Methods for detecting tau protein in saliva samples

Abstract

The present invention relates to an in vitro method for detecting tau protein or fragments thereof in a saliva sample using specific binding molecules, such as antibodies, directed against a major epitope of tau. The present invention has application in the diagnosis of tauopathies.

Description

[Technical Field]

[0001] The present invention relates to an in vitro method for detecting tau protein or fragments thereof in saliva samples using specific binding molecules, such as antibodies, directed against major epitopes of tau. The present invention has application in the diagnosis of tauopathies. [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] Research into the causes of AD and other protein conformational diseases has a long history, but has not led to the expected major advances in diagnostics and therapeutics. One reason for this limited progress is believed to be the lack of high-affinity specific binding molecules targeting key epitopes of tau. This shortcoming was addressed by the creation of the specific binding molecules disclosed in PCT Application No. PCT / EP2021 / 069160, filed in the name of WisTa Laboratories Ltd. (incorporated herein by reference in its entirety). 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. PCT Application No. PCT / EP2021 / 069160 describes the use of specific binding molecules in a sample, which may be a plasma sample, a whole blood sample, a brain lysate, or a cerebrospinal fluid (CSF) sample.

[0004] H. Pekeles et al. (Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring 11 (2019) 53-6054) describe the development and validation of a salivary tau biomarker in Alzheimer's disease. The authors describe a significant increase in the ratio of phosphorylated tau to total tau (p-tau / t-tau) for the S396 phosphorylation site. However, the authors acknowledge that there is a large variability in salivary tau levels among AD patients, limiting the use of this test as a clinical biomarker. Summary of the Invention [Problem to be solved by the invention]

[0005] The present inventors have developed an assay for detecting tau protein or fragments thereof in a saliva sample, comprising contacting the sample with a first specific binding molecule that binds to a predominant fragment isolated from a proteolytically stable core paired helical fibril (PHF) (residues 297-391 of SEQ ID NO:1). The assay can utilize the specific binding molecules described in PCT Application No. PCT / EP2021 / 069160, which can offer advantages such as high affinity leading to high sensitivity. The present inventors have surprisingly determined that while the use of a first specific binding molecule that binds to residues 297-391 of SEQ ID NO:1 reliably enables the detection of salivary tau by a second specific binding molecule, the reverse use (a first specific binding molecule that binds outside residues 297-391 of SEQ ID NO:1 and a second specific binding molecule that binds within residues 297-391 of SEQ ID NO:1) can sometimes fail to detect salivary tau, even with a high-affinity specific binding molecule that binds to residues 297-391 of SEQ ID NO:1. [Means for solving the problem]

[0006] According to a first aspect, the present invention provides an in vitro method for detecting tau protein or a fragment thereof in a saliva sample, comprising contacting the sample with a first specific binding molecule, wherein the first specific binding molecule binds to an epitope within residues 297 to 391 of SEQ ID NO: 1.

[0007] According to a second aspect, the present invention provides an apparatus for use in a method according to the first aspect.

[0008] According to a third aspect, the present invention provides a kit comprising a specific binding molecule suitable for use in the method according to the first aspect and reagents for detecting tau protein or a fragment thereof in a sample from a patient, wherein the first specific binding molecule binds to an epitope within residues 297 to 391 of SEQ ID NO: 1. Please refer to the following figures: [Brief explanation of the drawings]

[0009] [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] mAb capture of dGAE aggregates. The indicated antibodies were coated onto a solid-phase ELISA and used to capture dGAE aggregates. Captured dGAE was detected using S1G2 scAb for all capture antibodies except S1G2 mAb, which was captured using S1D12 scAb as the detection antibody. [Figure 36] Western blot showing brain-derived tau labeled with the human-specific CB7 antibody, which binds to an N-terminal epitope (residues 13-25) not present in mouse tau. A band is present in the lane containing 20 μg protein homogenate from a 5-month-old L66+ / + mouse brain but is absent in the lanes containing samples from WT or L1+ / + brains. The protein ladder overlaid on the left side of the blot provides an approximation of the relative sizes of proteins on the gel; however, the apparent size of tau is known to be significantly larger than its actual molecular mass. [Figure 37] Western blot showing tau labeled with the human-specific CC7 antibody, which recognizes an epitope within residues 145–157. Human-specific tau was detected only in the brains of L66+ / + mice, but not in WT or L1+ / + samples. The protein ladder is shown in Figure 36. [Figure 38]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 36. [Figure 39] 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 36. [Figure 40] 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 41] A) A paired antibody ELISA of S1D12 capture and CB7 detection in brain homogenate samples from L66+ / + mice showed a gradual decrease in signal with age. B) When the assay direction was reversed, using S1G2 as the detector and CB7 as the capture in brain homogenate samples, a similar pattern of decreasing signal with age was observed. [Figure 42]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 43] (A) Plasma tau levels in healthy controls (HC) and patients with a confirmed diagnosis of Alzheimer's disease or mild cognitive impairment (AD / MCI). The concentration of core-proline regions measured using S1D12 capture beads paired with BT2 as a detector was significantly higher in healthy controls than in AD / MCI 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 44] Plasma tau levels in healthy controls (HC) and patients with a confirmed diagnosis of Alzheimer's disease or mild cognitive impairment (AD / MCI). The concentration of core-proline regions measured using S1D12 capture beads paired with HT7 detector is significantly higher in healthy controls than in AD / MCI samples. A total of 4 healthy control plasma samples and 34 AD / MCI samples were analyzed using the Simoa® assay. ****p<0.0001 [Figure 45] S1D12 (captured) / BT2 (detected) plasma tau measured by chemiluminescent ELISA was measured in AD samples from subjects with a confirmed clinical diagnosis of AD and in CU samples from age-matched subjects without cognitive impairment. [Figure 46] Simoa® calibrator curves were generated for the various antibody combination assays used in the human plasma experiments. [Figure 47]Immunoprecipitation and trypsin digestion LC-MS revealed the core region containing tau fragments in human plasma. Abundance of tau fragments detected in human plasma samples after immunoprecipitation (IP) and LC-MS analysis. For comparison, the fragments detected in a sample spiked with hTau40 without immunoprecipitation are also shown. [Figure 48] Core tau levels in mouse plasma are elevated by S1D12 mAb treatment. Using CA4 (355-367) and S1G2 (367-379) antibodies, core tau levels were significantly elevated (more than 100-fold increase) in S1D12-treated L66 mice compared with the L1 vehicle group. Individual mouse samples were analyzed in duplicate, and values ​​represent the average concentration of tau fragments detected by the combined CA4-S1G2 antibody pair. A more than three-fold increase was observed in the L66-treated group, whereas only a two-fold increase was observed in wild-type mice. n = 5 or 6, error bars represent SEM. Unpaired t-test was performed between vehicle and treatment groups; ****P<0.0001; **P<0.01 DETAILED DESCRIPTION OF THE INVENTION

[0010] According to a first aspect, the present invention provides an in vitro method for detecting tau protein or a fragment thereof in a saliva sample, comprising contacting the sample with a first specific binding molecule, wherein the first specific binding molecule binds to an epitope within residues 297 to 391 of SEQ ID NO: 1.

[0011] 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-F isoform of the microtubule-associated protein tau OS=Human (Homo sapiens) OX=9606 GN=MAPT MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPG SETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAG HVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPK TPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAK SRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHV PGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNI THVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMV DSPQLATLADEVSASLAKQGL 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 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPG SETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAG HVTQEPESGKVVQEGFLREPGPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEG GRHAPELLKHQLLGDLHQEGPPLKGAGGKERPGSKEEVDEDRDVDESSPQDSPPSKASPA QDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKVSTEIPASEPDGPSVGRAKGQDAPLE FTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEADLPEPSEKQPA AAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPCLSPKHPTPGSS DPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQK GQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREP KKVAVVRTPPKPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLD LSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEK LDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDT SPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL

[0012] "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. MADPRQEFDTMEDHAGDYTLLQDQEGDMDHGLKESPPQPPADDGAEEPGSETSDAKSTPTAEDVTAPLVDERAPDKQAAAQPHTEIPEGITAEEAGIGDTPNQEDQAAGHVTQARVASKDRTGNDEKKAKGADGKTGAKIATPRGAASPAQKGTSNATRIPAKTTPSPKTPPGSGEPPKSGERSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSASKSRLQTAPVPMPDLKNVRSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSG DTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL

[0013] 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): DNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAE

[0014] 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): IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAE

[0015] "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): IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGA

[0016] 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): VQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTF

[0017] 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).

[0018] 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): IVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTF

[0019] First specific binding molecule The method includes contacting the sample with a first specific binding molecule, wherein the first specific binding molecule binds to an epitope within residues 297-391 of SEQ ID NO: 1. The first specific binding molecule may be a specific binding molecule disclosed herein and binds to an epitope within residues 297-391 of SEQ ID NO: 1, preferably within residues 307-391 of SEQ ID NO: 1, and more preferably within residues 337-379 of SEQ ID NO: 1. The first specific binding molecule is described below. In this subheading, a reference to a specific binding molecule refers to a first specific binding molecule.

[0020] The epitope of the specific binding molecule may be within SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6 or SEQ ID NO:7.

[0021] 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 core or within the dGAE fragment. Thus, the epitope of the specific binding molecule can be within SEQ ID NO: 4.

[0022] 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.

[0023] 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. Thus, the epitope of the specific binding molecule may be within SEQ ID NO: 7.

[0024] Typically, a specific binding molecule binds to a polypeptide or protein molecule containing its epitope. Thus, a specific binding molecule can bind to SEQ ID NO: 1 or a fragment thereof comprising residues 297-391 of SEQ ID NO: 1. A specific binding molecule can 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 can bind to a PHF or dGAE fragment. A specific binding molecule can bind to a dGA fragment. A specific binding molecule can bind to a PHF core. The specific binding molecule may bind to a polypeptide or protein molecule comprising 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 1-319 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.

[0025] The first specific binding molecule may bind to an epitope within residues 307-391 of SEQ ID NO: 1. The first specific binding molecule may bind to an epitope within residues 337-379 of SEQ ID NO: 1. The first specific binding molecule may bind to an epitope within residues 337-349 of SEQ ID NO: 1. The first specific binding molecule may bind to an epitope within residues 337-355 of SEQ ID NO: 1. This epitope may be bound by the CDRs of the specific binding molecule referred to herein as "S1D12."

[0026] The first 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 comprises the sequence set forth in SEQ ID NO: 29 (VTGDSTTHDDL); Or, for each CDR sequence: (i) at least 85% identical thereto, and / or (ii) an amino acid sequence having one, two, or three amino acid substitutions thereto; Includes.

[0027] The first 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 is an amino acid sequence comprising the sequence shown in SEQ ID NO: 29 (VTGDSTTHDDL).

[0028] The first specific binding molecule can comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, each of which comprises the following 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 is 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) an amino acid sequence having one, two, three, or four amino acid substitutions thereto; Includes.

[0029] The first specific binding molecule comprises: (a) a VH domain comprising the sequence set forth in SEQ ID NO: 443 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSS); and / or (b) a VL domain comprising the sequence set forth in SEQ ID NO: 444 (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG); or a humanized variant thereof.

[0030] The first 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 with a K of less than about 500 pM. D and optionally, the specific binding is measured by surface plasmon resonance (SPR), and optionally, i. K of binding to SEQ ID NO: 1 D is between about 50 pM and about 150 pM, and / or ii. K for binding to SEQ ID NO: 5 D is about 300 pM to about 400 pM.

[0031] The first specific binding molecule can bind to an epitope consisting of 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."

[0032] The first 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 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 73 (GSSDRTPYTGV); Or, for each CDR sequence: (i) at least 85% identical thereto, and / or (ii) an amino acid sequence having one, two, or three amino acid substitutions thereto; Includes.

[0033] The first 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 is an amino acid sequence comprising the sequence shown in SEQ ID NO: 73 (GSSDRTPYTGV).

[0034] The first specific binding molecule can comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, each of which comprises the following 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 is an amino acid sequence comprising the sequence set forth in SEQ ID NO: 454 (FGSGTRLTVLG); Or, for each FR sequence, (i) at least 50% identical thereto, and / or (ii) an amino acid sequence having one, two, three, or four amino acid substitutions thereto; Includes.

[0035] The first specific binding molecule comprises: (a) a VH domain comprising the sequence set forth in SEQ ID NO: 455 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVSS); and / or (b) a VL domain comprising the sequence set forth in SEQ ID NO: 456 (QAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG); or a humanized variant thereof.

[0036] The first specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO:1 with a K of less than about 500 pM. D and optionally, the specific binding is measured by surface plasmon resonance (SPR), and optionally, i. K of binding to SEQ ID NO: 1 D is between about 100 pM and about 200 pM, and / or ii. K for binding to SEQ ID NO: 5 D is about 400 pM to about 500 pM.

[0037] The first specific binding molecule can compete for binding to SEQ ID NO: 1 with any specific binding molecule disclosed herein that binds to an epitope within residues 297-391 of SEQ ID NO: 1. The first specific binding molecule can compete for binding to SEQ ID NO: 1 with S1D12 or S1G2.

[0038] One of ordinary skill in the art can identify competing antibodies without undue experimentation or ingenuity (e.g., by using routine competitive binding assays). As used herein, a specific binding molecule that competes with another specific binding molecule does so by competition with specific binding to the same target.

[0039] In a preferred embodiment, the first specific binding molecule comprises the CDRs, optionally further framework regions, and optionally the VH and / or VL domains of a specific binding molecule selected from the group consisting of S1D12, S1G2 and CA4.

[0040] The first specific binding molecule may bind to an epitope consisting of residues 355-367 of SEQ ID NO: 1. Thus, the epitope may be within the amino acid sequence of SEQ ID NO: 330 (GSLDNITHVPGGG). This epitope may be bound by the CDRs of a specific binding molecule referred to herein as "CA4."

[0041] The first 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 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) an amino acid sequence having one, two, or three amino acid substitutions thereto; Includes.

[0042] The first 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 the sequence shown in SEQ ID NO: 97 (LQYDSTPLA).

[0043] The first specific binding molecule can comprise framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, each of which comprises the following amino acid sequence: VHFR1 comprises the sequence set forth in SEQ ID NO: 555 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO: 556 (WVRQAPGQALEWIS); VHFR3 comprises the sequence set forth in SEQ ID NO: 557 (RLSITRDTSKSQFSLSLSSVTTEDTAVYYCTR); VHFR4 comprises the sequence set forth in SEQ ID NO: 558 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO: 559 (DIQVTQSPSSLSASLTERVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO: 560 (WYQQKPGQAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO: 561 (DVPSRFSGSGSGTDYTLTITSLEADDTATYYC); VLFR4 comprises the sequence set forth in SEQ ID NO: 562 (FGGGTNVEIK); Or, for each FR sequence, (i) at least 50% identical thereto, and / or (ii) an amino acid sequence having one, two, three, or four amino acid substitutions thereto; Includes.

[0044] The first specific binding molecule comprises: (a) a VH domain comprising the sequence set forth in SEQ ID NO: 563 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSYSVYWVRQAPGQALEWISIMYASGRVDYNPALKSRLSITRDTSKSQFSLSLSSVTTEDTAVYYCTRGIENWGPGLLVTVSS); and / or (b) a VL domain comprising the sequence set forth in SEQ ID NO: 564 (DIQVTQSPSSLSASLTERVSITCRTSQSVNNYLSWYQQKPGQAPKLLIYYATRLYTDVPSRFSGSGSGTDYTLTITSLEADDTATYYCLQYDSTPLAFGGGTNVEIK); or a humanized variant thereof.

[0045] The first specific binding molecule can compete with CA4 for binding to SEQ ID NO:1.

[0046] The initial specific binding molecule may compete with S1D12, S1G2 or CA4 for binding to SEQ ID NO:1.

[0047] In a preferred embodiment, the first specific binding molecule comprises the CDRs, optionally further framework regions, and optionally the VH and / or VL domains of a specific binding molecule selected from the group consisting of S1D12 and S1G2.

[0048] The first specific binding molecule can comprise the CDRs of S1D12, S1G2, or CA4, or an alternative specific binding molecule having an epitope that is contiguous with or overlaps with any one or more of S1D12, S1G2, or CA4. For example, the first specific binding molecule can be any specific binding molecule disclosed herein that binds to an epitope within or overlapping residues 307-391 of SEQ ID NO: 1. The first specific binding molecule can also be a specific binding molecule disclosed herein that binds to an epitope at residues 337-379 of SEQ ID NO: 1. The first specific binding molecule can comprise the CDR sequences of a clone shown in Table 1, Table 2, Table 3, Table 4, Table 9, Table 10 (the epitope is within or overlaps with residues 307-391 of SEQ ID NO: 1), or Table 11.

[0049] Second specific binding molecule The method may further include contacting the sample with a second specific binding molecule. The second specific binding molecule binds to an epitope within SEQ ID NO: 1. Contacting the sample with the second specific binding molecule may be a separate step from contacting the sample with the first specific binding molecule. Contacting the sample with the second specific binding molecule occurs after contacting the sample with the first specific binding molecule. Second specific binding molecules are described below. In this subheading, references to specific binding molecules (not related to the first specific binding molecule) refer to second specific binding molecules.

[0050] The second specific binding molecule can be any specific binding molecule disclosed herein, such as, for example, the specific binding molecule described in PCT Application No. PCT / EP2021 / 069160, where the second specific binding molecule is different from the first specific binding molecule. The second specific binding molecule can be 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.

[0051] The epitope of the second specific binding molecule can be within SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6 or SEQ ID NO:7.

[0052] However, when the second specific binding molecule is different from the first specific binding molecule, the second specific binding molecule can have any combination of the characteristics described for the first specific binding molecule. For example, the epitope and / or any one or more sequences of the second specific binding molecule can be as described above for the first specific binding molecule. Alternatively, the epitope and / or any one or more sequences of the second specific binding molecule can be different from those described above for the first specific binding molecule. The epitope of the second specific binding molecule may not be contained in any of SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7.

[0053] The second specific binding molecule can be a known specific binding molecule such as HT7, BT2, Tau12 or Tau146. The second specific binding molecule can be HT7 or BT2. BT2 and HT7 are described in US6010913A and in the article Merken et al 1992 - Affinity Purification of Human Tau Proteins and the Construction of a Sensitive Sandwich Enzyme-Linked Immunosorbent Assay for Human Tau Detection, both of which are incorporated herein by reference in their entirety.

[0054] The second specific binding molecule can bind to an epitope within residues 151-243 of SEQ ID NO:1.

[0055] The second specific binding molecule can bind to an epitope consisting of residues 194 to 198 of SEQ ID NO: 1. The second specific binding molecule can be BT2.

[0056] The second specific binding molecule can bind to an epitope consisting of residues 159 to 163 of SEQ ID NO: 1. The second specific binding molecule can be HT7.

[0057] The second specific binding molecule may compete with BT2 or HT7 for binding to SEQ ID NO:1.

[0058] The second specific binding molecule can comprise the CDRs of HT7, or an alternative specific binding molecule disclosed herein having adjacent or overlapping epitopes, e.g., 3aA6 and 3aD6, which bind to adjacent epitopes within residues 147-157 of SEQ ID NO:1.

[0059] Alternative second specific binding molecules for HT7 and / or BT2 may comprise the CDRs (optionally FW regions, and optionally further comprising the VH and / or VL domains) of the specific binding molecules of the clones shown in Table 8. For example, the second specific binding molecule may comprise the CDRs of 3aA6 or 3aD6. The second specific binding molecule may comprise the CDRs and FW regions of 3aA6 or 3aD6. The second specific binding molecule may comprise the VH and / or VL domains of 3aA6 or 3aD6.

[0060] The second 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 sequence set forth in SEQ ID NO: 208 (GTYSGANYGI); Or, for each CDR sequence: (i) at least 85% identical thereto, and / or (ii) an amino acid sequence having one, two, or three amino acid substitutions thereto; Including, The specific binding molecule binds to a polypeptide or protein molecule comprising the amino acid sequence of residues 147 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 "3aD6."

[0061] The second 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 sequence set forth in SEQ ID NO: 208 (GTYSGANYGI).

[0062] The second 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 sequence set forth in SEQ ID NO: 209 (ASYQNERSGV); Or, for each CDR sequence: (i) at least 85% identical thereto, and / or (ii) an amino acid sequence having one, two, or three amino acid substitutions thereto; Including, The specific binding molecule binds to a polypeptide or protein molecule comprising the amino acid sequence of residues 147 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 "3aA6."

[0063] The second specific binding molecule has a K of less than about 50 nM D and can bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 147 to 157 of SEQ ID NO: 1. D can be about 40 nM or less, about 30 nM or less, or about 20 nM or less. D may preferably bind to SEQ ID NO: 1 or SEQ ID NO: 191. K for binding to SEQ ID NO: 1 D K can be 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.

[0064] The second 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, where 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) QVRLQESGSSLVKPSQTLSLVCTVSGFPLTSNAVGWVRQAPGKAPEWLGLIDIDGDTAYNPALESRLSITRDTSKSQVSLSLSSVAIEDTAVYYCARHYDKWGYADSIDYWGPGLLVTVSSEG KSSGASGESKVDDQALLTQPSSVFGSLGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYDATTRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYQNERSGVFGSGTRLTVLG

[0065] The second 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, where 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVGSLGQRVSITCSGSDIGGADVGWFQQVPGSGLRTLIYDNDNRPSGVPDRFSGSKSGNTATLTISSLQPEDEADYFCGTYSGANYGIFGSGTRLTVLG

[0066] The second specific binding molecule can comprise the CDRs of BT2, or an alternative specific binding molecule disclosed herein having a nearby or overlapping epitope.

[0067] Alternative second specific binding molecules for HT7 and / or BT2 may comprise the CDRs (optionally FW regions, and optionally further comprising the VH and / or VL domains) of the specific binding molecules of the clones shown in Table 10. For example, the second specific binding molecule may comprise the CDRs of 3bD11, CB11, CA2, CB6, CA7, CA8, CB10, CC7, CB12, CC3, CA1, CA3, CD2, CC4, CD1, or CC5. The second specific binding molecule may comprise the CDRs and FW regions of 3bD11, CB11, CA2, CB6, CA7, CA8, CB10, CC7, CB12, CC3, CA1, CA3, CD2, CC4, CD1, or CC5. The second specific binding molecule can comprise the VH and / or VL domain of 3bD11, CB11, CA2, CB6, CA7, CA8, CB10, CC7, CB12, CC3, CA1, CA3, CD2, CC4, CD1, or CC5.

[0068] 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 amino acid sequence of VHCDR1 shown in Table 10; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 10; VHCDR3 comprises the amino acid sequence of VHCDR3 shown in Table 10; VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 10; VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 10; and VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 10; Or, for each CDR sequence: (i) at least 85% identical thereto, and / or (ii) an amino acid sequence having one, two, or three amino acid substitutions thereto; Including, wherein the specific binding molecule binds to an epitope within SEQ ID NO: 1. VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3 may be from a single clone shown in Table 10. The clone may be selected from the group consisting of 3bD11, CB11, CA2, CB6, CA7, CA8, CB10, CC7, CB12, CC3, CA1, CA3, CD2, CC4, CD1 and CC5.

[0069] General Characteristics of the First and / or Second Specific Binding Molecules The following describes features of general specific binding molecules, including details of the specific binding molecules described in PCT Application No. PCT / EP2021 / 069160. In this subheading, references to specific binding molecules (whether or not specifically related to either a first specific binding molecule or a second specific binding molecule) are references to general specific binding molecules, and combinations with any features of the first specific binding molecule or the second specific binding molecule are expressly contemplated, provided that the first specific binding molecule binds to an epitope within residues 297-391 of SEQ ID NO:1 (and thus references to specific binding molecules disclosed herein that do not bind to an epitope within residues 297-391 of SEQ ID NO:1 refer only to the second specific binding molecule).

[0070] The epitope of the specific binding molecule may be within residues 297-391 of SEQ ID NO: 1. Residues 297-391 of full-length tau are the predominant fragment isolated from the core of the proteolytically stable paired helical filament (PHF), also known as the PHF core fragment. Thus, the epitope of the specific binding molecule may be within the PHF or the dGAE fragment. Thus, the epitope of the specific binding molecule may be within SEQ ID NO: 4.

[0071] 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.

[0072] 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.

[0073] 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.

[0074] The epitope of the specific binding molecule is residues 306 to 391 of SEQ ID NO:1, residues 307 to 391 of SEQ ID NO:1, residues 337 to 355 of SEQ ID NO:1, residues 367 to 379 of SEQ ID NO:1, residues 331 to 360 of SEQ ID NO:1, residues 355 to 367 of SEQ ID NO:1, residues 379 to 391 of SEQ ID NO:1, residues 297 to 390 of SEQ ID NO:1, residues 369 to 390 of SEQ ID NO:1, residues 337 to 368 of SEQ ID NO:1, residues 337 to 379 of SEQ ID NO:1, residues 412 to 441 of SEQ ID NO:1, residues 1 to 49 of SEQ ID NO:1, residues 49 to 111 of SEQ ID NO:1, residues 147 to 157 of SEQ ID NO:1, residues 1 to 155 of SEQ ID NO:1, residues 1 to 238 of SEQ ID NO:1, residues 1 to 319 of SEQ ID NO:1 , residues 13-25 of SEQ ID NO:1, residues 49-113 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.

[0075] 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.

[0076] 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.

[0077] 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.

[0078] 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, for example, as described in Examples 5-12.

[0079] 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 ...."

[0080] 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.

[0081] 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.

[0082] 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.

[0083] 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.

[0084] 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.

[0085] 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.

[0086] 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.

[0087] 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.

[0088] 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.

[0089] 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.

[0090] 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.

[0091] 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 " / ".

[0092] 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).

[0093] 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).

[0094] 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).

[0095] 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.

[0096] 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%.

[0097] 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.

[0098] 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").

[0099] 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).

[0100] 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.

[0101] The VH domain may have the formula: VHFR1-VHCDR1-VHFR2-VHCDR2-VHFR3-VHCDR3-VHFR4.

[0102] The VL domain may have the formula: VLFR1-VLCDR1-VLFR2-VLCDR2-VLFR3-VLCDR3-VLFR4.

[0103] 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.

[0104] The specific binding molecule is (a) framework regions (FR) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, each of said FRs having 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.

[0105] 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%.

[0106] 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%.

[0107] 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.

[0108] 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.

[0109] 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.

[0110] 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.

[0111] 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.

[0112] 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.

[0113] 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").

[0114] 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").

[0115] 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").

[0116] The specific binding molecule is (a) SEQ ID NO: 443 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 444 (QAVLTQPSSVGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0117] The specific binding molecule is (a) SEQ ID NO: 445 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDY WGPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPT IKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 446 (QAVLTQPSSVGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLT VLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[0118] 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.

[0119] [Table 1]

[0120] The CDRs designated herein are defined based on Kabat. Those skilled in the art will recognize that other methods for 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.

[0121] 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.

[0122] 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 KD 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.

[0123] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTALTINSLQAEDEGDYYCVTGDSTTTHDDLVGSGTRLTVLG

[0124] 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).

[0125] 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."

[0126] 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).

[0127] 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).

[0128] 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.

[0129] 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%.

[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 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 shown 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.

[0131] 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."

[0132] 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).

[0133] 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.

[0134] 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."

[0135] 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."

[0136] 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."

[0137] The specific binding molecule is (a) SEQ ID NO: 455 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 456 (QAVVTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0138] The specific binding molecule is (a) SEQ ID NO: 457 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAID YWGPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGP TIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIE RTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 458 (QAVVTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTV ) a light chain comprising the sequence shown in These humanized variants may include:

[0139] 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."

[0140] 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).

[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: 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."

[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: 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).

[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: 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."

[0144] 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).

[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 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."

[0146] 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).

[0147] 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 with 100% identity to those listed above is referred to herein as "S2C6."

[0148] 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).

[0149] 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.

[0150] [Table 2-1] [Table 2-2]

[0151] 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.

[0152] 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.

[0153] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVVTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG

[0154] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCVRSYRTDGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVLTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTVIVASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0155] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDSDGEEGYNPALNSRLSITRDTSKNQVSLSLSRVTSEDTAVYYCGRTYRTDGYAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDRVMLTQPPSVGSPGQTVSITCSGSFIGISSVGWFQQLPGSGLRTVIFASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLS

[0156] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCVRSYRADGLAYGYVQAIDYWGPGLLLTIS SEGKSSGASGESKVDDQAVVTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIVASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0157] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVLTQPSSMSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0158] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLISNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALKSQYAASDPDTSKSQVSLSLSSVTSEDTAVYYCGRTYRTDGFAYGYVQAIDYWGPGLLLTIS SEGKSSGASGESKVDDQAVLTQPSSVGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0159] 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).

[0160] 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."

[0161] 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).

[0162] 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).

[0163] 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.

[0164] 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%.

[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: 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.

[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: 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."

[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: 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).

[0168] 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.

[0169] [Table 3]

[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 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.

[0171] 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.

[0172] 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).

[0173] 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."

[0174] 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).

[0175] 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).

[0176] 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.

[0177] 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%.

[0178] 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.

[0179] 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."

[0180] 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.

[0181] [Table 4]

[0182] 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.

[0183] 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.

[0184] 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).

[0185] 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."

[0186] 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).

[0187] 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).

[0188] 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.

[0189] 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%.

[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: 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.

[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: 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."

[0192] 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).

[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: 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.

[0194] 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."

[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: 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."

[0196] 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."

[0197] The specific binding molecule is (a) SEQ ID NO: 467 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSGSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 468 (QAVLTQPSSVGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0198] The specific binding molecule is (a) SEQ ID NO: 469 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSGSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLL VTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPC PPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTI SKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 470 (QAVLTQPSSVGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTV ) a light chain comprising the sequence shown in These humanized variants may include:

[0199] 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."

[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 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).

[0201] 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."

[0202] 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).

[0203] 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."

[0204] 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).

[0205] 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.

[0206] [Table 5]

[0207] 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.

[0208] 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.

[0209] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSGSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLG

[0210] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSGSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVSVSSEGKSS GASGESKVDDQAVLTQPSSVSGALGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYGAASRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSSDGGVFGSGTRLTVLG

[0211] 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) QVQLQESGPSLVKPSETLSLTTCTVSGFSLTNYGVGWVRQAPGKALEWLGNIYSGGSTYYNPALKSRLSITRDTSKSQVSLSLNSVTLEDTAVYYCGRGGVGSVDVWGPGLLVTVSSEGKSS GASGESKVDDQAVLTQPPSVSGSPGQRVSITCSGGRNNIGRGTFVDWYQQLPGSGLKTVIYGTDRRPPGVPDRFSGSKTGNAATLTITSLQAEDEADYWCATYDYSNDMIILGSGTRLTVLG

[0212] 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) QVRLQESGPSLVKPSQTLSLTCTVSGFSLTSYALGWVRQAPGRAPEWIGNIWRGGRIEYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCSRSGGDWGPGLLVTVSSEGKSSGA SGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGATSRASGVPDRFSGSRSENTATLTISSLQAEDEADYYCASYDRSESVVFGSGTRLTVLG

[0213] 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.

[0214] 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."

[0215] 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."

[0216] 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).

[0217] 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).

[0218] 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.

[0219] 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%.

[0220] 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.

[0221] 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."

[0222] 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).

[0223] 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."

[0224] 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).

[0225] 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."

[0226] 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).

[0227] 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."

[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 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).

[0229] 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.

[0230] 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."

[0231] 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."

[0232] 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."

[0233] The specific binding molecule is (a) SEQ ID NO: 479 (QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 480 (QAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0234] The specific binding molecule is (a) SEQ ID NO: 481 (QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYW GPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTI KPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 482 (QAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLT VLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[0235] 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.

[0236] [Table 6]

[0237] 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.

[0238] 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.

[0239] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNGVGWVRRAPGKVPEWVGDISSGGKVYGHPALKSRLSITRDTSKSQVSLSVSSVTSEDTAVYYCVRCRDGGVSYGYDSDYWGPGLLVTVSSEG KSSGASGESKVDDQAVVTQPSSVSKSLGQSVSITCSGSSSNVGYGDYVGWFQQVPGSAPKLLIYGVTERASGVPDRFSGSRSGNTATLTISSIQAEDEADYYCASYDDSSGGIFGSGTRLTVLG

[0240] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNGVGWVRQAPGKVPEWLGDISSVGKKYANPALKSRLSFTRDTSKSQVSLSLSSVTTEDTAVYYCVKCRDGGVTYGYDIDYWGPGLLVTASSEG KSSGASGESKVDDQAVVTQPSSVGSLGQSVSITCSGSSGNVGYGDYVSWFQQFHGSAPKLLIYGATNLASGVPARFSGSRSGNTATLTISSLHAEDEADYYCASYDSSSGGVFGSGTRLTVLG

[0241] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNGVGWVRQAPGKVPEWVGDISSSGKAYANPALKSRLSITRDTAKTQVFLSLSSVTTEDTAVYYCVRCRDGGVSYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPPSVGSPGQRVSITCSGSSNIGGGNYLSWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASFDTSSGGIFGAGTRLTVLG

[0242] 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) QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLG

[0243] 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).

[0244] 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."

[0245] 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).

[0246] 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).

[0247] 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.

[0248] 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%.

[0249] 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.

[0250] 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."

[0251] 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 The VLCDR3 can comprise an amino acid sequence comprising the sequence set forth in SEQ ID NO: 189 (ASADTNDGGV).

[0252] 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."

[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: 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.

[0254] [Table 7]

[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 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.

[0256] 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.

[0257] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNGVGWVRQAPGKVPEWVGDKSSAGKTYGNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCVRCRDGGVTYGYDVDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSLGQSVSITCSGSSSNVGYGDVVSWFQQFPGSAPKLLIFGTTTRASGVPDRFSGSRSGNAATLTINSLQAEDEADYYCASFDSDSGGIAGSGTRLTVLG

[0258] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNGVGWVRQAPGKVPEWLGDISSVGKKYANPALKSRLSFTRDTSKSQVSLSLSSVTTEDTAVYYCVKCRDGGVTYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSTGQTVSITCGSGSSSNVGLRNYVTWFQQVPGSAPKLLIYGATSRASGIPDRFSGSRSGNTATLIISSLQAEDEADYYCASADTNDGVFGSGTRLTVLG

[0259] 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).

[0260] 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."

[0261] 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).

[0262] 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).

[0263] 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.

[0264] 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%.

[0265] 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.

[0266] 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."

[0267] 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).

[0268] 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."

[0269] 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.

[0270] [Table 8]

[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 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.

[0272] 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.

[0273] 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) QVRLQESGSSLVKPSQTLSLVCTVSGFPLTSNAVGWVRQAPGKAPEWLGLIDIDGDTAYNPALESRLSITRDTSKSQVSLSLSSVAIEDTAVYYCARHYDKWGYADSIDYWGPGLLVTVSSEG KSSGASGESKVDDQALLTQPSSVFGSLGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYDATTRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYQNERSGVFGSGTRLTVLG

[0274] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVGSLGQRVSITCSGSDIGGADVGWFQQVPGSGLRTLIYDNDNRPSGVPDRFSGSKSGNTATLTISSLQPEDEADYFCGTYSGANYGIFGSGTRLTVLG

[0275] 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).

[0276] 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).

[0277] 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).

[0278] 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).

[0279] 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.

[0280] 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%.

[0281] 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.

[0282] 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."

[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: 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).

[0284] 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.

[0285] 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."

[0286] 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."

[0287] 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."

[0288] The specific binding molecule is (a) SEQ ID NO: 491 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 492 (QAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0289] The specific binding molecule is (a) SEQ ID NO: 493 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGL LVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKP CPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERT ISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 494 (QAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLT VLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[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: 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."

[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: 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).

[0292] 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."

[0293] 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).

[0294] 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."

[0295] 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).

[0296] 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.

[0297] [Table 9]

[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 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.

[0299] 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.

[0300] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLG

[0301] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDWGVAWVRQAPGKALEWLGTMRSGGTTDDNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGVHYAWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSGSLGQSVSITCSGSSSNVGDGRYVSWFQQVPGSAPKLLIYDTTSRASGVPDRFSGSRSGNTATLIITSLQAEDEADYYCASIDSGNNLLFGSGTRLTVLG

[0302] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDWGVAWVRQAPGKALEWLGTMRSGGTTDDNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGVHYAWGRGLLVTVSSEGKS SGASGESKVDDRVVRTQPSSVSKSLGQSVSITCSGSSSNVGAGNYVGWFQQVPGSAPKLLIYGATNRASGVPARFSGSKSGVTATLTITSLQAEDEADYYCASIDTSRSHIFGSGTRLTVLG

[0303] 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) QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSWGVAWVRQAPGKALEWLGTMRSGGGTEYNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGIHYAWGRGLLVSVSSEGKS SGASGESKVDDQAVLTQLSSVGSLGQRVSITCSGSSSNVGDGDYVGWFQQLPGSAPKLLIYSARNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCASIDTSRSHIFGSGTRLTVLG

[0304] 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. (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The amino acid sequence may be within the range of

[0305] 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."

[0306] The epitope is SEQ ID NO: 255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The epitope may comprise the amino acid sequence of SEQ ID NO: 255. (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) 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

[0307] The epitope is SEQ ID NO: 255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The epitope may consist of the amino acid sequence of SEQ ID NO: 255. (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) 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

[0308] 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."

[0309] 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).

[0310] 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 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR) The amino acid sequence may be within the range of

[0311] 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."

[0312] The epitope is SEQ ID NO: 293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR) The epitope may comprise the amino acid sequence of SEQ ID NO: 293 (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

[0313] The epitope is SEQ ID NO: 293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR) The epitope may consist of the amino acid sequence of SEQ ID NO: 293 (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

[0314] 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."

[0315] 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).

[0316] 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. (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAA GHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The amino acid sequence may be within the range of

[0317] 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."

[0318] The epitope is SEQ ID NO: 260 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAA GHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The epitope may comprise the amino acid sequence of SEQ ID NO: 260. (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

[0319] The epitope is SEQ ID NO: 260 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAA GHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The epitope may consist of the amino acid sequence of SEQ ID NO: 260. (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

[0320] 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."

[0321] 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).

[0322] 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. (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAP PGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT) The amino acid sequence may be within the range of

[0323] 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."

[0324] 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."

[0325] The epitope is SEQ ID NO: 264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAP PGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT) The epitope may comprise the amino acid sequence of SEQ ID NO: 264. (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

[0326] The epitope is SEQ ID NO: 264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKT KIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHV PGGGSVQIVYKPVDLSKVT) The epitope may consist of the amino acid sequence of SEQ ID NO: 264. (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

[0327] 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."

[0328] 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).

[0329] 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.

[0330] 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."

[0331] 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."

[0332] 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."

[0333] The specific binding molecule is (a) SEQ ID NO: 503 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFDSYYVGWVRQAPGKALEWLGNIYSTGRAFYNPALKSRLSITRDTSKSQVSLSVSSVTIEDTALYYCVRGSYYHGGGNGMVDFFDYWSPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 504 (QVVRTQPSSVSGGSLGQRVSITCSGSSSNVGYGNYVGWFQQVPGSAPKLLIYAATSRASGVPDRFSGSRSGNTATLTIDSLQAEDEADYYCSSYQRGNTGVFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0334] The specific binding molecule is (a) SEQ ID NO: 505 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFDSYYVGWVRQAPGKALEWLGNIYSTGRAFYNPALKSRLSITRDTSKSQVSLSVSSVTIEDTALYYCVRGSYYHGGGNGMVDFFD YWSPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGP TIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIE RTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 506 (QVVRTQPSSVGSLGQRVSITCSGSSSNVGYGNYVGWFQQVPGSAPKLLIYAATSRASGVPDRFSGSRSGNTATLTIDSLQAEDEADYYCSSYQRGNTGVFGSGTRLT VLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[0335] 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."

[0336] 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).

[0337] 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."

[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: 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).

[0339] 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).

[0340] 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."

[0341] 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).

[0342] 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).

[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: 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."

[0344] 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).

[0345] 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.

[0346] 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."

[0347] 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."

[0348] 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."

[0349] The specific binding molecule is (a) SEQ ID NO: 515 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTNYRVGWVRQAPGKALEWVSNIRSGGTTWYNPALKSRLSITADTSKSQVSLSLSSVTTEDTAVYYCARDSSGDLYAYDYWGPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 516 (QAVLTQPSSVSRSLGQSVSMTCSGSSSNVGYGNYMAWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSTSGGVFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0350] The specific binding molecule is (a) SEQ ID NO: 517 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTNYRVGWVRQAPGKALEWVSNIRSGGTTWYNPALKSRLSITADTSKSQVSLSLSSVTTEDTAVYYCARDSSGDLYAYDYWGP GLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIK PCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERT ISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 518 (QAVLTQPSSVSRSLGQSVSMTCSGSSSNVGYGNYMAWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSTSGGVFGSGTRLT VLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[0351] 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).

[0352] 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."

[0353] 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).

[0354] 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).

[0355] 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 having 100% identity to those listed above is referred to herein as "CC7."

[0356] 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).

[0357] 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.

[0358] 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."

[0359] 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."

[0360] 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."

[0361] The specific binding molecule is (a) SEQ ID NO: 527 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSS) and / or a VH domain comprising the sequence set forth in (b) SEQ ID NO: 528 (RVVRTQPSSVGSLGQRVSITCSGSYITGSSVGWFQQVPGSGLKTVIYDNNDRPSGVPDRFSGSKSGDTATLTISSLQAEDEADYYCASYDTSNIGLFGSGTRLTVLG) a VL domain comprising the sequence shown in These humanized variants may include:

[0362] The specific binding molecule is (a) SEQ ID NO: 529 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWG PGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTI KPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIER TISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) and / or a heavy chain comprising the sequence shown in (b) SEQ ID NO: 530 (RVVRTQPSSVGSLGQRVSITCSGSYITGSSVGWFQQVPGSGLKTVIYDNNDRPSGVPDRFSGSKSGDTATLTISSLQAEDEADYYCASYDTSNIGLFGSGTRLTVL GGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS) a light chain comprising the sequence shown in These humanized variants may include:

[0363] 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. (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA) The amino acid sequence may be within the range of

[0364] 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."

[0365] The epitope is SEQ ID NO: 294 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA) The epitope may comprise the amino acid sequence of SEQ ID NO: 294. (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

[0366] The epitope is SEQ ID NO: 294 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA) The epitope may consist of the amino acid sequence of SEQ ID NO: 294 (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

[0367] 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."

[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: 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).

[0369] 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."

[0370] 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).

[0371] 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. (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The amino acid sequence may be within the range of

[0372] 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."

[0373] The epitope is SEQ ID NO: 295 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The epitope may comprise the amino acid sequence of SEQ ID NO: 295. (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

[0374] The epitope is SEQ ID NO: 295 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS) The epitope may consist of the amino acid sequence of SEQ ID NO: 295. (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

[0375] 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."

[0376] 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. (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGST) The amino acid sequence may be within the range of

[0377] 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."

[0378] The epitope is SEQ ID NO: 300 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQT APVPMPDLKNVKSKIGST) The epitope may comprise the amino acid sequence of SEQ ID NO: 300. (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

[0379] The epitope is SEQ ID NO: 300 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQT APVPMPDLKNVKSKIGST) The epitope may consist of the amino acid sequence of SEQ ID NO: 300. (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

[0380] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLC...

Claims

1. 1. An in vitro method for detecting tau protein or a fragment thereof in a saliva sample, comprising contacting the sample with a first specific binding molecule, wherein the first specific binding molecule binds to an epitope within residues 297-391 of SEQ ID NO:

1.

2. The method of claim 1, wherein the first specific binding molecule binds to an epitope within residues 307-391 of SEQ ID NO:

1.

3. The method of claim 1 or 2, wherein the first specific binding molecule binds to an epitope within residues 337-379 of SEQ ID NO:

1.

4. The method of any one of claims 1 to 3, wherein the first specific binding molecule binds to an epitope consisting of residues 337 to 349 of SEQ ID NO:

1.

5. The method of any one of claims 1 to 4, wherein the first specific binding molecule binds to an epitope consisting of residues 337 to 355 of SEQ ID NO:

1.

6. The first specific binding molecule comprises CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having an amino acid sequence VHCDR1 comprises the sequence set forth 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 set forth in SEQ ID NO:24 (SGSSSNVGGGGNSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO:26 (DTNSRPS); VLCDR3 comprises 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 therein The method according to any one of claims 1 to 5, comprising an amino acid sequence having the formula:

7. The first specific binding molecule comprises CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having an amino acid sequence VHCDR1 comprises the sequence set forth 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 set forth in SEQ ID NO:24 (SGSSSNVGGGGNSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO:26 (DTNSRPS); and The method of any one of claims 1 to 6, wherein VLCDR3 comprises the sequence shown in SEQ ID NO: 29 (VTGDSTTHDDL).

8. A first specific binding molecule comprises framework regions (FRs) 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 (RLDITRDTSKNQISLSLSSVTTDDAA VYYCTR); 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 comprises 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 therein The method of any one of claims 1 to 7, comprising an amino acid sequence having the formula:

9. The first specific binding molecule comprises: (a) a VH domain comprising the sequence set forth in SEQ ID NO: 443 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAA VYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSS); and / or (b) the VL domain comprises the sequence set forth in SEQ ID NO: 444 (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG), or a humanized variant thereof.

10. The first specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337-355 of SEQ ID NO:1 with a K of less than about 500 pM. Ｄ and optionally, the specific binding is measured by surface plasmon resonance (SPR), and optionally i. K for binding to SEQ ID NO:1 Ｄ is about 50 pM to about 150 pM, and / or ii. K of binding to SEQ ID NO:5 Ｄ is about 300 pM to about 400 pM; The method according to any one of claims 1 to 9.

11. The method of any one of claims 1 to 3, wherein the first specific binding molecule binds to an epitope consisting of residues 367 to 379 of SEQ ID NO:

1.

12. The first specific binding molecule comprises CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having an 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 (GIDTGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO:54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO:63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO:70 (ASDGRPS); VLCDR3 comprises the 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 therein The method of any one of claims 1 to 3 and 11, comprising an amino acid sequence having the formula:

13. The first specific binding molecule comprises CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having an 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 (GIDTGEEGYNPALNS); VHCDR3 comprises the sequence set forth in SEQ ID NO:54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO:63 (SGSFIGISSVG); VLCDR2 comprises the sequence set forth in SEQ ID NO:70 (ASDGRPS); and VLCDR3 comprises the sequence set forth in SEQ ID NO: 73 (GSSDRTPYTGV); The method according to any one of claims 1 to 3 and 11 to 12.

14. A first specific binding molecule comprises framework regions (FRs) 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 is an amino acid sequence comprising the 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 therein The method of any one of claims 1 to 3 and 11 to 13, comprising an amino acid sequence having the formula:

15. The first specific binding molecule comprises: (a) a VH domain comprising the sequence set forth in SEQ ID NO: 455 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVSS); and / or (b) the method of any one of claims 1 to 3 and 11 to 14, comprising a VL domain comprising the sequence set forth in SEQ ID NO: 456 (QAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG), or a humanized variant thereof.

16. The first specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367-379 of SEQ ID NO:1 with a K of less than about 500 pM. Ｄ and optionally, the specific binding is measured by surface plasmon resonance (SPR), and optionally i. K for binding to SEQ ID NO:1 Ｄ is about 100 pM to about 200 pM, and / or ii. K of binding to SEQ ID NO:5 Ｄ is about 400 pM to about 500 pM; The method according to any one of claims 1 to 3 and 11 to 15.

17. The method of any one of claims 1 to 3, wherein the first specific binding molecule binds to an epitope consisting of residues 355 to 367 of SEQ ID NO:

1.

18. The first specific binding molecule comprises CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having an 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 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 therein The amino acid sequence of 18. The method according to any one of claims 1 to 3 and 17.

19. The first specific binding molecule comprises CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having an 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 The method of any one of claims 1 to 3 and 17 to 18, wherein the VLCDR3 comprises the sequence shown in SEQ ID NO: 97 (LQYDSTPLA).

20. A first specific binding molecule comprises framework regions (FRs) 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:555 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence set forth in SEQ ID NO:556 (WVRQAPGQALEWIS); VHFR3 comprises the sequence set forth in SEQ ID NO:557 (RLSITRDTSKSQFSLSLSSSVTTEDTAVYYCTR); VHFR4 comprises the sequence set forth in SEQ ID NO:558 (WGPGLLVTVSS); VLFR1 comprises the sequence set forth in SEQ ID NO:559 (DIQVTQSPSSLSASLTERVSITC); VLFR2 comprises the sequence set forth in SEQ ID NO:560 (WYQQKPGQAPKLLIY); VLFR3 comprises the sequence set forth in SEQ ID NO:561 (DVPSRFSGSGSGTDYTLTITSLEADDTATYYC); VLFR4 comprises the sequence set forth in SEQ ID NO:562 (FGGGTNVEIK); Or, for each FR sequence, (i) at least 50% identical thereto; and / or (ii) 1, 2, 3, 4, or 5 amino acid substitutions therein The method of any one of claims 1 to 3 and 17 to 19, comprising an amino acid sequence having the formula:

21. The first specific binding molecule comprises: (a) a VH domain comprising the sequence set forth in SEQ ID NO: 563 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSVTSYSVYWVRQAPGQALEWISIMYASGRVDYNPALKSRLSITRDTSKSQFSLSLSSSVTTEDTAVYYCTRGIENWGPGLLVTVSS); and / or (b) The method of any one of claims 1 to 3 and 17 to 20, comprising a VL domain comprising the sequence set forth in SEQ ID NO: 564 (DIQVTQSPSSLSASLTERVSITCRTSQSVNNYLSWYQQKPGQAPKLLIYYATRLYTDVPSRFSGSGSGTDYTLTITSLEADDTATYYCLQYDSTPLAFGGGTNVEIK), or a humanized variant thereof.

22. 22. The method of any one of claims 1 to 21, wherein the first specific binding molecule competes with S1D12, S1G2 or CA4 for binding to SEQ ID NO:

1.

23. 23. The method of any one of claims 1 to 22, further comprising contacting the sample with a second specific binding molecule.

24. 24. The method of claim 23, wherein the second specific binding molecule binds to an epitope within residues 151-243 of SEQ ID NO:

1.

25. The method of claim 23 or 24, wherein the second specific binding molecule binds to an epitope consisting of residues 194-198 of SEQ ID NO:

1.

26. The method of any one of claims 23 to 25, wherein the second specific binding molecule is BT2.

27. The method of claim 23 or 24, wherein the second specific binding molecule binds to an epitope consisting of residues 159-163 of SEQ ID NO:

1.

28. 30. The method of any one of claims 23, 24 or 27, wherein the second specific binding molecule is HT7.

29. 28. The method of any one of claims 23 to 25 or 27, wherein the second specific binding molecule competes with BT2 or HT7 for binding to SEQ ID NO:

1.

30. The method of any one of claims 23 to 28, wherein the first specific binding molecule is S1D12 or S1G2 and the second specific binding molecule is BT2 or HT7.

31. The second specific binding molecule comprises 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 (LIDDVDGDAAYDPALKS); 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 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 therein comprising an amino acid sequence having the formula:

24. The method of claim 23, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising the amino acid sequence of residues 147-157 of SEQ ID NO:

1.

32. The second specific binding molecule comprises 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: 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 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 therein comprising an amino acid sequence having the formula:

24. The method of claim 23, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising the amino acid sequence of residues 147-157 of SEQ ID NO:

1.

33. The second specific binding molecule comprises CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, each of said CDRs having the amino acid sequence VHCDR1 comprises the amino acid sequence of VHCDR1 shown in Table 10; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 10; VHCDR3 comprises the amino acid sequence of VHCDR3 shown in Table 10; VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 10; VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 10; and VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 10; Or, for each CDR sequence: (i) at least 85% identical thereto; and / or (ii) one, two or three amino acid substitutions therein comprising an amino acid sequence having the formula:

24. The method of claim 23, wherein the specific binding molecule binds to an epitope within SEQ ID NO:

1.

34. 34. The method of claim 33, wherein the second specific binding molecule comprises a CDR of a clone selected from the group consisting of 3bD11, CB11, CA2, CB6, CA7, CA8, CB10, CC7, CB12, CC3, CA1, CA3, CD2, CC4, CD1 and CC5.

35. The first and / or second specific binding molecule may be an immunoglobin, an immunoglobulin Fab region, an Fab', an Fv, an Fv-Fc, a single chain Fv (scFv), an scFv-Fc, an (scFv) ２ , a diabody, a triabody, a tetrabody, a bispecific t cell engager (BiTE), an intein, a VNAR domain, a single domain antibody (sdAb) or a VH domain.

36. 36. The method of any one of claims 1 to 35, wherein the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO:

1.

37. 37. The method of any one of claims 1 to 36, wherein the fragment comprises at least 4, 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, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 35, at least 40, at least 45, 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 90, at least 91, at least 92, at least 93, at least 94, or 95 consecutive amino acid residues from residues 297 to 391 of SEQ ID NO:

1.

38. 38. The method of any one of claims 1 to 37, wherein the fragment comprises at least 4, 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, at least 20, at least 21, at least 22, at least 23, at least 24, at least 25, at least 26, at least 27, at least 28, at least 29, at least 30, at least 35, at least 40, at least 45, 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 90, at least 91, at least 92, or 93 consecutive amino acid residues from residues 151 to 243 of SEQ ID NO:

1.

39. the fragment comprises at least 30 consecutive amino acid residues from residue 113 to residue 379 of SEQ ID NO:1; (a) at least four contiguous amino acid residues from residue 297 to residue 391 of SEQ ID NO:1; and / or (b) at least four consecutive amino acid residues from residues 151 to 243 of SEQ ID NO:

1.

40. 40. The method of any one of claims 1 to 39, wherein the fragment comprises at least 30 contiguous amino acid residues from residues 297 to 391 of SEQ ID NO:1 and / or at least 30 contiguous amino acid residues from residues 151 to 243 of SEQ ID NO:

1.

41. 41. The method of any one of claims 1 to 40, wherein the fragment comprises amino acid residues 337 to 349 of SEQ ID NO:1 and / or amino acid residues 370 to 374 of SEQ ID NO:

1.

42. 42. The method of any one of claims 1 to 41, wherein the fragment comprises amino acid residues 194 to 198 of SEQ ID NO:1 and / or amino acid residues 159 to 163 of SEQ ID NO:

1.

43. the fragment is from within residues 113-379 of SEQ ID NO:1 and is at least 30, at least 35, at least 40, at least 45, 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 90, at least 95, at least 100, at least 105, at least 110, at least 115, at least 120, at least 125, at least 130, at least 135, at least 140, at least 145, at least 150, at least 155, at least 160, at least 165, 43. The method of any one of claims 1 to 42, comprising at least 170, at least 175, at least 180, at least 185, at least 190, at least 195, at least 200, at least 205, at least 210, at least 215, at least 220, at least 225, at least 230, at least 235, at least 240, at least 245, at least 250, at least 255, at least 260, at least 261, at least 262, at least 263, at least 264, at least 265, at least 266 or 267 consecutive amino acid residues.

44. the fragment comprises at least 156 consecutive amino acid residues from residue 113 to residue 379 of SEQ ID NO:1, and (a) at least 53 contiguous amino acid residues from residues 297 to 391 of SEQ ID NO:1 (optionally including residues 337 to 349 of SEQ ID NO:1); and / or (b) at least 50 contiguous amino acid residues from residues 151 to 243 of SEQ ID NO:1, optionally including residues 194 to 198 of SEQ ID NO:

1.

45. the fragment comprises at least 181 consecutive amino acid residues from residue 113 to residue 379 of SEQ ID NO:1; (a) at least 78 contiguous amino acid residues from residues 297 to 391 of SEQ ID NO:1 (optionally including residues 370 to 374 of SEQ ID NO:1); and / or (b) at least 50 contiguous amino acid residues from residues 151 to 243 of SEQ ID NO:1, optionally including residues 194 to 198 of SEQ ID NO:

1.

46. the fragment comprises at least 191 consecutive amino acid residues from residue 113 to residue 379 of SEQ ID NO:1; (a) at least 53 contiguous amino acid residues from residues 297 to 391 of SEQ ID NO:1 (optionally including residues 337 to 349 of SEQ ID NO:1); and / or (b) at least 85 contiguous amino acid residues from residues 151 to 243 of SEQ ID NO:1, optionally including residues 159 to 163 of SEQ ID NO:

1.

47. the fragment comprises at least 216 consecutive amino acid residues from residue 113 to residue 379 of SEQ ID NO:1; (a) at least 78 contiguous amino acid residues from residues 297 to 391 of SEQ ID NO:1 (optionally including residues 370 to 374 of SEQ ID NO:1); and / or (b) at least 85 contiguous amino acid residues from residues 151 to 243 of SEQ ID NO:1, optionally including residues 159 to 163 of SEQ ID NO:

1.

48. The fragment (a) amino acid residues 194 to 349 of SEQ ID NO:1; (b) amino acid residues 159-349 of SEQ ID NO:1; (c) amino acid residues 194 to 374 of SEQ ID NO:1; (d) amino acid residues 159-374 of SEQ ID NO:1; (e) amino acid residues 195 to 370 of SEQ ID NO:1; (f) amino acid residues 159-379 of SEQ ID NO:1; (g) amino acid residues 113-224 of SEQ ID NO:1; (h) amino acid residues 113 to 349 of SEQ ID NO:1; or (i) amino acid residues 113 to 370 of SEQ ID NO:1 The method of any one of claims 1 to 47, comprising:

49. The amino acid sequence of the fragment is (a) amino acid residues within residues 113 to 370 of SEQ ID NO:1; (b) amino acid residues within residues 113 to 349 of SEQ ID NO:1; (c) amino acid residues within residues 113 to 224 of SEQ ID NO:1; (d) amino acid residues within residues 159 to 379 of SEQ ID NO:1; (e) amino acid residues within residues 195-370 of SEQ ID NO:1; (d) amino acid residues within residues 194 to 349 of SEQ ID NO:1; (g) amino acid residues within residues 159 to 349 of SEQ ID NO:1; (h) an amino acid residue within residues 194 to 374 of SEQ ID NO:1; or (i) amino acid residues within residues 159 to 374 of SEQ ID NO:1 The method according to any one of claims 1 to 48, comprising:

50. The method according to any one of claims 1 to 49, wherein the amino acid sequence of the fragment consists of amino acid residues 113 to 379 of SEQ ID NO:

1.

51. 51. The method of any one of claims 1 to 50, further comprising determining the concentration of tau protein fragments in the sample.

52. A diagnostic device for use in a method according to any one of claims 1 to 51.

53. 52. A kit comprising a specific binding molecule suitable for use in the method of any one of claims 1 to 51 and reagents for detecting tau protein or a fragment thereof in a saliva sample, wherein the first specific binding molecule binds to an epitope within residues 297 to 391 of SEQ ID NO:1.

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