantitative assay uses a Biacore machine which can measure the extent of interactions using surface plasmon resonance technology. Another suitable quantitative cross-blocking assay uses an ELISA-based approach to measure competition between antibodies or other binding agents in terms of their binding to sclerostin. 25 BIACORE CROSS-BLOCKING ASSAY The following generally describes a suitable Biacore assay for determining whether an antibody or other binding agent cross-blocks or is capable of cross-blocking according to the invention. For convenience reference is made to two antibodies, but it will be appreciated that the assay can be used with any of the sclerostin binding agents described herein. 30 The Biacore machine (for example the Biacore 3000) is operated in line with the manufacturer's recommendations. Thus in one cross-blocking assay, sclerostin is coupled to a CM5 Biacore chip using standard amine coupling chemistry to generate a sclerostin-coated surface. Typically 200 800 resonance units of sclerostin would be coupled to the chip (an amount that gives easily SEA 180391 lvI 60117-223 115 WO 2006/119062 PCT/US2006/016345 measurable levels of binding but that is readily saturable by the concentrations of test reagent being used). The two antibodies (termed A* and B*) to be assessed for their ability to cross block each other are mixed at a one to one molar ratio of binding sites in a suitable buffer to 5 create the test mixture.. When calculating the concentrations on a binding site basis the molecular weight of an antibody is assumed to be the total molecular weight of the antibody divided by the number of sclerostin binding sites on that antibody. The concentration of each antibody in the test mix should be high enough to readily saturate the binding sites for that antibody on the sclerostin molecules captured on the 10 Biacore chip. The antibodies in the mixture are at the same molar concentration (on a binding basis) and that concentration would typically be between 1.00 and 1.5 micromolar (on a binding site basis). Separate solutions containing antibody A* alone and antibody B* alone are also prepared. Antibody A* and antibody B* in these solutions should be in the same buffer and at 15 the same concentration as in the test mix. The test mixture is passed over the sclerostin-coated Biacore chip and the total amount of binding recorded. The chip is then treated in such a way as to remove the bound antibodies without damaging the chip-bound sclergstin. Typically this is done by treating the chip with 30 mM HCl for 60 seconds. 20 The solution of antibody A* alone is then passed over the sclerostin-coated surface and the amount of binding recorded. The chip is again treated to remove all of the bound antibody without damaging the chip-bound sclerostin. The solution of antibody B* alone is then passed over the sclerostin-coated surface and the amount of binding recorded. 25 The maximum theoretical binding of the mixture of antibody A* and antibody B* is next calculated, and is the sum of the binding of each antibody when passed over the sclerostin surface alone. If the actual recorded binding of the mixture is less than this theoretical maximum then the two antibodies are cross-blocking each other. Thus, in general, a cross-blocking antibody or other binding agent according to 30 the invention is one which will bind to sclerostin in the above Biacore cross-blocking assay such that during the assay and in the presence of a second antibody or other binding agent of the invention the recorded binding is between 80% and 0.1% (e.g. 80% to 4%) of the maximum theoretical binding, specifically between 75% and 0.1% (e.g. 75% to 4%) of the maximum theoretical binding, and more specifically between 70% and 0.1% (e.g. 70% to 4%) of maximum SEA 1803911v 60117-223 116 WO 2006/119062 PCT/US2006/016345 theoretical binding (as just defined above) of the two antibodies or binding agents in combination. The Biacore assay described above is a primary assay used to determine if antibodies or other binding agents cross-block each other according to the invention. On rare 5 occasions particular antibodies or other binding agents may not bind to sclerostin coupled via amine chemistry to a CM5 Biacore chip (this usually occurs when the relevant binding site on sclerostin is masked or destroyed by the coupling to the chip). In such cases cross-blocking can be determined using a tagged version of Sclerostin, for example N-terminal His-tagged Sclergstin (R & D Systems, Minneapolis, MN, USA; 2005 cat# 1406-ST-025). In this particular 10 format, an anti-His antibody would be coupled to the Biacore chip and then the His-tagged Sclerostin would be passed over the surface of the chip and captured by the anti-His antibody. The cross blocking analysis would be carried out essentially as described above, except that after each chip regeneration cycle, new His-tagged sclerostin would be loaded back onto the anti-His antibody coated surface. In addition to the example given using N-terminal His-tagged 15 Sclerostin, C-terminal His-tagged sclerostin could alternatively be used. Furthermore, various other tags and tag binding protein combinations that are known in the art could be used for such a cross-blocking analysis (e.g. HA tag with anti-HA antibodies; FLAG tag with anti-FLAG antibodies; biotin tag with streptavidin). 20 ELISA-BASED CROSS-BLOCKING ASSAY The following generally describes an ELISA assay for determining whether an anti-sclerostin antibody or other sclerostin binding agent cross-blocks or is capable of cross blocking according to the invention. For convenience, reference is made to two antibodies (Ab 25 X and Ab-Y), but it will be appreciated that the assay can be used with any of the sclerostin binding agents described herein. The general principal of the assay is to have an anti-sclerostin antibody coated onto the wells of an ELISA plate. An excess amount of a second, potentially cross-blocking, anti-sclerostin antibody is added in solution (i.e. not bound to the ELISA plate). A limited 30 amount of sclerostin is then added to the wells. The coated antibody and the antibody in solution compete for binding of the limited number of sclerostin molecules. The plate is washed to remove sclerostin that has not been bound by the coated antibody and to also remove the second, solution phase antibody as well as any complexes formed between the second, solution phase antibody and sclerostin. The amount of bound sclerostin is then measured using an SEA Mn3911 60117-rn 117 WO 2006/119062 PCT/US2006/016345 appropriate sclerostin detection reagent. An antibody in solution that is able to cross-block the coated antibody will be able to cause a decrease in the number of sclerostin molecules that the coated antibody can bind relative to the number of sclerostin molecules that the coated antibody can bind in the absence of the second, solution phase, antibody. 5 This assay is described in more detail further below for Ab-X and Ab-Y. In the instance where Ab-X is chosen to be the immobilized antibody, it is coated onto the wells of the ELISA plate, after which the plates are blocked with a suitable blocking solution to minimize non-specific binding of reagents that are subsequently added. An excess amount of Ab-Y is then added to the ELISA plate such that the moles of Ab-Y sclerostin binding sites per well are 1 Q at least 10 fold higher than the moles of Ab-X sclerostin binding sites that were used, per well, during the coating of the ELISA plate. Sclerostin is then added such that the moles of sclerostin added per well are at least 25-fold lower than the moles of Ab-X sclerostin binding sites that were used for coating each well. Following a suitable incubation period the ELISA plate is washed and a sclerostin detection reagent is added to measure the amount of sclerostin 15 specifically bound by the coated anti-sclerostin antibody (in this case Ab-X). The background signal for the assay is defined as the signal obtained in wells with the coated antibody (in this case Ab-X), second solution phase antibody (in this case Ab-Y), sclerostin buffer only (i.e. no sclerostin) and sclerostin detection reagents. The positive control signal for the assay is defined as the signal obtained in wells with the coated antibody (in this case Ab-X), second solution 20 phase antibody buffer only (i.e. no second solution phase antibody), sclerostin and sclerostin detection reagents. The ELISA assay needs to be run in such a manner so as to have the positive control signal be at least 6 times the background signal. To avoid any artifacts (e.g. significantly different affinities between Ab-X and Ab-Y for sclerostin) resulting from the choice of which antibody to use as the coating antibody 25 and which to use as the second (competitor) antibody, the cross-blocking assay needs to be run in two formats: 1) format 1 is where Ab-X is the antibody that is coated onto the ELISA plate and Ab-Y is the competitor antibody that is in solution 30 and 2) format 2 is where Ab-Y is the antibody that is coated onto the ELISA plate and Ab-X is the competitor antibody that is in solution. SEA 1803911vl 60117-223 118 WO 2006/119062 PCTIUS2006/016345 Ab-X and Ab-Y are defined as cross-blocking if, either in format 1 or in format 2, the solution phase anti-sclerostin antibody is able to cause a reduction of between 60% and 100%, specifically between 70% and 100%, and more specifically between 80% and 100%, of the sclerostin detection signal (i.e. the amount of sclerostin bound by the coated antibody) as 5 compared to the sclerostin detection signal obtained in the absence of the solution phase anti sclerostin antibody (i.e. the positive control wells). An example of such an ELISA-based cross blocking assay can be found in Example 7 ("ELISA-based cross-blocking assay"). 10 CELL BASED NEUTRALIZATION ASSAY Mineralization by osteoblast-lineage cells in culture, either primary cells or cell lines, is used as an in vitro model of bone formation. Mineralization takes from about one to six weeks to occur beginning with the induction of osteoblast-lineage cell differentiation by one or 15 more differentiation agents. The overall sequence of events involves cell proliferation, differentiation, extracellular matrix production, matrix maturation and finally deposition of mineral, which refers to crystallization and/or deposition of calcium phosphate. This sequence of events starting with cell proliferation and differentiation, and ending with deposition of mineral is referred to herein as mineralization. Measurement of calcium (mineral) is the output 20 of the assay. MC3T3-El cells (Sudo H, Kodama H-A, Amagai Y, Yamamoto S, Kasai S. 1983. In vitro differentiation and calcification in a new clonal osteogenic cell line derived from newborn mouse calvaria. J. Cell Biol. 96:191-198) and subclones of the original cell line can form mineral in culture upon growth in the presence of differentiating agents. Such subclones 25 include MC3T3-E1-BF (Smith E, Redman R, Logg C, Coetzee G, Kasahara N, Frenkel 13. 2000. Glucocorticoids inhibit developmental stage-specific osteoblast cell cycle. J. Biol. Chem. 275:19992-20001). For both the MC3T3-El-BF subclone as well as the original MC3T3-El cells, sclerostin can inhibit one or more of the sequence of events leading up to and including mineral deposition (i e. sclerostin inhibits mineralization). Anti-sclerostin antibodies that are 30 able to neutralize sclerostin's inhibitory activity allow for mineralization of the culture in the presence of sclerostin such that there is a statistically significant increase in deposition of calcium phosphate (measured as calcium) as compared to the amount of calcium measured in the sclerostin-only (i.e. no antibody) treatment group. The antibodies used in the cell based mineralization assay experiments shown in Figures 22, 23 and 24 have molecular weights of 35 about 145 Kd and have 2 sclerostin binding sites per antibody molecule. SEA 180391vl 60117-2Z 119 WO 2006/119062 PCT/US2006/016345 When running the assay with the goal of determining whether a particular anti sclerostin antibody or anti-sclerostin binding agent can neutralize sclerostin (I.e., is a sclerostin neutralizing antibody or derivative thereof, or is a sclerostin neutralizing binding agent), the amount of sclerostin used in the assay needs to be the minimum amount of sclerostin that causes 5 at least a 70%, statistically significant, reduction in deposition of calcium phosphate (measured as calcium) in the sclerostin-only group, as compared to the amount of calcium measured in the no sclerostin group. An anti-sclerostin neutralizing antibody or an anti-sclerostin neutralizing binding agent is defined as one that causes a statistically significant increase in deposition of calcium phosphate (measured as calcium) as compared to the amount of calcium measured in the 10 sclerostin-only (i.e. no antibody, no binding agent) treatment group. To determine whether an anti-sclerostin antibody or an anti-sclerostin binding agent is neutralizing or not, the amount of anti-sclerostin antibody or anti-sclerostin binding agent used in the assay needs to be such that there is an excess of moles of sclerostin binding sites per well as compared to the number of moles of sclerostin per well. Depending on the potency of the antibody, the fold excess that may 15 be required can be 24, 18, 12, 6, 3, or 1.5, and one of skill is familiar with the routine practice of testing more than one concentration of binding agent. For example, a very potent anti-sclerostin neutralizing antibody or anti-sclerostin neutralizing binding agent will be able to neutralize sclerostin even when there is less than a 6-fold excess of moles of sclerostin binding sites per well as compared to the number of moles of sclerostin per well. A less potent anti-sclerostin 20 neutralizing antibody or anti-sclerostin neutralizing binding agent will be able to neutralize sclerostin only at a 12, 18 or 24 fold excess. Sclerostin binding agents within this full range of potencies are suitable as neutralizing sclerostin binding agents. Exemplary cell based mineralization assays are described in detail in Example 8. Anti-sclerostin antibodies and derivatives thereof that can neutralize human 25 sclerostin, and sclerostin binding agents that can neutralize human sclerostin may be of use in the treatment of human conditions/disorders that are caused by, associated with, or result in at least one of low bone formation, low bone mineral density, low bone mineral content, low bone mass, low bone quality and low bone strength. 30 RN VIVO NEUTRALIZATION ASSAY Increases in various parameters associated with, or that result from, the stimulation of new bone formation can be measured as an output from in vivo testing of sclerostin binding agents in order to identify those binding agents that are able to neutralize sclerostin and thus able to cause stimulation of new bone formation. Such parameters include SEA 1803911vI 60117.223 120 WO 2006/119062 PCT/US2006/016345 various serum anabolic markers [e.g. osteocalcin, PlNP (n-terminal propeptide of type 1 procollagen)], histomorphometric markers of bone formation (e.g. osteoblast surface/bone surface; bone formation rate/bone surface; trabecular thickness), bone mineral density, bone mineral content, bone mass, bone quality and bone strength. A sclerostin neutralizing binding 5 agent is defined as one capable of causing a statistically significant increase, as compared to vehicle treated animals, in any parameter associated with, or that results from, the stimulation of new bone formation. Such in vivo testing can be performed in any suitable mammal (e.g. mouse, rat, monkey). An example of such in vivo testing can be found in Example 5 ("In vivo testing of anti-sclerostin monoclonal antibodies"). 10 Although the amino acid sequence of sclerostin is not 100% identical across mammalian species (e.g. mouse sclerostin is not 100% identical to human sclerostin), it will be appreciated by one skilled in the art that a sclerostin binding agent that can neutralize, in vivo, the sclerostin of a certain species (e.g. mouse) and that also can bind human sclerostin in vitro is very likely to be able to neutralize human sclerostin in vivo. Thus, such a human sclerostin 15 binding agent (e.g. anti-human sclerostin antibody) may be of use in the treatment of human conditions/disorders that are caused by, associated with, or result in at least one of low bone formation, low bone mineral density, low bone mineral content, low bone mass, low bone quality and low bone strength. Mice in which homologous recombination had been used to delete the mouse sclerostin gene and insert the human sclerostin gene in its place (i.e. human 20 sclerostin gene knock-in mice or human SOST knock-in mice) would be an example of an additional in vivo system. Pharmaceutical compositions are provided, comprising one of the above-described binding agents such as at least one of antibody Ab-A, Ab-B, Ab-C, Ab-D and Ab- I toAb-24 to human sclerostin, along with a pharmaceutically or physiologically acceptable 25 carrier, excipient, or diluent. Pharmaceutical compositions and methods of treatment are disclosed in copending Application Serial No. 10/868,497, filed June 16, 2004, which claims priority to Serial No. 60/478,977, both of which are incorporated by reference herein. The development of suitable dosing and treatment regimens for using the 30 particular compositions described herein in a variety of treatment regimens, including e.g., subcutaneous, oral, parenteral, intravenous, intranasal, and intramuscular administration and formulation, is well known in the art, some of which are briefly discussed below for general purposes of illustration. SEA 180391 Iv 60117-223 121 WO 2006/119062 PCT/US2006/016345 In certain applications, the pharmaceutical compositions disclosed herein may be delivered via oral administration to an animal. As such, these compositions may be formulated with an inert diluent or with an assimilable edible carrier, or they may be enclosed in hard- or soft-shell gelatin capsule, or they may be compressed into tablets, or they may be incorporated 5 directly with the food of the diet. In certain circumstances it will be desirable to deliver the pharmaceutical compositions disclosed herein subcutaneously, parenterally, intravenously, intramuscularly, or even intraperitoneally. Such approaches are well known to the skilled artisan, some of which are further described, for example, in U.S. Patent No. 5,543,158; U.S. Patent No. 5,641,515 and 10 U.S. Patent No. 5,399,363. In certain embodiments, solutions of the active compounds as free base or pharmacologically acceptable salts may be prepared in water suitably mixed with a surfactant, such as hydroxypropylcellulose. Dispersions may also be prepared in glycerol, liquid polyethylene glycols, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations generally will contain a preservative to prevent the growth of 15 microorganisms. Illustrative pharmaceutical forms suitable for injectable use include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersions (for example, see U.S. Patent No. 5,466,468). In all cases the form must be sterile and must be fluid to the extent that easy syringability exists. It 20 must be stable under the conditions of manufacture and storage and must be preserved against the contaminating action of microorganisms, such as bacteria and fungi. The carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (e.g., glycerol, propylene glycol, and liquid polyethylene glycol, and the like), suitable mixtures thereof, and/or vegetable oils. Proper fluidity may be maintained, for example, by the use of a coating, such as 25 lecithin, by the maintenance of the required particle size in the case of dispersion and/or by the use of surfactants. The prevention of the action of microorganisms can be facilitated by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like. In many cases, it will be preferable to include isotonic agents, for example, sugars or sodium chloride. Prolonged absorption of the injectable compositions can be 30 brought about by the use in the compositions of agents delaying absorption, for example, aluminum monostearate and gelatin. In one embodiment, for parenteral administration in an aqueous solution, the solution should be suitably buffered if necessary and the liquid diluent first rendered isotonic SEA 1803911vl 60117-223 122 WO 2006/119062 PCT/US2006/016345 with sufficient saline or glucose. These particular aqueous solutions are especially suitable for intravenous, intramuscular, subcutaneous and intraperitoneal administration. In this connection, a sterile aqueous medium that can be employed will be known to those of skill in the art in light of the present disclosure. For example, one dosage may be dissolved in I ml of isotonic NaCl 5 solution and either added to 1000 ml of hypodermoclysis fluid or injected at the proposed site of infusion, (see for example, Remington's Pharmaceutical Sciences, 15th ed., pp. 1035-1038 and 1570-1580). Some variation in dosage will necessarily occur depending on the condition of the subject being treated. Moreover, for human administration, preparations will of course preferably meet sterility, pyrogenicity, and the general safety and purity standards as required by 10 FDA Office of Biologics standards. In another embodiment of the invention, the compositions disclosed herein may be formulated in a neutral or salt form. Illustrative pharmaceutically-acceptable salts include the acid addition salts (formed with the free amino groups of the protein) and which are formed with inorganic acids such as, for example, hydrochloric or phosphoric acids, or such organic acids as 15 acetic, oxalic, tartaric, mandelic, and the like. Salts formed with the free carboxyl groups can also be derived from inorganic bases such as, for example, sodium, potassium, ammonium, calcium, or ferric hydroxides, and such organic bases as isopropylamine, trimethylamine, histidine, procaine and the like. Upon formulation, solutions will be administered in a manner compatible with the dosage formulation and in such amount as is therapeutically effective. 20 The carriers can further comprise any and all solvents, dispersion media, vehicles, coatings, diluents, antibacterial and antifungal agents, isotonic and absorption delaying agents, buffers, carrier solutions, suspensions, colloids, and the like. The use of such media and agents for pharmaceutical active substances is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, its use in the therapeutic 25 compositions is contemplated. Supplemennry active ingredients can also be incorporated into the compositions. The phrase "pharmaceutically-acceptable" refers to molecular entities and compositions that do not produce an allergic or similar untoward reaction when administered to a human. In certain embodiments, liposomes, nanocapsules, microparticles, lipid particles, 3 vesicles, and the like, are used for the introduction of the compositions of the present invention into suitable host cells/organisms. In particular, the compositions of the present invention may be formulated for delivery either encapsulated in a lipid particle, a liposome, a vesicle, a SEA 1803911vl 60117-223 123 WO 2006/119062 PCT/US2006/016345 nanosphere, or a nanoparticle or the like. Alternatively, compositions of the present invention can be bound, either covalently or non-covalently, to the surface of such carrier vehicles. The formation and use of liposome and liposome-like preparations as potential drug carriers is generally known to those of skill in the art (see for example, Lasic, Tends 5 Biotechnol. 16(7):307-21, 1998; Takakura, Nippon Rinsho 56(3):691-95, 1998; Chandran et al., Indian J. Exp. Biol. 35(8):801-09, 1997; Margalit, Crit. Rev. Ther. Drug Carrier Syst. 12(2 3):233-61, 1995; U.S. Patent No. 5,567,434; U.S. Patent No. 5,552,157; U.S. Patent No. 5,565,213; U.S. Patent No. 5,738,868 and U.S. Patent No. 5,795,587, each specifically incorporated herein by reference in its entirety). The use of liposomes does not appear to be 10 associated with autoimmune responses or unacceptable toxicity after systemic delivery. In certain embodiments, liposomes are formed from phospholipids that are dispersed in an aqueous medium and spontaneously form multilamellar concentric bilayer vesicles (also termed multilamellar vesicles (MLVs)). Alternatively, in other embodiments, the invention provides for 15 pharmaceutically-acceptable nanocapsule formulations of the compositions of the present invention. Nanocapsules can generally entrap compounds in a stable and reproducible way (see, for example, Quintanar-Guerrero et al., Drug Dev. Ind Pharm. 24(12):1113-28, 1998). To avoid side effects due to intracellular polymeric overloading, such ultrafine particles (sized around 0.1pm) may be designed using polymers able to be degraded in vivo. Such particles can 20 be made as described, for example, by Couvreur et al., Crit. Rev. Ther. Drug Carrier Syst. 5(1):1-20, 1988; zur Muhlen et al., Eur. J. Pharm. Biopharm. 45(2):149-55, 1998; Zambaux et al., J Controlled Release 50(1-3):31-40, 1998; and U.S. Patent No. 5,145,684. In addition, pharmaceutical compositions of the present invention may be placed within containers, along with packaging material that provides instructions regarding the use of 25 such pharmaceutical compositions. Generally, such instructions will include a tangible expression describing the reagent concentration, as well as within certain embodiments, relative amounts of excipient ingredients or diluents (e.g, water, saline or PBS) that may be necessary to reconstitute the pharmaceutical composition. 30 The dose administered may range from 0.01 mg/kg to 100 mg/kg of body weight. As will be evident to one of skill in the art, the amount and frequency of administration will depend, of course, on such factors as the nature and severity of the indication being treated, the SEA 180391My 60117-23 124 WO 2006/119062 PCT/US2006/016345 desired response, the condition of the patient, and so forth. Typically, the compositions may be administered by a variety of techniques, as noted above. Increases in bone mineral content and/or bone mineral density may be determined directly through the use of X-rays (e.g., Dual Energy X-ray Absorptometry or 5 "DEXA"), or by inference through the measurement of 1) markers of bone formation and/or osteoblast activity, such as, but not limited to, osteoblast specific alkaline phosphatase, osteocalcin, type 1 procollagen C' propeptide (PICP), total alkaline phosphatase (see Comier, Curr. Opin. in Rheu. 7:243(1995)) and serum procollagen 1 N-terminal propeptide (P1NP) and/or 2) markers of bone resorption and/or osteoclast activity including, but not limited to, 10 pyridinoline, deoxypryridinoline, N-telopeptide, urinary hydroxyproline, plasma tartrate resistant acid phosphatases, and galactosyl hydroxylysine; (see Comier, id), serum TRAP 5b (tartrate-resistant acid phosphatase isoform 5b) and serum cross-linked C-telopeptide (sCTXI). The amount of bone mass may also be calculated from body weights or by using other methods (see Guinness-Hey, Metab. Bone Dis. Relat. Res. 5:177-181, 1984).Animals and particular 15 animal models are used in the art for testing the effect of the compositions and methods of the invention on, for example, parameters of bone loss, bone resorption, bone formation, bone strength or bone mineralization that mimic conditions of human disease such as osteoporosis and osteopenias. Examples of such models include the ovariectomized rat model (Kalu, D.N., The ovariectomized rat model ofpostmenopausal bone loss. Bone and Mineral 15:175-192 (1991); 20 Frost, H.M. and Jee, W.S.S. On the rat model of human osteopenias and osteoporosis. Bone and Mineral 18:227-236 (1992); and Jee, W.S.S. and Yao, W., Overview: animal models of osteopenia and osteoporosis. J Musculoskel. Neuron. Interact. 1:193-207 (2001)). Particular conditions which may be treated by the compositions of the present invention include dysplasias, wherein growth or development of bone is abnormal and a wide 25 variety of causes of osteopenia, osteoporosis and bone loss. Representative examples of such conditions include achondroplasia, cleidocranial dysostosis, enchondromatosis, fibrous dysplasia, Gaucher's Disease, hypophosphatemic rickets, Marfan's syndrome, multiple hereditary exotoses, neurofibromatosis, osteogenesis imperfecta, osteopetrosis, osteopoikilosis, sclerotic lesions, pseudoarthrosis, and pyogenic osteomyelitis, periodontal disease, anti-epileptic 30 drug induced bone loss, primary and secondary hyperparathyroidism, familial hyperparathyroidism syndromes, weightlessness induced bone loss, osteoporosis in men, postmenopausal bone loss, osteoarthritis, renal osteodystrophy, infiltrative disorders of bone, oral bone loss, osteonecrosis of the jaw, juvenile Paget's disease, melorheostosis, metabolic bone diseases, mastocytosis, sickle cell anemia/disease, organ transplant related bone loss, SEA 180391 lv 60117-23 125 WO 2006/119062 PCT/US2006/016345 kidney transplant related bone loss, systemic lupus erythematosus, ankylosing spondylitis, epilepsy, juvenile arthritides, thalassemia, mucopolysaccharidoses, fabry disease, turner syndrome, Down Syndrome, Klinefelter Syndrome, leprosy, Perthes'Disease, adolescent idiopathic scoliosis, infantile onset multi-system inflammatory disease, Winchester Syndrome, 5 Menkes Disease, Wilson's Disease, ischemic bone disease (such as Legg-Calve-Perthes disease, regional migratory osteoporosis), anemic states, conditions caused by steroids, glucocorticoid induced bone loss, heparin-induced bone loss, bone marrow disorders, scurvy, malnutrition, calcium deficiency, idiopathic osteopenia or osteoporosis, congenital osteopenia or osteoporosis, alcoholism, chronic liver disease, postmenopausal state, chronic inflammatory conditions, 10 rheumatoid arthritis, inflammatory bowel disease, ulcerative colitis, inflammatory colitis, Crohn's disease, oligomenorrhea, amenorrhea, pregnancy, diabetes mellitus, hyperthyroidism, thyroid disorders, parathyroid disorders, Cushing's disease, acromegaly, hypogonadism, immobilization or disuse, reflex sympathetic dystrophy syndrome, regional osteoporosis, osteomalacia, bone loss associated with joint replacement, HIV associated bone loss, bone loss 15 associated with loss of growth hormone, bone loss associated with cystic fibrosis, fibrous dysplasia, chemotherapy associated bone loss, tumor induced bone loss, cancer-related bone loss, hormone ablative bone loss, multiple myeloma, drug-induced bone loss, anorexia nervosa, disease associated facial bone loss, disease associated cranial bone loss, disease associated bone loss of the jaw, disease associated bone loss of the skull, and bone loss associated with space 20 travel. Further conditions relate to bone loss associated with aging, including facial bone loss associated with aging, cranial bone loss associated with aging, jaw bone loss associated with aging, and skull bone loss associated with aging. Compositions of the present invention may also be useful for improving outcomes in orthopedic procedures, dental procedures, implant surgery, joint replacement, bone 25 grafting, bone cosmetic surgery and bone repair such as fracture healing, nonunion healing, delayed union healing and facial reconstruction. One or more compositions may be administered before, during and/or after the procedure, replacement, graft, surgery or repair. The invention also provides a diagnostic kit comprising at least one anti sclerostin binding agent according to the present invention. The binding agent may be an 30 antibody. In addition, such a kit may optionally comprise one or more of the following: (1) instructions for using the one or more binding agent(s) for screening, diagnosis, prognosis, therapeutic monitoring or any combination of these applications; SEA 8Mo9v1 60117-2 126 WO 2006/119062 PCTIUS2006/016345 4) a iaoeiea omding partner to the anti-sclerostin binding agent(s); (3) a solid phase (such as a reagent strip) upon which the anti-sclerostin binding agent(s) is immobilized; and (4) a label or insert indicating regulatory approval for screening, diagnostic, 5 prognostic or therapeutic use or any combination thereof. If no labeled binding partner to the binding agent(s) is provided, the binding agent(s) itself can be labeled with one or more of a detectable marker(s), e.g. a chemiluminescent, enzymatic, fluorescent, or radioactive moiety. The following examples are offered by way of illustration, and not by way of 10 limitation. EXAMPLES EXAMPLE I Recombinant Expression of Sclerostin 15 Recombinant human sclerostin/SOST is commercially available from R&D Systems (Minneapolis, MN, USA; 2006 cat# 1406-ST-025). Additionally, recombinant mouse sclerostin/SOST is commercially available from R&D Systems (Minneapolis, MN, USA; 2006 cat# 1589-ST-025). Alternatively, the different species of sclerostin can be expressed transiently in 20 serum-free suspension adapted 293T or 293EBNA cells. Transfections can be performed as 500 mL or IL cultures. The following reagents and materials are available from Gibco BRL (now Invitrogen, Carlsbad, CA). Catalog numbers are listed in parentheses: serum-free DMEM (21068-028); DMEM/F12 (3:1) (21068/11765); IX Insulin-Transferrin-Selenium Supplement (51500-056); IX Pen Strep Glut (10378-016); 2mM l-Qlutamine (25030-081); 20 mM HEPES 25 (15630-080); 0.01% Pluronic F68 (24040-032). Briefly, the cell inoculum (5.0-10.0 X 105 cells/mL X culture volume) is centrifuged at 2,500 RPM for 10 minutes at 4*C to remove the conditioned medium. The cells are resuspended in serum-free DMEM and centrifuged again at 2,500 RPM for 10 minutes at 4*C. After aspirating the wash solution, the cells are resuspended in 30 growth medium [DMEM/F12 (3:1) + IX Insulin-Transferrin-Selenium Supplement + 1X Pen Strep Glut + 2mM L-Glutamine +20 mM HEPES + 0.01% Pluronic F68] in a 1L or 3L spinner flask culture. The spinner flask culture is maintained on magnetic stir plate at 125 RPM which is placed in a humidified incubator maintained at 37*C and 5% C0 2 . The mammalian SEA 1803911v 60117-223 127 WO 2006/119062 PCT/US2006/016345 expression plasmid DNA (e.g. pcDNA3.1, pCEP4, Invitrogen Life Technologies, Carlsbad, CA), containing the complete coding region (and stop codon) of sclerostin with a Kozak consensus sequence (e.g., CCACC) directly 5' of the start site ATG, is complexed to the transfection reagent in a 50 mL conical tube. 5 The DNA-transfection reagent complex can be prepared in 5-10% of the final culture volume in serum-free DMEM or OPTI-MEM. The transfection reagents that can be used for this purpose include X-tremeGene RO- 1539 (Roche Applied Science, Indianapolis, IN), FuGene6 (Roche Applied Science, Indianapolis, IN ), Lipofectamine 2000 (Invitrogen, Carlsbad, CA) and 293fectin (Invitrogen, Carlsbad, CA). 1-5 pg plasmid DNA/mL culture is 10 first added to serum-free DMEM, followed by 1-5 sl transfection reagent/mL culture. The complexes can be incubated at room temperature for approximately 10-30 minutes and then added to the cells in the spinner flask. The transfection/expression can be performed for 4-7 days, after which the conditioned medium (CM) is harvested by centrifugation at 4,000 RPM for 60 minutes at 4C. 15 EXAMPLE 2 PURIFICATION OF RECOMBINANT SCLEROSTIN Recombinant sclerostin was purified from mammalian host cells as follows. All 20 purification processes were carried out at room temperature. One purification scheme was used to purify various species of sclerostin, including murine and human sclerostin. The purification scheme used affinity chromatography followed by cation exchange chromatography. Heparin Chromatography 25 The mammalian host cell conditioned medium (CM) was centrifuged in a Beckman J6-M1 centrifuge at 4000 rpm for hour at 4*C to remove cell debris. The CM supernatant was then filtered through a sterile 0.2 pm filter. (At this point the sterile filtered CM may be optionally stored frozen until purification.) If the CM was frozen, it was thawed at the following temperatures, or combination thereof: 4*C, room temperature or warm water. 30 Following thawing the CM was filtered through a sterile 0.2 pm filter and optionally concentrated by tangential flow ultrafiltration (1FF) using a 10 kD molecular weight cut-off membrane. The CM concentrate was filtered through a sterile 0.2 pm filter and then loaded onto a Heparin High Performance (Heparin HP) column (GE Healthcare, formerly Amersham SEA 180391 lvI 60117-.3 128 WO 2006/119062 PCTIUS2006/016345 Biosciences) equilibrated in PBS. Alternatively, the filtered CM supernatant may be loaded directly onto the Heparin HP column equilibrated in PBS. After loading, the Heparin HP column was washed with PBS until the absorbance at 280 nm of the flow-through returned to baseline (i.e., absorbance measured before loading 5 QM supernatant). The sclerostin was then eluted from the column using a linear gradient from 150 mM to 2M sodium chloride in PBS. The absorbance at 280 nm of the eluate was monitored and fractions containing protein were collected. The fractions were then assayed by Coomassie stained SDS-PAGE to identify fractions containing a polypeptide that migrates at the size of glycosylated sclerostin. The appropriate fractions from the column were combined to make the 10 Heparin HP pool. Cation Exchange Chromatography The sclerostin eluted from the Heparin HP column was further purified by cation exchange chromatography using SP High Performance (SPHP) chromatography media (GE 15 Healthcare, formerly Amersham Biosciences). The Heparin HP pool was buffer exchanged into PBS by dialysis using 10,000 MWCO membranes (Pierce Slide-A-Lyzer). The dialyzed Heparin HP pool was then loaded onto an SPHP column equilibrated in PBS. After loading, the column was washed with PBS until the absorbance at 280 nm of the flow-through returned to baseline. The sclerostin was then eluted from the SPHP column using a linear gradient from 150 20 mM to 1 M sodium chloride in PBS. The absorbance at 280 nm of the eluate was monitored and the eluted sclerostin was collected in fractions. The fractions were then assayed by Coomassie stained SDS-PAGE to identify fractions containing a polypeptide that migrates at the size of glycosylated sclerostin. The appropriate fractions from the column were combined to make the SPHP pool. 25 Formulation Following purification, the SPHP pool was formulated in PBS by dialysis using 10,000 MWCQ membranes (Pierce Slide-A-Lyzer). If concentration of sclerostin was necessary, a centrifugal device (Amicon Centricon or Centriprep) with a 10,000 MWCO 30 membrane was used. Following formulation the sclerostin was filtered through a sterile 0.2 pm filter and stored at 4 0 C or frozen. EXAMPLE 3 35 PEPTE BINDING ELIsA SEA 1803911 y 60117-223 129 WO 2006/119062 PCT/US2006/016345 A series of overlapping peptides (each peptide being approximately 20-25 amino acids long) were synthesized based on the known amino acid sequence of rat sclerostin (SEQ ID NO:98). The peptides were designed such that they all contained a reduced cysteine residue; an 5 additional cysteine was included at the C-terminus of each peptide which did not already contain one in its sequence. This enabled the peptides to be bound to the assay plates by covalent coupling, using commercially available sulfhydryl binding plates (Costar), at a concentration of Ipg/ml, in phosphate buffered saline (PBS: pH 6.5) containing 1 mM EDTA. Following incubation for 1 hour at room temperature, the plates were washed three times with PBS 10 containing 0.5% Tween 20. The plates were blocked by incubation with a PBS solution containing 0.5% fish skin gelatin (Sigma) for 30 minutes at room temperature and then washed three times in PBS containing 0.5% Tween 20. Antibodies to be tested were diluted to lpg/ml in PBS containing 0.5% fish skin gelatin and incubated with the peptide-coated plates for 1 hour at room temperature. 15 Excess antibody was removed by three washes with PBS, 0.5% Tween 20. The plates were then incubated with an appropriate secondary antibody conjugated to horseradish peroxidase (diluted appropriately in PBS containing 0.5% Tween 20) and capable of binding to the antibody of interest. The plates were then washed three times: once with PBS containing 0.5% Tween.20, and twice with PBS. Finally the plates were incubated with a horseradish peroxidase 20 chromogenic substrate (TMB-Stable Stop, RDI) for 5 minutes at room temperature, the color development was stopped with acid, and the plates' optical density measured at 450nm. Materials 25 Costar's Sulfhydryl Binding Plates (VWR # 29442-278) Coating Buffer: 1XPBS PH 6.5 + 1mM EDTA Blocking Buffer: IX PBS +0.5% Fish Skin Gelatin (PBS from CS; FSG from Sigma# G 7765) Wash Buffer: IX PBS + 0.5% Tween 20 30 Rat Sclerostin peptides Antibody Samples: Transient Ab, Purified recombinant Ab, rabbit Serum, etc. Appropriate secondary Ab: Goat-anti-Rabbit/Mouse-HRP (Jackson Immuno Research, 115 036-072) TMB-Stable Stop (RDI# RDI-TMBSX-1L) SEA 1803911vl 60117-23 130 WO 2006/119062 PCTIUS2006/016345 0.5M HCl Methods were as follows: 1. Coat plates with 1 00pl/well of rat sclerostin peptide diluted in 1XPBS PH 6.5 + 1mM 5 EDTA at 1 pjg/ml. Incubate plates 1 hour at room temperature. (Plates should be used within 30 minutes of opening). 2. Wash plates 3X with wash buffer. 3. Block plates with 200ul/well blocking buffer. Incubate plates 30 minutes at room temp. 4. Repeat washing as described in (2). 10 5. Incubate plates with 50ul/well of samples diluted in blocking buffer - Serum titers starting at 1:100; Transient Recombinant Ab use neat; Purified recombinant Ab use at Spjg/ml (all samples run in duplicates). Incubate plates lh at room temp. 6. Wash plates as described in (2). 7. Incubate plates with 50o/well of appropriate Secondary Antibody (HRP labeled) diluted 15 1:1600 in Blocking Buffer. Incubate plates 1 hour at room temperature. 8. Wash plates 1X wash buffer, 2x PBS 9. Incubate plates with 50W1/well of TMB, 5 minutes at room temp. 10. Stop reaction with 50sl/well 0.5M HCl. 11. Read plates at 450 nm wavelength. 20 The following peptides sequences were screened as described above: QGWQAFKNDATEIIPGLREYPEPP(SEQ ID NO:82) TEIIPGLREYPEPPQELENN (SEQ ID NO:83) PEPPQELENNQTMNRAENGG (SEQ ID NO:84) 25 ENGGRPPHHPYDTIKDVSEYS (SEQ ID NO:85) CRELHYTRFVTDGP (SEQ ID NO:86) CRELHYTRFVTDGPSRSAKPVTELV (SEQ ID NO:87) CRSAKPVTELVSSGQSGPRARLL (SEQ ID NO:88) CGPARLLPNAIGRVKWWRPNGPDFR (SEQ ID NO:89) 30 RAQRVQLLCPQGAAPRSRKV (SEQ ID NO:90) PGGAAPRSRKVRLVAS (SEQ ID NQ:91) KRLTRFHNQSELKDFGPETARPQ (SEQ ID NO:92) IPDRYAQRVQLLSP3G (SEQ ID NO:93) SELKDFGPETARPQKGRKPRPRAR (SEQ ID NO:94) SEA 180391v1 6017-223 131 WO 2006/119062 PCT/US2006/016345 KGRKPRPRARGAKANQAELENAY (SEQ ID NO:95) PNAIGRVKWWRPNGPDFR (SEQ ID NO:96) KWWRPNGPDFRCIPDRYRAQRV (SEQ ID NO:97). A high-affinity neutralizing antibody (Ab-19) bound to two 5 overlapping peptide sequences: PNAIGRVKWWRPNQPDFR (SEQ ID NO:96) and KWWRPNGPDFRCIPDRYRAQRV (SEQ ID NO:97). This procedure allows the recognition of epitopes for antibodies that react with apparent linear epitopes. Peptides that contain all or part of the antibody binding site will bind antibody and thus be detected. 10 EXAMPLE 4 IDENTIFICATION OF HUMAN SCLEROSTIN EPITOPES Sclerostin structure 15 Mature form (signal peptide removed) human sclerostin is a 190 amino acid protein (Figure 8). Figure 9 shows a schematic of the general structure of sclerostin with an N terminal arm (from the N-terminal Q to Cysteinel) and a C-terminal arm (from Cysteine8 to the terminal Y). Sandwiched in between these two arms there is the cystine-knot structure and three loops which are designated LoopI, Loop2 and Loop 3. The four disulfide bonds in sclerostin 20 are Cys1 at sequence position 57 linked to Cys5 at sequence position 111 (referred to as Cl-C5), Cys2 at sequence position 71 linked to Cys6 at sequence position 125 (referred to as C2-C6), Cys3 at sequence position 82 linked to Cys7 at sequence position 142 (referred to as C3-C7), Cys4 at sequence position 86 linked to Cys8 at sequence position 144 (referred to as C4-C8). The eight-membered ring structure is formed via C3-C7 and C4-C8 disulfide bonding. This ring 25 structure, together with the Cl-C5 disulfide bond penetrating through the ring, forms a typical cystine-knot. C2-C6, which is not part of the cystine-knot, brings two large loop structures, loop 1 (residues 57 to 82) and loop 3 (residues 111 to 142) close together. Loop 2 goes from C4 (residue 86) to C5 (residue 111). 30 Experimental The general approach for characterizing the epitopes bound by anti-sclerostin monoclonal antibodies involved fragmenting human Sclerostin into peptides with different proteases, determining the sequence of the various human sclerostin peptides, isolating these peptides and testing each of them for their ability to bind to a particular monoclonal antibody SEA 180391vl (0117-M 132 WO 2006/119062 PCT/US2006/016345 using a Biacore-based "human sclerostin peptide epitope competition binding assay.". The resulting data permitted the location of the binding epitope to be determined. The peptide digests were subjected to HPLC peptide mapping; the individual peaks were collected, and the peptides identified and mapped by matrix assisted laser desorption 5 mass spectrometry (MALDI-MS) and electrospray ionization LC-MS (ESI-LC-MS) analyses. and/or by N-terminal sequencing. All HPLC analyses for these studies were performed using a reverse-phase C8 column (2.1 mm i.d. x 15 cm length). HPLC peptide mapping was performed with a linear gradient from 0.05% trifloroacetic acid (mobile phase A) to 90% acetonitrile in 0.05% trifuoroacetic acid. Columns were developed over 50 minutes at a flow rate of 0.2 10 ml/min. Trypsin and AspN Endoproteinase Digestions Mature form human sclerostin was digested with trypsin, which cleaves after arginine and lysine, or with AspN. About 200 pg of sclerostin at 0.5-1.0 mg/ml was incubated 15 in PBS (pH 7.2) for 20 hrs at 37*C with 8 ig of either trypsin or AspN. Trypsin digestion HPLC chromatography ofithe trypsin digests yielded several major peaks (Fig. 1 OA). Sequence analysis was conducted on the peptide peaks recovered from HPLC after 20 trypsin digestion. On-line ESI LC-MS analysis of the peptide digest was also performed to determine the precise mass of the peptides that were separated by HPLC. The identity of the peptides present in the peptide peaks was thus determined (Fig. 11). Figure 13 shows the alignment of various peptide sequences (T19.2, T20, T20.6, T21-22) along the sclerostin sequence. The number following each T (e.g., T19.2) reflects the retention time. T19.2 contains 25 two peptides (one from loop 1 and one from loop 3) linked by the C2-C6 disulfide bond. T20 contains two peptides held together by the cystine-knot structure, with intact loops 1 and 3 held together by the C2-C6 disulfide and with most of loop 2 absent. T20.6 contains four sequences held together by the cystine-knot structure, but is missing part of loop 1 and 3 (the T19.2 part) and is missing most of loop 2. T21-22 is almost identical to T'20 but has 3 additional amino 30 acids in the loop 2 region. AspN Digaestion HPLC chromatography of the AspN digests yielded several major peaks (Fig. 1OB). Sequence analysis was conducted on the peptide peaks recovered from WLC. On SEA 1803911v 60117-223 133 WO 2006/119062 PCT/US2006/016345 line ESI LC-MS analysis of the peptide digest was also performed to determine the precise mass of the peptides that were separated by HPLC. The identity of the peptides present in the peptide peaks from the AspN digestion was thus determined (Fig. 12). Figure 14 shows the alignment of various peptide sequences (AspN14.6, AspN1 8.6, AspN22.7-23.5) along the sclerostin 5 sequence. The number following each AspN (e.g. AspNl 8.6) reflects the retention time. AspN14.6 contains three short peptides from both the N- and C-terminal arms of sclerostin, while AspN18.6 is a larger peptide from the N-terminal arm of sclerostin. AspN22.7-23.5 contains a single peptide fragment of 104 amino acids the encompasses all eight cysteines (the four disulfide bonds), the cystine-knot and all of loops 1, 2 and 3. 10 The strategy for characterizing the epitopes was to use these various trypsin and AspN generated human sclerostin peptides and determine which peptides could still be bound by the various Antibodies (Ab-A, Ab-B, Ab-C and Ab-D). Specifically this was tested in a Biacore-based "human sclerostin peptide epitope competition binding assay" where the binding of a particular monoclonal antibody to human sclerostin immobilized on the Biacore chip was 15 determine in the presence or absence of each of the various isolated trypsin and AspN HPLC peptide fractions. In the absence of any competing peptides, the particular monoclonal antibody was able to bind the human sclerostin on the chip and produce a resonance unit, RU, response. Preincubation of the particular monoclonal antibody with intact human sclerostin in solution, followed by testing of binding to the chip, demonstrated that the binding of the Mab to human 20 sclerostin in solution prevented the binding of the Mab to the human sclerostin on the chip, thus validating the general principal of this competition assay. This general procedure was repeated individually for each peptide. A robust RU response was taken to indicate that the particular peptide being tested could not bind the Mab in solution (hence the Mab was free to bind the human sclerostin that had been immobilized on the 25 chip). Conversely, the absence of a robust RU response indicated that the Mab was able to bind the sclerostin peptide in solution. These binding patterns, couple with the known identity of the various sclerostin peptides, were used to determine the epitopes of sclerostin that were bound by anti-sclerostin antibodies Ab-A, Ab-B, Ab-C and Ab-D. 30 BI3ACORE-BASED HUMAN SCLEROSTIN PEPTIDE EPITOPE COMPETITION BINDING ASSAY Preparation of human sclerostin surface: Immobilization of mature form human sclerostin to a BIAcore sensor chip (CM5) surface was performed according to manufacturer's instructions. Briefly, carboxyl groups on the SEA 180391v 60117-223 134 WO 2006/119062 PCT/US2006/016345 sensor chip surfaces were activated by injecting 60 pL of a mixture containing 0.2 M N-ethyl N'-(dimethylaminopropyl) carbodiimide (EDC) and 0.05 M N-hydroxysuccinimide (NHS). Human sclerostin was diluted in 10 mM sodium acetate, pH 4.0 at a concentration of 20 pg/mL followed by injecting over the activated CM5 surface. Excess reactive groups on the surfaces 5 were deactivated by injecting 60 pL of 1 M ethanolamine. Final immobilized levels were 5000 resonance units (RU) for the human sclerostin surface. A blank, mock-coupled reference surface was also prepared on the sensor chips. Binding specificity analysis: 10 1X Phosphate-buffered saline without calcium chloride or magnesium chloride was from Gibco/Invitrogen, Carlsbad, CA. Bovine serum albumin, fraction V, IgG-free was from Sigma-Aldrich, St. Louis, MO. Each Mab (2 nM) was separately incubated with 20 nM human sclerostin or a particular human sclerostin peptide (note: there are 3 unlinked peptides in AspN14.6) in sample buffer (1X PBS + 0.005% P-20 + 0.1 mg/mL BSA) before injection over 15 the immobilized human sclerostin surface. The flow rate for sample injection was 5 pLmin followed by surface regeneration using 1 M NaCl in 8 mM Glycine, pH 2.0 at 30 pL/min for 30 seconds. The data was analyzed using BlAevaluation 3.2, and is presented in Figure 15 (Ab-A), Figure 16 (Ab-B), Figure 17 (Ab-C) and Figure 18 (Ab-D). 20 Loop 2 and T20.6 epitopes: The sclerostin peptide binding pattern for two representative antibodies (Ab-A and Ab-B) were virtually identical (Fig. 15 and Fig. 16) and showed that both of these Antibodies could only bind the AspN22.7-23.5 peptide. The unique difference between AspN22.7-23.5 and all the other sclerostin peptides is that AspN22.7-23.5 contains an intact 25 loop 2. This shows that Ab-A and Ab-B bind the loop 2 region of sclerostin thus defining the loop 2 epitope (Fig. 19A). The sclerostin peptide binding pattern for Ab-C and Ab-D were virtually identical to each other (Fig. 17 and Fig. 18) but completely distinct from that found for Ab-A and Ab-B. Of the peptides tested in this Example, the most diminutive peptide that Ab-C and Ab-D could bind to was the T20.6 peptide. This result defines the T20.6 epitope (Fig. 19B). 30 Protease protection assay: The general principle of this assay is that binding of a Mab to sclerostin can result in protection of certain specific protease cleavage sites and this information can be used to determine the region of sclerostin to where the Mab binds. SEA 1803911vi 60117-M 135 WO 2006/119062 PCTIUS2006/016345 "T20.6 derivative 1 (cystine-knot +4 arms)" epitope: Figure 20 shows the HPLC peptide maps for a human sclerostin Ab-D complex (Fig 20A: human sclerostin was preincubated at a 1:1 molar ratio with Ab-D prior to digestion 5 with trypsin as described above) and human sclerostin alone (Fig 20B: human sclerostin was digested with trypsin as described above). The peptide peaks of T19.2 and T2Q.6 in Figure 20A showed a clear reduction in their respective peak height, as compared to Figure 20B. This reduction in peak heights was accompanied by an increase in peak height for peptides 'I20 and T21-22. These data indicate that basic amino acid residues in loop I and loop 3, which in the 10 absence of Ab-D were cleaved by trypsin to generate peptides T19.2 and T20.6, were resistant to cleavage by trypsin when Ab-D was prebound to sclerostin. The presence of T20, T20.6 and T21-22 indicates that loop 2 was still cleaved efficiently when Ab-D was prebound to sclerostin. These data indicate that Ab-D bound on the loop 1 and loop 3 side of the T20.6 epitope thus defining the smaller "T20.6 derivative 1 (cystine-knot + 4 arms)" epitope shown in Figure 21. 15 ExAMPLE 5 IN VIVO TESTING OF ANTI-SCLEROSTIN MONOCLONAL ANTIBODIES IN MICE Four week-old BDF1 male mice were obtained from Charles River laboratories 20 (Raleigh, NC) and housed in clean caging, five animals per cage. Room temperature was maintained between 68 and 72*F, and relative humidity was maintained between 34 and 73%. The laboratory housing the cages had a 12-hour light/dark cycle and met all AAALAC specifications. Clinical observations of all mice on study occurred once daily. Purified anti-sclerostin monoclonal antibodies (Ab-A Fig. 1; Ab-B Fig.2; Ab-C 25 Fig.3; Ab-D Fig.4) were diluted in sterile Dulbecco's phosphate buffered saline. Mice were injected with anti-sclerostin Antibodies or PBS vehicle subcutaneously at 21 sI per gram body weight, two times per week (Monday and Thursday) at 25 mg/kg. Human PTH (1-34) was diluted in PTH buffer (0.001 N HCl, 0.15 M NaCl, 2% BSA), and dosed subcutaneously at 21 i per gram body weight five times per week (Monday, Tuesday, Wednesday, Thursday, Friday) at 30 100 pg/kg as a positive control (Figures 5 and 6). Number of mice per group was N=5 in Fig 5 and 6, and N=6 in Figure 7. PImus in vvo Bone Densitometry SEA 1803911Ivl 60117-2n 136 WO 2006/119062 PCT/US2006/016345 Bone mineral density (BMD) was determined weekly at the proximal tibial metaphysis and lumbar vertebrae by peripheral Dual Energy X-ray Absorptometry (pDEXA) with the PlXImus2 system from GE/Lunar Medical Systems, Madison, WI. A 25mm 2 region of interest (ROI) was placed to include the proximal articular surface, the epiphysis, and the 5 proximal end on the metaphysis of the tibia. A region of interest (ROI) was placed to include the lumbar vertebrae (L1-L5). The proximal tibia and lumbar regions were analyzed to determine total bone mineral density. Group means were reported i Standard Deviation and compared to the vehicle treatment group for statistical analysis. 10 Statistical analysis Statistical analysis was performed with a Dunnett's and Tukey-Kramer (using MS Excel and JMP v. 5.0. for the BMD data). Group means for each data set were considered significantly different when the P value was less than 0.05 (P < 0.05). 15 Sclerostin neutralizing activity of antibodies The statistically significant increases in BMD as compared to vehicle seen for each of Ab-A (Figure 5), Ab-B (Figure 5), Ab-C (Figure 6) and Ab-D (Figure 7) demonstrates that these four antibodies are sclerostin neutralizing antibodies. Furthermore this data shows that, for anti-sclerostin antibodies that bind mouse sclerostin, treatment and analysis of mice as 20 described above can be used to identify sclerostin neutralizing antibodies. EXAMPLE 6 SCREENING ASSAY FOR ANTIBODIES THAT LOCK BINDING OF AN ANTIBODY TO HUMAN SCLEROSTIN 25 Human sclerostin was coupled to a CM5 Biacore chip using standard amine coupling chemistry to generate a sclerostin coated surface. 300 resonance units of sclerostin were coupled to the surface. The antibodies to be tested were diluted to a concentration of 200ug/ml in HBS 30 EP buffer (being 10 mM HEPES pH 7.4, 150 mM NaCl, 3 mM EDTA, 0.005% (v/v) Surfactant P20) and then mixed in a one to one molar ratio (on a binding site basis) to generate the test mixture. This test mixture thus contained each antibody at a concentration of 100ug/ml (1.3um on a binding site basis). Separate solutions containing each of the antibodies in the test mix alone were also prepared. These solutions contained the individual antibodies in HBS-EP buffer 35 at a concentration of 100ug/ml (1.3um on a binding site basis). SEA 180391 vi 60117-223 137 WO 2006/119062 PCT/US2006/016345 20 pL of the test mixture was passed over the sclerostin-coated chip at a flow rate of 10 pLUmin and the amount of binding recorded. The chip was then treated with two 60 second pulses of 30 mM HCl to remove all of the bound antibody. A solution containing only one of the antibodies of the test mixture (at 1.3pM in the-same buffer as the test mixture on a 5 binding site basis) was then passed over the chip in the same manner as the test mixture and the amount of binding recorded. The chip was again treated to remove all of the bound antibody and finally a solution containing the other antibody from the test mixture alone (at 1.3pM in the same buffer as the test mixture on a binding site basis) was passed over the chip and the amount of binding recorded. 10 The table below show the results from cross-blocking assays on a range of different antibodies. The values in each square of the table represent the amount of binding (in RU) seen when the antibodies (at 1.3pM on a binding site basis) or buffer indicated in the top row of the table were mixed with the antibodies (at 1.3uM on a binding site basis) or buffer indicated in the first column of the table. 15 Buffer Ab-4 Ab-13 Ab-A Ab-3 Ab-19 Buffer -0.5 693 428.5 707.3 316.1 649.9 Ab.4 687.7 795.1 1018.2 860.5 869.3 822.5 Ab-13 425.6 1011.3 442.7 1108.4 431.9 1042.4 Ab-A 692.4 833.1 1080.4 738.5 946 868.1 AW- 365.5 845.1 428.2 952.2 344.4 895.7 Ab-19 618.1 788.6 1022.5 863.3 891.5 658.7 Using the mean binding value (in RU) for each combination of antibodies in the 20 above table (since each combination appears twice) it is possible to calculate the percentage of the theoretical binding shown by each combination of antibodies. The theoretical binding being calculated as the sum of the average values for the components of each test mixture when assayed alone (i.e., antibody and buffer). Buffer Ab-4 Ab-13 Ab-A Ab-3 Ab-19 Suffer b~4" _90.75 60.45 85.4 60.75 Ab-13 96.9 58.0 97.0 Ab-A 93.5 65.0 lb-3 194.4 Ab-19 25 From the above data it is clear that Ab-4, Ab-A and Ab-19 cross-block each SEA 1803911vI 60117-M3 138 WO 2006/119062 PCT/US2006/016345 other. Similarly Ab-13 and Ab-3 cross block each other. EXAMPLE 7 EUSA-BASED CROSS-BLOCKING ASSAY 5 Liquid volumes used in this example would be those typically used in 96-well plate EUSAs (e.g. 50-200 s1/well). Ab-X and Ab-Y, in this example are assumed to have molecular weights of about 145 Kd and to have 2 sclerostin binding sites per antibody molecule. An anti-sclerostin antibody (Ab-X) is coated (e.g. 50s of 1 pg/ml) onto a 96-well ELISA plate [e.g. Coming 96 Well EIA/RIA Flat Bottom Microplate (Product # 3590), Corning Inc., Acton, 10 MA] for at least one hour. After this coating step the antibody solution is removed, the plate is washed once or twice with wash solution (e.g., PBS and 0.05% Tween 20) and is then blocked using an appropriate blocking solution (e.g., PBS, 1% BSA, 1% goat serum and 0.5% Tween 20) and procedures known in the art. Blocking solution is then removed from the ELISA plate and a second anti-sclerostin antibody (Ab-Y), which is being tested for it's ability to cross-block the 15 coated antibody, is added in excess (e.g. 50pl of 10 pg/ml) in blocking solution to the appropriate wells of the ELISA plate. Following this, a limited amount (e.g. 5041 of 10 ng/ml) of sclerostin in blocking solution is then added to the appropriate wells and the plate is incubated for at least one hour at room temperature while shaking. The plate is then washed 2-4 times with wash solution. An appropriate amount of a sclerostin detection reagent [e.g., biotinylated anti 20 sclerostin polyclonal antibody that has been pre-complexed with an appropriate amount of a streptavidin-horseradish peroxidase (HRP) conjugate] in blocking solution is added to the ELISA plate and incubated for at least one hour at room temperature. The plate is then washed at least 4 times with wash solution and is developed with an appropriate reagent [e.g HRP substrates such as TMB colorimetricc) or various HRP luminescent substrates]. The background 25 signal for the assay is defined as the signal obtained in wells with the coated antibody (in this case Ab-X), second solution phase antibody (in this case Ab-Y), sclerostin buffer only (i.e. no sclerostin) and sclerostin detection reagents. The positive control signal for the assay is defined as the signal obtained in wells with the coated antibody (in this case Ab-X), second solution phase antibody buffer only (i.e. no second solution phase antibody), sclerostin and sclerostin 30 detection reagents. The ELISA assay needs to be run in such a manner so as to have the positive control signal be at least 6 times the background signal. To avoid any artifacts (e.g. significantly different affinities between Ab-X and Ab-Y for sclerostin) resulting from the choice of which antibody to use as the coating antibody and which to use as the second (competitor) antibody, the cross-blocking assay needs to be run SEA 180391My 60117-n3 139 WO 2006/119062 PCT/US2006/016345 in two formats: 1) format 1 is where Ab-X is the antibody that is coated onto the ELISA plate and Ab-Y is the competitor antibody that is in solution and 5 2) format 2 is where Ab-Y is the antibody that is coated onto the ELISA plate and Ab-X is the competitor antibody that is in sQlution. Ab-X and Ab-Y are defined as cross-blocking if, either in format 1 or in format 2, the solution phase anti-sclerostin antibody is able to cause a reduction of between 60% and 100%, specifically between 70% and 100%, and more specifically between 80% and 100%, of 10 the sclerostin detection signal (i.e. the amount of sclerostin bound by the coated antibody) as compared to the sclerostin detection signal obtained in the absence of the solution phase anti sclerostin antibody (i.e. the positive control wells). In the event that a tagged version of sclerostin is used in the ELISA, such as a N terminal His-tagged Sclerostin (R&D Systems, Minneapolis, MN, USA; 2005 cat# 1406-ST 15 025) then an appropriate type of sclerostin detection reagent would include an HRP labeled anti His antibody. In addition to using N-terminal His-tagged Sclerostin, one could also use C terminal His-tagged Sclerostin. Furthermore, various other tags and tag binding protein combinations that are known in the art could be used in this ELISA-based cross-blocking assay (e.g., HA tag with anti-HA antibodies; FLAG tag with anti-FLAG antibodies; biotin tag with 20 streptavidin). EXAMPLE 8 CELL BASED MINERALIZATION ASSAY FOR IDENTIFYING AGENTS ABLE TO ANTAGONIZE SCLEROSTN AcTIviTY 25 Introduction Mineralization by osteoblast-lineage cells in culture, either primary cells or cell lines, is used as an in vitro model of bone formation. Mineralization takes from about one to six weeks to occur beginning with the induction of osteoblast-lineage cell differentiation by one or 30 more differentiation agents. The overall sequence of events involves cell proliferation, differentiation, extracellular matrix production, matrix maturation and finally deposition of mineral, which refers to crystallization and/or deposition of calcium phosphate. This sequence of events starting with cell proliferation and differentiation, and ending with deposition of mineral is referred to herein as mineralization. Measurement of calcium (mineral) is the output 35 of the assay. SEA 18039110 60117-M 140 WO 2006/119062 PCT/US2006/016345 Deposition of mineral has a strong biophysical characteristic, in that once mineral "seeds" begin to form, the total amount of mineral that will be deposited in the entire culture can sometimes be deposited quite rapidly, such as within a few days thereafter. The timing and extent of mineral deposition in culture is influenced, in part, by the particular osteoblast-lineage 5 cells/cell-line being used, the growth conditions, the choice of differentiation agents and the particular lot number of serum used in the cell culture media. For osteoblast-lineage cell/cell line mineralization cultures, at least eight to fifteen serum lots from more than one supplier should be tested in order to identify a particular serum lot that allows for mineralization to take place. 10 MC3T3-El cells (Sudo H et al., In vitro differentiation and calcifcation in a new clonal osteogenic cell line derivedfrom newborn mouse calvaria. J. Cell Biol. 96:191-198) and subclones of the original cell line can form mineral in culture upon growth in the presence of differentiating agents. Such subclones include MC3T3-E1-BF (Smith E, Redman R, I-ogg C, Coetzee Q, Kasahara N, Frenkel B. 2000. Glucocorticoids inhibit developmental stage-specfc 15 osteoblast cell cycle. J Biol Chem 275:19992-20001). Identification of Sclerostin Neutralizing Antibodies MC3T3-E1-BF cells were used for the mineralization assay. Ascorbic acid and B-glycerophosphate were used to induce MC3T3-El-BF cell differentiation leading to mineral 20 deposition. The specific screening protocol, in 96-well format, involved plating cells on a Wednesday, followed by seven media changes (as described further below) over a 12-day period with most of the mineral deposition taking place in the final approximately eighteen hours (e.g. Sunday night through Monday). For any given treatment, 3 wells were used (N=3). The specific timing, and extent, of mineral deposition may vary depending, in part, on the particular 25 serum lot number being used. Control experiments will allow such variables to be accounted for, as is well know in the art of cell culture experimentation generally. In this assay system sclerostin inhibited one or more of the sequence of events leading up to and including mineral deposition (i.e., sclerostin inhibited mineralization). Anti sclerostin antibodies that were able to neutralize sclerostin's inhibitory activity allowed for 30 mineralization of the culture in the presence of sclerostin such that there was a statistically significant increase in deposition of calcium phosphate (measured as calcium) as compared to the amount of calcium measured in the sclerostin-only (i.e., no antibody) treatment group. For statistical analysis (using MS Excel and JMP) a 1-way-ANQVA followed by Dunnett's comparison was used to determine differences between groups. Group means for each data set SEA 1803911v 60117-2 141 WO 2006/119062 PCT/US2006/016345 were considered significantly different when the P value was less than 0.05 (P <0.05). A representative result from running this assay is shown in Figure 22. In the absence of recombinant mouse sclerostin, the sequence of events leading up to and including mineral deposition proceeded normally. Calcium levels in each treatment group are shown as means i 5 Standard Error of the Mean (SEM). In this exemplary experiment calcium levels from the calcium assay were -31 pg/ml. However, addition of recombinant mouse sclerostin caused inhibition of mineralization, and calcium was reduced by- 85%. Addition of anti-sclerostin monoclonal antibody Ab-19 or Ab-4 along with the recombinant sclerostin resulted in a statistically significant increase in mineral deposition, as compared to the sclerostin-only group, 10 because the inhibitory activity of sclerostin was neutralized by either antibody. The results from this experiment indicate that Ab-19 and Ab-4 are sclerostin neutralizing monoclonal antibodies (Mabs). Figure 23 shows a very similar result using recombinant human sclerostin and two humanized anti-sclerostin Mabs. Figure 24 also shows a very similar result using 15 recombinant human sclerostin and mouse and humanized anti-sclerostin Mabs as indicated. The antibodies used for the experiments shown in Fig 22, 23 and 24 have molecular weights of about 145 Kd and have 2 sclerostin binding sites per antibody molecule. A detailed MC3T3-El-BF cell culture protocol is described below. 20 Reagents and Medias Reagents Company Catalog # Alpha-MEM Gibco-Invitrogen 12571-048 25 Ascorbic acid Sigma A4544 Beta-glycerophosphate Sigma 06376 1 OOX PenStrepGlutamine Gibco-Invitrogen 10378-016 Dimethylsulphoxide (DMSO) Sigma D5879 or D2650 Fetal bovine serum (FBS) Cansera CS-C08-500 (lot # SF50310) 30 or Fetal bovine serum (FBS) TerraCell Int. CS-C08-1000A (lot # SF-20308) Alpha-MEM is usually manufactured with a 1 year expiration date. Alpha-MEM that was not older than 6-months post-manufacture date was used for the cell culture. 35 Expansion Medium (Alpha-MEM/IOFBS/PenStrepGlu) was prepared as follows: SEA 1803911v 60117-223 142 WO 2006/119062 PCT/US2006/016345 A 500 ml bottle of FBS was thawed and filter sterilized through a .0.22 micron filter. 100 mIs of this FBS was added to 1 liter of Alpha-MEM followed by the addition of 10 mIs of I 00x PenStrepGlutamine. Unused FBS was aliquoted and refrozen for later use. 5 Differentiation Medium (Alpha-MEM/10%FBS/PenStrepGlu, + 50 sg/mi ascorbic acid, + 10 mM beta-glycerophosphate) was prepared as follows: 100 mis of Differentiation Medium was prepared by supplementing 100 mls of Expansion Medium with ascorbic acid and beta-glycerophosphate as follows: 10 Stock conc Volume Final Conc. (see below) Ascorbic acid 10 mg/ml 0.5 mIs 100 sg/ml (50ug/ml + 50j g/ml) p-glycerophosphate 1 M 1.0 mIs 10 mM 15 Differentiation Medium was made by supplementing Expansion Medium only on the day that the Differentiation media was going to be used for cell culture. The final concentration of ascorbic acid in Differentiation medium is 100 gg/ml because Alpha-MEM already contains 50 g/ml ascorbic acid. Ascorbic acid stock solution (10 mg/ml) was made and aliquoted for freezing at -80'C. Each aliquot was only used once (i.e. not refrozen). Beta 20 glycerophosphate stock solution (1 M) was made and aliquoted for freezing at -20*C. Each aliquot was frozen and thawed a maximum of 5 times before being discarded. Cell Culture for expansion of MC3T3-El-BF cells. 25 Cell culture was performed at 37 0 C and 5% C0 2 . A cell bank was generated for the purposes of screening for sclerostin neutralizing antibodies. The cell bank was created as follows: One vial of frozen MC3T3-El-BF cells was thawed by agitation in a 37 0 C water bath. The thawed cells were put into 10 mIs of Expansion Medium (Alpha 30 MEM/10%FBS/PenStrepGlu) in a 50 ml tube and gently spun down for 5 minutes. The cells were then resuspended in 4 mls of Alpha-MEM/10%FBS/PenStrepGlu. After determining the number of cells using trypan blue and hemacytometer, 1 x 106 cells were plated in 50 mls Alpha-MEMI10%FBS/PenStrepGlu media in one T175 flask. When this passage was confluent (at approximately 7 days), the cells were SEA 1803911yA 60117-M 143 WO 2006/119062 PCT/US2006/016345 trypsinized with trypsWEDTA (0.05% Trypsin; 0.53 mM EDTA), gently spun down for 5 minutes and then resuspended in 5 mis Alpha-MEM/1 0%FBS/PenStrepGlu. After determining the number of cells using trypan blue and hemacytometer, cells were plated at 1 x 106 cells in 50 mis Alpha-MEM/10%FBS/PenStrepGlu media per one T175 flask. The number of T175 flasks 5 used for plating at this point depended upon the total cell number available and the desired number of flasks that were to be taken forward to the next passage. Extra cells were frozen down at l-2x10 6 live cells/ml in 900/FBS/10%DMSQ. When this passage was confluent (about 3-4 days), the cells were trypsinized with trypsin/EDTA (0.05% Trypsin; 0.53 mM ED)TA), gently spun down for 5 minutes and then 10 resuspended in 5 mis Alpha-MEM/10%FBS/PenStrepGlu. After determining the number of cells using trypan blue and hemacytometer, cells were plated at 1 x 106 cells in 50 mis Alpha MEM/10%FBS/PenStrepGlu media per one T175 flask. The number of T175 flasks used for plating at this point depended upon the total cell number available and the desired number of flasks that were to be taken forward to the next passage. Extra cells were frozen down at 1 15 2x10 6 live cells/mi in 90%FBS/l0%DMSO. When this passage was confluent (about 3-4 days), the cells were trypsinized with trypsin/EDTA (0.05% Trypsin; 0.53 mM EDTA), gently spun down for 5 minutes and then resuspended in 5 mis Alpha-MEM/10%FBS/PenStrepGlu. After determining the number of cells using trypan blue and hemacytometer, cells were plated at 1 x 106 cells in 50 mls Alpha 20 MEM/10%FBSPenStrepGlu media per one T175 flask. The number of T175 flasks used for plating at this point depended upon the total cell number available and the desired number of flasks that were to be taken forward to the next passage. Extra cells were frozen down at 1 2x1Q 6 live cells/ml in 90%FBS/10%DMSO. When this passage was confluent (about 3-4 days), the cells were trypsinized with 25 trypsin/EDTA (0.05% Trypsin; 0.53 mM EDTA), gently spun down for 5 minutes and then resuspended in 5 mis Alpha-MEM/10%FBS/PenStrepGlu. After determining the number of cells using trypan blue and hemacytometer, the cells were frozen down at 1-2x10 6 live cells/mi in 90%FBS/10/oDMSO. This "final passage" of frozen cells was the passage that was used for the screening assay. 30 Cell Culture for mineralizing MC3T3-El-BF cells. Cell culture was performed at 37*C and 5% C0 2 . It is desirable to minimize temperature and % CO 2 fluctuations during the mineralization cell culture procedure. This can SEA 18039l1vl 60117-223 144 WO 2006/119062 PCTIUS2006/016345 be achieved by minimizing the time that plates spend out of the incubator during feeding and also by minimizing the number of times the incubator door is opened and closed during the mineralization cell culture procedure. In this regard having a tissue culture incubator that is dedicated exclusively for the mineralization cell culture (and thus not opened and closed more 5 than is necessary) can be helpful. An appropriate number of "final passage" vials prepared as described above were thawed by agitation in a 37*C water bath. The thawed cells were put into 10 mIs of Expansion Medium (Alpha-MEM/10%FBS/PenStrepOlu) in a 50 ml tube and gently spun down for 5 minutes. The cells were then resuspended in 4 mls of Alpha-MEM/10%FBS/PenStrepGlu. 10 After determining the number of cells by trypan blue and hemacytometer, 2500 cells were plated in 200 microliters of Expansion media per well on collagen I coated 96-well plates (Becton Dickinson Labware, cat # 354407). To avoid a mineralization plate-edge effect, cells were not plated in the outermost row/column all the way around the plate. Instead 200 microliters of PBS was added to these 15 wells. Exemplary cell culture procedure In the following procedure, the starting day for plating the cells is indicated to be a Wednesday. If a different day of the week is used as the starting day for plating the cells, that 20 day will trigger the daily schedule for removing and adding media during the entire process as indicated below. Fqr example, if the cells are plated on a Tuesday, media should not be removed and added on the first Friday and Saturday, nor on the second Friday and Saturday. With a Tuesday start, the plates would be prepared for the calcium assay on the final Sunday. 25 Cells were plated on a Wednesday at 2500 cells in 200 pl of Expansion media. On Thursday all of the Expansion media was removed and 200 pi of Differentiation Media was added. On Friday 100 d of media was removed and 100 pl of fresh Differentiation Media was added. On Monday 100 sW of media was removed and 100 pl of fresh Differentiation Media was added. 30 On Tuesday 100 p of media was removed and 100 sd of fresh Differentiation Media was added. On Wednesday 100 pL of media was removed and 100 p of fresh Differentiation Media was added. On Thursday 100 pl of media was removed and 100 p1 of fresh Differentiation Media was added. SEA 180391 l 60117-223 145 WO 2006/119062 PCTIUS2006/016345 On Friday 100 pl of media was removed and 100 pi of fresh Differentiation Media was added. On the following Monday plates were prepared for the calcium assay as follows: Plates were washed once with 10 mM Tris, HCl pH 7-8. 5 Working under a fume hood, 200 pl of 0.5 N HCi was added per well. Plates were then frozen at -80 0 C. Just prior to measuring calcium, the plates were freeze-thawed twice, and then trituration with a multichannel pipette was used to disperse the contents of the plate. The contents of the plate was then allowed to settle at 4*C for 30 minutes at which point an 10 appropriate amount of supernatant was removed for measuring calcium using a commercially available calcium kit. An exemplary and not-limiting kit is Calcium (CPC) Liquicolor, Cat. No. 0150-250, Stanbio Laboratory, Boeme, TX. In this cell based assay, sclerostin inhibits one or more of the sequence of events leading up to and including mineral deposition (i.e. sclerostin inhibits mineralization). Thus, in 15 experiments where sclerostin was included in the particular cell culture experiment, the recombinant sclerostin was added to the media starting on the first Thursday and every feeding day thereafter. In cases where an anti-sclerostin monoclonal antibody (Mab) was being tested for the ability to neutralize sclerostin, i.e. allow for mineralization by neutralizing sclerostin's ability to inhibit mineralization, the Mab was added to the media starting on the first Thursday 20 and every feeding day thereafter. According to the protocol, this was accomplished as follows: the Mab was preincubated with the recombinant sclerostin in Differentiation media for 45-60 minutes at 37*C and then this media was used for feeding the cells. Described above is a 12-day mineralization protocol for MC3T3-E1-BF cells. Using the same reagents and feeding protocol, the original MC3T3-E1 cells (Sudo H, Kodama 25 H-A, Amagai Y, Yamamoto S, Kasai S. 1983. In vitro differentiation and calcification in a new clonal osteogenic cell line derivedfrom newborn mouse calvaria. J Cell Biol 96:191-198) which we obtained from the RIKEN Cell Bank (RCB 1126, RIKEN BioResource Center 3-1-1 Koyadai,Tsukuba-shi, Ibaraki 305-0074 Japan) took longer to mineralize (20 days total for mineralization) than the MC3T3-El-BF cells. Mineralization of the original MC3T3-E1 cells 30 was inhibited by recombinant sclerostin and this inhibition was blocked using a sclerostin neutralizing antibody. EXAMPLE 9 ANTI-SCLEROSTIN ANTIBODY PROTECTS FROM INFLAMMATION-INDUCED BONE Loss iN THE CD4 SEA 1803911v1 60117-223 146 WO 2006/119062 PCTIUS2006/016345 CD45RB'" TRANSFER MODEL OF COLIS IN SCID MICE Summary of model 5 Injection of the CD45RB"g subset of CD4+ T cells into C.B-17 scid mice results in chronic intestinal inflammation with characteristics similar to those of human inflammatory bowel disease (IBD). Diarrhoea and wasting disease is noted 3-5 weeks after cell transfer with severe leukocyte infiltration into the colon accompanied by epithelial cell hyperplasia and granuloma formation. C.B-17 scid mice which receive the reciprocal subset of CD4+ cells, those 10 which express CD45RJlw, do not exhibit colitis and have a weight gain indistinguishable from uninjected scid mice. In addition to colitis symptoms, the CD4+ CD45RB"* T cell transfer model of colitis is accompanied by a reduction in bone mineral density (BMiD), thought to be primarily through inflammatory mechanisms rather than dietary malabsorption (Byrne, F. R. et al., Gut 54:78-86, 2005). 15 Induction of colitis and inflammation-induced bone loss Spleens were taken from female balb/c mice and disrupted through a 70PM cell strainer. The CD4+ population was then enriched by negative selection with Dynabeads using antibodies against B220, MAC-1, CD8 and I-Ad. The enriched population was then stained with 20 FITC conjugated anti-CD4 and PE conjugated anti-CD45RB and fractionated into CD4+CD45RBhi' and CD4+CD45RB"" populations by two-color sorting on a Moflo (Dakocytomation). The CD45RB9'" and CD45RU'ow populations were defined as the brightest staining 40% and the dullest staining 20% of CD4+ cells respectively. 5 x 10 5 cells were then injected i.p. into C.B-17 scid mice on day 0 and the development of colitis was monitored 25 through the appearance of soft stools or diarrhoea and weight loss. Bone mineral density measurements were taken at the termination of the study (day 88). Effect of anti-Sclerostin treatment on colitis symptoms and BMD 30 Ab-A IgG was dosed at 10mg/kg s.c. from the day prior to CD4+CD45RB' cell transfer and compared with mice which received the negative control antibody 101.4 also dosed at 10mg/kg s.c.. The antibodies were dosed weekly thereafter. A group of mice which received non-pathogenic CD4+CD45RB** cells and were dosed with 10mg/kg 101.4 was studied as a control. At the termination of the study (day 88) the bone mineral density was measured and SEA 180391 vi 60117-M 147 WO 2006/119062 PCT/US2006/016345 sections of the colon taken for analysis of cell infiltration and assessment of histological damage. a) No effect on colitis symptoms 5 Typical colitis symptoms such as weight loss and infiltration of inflammatory cells into the colon were unaffected by treatment with Ab-A. Similarly there was no improvement of histological damage to the colon after treatment with Ab-A. b) Inhibition of inflammation-induced loss of bone mineral density. 10 Qn day 88 after transfer of cells into C.B-17 scid mice, the bone mineral density was measured (total BMD, vertebrae BMD and femur BMD). In comparison to control mice which received CD4+CD45RB"* non-pathogenic cells, mice which received CD4+ CD45RB h'9 T cells and the negative control antibody 101.4 had reduced bone mineral density, as shown in Figure 25. In contrast, no reduction in BMD was noted after treatment with Ab-A. Total, 15 vertebrae and femur measurements of BMI) were significantly higher in mice receiving CD4+ CD45RBaI T cells and treated with Ab-A than mice receiving CD4+ CD45RB"* T cells and treated with 101.4 (P<0.001 by Bonferroni multiple comparison test). EXAMPLE 10 20 KiNExA-BASED DETERMINATION OF AFFINITY (KD) OF ANTI-SCLEROSTIN ANTIBODIES FOR HUMAN SCLEROSTIN The affinity of several anti-sclerostin antibodies to human sclerostin was assessed by a solution equilibrium binding analysis using KinExA* 3000 (Sapidyne Instruments Inc., Boise, ID). For these 25 measurements, Reacti-Gel 6x beads (Pierce, Rockford, IL) were pre-coated with 40 pg/ml human sclerostin in 50 mM Na2CO3, pH 9.6 at 4*C overnight. The beads were then blocked with 1 mg/ml BSA in 1 M Tris-HCl, pH 7.5 at 4*C for two hours. 10 pM, 30 pM, or 100 pM of the antibody was mixed with various concentrations of human sclerostin, ranging in concentration from 0.1 pM to 1 nM, and equilibrated at room temperature for over 8 hours in PBS with 0.1 mg/ml BSA and 0.005% P20. 30 The mixtures were then passed over the human sclerostin coated beads. The amount of bead-bound anti-sclerostin antibody was quantified using fluorescent Cy5-labeled goat anti-mouse-IgG or fluorescent Cy5-labeled goat anti-human-IgG antibodies (Jackson Immuno Research, West Grove, PA) for the mouse or human antibody samples, respectively. The amount of fluorescent signal measured was proportional to the concentration of free anti-sclerostin antibody in each reaction mixture at SEA 1803911vl 60117-223 148 WO 2006/119062 PCT/US2006/016345 equilibrium. The dissociation equilibrium constant (KD) was obtained from nonlinear regression of the competition curves using a n-curve one-site homogeneous binding model provided in the KinExA Pro software. Results of the KinExA assays for the selected antibodies are summarized in the table below. Antibodies Antigen KD (pM) 95% confidence Interval Ab-13 Human Sclerostin 0.6 0.4 - 0.8 pM Ab-4 Human Sclerostin 3 1.8 - 4 pM Ab-19 Human Sclerostin 3 1.7 - 4 pM Ab-14 Human Scierostin 1 - 0.5 - 2 pM Ab-5 Human Sclerostin 6 4.3 - 8 pM Ab-23 Human Sderostin 4 2.1 - 8 pM 5 EXAMPLE 11 BIACORE METHOD FOR DETERMINING THE AFFINITY OF HUMANISED ANTI-SCLEROSTTN ANTIBODIES FOR HUMAN SCLEROSTIN. 10 The BlAcore technology monitors the binding between biomolecules in real time and without the requirement for labelling. One of the interactants, termed the ligand, is either immobilised directly or captured on the immobilised surface while the other, termed the analyte, flows in solution over the captured surface. The sensor detects the change in mass on the sensor 15 surface as the analyte binds to the ligand to form a complex on the surface. This corresponds to the association process. The dissociation process is monitored when the analyte is replaced by buffer. In the affinity BIAcore assay, the ligand is the anti-sclerostin antibody and the analyte is sclerostin. 20 Instrument Biacore @ 3000, Biacore AB, Uppsala, Sweden Sensorchip CM5 (research grade) Catalogue Number: BR-1001-14, Biacore AB, Uppsala, Sweden. Chips 25 were stored at 4 *C. BIAnormalising solution 70% (w/w) Glycerol. Part of BIAmaintenance Kit Catalogue Number: BR-1002-51, Biacore AB, Uppsala, Sweden. The BLAmaintenance kit was stored at 4 "C. SEA 1803911v 60117-22 149 WO 2006/119062 PCT/US2006/016345 Amine Coupling Kit Catalogue Number: BR-1000-50, Biacore AB, Uppsala, Sweden. Ethyl-3-(3-dimethylaminopropyl) carbodiimide hydrochloride (EDC). Made up to 75 mg/mL in 5 distilled water and stored in 200 pL aliquots at -70 "C. N-Hydroxysuccinimide (NHS). Made up to 11.5 mg/mL in distilled water and stored in 200 pL aliquots at -70 *C. 1 M Ethanolamine hydrochloride-NaOH pH 8.5. Stored in 200 pL aliquots at -70 *C. Buffers 10 Running buffer for immobilising capture antibody: HBS-EP (being 0.01 M HEPES pH 7.4, 0.15 M NaCl, 3 mM EDTA, 0.005 % Surfactant P20). Catalogue Number: BR-1001-88, Biacore AB, Uppsala, Sweden. Buffer stored at 4 *C. Immobilisation buffer: Acetate 5.0 (being 10 mM sodium acetate pH 5.0). Catalogue number BR-1003-51, Biacore AB, Uppsala, Sweden. Buffer stored at 4 *C. 15 Running buffer for binding assay: HBS-EP (being 0.01 M HEPES pH 7.4, 0.15 M NaCI, 3 mM EDTA, 0.005 % Surfactant P20, Catalogue Number: BR-1001-88, Biacore AB, Uppsala, Sweden) with CM-Dextran added at 1 mg/mL (Catalogue Number 27560, Fluka BioChemika, Buchs, Switzerland). Buffer stored at 4 *C. 20 Ligand capture Affinipure F(ab') 2 fragment goat anti-human IgG, Fc fragment specific. Jackson ImmunoResearch Inc (Pennsylvania, USA) Catalogue number: 109-006-098. Reagent stored at 4*C. 25 Ligand Humanised anti-human sclerostin antibodies Ab5, Abl4 and Ab20. Anayt 30 Recombinant human sclerostin. Aliquots stored at -70*C and thawed once for each assay. Regeneration Solution SEA 1803911vt 60117-223 150 WO 2006/119062 PCT/US2006/016345 40 mM HCl prepared by dilution with distilled water from an 11.6 M stock solution (BDH, Poole, England. Catalogue number: 101254H). 5 mM NaQH prepared by dilution with distilled water from a 50 mM stock solution. Catalogue number. BR-1003-58, Biacore AB, Uppsala, Sweden. 5 Assay Method The assay format was capture of the anti-sclerostin antibody by immobilised anti-human IgG-Fc then titration of the sclerostin over the captured surface. An example of the procedure is given below: 10 BIA (Biamolecular Interaction Analysis) was performed using a BIAcore 3000 (BIAcore AB). Affinipure F(ab')2 Fragment goat anti-human IgQ, Fc fragment specific (Jackson ImmunoResearch) was immobilised on a CM5 Sensor Chip via amine coupling chemistry to a capture level of ~4000 response units (RUs). HBS-EP buffer (10mM HEPES pH 7.4, 0.15 M 15 NaCl, 3 mM EDTA, 0.005 % Surfactant P20, BlAcore AB) containing 1 mg/mL CM-Dextran was used as the running buffer with a flow rate of 10 pl/min. A 10 1 injection of the anti sclerostin antibody at -5 pgmL was used for capture by the immobilised anti-human IgG-Fc. Antibody capture levels were typically 100-200 RU. Sclerostin was titrated over the captured anti-sclerostin antibody at various concentrations at a flow rate of 30 pI/min. The surface was 20 regenerated by two 10 .L injections of 40 mM HCl, followed by a 5 pL injection of 5 mM NaOH at a flowrate of 1 OL/min. Background subtraction binding curves were analysed using the BlAevaluation software (version 3.2) following standard procedures. Kinetic parameters were determined from the 25 fitting algorithm. The kinetic data and calculated dissociation constants are given in Table 2. TABLE 2: Affinity of anti-sclerostin antibodies for sclerostin 30 Antibod ka (/Ms) kd (1/s) Kd lAb- 1.78E+06 1.74-04 97.8 Ab-143.30E+06 /-66 1.48 A-20 2.6E+O6 .16E-05 15.8 EXAMPLE 12 SEA 1803911v1 60117-223 151 WO 2006/119062 PCT/US2006/016345 IN VIVO TESTING OF ANTI-SCLEROSTIN MONOCLONAL ANTIBODIES IN CYNOMOLGOUS MONKEYS Thirty-three, approximately 3-5 year old, female cynomolgus monkeys (Macaca fascicularis) were used in this 2- month study. The study contained 11 groups: 5 Group 1: vehicle (N=4) Group 2: Ab-23 (N=2, dose 3 mg/kg) Group 3: Ab-23 (N=3, dose 10 mg/kg) Group 4: Ab-23 (N=3, dose 30 mg/kg) Group 5: Ab-5 (N=3, dose 3 mg/kg) 10 Group 6: Ab-5 (N=3, dose 10 mg/kg) Group 7: Ab-5 (N=3, dose 30 mg/kg) Group 8: Ab-14 (N=3, dose 3 mg/kg) Group 9: Ab-14 (N=3, dose 10 mg/kg) Group 10: Ab-14 (N=3, dose 30 mg/kg) 15 Group 11: Parathyroid Hormone (1-3 4 ) [PTH (1-34)] (N=3, dose 10 ug/kg) All dosing was subcutaneous. PTH (1-34) was dosed everyday, monoclonal antibodies (Mabs) were dosed twice (first dose at the beginning of the study and second dose at the one month time point). For assessment of bone parameters (e.g. bone mineral density) pQCT (peripheral 20 quantitative computed tomography) and DXA (dual energy X-ray absorptiometry) scans were performed prior to the beginning of the study (to obtain baseline values) and after a month (prior to the second dose of Mab) and finally at the end of the study (2-month time point) at which point the monkeys were necropsied for further analysis (e.g. histomorphometric analysis). Animals were fluorochrome labeled (days 14, 24, 47, and 57) for dynamic histomorphometry. 25 Serum was collected at various time points during the study [day I pre-dose (the day of the first Mab dose), day 1 twelve hours post-dose, day 2, day 3, day 5, day 7, day 14,.day 21, day 28, day 29 twelve hours post-dose (day 29 was the day of the second and final Mab dose), day 30, day 31, day 33, day 35, day 42, day 49 and day 56]. Three bone-related serum biomarkers were measured using commercially available kits: 30 Osteocalcin (OC) (DSL Osteocalcin Radioimmunoassay Kit; Diagnostic Systems Laboratories, Inc.,Webster, TX, USA) N-terminal Propeptide of Type I Procollagen (P1NP) (P1NP Radioimmunoassay Kit; Orion Diagnostica, Espoo, Finland) SEA 180391 vi 60117-M 152 WO 2006/119062 PCT/US2006/016345 C-telopeptide fragments of collagen type I al chains (sCTXI) (Serum CrossLaps* ELISA; Nordic Bioscience Diagnostics A/S, Herlev, Denmark). pQCT and DXA scans yielded data on various bone parameters (including bone mineral density (BMD) and bone mineral content) across numerous skeletal sites (including 5 tibial metaphysis and diaphysis, radial metaphysis and diaphysis, femur neck, lumbar vertebrae). Analysis of this bone data (percent change from baseline for each animal) and the anabolic (OC, PlNP) serum biomarker data (percent change from baseline for each animal) revealed statistically significant increases, versus the vehicle group, in some parameters at some of the time points and doses for each Mab. This bone parameter data, serum biomarker data, as well as 10 the histomorphometric data, indicated that each of the 3 Mabs (Ab-23, Ab-5 and Ab-14) was able to neutralize sclerostin in cynomolgous monkeys. This activity was most robust for Ab-23 and Ab-5, particularly at the highest dose (30 mg/kg), with a clear increase in bone formation (anabolic effect) as well as net gains in bone (e.g. BMD). Statistically significant increases in bone parameters and anabolic histomorphometric parameters were also found for the positive 15 control group (PTH (1-34)).. Serum bone formation markers (PlNP, osteocalcin) were increased (p<0.05 vs vehicle (VEI)) at various time points and doses, but particularly in the 30 mg/kg groups for Ab 23 and Ab-5. Histomorphometric analysis revealed dramatic increases (p<0.05 vs VEH) in bone formation rates in cancellous bone at lumbar vertebra and proximal tibia (up to 5-fold increase), 20 as well as at the endocortical surface of the femur midshaft (up to 10-fold increase) at the higher doses of Ab-23 and Ab-5. Trabecular thickness was increased with high dose Ab-23 and Ab-5 in lumbar vertebrae (>60%, p<0.05 vs VEH). 13y study end (2 months), areal BMD, as percent change from baseline, was increased (p<0.05 vs VEH) at the femur neck, ultra-distal radius (Ab 23, 30 mg/kg), and lumbar vertebrae (Ab-5, 30 mg/kg). The increases in areal BMD at the 25 lumbar vertebrae were accompanied by increases in vertebral strength (97% increase in vertebral maximal load for Ab-23, 30 mg/kg; p<0.05 vs VEH); baseline values for lumbar areal BMD prior to Mab dosing were statistically similar across all groups. In summary, short-term administration of sclerostin-neutralizing Mabs in cynomolgous monkeys resulted, in part, in increases in bone formation, BM) and vertebral bone strength. 30 From the foregoing, although specific embodiments of the invention have been described herein for purposes of illustration, various modifications may be made without deviating from the spirit and scope of the invention. Accordingly, the invention is not limited SSA 1so391vI 60117-M 153 WO 2006/119062 PCTIUS2006/016345 except as by the appended claims. All publications, published patent applications, and patent documents disclosed herein are hereby incorporated by reference. SEA 1039l1vi 60117-n3 154

Claims (66)

1. A composition comprising a polypeptide having the amino acid sequence 5 of SEQ ID NO:6.

2. A composition comprising a polypeptide having the amino acid sequence of SEQ ID NO:63.

3. A composition comprising a polypeptide having the amino acid sequence of SEQ ID NO:64 10

4. A composition comprising a polypeptide having the amino acid sequence of SEQ ID NO:65.

5. A composition comprising a polypeptide having the amino acid sequence of SEQ ID NO:66.

6. A composition comprising a polypeptide having the amino acid sequence 15 of SEQ ID NO:67.

7. A composition comprising a polypeptide having the amino acid sequence of SEQ ID NO:68.

8 A composition comprising a polypeptide having the amino acid sequence of SEQ ID NQ:69. 20

9. A composition comprising at least one polypeptide of the amino acid sequence of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 or SEQ ID NO:5.

10. The composition of claim 9 comprising at least two of the amino acid sequences of SEQ ID N0:2, SEQ ID NO:3, SEQ I) NO:4 and SEQ ID NO:5.

11. The composition of claim 9 comprising at least three of the amino acid 25 sequences of SEQ ID NO:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NO:5.

12. The composition of claim 9 comprising said four of the amino acid sequences of SEQ ID NQ:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID NQ:5.

13. A composition comprising a polypeptide having the amino acid sequences of SEQ ID NQ:2, SEQ ID NO:3, SEQ ID NO:4 and SEQ ID) NO:5, wherein SEQ ID NO:2 and 4 30 are joined by a disulfide bond at amino acid positions 57 and 111 with reference to SEQ ID NO:1, and SEQ ID NO:3 and 5 are joined by at least one of(a) a disulfide bond at amino acid positions 82 and 142 with reference to SEQ ID NO: 1, and (b) a disulfide bond at amino acid positions 86 and 144 with reference to SEQ ID NO:1. SEA 180391 vl 60117-M 155 WO 2006/119062 PCT/US2006/016345

14. The composition of any one of claims 1-12 wherein each of said polypeptides retains the tertiary structure of the corresponding polypeptide region of human scierostin of SEQ ID NO:1.

15. A polypeptide consisting essentially of a multiply truncated human 5 sclerostin protein of SEQ ID NO:1, wherein amino acids 1-50, 65-72, 91-100, 118-137, and 150 190 of SEQ ID NO:1 are absent from said polypeptide.

16. A composition comprising at least one polypeptide consisting essentially of the amino acid sequence of SEQ ID NO:70, SEQ ID NO:71, SEQ ID) NO:72 or SEQ ID NO:73. 10

17. The composition of claim 16 comprising at least two of the amino acid sequences of SEQ ID NO:70, SEQ ID NO:7 1, SEQ ID NO:72 and SEQ ID NO:73.

18. The composition of claim 16 comprising at least three of the amino acid sequences of SEQ ID NO:70, SEQ ID NQ:7 1, SEQ D NO:72 and SEQ ID NO:73.

19. The composition of claim 16 comprising said four of the amino acid 15 sequences of SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72 and SEQ ID NO:73.

20. A composition comprising a polypeptide having the amino acid sequences of SEQ ID NO:70, SEQ ID NO:71, SEQ ID NO:72 and SEQ ID NO:73, wherein SEQ ID NO:72 and 73 are joined by a disulfide bond at amino acid positions 57 and 111 with reference to SEQ ID NO:1, and SEQ ID NO:70 and 71 are joined by at least one of(a) a disulfide bond at 20 amino acid positions 82 and 142 with reference to SEQ I) NO:1, and (b) a disulfide bond at amino acid positions 86 and 144 with reference to SEQ ID NO: 1.

21. The composition of any one of claims 16-20 wherein each of said polypeptides retains the tertiary structure of the corresponding polypeptide region of human sclerostin of SEQ ID NO: 1. 25

22. A polypeptide consisting essentially of a multiply truncated human sclerostin protein of SEQ ID NO:1, wherein amino acids 1-56, 65-72, 87-110, 118-137, and 145 190 of SEQ ID NO: 1 are absent from said polypeptide.

23. The polypeptide of claim 22, wherein said polypeptide is obtained by tryptic digestion of human sclerostin. 30

24. The polypeptide of claim 23, wherein said human sclerostin is treated with trypsin to achieve complete trypsin digestion and said polypeptide is isolated by HPLC.

25. A portion of human sclerostin comprising amino acids 51-64, 73-90, 101 117, and 138-149 of SEQ ID NO:1, wherein said portion has at least one of: (a) a disuifide bond between amino acids 57 and 111; SEA 1803911vi 60117.2 156 WO 2006/119062 PCT/US2006/016345 -(b) a disufide bond between amino acids 82 and 142; and (b) a disulfide bond between amino acids 86 and 144.

26. The portion of human sclerostin of claim 25, having at least two of said disulfide bonds. 5

27. The portion of human sclerostin of claim 25, having said three disulfide bonds.

28. A portion of human sclerostin comprising amino acids 57-64, 73-86, 111 117, and 138-144 of SEQ ID NO:1, wherein said portion has at least one of: (a) a disulfide bond between amino acids 57 and 111; 10 (b) a disulfide bond between amino acids 82 and 142; and (c) a disulfide bond between amino acids 86 and 144.

29. The portion of human sclerostin of claim 28, having at least two of said disufide bonds.

30. The portion of human sclerostin of claim 28, having said three disulfide 15 bonds.

31. A polypeptide consisting essentially of a human sclerostin protein of SEQ ID NO: 1 truncated at the C-terminal and N-terminal ends, wherein amino acids 1-85 and 112 190 of SEQ ID NO: 1 are absent from said polypeptide.

32. A portion of human sclerostin, comprising amino acids 86-111 of SEQ ID 20 NO:1.

33. A portion of human sclerostin, comprising SEQ ID NO:6.

34. A portion of human sclerostin, comprising SEQ ID NO:63.

35. A portion of human sclerostin, comprising SEQ ID NO:64.

36. A portion of human sclerostin, comprising SEQ ID NO:65. 25

37. A portion of human sclerostin, comprising SEQ ID NO:66.

38. A portion of human sclerostin, comprising SEQ UD NO:67.

39. A portion of human sclerostin, comprising SEQ ID NO:68.

40. A portion of human sclerostin, comprising SEQ ID NO:69.

41. A portion of rat sclerostin, comprising SEQ IDNO:96. 30

42. A portion of rat sclerostin, comprising SEQ ID NO:97.

43. A method of producing a portion of human sclerostin, comprising the steps of: (a) treating human sclerostin with trypsin to achieve complete tryptic digestion; SEA 190391M 60117-n3 157 WO 2006/119062 PCTIUS2006/016345 (b) collecting the tryptic digest sample having average molecular mass of 7122.OD (theoretical mass 7121.5D) or retention time of about 20.6 minutes as determined by elution from a reverse-phase HPLC column with linear gradient from 0.05% trifluoroacetic acid to 90% acetonitrile in 0.05% TFA at a flow rate of 0.2ml/min; 5 and (c) purifying said portion.

44. A polypeptide of SEQ ID NQ:6.

45. A polypeptide of SEQ ID NO:2.

46. A polypeptide of SEQ ID NO:3. 10

47. A polypeptide of SEQ ID NO:4.

48. A polypeptide of SEQ ID NO:5.

49. A polypeptide of SEQ ID NO:2, SEQ ID NO:3, SEQ ID) NO:4 and SEQ D) NO:5.

50. A polypeptide of SEQ ID NO:96. 15

51. A polypeptide of SEQ ID NO:97.

52. A polypeptide of SEQ ID NO:63.

53. A polypeptide of SEQ ID NO:64

54. A polypeptide of SEQ ID NO:65.

55. A polypeptide of SEQ ID NO:66. 20

56. A polypeptide-of SEQ D NO: 67 .

57. A polypeptide of SEQ ID N0:68.

58. A polypeptide of SEQ ID NO:69.

59. A polypeptide of SEQ ID NO:70.

60. A polypeptide of SEQ ID NO:71. 25

61. A polypeptide of SEQ ID N0: 7 2 .

62. A polypeptide of SEQ ID NO:73.

63. A polypeptide of SEQ ID NO:70, SEQ ID NO:7 1, SEQ ID NO:72 and SEQ ID NO:73.

64. A method of generating an antibody comprising administering to an 30 animal a polypeptide according to any of claims 1-42 and 44-63.

65. The method according to claim 64 wherein the animal is a mammal.

66. A vaccine comprising at least one polypeptide comprising one or more of the epitopes of SEQ ID NO:2, 3, 4, 5, 6, 70, 71, 72, and 73. SEA 1803911vl 60117-223 158