Anti-tau antibody

Abstract

The present invention relates to specific binding molecules, such as antibodies, directed against major epitopes of tau. The specific binding molecules of the invention find application in methods for the diagnosis and treatment of tauopathies, including Alzheimer's disease.

Description

[Technical Field]

[0001] The present invention relates to specific binding molecules, such as antibodies, directed against major epitopes of tau. The specific binding molecules of the invention find application in methods for the diagnosis and treatment of tauopathies, including Alzheimer's disease. [Background technology]

[0002] Disorders related to tau are collectively referred to as neurodegenerative tauopathies. Alzheimer's disease (AD) is part of this group of neurodegenerative diseases. Dementia conditions such as Alzheimer's disease (AD) are often characterized by the gradual accumulation of intracellular and / or extracellular deposits of proteinaceous structures, such as β-amyloid plaques and neurofibrillary tangles (NFTs) composed of tau, in the brains of affected individuals. The appearance of tau aggregate lesions is significantly correlated with pathological neurofibrillary degeneration and brain atrophy, as well as cognitive impairment. In AD, tau protein self-assembles to form paired helical fibrils (PHFs) and linear fibrils, which constitute neurofibrillary tangles in neurons and dystrophic neurites in the brain. The formation of amyloid fibrils by misfolded proteins is a hallmark of many different diseases, each characterized by a specific precursor protein, collectively known as amyloidoses.

[0003] The long history of research into the causes of AD and other protein conformational disorders has not led to much-needed major advances in diagnostics or therapeutics. One reason for the limited progress is believed to be the lack of high-affinity specific binding molecules that target major epitopes of tau. The inventors address this shortcoming through the creation of the specific binding molecules disclosed herein. The disclosed specific binding molecules are derived from antibodies isolated from sheep immunized with full-length tau protein and truncated tau fragments from the core of PHFs. The use of sheep as a source of specific binding molecules is believed to have contributed to the high affinity of the specific binding molecules of the present invention. Summary of the Invention [Means for solving the problem]

[0004] According to a first aspect, the present invention provides a specific binding molecule that binds to an epitope within SEQ ID NO:1 with a higher binding affinity than the binding affinity with which antibody mAb423 binds to the epitope within SEQ ID NO:1.

[0005] According to a second aspect, the present invention provides a composition comprising a specific binding molecule according to the first aspect of the invention, wherein at least 90% of the specific binding molecules in the composition that bind to an epitope within SEQ ID NO: 1 have a K of less than 25 nM. D The present invention provides a composition that binds

[0006] According to a third aspect, the present invention provides a nucleic acid molecule comprising a nucleic acid sequence encoding a specific binding molecule according to the first aspect of the invention.

[0007] According to a fourth aspect, the present invention provides a construct comprising a nucleic acid molecule of the third aspect of the invention.

[0008] According to a fifth aspect, the present invention provides a vector comprising a nucleic acid molecule of the third aspect of the invention or a construct of the fourth aspect of the invention.

[0009] According to a sixth aspect, the present invention provides a host cell comprising a nucleic acid molecule of the third aspect of the invention, a construct of the fourth aspect of the invention or a vector of the fifth aspect of the invention.

[0010] According to a seventh aspect, the present invention provides a method for preparing a specific binding molecule according to the first aspect of the invention, comprising the steps of: i) introducing a nucleic acid molecule according to the third aspect of the invention, a construct according to the fourth aspect of the invention or a vector according to the fifth aspect of the invention into a host cell; ii) expressing the nucleic acid molecule such that the specific binding molecule is produced; and iii) recovering the specific binding molecules, preferably by purification; The present invention provides a method comprising:

[0011] According to an eighth aspect, the present invention provides a specific binding molecule obtainable by a method according to the seventh aspect of the invention.

[0012] According to a ninth aspect, the present invention provides a pharmaceutical composition comprising a specific binding molecule according to the first aspect of the invention or a composition according to the second aspect of the invention and one or more pharmaceutically acceptable diluents, carriers or excipients.

[0013] According to a tenth aspect, the present invention provides a specific binding molecule according to the first aspect of the invention, a composition according to the second aspect of the invention or a pharmaceutical composition according to the ninth aspect of the invention for use in therapy.

[0014] According to an eleventh aspect, the present invention provides a specific binding molecule according to the first aspect of the invention, a composition according to the second aspect of the invention or a pharmaceutical composition according to the ninth aspect of the invention for use in the treatment of a tauopathy.

[0015] According to a twelfth aspect, the present invention provides a method for treating a tauopathy, the method comprising administering to a subject in need thereof a specific binding molecule according to the first aspect of the invention, a composition according to the second aspect of the invention or a pharmaceutical composition according to the ninth aspect of the invention.

[0016] According to a thirteenth aspect, the present invention provides an in vitro method of inhibiting aggregation of tau protein or a fragment thereof, the method comprising contacting tau protein or a fragment thereof with a specific binding molecule according to the first aspect of the invention.

[0017] According to a fourteenth aspect, the present invention provides an in vitro method for detecting tau protein or a fragment thereof in a sample, the method comprising contacting the sample with a specific binding molecule of the first aspect of the invention.

[0018] According to a fifteenth aspect, the present invention provides a diagnostic method comprising contacting a sample with a specific binding molecule of the first aspect of the invention.

[0019] According to a sixteenth aspect, the present invention provides a diagnostic device for use in a method according to the fifteenth aspect of the invention.

[0020] According to a seventeenth aspect, the present invention provides a kit for detecting tau protein or a fragment thereof in a sample, comprising a specific binding molecule according to the first aspect of the invention and a reagent.

[0021] Please refer to the following figures: [Brief explanation of the drawings]

[0022] [Figure 1] Alternative CDR definition of S1D12 by Kabat, Chothia and Martin. [Figure 2] Sequence of the predominant fragment isolated from the proteolytically stable core of paired helical fibrils (PHFs; Wischik et al., 1988). This fragment (termed "dGAE") contains residues 296-391 of full-length tau, was identified by cryo-electron microscopy as constituting the PHF core (Fitzpatrick et al., 2017), and encompasses the fragment shown in Figure 3 (residues 308-378). The location of epitopes for selected antibodies / scAbs is also shown. [Figure 3] PHF core shown in the context of PHF. [Figure 4] The location of the corresponding epitope relative to the same core sequence and the basic C-shaped subunit structure of the core. The 1D12 epitope forms a critical fold or "hairpin" in the C-shaped subunit. [Figure 5] Molecular modeling showing how the new dGAE unit gradually unfolds and becomes aligned with the existing oligomeric structure. [Figure 6]The attachment sequence is shown in three stages, corresponding to the gradual oligomeric binding of the major segments of dGAE and their epitopes. As can be seen, the hinge region recognized by 1D12 is the primary attachment site, followed by the symmetrical binding of the other domains. [Figure 7] (A) dGAE antigen-specific immune response of sheep polyclonal sera after various immunization rounds. (B) hT40 antigen-specific immune response of sheep polyclonal sera after various immunization rounds. MPBS-coated wells were included as negative controls. [Figure 8] ELISA-based characterization of the cross-reactivity of "E" group scAbs using hT40, dGA, and dGAE antigens. (A) E1E8 scAb, (B) E2B7 scAb, (C) E2C5 scAb, (D) E2E8 scAb, (E) E1B8 scAb. All of these scAbs, except E1B8, show specific dGAE binding and therefore require an accessible "391E" epitope at the C-terminus for immunoreactivity. E1B8 cross-reacts with dGA, and detailed mapping of its binding region is shown in Figure 9. [Figure 9] Fine mapping of E1B8 scAb showing specific binding to a tau peptide corresponding to amino acids 313–336 on the hT40 protein. [Figure 10] ELISA-based characterization of the cross-reactivity of "NS" group scAbs with various short tau fragments with numbers corresponding to hT40 amino acid residues: (A) 337-368, (B) 275-305, (C) 266-359 (R1-3), (D) 360-378, (E) 369-391, (F) 369-390. A summary of specific NS scAb binding to these shorter antigens is shown in Table 16. [Figure 11]ELISA-based characterization of the cross-reactivity of "S" group scAbs with various short tau fragments numbered based on the corresponding amino acid residues on the hT40 molecule: (A) 186-350, (B) 275-305, (C-D) 266-359 (R1-3), (E-I) 297-391, (J) 360-378, (K-N) 369-391, (O-R) 369-390. A summary of specific "S" scAb binding to these shorter antigens is shown in Table 16. [Figure 12] ELISA-based characterization of the cross-reactivity of "C" group scAbs with various short tau fragments numbered based on the corresponding amino acid residues on the hT40 molecule: (A) 1-49, (B) 1-155, (C-D) 1-319, (E) 113-251, (F) 113-319, (G) 186-350, (H) 239-441, (I) 266-359, (R1-3), (J) 297-441, (K) 348-441, (L) 391-441. A summary of specific "C" scAb binding to these shorter antigens is shown in Table 17. [Figure 13] Cross-reactivity of "412" group scAbs with hT40. (A) Binding of scAbs to the biotinylated 412-441 peptide used as antigen for selection of C-terminal binders is shown. (B) Binding profile of four scAbs shown to be cross-reactive in the hT40 binding ELISA. [Figure 14] ELISA-based characterization of the cross-reactivity of "3a" and "3b" group scAbs with various short tau fragments numbered based on the corresponding amino acid residues on the hT40 molecule: (A) 1-49, (B) 1-111, (C-D) 1-155, (E) 113-251. A summary of specific "3a" and "3b" group scAb binding to these shorter antigens is shown in Table 18. [Figure 15] (A) Immunoreactivity of CE2 scAb to the parent peptide and a series of alanine-substituted residues at the positions indicated in Table 19. (B) Percent binding of 500 nM scAb to each of these ASM peptides relative to the parent peptide. [Figure 16](A-B) Immunoreactivity of S1D12 scAb to the parent peptide and a series of alanine-substituted residues at the positions indicated in Table 20. (C) Percent binding of 500 nM scAb to each of these ASM peptides relative to the parent peptide. [Figure 17] (A-B) Immunoreactivity of ME12 scAb to the parent peptide and a series of alanine-substituted residues at the positions indicated in Table 20. (C) Percent binding of 100 nM scAb to each of these ASM peptides relative to the parent peptide. [Figure 18] (A) Immunoreactivity of CA4 scAb to the parent peptide and a series of alanine-substituted residues at the positions indicated in Table 21. (B) Percent binding of 500 nM scAb to each of these ASM peptides relative to the parent peptide. [Figure 19] (A-B) Immunoreactivity of S1G2 scAb to the parent peptide and a series of alanine-substituted residues at the positions indicated in Table 22. (C) Percent binding of 500 nM scAb to each of these ASM peptides relative to the parent peptide. [Figure 20] Binding rates of various 367-379 region scAbs to ASM peptides relative to the parent peptide. Tested scAbs included (A) S1B1, (B) CA12, (C) CB2, (D) CB8, (E) S1D9, (F) S1G10, (G) S2C6, (H) S1F4, (I) MC5, and (J) MD12. The critical binding residues of these scAbs were similar to those of the representative clone S1G2, and alanine substitutions at positions 370, 373, 374, 377, or 378 resulted in decreased antibody binding. [Figure 21] Ranking of binding affinities of anti-tau scAbs using hT40. The relative binding affinities of test scAbs were ranked using scAbs with known kD values, such as NS2A1 and S1D12, and those with similar binding profiles were shortlisted and selected for Biacore analysis. (A) "S" group clones, (B-C) "C" clones, (D) "412" clone, (E) "3a" clone. [Figure 22] Schematic of the sandwich ELISA format for calculating the LoD of various antibody pairs. [Figure 23] Schematic of the sandwich ELISA format for calculating LoD, in which S1G2 mAb was used as the capture antibody and HRP-conjugated S1D12 mAb was used for detection. [Figure 24] Sandwich ELISA graph showing the LoD achieved using S1G2 mAb as capture antibody and HRP-labeled S1D12 mAb for detection. Antibody binding was measured using chemiluminescence, and for this assay setup, the LOD for hT40 is approximately 1 ng / ml. [Figure 25] ELISA #1 hT40 standard curve generated using S1D12 mAb capture and CB7 scAb detection. Concentrations were determined for four spiked samples—Samples A, B, C, and D—by plotting their respective absorbance values ​​on this standard curve. Sample C did not produce a binding signal, thus confirming the absence of any tau species with N-terminal regions in the mixture. The concentrations and types of tau species estimated from this assay are provided in Table 29. [Figure 26] ELISA#2 dGAE standard curve generated using S1D12 mAb capture and E2E8 scAb detection. Concentrations were determined for four spiked samples—Samples A, B, C, and D—by plotting their respective absorbance values ​​on this standard curve. Samples A, C, and D did not produce any binding signal, thus confirming the absence of dGAE species in these mixtures. The concentrations and types of tau species estimated from this assay are provided in Table 29. [Figure 27] ELISA#3 average standard curve generated using S1D12 mAb capture and S1G2 scAb detection. Concentrations were determined for four spiked samples—Samples A, B, C, and D—by plotting their respective absorbance values ​​on this standard curve. The concentrations and types of tau species estimated from this assay are provided in Table 29. [Figure 28]Comparison of the binding profiles of various SDS (± Triton X-100)-treated dGAE monomers or aggregates in a sandwich ELISA system. S1D12 mAb was used as the capture antibody, and S1G2 was used as the detection scAb. Here, the effect of SDS + Triton X-100 on the recovery of immunoreactivity is noted. This mAb-scAb pair combination can detect approximately 2 ng / ml dGAE aggregates in a simple sandwich ELISA. [Figure 29] A) Human tau (hT40) and L66 cDNA with point mutations P301S and G335D (2N4R tau, 441 amino acids). B) L1 cDNA encodes human tau amino acid residues 296-390 together with a signal sequence and the mouse Thy1 expression sequence as described in Melis et al., 2015. [Figure 30] (A) Detection of tau protein in 50 μg brain homogenates isolated from wild-type, L1, L66+ / -, and L66+ / + mice using S1D12 mAb capture and S-1G2 scAb detection. All four samples have similar tau levels when detected using a combination of core region-specific antibody pairs. (B) Detection of tau protein in 50 μg brain homogenates isolated from wild-type, L1, L66+ / -, and L66+ / + mice using S1D12 mAb capture and CB7 scAb detection. CB7 scAb directed against the N' terminus can specifically detect human tau in line 66 homozygous and heterozygous samples, allowing for differentiation of expression levels between these two groups. [Figure 31] Plasma tau levels in WT (5-month-old: 1.947 ng / ml), (9-month-old: 2.177 ng / ml); L66 (both 5-month-old) (+ / -: 0.567 ng / ml), (+ / +: 1.937 ng / ml); and L1 (5-month-old: 12.355 ng / ml) (9-month-old: 13.661 ng / ml). Data collected using S1D12 mAb capture and S1G2 scAb detection. Tau species concentrations were determined using standard curves of hT40 for WT and L66 and dGA (296-390) for L1. [Figure 32]Detection of plasma tau levels in strain 66+ / + mouse sample number 23 at 1.5 months using two different sandwich ELISA pair combinations and comparison with age-matched wild-type mouse plasma. (A) Chemiluminescent signal readouts for strain 66+ / + and wild-type mice using S1D12 mAb capture and CB7 scAb detection are shown. (b) Signal readouts for the same sample using S1D12 mAb capture and S1G2 scAb detection. Strain 66+ / + mice show at least a 1000-fold increase in signal intensity compared to wild-type mice when using the S1D12 mAb-CB7 scAb pair combination, which specifically detects N-terminal hT40 in this sample. [Figure 33] Plasma tau levels in AD samples compared to age-matched controls using the S1D12-S1G12 (core region) and S1D12-CB7 (N-terminus) detection pairs. [Figure 34] Sandwich ELISA graphs showing increased immunoreactivity of core region scAbs for dGAE "total," "supernatant," and "pellet" agglutination-inhibited samples prepared in the presence of LMTM. dGAE monomer was included as an assay control to indicate the binding profile of each test scAb to their corresponding epitope in non-agglutinated samples. (A-C) CA4 scAb, (D-F) CA9, (G-I) CB3 scAb, (J-L) CE2 scAb, (M-O) CE3, (P-R) S1D12 scAb. The lack of antibody binding in some dGAE + LMTM pellet samples corresponds to the lack of protein seen in this group, as confirmed by SDS gels (data not shown). [Figure 35] Exemplary data plots of S1D12 scAb-mediated inhibition of dGAE aggregation. [Figure 36]Ranking of the aggregation-inhibitory properties of anti-tau scAbs by the Thioflavin T assay. Aggregation-inhibitory dGAE was quantified by calculating the percent change from aggregates in the absence of scAb. scAbs 3bA3, 3aD6, and 3aD3 were used as negative controls and show no cross-reactivity with dGAE (data not shown). n = 3, error bars represent SD, NS = not significant. * = P < 0.05, ** = P < 0.01, *** = P < 0.001 (one-way analysis of variance (ANOVA) and Dunnett's post-hoc test compared to scAb 3aD3). [Figure 37] Schematic of a tau-tau immunoassay to rank the inhibitory effects of anti-tau scAbs on the aggregation of truncated tau containing the core repeat domain. (a) Addition of dGAE to wells pre-coated with dGA results in tau-tau aggregation, and the presence of dGAE is detected using the 391E epitope-specific E2E8 scAb. (b) When dGAE is pre-incubated with a core region-binding scAb, this binding event inhibits the dGAE-dGA interaction, as measured by the loss of antibody detection by the E2E8 scAb. [Figure 38] Ranking of the aggregation inhibitory properties of anti-tau scAbs by tau-tau immunoassay (B50). A - Example of B50 quantification for NS2A1 and 3aD6 (negative control). Quantification of the aggregation inhibitory properties was performed by calculating the B50 value (concentration of scAb at which 50% of dGAE binding to dGA is evident). Error bars = SD, n = 4, -ve = negative control. b - Summary of B50 ranking of the scAb panel. [Figure 39] mAb capture of dGAE aggregates. [Figure 40] Experimental design to examine the effects of intraperitoneal administration of S1D12 in Line 1, Line 66, and WT mice. Animals will receive intraperitoneal (ip) injections of either vehicle or S1D12 (10 or 50 mg / kg) once a week (every Tuesday) for 12 (Group 1), 8 (Group 2), or 4 (Group 3) consecutive weeks. The age of mice at the end of the experiment will be the same for all three groups (i.e., 6 months of age). [Figure 41]Western blot showing tau labeled with human-specific CB7 antibody. A band is present in the lane containing 20 μg protein homogenate from a 5-month-old L66+ / + mouse brain, but is absent in either the WT or L1+ / + lanes. The protein ladder overlaid on the left side of the blot provides an approximation of the relative sizes of the proteins on the gel, although the apparent size of tau is known to be much larger than its actual molecular mass. [Figure 42] Western blot showing tau labeled with human-specific CC7. Results and ladder as described in Figure 41. [Figure 43] Western blot labeled with S1D12 tau core antibody. Bands are present in the lane containing 20 μg protein homogenate from 5-month-old L66+ / +, L1, and WT mouse brains. Mouse tau (indicated by the lower arrow) appears as a band of approximately 55 kDa in each of the samples. Human tau (indicated by the upper arrow) appears as a 68 kDa protein present only in the L66+ / + sample. Protein ladder is the same as in Figure 41. [Figure 44] Western blot labeled with S1G2 core antibody. Bands are present in the lane containing 20 μg protein homogenate from 5-month-old L66+ / +, L1+ / +, and WT mouse brains. Mouse tau (indicated by the lower arrow) appears as a band at approximately 55 kDa in each of the samples. Human tau (indicated by the upper arrow) appears at approximately 68 kDa, but only in the L66+ / + sample. Using this antibody, a band at approximately 10 kDa is visible in the L1+ / + sample. The protein ladder is the same as in Figure 41. [Figure 45] Sequence comparison of human and mouse tau. The sequences shown consist of SEQ ID NO: 1 for human tau (two gaps have been introduced to allow sequence alignment) and SEQ ID NO: 589 for mouse tau. The protein regions carrying the epitopes of the candidate antibodies are overlaid. Neither the CB7 nor CC7 binding regions of human tau are present in mouse tau. In contrast, the protein regions carrying the epitopes of antibodies S1D12 and S1G2 show 100% homology between the two species. [Figure 46] A) Paired antibody ELISA with S1D12 capture and CB7 detection shows a gradual decrease in signal with increasing age in L66+ / + mice. B) A similar pattern is observed when the assay is reversed and CB7 is used as capture with S1G2 as the detector. [Figure 47] Paired antibody ELISA with CB7 capture and HT7 detection shows a gradual increase in signal with age in L66+ / + mice, suggesting the accumulation of small fragments with intact N-termini generated by some kind of truncation event between the core and N'-terminal regions of tau protein or protein fragments. [Figure 48] (A) Plasma tau levels in healthy controls (HC) and patients with a confirmed diagnosis of Alzheimer's disease (AD / MCI). The concentration of core-proline regions measured using S1D12 capture beads paired with BT2 as a detector is significantly higher in healthy controls than in AD samples. A total of 12 healthy control plasma samples and 42 AD / MCI samples were analyzed using the Simoa® assay. ****p<0.0001. (B) NT1 assay data (Chen et al., 2019) reported that the use of Tau12-BT2 antibody detects a slight increase in NT-1 plasma tau levels in AD-MCI (AD biomarker positive - mild cognitive impairment) and AD (AD biomarker positive - clinical AD) patients compared with NCs (normal controls). [Figure 49] Plasma tau levels in healthy controls (HC) and patients with a confirmed diagnosis of Alzheimer's disease (AD / MCI). The concentration of the core-proline region measured using S1D12 capture beads paired with HT7 detector is significantly higher in healthy controls than in AD samples. A total of 4 healthy control plasma samples and 34 AD / MCI samples were analyzed using the Simoa® assay. ****p<0.0001 [Figure 50]LMTM treatment of L66+ / - mice increases plasma tau levels. (A) The NT1 assay using BT2 and HT7 antibodies detects a slight increase in human-specific N-terminal tau levels in the plasma of L66+ / - mice receiving LMTM (15 mg / kg). (B) Similarly, the core-proline assay using S1D2 and BT2 antibodies measured higher levels of tau in the plasma of LMTM-treated mice, concentrations significantly higher than those seen using the human-specific NT1 assay. The increased levels in treated mice suggest improved clearance of pathological tau from the brain into the blood. [Figure 51] Figure 1 shows S1D12 mAb concentrations in mouse plasma at various time points. Values ​​plotted are the mean concentrations for groups of mice analyzed at 24, 48, 72 hours and 7, 14, and 31 days after administration of a single 30 mg / kg dose of S1D12 mAb. [Figure 52] Comparison of free S1D12 mAb concentrations in plasma of WT mice 7 days after single or repeated doses of 30 mg / kg. Values ​​plotted are mean concentrations (+standard error) for groups of n=6 mice. [Figure 53] Detection of S1D12 in the brains of wild-type, L1, and L66+ / + mice that received S1D12 mAb at a dose of 30 mg / kg weekly for 6 weeks. Values ​​are expressed as the percentage of brain S1D12 concentration relative to plasma in treated mice (mean + standard error; n = 6). [Figure 54] Comparison of the ratio of human to mouse tau in brain homogenates from the L66+ / + vehicle-treated and S1D12 mAb-treated groups. Decreased human tau levels were observed in the brains of mAb-treated mice using the core region antibody S1G2 for detection by Western blot. Plotted values ​​are the ratio of human to mouse tau protein band density (mean + standard error; n = 6) for each group. *p<0.05 [Figure 55]Sarkosyl-insoluble tau levels detected in brain homogenates from vehicle- and S1D12 mAb-treated L66+ / + mice using a core-proline region-specific antibody pair combination (S1G2-BT2). A 5- to 6-fold reduction in core-proline fragment levels was observed in mAb-treated mice compared to the vehicle group. Individual mouse samples were analyzed in duplicate, and values ​​represent the average relative luminescence readings for each group. (Mean + standard error; n = 6). [Figure 56] Plasma tau levels increase after S1D12 mAb treatment in mice. Using S1G2 (367-379) and BT2 (194-198) antibodies, human-specific core-proline domain tau levels were elevated in S1D12 mAb-treated mice compared to the vehicle group. Individual mouse samples were analyzed in duplicate, and values ​​represent the average concentration of tau fragments detected by the combined S1G2-BT2 antibody pair. For L66, a more than three-fold increase was achieved in the treatment group, whereas the difference was not statistically significant in L1 and wild-type mice (n = 6, mean + standard error). An unpaired t-test was performed between the vehicle and treatment groups; **P ≤ 0.01, ns, no significant difference. [Figure 57] Plasma tau levels of N-terminal tau are increased by S1D12 treatment in L66 mice. Using BT2 (194-198) and Tau 12 (6-18) antibodies, human-specific N-terminal tau levels were elevated in S1D12 mAb-treated mice compared to the vehicle group. Individual mouse samples were analyzed in duplicate, and values ​​represent the average concentration of tau fragments detected by the BT2-Tau12 antibody pair combination (n = 6, standard error bars); unpaired t-test was performed between vehicle and treatment groups, ***P ≤ 0.001. [Figure 58]Plasma tau levels of N-terminal tau are increased by S1D12 treatment in L66 mice. Using BT2 (194-198) and HT7 (159-163) antibodies, human-specific proline tau levels were elevated in S1D12 mAb-treated mice compared to the vehicle group; however, the difference was not statistically significant. Individual mouse samples were analyzed in duplicate, and values ​​represent the average concentration of tau fragments detected by the BT2-HT7 antibody pair combination (n = 6; standard error bars). [Figure 59] Transmission electron microscopy images of dGAE assembled in the presence and absence of antibodies: (A) dGAE (100 μM); (B) dGAE (25 μM); (C) dGAE (10 μM); (D) dGAE (100 μM) + s1D12 (25 μM; 4:1); (E) dGAE (25 μM) + s1D12 (25 μM; 1:1); (F) dGAE (10 μM) + s1D12 (2.5 μM; 4:1); (G) dGAE (10 μM) + anti-ovalbumin (2.5 μM; 4:1); (H) s1D12 (25 μM); (I) anti-ovalbumin (2.5 μM). Fibrils were observed only in the dGAE control prepared in the absence of s1D12 (A–C) or in the presence of the non-tau IgG antibody anti-ovalbumin (G). When s1D12 was added to the assembly mixture at either a 1:1 or 4:1 dGAE protein:antibody ratio (D, E, and F), no fibril formation was observed. Fibrils were also absent in the antibody control in the absence of dGAE (H and I). Scale bar (on I for all panels), 200 nm. [Figure 60] CD spectra in millidegrees (mdeg) for (A) 100 μM dGAE and 25 μM s1D12 (4:1 ratio) with (dashed line) and without (solid line), and antibody alone (dotted line), and (B) subtracted antibody spectrum. dGAE (solid line) exhibits a β-sheet conformation (positive at approximately 200 nm, negative at approximately 220 nm), whereas subtraction of the s1D12 spectrum reveals a random coil (negative at approximately 200 nm, positive at approximately 220 nm) (B; dashed and dotted lines), indicating that dGAE does not assemble into fibrils. [Figure 61]Fluorescence of samples incubated with ThS. An emission peak at 483 nm is clearly observed with 25 (A, 1:1) and 100 μM (B, 4:1) dGAE (solid line), but this disappears when s1D12 is included in the assembly mixture (dashed line), indicating that only the s1D12-free sample contains self-assembled amyloid fibrils. The dotted line indicates that s1D12 alone does not contribute to the fluorescence. DETAILED DESCRIPTION OF THE INVENTION

[0023] According to a first aspect, the present invention provides a specific binding molecule that binds to an epitope within SEQ ID NO:1 with a higher binding affinity than the binding affinity with which antibody mAb423 binds to the epitope within SEQ ID NO:1.

[0024] All residue numbers in tau protein sequences and structures in this disclosure refer to residues in SEQ ID NO: 1, the sequence of the four-repeat isoform 2N4R (Uniprot ID P10636-8) of human tau protein, or homologous positions in other species or variants thereof. Human tau isoform 2N4R (Uniprot ID P10636-8) corresponds to amino acids 1-124, 376-394, and 461-758 of full-length tau, Uniprot ID P10636 or P10636-1, provided as SEQ ID NO: 2. SEQ ID NO: 2 relates to the long form of tau found in the peripheral nervous system (PNS), but not the central nervous system (CNS). As used herein, reference to "full-length" tau refers to SEQ ID NO: 1 (the relevant sequence for the CNS), and not to SEQ ID NO: 2 (which is not relevant in the CNS). SEQ ID NO: 1 (Isoform Tau-F, also known as Tau-4, 2N4R, 441 amino acids): >sp|P10636-8|Tau_Human Tau isoform, a microtubule-associated protein. OS=Human (Homo sapiens) OX=9606 GN=MAPT [C1] MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGD TPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPT REPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHH KPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL SEQ ID NO:2 (full-length human tau, isoform PNS-Tau, 758 amino acids); >sp|P10636-1|Tau_Human Microtubule-associated protein tau OS=Human (Homo sapiens) OX=9606 GN=MAPT PE=1 SV=5 [Case 2] MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQEPESGKVVQEGFLREPGPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEGGRHAPELLK HQLLGDLHQEGPPLKGAGGKERPGSKEEVDEDRDVDESSPQDSPPSKASPAQDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKVSTEIPASEPDGPSVGRAKGQDAPLEFTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEADLPEPSEKQPAAAPRGKPVSRVPQLKARMV SKSKDGTGSDDKKAKAKTSTRSSAKTLKNRPCLSPKHPTPGSSDPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMP DLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL

[0025] "Mouse Tau" as used herein refers to the isoform Tau-A having the sequence of Uniprot ID P10637-2, provided as SEQ ID NO:589. [C3] MADPRQEFDTMEDHAGDYTLLQDQEGDMDHGLKESPPQPPADDGAEEPGSETSDAKSTPTAEDVTAPLVDERAPDKQAAAQPHTEIPEGITAEEAGIGDTPNQEDQAAGHVTQARVASKDRTGNDEKKAKGADGKTGAKIATPRGAASPAQKGTSNATRIPAKTTPSPKTPPGSGEPPKSGERSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSASKSRLQTAPVPMPDLKNVRSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSG DTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL

[0026] dGAE97 refers to a 97-residue fragment of Tau (2N4R) N-terminal at residue Asp-295 and C-terminal at residue Glu-391, as set forth in SEQ ID NO: 3, or at homologous positions in other species (these residues are mentioned with reference to the human or mouse Tau sequence with which this region is identical). As will be apparent to those skilled in the art, dGAE97 also corresponds to a fragment of the isoform PNS-Tau (P10636-1), N-terminal at Asp-612 and C-terminal at Glu-708. SEQ ID NO:3 (dGAE97, human / mouse, 97 amino acids): [C4] DNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAE

[0027] dGAE95 refers to a 95-residue fragment of tau(2N4R) N-terminal at residue Ile-297 and C-terminal at residue Glu-391, as set forth in SEQ ID NO:4, or at homologous positions in other species (these residues are referred to with reference to the human or mouse tau sequence with which this region is identical). As will be apparent to those skilled in the art, dGAE95 also corresponds to a fragment of the isoform PNS-Tau(P10636-1) N-terminal at Ile-614 and C-terminal at Glu-708. This sequence is sometimes simply referred to as "dGAE." Residues 297-391 of tau(2N4R) are also known as the predominant fragment isolated from the proteolytically stable core of the paired helical fibril (PHF). SEQ ID NO: 4 (dGAE95 or "dGAE", human / mouse, 95 amino acids): [5] IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAE

[0028] "dGA" refers to a 94-residue fragment of tau (2N4R) N-terminal at residue Ile-297 and C-terminal at residue Ala-390, as set forth in SEQ ID NO: 5, or at homologous positions in other species (these residues are mentioned with reference to the human or mouse tau sequence with which this region is identical). SEQ ID NO: 5 (dGA, human / mouse, 94 amino acids): [6] IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGA

[0029] dGAE73 refers to a fragment of tau (2N4R) N-terminal at residue Val-306 and C-terminal at residue Phe-378, as set forth in SEQ ID NO: 6, or at homologous positions in other species (these residues are mentioned with reference to the human or mouse tau sequence to which this region is identical). This fragment corresponds to residues 306-378 of the sequence identified by cryo-EM as the core of PHFs isolated from AD brain tissue (Fitzpatrick et al., 2017; Nature). The core may extend beyond these residues, but is limited by the resolution of cryo-EM. As will be apparent to those skilled in the art, dGAE73 also corresponds to a fragment of the isoform PNS-Tau (P10636-1), N-terminal at Val-623 and C-terminal at Phe-695. SEQ ID NO: 6 (dGAE73, human / mouse, 73 amino acids): [7] VQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTF

[0030] The PHF core refers to residues 296-391 of tau(2N4R) as set forth in SEQ ID NO: 3 or homologous positions in other species (these residues are mentioned with reference to the human or mouse tau sequence with which this region is identical).

[0031] Further fragments of the PHF core are N-terminal at residue Ile-308 and C-terminal at residue Phe-378 as set forth in SEQ ID NO: 7, or residues 308-378 of tau(2N4R) at homologous positions in other species (these residues are mentioned with reference to the human or mouse tau sequence to which this region is identical). SEQ ID NO: 7 (dGAE71, residues 308-378 of 2N4R, human / mouse, 71 amino acids): [8] IVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTF

[0032] The epitope of the specific binding molecule may be within SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6 or SEQ ID NO:7.

[0033] The epitope of the specific binding molecule can be within residues 297-391 of SEQ ID NO: 1. Residues 297-391 of full-length tau are also known as the predominant fragment isolated from the proteolytically stable core of the paired helical fibril (PHF), i.e., the PHF core fragment. Thus, the epitope of the specific binding molecule can be within the PHF or the dGAE fragment. Thus, the epitope of the specific binding molecule can be within SEQ ID NO: 4.

[0034] The epitope of the specific binding molecule can be within residues 297-390 of SEQ ID NO: 1. Residues 297-390 of full-length tau are also known as the dGA fragment. Thus, the epitope of the specific binding molecule can be within the dGA fragment. Thus, the epitope of the specific binding molecule can be within SEQ ID NO: 5. The epitope of the specific binding molecule can be within dGAE73 and / or dGAE71. Thus, the epitope of the specific binding molecule can be within SEQ ID NO: 6 and / or SEQ ID NO: 7.

[0035] The epitope of the specific binding molecule may be within residues 308-378 of SEQ ID NO: 1. Residues 308-378 of full-length tau are also known as the PHF core. Thus, the epitope of the specific binding molecule may be within the PHF core. Therefore, the epitope of the specific binding molecule may be within SEQ ID NO: 7.

[0036] The epitope of the specific binding molecule can be within residues 297-386 of SEQ ID NO: 1. The epitope of the specific binding molecule can be within residues 306-391 of SEQ ID NO: 1. The epitope of the specific binding molecule can be within residues 306-386 of SEQ ID NO: 1.

[0037] The epitopes of the specific binding molecules are residues 337-355 of SEQ ID NO:1, residues 367-379 of SEQ ID NO:1, residues 331-360 of SEQ ID NO:1, residues 355-367 of SEQ ID NO:1, residues 379-391 of SEQ ID NO:1, residues 297-390 of SEQ ID NO:1, residues 369-390 of SEQ ID NO:1, residues 337-368 of SEQ ID NO:1, residues 412-441 of SEQ ID NO:1, residues 1-49 of SEQ ID NO:1, residues 49-111 of SEQ ID NO:1, residues 147-157 of SEQ ID NO:1, residues 1-155 of SEQ ID NO:1, residues 1-238 of SEQ ID NO:1, residues 1-319 of SEQ ID NO:1, residues 13-25 of SEQ ID NO:1, residues 412-441 of SEQ ID NO:1 1, residues 9-113 of SEQ ID NO:1, residues 49-155 of SEQ ID NO:1, residues 49-238 of SEQ ID NO:1, residues 113-238 of SEQ ID NO:1, residues 155-227 of SEQ ID NO:1, residues 155-238 of SEQ ID NO:1, residues 186-263 of SEQ ID NO:1, residues 186-350 of SEQ ID NO:1, residues 239-348 of SEQ ID NO:1, residues 266-359 of SEQ ID NO:1, residues 277-319 of SEQ ID NO:1, residues 319-331 of SEQ ID NO:1, residues 348-390 of SEQ ID NO:1, residues 348-441 of SEQ ID NO:1, residues 359-391 of SEQ ID NO:1 and residues 360-390 of SEQ ID NO:1.

[0038] The epitope of the specific binding molecule can be within an amino acid sequence selected from the group consisting of residues 337-355 of SEQ ID NO:1, residues 367-379 of SEQ ID NO:1, residues 331-360 of SEQ ID NO:1, residues 355-367 of SEQ ID NO:1, residues 379-391 of SEQ ID NO:1, residues 297-390 of SEQ ID NO:1, residues 369-390 of SEQ ID NO:1, residues 337-368 of SEQ ID NO:1, residues 412-441 of SEQ ID NO:1, residues 1-49 of SEQ ID NO:1, residues 49-111 of SEQ ID NO:1, and residues 147-157 of SEQ ID NO:1.

[0039] The epitope of the specific binding molecule can be within an amino acid sequence selected from the group consisting of residues 337-355 of SEQ ID NO:1, residues 367-379 of SEQ ID NO:1, residues 331-360 of SEQ ID NO:1, and residues 355-367 of SEQ ID NO:1.

[0040] The epitope of the specific binding molecule can be within an amino acid sequence selected from the group consisting of residues 341-353 of SEQ ID NO:1.

[0041] The epitope of a specific binding molecule of the invention can be any amino acid sequence of SEQ ID NO: 1 that is indicated to contain critical binding residues by ELISA or alanine scanning mutagenesis, e.g., as described in Examples 5-12.

[0042] An epitope, as described herein, can be identified as "comprising" a certain amino acid sequence or by the phrase "a specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising the residues ...." As will be apparent to one of skill in the art, when a specific binding molecule binds to a polypeptide or protein molecule comprising that epitope, it will also bind to a polypeptide or protein molecule consisting of that epitope. Thus, as used herein, the phrase "a specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising the residues ..." can alternatively be replaced, whenever it appears, with the phrase "a specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence consisting of the residues ..."; the phrase "a specific binding molecule binds to a polypeptide or protein molecule consisting of an amino acid sequence comprising the residues ..."; or the phrase "a specific binding molecule binds to a polypeptide or protein molecule consisting of an amino acid sequence consisting of the residues ...."

[0043] Those skilled in the art will recognize that not all residues within an epitope are essential. A specific binding molecule may retain binding to an amino acid sequence that has at least 70% identity to an epitope. The specific binding molecule may bind to any of the epitopes disclosed herein or an amino acid sequence that has at least 70% identity thereto.

[0044] A specific binding molecule may retain binding to an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to an epitope. The specific binding molecule may bind to any of the epitopes disclosed herein or an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity thereto.

[0045] In embodiments of the invention in which a specific binding molecule retains binding to an amino acid sequence that has less than 100% sequence identity with the amino acid sequence of SEQ ID NO:1 (or any of SEQ ID NOs:3-7 or any other epitope defined herein), the epitope sequence may be altered by substitution, addition, or deletion of an appropriate number of amino acids in the sequence of SEQ ID NO:1 (or any of SEQ ID NOs:3-7 or any other epitope defined herein). In another embodiment of the invention, the epitope may be modified by substitution, addition, or deletion of up to two amino acids relative to SEQ ID NO:1 (or any of SEQ ID NOs:3-7 or any other epitope defined herein), provided that the resulting epitope sequence has at least 85% or 90% sequence identity with SEQ ID NO:1 (or any of SEQ ID NOs:3-7 or any other epitope defined herein), as set forth above. "Substitution, addition, or deletion" includes combinations of substitutions, additions, and deletions.

[0046] When an epitope sequence is modified by substituting a specific amino acid residue, the substitution may be a conservative amino acid substitution. As used herein, the term "conservative amino acid substitution" refers to an amino acid substitution in which an amino acid residue is replaced with another amino acid residue having a similar side chain. Amino acids with similar side chains tend to have similar properties, and therefore, conservative substitutions of amino acids important to the structure or function of a polypeptide may be expected to have less of an effect on the polypeptide structure / function than non-conservative amino acid substitutions at the same position. Families of amino acid residues having similar side chains have been defined in the art, including basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., asparagine, glutamine, serine, threonine, tyrosine), nonpolar side chains (e.g., glycine, cysteine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Thus, conservative amino acid substitutions can be considered as those in which a particular amino acid residue is replaced with a different amino acid from the same family. However, substitutions of epitope residues can also be non-conservative, in which one amino acid is replaced with another amino acid having a side chain belonging to a different family.

[0047] An epitope can be at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 amino acids in length. An epitope can be 5 to 20 amino acids in length. An epitope can be 5 to 15 amino acids in length. An epitope can be 5 to 12 amino acids in length. An epitope can be 6 to 12 amino acids in length. An epitope can be 7 to 12 amino acids in length.

[0048] As used herein, the term "within" means "contained within" or "completely within." Residues considered essential for binding of a specific binding molecule to its target are not outside the epitope. Residues outside the epitope do not significantly contribute to binding. For example, if the epitope of a specific binding molecule is within residues 337-355 of SEQ ID NO: 1, residues outside residues 337-355 do not significantly contribute to binding.

[0049] An epitope can include any residue within SEQ ID NO: 1 to which a specific binding molecule binds. The epitope can be a continuous or discontinuous epitope.

[0050] A continuous epitope can be any contiguous residues within SEQ ID NO: 1 to which a specific binding molecule binds. Contiguous residues are adjacent to each other in the primary structure of the polypeptide.

[0051] A discontinuous epitope can be any non-contiguous residues within SEQ ID NO: 1 to which a specific binding molecule binds. Discontinuous epitopes are typically formed by non-contiguous residues that are closely spaced in three-dimensional space due to folding of the polypeptide.

[0052] Typically, a specific binding molecule binds to a polypeptide or protein molecule containing its epitope. Thus, a specific binding molecule may bind to SEQ ID NO: 1 or a fragment thereof. A specific molecule may bind to SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6 and / or SEQ ID NO: 7. A specific binding molecule may bind to a PHF or dGAE fragment. A specific binding molecule may bind to a dGA fragment. A specific binding molecule may bind to a PHF core. The specific binding molecule is selected from the group consisting of residues 337-355 of SEQ ID NO:1, residues 367-379 of SEQ ID NO:1, residues 331-360 of SEQ ID NO:1, residues 355-367 of SEQ ID NO:1, residues 379-391 of SEQ ID NO:1, residues 297-390 of SEQ ID NO:1, residues 369-390 of SEQ ID NO:1, residues 337-368 of SEQ ID NO:1, residues 412-441 of SEQ ID NO:1, residues 1-49 of SEQ ID NO:1, residues 49-111 of SEQ ID NO:1, residues 147-157 of SEQ ID NO:1, residues 1-155 of SEQ ID NO:1, residues 1-238 of SEQ ID NO:1, residues 1-319 of SEQ ID NO:1, residues 13-25 of SEQ ID NO:1, residues 49-113 ... residues 49 to 155 of SEQ ID NO:1, residues 49 to 238 of SEQ ID NO:1, residues 113 to 238 of SEQ ID NO:1, residues 155 to 227 of SEQ ID NO:1, residues 155 to 238 of SEQ ID NO:1, residues 186 to 263 of SEQ ID NO:1, residues 186 to 350 of SEQ ID NO:1, residues 239 to 348 of SEQ ID NO:1, residues 266 to 359 of SEQ ID NO:1, residues 277 to 319 of SEQ ID NO:1, residues 319 to 331 of SEQ ID NO:1, residues 348 to 390 of SEQ ID NO:1, residues 348 to 441 of SEQ ID NO:1, residues 359 to 391 of SEQ ID NO:1, and residues 360 to 390 of SEQ ID NO:1.

[0053] The specific binding molecule may bind to a polypeptide or protein molecule comprising the amino acid sequence of residues 341-353 of SEQ ID NO:1.

[0054] In the sequences below, " / " means "or" and indicates that the residues we have indicated can differ as specified. In this context, "-" means a gap or no amino acid. X is any amino acid. For example, "N / S" means a residue that can be either N or S. Similarly, "G / -" means a residue that can be either G or absent. Similarly, "H / F / Y" means that the residue can be H, F, or Y. When sequence identity values ​​are specified, the sequence identity can be calculated starting from any one of the residues separated by " / ".

[0055] An epitope of a specific binding molecule can be within the amino acid sequence comprising residues 337-355 of SEQ ID NO: 1. An epitope of a specific binding molecule within the amino acid sequence comprising residues 337-355 of SEQ ID NO: 1 can be within the amino acid sequence comprising residues 341-353 of SEQ ID NO: 1. Thus, an epitope can be within the amino acid sequence of SEQ ID NO: 8 (VEVKSEKLDFKDR).

[0056] The epitope may be within the amino acid sequence comprising residues 337-349 of SEQ ID NO:1, preferably within the amino acid sequence comprising residues 337-355 of SEQ ID NO:1. This epitope may be bound by the CDRs of a specific binding molecule referred to herein as "S1D12." The epitope may comprise the amino acid sequence of SEQ ID NO:8 (VEVKSEKLDFKDR). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO:8 (VEVKSEKLDFKDR). Essential residues of the epitope may be residues 343 (K), 346 (F), and / or 349 (R) (numbering according to SEQ ID NO:1). The epitope may comprise the amino acid sequence of SEQ ID NO:9 (XXXXXXXKXXFXXR, where X is any amino acid). The epitope may comprise the amino acid sequence of SEQ ID NO: 8, in which any one or more residues other than residue numbers 343 (K), 346 (F), and / or 349 (R) are replaced by a non-conservative amino acid substitution (numbering according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 8, in which any one or more residues other than residue numbers 343 (K), 346 (F), and / or 349 (R) are replaced by a conservative amino acid substitution (numbering according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 8, in which any one or more residues other than residue numbers 343 (K), 346 (F), and / or 349 (R) are replaced by a conservative amino acid substitution (numbering according to SEQ ID NO: 1), and in which any one or more residues other than residue numbers 343 (K), 346 (F), and / or 349 (R) are replaced by a non-conservative amino acid substitution (numbering according to SEQ ID NO: 1).

[0057] The epitope may consist of residues 337 to 349 of SEQ ID NO: 1, preferably residues 337 to 355 of SEQ ID NO: 1. The epitope may consist of the amino acid sequence of SEQ ID NO: 8 (VEVKSEKLDFKDR). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 8 (VEVKSEKLDFKDR).

[0058] A specific binding molecule may bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 355 of SEQ ID NO: 1. The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of the CDRs having the amino acid sequence: VHCDR1 comprises the sequence shown in SEQ ID NO: 10 (N / SNAVG); VHCDR2 comprises the sequence shown in SEQ ID NO: 11 (GCSSDGT / KCYY / HNSALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 12 (GH / F / YYS / PI / VYGYDYL / SGTIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 13 (SGSSSNVG / -GG / RNS / DVG / A); VLCDR2 comprises the sequence shown in SEQ ID NO: 14 (D / N / GTN / TSRPS); VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 15 (V / AT / SGDST / ST / AH / ID / NDL / I); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having Includes:

[0059] The sequence identity is at least about 85% sequence identity, and thus may be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0060] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG) or SEQ ID NO: 17 (SNAVG); VHCDR2 comprises the sequence shown in SEQ ID NO: 18 (GCSSDGTCYYNSALKS), SEQ ID NO: 19 (GCSSDGKCYHNSALKS) or SEQ ID NO: 20 (GCSSDGKCYYNSALKS); VHCDR3 comprises the sequence shown in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY), SEQ ID NO: 22 (GFYSIYGYDYSGTIDY) or SEQ ID NO: 23 (GYYPVYGYDYLGTIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 24 (SGSSSNVGGGNSVG) or SEQ ID NO: 25 (SGSSSNVGRNDVA); VLCDR2 comprises the sequence shown in SEQ ID NO: 26 (DTNSRPS), SEQ ID NO: 27 (NTNSRPS) or SEQ ID NO: 28 (GTTSRPS); VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 29 (VTGDSTTHDDL), SEQ ID NO: 30 (VTGDSSTHDDL), or SEQ ID NO: 31 (ASGDSSAINDI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 355 of SEQ ID NO:1.

[0061] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 18 (GCSSDGTCYYNSALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 24 (SGSSSNVGGGNSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO:26 (DTNSRPS); VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 29 (VTGDSTTHDDL); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 355 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "S1D12" (or abbreviated "1D12").

[0062] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 18 (GCSSDGTCYYNSALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 24 (SGSSSNVGGGNSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 26 (DTNSRPS); and VLCDR3 comprises an amino acid sequence that includes the sequence set forth in SEQ ID NO: 29 (VTGDSTTHDDL).

[0063] Any specific binding molecule disclosed herein may be further defined by reference to one or more framework regions (FR), which are non-CDR sequences that together with the CDR sequences form the variable domain.

[0064] The VH domain may have the formula: VHFR1-VHCDR1-VHFR2-VHCDR2-VHFR3-VHCDR3-VHFR4.

[0065] The VL domain may have the formula: VLFR1-VLCDR1-VLFR2-VLCDR2-VLFR3-VLCDR3-VLFR4.

[0066] Those skilled in the art can identify CDR and framework regions within the amino acid sequence of a variable domain using known methods described elsewhere herein. Therefore, any specific binding molecule disclosed herein can be defined by reference to its CDRs and FRs. In some instances, some FR residues may contribute to the affinity with which a specific binding molecule binds to its target. However, without being bound by theory, replacement of FR residues is more likely to maintain function than replacement of CDR residues. FR residues may often be replaced with corresponding residues from human sequences, for example, during humanization. Thus, FR sequences may be more tolerant of amino acid substitutions than CDR sequences.

[0067] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence from any specific binding molecule disclosed herein; or for each FR sequence: (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of said CDRs may comprise an amino acid sequence from any specific binding molecule disclosed herein, or for each CDR sequence: (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having Includes:

[0068] The sequence identity in the CDR sequences is at least about 85% sequence identity, and thus may be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0069] The sequence identity in the FR sequence is at least about 50% sequence identity, and therefore can be at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0070] A FR sequence can be a humanized sequence if it has at least 50% identity (but less than 100%) with the FR sequences disclosed as part of the specific binding molecules disclosed herein, i.e., the only changes in amino acid sequence can be those necessary to humanize the sequence.

[0071] An FR sequence can be a humanized sequence if it has 1, 2, 3, 4, or 5 amino acid substitutions compared to the FR sequence disclosed as part of the specific binding molecules disclosed herein, i.e., the only substitutions required to humanize the sequence can be those necessary.

[0072] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which comprises an amino acid sequence from any of the specific binding molecules disclosed herein; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of said CDRs comprises an amino acid sequence from any of the specific binding molecules disclosed herein.

[0073] Typically, each of the FRs will be from the same specific binding molecule disclosed herein. Typically, each of the CDRs will be from the same specific binding molecule disclosed herein. Typically, there will be no additional intervening amino acid residues between the defined FR and CDR; thus, each of the FRs and each of the CDRs can be said to consist of an amino acid sequence from any of the specific binding molecules disclosed herein.

[0074] As used herein, the phrase "comprising CDRs" also encompasses specific binding molecules comprising the CDRs and FRs of the specific binding molecules disclosed herein, including variants of the FRs, including those described above, such as humanized FRs. It also encompasses specific binding molecules comprising the VH and / or VL domains of the specific binding molecules disclosed herein, including variants of the FRs, including those described above, such as humanized FRs. It also encompasses specific binding molecules comprising the heavy and / or light chains of the specific binding molecules disclosed herein, including variants of the FRs and constant regions, including those described above, such as humanized FRs and humanized constant regions.

[0075] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN); VHFR2 comprises the sequence set forth in SEQ ID NO: 436 (WVRQAPGKVPESLV); VHFR3 comprises the sequence set forth in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR); VHFR4 comprises the sequence set forth in SEQ ID NO: 438 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 440 (WYQHLPGSGLKTIIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 442 (VGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having Includes:

[0076] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN); VHFR2 comprises the sequence set forth in SEQ ID NO: 436 (WVRQAPGKVPESLV); VHFR3 comprises the sequence set forth in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR); VHFR4 comprises the sequence set forth in SEQ ID NO: 438 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 440 (WYQHLPGSGLKTIIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 442 (VGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 355 of SEQ ID NO: 1. A specific binding molecule comprising a FR having 100% identity to those listed above is referred to herein as "S1D12" (or abbreviated as "1D12").

[0077] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN); VHFR2 comprises the sequence set forth in SEQ ID NO: 436 (WVRQAPGKVPESLV); VHFR3 comprises the sequence set forth in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR); VHFR4 comprises the sequence set forth in SEQ ID NO: 438 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 440 (WYQHLPGSGLKTIIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 442 (VGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 18 (GCSSDGTCYYNSALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 24 (SGSSSNVGGGNSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO:26 (DTNSRPS); VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 29 (VTGDSTTHDDL); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 355 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "S1D12" (or abbreviated "1D12").

[0078] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN); VHFR2 comprises the sequence set forth in SEQ ID NO: 436 (WVRQAPGKVPESLV); VHFR3 comprises the sequence set forth in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR); VHFR4 comprises the sequence set forth in SEQ ID NO: 438 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 440 (WYQHLPGSGLKTIIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 442 (VGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 18 (GCSSDGTCYYNSALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 24 (SGSSSNVGGGNSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO:26 (DTNSRPS); VLCDR3 has the amino acid sequence shown in SEQ ID NO: 29 (VTGDSTTHDDL). and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 355 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "S1D12" (or abbreviated "1D12").

[0079] The specific binding molecule is (a) SEQ ID NO: 443 [9] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 444 [C10] (QAVLTQPSSVGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0080] The specific binding molecule is (a) SEQ ID NO: 445 [C11] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDY WGPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPT IKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 446 [C12] (QAVLTQPSSVGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLT VLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[0081] The specific binding molecule may comprise the CDR sequences of the clones presented below in Table 1. The epitope may be within residues 337-355 of SEQ ID NO:1.

[0082] [Table 1]

[0083] The CDRs designated herein are defined based on Kabat. Those skilled in the art will recognize that other methods of identifying CDRs are available, such as Chothia and Martin. Alternative CDR definition methods may sometimes result in changes in the residues defined as belonging to one or more CDRs. For example, an alternative CDR definition for S1D12 based on Chothia and Martin is shown in Figure 1. Any alternative CDR definition for the specific binding molecule sequences disclosed herein is within the scope of the present invention.

[0084] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 1; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 1; VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 1; VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 1; VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 1; and VLCDR3 comprises an amino acid sequence of the VLCDR3 amino acid sequence shown in Table 1; or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 355 of SEQ ID NO:1.

[0085] A specific binding molecule has a K of less than about 500 pM for a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337-355 of SEQ ID NO:1. D It can be bonded with K D may be less than about 400 pM, less than about 300 pM, less than about 200 pM, or less than about 150 pM. D is preferably the K for binding to SEQ ID NO: 1 or SEQ ID NO: 5 D The K for binding to SEQ ID NO: 1 can be D The K for binding to SEQ ID NO: 1 can be from about 50 pM to about 150 pM. D can be about 101 pM or 122 pM, and optionally the specific binding molecule comprises the CDRs of S1D12. D The K for binding to SEQ ID NO: 5 can be about 300 pM to about 400 pM. D can be about 344 pM, and optionally the specific binding molecule comprises a CDR of S1D12.

[0086] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 32, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337-355 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 30. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 32. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 30, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 32. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 32. SEQ ID NO: 32 (S1D12 amino acid sequence) [C13] QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTALTINSLQAEDEGDYYCVTGDSTTTHDDLVGSGTRLTVLG

[0087] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 367 to 379 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 33 (GNKKIETHKLTFR).

[0088] The epitope can be within the amino acid sequence comprising residues 367 to 379 of SEQ ID NO: 1. This epitope can be bound by the CDRs of a specific binding molecule referred to herein as "S1G2."

[0089] The epitope may comprise the amino acid sequence of SEQ ID NO: 33 (GNKKIETHKLTFR). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 33 (GNKKIETHKLTFR). The essential residues of the epitope may be residues 370 (K) and / or 374 (H) (numbering according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 34 (XXXKXXXHXXXXX, where X is any amino acid). The epitope may comprise the amino acid sequence of SEQ ID NO: 33, in which any one or more residues other than residues 370 (K) and / or 374 (H) are replaced by non-conservative amino acid substitutions (numbering according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 33, in which any one or more residues other than residue numbers 370(K) and / or 374(H) are replaced by a conservative amino acid substitution (numbering according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 33, in which any one or more residues other than residue numbers 370(K) and / or 374(H) are replaced by a conservative amino acid substitution (numbering according to SEQ ID NO: 1), and in which any one or more residues other than residue numbers 370(K) and / or 374(H) are replaced by a non-conservative amino acid substitution (numbering according to SEQ ID NO: 1).

[0090] The epitope may consist of the amino acid sequence of SEQ ID NO: 33 (GNKKIETHKLTFR). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 33 (GNKKIETHKLTFR).

[0091] A specific binding molecule may bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367 to 379 of SEQ ID NO: 1. The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of the CDRs having the amino acid sequence: VHCDR1 comprises the sequence set forth in SEQ ID NO: 35 (S / TN / YS / A / YVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 36 (G / S / NI / VD / YT / SD / TGE / Y / D / RE / T / AG / Y / FY / FNPA / VLN / KS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 37 (S / TY / V / AR / NA / T / G / SD / - G / - L / Y / F / - A / - Y / HG / PY / DVQ / YA / YID / EY / R / K) or SEQ ID NO: 265 (GSYYHGGGNGMVDFFDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 38 (SGS / RF / Y / DI / L / VG / SI / S / RSS / R / A / GVG) or SEQ ID NO: 39 (SGSSSNVGYGNYVG), VLCDR2 comprises the sequence shown in SEQ ID NO: 40 (A / DS / AD / S / TG / SRP / AS); VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 41 (G / SS / I / VS / F / Y / TD / G / A / QR / P / - T / - P / Q / D / GY / R / H / NT / NG / YV / I / L); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having Includes:

[0092] The sequence identity is at least about 85% sequence identity, and thus may be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0093] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence shown in SEQ ID NO: 42 (SNSVG), SEQ ID NO: 17 (SNAVG), SEQ ID NO: 44 (SYYVG) or SEQ ID NO: 45 (TNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 46 (GIDTDGEEGYNPALNS), SEQ ID NO: 47 (SVDSDGYTYYNPALKS), SEQ ID NO: 48 (GIDSDGEEGYNPALNS), SEQ ID NO: 49 (GIDSDGEEGYNPALKS), SEQ ID NO: 50 (SVDSDGDTYYNPALKS), SEQ ID NO: 51 (GIDTDGEEGYNPALKS), SEQ ID NO: 52 (NIYSTGRAFYNPALKS) or SEQ ID NO: 53 (GIDTDGEEGFNPVLKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY), SEQ ID NO: 55 (SYRTDGLAYGYVQAIDY), SEQ ID NO: 56 (SVNGHPDVYYIDR), SEQ ID NO: 57 (TYRTDGYAYGYVQAIDY), SEQ ID NO: 58 (SYRSDGLAYGYVQAIDY), SEQ ID NO: 59 (SANGHPDVYYIDK), SEQ ID NO: 60 (TYRTDGFAYGYVQAIDY), SEQ ID NO: 61 (SYRTDGLAYGYVQAIEY) or SEQ ID NO: 265 (GSYYHGGGNGMVDFFDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 63 (SGSFIGISSVG); SEQ ID NO: 64 (SGSYISSSRVG); SEQ ID NO: 65 (SGSDLGSSRVG); SEQ ID NO: 66 (SGSYIGSSAVG); SEQ ID NO: 67 (SGRFIGISSVG); SEQ ID NO: 68 (SGSYIGSSGVG); or SEQ ID NO: 69 (SGSYVSRSRVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); SEQ ID NO: 71 (DSSSRPS); or SEQ ID NO: 72 (AATSRAS); VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO:73 (GSSDRTPYTGV); SEQ ID NO:74 (GSSDRTQYTGV); SEQ ID NO:75 (GVFGDRNYI); SEQ ID NO:76 (GIFGDRNYI); SEQ ID NO:77 (GSTAPTPHTGV); SEQ ID NO:78 (SSYQRGNTGV); SEQ ID NO:79 (GSSDRTQYTGL); or SEQ ID NO:80 (GIYGDRNYI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367 to 379 of SEQ ID NO:1.

[0094] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 73 (GSSDRTPYTGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "S1G2."

[0095] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); and VLCDR3 comprises an amino acid sequence that includes the sequence set forth in SEQ ID NO: 73 (GSSDRTPYTGV).

[0096] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 448 (WVRQAPGKAPEWVA); VHFR3 comprises the sequence set forth in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR); VHFR4 comprises the sequence set forth in SEQ ID NO: 450 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 452 (WFQQLPGSGLRTIIV); VLFR3 comprises the sequence set forth in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 454 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having Includes:

[0097] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 448 (WVRQAPGKAPEWVA); VHFR3 comprises the sequence set forth in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR); VHFR4 comprises the sequence set forth in SEQ ID NO: 450 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 452 (WFQQLPGSGLRTIIV); VLFR3 comprises the sequence set forth in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 454 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. A specific binding molecule comprising a FR having 100% identity to those listed above is referred to herein as "S1G2."

[0098] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 448 (WVRQAPGKAPEWVA); VHFR3 comprises the sequence set forth in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR); VHFR4 comprises the sequence set forth in SEQ ID NO: 450 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 452 (WFQQLPGSGLRTIIV); VLFR3 comprises the sequence set forth in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 454 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 73 (GSSDRTPYTGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "S1G2."

[0099] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 448 (WVRQAPGKAPEWVA); VHFR3 comprises the sequence set forth in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR); VHFR4 comprises the sequence set forth in SEQ ID NO: 450 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 452 (WFQQLPGSGLRTIIV); VLFR3 comprises the sequence set forth in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 454 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); and VLCDR3 has the amino acid sequence GSSDRTPYTGV, which comprises the sequence set forth in SEQ ID NO: 73 (GSSDRTPYTGV). and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "S1G2."

[0100] The specific binding molecule is (a) SEQ ID NO: 455 [C14] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 456 [C15] (QAVVTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0101] The specific binding molecule is (a) SEQ ID NO: 457 [C16] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAID YWGPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGP TIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIE RTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 458 [C17] (QAVVTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTV ) a light chain comprising the sequence shown in These humanized variants may include:

[0102] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 55 (SYRTDGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "S1B1."

[0103] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 55 (SYRTDGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); VLCDR3 comprises an amino acid sequence comprising the sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV).

[0104] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 48 (GIDSDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 57 (TYRTDGYAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "S1D9."

[0105] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 48 (GIDSDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 57 (TYRTDGYAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); VLCDR3 comprises an amino acid sequence comprising the sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV).

[0106] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "S1F4."

[0107] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); VLCDR3 comprises an amino acid sequence comprising the sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV).

[0108] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "S1G10."

[0109] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); VLCDR3 comprises an amino acid sequence comprising the sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV).

[0110] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 51 (GIDTDGEEGYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 60 (TYRTDGFAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "S2C6."

[0111] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 51 (GIDTDGEEGYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 60 (TYRTDGFAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); VLCDR3 comprises an amino acid sequence comprising the sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV).

[0112] The specific binding molecule may comprise the CDR sequences of the clones presented below in Table 2. The epitope may be within residues 367-379 of SEQ ID NO:1.

[0113] [Table 2] JPEG0007796719000003.jpg246170

[0114] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 2; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 2; VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 2; VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 2; VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 2; and VLCDR3 comprises an amino acid sequence of the VLCDR3 amino acid sequence shown in Table 2; or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367 to 379 of SEQ ID NO:1.

[0115] A specific binding molecule has a K of less than about 500 pM for a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO:1. D It can be bonded with K D may be less than about 400 pM, less than about 300 pM, or less than about 200 pM. D is preferably the K for binding to SEQ ID NO: 1 or SEQ ID NO: 5 D The K for binding to SEQ ID NO: 1 can be D The K for binding to SEQ ID NO: 1 can be from about 100 pM to about 200 pM. D can be about 140 pM or 170 pM, and optionally the specific binding molecule comprises the CDRs of S1G2. D The K for binding to SEQ ID NO: 5 can be about 400 pM to about 500 pM. D can be about 447 pM, and optionally the specific binding molecule comprises the CDRs of S1G2.

[0116] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 81, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 81. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 81. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 81, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 81. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 81. SEQ ID NO: 81 (S1G2 amino acid sequence) [C18] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVVTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG

[0117] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 412, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 412. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 412. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 412, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 412. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 412. SEQ ID NO: 412 (S1B1 amino acid sequence) [C19] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCVRSYRTDGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVLTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTVIVASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0118] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 413, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 413. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 413. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 413, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 413. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 413. SEQ ID NO: 413 (S1D9 amino acid sequence)

[20] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDSDGEEGYNPALNSRLSITRDTSKNQVSLSLSRVTSEDTAVYYCGRTYRTDGYAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDRVMLTQPPSVGSPGQTVSITCSGSFIGISSVGWFQQLPGSGLRTVIFASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLS

[0119] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 414, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 414. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 414. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 414, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 414. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 414. SEQ ID NO: 414 (S1F4 amino acid sequence)

[21] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCVRSYRADGLAYGYVQAIDYWGPGLLLTIS SEGKSSGASGESKVDDQAVVTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIVASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0120] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 415, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 415. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 415. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 415, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 415. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 415. SEQ ID NO: 415 (S1G10 amino acid sequence)

[22] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVLTQPSSMSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0121] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 416, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 416. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 416. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 416, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 416. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 416. SEQ ID NO: 416 (S2C6 amino acid sequence)

[23] QVQLQESGPSLVKPSQTLSLTCTVSGFSLISNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALKSQYAASDPDTSKSQVSLSLSSVTSEDTAVYYCGRTYRTDGFAYGYVQAIDYWGPGLLLTIS SEGKSSGASGESKVDDQAVLTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0122] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 337 to 368 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN).

[0123] The epitope can be within the amino acid sequence comprising residues 337 to 368 of SEQ ID NO: 1. This epitope can be bound by the CDRs of a specific binding molecule referred to herein as "NS2A3."

[0124] The epitope may comprise the amino acid sequence of SEQ ID NO: 82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN).

[0125] The epitope may consist of the amino acid sequence of SEQ ID NO: 82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN).

[0126] A specific binding molecule may bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 368 of SEQ ID NO: 1. The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of the CDRs having the amino acid sequence: VHCDR1 comprises the sequence set forth in SEQ ID NO: 83 (SYSVY), VHCDR2 comprises the sequence set forth in SEQ ID NO: 84 (IMYASGRVDYNPALKS), VHCDR3 comprises the sequence set forth in SEQ ID NO: 85 (GIEN / D), VLCDR1 comprises the sequence set forth in SEQ ID NO: 86 (RTS / NQ / ES / NV / IN / G / DN / SY / GLS / A), VLCDR2 comprises the sequence set forth in SEQ ID NO: 87 (YATYLY / HT), VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 88 (LQYD / G / ES / TTPLA / T), or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having Includes:

[0127] The sequence identity is at least about 85% sequence identity, and thus may be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0128] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 83 (SYSVY); VHCDR2 comprises the sequence set forth in SEQ ID NO: 84 (IMYASGRVDYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 89 (GIEN) or SEQ ID NO: 90 (GIED); VLCDR1 comprises the sequence shown in SEQ ID NO: 91 (RTSQSVNNYLS), SEQ ID NO: 92 (RTNESVGNYLS), SEQ ID NO: 93 (RTSQNIDNGLA) or SEQ ID NO: 94 (RTSQSVGSYLS); VLCDR2 comprises the sequence shown in SEQ ID NO: 95 (YATRLYT) or SEQ ID NO: 96 (YATRLHT); VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 97 (LQYDSTPLA), SEQ ID NO: 98 (LQYDSTPLT), SEQ ID NO: 99 (LQYESTPLA) or SEQ ID NO: 100 (LQYGTTPLA); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 368 of SEQ ID NO:1.

[0129] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 83 (SYSVY); VHCDR2 comprises the sequence set forth in SEQ ID NO: 84 (IMYASGRVDYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO:89 (GIEN); VLCDR1 comprises the sequence set forth in SEQ ID NO: 91 (RTSQSVNNYLS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 95 (YATRLYT); VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 97 (LQYDSTPLA); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337-368 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "NS2A3."

[0130] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 83 (SYSVY); VHCDR2 comprises the sequence set forth in SEQ ID NO: 84 (IMYASGRVDYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO:89 (GIEN); VLCDR1 comprises the sequence set forth in SEQ ID NO: 91 (RTSQSVNNYLS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 95 (YATRLYT); and VLCDR3 comprises an amino acid sequence that includes the sequence set forth in SEQ ID NO: 97 (LQYDSTPLA).

[0131] The specific binding molecule may comprise the CDR sequences of the clones presented below in Table 3. The epitope may be within residues 337-368 of SEQ ID NO:1.

[0132] [Table 3]

[0133] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 3; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 3; The VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 3; VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 3; VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 3; and VLCDR3 comprises an amino acid sequence of a VLCDR3 amino acid sequence shown in Table 3; or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 368 of SEQ ID NO:1.

[0134] A specific binding molecule has a K of less than 25 nM, preferably less than 20 nM, 15 nM or 10 nM, for a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337-368 of SEQ ID NO:1. D It can be bonded with K D is preferably the K for binding to SEQ ID NO: 1 or SEQ ID NO: 5 D It could be.

[0135] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 369 to 390 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 101 (KKIETHKLTFRENAKAKTDHGA).

[0136] The epitope can be within the amino acid sequence comprising residues 369 to 390 of SEQ ID NO: 1. This epitope can be bound by the CDRs of a specific binding molecule referred to herein as "NS4E3."

[0137] The epitope may comprise the amino acid sequence of SEQ ID NO: 101 (KKIETHKLTFRENAKAKTDHGA). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 101 (KKIETHKLTFRENAKAKTDHGA).

[0138] The epitope may consist of the amino acid sequence of SEQ ID NO: 101 (KKIETHKLTFRENAKAKTDHGA). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 101 (KKIETHKLTFRENAKAKTDHGA).

[0139] A specific binding molecule may bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 369 to 390 of SEQ ID NO: 1. The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of the CDRs having the amino acid sequence: VHCDR1 comprises the sequence set forth in SEQ ID NO: 102 (RESIA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 103 (GVGIDGTSYYSPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 104 (NYIDFEY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 105 (SGSS / N / YS / N / - N / - V / - G / IY / S / A / GE / G / SD / N / TY / G / DVN / S / G); VLCDR2 comprises the sequence set forth in SEQ ID NO: 106 (G / RT / N / ST / SN / T / RRP / AS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 107 (L / A / GSYDR / T / G / SS / TG / NS / R / - N / G / S / IF / I / V); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having Includes:

[0140] The sequence identity is at least about 85% sequence identity, and thus may be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0141] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 102 (RESIA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 103 (GVGIDGTSYYSPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 104 (NYIDFEY); VLCDR1 comprises the sequence shown in SEQ ID NO: 108 (SGSSSNVGYEDYVN), SEQ ID NO: 109 (SGSNIAGNGVG), SEQ ID NO: 110 (SGSSNNVGSGDYVS) or SEQ ID NO: 111 (SGSYIGSTDVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 112 (GTTNRPS), SEQ ID NO: 113 (GSTRRPS), SEQ ID NO: 114 (RNSNRPS), or SEQ ID NO: 115 (RTTTRAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 116 (LSYDRSGSNF), SEQ ID NO: 117 (ASYDTSNRGI), SEQ ID NO: 118 (GSYDGTNSF) or SEQ ID NO: 119 (ASYDSNNSIV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 369 to 390 of SEQ ID NO:1.

[0142] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 102 (RESIA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 103 (GVGIDGTSYYSPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 104 (NYIDFEY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 108 (SGSSSNVGYEDYVN); VLCDR2 comprises the sequence set forth in SEQ ID NO: 112 (GTTNRPS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 116 (LSYDRSGSNF); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 369-390 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "NS4E4."

[0143] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 102 (RESIA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 103 (GVGIDGTSYYSPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 104 (NYIDFEY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 108 (SGSSSNVGYEDYVN); VLCDR2 comprises the sequence set forth in SEQ ID NO: 112 (GTTNRPS); and VLCDR3 can comprise an amino acid sequence including the sequence set forth in SEQ ID NO: 116 (LSYDRSGSNF). The specific binding molecule can comprise the CDR sequences of the clones presented in Table 4 below. The epitope can be within residues 369-390 of SEQ ID NO: 1.

[0144] [Table 4]

[0145] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 4; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 4; VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 4; VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 4; VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 4; and VLCDR3 comprises an amino acid sequence of a VLCDR3 amino acid sequence shown in Table 4; or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 369 to 390 of SEQ ID NO:1.

[0146] A specific binding molecule has a K of less than 25 nM, preferably less than 20 nM, 15 nM or 10 nM, for a polypeptide or protein molecule comprising an amino acid sequence comprising residues 369-390 of SEQ ID NO:1. D It can be bonded with K D is preferably the K for binding to SEQ ID NO: 1 or SEQ ID NO: 5 D It could be.

[0147] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL).

[0148] The epitope can be within the amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. This epitope can be bound by the CDR of a specific binding molecule designated herein as "412E10."

[0149] The epitope may comprise the amino acid sequence of SEQ ID NO: 120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL).

[0150] The epitope may consist of the amino acid sequence of SEQ ID NO: 120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL).

[0151] A specific binding molecule may bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of the CDRs having the amino acid sequence: VHCDR1 comprises the sequence set forth in SEQ ID NO: 121 (S / ND / YS / G / AV / LA / G); VHCDR2 comprises the sequence set forth in SEQ ID NO: 122 (A / NS / IG / Y / WS / RS / GGN / S / RK / T / IY / EYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 123 (GI / GI / VA / GG / SVDV) or SEQ ID NO: 124 (SGGD); VLCDR1 comprises the sequence set forth in SEQ ID NO: 125 (SGS / GS / NNV / IGY / RGN / D / TY / FVG / D); VLCDR2 comprises the sequence set forth in SEQ ID NO: 126 (GT / AA / D / TI / S / RRA / PS / P); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 127 (AS / TYQ / DS / Y / RN / SY / D / N / EA / G / D / S- / G / M / V- / IF / V / I); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having Includes:

[0152] The sequence identity is at least about 85% sequence identity, and thus may be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0153] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 128 (SDSVA), SEQ ID NO: 129 (NYGVG), or SEQ ID NO: 130 (SYALG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS), SEQ ID NO: 132 (NIWRGGRIEYNPALKS) or SEQ ID NO: 133 (NIYSGGSTYYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 134 (GIIAGVDV), SEQ ID NO: 135 (GGVGSVDV) or SEQ ID NO: 124 (SGGD); VLCDR1 comprises the sequences set forth in SEQ ID NO: 39 (SGSSSNVGYGNYVG), SEQ ID NO: 137 (SGGRNNIGRGTFVD) and SEQ ID NO: 138 (SGSSSNVGYGDYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 139 (GTAIRAS), SEQ ID NO: 140 (GAASRAS), SEQ ID NO: 141 (GATSRAS) or SEQ ID NO: 142 (GTDRRPP); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 143 (ASYQSNYAF), SEQ ID NO: 144 (ASYDRSESVV), SEQ ID NO: 145 (ASYDSSDGGV) or SEQ ID NO: 146 (ATYDYSNDMII); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO:1.

[0154] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 128 (SDSVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 134 (GIIAGVDV); VLCDR1 comprises the sequence set forth in SEQ ID NO: 39 (SGSSSNVGYGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 139 (GTAIRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 143 (ASYQSNYAF); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "412E10."

[0155] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 128 (SDSVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 134 (GIIAGVDV); VLCDR1 comprises the sequence set forth in SEQ ID NO: 39 (SGSSSNVGYGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 139 (GTAIRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 143 (ASYQSNYAF).

[0156] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI); VHFR2 comprises the sequence set forth in SEQ ID NO: 460 (WVRQAPGKVPEWLG); VHFR3 comprises the sequence set forth in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 462 (WGRGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 464 (WYQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 466 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having Includes:

[0157] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI); VHFR2 comprises the sequence set forth in SEQ ID NO: 460 (WVRQAPGKVPEWLG); VHFR3 comprises the sequence set forth in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 462 (WGRGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 464 (WYQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 466 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. A specific binding molecule comprising a FR having 100% identity to the above-listed FR is referred to herein as "412E10."

[0158] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI); VHFR2 comprises the sequence set forth in SEQ ID NO: 460 (WVRQAPGKVPEWLG); VHFR3 comprises the sequence set forth in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 462 (WGRGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 464 (WYQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 466 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 128 (SDSVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 134 (GIIAGVDV); VLCDR1 comprises the sequence set forth in SEQ ID NO: 39 (SGSSSNVGYGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 139 (GTAIRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 143 (ASYQSNYAF); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "412E10."

[0159] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI); VHFR2 comprises the sequence set forth in SEQ ID NO: 460 (WVRQAPGKVPEWLG); VHFR3 comprises the sequence set forth in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 462 (WGRGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 464 (WYQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 466 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 128 (SDSVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 134 (GIIAGVDV); VLCDR1 comprises the sequence set forth in SEQ ID NO: 39 (SGSSSNVGYGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 139 (GTAIRAS); and VLCDR3 comprises an amino acid sequence comprising the sequence set forth in SEQ ID NO: 143 (ASYQSNYAF), and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "412E10."

[0160] The specific binding molecule is (a) SEQ ID NO: 467

[24] (QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSGSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 468

[25] (QAVLTQPSSVGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0161] The specific binding molecule is (a) SEQ ID NO: 469

[26] (QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSGSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLL VTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPC PPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTI SKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 470

[27] (QAVLTQPSSVGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTV ) a light chain comprising the sequence shown in These humanized variants may include:

[0162] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 128 (SDSVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 134 (GIIAGVDV); VLCDR1 comprises the sequence set forth in SEQ ID NO: 138 (SGSSSNVGYGDYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 140 (GAASRAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 145 (ASYDSSDGGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "412B9."

[0163] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 128 (SDSVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 134 (GIIAGVDV); VLCDR1 comprises the sequence set forth in SEQ ID NO: 138 (SGSSSNVGYGDYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 140 (GAASRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 145 (ASYDSSDGGV).

[0164] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 129 (NYGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 133 (NIYSGGSTYYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 135 (GGVGSVDV); VLCDR1 comprises the sequence set forth in SEQ ID NO: 137 (SGGRNNIGRGTFVD); VLCDR2 comprises the sequence set forth in SEQ ID NO: 142 (GTDRRPP); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 146 (ATYDYSNDMII); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "412E6."

[0165] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 129 (NYGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 133 (NIYSGGSTYYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 135 (GGVGSVDV); VLCDR1 comprises the sequence set forth in SEQ ID NO: 137 (SGGRNNIGRGTFVD); VLCDR2 comprises the sequence set forth in SEQ ID NO: 142 (GTDRRPP); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 146 (ATYDYSNDMII).

[0166] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 130 (SYALG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 132 (NIWRGGRIEYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 124 (SGGD); VLCDR1 comprises the sequence set forth in SEQ ID NO: 39 (SGSSSNVGYGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 144 (ASYDRSESVV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "412G11."

[0167] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 130 (SYALG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 132 (NIWRGGRIEYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 124 (SGGD); VLCDR1 comprises the sequence set forth in SEQ ID NO: 39 (SGSSSNVGYGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 144 (ASYDRSESVV).

[0168] The specific binding molecule may comprise the CDR sequences of the clones presented below in Table 5. The epitope may be within residues 412-441 of SEQ ID NO:1.

[0169] [Table 5]

[0170] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 5; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 5; the VHCDR3 comprises a VHCDR3 amino acid sequence shown in Table 5; VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 5; VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 5; and VLCDR3 comprises an amino acid sequence of a VLCDR3 amino acid sequence shown in Table 5; or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO:1.

[0171] A specific binding molecule has a K of less than about 25 nM for a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO:1. D It can be bonded with K D may be less than about 20 nM, less than about 15 nM, or less than about 10 nM. D is preferably the K for binding to SEQ ID NO: 1 or SEQ ID NO: 120 D The K for binding to SEQ ID NO: 1 can be D The K for binding to SEQ ID NO: 1 can be from about 1 nM to about 10 nM. D can be about 3.16 nM or 9.0 nM, and optionally the specific binding molecule comprises the CDRs of 412E10.

[0172] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 147, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412-441 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 147. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 147. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 147, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 147. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 147. SEQ ID NO: 147 (412E10 amino acid sequence)

[28] QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSGSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLG

[0173] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 417, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412-441 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 417. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 417. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 417, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 417. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 417. SEQ ID NO: 417 (412B9 amino acid sequence)

[29] QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSGSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVSVSSEGKSS GASGESKVDDQAVLTQPSSVSGALGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYGAASRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSSDGGVFGSGTRLTVLG

[0174] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 418, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412-441 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 418. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 418. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 418, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 418. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 418. SEQ ID NO: 418 (412E6 amino acid sequence)

[30] QVQLQESGPSLVKPSETLSLTTCTVSGFSLTNYGVGWVRQAPGKALEWLGNIYSGGSTYYNPALKSRLSITRDTSKSQVSLSLNSVTLEDTAVYYCGRGGVGSVDVWGPGLLVTVSSEGKSS GASGESKVDDQAVLTQPPSVSGSPGQRVSITCSGGRNNIGRGTFVDWYQQLPGSGLKTVIYGTDRRPPGVPDRFSGSKTGNAATLTITSLQAEDEADYWCATYDYSNDMIILGSGTRLTVLG

[0175] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 434, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412-441 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 434. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 434. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 434, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 434. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 434. SEQ ID NO: 434 (412G11 amino acid sequence)

[31] QVRLQESGPSLVKPSQTLSLTCTVSGFSLTSYALGWVRQAPGRAPEWIGNIWRGGRIEYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCSRSGGDWGPGLLVTVSSEGKSSGA SGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGATSRASGVPDRFSGSRSENTATLTISSLQAEDEADYYCASYDRSESVVFGSGTRLTVLG

[0176] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ). Preferably, the epitope of the specific binding molecule within the amino acid sequence comprising residues 1-49 of SEQ ID NO: 1 can be within the amino acid sequence comprising residues 1-15 of SEQ ID NO: 1.

[0177] The epitope can be within the amino acid sequence comprising residues 1 to 49 of SEQ ID NO: 1. This epitope can be bound by the CDRs of a specific binding molecule referred to herein as "3aG3."

[0178] The epitope can be within the amino acid sequence comprising residues 1 to 49 of SEQ ID NO: 1, preferably within the amino acid sequence comprising residues 1 to 15 of SEQ ID NO: 1. This epitope can be bound by the CDRs of the specific binding molecule referred to herein as "3bG4."

[0179] The epitope may comprise the amino acid sequence of SEQ ID NO: 148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ).

[0180] The epitope may consist of the amino acid sequence of SEQ ID NO: 148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ).

[0181] A specific binding molecule may bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1 to 49 of SEQ ID NO: 1. The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of the CDRs having the amino acid sequence: VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 150 (DIS / ASS / V / GGKA / K / VYA / S / GN / HPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 151 (CRDGGVS / TYGYDI / SDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 152 (SGSS / TS / GNI / VGG / S / YGN / DY / DL / VS / G); VLCDR2 comprises the sequence set forth in SEQ ID NO: 153 (GA / VTS / N / ER / LAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 154 (A / GSF / YDT / S / DS / NSGGI / V); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having Includes:

[0182] The sequence identity is at least about 85% sequence identity, and thus may be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0183] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 155 (DISSSGKAYANPALKS), SEQ ID NO: 156 (DISSGGKVYGHPALKS), SEQ ID NO: 157 (DISSVGKKYANPALKS) or SEQ ID NO: 158 (DIASSGKAYSNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 159 (CRDGGVSYGYDIDY), SEQ ID NO: 160 (CRDGGVSYGYDSDY) or SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 163 (SGSSSNIGGGNYLS), SEQ ID NO: 138 (SGSSSNVGYGDYVG), SEQ ID NO: 165 (SGSSGNVGYGDYVS) or SEQ ID NO: 166 (SGSTSNVGSGNDVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS), SEQ ID NO: 168 (GVTERAS), SEQ ID NO: 169 (GATNLAS), or SEQ ID NO: 170 (GATNRAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 171 (ASFDTSSGGI), SEQ ID NO: 172 (ASYDDSSGGI), SEQ ID NO: 173 (ASYDSSSGGV) or SEQ ID NO: 174 (GSYDSNSGGI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1 to 49 of SEQ ID NO:1.

[0184] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 155 (DISSSGKAYANPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 159 (CRDGGVSYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 163 (SGSSSNIGGGNYLS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 171 (ASFDTSSGGI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "3aG3."

[0185] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 155 (DISSSGKAYANPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 159 (CRDGGVSYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 163 (SGSSSNIGGGNYLS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 171 (ASFDTSSGGI).

[0186] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 156 (DISSGGKVYGHPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 160 (CRDGGVSYGYDSDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 138 (SGSSSNVGYGDYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 168 (GVTERAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 172 (ASYDDSSGGI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "3aD3."

[0187] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 156 (DISSGGKVYGHPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 160 (CRDGGVSYGYDSDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 138 (SGSSSNVGYGDYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 168 (GVTERAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 172 (ASYDDSSGGI).

[0188] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 157 (DISSVGKKYANPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 165 (SGSSGNVGYGDYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 169 (GATNLAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 173 (ASYDSSSGGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "3aH6."

[0189] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 157 (DISSVGKKYANPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 165 (SGSSGNVGYGDYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 169 (GATNLAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 173 (ASYDSSSGGV).

[0190] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 158 (DIASSGKAYSNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 166 (SGSTSNVGSGNDVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 170 (GATNRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 174 (GSYDSNSGGI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "3bG4."

[0191] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 158 (DIASSGKAYSNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 166 (SGSTSNVGSGNDVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 170 (GATNRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 174 (GSYDSNSGGI).

[0192] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI); VHFR2 comprises the sequence set forth in SEQ ID NO: 472 (WVRQAPGKVPEWVG); VHFR3 comprises the sequence set forth in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR); VHFR4 comprises the sequence set forth in SEQ ID NO: 474 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 476 (WFQQVPGSAPKLLFY); VLFR3 comprises the sequence set forth in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 478 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having Includes:

[0193] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI); VHFR2 comprises the sequence set forth in SEQ ID NO: 472 (WVRQAPGKVPEWVG); VHFR3 comprises the sequence set forth in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR); VHFR4 comprises the sequence set forth in SEQ ID NO: 474 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 476 (WFQQVPGSAPKLLFY); VLFR3 comprises the sequence set forth in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 478 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. A specific binding molecule comprising a FR having 100% identity to those listed above is referred to herein as "3bG4."

[0194] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI); VHFR2 comprises the sequence set forth in SEQ ID NO: 472 (WVRQAPGKVPEWVG); VHFR3 comprises the sequence set forth in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR); VHFR4 comprises the sequence set forth in SEQ ID NO: 474 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 476 (WFQQVPGSAPKLLFY); VLFR3 comprises the sequence set forth in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 478 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 158 (DIASSGKAYSNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 166 (SGSTSNVGSGNDVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 170 (GATNRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 174 (GSYDSNSGGI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "3bG4."

[0195] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI); VHFR2 comprises the sequence set forth in SEQ ID NO: 472 (WVRQAPGKVPEWVG); VHFR3 comprises the sequence set forth in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR); VHFR4 comprises the sequence set forth in SEQ ID NO: 474 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 476 (WFQQVPGSAPKLLFY); VLFR3 comprises the sequence set forth in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 478 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 158 (DIASSGKAYSNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 166 (SGSTSNVGSGNDVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 170 (GATNRAS); and VLCDR3 comprises an amino acid sequence comprising the sequence set forth in SEQ ID NO: 174 (GSYDSNSGGI), and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "3bG4."

[0196] The specific binding molecule is (a) SEQ ID NO: 479

[32] (QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 480

[33] (QAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0197] The specific binding molecule is (a) SEQ ID NO: 481

[34] (QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYW GPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTI KPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 482

[35] (QAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLT VLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[0198] The specific binding molecule may comprise the CDR sequences of the clones presented below in Table 6. The epitope may be within residues 1-49 of SEQ ID NO:1.

[0199] [Table 6]

[0200] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 6; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 6; VHCDR3 comprises a VHCDR3 amino acid sequence shown in Table 6; VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 6; VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 6; and VLCDR3 comprises an amino acid sequence of a VLCDR3 amino acid sequence shown in Table 6; or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1 to 49 of SEQ ID NO:1.

[0201] A specific binding molecule has a K of less than about 25 nM for a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO:1. D It can be bonded with K D may be less than about 20 nM, less than about 15 nM, or less than about 10 nM. D is preferably the K for binding to SEQ ID NO: 1 or SEQ ID NO: 148 D The K for binding to SEQ ID NO: 1 can be D The K for binding to SEQ ID NO: 1 can be from about 1 nM to about 20 nM. D The K for binding to SEQ ID NO: 1 can be from about 1 nM to about 10 nM. Dcan be about 19.1 nM, and optionally the specific binding molecule comprises the CDRs of 3aD3. D can be about 3.6 nM, and optionally the specific binding molecule comprises the CDRs of 3aH6. D can be about 6.1 nM, and optionally the specific binding molecule comprises the CDRs of 3aG3. D can be about 8.9 nM, and optionally the specific binding molecule comprises the CDRs of 3bG4.

[0202] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 422, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 422. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 422. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 422, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 422. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 422. SEQ ID NO: 422 (3aD3 amino acid sequence)

[36] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNGVGWVRRAPGKVPEWVGDISSGGKVYGHPALKSRLSITRDTSKSQVSLSVSSVTSEDTAVYYCVRCRDGGVSYGYDSDYWGPGLLVTVSSEG KSSGASGESKVDDQAVVTQPSSVSKSLGQSVSITCSGSSSNVGYGDYVGWFQQVPGSAPKLLIYGVTERASGVPDRFSGSRSGNTATLTISSIQAEDEADYYCASYDDSSGGIFGSGTRLTVLG

[0203] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 423, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 423. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 423. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 423, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 423. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 423. SEQ ID NO: 423 (3aH6 amino acid sequence)

[37] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNGVGWVRQAPGKVPEWLGDISSVGKKYANPALKSRLSFTRDTSKSQVSLSLSSVTTEDTAVYYCVKCRDGGVTYGYDIDYWGPGLLVTASSEG KSSGASGESKVDDQAVVTQPSSVGSLGQSVSITCSGSSGNVGYGDYVSWFQQFHGSAPKLLIYGATNLASGVPARFSGSRSGNTATLTISSLHAEDEADYYCASYDSSSGGVFGSGTRLTVLG

[0204] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 424, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 424. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 424. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 424, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 424. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 424. SEQ ID NO: 424 (3aG3 amino acid sequence)

[38] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNGVGWVRQAPGKVPEWVGDISSSGKAYANPALKSRLSITRDTAKTQVFLSLSSVTTEDTAVYYCVRCRDGGVSYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPPSVGSPGQRVSITCSGSSNIGGGNYLSWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASFDTSSGGIFGAGTRLTVLG

[0205] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 425, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-49 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 425. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 425. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 425, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 425. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 425. SEQ ID NO: 425 (3bG4 amino acid sequence)

[39] QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLG

[0206] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 49 to 111 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT).

[0207] The epitope may be within the amino acid sequence comprising residues 49 to 111 of SEQ ID NO: 1. This epitope may be bound by the CDRs of a specific binding molecule designated herein as "3bF4."

[0208] The epitope may comprise the amino acid sequence of SEQ ID NO: 175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT).

[0209] The epitope may consist of the amino acid sequence of SEQ ID NO: 175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT).

[0210] A specific binding molecule may bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 49 to 111 of SEQ ID NO: 1. The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of the CDRs having the amino acid sequence: VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 176 (DI / KSSV / AGKK / TYA / GNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 177 (CRDGGVTYGYDI / VDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 178 (SGSSSNVGL / YR / GN / DY / VVT / S); VLCDR2 comprises the sequence set forth in SEQ ID NO: 179 (GA / TTS / TRAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 180 (ASA / FDT / SN / DD / SGGV / I); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having Includes:

[0211] The sequence identity is at least about 85% sequence identity, and thus may be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0212] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 157 (DISSVGKKYANPALKS) or SEQ ID NO: 182 (DKSSAGKTYGNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY) or SEQ ID NO: 184 (CRDGGVTYGYDVDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 185 (SGSSSNVGLRNYVT) or SEQ ID NO: 186 (SGSSSNVGYGDVVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS) or SEQ ID NO: 188 (GTTTRAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 189 (ASADTNDGGV) or SEQ ID NO: 190 (ASFDSDSGGI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 49 to 111 of SEQ ID NO:1.

[0213] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 157 (DISSVGKKYANPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 185 (SGSSSNVGLRNYVT); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 189 (ASADTNDGGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 49 to 111 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "3bF4."

[0214] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 157 (DISSVGKKYANPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 186 (SGSSSNVGYGDVVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 189 (ASADTNDGGV).

[0215] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 182 (DKSSAGKTYGNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 184 (CRDGGVTYGYDVDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 186 (SGSSSNVGYGDVVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 188 (GTTTRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 190 (ASFDSDSGGI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 49 to 111 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "3aB7."

[0216] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 149 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 182 (DKSSAGKTYGNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 184 (CRDGGVTYGYDVDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 186 (SGSSSNVGYGDVVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 188 (GTTTRAS); and VLCDR3 can comprise an amino acid sequence including the sequence set forth in SEQ ID NO: 190 (ASFDSDSGGI). The specific binding molecule can comprise the CDR sequences of the clones presented in Table 7 below. The epitope can be within residues 49-111 of SEQ ID NO: 1.

[0217] [Table 7]

[0218] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 7; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 7; the VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 7; VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 7; VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 7; and VLCDR3 comprises an amino acid sequence of a VLCDR3 amino acid sequence shown in Table 7; or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 49 to 111 of SEQ ID NO:1.

[0219] A specific binding molecule has a K of less than about 250 nM for a polypeptide or protein molecule comprising an amino acid sequence comprising residues 49-111 of SEQ ID NO:1. D It can be bonded with K D may be less than about 200 nM, less than about 150 nM, or less than about 100 nM. D is preferably the K for binding to SEQ ID NO: 1 or SEQ ID NO: 175 D The K for binding to SEQ ID NO: 1 can be D The K for binding to SEQ ID NO: 1 can be from about 1 nM to about 20 nM. D The K for binding to SEQ ID NO: 1 can be from about 50 nM to about 150 nM. D The K for binding to SEQ ID NO: 1 can be about 69 nM, and optionally the specific binding molecule comprises the CDRs of 3aB7. D can be about 140 nM, and optionally the specific binding molecule comprises the CDRs of 3bF4.

[0220] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 420, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 49-111 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 420. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 420. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 420, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 420. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 420. SEQ ID NO: 420 (3aB7 amino acid sequence)

[40] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNGVGWVRQAPGKVPEWVGDKSSAGKTYGNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCVRCRDGGVTYGYDVDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSLGQSVSITCSGSSSNVGYGDVVSWFQQFPGSAPKLLIFGTTTRASGVPDRFSGSRSGNAATLTINSLQAEDEADYYCASFDSDSGGIAGSGTRLTVLG

[0221] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 421, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 49-111 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 421. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 421. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 421, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 421. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 421. SEQ ID NO: 421 (3bF4 amino acid sequence)

[41] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNGVGWVRQAPGKVPEWLGDISSVGKKYANPALKSRLSFTRDTSKSQVSLSLSSVTTEDTAVYYCVKCRDGGVTYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSTGQTVSITCGSGSSSNVGLRNYVTWFQQVPGSAPKLLIYGATSRASGIPDRFSGSRSGNTATLIISSLQAEDEADYYCASADTNDGVFGSGTRLTVLG

[0222] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 146 to 157 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 191 (GKTKIATPRGA).

[0223] The epitope may be within the amino acid sequence comprising residues 147 to 157 of SEQ ID NO: 1. This epitope may be bound by the CDRs of a specific binding molecule designated herein as "3aD6."

[0224] The epitope may comprise the amino acid sequence of SEQ ID NO: 191 (GKTKIATPRGA). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 191 (GKTKIATPRGA).

[0225] The epitope may consist of the amino acid sequence of SEQ ID NO: 191 (GKTKIATPRGA). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 191 (GKTKIATPRGA).

[0226] A specific binding molecule may bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 147 to 157 of SEQ ID NO: 1. The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of the CDRs having the amino acid sequence: VHCDR1 comprises the sequence set forth in SEQ ID NO: 192 (SNAVI / G); VHCDR2 comprises the sequence set forth in SEQ ID NO: 193 (LIDV / IDGDA / TAYD / NPALK / ES); VHCDR3 comprises the sequence set forth in SEQ ID NO: 194 (D / HYG / DS / KWGYV / AS / DD / SIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 195 (SGSD / S - / S - / N - / VI / GG / YGA / DD / YVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 196 (DN / AD / TN / TRP / AS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 197 (G / AT / SYS / QG / NA / EN / RY / SGI / V); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having Includes:

[0227] The sequence identity is at least about 85% sequence identity, and thus may be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0228] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence shown in SEQ ID NO: 198 (SNAVI) or SEQ ID NO: 17 (SNAVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 200 (LIDVDGDAAYDPALKS) or SEQ ID NO: 201 (LIDIDGDTAYNPALES); VHCDR3 comprises the sequence set forth in SEQ ID NO: 202 (DYGSWGYVSDIDY) or SEQ ID NO: 203 (HYDKWGYADSIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 204 (SGSDIGGADVG) or SEQ ID NO: 138 (SGSSSNVGYGDYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 206 (DNDNRPS) or SEQ ID NO: 207 (DATTRAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 208 (GTYSGANYGI) or SEQ ID NO: 209 (ASYQNERSGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 147 to 157 of SEQ ID NO:1.

[0229] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 198 (SNAVI); VHCDR2 comprises the sequence set forth in SEQ ID NO: 200 (LIDVDGDAAYDPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 202 (DYGSWGYVSDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 204 (SGSDIGGADVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 206 (DNDNRPS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 208 (GTYSGANYGI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 147-157 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "3aD6."

[0230] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 198 (SNAVI); VHCDR2 comprises the sequence set forth in SEQ ID NO: 200 (LIDVDGDAAYDPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 202 (DYGSWGYVSDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 204 (SGSDIGGADVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 206 (DNDNRPS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 208 (GTYSGANYGI).

[0231] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence shown in SEQ ID NO: 17 (SNAVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 201 (LIDIDGDTAYNPALES); VHCDR3 comprises the sequence set forth in SEQ ID NO: 203 (HYDKWGYADSIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 138 (SGSSSNVGYGDYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 207 (DATTRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 209 (ASYQNERSGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 147-157 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "3aA6."

[0232] The specific binding molecule may comprise the CDR sequences of the clones presented below in Table 8. The epitope may be within residues 147-157 of SEQ ID NO:1.

[0233] [Table 8]

[0234] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 8; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 8; the VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 8; VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 8; VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 8; and VLCDR3 comprises an amino acid sequence of a VLCDR3 amino acid sequence shown in Table 8; or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 147 to 157 of SEQ ID NO:1.

[0235] A specific binding molecule has a K of less than about 50 nM for a polypeptide or protein molecule comprising an amino acid sequence comprising residues 147-157 of SEQ ID NO:1. D It can be bonded with K D may be less than about 40 nM, less than about 30 nM, or less than about 20 nM. D is preferably the K for binding to SEQ ID NO: 1 or SEQ ID NO: 191 D The K for binding to SEQ ID NO: 1 can be D The K for binding to SEQ ID NO: 1 can be from about 10 nM to about 20 nM. D can be about 16.5 nM, and optionally, the specific binding molecule comprises the CDRs of 3aD6.

[0236] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 418, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 147-157 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 418. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 418. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 418, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 418. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 418. SEQ ID NO: 418 (3aA6 amino acid sequence)

[42] QVRLQESGSSLVKPSQTLSLVCTVSGFPLTSNAVGWVRQAPGKAPEWLGLIDIDGDTAYNPALESRLSITRDTSKSQVSLSLSSVAIEDTAVYYCARHYDKWGYADSIDYWGPGLLVTVSSEG KSSGASGESKVDDQALLTQPSSVFGSLGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYDATTRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYQNERSGVFGSGTRLTVLG

[0237] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 419, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 147-157 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 419. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 419. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 419, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 419. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 419. SEQ ID NO: 419 (3aD6 amino acid sequence)

[43] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVGSLGQRVSITCSGSDIGGADVGWFQQVPGSGLRTLIYDNDNRPSGVPDRFSGSKSGNTATLTISSLQPEDEADYFCGTYSGANYGIFGSGTRLTVLG

[0238] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 379 to 391 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 221 (RENAKAKTDHGAE).

[0239] The epitope may comprise the amino acid sequence of SEQ ID NO:221 (RENAKAKTDHGAE). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO:221 (RENAKAKTDHGAE). The epitope may be within the amino acid sequence comprising residues 379-391 of SEQ ID NO:1. This epitope may be bound by the CDRs of a specific binding molecule referred to herein as "E2E8." The essential residue of the epitope may be residue 391 (E) (numbering according to SEQ ID NO:1). The epitope may comprise the amino acid sequence of SEQ ID NO:222 (XXXXXXXXXXXXE, where X is any amino acid). The epitope may comprise the amino acid sequence of SEQ ID NO:8, in which any one or more residues other than residue 391 (E) are replaced by non-conservative amino acid substitutions (numbering according to SEQ ID NO:1). An epitope may comprise the amino acid sequence of SEQ ID NO: 221, in which any one or more residues other than residue number 391(E) are replaced by a conservative amino acid substitution (numbering according to SEQ ID NO: 1). An epitope may comprise the amino acid sequence of SEQ ID NO: 221, in which any one or more residues other than residue number 391(E) are replaced by a conservative amino acid substitution (numbering according to SEQ ID NO: 1), and in which any one or more residues other than residue number 391(E) are replaced by a non-conservative amino acid substitution (numbering according to SEQ ID NO: 1).

[0240] The epitope may comprise the amino acid sequence of SEQ ID NO: 221 (RENAKAKTDHGAE). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 221 (RENAKAKTDHGAE).

[0241] The epitope may consist of the amino acid sequence of SEQ ID NO: 221 (RENAKAKTDHGAE). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 221 (RENAKAKTDHGAE).

[0242] A specific binding molecule may bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379 to 391 of SEQ ID NO: 1. The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of the CDRs having the amino acid sequence: VHCDR1 comprises the sequence set forth in SEQ ID NO: 223 (D / SR / WGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 224 (TMRSGGT / GI / TD / EY / DNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 225 (GYLSGD / I / VR / HYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 226 (SGSR / SSD / NI / VGY / D / AGN / D / RYVS / G); VLCDR2 comprises the sequence set forth in SEQ ID NO: 227 (D / S / GT / AN / R / TT / N / SRAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 228 (AN / SIDS / TS / GR / NS / NH / LL / I); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having Includes:

[0243] The sequence identity is at least about 85% sequence identity, and thus may be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0244] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 229 (DRGVA), SEQ ID NO: 230 (DWGVA) or SEQ ID NO: 231 (SWGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 232 (TMRSGGTIDYNPALKS), SEQ ID NO: 233 (TMRSGGGTEYNPALKS) or SEQ ID NO: 234 (TMRSGGTTDDNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 235 (GYLSGDRYA), SEQ ID NO: 236 (GYLSGIHYA) or SEQ ID NO: 237 (GYLSGVHYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 238 (SGSRSDIGYGNYVS), SEQ ID NO: 239 (SGSSSNVGAGNYVG), SEQ ID NO: 240 (SGSSSNVGDGDYVG) or SEQ ID NO: 241 (SGSSSNVGDGRYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 242 (DTNTRAS), SEQ ID NO: 243 (DTTSRAS), SEQ ID NO: 170 (GATNRAS), or SEQ ID NO: 244 (SARNRAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 245 (ANIDSSRSHL), SEQ ID NO: 246 (ASIDSGNNLL) or SEQ ID NO: 247 (ASIDTSRSHI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379 to 391 of SEQ ID NO:1.

[0245] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 229 (DRGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 232 (TMRSGGTIDYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 235 (GYLSGDRYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 238 (SGSRSDIGYGNYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 242 (DTNTRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 245 (ANIDSSRSHL); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379 to 391 of SEQ ID NO: 1. A specific binding molecule comprising CDRs with 100% identity to those listed above is referred to herein as "E2E8."

[0246] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 229 (DRGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 232 (TMRSGGTIDYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 235 (GYLSGDRYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 238 (SGSRSDIGYGNYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 242 (DTNTRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 245 (ANIDSSRSHL).

[0247] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 484 (WVRQAPGKALEWVG); VHFR3 comprises the sequence set forth in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 486 (WGRGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC); VLFR2 comprises the sequence set forth in SEQ ID NO: 488 (WFQQIPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 490 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having Includes:

[0248] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 484 (WVRQAPGKALEWVG); VHFR3 comprises the sequence set forth in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 486 (WGRGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC); VLFR2 comprises the sequence set forth in SEQ ID NO: 488 (WFQQIPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 490 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379 to 391 of SEQ ID NO: 1. A specific binding molecule comprising FRs having 100% identity to those listed above is referred to herein as "E2E8."

[0249] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 484 (WVRQAPGKALEWVG); VHFR3 comprises the sequence set forth in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 486 (WGRGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC); VLFR2 comprises the sequence set forth in SEQ ID NO: 488 (WFQQIPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 490 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 229 (DRGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 232 (TMRSGGTIDYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 235 (GYLSGDRYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 238 (SGSRSDIGYGNYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 242 (DTNTRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 245 (ANIDSSRSHL); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379 to 391 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "E2E8."

[0250] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 484 (WVRQAPGKALEWVG); VHFR3 comprises the sequence set forth in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 486 (WGRGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC); VLFR2 comprises the sequence set forth in SEQ ID NO: 488 (WFQQIPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC); VLFR4 has an amino acid sequence comprising the sequence set forth in SEQ ID NO: 490 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 229 (DRGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 232 (TMRSGGTIDYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 235 (GYLSGDRYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 238 (SGSRSDIGYGNYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 242 (DTNTRAS); and VLCDR3 comprises an amino acid sequence comprising the sequence set forth in SEQ ID NO: 245 (ANIDSSRSHL), and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379-391 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "E2E8."

[0251] The specific binding molecule is (a) SEQ ID NO: 491

[44] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 492

[45] (QAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0252] The specific binding molecule is (a) SEQ ID NO: 493

[46] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGL LVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKP CPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERT ISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 494

[47] (QAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLT VLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[0253] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 230 (DWGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 234 (TMRSGGTTDDNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 237 (GYLSGVHYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 241 (SGSSSNVGDGRYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 243 (DTTSRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 246 (ASIDSGNNLL); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379 to 391 of SEQ ID NO: 1. A specific binding molecule comprising CDRs with 100% identity to those listed above is referred to herein as "E1E8."

[0254] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 230 (DWGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 234 (TMRSGGTTDDNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 237 (GYLSGVHYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 241 (SGSSSNVGDGRYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 243 (DTTSRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 246 (ASIDSGNNLL).

[0255] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 230 (DWGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 234 (TMRSGGTTDDNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 237 (GYLSGVHYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 239 (SGSSSNVGAGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (GATNRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 247 (ASIDTSRSHI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379 to 391 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "E2A6."

[0256] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 230 (DWGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 234 (TMRSGGTTDDNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 237 (GYLSGVHYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 239 (SGSSSNVGAGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (GATNRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 247 (ASIDTSRSHI).

[0257] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 231 (SWGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 233 (TMRSGGGTEYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 236 (GYLSGIHYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 240 (SGSSSNVGDGDYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 244 (SARNRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 247 (ASIDTSRSHI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379 to 391 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "E2B7."

[0258] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 231 (SWGVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 233 (TMRSGGGTEYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 236 (GYLSGIHYA); VLCDR1 comprises the sequence set forth in SEQ ID NO: 240 (SGSSSNVGDGDYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 244 (SARNRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 247 (ASIDTSRSHI).

[0259] The specific binding molecule may comprise the CDR sequences of the clones presented below in Table 9. The epitope may be within residues 379-391 of SEQ ID NO:1.

[0260] [Table 9]

[0261] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 9; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 9; the VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 9; VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 9; VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 9; and VLCDR3 comprises an amino acid sequence shown in Table 9; or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379 to 391 of SEQ ID NO:1.

[0262] A specific binding molecule has a K of less than about 25 nM for a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379-391 of SEQ ID NO:1. D It can be bonded with K D may be less than about 20 nM, less than about 15 nM, or less than about 10 nM. D is preferably the K for binding to SEQ ID NO: 4 D The specific binding molecule may have no detectable binding to SEQ ID NO: 1. The K for binding to SEQ ID NO: 4 D The K for binding to SEQ ID NO: 4 can be from about 300 pM to about 10 nM. D The K for binding to SEQ ID NO: 4 can be from about 300 pM to about 500 pM. D The K for binding to SEQ ID NO: 4 can be from about 1 nM to about 10 nM. DThe K for binding to SEQ ID NO: 4 can be about 401 pM, and optionally the specific binding molecule comprises the CDRs of E1E8. D can be about 6.3 nM, and optionally the specific binding molecule comprises the CDRs of E1E8.

[0263] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 248, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379-391 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 248. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 248. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 248, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 248. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 248. SEQ ID NO: 248 (E2E8 amino acid sequence)

[48] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLG

[0264] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 250, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379-391 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 250. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 250. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 250, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 250. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 250. SEQ ID NO: 250 (E1E8 amino acid sequence)

[49] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDWGVAWVRQAPGKALEWLGTMRSGGTTDDNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGVHYAWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSGSLGQSVSITCSGSSSNVGDGRYVSWFQQVPGSAPKLLIYDTTSRASGVPDRFSGSRSGNTATLIITSLQAEDEADYYCASIDSGNNLLFGSGTRLTVLG

[0265] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 252, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379-391 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 252. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 252. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 252, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 252. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 252. SEQ ID NO: 252 (E2A6 amino acid sequence)

[50] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDWGVAWVRQAPGKALEWLGTMRSGGTTDDNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGVHYAWGRGLLVTVSSEGKS SGASGESKVDDRVVRTQPSSVSKSLGQSVSITCSGSSSNVGAGNYVGWFQQVPGSAPKLLIYGATNRASGVPARFSGSKSGVTATLTITSLQAEDEADYYCASIDTSRSHIFGSGTRLTVLG

[0266] A specific binding molecule can comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 254, and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379-391 of SEQ ID NO: 1. The CDRs of the specific binding molecule can be at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identical to the CDRs of SEQ ID NO: 254. The CDRs can be 100% identical to the CDRs of SEQ ID NO: 254. A specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 254, and the CDRs are 100% identical to the CDRs of SEQ ID NO: 254. A specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 254. SEQ ID NO: 254 (E2B7 amino acid sequence)

[51] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSWGVAWVRQAPGKALEWLGTMRSGGGTEYNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGIHYAWGRGLLVSVSSEGKS SGASGESKVDDQAVLTQLSSVGSLGQRVSITCSGSSSNVGDGDYVGWFQQLPGSAPKLLIYSARNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCASIDTSRSHIFGSGTRLTVLG

[0267] The epitope of the specific binding molecule may be within the amino acid sequence comprising residues 113 to 238 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence comprising residues 113 to 238 of SEQ ID NO: 255.

[52] (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIP AKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTP PKSPSS) The amino acid sequence may be within the range of

[0268] The epitope can be within the amino acid sequence comprising residues 113 to 238 of SEQ ID NO: 1. This epitope can be bound by the CDR of a specific binding molecule designated herein as "CB11."

[0269] The epitope is SEQ ID NO: 255

[53] (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIP AKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTP PKSPSS) The epitope may comprise the amino acid sequence of SEQ ID NO: 255.

[54] (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIP AKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTP PKSPSS) The amino acid sequence may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0270] The epitope is SEQ ID NO: 255

[55] (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIP AKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTP PKSPSS) The epitope may consist of the amino acid sequence of SEQ ID NO: 255.

[56] (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIP AKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTP PKSPSS) The amino acid sequence may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0271] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 198 (SNAVI); VHCDR2 comprises the sequence set forth in SEQ ID NO: 200 (LIDVDGDAAYDPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 202 (DYGSWGYVSDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 256 (SGSNIGSNDVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 257 (DNNNRPS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 258 (GGYAGSSSNFL); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 113 to 238 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CB11."

[0272] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 198 (SNAVI); VHCDR2 comprises the sequence set forth in SEQ ID NO: 200 (LIDVDGDAAYDPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 202 (DYGSWGYVSDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 256 (SGSNIGSNDVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 257 (DNNNRPS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 258 (GGYAGSSSNFL).

[0273] The epitope of the specific binding molecule may be within the amino acid sequence comprising residues 1 to 155 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence comprising residues 1 to 155 of SEQ ID NO: 293

[57] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR) The amino acid sequence may be within the range of

[0274] The epitope can be within the amino acid sequence comprising residues 1 to 155 of SEQ ID NO: 1. This epitope can be bound by the CDR of a specific binding molecule referred to herein as "CA2."

[0275] The epitope is SEQ ID NO: 293

[58] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR) The epitope may comprise the amino acid sequence of SEQ ID NO: 293

[59] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR) The amino acid sequence may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0276] The epitope is SEQ ID NO: 293

[60] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR) The epitope may consist of the amino acid sequence of SEQ ID NO: 293

[61] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR) The amino acid sequence may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0277] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 259 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 157 (DISSVGKKYANPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 165 (SGSSGNVGYGDYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 169 (GATNLAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 173 (ASYDSSSGGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-155 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CA2."

[0278] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 259 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 157 (DISSVGKKYANPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 165 (SGSSGNVGYGDYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 169 (GATNLAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 173 (ASYDSSSGGV).

[0279] The epitope of the specific binding molecule may be within the amino acid sequence comprising residues 1 to 238 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence comprising residues 1 to 238 of SEQ ID NO: 260.

[62] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAA GHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The amino acid sequence may be within the range of

[0280] The epitope can be within the amino acid sequence comprising residues 1 to 238 of SEQ ID NO: 1. This epitope can be bound by the CDRs of a specific binding molecule designated herein as "CB6."

[0281] The epitope is SEQ ID NO: 260

[63] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAA GHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The epitope may comprise the amino acid sequence of SEQ ID NO: 260.

[64] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAA GHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The amino acid sequence may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0282] The epitope is SEQ ID NO: 260

[65] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAA GHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The epitope may consist of the amino acid sequence of SEQ ID NO: 260.

[66] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAA GHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The amino acid sequence may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0283] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 259 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 157 (DISSVGKKYANPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 261 (SGSSSNIGTGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 262 (GAVTRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 263 (ASYDSTSGGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1 to 238 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CB6."

[0284] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 259 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 157 (DISSVGKKYANPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 261 (SGSSSNIGTGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 262 (GAVTRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 263 (ASYDSTSGGV).

[0285] The epitope of the specific binding molecule may be within the amino acid sequence comprising residues 1 to 319 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence comprising residues 1 to 319 of SEQ ID NO: 264.

[67] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAP PGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT) The amino acid sequence may be within the range of

[0286] The epitope can be within the amino acid sequence comprising residues 1 to 319 of SEQ ID NO: 1. This epitope can be bound by the CDRs of the specific binding molecules designated herein as "CA7," "CA8," and "CB10."

[0287] The epitope within the amino acid sequence comprising residues 1 to 319 of SEQ ID NO: 1 may preferably be within the amino acid sequence comprising residues 37 to 49 of SEQ ID NO: 1. This epitope may be bound by at least the CDRs of the specific binding molecule referred to herein as "CA7."

[0288] The epitope is SEQ ID NO: 264

[68] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAP PGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT) The epitope may comprise the amino acid sequence of SEQ ID NO: 264.

[69] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAP PGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT) The amino acid sequence may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0289] The epitope is SEQ ID NO: 264

[70] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKT KIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHV PGGGSVQIVYKPVDLSKVT) The epitope may consist of the amino acid sequence of SEQ ID NO: 264.

[71] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAP PGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT) The amino acid sequence may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0290] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 44 (SYYVG); VHCDR2 comprises the sequence set forth in SEQ ID NO:52 (NIYSTGRAFYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 265 (GSYYHGGGNGMVDFFDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 39 (SGSSSNVGYGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 72 (AATSRAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 78 (SSYQRGNTGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-319 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CA7."

[0291] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 44 (SYYVG); VHCDR2 comprises the sequence set forth in SEQ ID NO:52 (NIYSTGRAFYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 265 (GSYYHGGGNGMVDFFDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 39 (SGSSSNVGYGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 72 (AATSRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 78 (SSYQRGNTGV).

[0292] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD); VHFR2 comprises the sequence set forth in SEQ ID NO: 496 (WVRQAPGKALEWLG); VHFR3 comprises the sequence set forth in SEQ ID NO: 497 (RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR); VHFR4 comprises the sequence set forth in SEQ ID NO: 498 (WSPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 499 (QVVRTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 500 (WFQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 501 (GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 502 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having Includes:

[0293] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD); VHFR2 comprises the sequence set forth in SEQ ID NO: 496 (WVRQAPGKALEWLG); VHFR3 comprises the sequence set forth in SEQ ID NO: 497 (RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR); VHFR4 comprises the sequence set forth in SEQ ID NO: 498 (WSPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 499 (QVVRTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 500 (WFQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 501 (GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 502 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-319 of SEQ ID NO: 1. A specific binding molecule comprising a FR having 100% identity to those listed above is referred to herein as "CA7."

[0294] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD); VHFR2 comprises the sequence set forth in SEQ ID NO: 496 (WVRQAPGKALEWLG); VHFR3 comprises the sequence set forth in SEQ ID NO: 497 (RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR); VHFR4 comprises the sequence set forth in SEQ ID NO: 498 (WSPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 499 (QVVRTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 500 (WFQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 501 (GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 502 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 44 (SYYVG); VHCDR2 comprises the sequence set forth in SEQ ID NO:52 (NIYSTGRAFYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 265 (GSYYHGGGNGMVDFFDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 39 (SGSSSNVGYGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 72 (AATSRAS); and VLCDR3 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 78 (SSYQRGNTGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-319 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "CA7."

[0295] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD); VHFR2 comprises the sequence set forth in SEQ ID NO: 496 (WVRQAPGKALEWLG); VHFR3 comprises the sequence set forth in SEQ ID NO: 497 (RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR); VHFR4 comprises the sequence set forth in SEQ ID NO: 498 (WSPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 499 (QVVRTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 500 (WFQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 501 (GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 502 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 44 (SYYVG); VHCDR2 comprises the sequence set forth in SEQ ID NO:52 (NIYSTGRAFYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 265 (GSYYHGGGNGMVDFFDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 39 (SGSSSNVGYGNYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 72 (AATSRAS); and VLCDR3 comprises an amino acid sequence comprising the sequence set forth in SEQ ID NO: 78 (SSYQRGNTGV), and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-319 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "CA7."

[0296] The specific binding molecule is (a) SEQ ID NO: 503

[72] (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFDSYYVGWVRQAPGKALEWLGNIYSTGRAFYNPALKSRLSITRDTSKSQVSLSVSSVTIEDTALYYCVRGSYYHGGGNGMVDFFDYWSPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 504

[73] (QVVRTQPSSVSGGSLGQRVSITCSGSSSNVGYGNYVGWFQQVPGSAPKLLIYAATSRASGVPDRFSGSRSGNTATLTIDSLQAEDEADYYCSSYQRGNTGVFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0297] The specific binding molecule is (a) SEQ ID NO: 505

[74] (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFDSYYVGWVRQAPGKALEWLGNIYSTGRAFYNPALKSRLSITRDTSKSQVSLSVSSVTIEDTALYYCVRGSYYHGGGNGMVDFFD YWSPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGP TIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIE RTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 506

[75] (QVVRTQPSSVGSLGQRVSITCSGSSSNVGYGNYVGWFQQVPGSAPKLLIYAATSRASGVPDRFSGSRSGNTATLTIDSLQAEDEADYYCSSYQRGNTGVFGSGTRLT VLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[0298] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 266 (SNAVV); VHCDR2 comprises the sequence set forth in SEQ ID NO: 267 (AIDKDGDTIYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 268 (DPSGWGYPDVDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 269 (SGTYIGSSDVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 270 (GTSSRPS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 271 (ATYESSYHNSV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-319 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CA8."

[0299] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 266 (SNAVV); VHCDR2 comprises the sequence set forth in SEQ ID NO: 267 (AIDKDGDTIYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 268 (DPSGWGYPDVDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 269 (SGTYIGSSDVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 270 (GTSSRPS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 271 (ATYESSYHNSV).

[0300] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 272 (SNTVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 273 (EINSGGSTYYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 274 (GARSTYAAY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 275 (SGSSSDVGYSTWVY); VLCDR2 comprises the sequence set forth in SEQ ID NO: 276 (HISNRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 277 (AAYDSSNNVWI); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1-319 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CB10."

[0301] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 272 (SNTVA); VHCDR2 comprises the sequence set forth in SEQ ID NO: 273 (EINSGGSTYYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 274 (GARSTYAAY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 275 (SGSSSDVGYSTWVY); VLCDR2 comprises the sequence set forth in SEQ ID NO: 276 (HISNRAS); and The VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 277 (AAYDSSNNVWI).

[0302] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 13 to 25 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 278 (DHAGTYGLGDRKD).

[0303] The epitope can be within the amino acid sequence comprising residues 13 to 25 of SEQ ID NO: 1. This epitope can be bound by the CDRs of a specific binding molecule designated herein as "CB7."

[0304] The epitope may comprise the amino acid sequence of SEQ ID NO: 278 (DHAGTYGLGDRKD). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 278 (DHAGTYGLGDRKD).

[0305] The epitope may consist of the amino acid sequence of SEQ ID NO: 278 (DHAGTYGLGDRKD). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 278 (DHAGTYGLGDRKD).

[0306] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 279 (NYRVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 280 (NIRSGGTTWYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 281 (DSSGDLYAYDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 282 (SGSSSNVGYGNYMA); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 263 (ASYDSTSGGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 13 to 25 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CB7."

[0307] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 279 (NYRVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 280 (NIRSGGTTWYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 281 (DSSGDLYAYDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 282 (SGSSSNVGYGNYMA); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 263 (ASYDSTSGGV).

[0308] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 508 (WVRQAPGKALEWVS); VHFR3 comprises the sequence set forth in SEQ ID NO: 509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 510 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 511 (QAVLTQPSSVSRSLGQSVSMTC); VLFR2 comprises the sequence set forth in SEQ ID NO: 512 (WFQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 513 (GVPDRFSGSRSGNTATLTISSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 514 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having Includes:

[0309] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 508 (WVRQAPGKALEWVS); VHFR3 comprises the sequence set forth in SEQ ID NO: 509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 510 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 511 (QAVLTQPSSVSRSLGQSVSMTC); VLFR2 comprises the sequence set forth in SEQ ID NO: 512 (WFQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 513 (GVPDRFSGSRSGNTATLTISSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 514 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 13 to 25 of SEQ ID NO: 1. A specific binding molecule comprising a FR having 100% identity to those listed above is referred to herein as "CB7."

[0310] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 508 (WVRQAPGKALEWVS); VHFR3 comprises the sequence set forth in SEQ ID NO: 509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 510 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 511 (QAVLTQPSSVSRSLGQSVSMTC); VLFR2 comprises the sequence set forth in SEQ ID NO: 512 (WFQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 513 (GVPDRFSGSRSGNTATLTISSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 514 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 279 (NYRVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 280 (NIRSGGTTWYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 281 (DSSGDLYAYDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 282 (SGSSSNVGYGNYMA); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 263 (ASYDSTSGGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 13 to 25 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "CB7."

[0311] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 508 (WVRQAPGKALEWVS); VHFR3 comprises the sequence set forth in SEQ ID NO: 509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 510 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 511 (QAVLTQPSSVSRSLGQSVSMTC); VLFR2 comprises the sequence set forth in SEQ ID NO: 512 (WFQQVPGSAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 513 (GVPDRFSGSRSGNTATLTISSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 514 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 279 (NYRVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 280 (NIRSGGTTWYNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 281 (DSSGDLYAYDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 282 (SGSSSNVGYGNYMA); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 comprises an amino acid sequence comprising the sequence set forth in SEQ ID NO: 263 (ASYDSTSGGV), and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 13-25 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "CB7."

[0312] The specific binding molecule is (a) SEQ ID NO: 515

[76] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTNYRVGWVRQAPGKALEWVSNIRSGGTTWYNPALKSRLSITADTSKSQVSLSLSSVTTEDTAVYYCARDSSGDLYAYDYWGPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 516

[77] (QAVLTQPSSVSRSLGQSVSMTCSGSSSNVGYGNYMAWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSTSGGVFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0313] The specific binding molecule is (a) SEQ ID NO: 517

[78] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTNYRVGWVRQAPGKALEWVSNIRSGGTTWYNPALKSRLSITADTSKSQVSLSLSSVTTEDTAVYYCARDSSGDLYAYDYWGP GLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIK PCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERT ISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 518

[79] (QAVLTQPSSVSRSLGQSVSMTCSGSSSNVGYGNYMAWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSTSGGVFGSGTRLT VLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[0314] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 145 to 157 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 283 (ADGKTKIATPRGA).

[0315] The epitope can be within the amino acid sequence comprising residues 145 to 157 of SEQ ID NO: 1. This epitope can be bound by the CDR of a specific binding molecule designated herein as "CC7."

[0316] The epitope may comprise the amino acid sequence of SEQ ID NO: 283 (ADGKTKIATPRGA). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 283 (ADGKTKIATPRGA).

[0317] The epitope may consist of the amino acid sequence of SEQ ID NO: 283 (ADGKTKIATPRGA). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 283 (ADGKTKIATPRGA).

[0318] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 198 (SNAVI); VHCDR2 comprises the sequence set forth in SEQ ID NO: 200 (LIDVDGDAAYDPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 202 (DYGSWGYVSDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 292 (SGSYITGSSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 284 (DNNDRPS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 285 (ASYDTSNIGL); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 145 to 157 of SEQ ID NO: 1. A specific binding molecule comprising CDRs with 100% identity to those listed above is referred to herein as "CC7."

[0319] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 198 (SNAVI); VHCDR2 comprises the sequence set forth in SEQ ID NO: 200 (LIDVDGDAAYDPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 202 (DYGSWGYVSDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 292 (SGSYITGSSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 284 (DNNDRPS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 285 (ASYDTSNIGL).

[0320] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 520 (WVRQAPGKAPEWVA); VHFR3 comprises the sequence set forth in SEQ ID NO: 521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 522 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 523 (RVVRTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 524 (WFQQVPGSGLKTVIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 525 (GVPDRFSGSKSGDTATLTISSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 526 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having Includes:

[0321] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 520 (WVRQAPGKAPEWVA); VHFR3 comprises the sequence set forth in SEQ ID NO: 521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 522 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 523 (RVVRTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 524 (WFQQVPGSGLKTVIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 525 (GVPDRFSGSKSGDTATLTISSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 526 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 145 to 157 of SEQ ID NO: 1. A specific binding molecule comprising a FR having 100% identity to those listed above is referred to herein as "CC7."

[0322] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 520 (WVRQAPGKAPEWVA); VHFR3 comprises the sequence set forth in SEQ ID NO: 521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 522 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 523 (RVVRTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 524 (WFQQVPGSGLKTVIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 525 (GVPDRFSGSKSGDTATLTISSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 526 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 198 (SNAVI); VHCDR2 comprises the sequence set forth in SEQ ID NO: 200 (LIDVDGDAAYDPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 202 (DYGSWGYVSDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 292 (SGSYITGSSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 284 (DNNDRPS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 285 (ASYDTSNIGL); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 145 to 157 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "CC7."

[0323] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 520 (WVRQAPGKAPEWVA); VHFR3 comprises the sequence set forth in SEQ ID NO: 521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR); VHFR4 comprises the sequence set forth in SEQ ID NO: 522 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 523 (RVVRTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 524 (WFQQVPGSGLKTVIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 525 (GVPDRFSGSKSGDTATLTISSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 526 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having FR; and (b)CDR VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 wherein each of the CDRs comprises the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 198 (SNAVI); VHCDR2 comprises the sequence set forth in SEQ ID NO: 200 (LIDVDGDAAYDPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 202 (DYGSWGYVSDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 292 (SGSYITGSSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 284 (DNNDRPS); and VLCDR3 comprises an amino acid sequence comprising the sequence set forth in SEQ ID NO: 285 (ASYDTSNIGL), and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 145-157 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to those listed above is referred to herein as "CC7."

[0324] The specific binding molecule is (a) SEQ ID NO: 527

[80] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 528

[81] (RVVRTQPSSVGSLGQRVSITCSGSYITGSSVGWFQQVPGSGLKTVIYDNNDRPSGVPDRFSGSKSGDTATLTISSLQAEDEADYYCASYDTSNIGLFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0325] The specific binding molecule is (a) SEQ ID NO: 529

[82] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWG PGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTI KPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 530

[83] (RVVRTQPSSVGSLGQRVSITCSGSYITGSSVGWFQQVPGSGLKTVIYDNNDRPSGVPDRFSGSKSGDTATLTISSLQAEDEADYYCASYDTSNIGLFGSGTRLTVL GGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[0326] The epitope of the specific binding molecule may be within the amino acid sequence comprising residues 155 to 227 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence comprising residues 155 to 227 of SEQ ID NO: 294.

[84] (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA) The amino acid sequence may be within the range of

[0327] The epitope may be within the amino acid sequence comprising residues 155 to 227 of SEQ ID NO: 1. This epitope may be bound by the CDRs of the specific binding molecules designated herein as "CB12" and "CC3."

[0328] The epitope is SEQ ID NO: 294

[85] (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA) The epitope may comprise the amino acid sequence of SEQ ID NO: 294.

[86] (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA) The amino acid sequence may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0329] The epitope is SEQ ID NO: 294

[87] (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA) The epitope may consist of the amino acid sequence of SEQ ID NO: 294

[88] (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA) The amino acid sequence may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0330] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 259 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 182 (DKSSAGKTYGNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 286 (CRDGGVSYGYDVDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 287 (SGSSSNVGGDYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 288 (DTTSRPS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 289 (ASVDKTTGGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 155 to 227 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CB12."

[0331] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 259 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 182 (DKSSAGKTYGNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 286 (CRDGGVSYGYDVDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 287 (SGSSSNVGGDYVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 288 (DTTSRPS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 289 (ASVDKTTGGV).

[0332] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 259 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 182 (DKSSAGKTYGNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 286 (CRDGGVSYGYDVDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 290 (SGSSSNVGYGTYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 188 (GTTTRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 291 (ASYDTGSGGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 155 to 227 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CC3."

[0333] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 259 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 182 (DKSSAGKTYGNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 286 (CRDGGVSYGYDVDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 290 (SGSSSNVGYGTYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 188 (GTTTRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 291 (ASYDTGSGGV).

[0334] The epitope of the specific binding molecule may be within the amino acid sequence comprising residues 155 to 238 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence comprising residues 155 to 238 of SEQ ID NO: 295.

[89] (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The amino acid sequence may be within the range of

[0335] The epitope can be within the amino acid sequence comprising residues 155 to 238 of SEQ ID NO: 1. This epitope can be bound by the CDRs of a specific binding molecule designated herein as "CA1."

[0336] The epitope is SEQ ID NO: 295

[90] (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The epitope may comprise the amino acid sequence of SEQ ID NO: 295.

[91] (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The amino acid sequence may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0337] The epitope is SEQ ID NO: 295

[92] (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The epitope may consist of the amino acid sequence of SEQ ID NO: 295.

[93] (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The amino acid sequence may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0338] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 198 (SNAVI); VHCDR2 comprises the sequence set forth in SEQ ID NO: 296 (DIRADGATNYNAALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 297 (PGNYYYGAGRDVARLAD); VLCDR1 comprises the sequence set forth in SEQ ID NO: 298 (SGSSSNIGGGNAVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 288 (DTTSRPS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 299 (AAMDSSSLIGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 155 to 238 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CA1."

[0339] The epitope of the specific binding molecule may be within the amino acid sequence comprising residues 186 to 263 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence comprising residues 186 to 263 of SEQ ID NO: 300.

[94] (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGST) The amino acid sequence may be within the range of

[0340] The epitope can be within the amino acid sequence comprising residues 186 to 263 of SEQ ID NO: 1. This epitope can be bound by the CDR of a specific binding molecule referred to herein as "CA3."

[0341] The epitope is SEQ ID NO: 300

[95] (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQT APVPMPDLKNVKSKIGST) The epitope may comprise the amino acid sequence of SEQ ID NO: 300.

[96] (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQT APVPMPDLKNVKSKIGST) The amino acid sequence may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0342] The epitope is SEQ ID NO: 300

[97] (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQT APVPMPDLKNVKSKIGST) The epitope may consist of the amino acid sequence of SEQ ID NO: 300.

[98] (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQT APVPMPDLKNVKSKIGST) The amino acid sequence may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0343] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 259 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 182 (DKSSAGKTYGNPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 184 (CRDGGVTYGYDVDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 301 (SGSSGNIGYDDYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 302 (GATRRSS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 303 (ASYDSSGGGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 186 to 263 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CA3."

[0344] The epitope of the specific binding molecule may be within the amino acid sequence comprising residues 186 to 350 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence comprising residues 186 to 350 of SEQ ID NO: 304.

[99] (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRV) The amino acid sequence may be within the range of

[0345] The epitope can be within the amino acid sequence comprising residues 186 to 350 of SEQ ID NO: 1. This epitope can be bound by the CDR of a specific binding molecule referred to herein as "CD2."

[0346] The epitope is SEQ ID NO: 304

[100] (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRV) The epitope may comprise the amino acid sequence of SEQ ID NO: 304. [C101] (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRV) The amino acid sequence may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0347] The epitope is SEQ ID NO: 304 [C102] (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRV) The epitope may consist of the amino acid sequence of SEQ ID NO: 304. [C103] (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRV) The amino acid sequence may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0348] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 198 (SNAVI); VHCDR2 comprises the sequence set forth in SEQ ID NO: 200 (LIDVDGDAAYDPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 202 (DYGSWGYVSDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 305 (SGSNIGDADVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 306 (YNENRPS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 307 (GSYAGDTYNHGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 186 to 350 of SEQ ID NO: 1. A specific binding molecule comprising a CDR having 100% identity to those listed above is referred to herein as "CD2."

[0349] The epitope of the specific binding molecule may be within the amino acid sequence comprising residues 239 to 348 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence comprising residues 239 to 348 of SEQ ID NO: 308. [C104] (AKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKD) The amino acid sequence may be within the range of

[0350] The epitope can be within the amino acid sequence comprising residues 239 to 348 of SEQ ID NO: 1. This epitope can be bound by the CDR of a specific binding molecule designated herein as "CB9."

[0351] The epitope is 308 [C105] (AKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKD) The epitope may comprise the amino acid sequence of 308

[106] (AKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKD) The amino acid sequence may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0352] The epitope is 308 [C107] (AKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIK HVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKD) The epitope may consist of the amino acid sequence of 308 [C108] (AKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKD) The amino acid sequence may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0353] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 48 (GIDSDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 67 (SGRFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 239 to 348 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CB9."

[0354] The epitope of the specific binding molecule may be within the amino acid sequence comprising residues 266 to 359 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence comprising residues 266 to 359 of SEQ ID NO: 309. [C109] (LKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDN) The amino acid sequence may be within the range of

[0355] The epitope can be within the amino acid sequence comprising residues 266 to 359 of SEQ ID NO: 1. This epitope can be bound by the CDR of a specific binding molecule designated herein as "CG11."

[0356] The epitope is SEQ ID NO: 309 [C110] (LKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDN) The epitope may comprise the amino acid sequence of SEQ ID NO: 309. [C111] (LKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDN) The amino acid sequence may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0357] The epitope is SEQ ID NO: 309 [C112] (LKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDN) The epitope may consist of the amino acid sequence of SEQ ID NO: 309. [C113] (LKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDN) The amino acid sequence may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0358] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 310 (NYPVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 311 (NIENDGSANYASALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 312 (EFGGSDGYTYFVDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 313 (SGSSSNVGYGNYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 314 (ASYDGSSSGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 266 to 359 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CG11."

[0359] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 277 to 319 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 315 (IINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[0360] The epitope can be within the amino acid sequence comprising residues 277 to 319 of SEQ ID NO: 1. This epitope can be bound by the CDRs of the specific binding molecule designated herein as "CA10."

[0361] The epitope may comprise the amino acid sequence of SEQ ID NO: 315 (IINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 315 (IINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[0362] The epitope may consist of the amino acid sequence of SEQ ID NO: 315 (IINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 315 (IINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[0363] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 259 (SNGVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 157 (DISSVGKKYANPALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 161 (CRDGGVTYGYDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 316 (SGSSSNVGYGNYVT); VLCDR2 comprises the sequence set forth in SEQ ID NO: 317 (DATTRVS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 318 (AAHDSSSGGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 277-319 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CA10."

[0364] The epitope of the specific binding molecule may be within the amino acid sequence comprising residues 297 to 390 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence comprising residues 297 to 390 of SEQ ID NO: 5. [C114] (IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGA) The amino acid sequence may be within the range of

[0365] The epitope can be within the amino acid sequence comprising residues 297 to 390 of SEQ ID NO: 1. This epitope can be bound by the CDR of a specific binding molecule designated herein as "CC12."

[0366] The epitope is SEQ ID NO:5 [C115] (IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGA) The epitope may comprise the amino acid sequence of SEQ ID NO: 5. [C116] (IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGA) The amino acid sequence may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0367] The epitope is SEQ ID NO:5 [C117] (IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGA) The epitope may consist of the amino acid sequence of SEQ ID NO: 5. [C118] (IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGA) The amino acid sequence may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity to

[0368] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 42 (SNSVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 48 (GIDSDGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 67 (SGRFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO: 70 (ASDGRPS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 74 (GSSDRTQYTGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 297-390 of SEQ ID NO: 1. A specific binding molecule comprising CDRs having 100% identity to those listed above is referred to herein as "CC12."

[0369] The epitope of the specific binding molecule can be within the amino acid sequence comprising residues 319 to 331 of SEQ ID NO: 1. Thus, the epitope can be within the amino acid sequence of SEQ ID NO: 319 (TSKCGSLGNIHHK).

[0370] The epitope may be within the amino acid sequence comprising residues 319-331 of SEQ ID NO: 1. This epitope may be bound by the CDRs of a specific binding molecule referred to herein as "CE2" or "E1B8." Essential residues of the epitope may be residues 323 (G), 324 (S), 325 (L), 326 (G), 327 (N), and / or 328 (I) (numbering according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 320 (XXXXGSLGNIXXX, where X is any amino acid). The epitope may comprise the amino acid sequence of SEQ ID NO: 319, in which any one or more residues other than residues 323 (G), 324 (S), 325 (L), 326 (G), 327 (N), and / or 328 (I) are replaced by non-conservative amino acid substitutions (numbering according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 319, in which any one or more residues other than residue numbers 323(G), 324(S), 325(L), 326(G), 327(N), and / or 328(I) are replaced by a conservative amino acid substitution (numbering according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 319, in which any one or more residues other than residue numbers 323(G), 324(S), 325(L), 326(G), 327(N), and / or 328(I) are replaced by a conservative amino acid substitution (numbering according to SEQ ID NO: 1), and in which any one or more residues other than residue numbers 323(G), 324(S), 325(L), 326(G), 327(N), and / or 328(I) are replaced by a non-conservative amino acid substitution (numbering according to SEQ ID NO: 1).

[0371] The epitope may comprise the amino acid sequence of SEQ ID NO: 319 (TSKCGSLGNIHHK). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 319 (TSKCGSLGNIHHK).

[0372] The epitope may consist of the amino acid sequence of SEQ ID NO: 319 (TSKCGSLGNIHHK). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity to SEQ ID NO: 319 (TSKCGSLGNIHHK).

[0373] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 310 (NYPVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 311 (NIENDGSANYASALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 312 (EFGGSDGYTYFVDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 313 (SGSSSNVGYGNYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 comprises the amino acid sequence set forth in SEQ ID NO: 314 (ASYDGSSSGV); or For each CDR sequence, (i) at least 85% identical thereto, and / or (ii) one, two, or three amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 319 to 331 of SEQ ID NO: 1. Specific binding molecules comprising CDRs with 100% identity to those listed above are referred to herein as "CE2" or "E1B8."

[0374] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the sequence set forth in SEQ ID NO: 310 (NYPVG); VHCDR2 comprises the sequence set forth in SEQ ID NO: 311 (NIENDGSANYASALKS); VHCDR3 comprises the sequence set forth in SEQ ID NO: 312 (EFGGSDGYTYFVDIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO: 313 (SGSSSNVGYGNYVS); VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 314 (ASYDGSSSGV).

[0375] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 531 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 532 (WVRQAPGKALEWIG); VHFR3 comprises the sequence set forth in SEQ ID NO: 533 (RLSITRDTSKNQVSLSLSSATTEDTAVYYCGR); VHFR4 comprises the sequence set forth in SEQ ID NO: 534 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 535 (QAVLTQPSSVSKSLGQSVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 536 (WFQQVPGSAPKILIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 537 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 538 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having Includes:

[0376] The specific binding molecule may comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has the amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 531 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 532 (WVRQAPGKALEWIG); VHFR3 comprises the sequence set forth in SEQ ID NO: 533 (RLSITRDTSKNQVSLSLSSATTEDTAVYYCGR); VHFR4 comprises the sequence set forth in SEQ ID NO: 534 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 535 (QAVLTQPSSVSKSLGQSVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 536 (WFQQVPGSAPKILIY); VLFR3 comprises the sequence set forth in SEQ ID NO: n537 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC); VLFR4 comprises the amino acid sequence set forth in SEQ ID NO: 538 (FGSGTRLTVLG); or For each FR sequence, (i) at least 50% identical thereto, and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions thereto an amino acid sequence having and the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 319 to 331 of SEQ ID NO: 1. A specific binding molecule comprising a FR having 100% identity to those listed above is referred to herein as "CE2."

[0377] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of which has an amino acid sequence VHFR1 comprises the sequence set forth in SEQ ID NO: 531 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 532 (WVRQAPGKALEWIG); VHFR3 comprises the sequenc...

Claims

1. An anti-tau antibody or antigen-binding fragment thereof that binds to an epitope within amino acid residues 337 to 355 of the amino acid sequence set forth in SEQ ID NO: 1, comprising a VH domain comprising the sequence set forth in SEQ ID NO: 443 and a VL domain comprising the sequence set forth in SEQ ID NO:

444.

2. (a) the antibody or antigen-binding fragment thereof is humanized, and / or (b) the antibody is a monoclonal antibody, or the antigen-binding fragment is a Fab or F(ab') ２ The anti-tau antibody or antigen-binding fragment thereof of claim 1 , which is an antibody fragment or an scFv molecule.

3. 3. A composition comprising the anti-tau antibody or antigen-binding fragment thereof of claim 1 or 2, wherein at least 90% of the anti-tau antibody or antigen-binding fragment thereof in the composition has a K of less than 25 nM. Ｄ A composition that binds to an epitope within SEQ ID NO:

1.

4. A nucleic acid molecule comprising a nucleic acid sequence encoding the anti-tau antibody or antigen-binding fragment thereof according to claim 1 or 2.

5. The nucleic acid molecule of claim 4, comprising the nucleic acid sequence set forth in SEQ ID NO:

380.

6. A construct comprising the nucleic acid molecule of claim 4 or 5.

7. A vector comprising the nucleic acid molecule of claim 4 or 5 or the construct of claim 6.

8. A host cell comprising a nucleic acid molecule according to claim 4 or 5, a construct according to claim 6 or a vector according to claim 7.

9. A method for preparing the anti-tau antibody or antigen-binding fragment thereof according to claim 1 or 2, comprising: i) introducing the nucleic acid molecule of claim 4 or 5, the construct of claim 6 or the vector of claim 7 into a host cell; ii) expressing the nucleic acid molecule to produce the anti-tau antibody or antigen-binding fragment thereof; and iii) recovering the anti-tau antibody or antigen-binding fragment thereof. A method comprising:

10. 10. The method of claim 9, wherein step iii) comprises recovering the anti-tau antibody or antigen-binding fragment thereof by purification.

11. A pharmaceutical composition comprising the anti-tau antibody or antigen-binding fragment thereof of claim 1 or 2 or the composition of claim 3, and one or more pharmaceutically acceptable diluents, carriers, or excipients.

12. 12. The pharmaceutical composition of claim 11 for use in a method for the treatment of a tauopathy.

13. The tauopathies include Alzheimer's disease, primary age-related tauopathy (PART), neurofibrillary tangle-predominant senile dementia, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD), frontotemporal dementia linked to chromosome 17 (FTDP-17), Pick's disease, disinhibition-dementia-parkinsonism-amystrophy complex (DDPAC), pallidopontonigral degeneration (PPND), Guam-type ALS syndrome; pallido-nigro-luysian degeneration (PNLD), and argyrophilic grain dementia.

13. The pharmaceutical composition of claim 12, wherein the disease is selected from the group consisting of: dementia with Lewy bodies (DLB), postencephalitic parkinsonism (PEP), dementia pugilistica (DP), traumatic brain injury (TBI), stroke, ischemia, Litiko-Bodig disease (Guam Parkinsonism-Dementia Complex), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis (SSPE), lead encephalopathy, tuberous sclerosis complex, pantothenate kinase-associated neurodegeneration, lipofuscinosis, and mild cognitive impairment (MCI).

14. An in vitro method for inhibiting aggregation of tau protein or a fragment thereof, comprising contacting the tau protein or a fragment thereof with an anti-tau antibody or an antigen-binding fragment thereof according to claim 1 or 2.

15. An in vitro method for detecting tau protein or a fragment thereof in a sample, comprising contacting the sample with an anti-tau antibody or antigen-binding fragment thereof according to claim 1 or 2.

16. 16. An in vitro method for detecting tau protein or a fragment thereof according to claim 15, comprising:

10. A method comprising contacting the sample with at least one pair of a first and a second anti-tau antibody or antigen-binding fragment thereof, the pair being a pair of a first anti-tau antibody or antigen-binding fragment thereof according to claim 1 or 2 and a second anti-tau antibody or antigen-binding fragment thereof that binds to an epitope within residues 367-379 of SEQ ID NO: 1, wherein the second anti-tau antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising, as heavy chain CDR1-3, the amino acid sequences set forth in SEQ ID NOs: 42, 46 and 54, respectively, in that order, and a light chain variable region comprising, as light chain CDR1-3, the amino acid sequences set forth in SEQ ID NOs: 63, 70 and 73, respectively.

17. (i) the sample is a plasma sample; and / or 16. The in vitro method for detecting tau protein or a fragment thereof according to claim 15, further comprising the step of (ii) denaturing the tau protein or a fragment thereof before contacting the sample with the anti-tau antibody or antigen-binding fragment thereof.

18. A diagnostic device comprising the anti-tau antibody or antigen-binding fragment thereof of claim 1 or 2 for use in the method of claim 16 or 17.

19. A kit comprising the anti-tau antibody or antigen-binding fragment thereof according to claim 1 or 2 and a reagent for detecting tau protein or a fragment thereof in a sample.

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