Method for detecting TAU protein fragment in sample

Abstract

The present invention relates to an in vitro method for detecting a tau protein fragment in a patient sample, wherein the amino acid sequence of the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO: 1. The methods may use specific binding molecules (e.g., antibodies) directed against tau key epitopes. The invention can be used for diagnosing tauopathy.

Description

Technical Field

[0001] The present invention relates to an in vitro method for detecting a tau protein fragment in a patient's sample, wherein the amino acid sequence of the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO:1. The method can use specific binding molecules (e.g., antibodies) directed against key tau epitopes. The present invention can be used for the diagnosis of tauopathy. Background Art

[0002] Diseases associated with tau are collectively referred to as neurodegenerative tauopathies. Alzheimer's disease (AD) belongs to this class of neurodegenerative diseases. A common feature of dementias such as Alzheimer's disease (AD) is the progressive accumulation of intracellular and / or extracellular deposits of protein structures composed of tau, such as beta-amyloid plaques and neurofibrillary tangles (NFTs), in the brains of affected patients. The presence of tau aggregates is strongly associated with pathological neurofibrillary degeneration and brain atrophy, as well as cognitive impairment. In AD, tau proteins self-assemble to form paired helical filaments (PHFs) and straight filaments, which constitute neurofibrillary tangles within neurons and dystrophic neurites in the brain. Protein misfolding to form amyloid fibrils is a hallmark of many different diseases, collectively known as amyloidosis, each characterized by a specific precursor protein.

[0003] Long-term research on the causes of AD and other protein conformational disorders has not brought the expected major progress in diagnosis or treatment. One reason for the limited progress is believed to be the lack of high-affinity specific binding molecules targeting key epitopes of tau. This defect is solved by the disclosed generation of specific binding molecules described in PCT application No. PCT / EP2021 / 069160, filed in the name of WisTa Laboratories Ltd (the entire contents of which are incorporated herein by reference). The disclosed specific binding molecules are derived from antibodies isolated from sheep immunized with full-length tau protein and truncated tau fragments from the PHF core. The use of sheep as a source of specific binding molecules is believed to contribute to the high affinity of the specific binding molecules of the present invention. PCT / EP2021 / 069160 describes the detection of tau in brain lysates and plasma samples of, for example, AD models and AD or mild cognitive impairment (MCI) patients based on specific binding molecules. However, PCT / EP2021 / 069160 does not disclose the identity of the fragments detected in patient samples. Chen et al. (2019) Alzheimers Dement. 15(3):487–496 reviewed the complexity of extracellular tau and the limited progress in developing blood-based screens for Alzheimer's disease. Chen et al. concluded that "most plasma tau is full-length" and proposed the use of N-terminal assays in a diagnostic setting. Two N-terminal assays (NT1 and NT2) were described. NT1 requires a minimal sequence of residues 6 to 198 of full-length tau. NT2 requires a longer sequence of residues 6 to 224 of full-length tau. Chen et al. proposed the use of the N-terminal NT1 assay more often in a diagnostic setting, rather than the NT2 assay (which detects longer fragments).

[0004] The inventors have developed an assay for detecting a tau protein fragment in a patient sample, wherein the amino acid sequence of the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO: 1. The inventors have conducted multiple Assays and mass spectrometry to detect tau levels in human plasma have shown that "extended core" fragments of tau (having residues only within residues 113 to 379 of SEQ ID NO: 1) are released into plasma and appear to be part of the normal processing of tau protein. The inventors have demonstrated that such fragments are significantly reduced in Alzheimer's disease plasma samples compared to cognitively unimpaired control plasma. These assays can use one or more specific binding molecules described in PCT Application No. PCT / EP2021 / 069160, which can provide advantages including increased sensitivity due to high affinity. The inventors also unexpectedly discovered that using a first specific binding molecule that binds to residues 297 to 391 of SEQ ID NO: 1 enables a second specific binding molecule to robustly detect tau fragments, but using it in reverse (the first specific binding molecule binds outside residues 297 to 391 of SEQ ID NO: 1 and the second specific binding molecule binds within residues 297 to 391 of SEQ ID NO: 1) may not detect tau fragments, even if a high-affinity specific binding molecule that binds to residues 297 to 391 of SEQ ID NO: 1 is used. Summary of the Invention

[0005] According to a first aspect, the present invention provides an in vitro method for detecting a tau protein fragment in a patient's sample, wherein the amino acid sequence of the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO:1.

[0006] According to a second aspect, the present invention provides a diagnostic method comprising detecting a tau protein fragment in a patient sample, wherein the amino acid sequence of the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO:1.

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

[0008] According to a fourth aspect, the present invention provides a kit comprising a specific binding molecule suitable for use in the method according to the first aspect or the second aspect and a reagent for detecting a tau protein fragment in a patient's sample, wherein the amino acid sequence of the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO:1. BRIEF DESCRIPTION OF THE DRAWINGS

[0009] Refer to some of the following drawings:

[0010] Figure 1 . Alternative CDR definitions for S1D12 according to Kabat, Chothia, and Martin.

[0011] Figure 2 Sequence of the major fragment isolated from the proteolytically stable core of paired helical filaments (PHFs; Wischik et al., 1988). This fragment (termed “dGAE”) encompasses residues 296–391 of full-length tau and includes a fragment (residues 308–378) identified by cryo-electron microscopy as constituting the PHF core (Fitzpatrick et al., 2017). Figure 3 The positions of the epitopes of selected antibodies / scAbs are also shown.

[0012] Figure 3 . PHF core shown in the context of PHF.

[0013] Figure 4 The same core sequence and corresponding epitope location relative to the basic C-shaped subunit structure of the core. The 1D12 epitope forms a key fold or "hairpin" of the C-shaped subunit.

[0014] Figure 5 Molecular modeling showing how the new dGAE unit gradually unfolds and becomes consistent with the structure of the existing oligomer.

[0015] Figure 6 The attachment sequence corresponds to the three stages of the gradual incorporation of the key dGAE fragment and its epitope into the oligomer. It can be seen that the hinge region recognized by 1D12 is the primary attachment site, followed by the symmetrical and stepwise incorporation of the other domains.

[0016] Figure 7 (A) dGAE antigen-specific immune response of sheep polyclonal sera after multiple rounds of immunization. (B) hT40 antigen-specific immune response of sheep polyclonal sera after multiple rounds of immunization. Wells coated with MPBS served as negative controls.

[0017] Figure 8 ELISA-based characterization of the cross-reactivity of the “E” group of 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, exhibited specific dGAE binding and thus required the C-terminally accessible “391E” epitope to generate an immune response. E1B8 cross-reacted with dGA, and a detailed map of its binding region is available in Figure 9 Shown in.

[0018] Figure 9Detailed profile of the E1B8 scAb showing specific binding to a tau peptide representing amino acids 313-336 of the hT40 protein.

[0019] Figure 10 ELISA-based characterization of the cross-reactivity of the "NS" panel of scAbs using various short tau fragments, numbered corresponding to amino acid residues of hT40. (A) 337-368, (B) 275-305, (C) 266-359 (R1-3), (D) 360-378, (E) 369-391, (F) 369-390. A summary of the specific NS scAbs that bind to these shorter antigens is shown in Table 16.

[0020] Figure 11 ELISA-based characterization of the cross-reactivity of the "S" panel of scAbs using various short tau fragments, numbered according to their corresponding amino acid residues on the hT40 molecule. (A) 186-350, (B) 275-305, (CD) 266-359 (R1-3), (EI) 297-391, (J) 360-378, (KN) 369-391, (OR) 369-390. A summary of the specific "S" scAbs that bind to these shorter antigens is shown in Table 16.

[0021] Figure 12 ELISA-based characterization of the cross-reactivity of the "C" panel of scAbs using various short tau fragments, numbered according to their corresponding amino acid residues on the hT40 molecule. (A) 1-49, (B) 1-155, (CD) 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 the specific "C" scAbs that bind to these shorter antigens is shown in Table 17.

[0022] Figure 13 Cross-reactivity of the "412" panel of scAbs with hT40. (A) Shows binding of scAbs to the biotinylated 412-441 peptide, used as an antigen to select for antibodies binding to the C-terminus. (B) Shows the binding profiles of four cross-reactive scAbs in an hT40 binding ELISA.

[0023] Figure 14ELISA-based characterization of cross-reactivity of '3a' & '3b' group scAbs using various short tau fragments, numbered according to their corresponding amino acid residues on the hT40 molecule. (A) 1-49, (B) 1-111, (C) 1-155, (D) 113-251. A summary of specific '3a' & '3b' group scAbs binding to these shorter antigens is shown in Table 18.

[0024] Figure 15 (A) Immunoreactivity of CE2 scAb against the parent peptide and a series of alanine substituted residues at the positions shown in Table 19. (B) Percent binding of 500 nM scAb to each of these ASM peptides relative to the parent peptide.

[0025] Figure 16 (AB) Immunoreactivity of S1D12 scAb against the parent peptide and a series of alanine substituted residues at the positions shown in Table 20. (C) Percent binding of 500 nM scAb to each of these ASM peptides relative to the parent peptide.

[0026] Figure 17 (AB) Immunoreactivity of ME12 scAb against the parent peptide and a series of alanine substituted residues at the positions shown in Table 20. (C) Percent binding of 100 nM scAb to each of these ASM peptides relative to the parent peptide.

[0027] Figure 18 (A) Immunoreactivity of CA4 scAb against the parent peptide and a series of alanine substituted residues at the positions shown in Table 21. (B) Percent binding of 500 nM scAb to each of these ASM peptides relative to the parent peptide.

[0028] Figure 19 (AB) Immunoreactivity of S1G2 scAb against the parent peptide and a series of alanine substituted residues at the positions shown in Table 22. (C) Percent binding of 500 nM scAb to each of these ASM peptides relative to the parent peptide.

[0029] Figure 20 Percent binding of various scAbs to the ASM peptide relative to the parent peptide in the 367-379 region. The scAbs tested included (A) S1B1, (B) CA12, (C) CB2, (D) CB8, (E) S1D9, (F) S1G10, (G) S2C6, (H) S1F4, (I) MC5, and (J) MD12. The key binding residues of these scAbs are similar to those of the representative clone S1G2, with alanine substitutions at positions 370, 373, 374, 377, or 378 resulting in reduced antibody binding.

[0030] Figure 21 . Use hT40 to rank the binding affinity of anti-TauscAb. D scAbs with similar binding characteristics (e.g., NS2A1 and S1D12) were used to rank the relative binding affinities of the tested scAbs, and scAbs with similar binding characteristics were shortlisted and selected for Biacore analysis. (A) "S" group clones, (B-C) "C" clones, (D) "412" clones, (E) "3a" clones.

[0031] Figure 22 Schematic diagram of the sandwich ELISA method used to calculate the limit of detection (LoD) for various antibody pairings.

[0032] Figure 23 Schematic diagram of the sandwich ELISA method using S1G2 mAb as capture antibody and HRP-conjugated S1D12 mAb for detection to calculate LoD.

[0033] Figure 24 Graph showing the LoD achieved using a sandwich ELISA using S1G2 mAb as the capture antibody and HRP-labeled S1D12 mAb for detection. Antibody binding was measured using chemiluminescence, and the LOD for hT40 was approximately 1 ng / ml for this assay setup.

[0034] Figure 25 ELISA#1hT40 standard curve generated using S1D12 mAb capture and CB7 scAb detection. The concentrations of the four spiked samples (samples A, B, C, and D) were determined 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 an N-terminal region in this mixture. The concentrations and types of tau species inferred from this assay are shown in Table 29.

[0035] Figure 26 ELISA #2 dGAE standard curve generated using S1D12 mAb capture and E2E8 scAb detection. The concentrations of the four spiked samples (samples A, B, C, and D) were determined 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 inferred from this assay are shown in Table 29.

[0036] Figure 27ELISA #3 average standard curve generated using S1D12 mAb capture and S1G2 scAb detection. The concentrations of the four spiked samples (samples A, B, C, and D) were determined by plotting their respective absorbance values ​​on this standard curve. The concentrations and types of tau species inferred from this assay are shown in Table 29.

[0037] Figure 28 Comparison of the binding properties of various SDS (+ / - Triton X-100)-treated dGAE monomers or aggregates in a sandwich ELISA system. mAb S1D12 was used as the capture antibody, and S1G2 was used as the detection scAb. The effect of SDS + Triton X-100 on restoring immunoreactivity was noted. In a simple sandwich ELISA, the mAb paired with the scAb was able to detect approximately 2 ng / ml of dGAE aggregates.

[0038] Figure 29 A) L66 cDNA, containing human tau (hT40) and the point mutations P301S and G335D (2N4RTau, 441 amino acids). B) L1 cDNA, encoding human tau amino acid residues 296-390 with a signal sequence and a murine Thy1 expression sequence, as described in Melis et al., 2015.

[0039] Figure 30 (a) Detection of tau protein in 50 μg of brain homogenates isolated from WT, L1, L66+ / -, and L66+ / + mice using S1D12 mAb capture and S-1G2 scAb detection. All four samples had similar tau levels when probed using core region-specific antibody pairs. (b) Detection of tau protein in 50 μg of brain homogenates isolated from WT, L1, L66+ / -, and L66+ / + mice using S1D12 mAb capture and CB7 scAb detection. The N'-terminally directed CB7 scAb specifically detected human tau in Line66 homozygous and heterozygous samples and was able to distinguish expression levels between the two groups.

[0040] Figure 31Plasma tau levels in: WT (5 months: 1.947 ng / ml), (9 months: 2.177 ng / ml); L66 (both 5 months) (+ / -: 0.567 ng / ml), (+ / +: 1.937 ng / ml); and L1 (5 months: 12.355 ng / ml), (9 months: 13.661 ng / ml). Data were 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).

[0041] Figure 32 Two different sandwich ELISA pairs were used to detect plasma tau levels in samples from 1.5-month-old Line66+ / + mice (No. 23) and compared to plasma from age-matched wild-type mice. (A) Shows chemiluminescent signal readouts for Line66+ / + and wild-type mice using S1D12 mAb capture and CB7 scAb detection. (B) Signal readouts for the same samples using S1D12 mAb capture and S1G2 scAb detection. When the S1D12 mAb, which specifically detects N-terminal hT40 in the samples, was paired with the CB7 scAb, the signal intensity in Line66+ / + mice increased by at least 1000-fold compared to wild-type mice.

[0042] Figure 33 Plasma tau levels in paired AD samples and age-matched controls were detected using S1D12-S1G12 (targeting the core region) and S1D12-CB7 (targeting the N-terminus).

[0043] Figure 34 Sandwich ELISA graph showing increased immunoreactivity of core region scAbs with dGAE in aggregation inhibition samples ("Total," "Supernatant," and "Pellet") prepared in the presence of LMTM. dGAE monomer was included as an assay control to indicate the binding properties of each test scAb to its corresponding epitope in non-aggregated samples. (AC) CA4 scAb, (DF) CA9, (GI) CB3 scAb, (JL) CE2 scAb, (MO) CE3, (PR) S1D12 scAb. The lack of antibody binding in some dGAE + LMTM pellet samples corresponds to the absence of protein in this group, as confirmed by SDS gel (data not included).

[0044] Figure 35mAb capture of dGAE aggregates. The various antibodies shown were coated on a solid-phase ELISA and used to capture dGAE aggregates. With the exception of the S1G2 mAb, all capture antibodies used the S1G2 scAb to detect captured dGAE. For S1G2 mAb capture, the S1D12 scAb was used as the detection antibody.

[0045] Figure 36 Western blot showing brain-derived tau labeled with a human-specific CB7 antibody that binds to an N-terminal epitope (residues 13-25) not present in mouse tau. + / + The band was present in the lane containing 20 μg of protein homogenate from mouse brain, but not in the lane containing WT or L1 + / + The band is absent in the lane for the brain sample. The molecular weight of the protein standards added to the left of the blot provides an approximation of the relative sizes of the proteins in the gel, but it is well known that the apparent size of tau is much larger than the actual molecular weight.

[0046] Figure 37 Western blot shows tau labeled with human-specific CC7 antibody, which recognizes an epitope located within residues 145-157. Human-specific tau is only expressed at L66. + / + detected in the mouse brain, but not in WT or L1 + / + The protein standard molecular weight is as follows: Figure 36 shown.

[0047] Figure 38 Western blot using S1D12 tau core antibody. + / + Bands are present in the lanes of 20 μg protein homogenates of L1, L66, and WT mouse brain. Mouse tau (indicated by the arrow below) is shown as a band of approximately 55 kDa in each sample. + / + Human tau in the sample (indicated by the arrow above) is shown as a 68 kDa protein. Protein standard molecular weight is as follows Figure 36 shown.

[0048] Figure 39 Western blot using S1D12 core antibody. + / + 、L1 + / + The mouse tau in each sample (indicated by the arrow below) is shown as a band of approximately 55 kDa. + / + Human tau in the sample (indicated by the arrow above) is shown to be approximately 68 kDa. Using this antibody, + / +A band of approximately 10 kDa can be seen in the sample. Figure 36 shown.

[0049] Figure 40 Sequence comparison of human tau and mouse tau. For human tau, the sequence shown consists of SEQ ID NO: 1 (two gaps introduced to allow for sequence alignment); for mouse tau, the sequence shown consists of SEQ ID NO: 589. The protein regions containing candidate antibody epitopes overlap. Neither the CB7 nor the CC7 binding regions in human tau are present in mouse tau. In contrast, the protein regions containing the epitopes for antibodies S1D12 and S1G2 show 100% homology between the two species.

[0050] Figure 41 A) Paired antibody ELISA using S1D12 capture and CB7 detection shows that + / + In mouse brain homogenate samples, the signal gradually decreases with age. B) When the direction of the assay is reversed, using CB7 as the capture agent and S1D12 as the detector for brain homogenate samples, a similar pattern of signal decrease with age is observed.

[0051] Figure 42 . ELISA using paired antibodies CB7 capture and HT7 detection showed that against L66 + / + In mice, the signal gradually increased with age, suggesting that truncations between the core and N-terminal regions of tau proteins or protein fragments result in the accumulation of smaller fragments with intact N-termini.

[0052] Figure 43 (A) Plasma tau levels in healthy controls (HC) and patients diagnosed with Alzheimer's disease or mild cognitive impairment (AD / MCI). The concentration of the core proline region measured using S1D12 capture beads paired with the detector BT2 was significantly higher in healthy controls than in AD / MCI samples. The assay analyzed a total of 12 healthy control plasma samples and 42 AD / MCI samples. ****p < 0.0001. (B) Data from the NT1 assay (Chen et al., 2019) reported that using the Tau12-BT2 antibody, NT-1 plasma tau levels were slightly increased in patients with AD-MCI (AD biomarker positive - mild cognitive impairment) and AD (AD biomarker positive - clinical AD) compared to NC (normal controls).

[0053] Figure 44Plasma tau levels in healthy controls (HC) and patients diagnosed with Alzheimer's disease or mild cognitive impairment (AD / MCI). The concentration of the core proline region measured using S1D12 capture beads paired with the detector HT7 was 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. ****p<0.0001.

[0054] Figure 45 Plasma tau was measured by S1D12 (capture agent) / BT2 (detector agent) chemiluminescent ELISA, AD: samples from subjects with clinically confirmed AD; CU: samples from age-matched subjects without cognitive impairment.

[0055] Figure 46 .Generated by assaying various antibody combinations used in human plasma experiments Calibration curve.

[0056] Figure 47 Immunoprecipitation and trypsin digestion LC-MS reveal core-region-containing tau fragments in human plasma. Tau fragments were detected by abundance in human plasma samples following immunoprecipitation (IP) and LC-MS analysis. Fragments detected from samples spiked with htau40 without immunoprecipitation were also used for comparison.

[0057] Figure 48 .Core tau levels in mouse plasma were increased by S1D12 mAb treatment. Using CA4 (355-367) and S1G2 (367-379) antibodies, core region tau levels in L66 mice treated with S1D12 were significantly elevated (more than 100-fold) compared to the vehicle group in L1. Individual mouse samples were analyzed in duplicate, and the values ​​represent the average concentration of tau fragments detected by the CA4-S1G2 antibody pairing. The treatment group achieved more than a three-fold increase in L66, while an increase of less than two-fold was observed in wild-type mice. n=5 or 6, error bars represent SEM, unpaired t-test was performed between the vehicle group and the treatment group, ****P<0.0001; **P<0.01. DETAILED DESCRIPTION

[0058] According to a first aspect, the present invention provides an in vitro method for detecting a tau protein fragment in a patient's sample, wherein the amino acid sequence of the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO:1.

[0059] All residue numbers of the sequence and structure of the Tau protein in this disclosure refer to the residues of SEQ ID NO: 1, which is the sequence of the four-repeat isoform 2N4R of the human Tau protein (Uniprot ID P10636-8), 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 a longer form of Tau found in the peripheral nervous system (PNS) rather than the central nervous system (CNS). As used herein, reference to "full-length" tau refers to SEQ ID NO: 1 (the relevant sequence of the CNS) rather than SEQ ID NO: 2 (not related to the CNS).

[0060] SEQ ID NO: 1 (isoform Tau-F, also known as Tau-4, 2N4R, 441 amino acids):

[0061] >sp|P10636-8|TAU_HUMAN microtubule-associated protein tau isoform Tau-FOS=Homo sapiens OX=9606GN=MAPT

[0062] MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPG

[0063] SETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAG

[0064] HVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPK

[0065] TPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAK

[0066] SRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHV

[0067] PGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNI

[0068] THVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMV

[0069] DSPQLATLADEVSASLAKQGL

[0070] SEQ ID NO:2 (Full-length human Tau, isoform PNS-Tau, 758 amino acids):

[0071] >sp|P10636-1|TAU_HUMAN Microtubule-associated protein tau OS=Homo sapiens OX=9606 GN=MAPT PE=1 SV=5

[0072] MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPG

[0073] SETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAG

[0074] HVTQEPESGKVVQEGFLREPGPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEG

[0075] GRHAPELLKHQLLGDLHQEGPPLKGAGGKERPGSKEEVDEDRDVDESSPQDSPPSKASPA

[0076] QDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKVSTEIPASEPDGPSVGRAKGQDAPLE

[0077] FTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEADLPEPSEKQPA

[0078] AAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPCLSPKHPTPGSS

[0079] DPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQK

[0080] GQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREP

[0081] KKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLD

[0082] LSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEK

[0083] LDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDT

[0084] SPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL

[0085] As used herein, "mouse tau" refers to isoform Tau-A having the sequence of Uniprot ID P10637-2, provided as SEQ ID NO:589:

[0086] MADPRQEFDTMEDHAGDYTLLQDQEGDMDHGLKESPPQPPADDGAEEPGSETSDAKSTPTAEDVTAPLV

[0087] DERAPDKQAAAQPHTEIPEGITAEEAGIGDTPNQEDQAAGHVTQARVASKDRTGNDEKKAKGADGKTGA

[0088] KIATPRGAASPAQKGTSNATRIPAKTTPSPKTPPGSGEPPKSGERSGYSSPGSPGTPGSRSRTPSLPTPPTREP

[0089] KKVAVVRTPPKSPSASKSRLQTAPVPMPDLKNVRSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGS

[0090] KDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHV

[0091] PGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVS

[0092] ASLAKQGL

[0093] dGAE97 refers to a 97-residue fragment of Tau (2N4R), as set forth in SEQ ID NO: 3, wherein the N-terminus is located at residue Asp-295 and the C-terminus is located at residue Glu-391, or at homologous positions in other species (the residues mentioned are referenced to the human or mouse Tau sequence, which are identical in this region). It will be apparent to those skilled in the art that dGAE97 also corresponds to a fragment of the isoform PNS-Tau (P10636-1), wherein the N-terminus is located at Asp-612 and the C-terminus is located at Glu-708.

[0094] SEQ ID NO: 3 (dGAE97, human / mouse, 97 amino acids):

[0095] DNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAE

[0096] dGAE95 refers to a 95-residue fragment of Tau (2N4R), as set forth in SEQ ID NO: 4, wherein the N-terminus is located at residue Ile-297 and the C-terminus is located at residue Glu-391, or at homologous positions in other species (the residues mentioned are referenced to the human or mouse Tau sequence, which are identical in this region). It will be apparent to those skilled in the art that dGAE95 also corresponds to a fragment of the isoform PNS-Tau (P10636-1), wherein the N-terminus is located at Ile-614 and the C-terminus is located at Glu-708. This sequence may sometimes be simply referred to as "dGAE". Residues 297 to 391 of Tau (2N4R) are also referred to as the major fragment that separates from the proteolytically stable core of the paired helical filaments (PHFs). Therefore, reference herein to "residues 297 to 391 of SEQ ID NO: 1" may replace reference to SEQ ID NO: 4.

[0097] SEQ ID NO: 4 (dGAE95 or "dGAE", human / mouse, 95 amino acids):

[0098] IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAE

[0099] "dGA" refers to the 94 residue fragment of Tau (2N4R) as set forth in SEQ ID NO:5, in which the N-terminus is located at residues Ile-297 and the C-terminus is located at residues Ala-390, or at homologous positions in other species (residues mentioned are referenced to the human or mouse Tau sequence, which are identical in this region).

[0100] SEQ ID NO: 5 (dGA, human / mouse, 94 amino acids):

[0101] IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGA

[0102] dGAE73 refers to a fragment of Tau (2N4R) as described in SEQ ID NO: 6, wherein the N-terminus is located at residue Val-306 and the C-terminus is located at residue Phe-378, or at homologous positions in other species (the residues mentioned are referenced to the human or mouse Tau sequence, which are identical in this region). The fragment corresponds to residues 306-378 of the sequence, which was identified by cryo-electron microscopy as the PHF core 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-electron microscopy. It is obvious to those skilled in the art that dGAE73 also corresponds to a fragment of the isoform PNS-Tau (P10636-1) with the N-terminus located at Val-623 and the C-terminus located at Phe-695.

[0103] SEQ ID NO: 6 (dGAE73, human / mouse, 73 amino acids):

[0104] VQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTF

[0105] The PHF core refers to residues 296 to 391 of Tau (2N4R) as described in SEQ ID NO: 3, or homologous positions in other species (residues mentioned refer to human or mouse Tau sequences, which are identical in this region).

[0106] Another fragment of the PHF core is residues 308-378 of Tau (2N4R), as set forth in SEQ ID NO:7, wherein the N-terminus is located at residues Ile-308 and the C-terminus is located at residues Phe-378, or at homologous positions in other species (residues mentioned are referenced to the human or mouse Tau sequence, which are identical in this region).

[0107] SEQ ID NO: 7 (dGAE71, residues 308 to 378 of 2N4R, human / mouse, 71 amino acids):

[0108] IVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTF

[0109] Tau fragments

[0110] The method can be an in vitro method for detecting a tau protein fragment. The amino acid sequence of the fragment can consist of amino acid residues within residues 113 to 379 of SEQ ID NO: 1. The inventors have identified a tau fragment that can be detected by a core binding specific binding molecule in plasma. The inventors have identified that the fragment omits certain N-terminal and C-terminal amino acid residues, specifically, the fragment does not include residues 1 to 112 or residues 380 to 441 of SEQ ID NO: 1.

[0111] The fragment can comprise 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, at least 170, or at least 175 contiguous amino acid residues of residues 113 to 379 of SEQ ID NO: 1.

[0112] As used herein, the term "contiguous" may be substituted for the term "linked," each term referring to amino acid residues that are found adjacent to each other in a primary amino acid sequence. Thus, a fragment may consist of consecutive or linked amino acid residues within residues 113 to 379 of SEQ ID NO: 1.

[0113] The fragment can comprise 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 161, at least 162, at least 163, at least 164, at least 165, at least 166, at least 167, at least 168, at least 169, at least 170, at least 171, at least 172, at least 173, at least 174, at least 175, at least 176, at least 177, at least 178, at least 179, at least 180 at least 261, at least 262, at least 263, at least 264, at least 265, at least 266, or 267 consecutive amino acid residues.

[0114] The fragment can comprise at least 155, at least 160, at least 165, 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 contiguous amino acid residues of residues 113 to 379 of SEQ ID NO: 1.

[0115] The fragment can be defined by any one or more of: the number of consecutive amino acid residues within residues 113 to 379 of SEQ ID NO: 1, the number of consecutive amino acid residues within residues 297 to 391 of SEQ ID NO: 1; the number of consecutive amino acid residues within residues 244 to 296 of SEQ ID NO: 1; the number of consecutive amino acid residues within residues 151 to 243 of SEQ ID NO: 1, and / or the number of consecutive amino acid residues within residues 113 to 150 of SEQ ID NO: 1. In any embodiment comprising amino acid residues 151 to 243 and amino acid residues 297 to 391 of SEQ ID NO: 1, residues 244 to 296 of SEQ ID NO: 1 may additionally be present and are typically present between residues 151 to 243 and residues 297 to 391 of SEQ ID NO: 1 such that the fragment comprises the consecutive amino acid residues of residues 151 to 243, residues 244 to 296, and residues 297 to 391 of SEQ ID NO: 1, which are consecutive amino acid residues within residues 113 to 379 of SEQ ID NO: 1.

[0116] The fragment can comprise 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, or at least 30 consecutive amino acid residues of residues 297 to 391 of SEQ ID NO: 1. Residues 297 to 391 of SEQ ID NO: 1 (see also SEQ ID NO: 4) correspond to the major fragment isolated from the proteolytically stable core of the paired helical filament (PHF).

[0117] The fragment can comprise 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 contiguous amino acid residues of residues 297 to 391 of SEQ ID NO: 1.

[0118] The fragment comprises at least 4 consecutive amino acid residues from residues 297 to 391 of SEQ ID NO: 1, and the at least 4 consecutive amino acid residues may comprise amino acid residues 337 to 349 of SEQ ID NO: 1 and / or amino acid residues 370 to 374 of SEQ ID NO: 1. The fragment may comprise an epitope of S1D12 and / or S1G2.

[0119] The fragment can comprise 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 of residues 297 to 391 of SEQ ID NO: 1.

[0120] The fragment may comprise 38 consecutive amino acid residues from residues 297 to 391 of SEQ ID NO: 1. The 38 consecutive amino acids may be residues 337 to 349 of SEQ ID NO: 1. The fragment may comprise epitopes of S1D12 and S1G2. The fragment may comprise epitopes of S1D12 and S1G2 and consecutive amino acid residues therebetween.

[0121] The fragment can comprise 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 of residues 297 to 391 of SEQ ID NO: 1.

[0122] The fragment can comprise 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 of residues 297 to 391 of SEQ ID NO: 1.

[0123] The fragment may comprise 53 consecutive amino acid residues from residues 297 to 391 of SEQ ID NO: 1. The 53 consecutive amino acids may be residues 297 to 349 of SEQ ID NO: 1. The fragment may comprise consecutive amino acid residues from residue 297 to the C-terminus of the S1D12 epitope.

[0124] The fragment may comprise 78 consecutive amino acid residues from residues 297 to 391 of SEQ ID NO: 1. The 78 consecutive amino acids may be residues 297 to 374 of SEQ ID NO: 1. The fragment may comprise consecutive amino acid residues from residue 297 to the C-terminus of the S1G2 epitope.

[0125] The fragment can comprise 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, or at least 30 consecutive amino acid residues of residues 151 to 243 of SEQ ID NO: 1. Two proline-rich domains are present between amino acid residues 151 to 243 of SEQ ID NO: 1. The fragment may comprise 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, or at least 30 consecutive amino acid residues of at least one proline-rich domain.

[0126] The fragment comprises at least 4 consecutive amino acid residues from residues 151 to 243 of SEQ ID NO: 1, and the at least 4 consecutive amino acid residues may comprise amino acid residues 194 to 198 of SEQ ID NO: 1 and / or amino acid residues 159 to 163 of SEQ ID NO: 1. The fragment may comprise an epitope of BT2 and / or HT7.

[0127] The fragment may comprise 48 consecutive amino acid residues from residues 151 to 243 of SEQ ID NO: 1. The 48 consecutive amino acids may be residues 159 to 198 of SEQ ID NO: 1. The fragment may comprise epitopes of BT2 and HT7. The fragment may comprise epitopes of BT2 and HT7 and consecutive amino acid residues therebetween.

[0128] The fragment can comprise 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 of residues 159 to 198 of SEQ ID NO: 1.

[0129] The fragment can comprise 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 of residues 159 to 198 of SEQ ID NO: 1.

[0130] The fragment may comprise 50 consecutive amino acid residues from residues 151 to 243 of SEQ ID NO: 1. The 50 consecutive amino acids may be residues 194 to 243 of SEQ ID NO: 1. The fragment may comprise consecutive amino acid residues from the N-terminus of the epitope of BT2 to residue 243.

[0131] The fragment may comprise 85 consecutive amino acid residues from residues 151 to 243 of SEQ ID NO: 1. The 85 consecutive amino acids may be residues 159 to 243 of SEQ ID NO: 1. The fragment may comprise consecutive amino acid residues from the N-terminus of the epitope of HT7 to residue 243.

[0132] The fragment can comprise 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 of residues 151 to 243 of SEQ ID NO: 1. Two proline-rich domains are present between amino acid residues 151 to 243 of SEQ ID NO: 1. The fragment can comprise 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 of at least one proline-rich domain.

[0133] The fragment can comprise 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 51, at least 52, at least 53, or 54 consecutive amino acid residues of residues 244 to 296 of SEQ ID NO: 1. Typically, the consecutive amino acid residues of residues 244 to 296 of SEQ ID NO: 1 will include residue 244 and / or residue 296 of SEQ ID NO: 1. The fragment may comprise all 54 consecutive amino acid residues of residues 244 to 296 of SEQ ID NO:1.

[0134] The fragment can comprise at least 1, at least 2, at least 3, 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 31, at least 32, at least 33, at least 34, at least 35, at least 36, at least 37, or 38 consecutive amino acid residues of residues 113 to 150 of SEQ ID NO: 1. Typically, the consecutive amino acid residues among residues 113 to 150 of SEQ ID NO: 1 include residue 150 of SEQ ID NO: 1. The fragment may comprise all 38 consecutive amino acid residues of residues 113 to 150 of SEQ ID NO:1.

[0135] The fragment may comprise at least 30 consecutive amino acid residues of residues 113 to 379 of SEQ ID NO: 1, and

[0136] (a) at least 4 consecutive amino acid residues from residues 297 to 391 of SEQ ID NO: 1; and / or

[0137] (b) at least 4 consecutive amino acid residues from residues 151 to 243 of SEQ ID NO: 1.

[0138] The fragment may comprise at least 156 consecutive amino acid residues of residues 113 to 379 of SEQ ID NO: 1, and

[0139] (a) at least 4 consecutive 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

[0140] (b) at least 4 contiguous amino acid residues of residues 151 to 243 of SEQ ID NO: 1, optionally including residues 194 to 198 of SEQ ID NO: 1.

[0141] The fragment may comprise at least 181 consecutive amino acid residues of residues 113 to 379 of SEQ ID NO: 1, and

[0142] (a) at least 4 consecutive 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

[0143] (b) at least 4 contiguous amino acid residues of residues 151 to 243 of SEQ ID NO: 1, optionally including residues 194 to 198 of SEQ ID NO: 1.

[0144] The fragment may comprise at least 191 consecutive amino acid residues of residues 113 to 379 of SEQ ID NO: 1, and

[0145] (a) at least 4 consecutive 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

[0146] (b) at least 4 contiguous amino acid residues of residues 151 to 243 of SEQ ID NO: 1, optionally including residues 159 to 163 of SEQ ID NO: 1.

[0147] The fragment may comprise at least 216 consecutive amino acid residues of residues 113 to 379 of SEQ ID NO: 1, and

[0148] (a) at least 4 consecutive 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

[0149] (b) at least 4 contiguous amino acid residues of residues 151 to 243 of SEQ ID NO: 1, optionally including residues 159 to 163 of SEQ ID NO: 1.

[0150] The fragment may comprise at least 156 consecutive amino acid residues of residues 113 to 379 of SEQ ID NO: 1, and

[0151] (a) at least 53 contiguous amino acid residues of residues 297 to 391 of SEQ ID NO: 1, optionally including residues 337 to 349 of SEQ ID NO: 1; and / or

[0152] (b) at least 50 contiguous amino acid residues of residues 151 to 243 of SEQ ID NO: 1, optionally including residues 194 to 198 of SEQ ID NO: 1.

[0153] The fragment may comprise at least 181 consecutive amino acid residues of residues 113 to 379 of SEQ ID NO: 1, and

[0154] (a) at least 78 contiguous amino acid residues of residues 297 to 391 of SEQ ID NO: 1, optionally including residues 370 to 374 of SEQ ID NO: 1; and / or

[0155] (b) at least 50 contiguous amino acid residues of residues 151 to 243 of SEQ ID NO: 1, optionally including residues 194 to 198 of SEQ ID NO: 1.

[0156] The fragment may comprise at least 191 consecutive amino acid residues of residues 113 to 379 of SEQ ID NO: 1, and

[0157] (a) at least 53 contiguous amino acid residues of residues 297 to 391 of SEQ ID NO: 1, optionally including residues 337 to 349 of SEQ ID NO: 1; and / or

[0158] (b) at least 85 contiguous amino acid residues of residues 151 to 243 of SEQ ID NO: 1, optionally including residues 159 to 163 of SEQ ID NO: 1.

[0159] The fragment may comprise at least 216 consecutive amino acid residues of residues 113 to 379 of SEQ ID NO: 1, and

[0160] (a) at least 78 contiguous amino acid residues of residues 297 to 391 of SEQ ID NO: 1, optionally including residues 370 to 374 of SEQ ID NO: 1; and / or

[0161] (b) at least 85 contiguous amino acid residues of residues 151 to 243 of SEQ ID NO: 1, optionally including residues 159 to 163 of SEQ ID NO: 1.

[0162] The fragment may comprise at least 30 consecutive amino acid residues of residues 297 to 391 of SEQ ID NO:1 and / or at least 30 consecutive amino acid residues of residues 151 to 243 of SEQ ID NO:1.

[0163] The fragment may comprise at least 50 consecutive amino acid residues of residues 297 to 391 of SEQ ID NO:1 and / or at least 50 consecutive amino acid residues of residues 151 to 243 of SEQ ID NO:1.

[0164] The fragment may comprise at least 75 consecutive amino acid residues of residues 297 to 391 of SEQ ID NO: 1 and / or at least 75 consecutive amino acid residues of residues 151 to 243 of SEQ ID NO: 1.

[0165] The fragment may comprise at least 38 consecutive amino acid residues of residues 297 to 391 of SEQ ID NO: 1 and / or at least 48 consecutive amino acid residues of residues 151 to 243 of SEQ ID NO: 1.

[0166] The fragment may comprise at least 53 consecutive amino acid residues of residues 297 to 391 of SEQ ID NO: 1 and / or at least 50 consecutive amino acid residues of residues 151 to 243 of SEQ ID NO: 1.

[0167] The fragment may comprise at least 78 consecutive amino acid residues of residues 297 to 391 of SEQ ID NO: 1 and / or at least 85 consecutive amino acid residues of residues 151 to 243 of SEQ ID NO: 1.

[0168] The fragment may comprise amino acid residues 337 to 349 of SEQ ID NO:1 and / or amino acid residues 370 to 374 of SEQ ID NO:1.

[0169] The fragment may comprise amino acid residues 194 to 198 of SEQ ID NO:1 and / or amino acid residues 159 to 163 of SEQ ID NO:1.

[0170] The fragment may comprise at least 140 consecutive amino acid residues of residues 113 to 379 of SEQ ID NO: 1, and

[0171] (a) at least 50 contiguous amino acid residues from residues 297 to 391 of SEQ ID NO: 1; and / or

[0172] (b) at least 50 contiguous amino acid residues from residues 151 to 243 of SEQ ID NO: 1.

[0173] The fragment may comprise at least 160 consecutive amino acid residues of residues 113 to 379 of SEQ ID NO: 1, and

[0174] (a) at least 60 contiguous amino acid residues from residues 297 to 391 of SEQ ID NO: 1; and / or

[0175] (b) at least 60 contiguous amino acid residues from residues 151 to 243 of SEQ ID NO: 1.

[0176] The N-terminal residue of the fragment may be a residue selected from the group consisting of all residues from residue 113 of SEQ ID NO:1 to residue 193 of SEQ ID NO:1.

[0177] The N-terminal residue of the fragment may be a residue selected from the group consisting of all residues from residue 113 of SEQ ID NO:1 to residue 159 of SEQ ID NO:1.

[0178] The N-terminal residue of the fragment may be a residue selected from the group consisting of all residues from residue 159 of SEQ ID NO:1 to residue 193 of SEQ ID NO:1.

[0179] The N-terminal residue of the fragment may be a residue selected from the group consisting of all residues from residue 163 of SEQ ID NO:1 to residue 193 of SEQ ID NO:1.

[0180] The N-terminal residue of the fragment may be residue 113 of SEQ ID NO:1.

[0181] The C-terminal residue of the fragment may be a residue selected from the group consisting of all residues from residue 350 of SEQ ID NO:1 to residue 379 of SEQ ID NO:1.

[0182] The C-terminal residue of the fragment may be a residue selected from the group consisting of all residues from residue 350 of SEQ ID NO:1 to residue 370 of SEQ ID NO:1.

[0183] The C-terminal residue of the fragment may be a residue selected from the group consisting of all residues from residue 350 of SEQ ID NO:1 to residue 374 of SEQ ID NO:1.

[0184] A fragment consisting of amino acid residues within residues 113 to 379 of SEQ ID NO: 1 may include the following amino acid residues:

[0185] (a) 194 to 349 of SEQ ID NO: 1;

[0186] (b) 159 to 349 of SEQ ID NO: 1;

[0187] (c) 194 to 374 of SEQ ID NO: 1;

[0188] (d) 159 to 374 of SEQ ID NO: 1;

[0189] (e) 195 to 370 of SEQ ID NO: 1;

[0190] (f) 159 to 379 of SEQ ID NO: 1;

[0191] (g) 113 to 224 of SEQ ID NO: 1;

[0192] (h) 113 to 349 of SEQ ID NO: 1; or

[0193] (i) 113 to 370 of SEQ ID NO: 1.

[0194] In summary, the data disclosed herein indicate that a fragment consisting of amino acid residues within residues 113 to 379 of SEQ ID NO: 1, comprising amino acid residues 194 to 349 of SEQ ID NO: 1, can be detected in human plasma using S1D12 as the first specific binding molecule and BT2 as the second specific binding molecule.

[0195] In summary, the data disclosed herein demonstrate that a fragment consisting of amino acid residues within residues 113 to 379 of SEQ ID NO: 1, comprising amino acid residues 159 to 349 of SEQ ID NO: 1, can be detected in human plasma using S1D12 as a first specific binding molecule and HT7 as a second specific binding molecule.

[0196] In summary, the data disclosed herein demonstrate that a fragment consisting of amino acid residues within residues 113 to 379 of SEQ ID NO: 1, comprising amino acids 194 to 374 of SEQ ID NO: 1, can be detected in human plasma using S1G2 as a first specific binding molecule and BT2 as a second specific binding molecule.

[0197] In summary, the data disclosed herein demonstrate that a fragment consisting of amino acid residues within residues 113 to 379 of SEQ ID NO: 1, comprising amino acids 159 to 374 of SEQ ID NO: 1, can be detected in human plasma using S1G2 as a first specific binding molecule and HT7 as a second specific binding molecule.

[0198] The inventor has conducted several Assays and mass spectrometry to detect tau levels in human plasma have shown that the release of "extended core" fragments of tau (within residues 113 to 379 of the consensus plasma tau sequence of SEQ ID NO: 1) into plasma appears to be part of the normal processing of tau protein. The inventors have demonstrated that such fragments are significantly reduced in Alzheimer's disease plasma samples compared to cognitively unimpaired controls. The folding of the extended core fragment may block the core epitope, which facilitates the detection of the core fragment by high-affinity specific binding molecules (such as S1D12 and S1G2 described in PCT application No. PCT / EP2021 / 069160).

[0199] The amino acid sequence of the fragment may consist of amino acid residues within the following residues:

[0200] (a) 113 to 370 of SEQ ID NO: 1;

[0201] (b) 113 to 349 of SEQ ID NO: 1;

[0202] (c) 113 to 224 of SEQ ID NO: 1;

[0203] (d) 159 to 379 of SEQ ID NO: 1;

[0204] (e) 195 to 370 of SEQ ID NO: 1;

[0205] (f) 194 to 349 of SEQ ID NO: 1;

[0206] (g) 159 to 349 of SEQ ID NO: 1;

[0207] (h) 194 to 374 of SEQ ID NO: 1; or

[0208] (i) 159 to 374 of SEQ ID NO: 1.

[0209] The fragment may consist of amino acid residues 113 to 379 of SEQ ID NO:1.

[0210] In alternative formulations of the first aspect of the invention, for any fragment defined herein with reference to one or more amino acid residues of SEQ ID NO: 1, the one or more amino acid residues may alternatively be expressed as "about" the same amino acid residue. For example, an alternative formulation of the phrase "the fragment may consist of amino acid residues 113 to 379 of SEQ ID NO: 1" is "the fragment may consist of amino acid residues from about 113 to about 379 of SEQ ID NO: 1." The term "about" in this context means plus or minus 10, or more preferably plus or minus 9, plus or minus 8, plus or minus 7, plus or minus 6, plus or minus 5, plus or minus 4, plus or minus 3, plus or minus 2, or plus or minus 1. In addition to using the word "about" to alternatively express a residue number, a range of residue numbers centered around that residue number may also be expressed. For example, an alternative formulation of the phrase "the fragment may consist of amino acid residues 113 to 379 of SEQ ID NO: 1" is "the fragment may consist of amino acid residues 103-123 to amino acid residues 369-389 of SEQ ID NO: 1."

[0211] Due to differences in individual genetic codes and / or somatic mutations, tau sequences can vary from individual to individual. Any fragment defined herein can be a sequence variant of the amino acid residues within residues 113 to 379 of SEQ ID NO: 1. Such sequence variants can be described accordingly as variant fragments, and fragments having amino acid residues corresponding to amino acid residues within residues 113 to 379 of SEQ ID NO: 1 can be described as wild-type or canonical fragments. Variant fragments can, for example, have at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity with wild-type or canonical fragments. Variant fragments can, for example, have at least one, at least two, at least three, at least four, at least five, at least six, at least seven, at least eight, at least nine or at least ten amino acid substitutions relative to wild-type or canonical fragments. Amino acid substitutions can be conservative amino acid substitutions.

[0212] The method may also include confirming the identity of the fragment. Confirmation of the identity of the fragment can be achieved, for example, by mass spectrometry analysis of the fragment. The mass spectrum can be liquid chromatography-mass spectrometry (LC-MS). Confirmation of the identity of the fragment can also be achieved by measuring one or more other tau fragments, wherein the fragment whose identity is to be confirmed can be referred to as the first fragment. Measuring one or more other tau fragments can include measuring shorter tau fragments and / or measuring longer tau fragments. According to the content of this disclosure and depending on the length of the first fragment, appropriate such assays are obvious to those skilled in the art. For example, using an antibody that targets closer to the N-terminus (e.g., Tau12 that binds to residues 6-18 of SEQ ID NO: 1) or an antibody that targets closer to the C-terminus (e.g., Tau46 that binds to residues 404-441). Measuring one or more other tau fragments can also include comparing the levels of shorter tau fragments and / or longer tau fragments with the levels of the first fragment. In the case where substantially no shorter tau fragments and / or longer tau fragments are detected, the identity of the first tau fragment can be confirmed. In cases where the shorter tau fragments and / or the longer tau fragments are below the lower limit of quantification, the identity of the first tau fragment can be confirmed.

[0213] The method can comprise detecting two or more tau fragments disclosed herein.

[0214] The method may further include determining the concentration of tau protein fragments in the sample.

[0215] The method involves detecting a tau protein fragment in a sample from a patient, wherein the amino acid sequence of the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO: 1. The method may further include detecting a tau protein or a fragment thereof. The tau protein may be full-length tau, and the additional fragments may not be limited to fragments consisting of amino acid residues within residues 113 to 379 of SEQ ID NO: 1. When the term "tau protein or a fragment thereof" is used herein, it generally refers to a fragment consisting of amino acid residues within residues 113 to 379 of SEQ ID NO: 1; however, it may also refer to full-length tau and the additional fragments may not be limited to fragments consisting of amino acid residues within residues 113 to 379 of SEQ ID NO: 1, and this only applies to the case where the method further includes detecting a tau protein or a fragment thereof, wherein the tau protein may be full-length tau and the additional fragments may not be limited to fragments consisting of amino acid residues within residues 113 to 379 of SEQ ID NO: 1.

[0216] first specific binding molecule

[0217] The method may comprise 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. The first specific binding molecule may be any specific binding molecule disclosed herein that binds to an epitope within residues 297 to 391 of SEQ ID NO: 1, preferably to an epitope within residues 307 to 391 of SEQ ID NO: 1, more preferably to an epitope within residues 337 to 379 of SEQ ID NO: 1. The first specific binding molecule is described below. Any reference to a specific binding molecule under this subheading refers to the first specific binding molecule.

[0218] The epitope of the first specific binding molecule may be located within SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7.

[0219] The epitope of the specific binding molecule can be located within residues 297 to 391 of SEQ ID NO: 1. Residues 297 to 391 of full-length Tau are also referred to as the major fragment separated from the proteolytically stable core of the paired helical filaments (PHFs) or PHF core fragments. Thus, the epitope of the specific binding molecule can be located within the PHF core or within the dGAE fragment. Thus, the epitope of the specific binding molecule can be located within SEQ ID NO: 4.

[0220] The epitope of the specific binding molecule can be located within residues 297 to 390 of SEQ ID NO: 1. Residues 297 to 390 of full-length Tau are also referred to as the dGA fragment. Thus, the epitope of the specific binding molecule can be located within the dGA fragment. Thus, the epitope of the specific binding molecule can be located within SEQ ID NO: 5. The epitope of the specific binding molecule can be located within dGAE73 and / or dGAE71. Thus, the epitope of the specific binding molecule can be located within SEQ ID NO: 6 and / or SEQ ID NO: 7.

[0221] The epitope of the specific binding molecule can be located within residues 308 to 378 of SEQ ID NO: 1. Residues 308 to 378 of full-length Tau are also referred to as the PHF core. Thus, the epitope of the specific binding molecule can be located within the PHF core. Thus, the epitope of the specific binding molecule can be located within SEQ ID NO: 7.

[0222] Typically, a specific binding molecule binds to a polypeptide or protein molecule that comprises its epitope. Thus, a specific binding molecule can bind to SEQ ID NO: 1 or a fragment thereof comprising residues 297 to 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 can bind to a polypeptide or protein molecule comprising an amino acid sequence selected from the group consisting of 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 1 to 319 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.

[0223] The first specific binding molecule can bind to an epitope within residues 307 to 391 of SEQ ID NO: 1. The first specific binding molecule can bind to an epitope within residues 337 to 379 of SEQ ID NO: 1. The first specific binding molecule can bind to an epitope consisting of residues 337 to 349 of SEQ ID NO: 1. The first specific binding molecule can bind to an epitope consisting of residues 337 to 355 of SEQ ID NO: 1. The epitope can bind to a CDR of a specific binding molecule (referred to herein as "S1D12").

[0224] The first specific binding molecule may comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0225] VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG);

[0226] VHCDR2 comprises the sequence shown in SEQ ID NO: 18 (GCSSDGTCYYNSALKS);

[0227] VHCDR3 comprises the sequence shown in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY);

[0228] VLCDR1 comprises the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0229] VLCDR2 comprises the sequence shown in SEQ ID NO: 26 ((DTNSRPS);

[0230] VLCDR3 comprises the sequence shown in SEQ ID NO: 29 (VTGDSTTHDDL);

[0231] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0232] (i) is at least 85% identical thereto, and / or

[0233] (ii) has one, two or three amino acid substitutions relative thereto.

[0234] The first specific binding molecule may comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0235] VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG);

[0236] VHCDR2 comprises the sequence shown in SEQ ID NO: 18 (GCSSDGTCYYNSALKS);

[0237] VHCDR3 comprises the sequence shown in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY);

[0238] VLCDR1 comprises the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0239] VLCDR2 comprises the sequence set forth in SEQ ID NO: 26 (DTNSRPS); and

[0240] VLCDR3 comprises the sequence shown in SEQ ID NO: 29 (VTGDSTTHDDL).

[0241] The first specific binding molecule may comprise framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0242] VHFR1 comprises the sequence set forth in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0243] VHFR2 comprises the sequence set forth in SEQ ID NO:436 (WVRQAPGKVPESLV);

[0244] VHFR3 comprises the sequence set forth in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0245] VHFR4 comprises the sequence set forth in SEQ ID NO:438 (WGPGLLVTVSS);

[0246] VLFR1 comprises the sequence shown in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC);

[0247] VLFR2 comprises the sequence set forth in SEQ ID NO: 440 (WYQHLPGSGLKTIIY);

[0248] VLFR3 comprises the sequence set forth in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0249] VLFR4 comprises the sequence shown in SEQ ID NO: 442 (VGSGTRLTVLG);

[0250] Or for each FR sequence, comprising an amino acid sequence having the following:

[0251] (i) is at least 50% identical thereto, and / or

[0252] (ii) has one, two, three, four or five amino acid substitutions relative thereto.

[0253] The first specific binding molecule may comprise the following, or a humanized variant thereof:

[0254] (a) a VH domain comprising SEQ ID NO: 443

[0255] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSS); and / or

[0256] (b) a VL domain comprising SEQ ID NO: 444

[0257] The sequence shown in (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG).

[0258] The first specific binding molecule can bind with a K of less than about 500 pM. D specifically binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 355 of SEQ ID NO: 1, optionally wherein the specific binding is measured by surface plasmon resonance (SPR), and optionally wherein,

[0259] iii. K combined with SEQ ID NO: 1 D is from about 50 pM to about 150 pM, and / or

[0260] iv. K combined with SEQ ID NO: 5 D From about 300 pM to about 400 pM.

[0261] The first specific binding molecule can bind to an epitope consisting of residues 367 to 379 of SEQ ID NO: 1. This epitope can bind to a CDR of a specific binding molecule (referred to herein as "S1G2").

[0262] The first specific binding molecule may comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0263] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0264] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0265] VHCDR3 comprises the sequence shown in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0266] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0267] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0268] VLCDR3 comprises the sequence set forth in SEQ ID NO:73 (GSSDRTPYTGV);

[0269] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0270] (i) is at least 85% identical thereto, and / or

[0271] (ii) has one, two or three amino acid substitutions relative thereto.

[0272] The first specific binding molecule may comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0273] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0274] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0275] VHCDR3 comprises the sequence shown in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0276] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0277] VLCDR2 comprises the sequence set forth in SEQ ID NO:70 (ASDGRPS); and

[0278] VLCDR3 comprises the sequence shown in SEQ ID NO: 73 (GSSDRTPYTGV).

[0279] The first specific binding molecule may comprise framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0280] VHFR1 comprises the sequence set forth in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0281] VHFR2 comprises the sequence set forth in SEQ ID NO: 448 (WVRQAPGKAPEWVA);

[0282] VHFR3 comprises the sequence set forth in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0283] VHFR4 comprises the sequence shown in SEQ ID NO: 450 (WGPGLLVTVSS);

[0284] VLFR1 comprises the sequence shown in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC);

[0285] VLFR2 comprises the sequence set forth in SEQ ID NO:452 (WFQQLPGSGLRTIIV);

[0286] VLFR3 comprises the sequence set forth in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0287] VLFR4 comprises the sequence shown in SEQ ID NO: 454 (FGSGTRLTVLG);

[0288] Or for each FR sequence, comprising an amino acid sequence having the following:

[0289] (i) is at least 50% identical thereto, and / or

[0290] (ii) has one, two, three, four or five amino acid substitutions relative thereto.

[0291] The first specific binding molecule may comprise the following, or a humanized variant thereof:

[0292] (a) a VH domain comprising SEQ ID NO: 455

[0293] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVSS); and / or

[0294] (b) a VL domain comprising SEQ ID NO: 456

[0295] The sequence shown is (QAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG).

[0296] The first specific binding molecule can bind with a K of less than about 500 pM. D specifically binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367 to 379 of SEQ ID NO: 1, optionally wherein the specific binding is measured by surface plasmon resonance (SPR), and optionally wherein,

[0297] iii. K combined with SEQ ID NO: 1 D From about 100 pM to about 200 pM, and / or

[0298] iv. K combined with SEQ ID NO: 5 D From about 400 pM to about 500 pM.

[0299] 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 to 391 of SEQ ID NO: 1. The first specific binding molecule can compete with S1D12 or S1G2 for binding to SEQ ID NO: 1.

[0300] Those skilled in the art can identify competing antibodies (e.g., by using conventional competition binding assays) without undue experimentation or inventiveness. As used herein, a specific binding molecule that competes with another specific binding molecule is achieved by competition involving specific binding to the same target.

[0301] In a preferred embodiment, the first specific binding molecule may comprise the CDRs of a specific binding molecule selected from the group consisting of S1D12, S1G2 and CA4, optionally further comprising framework regions, optionally comprising a VH domain and / or a VL domain.

[0302] The first specific binding molecule can bind to an epitope consisting of residues 355 to 367 of SEQ ID NO: 1. Thus, the epitope can be located within the amino acid sequence of SEQ ID NO: 330 (GSLDNITHVPGGG). This epitope can bind to a CDR of a specific binding molecule (referred to herein as "CA4").

[0303] The first specific binding molecule may comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0304] VHCDR1 comprises the sequence shown in SEQ ID NO: 83 (SYSVY);

[0305] VHCDR2 comprises the sequence set forth in SEQ ID NO: 84 (IMYASGRVDYNPALKS);

[0306] VHCDR3 comprises the sequence shown in SEQ ID NO:89 (GIEN);

[0307] VLCDR1 comprises the sequence shown in SEQ ID NO:91 (RTSQSVNNYLS);

[0308] VLCDR2 comprises the sequence set forth in SEQ ID NO:95 (YATRLYT); and

[0309] VLCDR3 comprises the sequence shown in SEQ ID NO:97 (LQYDSTPLA);

[0310] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0311] (i) is at least 85% identical thereto, and / or

[0312] (ii) has one, two or three amino acid substitutions relative thereto.

[0313] The first specific binding molecule may comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0314] VHCDR1 comprises the sequence shown in SEQ ID NO: 83 (SYSVY);

[0315] VHCDR2 comprises the sequence set forth in SEQ ID NO: 84 (IMYASGRVDYNPALKS);

[0316] VHCDR3 comprises the sequence shown in SEQ ID NO:89 (GIEN);

[0317] VLCDR1 comprises the sequence shown in SEQ ID NO:91 (RTSQSVNNYLS);

[0318] VLCDR2 comprises the sequence set forth in SEQ ID NO:95 (YATRLYT); and

[0319] VLCDR3 comprises the sequence shown in SEQ ID NO: 97 (LQYDSTPLA).

[0320] The first specific binding molecule may comprise framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0321] VHFR1 comprises the sequence set forth in SEQ ID NO: 555 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0322] VHFR2 comprises the sequence set forth in SEQ ID NO: 556 (WVRQAPGQALEWIS);

[0323] VHFR3 comprises the sequence set forth in SEQ ID NO: 557 (RLSITRDTSKSQFSLSLSSVTTEDTAVYYCTR);

[0324] VHFR4 comprises the sequence set forth in SEQ ID NO: 558 (WGPGLLVTVSS);

[0325] VLFR1 comprises the sequence shown in SEQ ID NO: 559 (DIQVTQSPSSLSASLTERVSITC);

[0326] VLFR2 comprises the sequence shown in SEQ ID NO: 560 (WYQQKPGQAPKLLIY);

[0327] VLFR3 comprises the sequence set forth in SEQ ID NO: 561 (DVPSRFSGSGSGTDYTLTITSLEADDTATYYC);

[0328] VLFR4 comprises the sequence shown in SEQ ID NO: 562 (FGGGTNVEIK);

[0329] Or for each FR sequence, comprising an amino acid sequence having the following:

[0330] (i) is at least 50% identical thereto, and / or

[0331] (ii) has one, two, three, four or five amino acid substitutions relative thereto.

[0332] The first specific binding molecule may comprise the following, or a humanized variant thereof:

[0333] (a) a VH domain comprising SEQ ID NO: 563

[0334] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSYSVYWVRQAPGQALEWISIMYASGRVDYNPALKSRLSITRDTSKSQFSLSLSSVTTEDTAVYYCTRGIENWGPGLLVTVSS); and / or

[0335] (b) a VL domain comprising SEQ ID NO: 564

[0336] The sequence shown in (DIQVTQSPSSLSASLTERVSITCRTSQSVNNYLSWYQQKPGQAPKLLIYYATRLYTDVPSRFSGSGSGT DYTLTITSLEADDTATYYCLQYDSTPLAFGGGTNVEIK).

[0337] The first specific binding molecule can compete with CA4 for binding to SEQ ID NO: 1.

[0338] The first specific binding molecule can compete with S1D12, S1G2, or CA4 for binding to SEQ ID NO: 1.

[0339] In a preferred embodiment, the first specific binding molecule may comprise the CDRs of a specific binding molecule selected from the group consisting of S1D12 and S1G2, optionally further comprising a framework region, optionally comprising a VH domain and / or a VL domain.

[0340] The first specific binding molecule can comprise the CDRs of S1D12, S1G2, or CA4, or an alternative specific binding molecule having an adjacent or overlapping epitope relative to 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 located within or overlapping residues 307 to 391 of SEQ ID NO: 1. The first specific binding molecule can be any specific binding molecule disclosed herein that binds to an epitope located within or overlapping residues 337 to 379 of SEQ ID NO: 1. The first specific binding molecule can comprise the CDR sequences of the clones listed in Table 1, Table 2, Table 3, Table 4, Table 9, Table 10 (wherein the epitope is located within or overlapping residues 307 to 391 of SEQ ID NO: 1), or Table 11.

[0341] Second specific binding molecule

[0342] The method can also 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 can be a separate step from contacting the sample with the first specific binding molecule. Contacting the sample with the second specific binding molecule is performed after contacting the sample with the first specific binding molecule. The second specific binding molecule is described below. Any reference to a specific binding molecule (not limited to being associated with the first specific binding molecule) under this subheading refers to the first specific binding molecule.

[0343] The second specific binding molecule can be any specific binding molecule disclosed herein, such as a specific binding molecule described in PCT Application No. PCT / EP2021 / 069160, wherein 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 the epitope in SEQ ID NO: 1 with a binding affinity greater than the binding affinity of the antibody mAb423 to the epitope in SEQ ID NO: 1.

[0344] The epitope of the second specific binding molecule may be located within SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7.

[0345] Under the premise that the second specific binding molecule is different from the first specific binding molecule, the second specific binding molecule can have any combination of the features described for the first specific binding molecule. For example, the epi-position 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 epi-position 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 epi-position of the second specific binding molecule can not be within SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6 or SEQ ID NO:7.

[0346] 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 US Pat. No. 6,010,913A and in the paper (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.

[0347] The second specific binding molecule can bind to an epitope within residues 151 to 243 of SEQ ID NO:1.

[0348] The second specific binding molecule may bind to an epitope consisting of residues 194 to 198 of SEQ ID NO: 1. The second specific binding molecule may be BT2.

[0349] The second specific binding molecule may bind to an epitope consisting of residues 159 to 163 of SEQ ID NO: 1. The second specific binding molecule may be HT7.

[0350] The second specific binding molecule can compete with BT2 or HT7 for binding to SEQ ID NO: 1.

[0351] The second specific binding molecule can comprise the CDRs of HT7 or an alternative specific binding molecule disclosed herein that has an adjacent or overlapping epitope, such as 3aA6 and 3aD6, which bind to an adjacent epitope within residues 147 to 157 of SEQ ID NO:1.

[0352] Alternative second specific binding molecules for HT7 and / or BT2 can comprise the CDRs (optionally also comprising a FW region and optional VH domain and / or VL domain) of the cloned specific binding molecules listed in Table 8. For example, the second specific binding molecule can comprise the CDRs of 3aA6 or 3aD6. The second specific binding molecule can comprise the CDRs and FW region of 3aA6 or 3aD6. The second specific binding molecule can comprise the VH domain and / or VL domain of 3aA6 or 3aD6.

[0353] The second specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0354] VHCDR1 comprises the sequence shown in SEQ ID NO: 198 (SNAVI);

[0355] VHCDR2 comprises the sequence shown in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[0356] VHCDR3 comprises the sequence shown in SEQ ID NO: 202 (DYGSWGYVSDIDY);

[0357] VLCDR1 comprises the sequence shown in SEQ ID NO: 204 (SGSDIGGADVG);

[0358] VLCDR2 comprises the sequence set forth in SEQ ID NO: 206 (DNDNRPS); and

[0359] VLCDR3 comprises the sequence shown in SEQ ID NO: 208 (GTYSGANYGI);

[0360] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0361] (i) is at least 85% identical thereto, and / or

[0362] (ii) has one, two or three amino acid substitutions relative thereto,

[0363] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "3aD6."

[0364] The second specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0365] VHCDR1 comprises the sequence shown in SEQ ID NO: 198 (SNAVI);

[0366] VHCDR2 comprises the sequence shown in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[0367] VHCDR3 comprises the sequence shown in SEQ ID NO: 202 (DYGSWGYVSDIDY);

[0368] VLCDR1 comprises the sequence shown in SEQ ID NO: 204 (SGSDIGGADVG);

[0369] VLCDR2 comprises the sequence set forth in SEQ ID NO: 206 (DNDNRPS); and

[0370] VLCDR3 comprises the sequence shown in SEQ ID NO: 208 (GTYSGANYGI).

[0371] The second specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0372] VHCDR1 comprises the sequence shown in SEQ ID NO: 17 (SNAVG);

[0373] VHCDR2 comprises the sequence shown in SEQ ID NO: 201 (LIDIDGDTAYNPALES);

[0374] VHCDR3 comprises the sequence shown in SEQ ID NO: 203 (HYDKWGYADSIDY);

[0375] VLCDR1 comprises the sequence shown in SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[0376] VLCDR2 comprises the sequence set forth in SEQ ID NO: 207 (DATTRAS); and

[0377] VLCDR3 comprises the sequence shown in SEQ ID NO: 209 (ASYQNERSGV);

[0378] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0379] (i) is at least 85% identical thereto, and / or

[0380] (ii) has one, two or three amino acid substitutions relative thereto,

[0381] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "3aA6".

[0382] The second specific binding molecule can be expressed with a K of less than about 50 nM. D Binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 147 to 157 of SEQ ID NO: 1. D The K may be less than about 40 nM, less than about 30 nM, or less than about 20 nM. D It can be preferably used in combination with SEQ ID NO: 1 or SEQ ID NO: 191. K combined with SEQ ID NO: 1 D The K binding to SEQ ID NO: 1 may be from about 10 nM to about 20 nM. D It may be about 16.5 nM, optionally wherein the specific binding molecule comprises the CDRs of 3aD6.

[0383] The second specific binding molecule can comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 418, 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. 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. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 418, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 418. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 418.

[0384] SEQ ID NO:418 (3aA6 amino acid sequence)

[0385] QVRLQESGSSLVKPSQTLSLVCTVSGFPLTSNAVGWVRQAPGKAPEWLGLIDIDGDTAYNPALESRLSITRDTSKSQVSLSLSSVAIEDTAVYYCARHYDKWGYADSIDYWGPGLLVTVSSEG KSSGASGESKVDDQALLTQPSSVFGSLGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYDATTRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYQNERSGVFGSGTRLTVLG

[0386] The second specific binding molecule can comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 419, 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. 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. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 419, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 419. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 419.

[0387] SEQ ID NO:419 (3aD6 amino acid sequence)

[0388] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSDIGGADVGWFQQVPGSGLRTLIYDNDNRPSGVPDRFSGSKSGNTATLTISSLQPEDEADYFCGTYSGANYGIFFSGTRLTVLG

[0389] The second specific binding molecule can comprise the CDRs of BT2, or the CDRs of an alternative specific binding molecule disclosed herein having an adjacent or overlapping epitope.

[0390] Alternative second specific binding molecules for HT7 and / or BT2 may comprise the CDRs (optionally also comprising a FW region and optional VH and / or VL domains) of the cloned specific binding molecules listed 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 region 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 VH domain and / or VL domain of 3bD11, CB11, CA2, CB6, CA7, CA8, CB10, CC7, CB12, CC3, CA1, CA3, CD2, CC4, CD1, or CC5.

[0391] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0392] VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 10;

[0393] VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 10;

[0394] VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 10;

[0395] VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 10;

[0396] VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 10; and

[0397] VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 10;

[0398] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0399] (i) is at least 85% identical thereto, and / or

[0400] (ii) has one, two or three amino acid substitutions relative thereto,

[0401] wherein the specific binding molecule binds to an epitope within SEQ ID NO: 1. VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3 may be derived from a single clone listed 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.

[0402] General characteristics of the first and / or second specific binding molecules

[0403] The following describes general features of specific binding molecules and includes details of the specific binding molecules described in PCT application No. PCT / EP2021 / 069160. Any reference to a specific binding molecule under this subheading (not limited to specifically relating to a first specific binding molecule or a second specific binding molecule) refers to a general specific binding molecule and expressly contemplates binding to any feature of the first specific binding molecule or the second specific binding molecule, provided that the first specific binding molecule binds to an epitope within residues 297 to 391 of SEQ ID NO: 1 (thus, a specific binding molecule disclosed herein that does not bind to an epitope within residues 297 to 391 of SEQ ID NO: 1 refers only to a second specific binding molecule).

[0404] The epitope of the specific binding molecule can be located within residues 297 to 391 of SEQ ID NO: 1. Residues 297 to 391 of full-length Tau are also referred to as the primary fragment separated from the proteolytically stable core of paired helical filaments (PHFs) or the PHF core fragment. Thus, the epitope of the specific binding molecule can be located within the PHF or within the dGAE fragment. Thus, the epitope of the specific binding molecule can be located within SEQ ID NO: 4.

[0405] The epitope of the specific binding molecule can be located within residues 297 to 390 of SEQ ID NO: 1. Residues 297 to 390 of full-length Tau are also referred to as the dGA fragment. Thus, the epitope of the specific binding molecule can be located within the dGA fragment. Thus, the epitope of the specific binding molecule can be located within SEQ ID NO: 5. The epitope of the specific binding molecule can be located within dGAE73 and / or dGAE71. Thus, the epitope of the specific binding molecule can be located within SEQ ID NO: 6 and / or SEQ ID NO: 7.

[0406] The epitope of the specific binding molecule can be located within residues 308 to 378 of SEQ ID NO: 1. Residues 308 to 378 of full-length Tau are also referred to as the PHF core. Thus, the epitope of the specific binding molecule can be located within the PHF core. Thus, the epitope of the specific binding molecule can be located within SEQ ID NO: 7.

[0407] The epitope of the specific binding molecule may be located within residues 297 to 386 of SEQ ID NO: 1. The epitope of the specific binding molecule may be located within residues 306 to 391 of SEQ ID NO: 1. The epitope of the specific binding molecule may be located within residues 306 to 386 of SEQ ID NO: 1.

[0408] The epitope of the specific binding molecule can be located within an amino acid sequence selected from the group consisting of 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 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 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 to 25 of SEQ ID NO: 1, residues 49 to 113 of SEQ ID NO: 1, 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 361 to 367 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.

[0409] The epitope of the specific binding molecule can be located within an amino acid sequence selected from the group consisting of 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 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, and residues 147 to 157 of SEQ ID NO: 1.

[0410] The epitope of the specific binding molecule may be located within an amino acid sequence selected from the group consisting of 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, and residues 355 to 367 of SEQ ID NO: 1.

[0411] The epitope of the specific binding molecule may be located within an amino acid sequence selected from residues 341 to 353 of SEQ ID NO:1.

[0412] The epitope of the specific binding molecule of the present invention can be any amino acid sequence in SEQ ID NO: 1, which is indicated to contain key binding residues by ELISA or alanine scanning mutagenesis, as described in Examples 5 to 12.

[0413] The epitopes described herein may be expressed as "comprising" a certain amino acid sequence, or as expressed by the phrase "a specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues..." As will be clear to one skilled in the art, when a specific binding molecule binds to a polypeptide or protein molecule comprising its epitope, the specific binding molecule will also bind to a polypeptide or protein molecule consisting of its epitope. Thus, as used herein, the phrase "a specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues...", wherever it appears, may alternatively be replaced by the phrase "a specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence consisting of residues..."; or the phrase "a specific binding molecule binds to a polypeptide or protein molecule consisting of an amino acid sequence comprising residues..."; or the phrase "a specific binding molecule binds to a polypeptide or protein molecule consisting of an amino acid sequence consisting of residues...".

[0414] Those skilled in the art will appreciate that not all residues within an epitope are essential. A specific binding molecule can retain binding to an amino acid sequence that is at least 70% identical to the epitope. A specific binding molecule can bind to any epitope disclosed herein or to an amino acid sequence that is at least 70% identical thereto.

[0415] The specific binding molecules can retain binding to an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to the epitope. The specific binding molecules can bind to any epitope disclosed herein or to an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical thereto.

[0416] In an embodiment of the invention, the specific binding molecule retains binding to an amino acid sequence having less than 100% sequence identity with the amino acid sequence of SEQ ID NO: 1 (or any one of SEQ ID NO: 3 to SEQ ID NO: 7, or any other epitope defined herein), which epitope sequence may be altered by substitution, insertion or deletion of an appropriate number of amino acids in the sequence of SEQ ID NO: 1 (or any one of SEQ ID NO: 3 to SEQ ID NO: 7, or any other epitope defined herein). In another embodiment of the invention, the epitope may be modified by substitution, insertion or deletion of up to 2 amino acids relative to SEQ ID NO: 1 (or any one of SEQ ID NO: 3 to SEQ ID NO: 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 one of SEQ ID NO: 3 to SEQ ID NO: 7, or any other epitope defined herein), as described above. "Substitution, insertion or deletion" includes combinations of substitutions, insertions and deletions.

[0417] When modifying the epitope sequence by replacing a specific amino acid residue, the replacement can be a conservative amino acid replacement. As used herein, the term "conservative amino acid replacement" refers to an amino acid replacement in which one of the amino acid residues is replaced by another amino acid residue with a similar side chain. Amino acids with similar side chains often have similar properties, so it can be expected that conservative replacements of amino acids important to the structure or function of the polypeptide will have less impact on the polypeptide structure / function than non-conservative amino acid replacements at the same position. Families of amino acid residues with 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), non-polar side chains (e.g., glycine, cysteine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Therefore, conservative amino acid replacement can be considered as a replacement in which a specific amino acid residue is replaced by different amino acids in the same family. However, substitutions of epitope residues may also be non-conservative substitutions, where one amino acid is replaced by another having a side chain belonging to a different family.

[0418] An epitope can be at least five, at least six, at least seven, at least eight, at least nine, at least ten, at least eleven, at least twelve, at least thirteen, at least fourteen, at least fifteen, at least sixteen, at least seventeen, at least eighteen, at least nineteen, or at least twenty amino acids in length. An epitope can be from 5 to 20 amino acids in length. An epitope can be from 5 to 15 amino acids in length. An epitope can be from 5 to 12 amino acids in length. An epitope can be from 6 to 12 amino acids in length. An epitope can be from 7 to 12 amino acids in length.

[0419] As used herein, the term "located within" means "contained within" or "completely within". None of the residues considered essential for binding of a specific binding molecule to its target are outside the epitope. Residues outside the epitope do not contribute significantly to binding. For example, when the epitope of the specific binding molecule is within residues 337 to 355 of SEQ ID NO: 1, residues outside of residues 337 to 355 do not contribute significantly to binding.

[0420] The epitope can comprise any residue within SEQ ID NO: 1 that binds to a specific binding molecule. The epitope can be a continuous epitope or a discontinuous epitope.

[0421] A contiguous epitope can be any contiguous residues within SEQ ID NO: 1 that bind to a specific binding molecule. Contiguous residues are adjacent to each other in the primary structure of the polypeptide.

[0422] A non-contiguous epitope can be any non-contiguous residue within SEQ ID NO: 1 that binds to a specific binding molecule. A non-contiguous epitope is typically formed by non-contiguous residues that occupy adjacent positions in three-dimensional space due to polypeptide folding.

[0423] Typically, a specific binding molecule binds to a polypeptide or protein molecule comprising its epitope. Thus, a specific binding molecule can bind to SEQ ID NO: 1 or a fragment thereof. 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 can bind to a polypeptide or protein molecule comprising an amino acid sequence selected from the group consisting of 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 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 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 1, residues 13 to 25 of SEQ ID NO: 1, residues 49 to 113 of SEQ ID NO: 1, 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 361 of SEQ ID NO: 1. Residues 360 to 390 of NO:1.

[0424] The specific binding molecule can bind to a polypeptide or protein molecule comprising the amino acid sequence of residues 341 to 353 of SEQ ID NO:1.

[0425] In the sequences herein, " / " means "or" and indicates that the inventors have shown that the residues can be varied as specified. In this case, "-" indicates a vacancy or the absence of an amino acid. X is any amino acid. For example, "N / S" indicates that the residue can be either N or S. Similarly, "G / -" indicates that the residue can be either G or absent. Similarly, "H / F / Y" indicates that the residue can be either H, F, or Y. When specifying a sequence identity value, the sequence identity can be calculated starting from any of the residues separated by " / ".

[0426] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 337 to 355 of SEQ ID NO: 1. The epitope of the specific binding molecule within the amino acid sequence comprising residues 337 to 355 of SEQ ID NO: 1 may be located within the amino acid sequence comprising residues 341 to 353 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 8 (VEVKSEKLDFKDR).

[0427] The epitope can be located within the amino acid sequence comprising residues 337 to 349 of SEQ ID NO: 1, preferably within the amino acid sequence comprising residues 337 to 355 of SEQ ID NO: 1. The epitope can bind to the CDRs of the specific binding molecule referred to herein as "S1D12". The epitope can comprise the amino acid sequence of SEQ ID NO: 8 (VEVKSEKLDFKDR). The epitope 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: 8 (VEVKSEKLDFKDR). The key residues of the epitope can be residues 343 (K), 346 (F) and / or 349 (R) (numbered according to SEQ ID NO: 1). The epitope can comprise the amino acid sequence of SEQ ID NO: 9 (XXXXXXXKXXFXXR, wherein X is any amino acid). The epitope may comprise the amino acid sequence of SEQ ID NO: 8, wherein any one or more residues other than residue numbers 343 (K), 346 (F) and / or 349 (R) are substituted with non-conservative amino acid substitutions (numbered according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 8, wherein any one or more residues other than residue numbers 343 (K), 346 (F) and / or 349 (R) are substituted with conservative amino acid substitutions (numbered according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 8, wherein any one or more residues other than residue numbers 343 (K), 346 (F) and / or 349 (R) are substituted with conservative amino acid substitutions (numbered according to SEQ ID NO: 1), and any one or more residues other than residue numbers 343 (K), 346 (F) and / or 349 (R) are substituted with non-conservative amino acid substitutions (numbered according to SEQ ID NO: 1).

[0428] 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 that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 8 (VEVKSEKLDFKDR).

[0429] The specific binding molecule can 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 can comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0430] VHCDR1 comprises the sequence shown in SEQ ID NO: 10 (N / SNAVG);

[0431] VHCDR2 comprises the sequence shown in SEQ ID NO: 11 (GCSSDGT / KCYY / HNSALKS);

[0432] VHCDR3 comprises the sequence shown in SEQ ID NO: 12 (GH / F / YYS / PI / VYGYDYL / SGTIDY);

[0433] VLCDR1 comprises the sequence shown in SEQ ID NO: 13 (SGSSSNVG / -GG / RNS / DVG / A);

[0434] VLCDR2 comprises the sequence shown in SEQ ID NO: 14 (D / N / GTN / TSRPS);

[0435] VLCDR3 comprises the sequence shown in SEQ ID NO: 15 (V / AT / SGDST / ST / AH / ID / NDL / I);

[0436] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0437] (i) is at least 85% identical thereto, and / or

[0438] (ii) has one, two or three amino acid substitutions relative thereto.

[0439] The sequence identity is at least about 85% sequence identity, and thus 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% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0440] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0441] VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG) or SEQ ID NO: 17 (SNAVG);

[0442] VHCDR2 comprises the sequence set forth in SEQ ID NO: 18 (GCSSDGTCYYNSALKS), SEQ ID NO: 19 (GCSSDGKCYHNSALKS), or SEQ ID NO: 20 (GCSSDGKCYYNSALKS);

[0443] VHCDR3 includes the sequence shown in SEQ ID NO:21 (GHYSIYGYDYLGTIDY), SEQ ID NO:22 (GFYSIYGYDYSGTIDY) or SEQ ID NO:23 (GYYPVYGYDYLGTIDY);

[0444] VLCDR1 comprises the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG) or SEQ ID NO:25 (SGSSSNVGRNDVA);

[0445] VLCDR2 comprises the sequence shown in SEQ ID NO: 26 (DTNSRPS), SEQ ID NO: 27 (NTNSRPS), or SEQ ID NO: 28 (GTTSRPS);

[0446] VLCDR3 comprises the sequence set forth in SEQ ID NO:29 (VTGDSTTHDDL), SEQ ID NO:30 (VTGDSSTHDDL), or SEQ ID NO:31 (ASGDSSAINDI);

[0447] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0448] (i) is at least 85% identical thereto, and / or

[0449] (ii) has one, two or three amino acid substitutions relative thereto,

[0450] The specific binding molecule binds to a polypeptide or protein molecule comprising the amino acid sequence of residues 337 to 355 of SEQ ID NO: 1.

[0451] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0452] VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG);

[0453] VHCDR2 comprises the sequence shown in SEQ ID NO: 18 (GCSSDGTCYYNSALKS);

[0454] VHCDR3 comprises the sequence shown in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY);

[0455] VLCDR1 comprises the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0456] VLCDR2 comprises the sequence shown in SEQ ID NO: 26 (DTNSRPS);

[0457] VLCDR3 comprises the sequence shown in SEQ ID NO: 29 (VTGDSTTHDDL);

[0458] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0459] (i) is at least 85% identical thereto, and / or

[0460] (ii) has one, two or three amino acid substitutions relative thereto,

[0461] 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 the above is referred to herein as "S1D12" (or abbreviated as "1D12").

[0462] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0463] VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG);

[0464] VHCDR2 comprises the sequence shown in SEQ ID NO: 18 (GCSSDGTCYYNSALKS);

[0465] VHCDR3 comprises the sequence shown in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY);

[0466] VLCDR1 comprises the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0467] VLCDR2 comprises the sequence set forth in SEQ ID NO: 26 (DTNSRPS); and

[0468] VLCDR3 comprises the sequence shown in SEQ ID NO: 29 (VTGDSTTHDDL).

[0469] Any specific binding molecule disclosed herein can be further defined with reference to one or more framework regions (FRs).The framework regions (FRs) are non-CDR sequences that together with the CDR sequences form the variable domains.

[0470] The VH domain may have the following structure: VHFR1-VHCDR1-VHFR2–VHCDR2-VHFR3–VHCDR3-VHFR4.

[0471] The VL domain may have the following formula: VLFR1-VLCDR1-VLFR2–VLCDR2-VLFR3–VLCDR3-VLFR4.

[0472] Those skilled in the art can use known methods described elsewhere herein to identify CDRs and framework regions within the amino acid sequence of the variable domain. Therefore, any specific binding molecule disclosed herein can be defined by reference to its CDRs and FRs. In some cases, some FR residues can contribute to the affinity of the specific binding molecule for binding to its target. However, without being bound by theory, replacing FR residues is more likely to retain function than replacing CDR residues. For example, in the humanization process, FR residues can generally be replaced by corresponding residues from human sequences. Therefore, FR sequences can be more tolerant to amino acid substitutions than CDR sequences.

[0473] The specific binding molecule may comprise:

[0474] (a) Framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises an amino acid sequence from any specific binding molecule disclosed herein; or for each FR sequence, comprises an amino acid sequence having the following:

[0475] (i) is at least 50% identical thereto, and / or

[0476] (ii) has one, two, three, four or five amino acid substitutions therewith; and

[0477] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises an amino acid sequence from any specific binding molecule disclosed herein, or for each CDR sequence, comprises an amino acid sequence having the following:

[0478] (i) is at least 85% identical thereto, and / or

[0479] (ii) has one, two or three amino acid substitutions relative thereto.

[0480] The sequence identity among the CDR sequences is at least about 85% sequence identity, and thus 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% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0481] The sequence identity in the FR sequences is at least about 50% sequence identity, and thus 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%.

[0482] When the FR sequence has at least 50% identity (but less than 100% identity) with the FR sequence disclosed in a portion of the specific binding molecules disclosed herein, the FR sequence can be a humanized sequence. In other words, the changes in the amino acid sequence can be the only changes required for sequence humanization.

[0483] When the FR sequence has one, two, three, four or five amino acid substitutions relative to the FR sequence disclosed in a portion of the specific binding molecules disclosed herein, the FR sequence can be a humanized sequence. In other words, the substitutions can be only those required for sequence humanization.

[0484] The specific binding molecule may comprise:

[0485] (a) framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises an amino acid sequence from any specific binding molecule disclosed herein; and

[0486] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises an amino acid sequence from any specific binding molecule disclosed herein.

[0487] Typically, each of the FRs is derived from the same specific binding molecule disclosed herein. Typically, each of the CDRs is derived from the same specific binding molecule disclosed herein. Typically, no additional amino acid residues are inserted between the defined FRs and CDRs; thus, it can be said that each of the FRs and each of the CDRs consists of an amino acid sequence derived from any specific binding molecule disclosed herein.

[0488] As used herein, the phrase "comprising CDRs" also encompasses specific binding molecules comprising CDRs and FRs of the specific binding molecules disclosed herein (including FR variants, including the aforementioned FR variants, e.g., humanized FRs). It also encompasses specific binding molecules comprising the VH and / or VL domains of the specific binding molecules disclosed herein (including FR variants, including the aforementioned FR variants, e.g., humanized FRs). It also encompasses specific binding molecules comprising the heavy and / or light chains of the specific binding molecules disclosed herein (including FR variants and constant regions, including the aforementioned FR variants and constant regions, e.g., humanized FRs and humanized constant regions).

[0489] The specific binding molecule may comprise framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0490] VHFR1 comprises the sequence set forth in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0491] VHFR2 comprises the sequence set forth in SEQ ID NO:436 (WVRQAPGKVPESLV);

[0492] VHFR3 comprises the sequence set forth in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0493] VHFR4 comprises the sequence set forth in SEQ ID NO:438 (WGPGLLVTVSS);

[0494] VLFR1 comprises the sequence shown in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC);

[0495] VLFR2 comprises the sequence set forth in SEQ ID NO: 440 (WYQHLPGSGLKTIIY);

[0496] VLFR3 comprises the sequence set forth in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0497] VLFR4 comprises the sequence shown in SEQ ID NO: 442 (VGSGTRLTVLG);

[0498] Or for each FR sequence, comprising an amino acid sequence having the following:

[0499] (i) is at least 50% identical thereto, and / or

[0500] (ii) has one, two, three, four or five amino acid substitutions relative thereto.

[0501] The specific binding molecule may comprise framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0502] VHFR1 comprises the sequence set forth in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0503] VHFR2 comprises the sequence set forth in SEQ ID NO:436 (WVRQAPGKVPESLV);

[0504] VHFR3 comprises the sequence set forth in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0505] VHFR4 comprises the sequence set forth in SEQ ID NO:438 (WGPGLLVTVSS);

[0506] VLFR1 comprises the sequence shown in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC);

[0507] VLFR2 comprises the sequence set forth in SEQ ID NO: 440 (WYQHLPGSGLKTIIY);

[0508] VLFR3 comprises the sequence set forth in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0509] VLFR4 comprises the sequence shown in SEQ ID NO: 442 (VGSGTRLTVLG);

[0510] Or for each FR sequence, comprising an amino acid sequence having the following:

[0511] (i) is at least 50% identical thereto, and / or

[0512] (ii) has one, two, three, four or five amino acid substitutions relative thereto,

[0513] The specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence consisting of residues 337 to 355 of SEQ ID NO: 1. A specific binding molecule comprising FRs having 100% identity to the above is referred to herein as "S1D12" (or abbreviated as "1D12").

[0514] The specific binding molecule may comprise:

[0515] (a) Framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0516] VHFR1 comprises the sequence set forth in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0517] VHFR2 comprises the sequence set forth in SEQ ID NO:436 (WVRQAPGKVPESLV);

[0518] VHFR3 comprises the sequence set forth in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0519] VHFR4 comprises the sequence set forth in SEQ ID NO:438 (WGPGLLVTVSS);

[0520] VLFR1 comprises the sequence shown in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC);

[0521] VLFR2 comprises the sequence set forth in SEQ ID NO: 440 (WYQHLPGSGLKTIIY);

[0522] VLFR3 comprises the sequence set forth in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0523] VLFR4 comprises the sequence shown in SEQ ID NO: 442 (VGSGTRLTVLG);

[0524] Or for each FR sequence, comprising an amino acid sequence having the following:

[0525] (i) is at least 50% identical thereto, and / or

[0526] (ii) has one, two, three, four or five amino acid substitutions therewith, and

[0527] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0528] VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG);

[0529] VHCDR2 comprises the sequence shown in SEQ ID NO: 18 (GCSSDGTCYYNSALKS);

[0530] VHCDR3 comprises the sequence shown in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY);

[0531] VLCDR1 comprises the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0532] VLCDR2 comprises the sequence shown in SEQ ID NO: 26 (DTNSRPS);

[0533] VLCDR3 comprises the sequence shown in SEQ ID NO: 29 (VTGDSTTHDDL);

[0534] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0535] (i) is at least 85% identical thereto, and / or

[0536] (ii) has one, two or three amino acid substitutions relative thereto,

[0537] The specific binding molecule binds to a polypeptide or protein molecule comprising the amino acid sequence of residues 337 to 355 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to the above is referred to herein as "S1D12" (or abbreviated as "1D12").

[0538] The specific binding molecule may comprise:

[0539] (a) Framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0540] VHFR1 comprises the sequence set forth in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0541] VHFR2 comprises the sequence set forth in SEQ ID NO:436 (WVRQAPGKVPESLV);

[0542] VHFR3 comprises the sequence set forth in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0543] VHFR4 comprises the sequence set forth in SEQ ID NO:438 (WGPGLLVTVSS);

[0544] VLFR1 comprises the sequence shown in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC);

[0545] VLFR2 comprises the sequence set forth in SEQ ID NO: 440 (WYQHLPGSGLKTIIY);

[0546] VLFR3 comprises the sequence set forth in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0547] VLFR4 comprises the sequence shown in SEQ ID NO: 442 (VGSGTRLTVLG);

[0548] Or for each FR sequence, comprising an amino acid sequence having the following:

[0549] (i) is at least 50% identical thereto, and / or

[0550] (ii) has one, two, three, four or five amino acid substitutions therewith; and

[0551] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0552] VHCDR1 comprises the sequence shown in SEQ ID NO: 16 (NNAVG);

[0553] VHCDR2 comprises the sequence shown in SEQ ID NO: 18 (GCSSDGTCYYNSALKS);

[0554] VHCDR3 comprises the sequence shown in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY);

[0555] VLCDR1 comprises the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0556] VLCDR2 comprises the sequence shown in SEQ ID NO: 26 (DTNSRPS);

[0557] VLCDR3 comprises the sequence shown in SEQ ID NO: 29 (VTGDSTTHDDL);

[0558] The specific binding molecule binds to a polypeptide or protein molecule comprising the amino acid sequence of residues 337 to 355 of SEQ ID NO: 1. A specific binding molecule comprising FRs and CDRs having 100% identity to the above is referred to herein as "S1D12" (or abbreviated as "1D12").

[0559] The specific binding molecule may comprise the following, or a humanized variant thereof:

[0560] (a) a VH domain comprising SEQ ID NO: 443

[0561] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSS); and / or

[0562] (b) a VL domain comprising SEQ ID NO: 444

[0563] The sequence shown in (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG).

[0564] The specific binding molecule may comprise the following, or a humanized variant thereof:

[0565] (a) a heavy chain comprising SEQ ID NO: 445

[0566] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWG PGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPC PPCKCPAPNLLGGPSVFIFPPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPK and / or

[0567] (b) a light chain comprising SEQ ID NO: 446

[0568] (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVC TITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTV EKSLSRADCS).

[0569]

[0570] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0571] VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 1;

[0572] VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 1;

[0573] VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 1;

[0574] VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 1;

[0575] VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 1; and

[0576] VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 1;

[0577] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0578] (i) is at least 85% identical thereto, and / or

[0579] (ii) has one, two or three amino acid substitutions relative thereto,

[0580] The specific binding molecule binds to a polypeptide or protein molecule comprising the amino acid sequence of residues 337 to 355 of SEQ ID NO: 1.

[0581] The specific binding molecule can be expressed with a K of less than about 500 pM. DBinds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 355 of SEQ ID NO: 1. D It can be less than about 400 pM, less than about 300 pM, less than about 200 pM, or less than about 150 pM. D It can be preferably used in combination with SEQ ID NO: 1 or SEQ ID NO: 5. K combined with SEQ ID NO: 1 D It can be from about 50 pM to about 150 pM. K binding to SEQ ID NO: 1 D It can be about 101 pM or 122 pM, optionally wherein the specific binding molecule comprises the CDRs of S1D12. K binding to SEQ ID NO: 5 D It can be from about 300 pM to about 400 pM. K binding to SEQ ID NO: 5 D It may be about 344 pM, optionally wherein the specific binding molecule comprises the CDRs of S1D12.

[0582] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 32, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 30. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 32. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 30, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 32. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 32.

[0583] SEQ ID NO:32 (S1D12 amino acid sequence)

[0584] QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG

[0585] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 367 to 379 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 33 (GNKKIETHKLTFR).

[0586] The epitope may be located within the amino acid sequence comprising residues 367 to 379 of SEQ ID NO: 1. The epitope may be bound by the CDRs of the specific binding molecule referred to herein as "S1G2".

[0587] 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 key residues of the epitope may be residues 370 (K) and / or 374 (H) (numbered according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 34 (XXXKXXXHXXXXX, wherein X is any amino acid). The epitope may comprise the amino acid sequence of SEQ ID NO: 33, wherein any one or more residues other than residue numbering 370 (K) and / or 374 (H) are replaced by non-conservative amino acid substitutions (numbered according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 33, wherein any one or more residues other than residue numbering 370 (K) and / or 374 (H) are replaced by conservative amino acid substitutions (numbered according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 33, wherein any one or more residues except residue numbers 370 (K) and / or 374 (H) are substituted by conservative amino acid substitutions (according to SEQ ID NO: 1 numbering), and any one or more residues except residue numbers 370 (K) and / or 374 (H) are substituted by non-conservative amino acid substitutions (according to SEQ ID NO: 1 numbering).

[0588] The epitope may consist of the amino acid sequence of SEQ ID NO: 33 (GNKKIETHKLTFR). The epitope may consist of an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 33 (GNKKIETHKLTFR).

[0589] The specific binding molecule can 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 can comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0590] VHCDR1 comprises the sequence shown in SEQ ID NO: 35 (S / TN / YS / A / YVG);

[0591] 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);

[0592] 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);

[0593] 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);

[0594] VLCDR2 comprises the sequence shown in SEQ ID NO:40 (A / DS / AD / S / TG / SRP / AS);

[0595] VLCDR3 comprises the sequence shown 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);

[0596] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0597] (i) is at least 85% identical thereto, and / or

[0598] (ii) has one, two or three amino acid substitutions relative thereto.

[0599] The sequence identity is at least about 85% sequence identity, and thus 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% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0600] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0601] VHCDR1 comprises the sequence set forth in SEQ ID NO:42 (SNSVG), SEQ ID NO:17 (SNAVG), SEQ ID NO:44 (SYYVG), or SEQ ID NO:45 (TNSVG);

[0602] VHCDR2 contains 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 The sequence shown in NO:51 (GIDTDGEEGYNPALKS), SEQ ID NO:52 (NIYSTGRAFYNPALKS) or SEQ ID NO:53 (GIDTDGEEGFNPVLKS);

[0603] VHCDR3 contains 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 The sequence shown in NO:59 (SANGHPDVYYIDK), SEQ ID NO:60 (TYRTDGFAYGYVQAIDY), SEQ ID NO:61 (SYRTDGLAYGYVQAIEY) or SEQ ID NO:265 (GSYYHGGGNGMVDFFDY);

[0604] 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);

[0605] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS); SEQ ID NO:71 (DSSSRPS); or SEQ ID NO:72 (AATSRAS);

[0606] VLCDR3 comprises 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);

[0607] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0608] (i) is at least 85% identical thereto, and / or

[0609] (ii) has one, two or three amino acid substitutions relative thereto,

[0610] 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.

[0611] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0612] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0613] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0614] VHCDR3 comprises the sequence shown in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0615] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0616] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0617] VLCDR3 comprises the sequence set forth in SEQ ID NO:73 (GSSDRTPYTGV);

[0618] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0619] (i) is at least 85% identical thereto, and / or

[0620] (ii) has one, two or three amino acid substitutions relative thereto,

[0621] 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. A specific binding molecule comprising CDRs having 100% identity to the above is referred to herein as "S1G2".

[0622] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0623] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0624] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0625] VHCDR3 comprises the sequence shown in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0626] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0627] VLCDR2 comprises the sequence set forth in SEQ ID NO:70 (ASDGRPS); and

[0628] VLCDR3 comprises the sequence shown in SEQ ID NO: 73 (GSSDRTPYTGV).

[0629] The specific binding molecule may comprise framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0630] VHFR1 comprises the sequence set forth in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0631] VHFR2 comprises the sequence set forth in SEQ ID NO: 448 (WVRQAPGKAPEWVA);

[0632] VHFR3 comprises the sequence set forth in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0633] VHFR4 comprises the sequence shown in SEQ ID NO: 450 (WGPGLLVTVSS);

[0634] VLFR1 comprises the sequence shown in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC);

[0635] VLFR2 comprises the sequence set forth in SEQ ID NO:452 (WFQQLPGSGLRTIIV);

[0636] VLFR3 comprises the sequence set forth in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0637] VLFR4 comprises the sequence shown in SEQ ID NO: 454 (FGSGTRLTVLG);

[0638] Or for each FR sequence, comprising an amino acid sequence having the following:

[0639] (i) is at least 50% identical thereto, and / or

[0640] (ii) has one, two, three, four or five amino acid substitutions relative thereto.

[0641] The specific binding molecule may comprise framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0642] VHFR1 comprises the sequence set forth in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0643] VHFR2 comprises the sequence set forth in SEQ ID NO: 448 (WVRQAPGKAPEWVA);

[0644] VHFR3 comprises the sequence set forth in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0645] VHFR4 comprises the sequence shown in SEQ ID NO: 450 (WGPGLLVTVSS);

[0646] VLFR1 comprises the sequence shown in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC);

[0647] VLFR2 comprises the sequence set forth in SEQ ID NO:452 (WFQQLPGSGLRTIIV);

[0648] VLFR3 comprises the sequence set forth in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0649] VLFR4 comprises the sequence shown in SEQ ID NO: 454 (FGSGTRLTVLG);

[0650] Or for each FR sequence, comprising an amino acid sequence having the following:

[0651] (i) is at least 50% identical thereto, and / or

[0652] (ii) has one, two, three, four or five amino acid substitutions relative thereto,

[0653] 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. A specific binding molecule comprising a FR that is 100% identical to the above FR is referred to herein as "S1G2."

[0654] The specific binding molecule may comprise:

[0655] (a) Framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0656] VHFR1 comprises the sequence set forth in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0657] VHFR2 comprises the sequence set forth in SEQ ID NO: 448 (WVRQAPGKAPEWVA);

[0658] VHFR3 comprises the sequence set forth in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0659] VHFR4 comprises the sequence shown in SEQ ID NO: 450 (WGPGLLVTVSS);

[0660] VLFR1 comprises the sequence shown in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC);

[0661] VLFR2 comprises the sequence set forth in SEQ ID NO:452 (WFQQLPGSGLRTIIV);

[0662] VLFR3 comprises the sequence set forth in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0663] VLFR4 comprises the sequence shown in SEQ ID NO: 454 (FGSGTRLTVLG);

[0664] Or for each FR sequence, comprising an amino acid sequence having the following:

[0665] (i) is at least 50% identical thereto, and / or

[0666] (ii) has one, two, three, four or five amino acid substitutions therewith; and

[0667] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0668] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0669] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0670] VHCDR3 comprises the sequence shown in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0671] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0672] VLCDR2 comprises the sequence set forth in SEQ ID NO:70 (ASDGRPS); and

[0673] VLCDR3 comprises the sequence shown in SEQ ID NO: 73 (GSSDRTPYTGV).

[0674] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0675] (i) is at least 85% identical thereto, and / or

[0676] (ii) has one, two or three amino acid substitutions relative thereto,

[0677] 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. A specific binding molecule comprising FRs and CDRs that are 100% identical to the above FRs and CDRs is referred to herein as "S1G2."

[0678] The specific binding molecule may comprise:

[0679] (a) Framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0680] VHFR1 comprises the sequence set forth in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0681] VHFR2 comprises the sequence set forth in SEQ ID NO: 448 (WVRQAPGKAPEWVA);

[0682] VHFR3 comprises the sequence set forth in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0683] VHFR4 comprises the sequence shown in SEQ ID NO: 450 (WGPGLLVTVSS);

[0684] VLFR1 comprises the sequence shown in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC);

[0685] VLFR2 comprises the sequence set forth in SEQ ID NO:452 (WFQQLPGSGLRTIIV);

[0686] VLFR3 comprises the sequence set forth in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0687] VLFR4 comprises the sequence shown in SEQ ID NO: 454 (FGSGTRLTVLG);

[0688] Or for each FR sequence, comprising an amino acid sequence having the following:

[0689] (i) is at least 50% identical thereto, and / or

[0690] (ii) has one, two, three, four or five amino acid substitutions therewith; and

[0691] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0692] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0693] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0694] VHCDR3 comprises the sequence shown in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0695] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0696] VLCDR2 comprises the sequence set forth in SEQ ID NO:70 (ASDGRPS); and

[0697] VLCDR3 comprises the sequence shown in SEQ ID NO: 73 (GSSDRTPYTGV).

[0698] 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. A specific binding molecule comprising FRs and CDRs that are 100% identical to the above FRs and CDRs is referred to herein as "S1G2."

[0699] The specific binding molecule may comprise the following, or a humanized variant thereof:

[0700] (a) a VH domain comprising SEQ ID NO: 455

[0701] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVSS); and / or

[0702] (b) a VL domain comprising SEQ ID NO: 456

[0703] The sequence shown is (QAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG).

[0704] The specific binding molecule may comprise the following, or a humanized variant thereof:

[0705] (a) a heavy chain comprising SEQ ID NO: 457

[0706] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYW GPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPC PPCKCPAPNLLGGPSVFIFPPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPK and / or

[0707] (b) a light chain comprising SEQ ID NO: 458

[0708] (QAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS).

[0709] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0710] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0711] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0712] VHCDR3 comprises the sequence shown in SEQ ID NO: 55 (SYRTDGLAYGYVQAIDY);

[0713] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0714] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0715] VLCDR3 comprises the sequence set forth in SEQ ID NO:74 (GSSDRTQYTGV);

[0716] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0717] (i) is at least 85% identical thereto, and / or

[0718] (ii) has one, two or three amino acid substitutions relative thereto,

[0719] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "S1B1".

[0720] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0721] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0722] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0723] VHCDR3 comprises the sequence shown in SEQ ID NO: 55 (SYRTDGLAYGYVQAIDY);

[0724] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0725] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0726] VLCDR3 comprises the sequence shown in SEQ ID NO: 74 (GSSDRTQYTGV).

[0727] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0728] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0729] VHCDR2 comprises the sequence shown in SEQ ID NO:48 (GIDSDGEEGYNPALNS);

[0730] VHCDR3 comprises the sequence shown in SEQ ID NO: 57 (TYRTDGYAYGYVQAIDY);

[0731] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0732] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0733] VLCDR3 comprises the sequence set forth in SEQ ID NO:74 (GSSDRTQYTGV);

[0734] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0735] (i) is at least 85% identical thereto, and / or

[0736] (ii) has one, two or three amino acid substitutions relative thereto,

[0737] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "S1D9".

[0738] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0739] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0740] VHCDR2 comprises the sequence shown in SEQ ID NO:48 (GIDSDGEEGYNPALNS);

[0741] VHCDR3 comprises the sequence shown in SEQ ID NO: 57 (TYRTDGYAYGYVQAIDY);

[0742] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0743] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0744] VLCDR3 comprises the sequence shown in SEQ ID NO: 74 (GSSDRTQYTGV).

[0745] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0746] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0747] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0748] VHCDR3 comprises the sequence shown in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0749] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0750] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0751] VLCDR3 comprises the sequence set forth in SEQ ID NO:74 (GSSDRTQYTGV);

[0752] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0753] (i) is at least 85% identical thereto, and / or

[0754] (ii) has one, two or three amino acid substitutions relative thereto,

[0755] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "S1F4."

[0756] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0757] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0758] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0759] VHCDR3 comprises the sequence shown in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0760] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0761] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0762] VLCDR3 comprises the sequence shown in SEQ ID NO: 74 (GSSDRTQYTGV).

[0763] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0764] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0765] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0766] VHCDR3 comprises the sequence shown in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0767] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0768] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0769] VLCDR3 comprises the sequence set forth in SEQ ID NO:74 (GSSDRTQYTGV);

[0770] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0771] (i) is at least 85% identical thereto, and / or

[0772] (ii) has one, two or three amino acid substitutions relative thereto,

[0773] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "S1G10."

[0774] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0775] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0776] VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0777] VHCDR3 comprises the sequence shown in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0778] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0779] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0780] VLCDR3 comprises the sequence shown in SEQ ID NO: 74 (GSSDRTQYTGV).

[0781] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0782] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0783] VHCDR2 comprises the sequence shown in SEQ ID NO:51 (GIDTDGEEGYNPALKS);

[0784] VHCDR3 comprises the sequence shown in SEQ ID NO:60 (TYRTDGFAYGYVQAIDY);

[0785] VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0786] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0787] VLCDR3 comprises the sequence set forth in SEQ ID NO:74 (GSSDRTQYTGV);

[0788] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0789] (i) is at least 85% identical thereto, and / or

[0790] (ii) has one, two or three amino acid substitutions relative thereto,

[0791] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "S2C6".

[0792] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0793] VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG);

[0794] VHCDR2 comprises the sequence shown in SEQ ID NO:51 (GIDTDGEEGYNPALKS);

[0795] VHCDR3 comprises the sequence set forth in SEQ ID NO:60 (TYRTDGFAYGYVQAIDY); VLCDR1 comprises the sequence set forth in SEQ ID NO:63 (SGSFIGISSVG);

[0796] VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0797] VLCDR3 comprises the sequence shown in SEQ ID NO: 74 (GSSDRTQYTGV).

[0798]

[0799]

[0800]

[0801] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0802] VHCDR1 includes the VHCDR1 amino acid sequence shown in Table 2;

[0803] VHCDR2 includes the VHCDR2 amino acid sequence shown in Table 2;

[0804] VHCDR3 includes the VHCDR3 amino acid sequence shown in Table 2;

[0805] VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 2;

[0806] VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 2; and

[0807] VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 2;

[0808] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0809] (i) is at least 85% identical thereto, and / or

[0810] (ii) has one, two or three amino acid substitutions relative thereto,

[0811] 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.

[0812] The specific binding molecule can be expressed with a K of less than about 500 pM. D Binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367 to 379 of SEQ ID NO: 1. DThe K may be less than about 400 pM, less than about 300 pM, or less than about 200 pM. D Preferably, it can be used in combination with SEQ ID NO: 1 or SEQ ID NO: 5. K combined with SEQ ID NO: 1 D It can be from about 100 pM to about 200 pM. K binding to SEQ ID NO: 1 D Can be about 140 pM or 170 pM, optionally wherein the specific binding molecule comprises the CDRs of S1G2. K binding to SEQ ID NO: 5 D It can be from about 400 pM to about 500 pM. K binding to SEQ ID NO: 5 D It may be about 447 pM, optionally wherein the specific binding molecule comprises the CDRs of S1G2.

[0813] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 81, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 81. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 81. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 81, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 81. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 81.

[0814] SEQ ID NO:81 (S1G2 amino acid sequence)

[0815] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG

[0816] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 412, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 412. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 412. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 412, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 412. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 412.

[0817] SEQ ID NO:412 (S1B1 amino acid sequence)

[0818] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCVRSYRTDGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTVIVASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0819] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 413, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 413. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 413. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 413, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 413. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 413.

[0820] SEQ ID NO:413 (S1D9 amino acid sequence)

[0821] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDSDGEEGYNPALNSRLSITRDTSKNQVSLSLSRVTSEDTAVYYCGRTYRTDGYAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDRVMLTQPPSVSGSPGQTVSITCSGSFIGISSVGWFQQLPGSGLRTVIFASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLS

[0822] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 414, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 414. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 414. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 414, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 414. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 414.

[0823] SEQ ID NO:414 (S1F4 amino acid sequence)

[0824] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCVRSYRADGLAYGYVQAIDYWGPGLLLTIS SEGKSSGASGESKVDDQAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTVIVASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0825] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 415, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 415. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 415. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 415, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 415. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 415.

[0826] SEQ ID NO:415 (S1G10 amino acid sequence)

[0827] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVLTQPSSMSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0828] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 416, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 416. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 416. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 416, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 416. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 416.

[0829] SEQ ID NO:416 (S2C6 amino acid sequence)

[0830] QVQLQESGPSLVKPSQTLSLTCTVSGFSLISNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALKSQYAASDPDTSKSQVSLSLSSVTSEDTAVYYCGRTYRTDGFAYGYVQAIDYWGPGLLLTIS SEGKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0831] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 337 to 368 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN).

[0832] The epitope may be located within the amino acid sequence comprising residues 337 to 368 of SEQ ID NO: 1. The epitope may bind to a CDR of the specific binding molecule referred to herein as "NS2A3."

[0833] The epitope may comprise the amino acid sequence of SEQ ID NO: 82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN). The epitope may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN).

[0834] The epitope may consist of the amino acid sequence of SEQ ID NO: 82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN). The epitope may consist of an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN).

[0835] The specific binding molecule can 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 can comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0836] VHCDR1 comprises the sequence shown in SEQ ID NO: 83 (SYSVY);

[0837] VHCDR2 comprises the sequence set forth in SEQ ID NO: 84 (IMYASGRVDYNPALKS);

[0838] VHCDR3 comprises the sequence shown in SEQ ID NO:85 (GIEN / D);

[0839] VLCDR1 comprises the sequence shown in SEQ ID NO:86 (RTS / NQ / ES / NV / IN / G / DN / SY / GLS / A);

[0840] VLCDR2 comprises the sequence shown in SEQ ID NO:87 (YATYLY / HT);

[0841] VLCDR3 comprises the sequence shown in SEQ ID NO:88 (LQYD / G / ES / TTPLA / T);

[0842] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0843] (i) is at least 85% identical thereto, and / or

[0844] (ii) has one, two or three amino acid substitutions relative thereto.

[0845] The sequence identity is at least about 85% sequence identity, and thus 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% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0846] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0847] VHCDR1 comprises the sequence shown in SEQ ID NO: 83 (SYSVY);

[0848] VHCDR2 comprises the sequence set forth in SEQ ID NO: 84 (IMYASGRVDYNPALKS);

[0849] VHCDR3 comprises the sequence shown in SEQ ID NO:89 (GIEN) or SEQ ID NO:90 (GIED);

[0850] 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);

[0851] VLCDR2 comprises the sequence shown in SEQ ID NO:95 (YATRLYT) or SEQ ID NO:96 (YATRLHT);

[0852] VLCDR3 comprises 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);

[0853] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0854] (i) is at least 85% identical thereto, and / or

[0855] (ii) has one, two or three amino acid substitutions relative thereto,

[0856] 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.

[0857] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0858] VHCDR1 comprises the sequence shown in SEQ ID NO: 83 (SYSVY);

[0859] VHCDR2 comprises the sequence set forth in SEQ ID NO: 84 (IMYASGRVDYNPALKS);

[0860] VHCDR3 comprises the sequence shown in SEQ ID NO:89 (GIEN);

[0861] VLCDR1 comprises the sequence shown in SEQ ID NO:91 (RTSQSVNNYLS);

[0862] VLCDR2 comprises the sequence shown in SEQ ID NO:95 (YATRLYT);

[0863] VLCDR3 comprises the sequence shown in SEQ ID NO:97 (LQYDSTPLA);

[0864] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0865] (i) is at least 85% identical thereto, and / or

[0866] (ii) has one, two or three amino acid substitutions relative thereto,

[0867] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "NS2A3".

[0868] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0869] VHCDR1 comprises the sequence shown in SEQ ID NO: 83 (SYSVY);

[0870] VHCDR2 comprises the sequence set forth in SEQ ID NO: 84 (IMYASGRVDYNPALKS);

[0871] VHCDR3 comprises the sequence shown in SEQ ID NO:89 (GIEN);

[0872] VLCDR1 comprises the sequence shown in SEQ ID NO:91 (RTSQSVNNYLS);

[0873] VLCDR2 comprises the sequence set forth in SEQ ID NO:95 (YATRLYT); and

[0874] VLCDR3 comprises the sequence shown in SEQ ID NO: 97 (LQYDSTPLA).

[0875]

[0876] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0877] VHCDR1 includes the VHCDR1 amino acid sequence shown in Table 3;

[0878] VHCDR2 includes the VHCDR2 amino acid sequence shown in Table 3;

[0879] VHCDR3 includes the VHCDR3 amino acid sequence shown in Table 3;

[0880] VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 3;

[0881] VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 3; and

[0882] VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 3;

[0883] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0884] (i) is at least 85% identical thereto, and / or

[0885] (ii) has one, two or three amino acid substitutions relative thereto,

[0886] 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.

[0887] The specific binding molecule can bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 368 of SEQ ID NO: 1, wherein D Less than 25 nM, preferably less than 20 nM, 15 nM or 10 nM. D It can be preferably used in combination with SEQ ID NO: 1 or SEQ ID NO: 5.

[0888] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 369 to 390 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 101 (KKIETHKLTFRENAKAKTDHGA).

[0889] The epitope may be located within the amino acid sequence comprising residues 369 to 390 of SEQ ID NO: 1. The epitope may bind to a CDR of the specific binding molecule referred to herein as "NS4E3."

[0890] The epitope may comprise the amino acid sequence of SEQ ID NO: 101 (KKIETHKLTFRENAKAKTDHGA). The epitope may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 101 (KKIETHKLTFRENAKAKTDHGA).

[0891] The epitope may consist of the amino acid sequence of SEQ ID NO: 101 (KKIETHKLTFRENAKAKTDHGA). The epitope may consist of an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 101 (KKIETHKLTFRENAKAKTDHGA).

[0892] The specific binding molecule can 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 can comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0893] VHCDR1 comprises the sequence shown in SEQ ID NO: 102 (RESIA);

[0894] VHCDR2 comprises the sequence shown in SEQ ID NO: 103 (GVGIDGTSYYSPALKS);

[0895] VHCDR3 comprises the sequence shown in SEQ ID NO: 104 (NYIDFEY);

[0896] VLCDR1 comprises the sequence shown in SEQ ID NO: 105 (SGSS / N / YS / N / -N / -V / -G / IY / S / A / GE / G / SD / N / TY / G / DVN / S / G);

[0897] VLCDR2 comprises the sequence shown in SEQ ID NO: 106 (G / RT / N / ST / SN / T / RRP / AS); and

[0898] VLCDR3 comprises the sequence set forth in SEQ ID NO: 107 (L / A / GSYDR / T / G / SS / TG / NS / R / -N / G / S / IF / I / V);

[0899] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0900] (i) is at least 85% identical thereto, and / or

[0901] (ii) has one, two or three amino acid substitutions relative thereto.

[0902] The sequence identity is at least about 85% sequence identity, and thus 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% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0903] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0904] VHCDR1 comprises the sequence shown in SEQ ID NO: 102 (RESIA);

[0905] VHCDR2 comprises the sequence shown in SEQ ID NO: 103 (GVGIDGTSYYSPALKS);

[0906] VHCDR3 comprises the sequence shown in SEQ ID NO: 104 (NYIDFEY);

[0907] VLCDR1 comprises the sequence set forth in SEQ ID NO: 108 (SGSSSNVGYEDYVN), SEQ ID NO: 109 (SGSNIAGNGVG), SEQ ID NO: 110 (SGSSNNVGSGDYVS), or SEQ ID NO: 111 (SGSYIGSTDVG);

[0908] VLCDR2 comprises the sequence shown in SEQ ID NO: 112 (GTTNRPS), SEQ ID NO: 113 (GSTRRPS), SEQ ID NO: 114 (RNSNRPS), or SEQ ID NO: 115 (RTTTRAS); and

[0909] VLCDR3 comprises 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);

[0910] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0911] (i) is at least 85% identical thereto, and / or

[0912] (ii) has one, two or three amino acid substitutions relative thereto,

[0913] 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.

[0914] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0915] VHCDR1 comprises the sequence shown in SEQ ID NO: 102 (RESIA);

[0916] VHCDR2 comprises the sequence shown in SEQ ID NO: 103 (GVGIDGTSYYSPALKS);

[0917] VHCDR3 comprises the sequence shown in SEQ ID NO: 104 (NYIDFEY);

[0918] VLCDR1 comprises the sequence shown in SEQ ID NO: 108 (SGSSSNVGYEDYVN);

[0919] VLCDR2 comprises the sequence set forth in SEQ ID NO: 112 (GTTNRPS); and

[0920] VLCDR3 comprises the sequence shown in SEQ ID NO: 116 (LSYDRSGSNF);

[0921] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0922] (i) is at least 85% identical thereto, and / or

[0923] (ii) has one, two or three amino acid substitutions relative thereto,

[0924] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "NS4E4."

[0925] The specific binding molecule may comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0926] VHCDR1 comprises the sequence shown in SEQ ID NO: 102 (RESIA);

[0927] VHCDR2 comprises the sequence shown in SEQ ID NO: 103 (GVGIDGTSYYSPALKS);

[0928] VHCDR3 comprises the sequence shown in SEQ ID NO: 104 (NYIDFEY);

[0929] VLCDR1 comprises the sequence shown in SEQ ID NO: 108 (SGSSSNVGYEDYVN);

[0930] VLCDR2 comprises the sequence set forth in SEQ ID NO: 112 (GTTNRPS); and

[0931] VLCDR3 comprises the sequence shown in SEQ ID NO: 116 (LSYDRSGSNF).

[0932]

[0933] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0934] VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 4;

[0935] VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 4;

[0936] VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 4;

[0937] VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 4;

[0938] VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 4; and

[0939] VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 4;

[0940] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0941] (i) is at least 85% identical thereto, and / or

[0942] (ii) has one, two or three amino acid substitutions relative thereto,

[0943] 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.

[0944] The specific binding molecule can bind to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 369 to 390 of SEQ ID NO: 1, wherein D Less than 25 nM, preferably less than 20 nM, 15 nM or 10 nM. D It can be preferably used in combination with SEQ ID NO: 1 or SEQ ID NO: 5.

[0945] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL).

[0946] The epitope may be located within the amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. The epitope may bind to a CDR of the specific binding molecule referred to herein as "412E10."

[0947] The epitope may comprise the amino acid sequence of SEQ ID NO: 120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL). The epitope may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL).

[0948] The epitope may consist of the amino acid sequence of SEQ ID NO: 120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL). The epitope may consist of an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL).

[0949] The specific binding molecule can 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 can comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0950] VHCDR1 comprises the sequence shown in SEQ ID NO: 121 (S / ND / YS / G / AV / LA / G);

[0951] VHCDR2 comprises the sequence set forth in SEQ ID NO: 122 (A / NS / IG / Y / WS / RS / GGN / S / RK / T / IY / EYNPALKS);

[0952] VHCDR3 comprises the sequence shown in SEQ ID NO: 123 (GI / GI / VA / GG / SVDV) or SEQ ID NO: 124 (SGGD);

[0953] VLCDR1 comprises the sequence shown in SEQ ID NO: 125 (SGS / GS / NNV / IGY / RGN / D / TY / FVG / D);

[0954] VLCDR2 comprises the sequence shown in SEQ ID NO: 126 (GT / AA / D / TI / S / RRA / PS / P); and

[0955] VLCDR3 comprises the sequence shown in SEQ ID NO: 127 (AS / TYQ / DS / Y / RN / SY / D / N / EA / G / D / S- / G / M / V- / IF / V / I);

[0956] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0957] (i) is at least 85% identical thereto, and / or

[0958] (ii) has one, two or three amino acid substitutions relative thereto.

[0959] The sequence identity is at least about 85% sequence identity, and thus 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% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0960] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0961] VHCDR1 comprises the sequence shown in SEQ ID NO: 128 (SDSVA), SEQ ID NO: 129 (NYGVG), or SEQ ID NO: 130 (SYALG);

[0962] VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS), SEQ ID NO: 132 (NIWRGGRIEYNPALKS), or SEQ ID NO: 133 (NIYSGGSTYYNPALKS);

[0963] VHCDR3 comprises the sequence shown in SEQ ID NO: 134 (GIIAGVDV), SEQ ID NO: 135 (GGVGSVDV), or SEQ ID NO: 124 (SGGD);

[0964] VLCDR1 comprises the sequences shown in SEQ ID NO:39 (SGSSSNVGYGNYVG), SEQ ID NO:137 (SGGRNNIGRGTFVD), and SEQ ID NO:138 (SGSSSNVGYGDYVG);

[0965] 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

[0966] VLCDR3 comprises the sequence shown in SEQ ID NO: 143 (ASYQSNYAF), SEQ ID NO: 144 (ASYDRSESVV), SEQ ID NO: 145 (ASYDSSDGGV), or SEQ ID NO: 146 (ATYDYSNDMII);

[0967] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0968] (i) is at least 85% identical thereto, and / or

[0969] (ii) has one, two or three amino acid substitutions relative thereto,

[0970] 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.

[0971] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0972] VHCDR1 comprises the sequence shown in SEQ ID NO: 128 (SDSVA);

[0973] VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[0974] VHCDR3 comprises the sequence shown in SEQ ID NO: 134 (GIIAGVDV);

[0975] VLCDR1 comprises the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[0976] VLCDR2 comprises the sequence set forth in SEQ ID NO: 139 (GTAIRAS); and

[0977] VLCDR3 comprises the sequence shown in SEQ ID NO: 143 (ASYQSNYAF);

[0978] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[0979] (i) is at least 85% identical thereto, and / or

[0980] (ii) has one, two or three amino acid substitutions relative thereto,

[0981] The specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence consisting of residues 412 to 441 of SEQ ID NO: 1. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "412E10."

[0982] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0983] VHCDR1 comprises the sequence shown in SEQ ID NO: 128 (SDSVA);

[0984] VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[0985] VHCDR3 comprises the sequence shown in SEQ ID NO: 134 (GIIAGVDV);

[0986] VLCDR1 comprises the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[0987] VLCDR2 comprises the sequence set forth in SEQ ID NO: 139 (GTAIRAS); and

[0988] VLCDR3 comprises the sequence shown in SEQ ID NO: 143 (ASYQSNYAF).

[0989] The specific binding molecule may comprise framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[0990] VHFR1 comprises the sequence set forth in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[0991] VHFR2 comprises the sequence set forth in SEQ ID NO: 460 (WVRQAPGKVPEWLG);

[0992] VHFR3 comprises the sequence set forth in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[0993] VHFR4 comprises the sequence set forth in SEQ ID NO:462 (WGRGLLVTVSS);

[0994] VLFR1 comprises the sequence shown in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC);

[0995] VLFR2 comprises the sequence set forth in SEQ ID NO: 464 (WYQQVPGSAPKLLIY);

[0996] VLFR3 comprises the sequence set forth in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[0997] VLFR4 comprises the sequence set forth in SEQ ID NO: 466 (FGSGTRLTVLG);

[0998] Or for each FR sequence, comprising an amino acid sequence having the following:

[0999] (i) is at least 50% identical thereto, and / or

[1000] (ii) has one, two, three, four or five amino acid substitutions relative thereto.

[1001] The specific binding molecule may comprise framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[1002] VHFR1 comprises the sequence set forth in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[1003] VHFR2 comprises the sequence set forth in SEQ ID NO: 460 (WVRQAPGKVPEWLG);

[1004] VHFR3 comprises the sequence set forth in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[1005] VHFR4 comprises the sequence set forth in SEQ ID NO:462 (WGRGLLVTVSS);

[1006] VLFR1 comprises the sequence shown in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC);

[1007] VLFR2 comprises the sequence set forth in SEQ ID NO: 464 (WYQQVPGSAPKLLIY);

[1008] VLFR3 comprises the sequence set forth in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[1009] VLFR4 comprises the sequence set forth in SEQ ID NO: 466 (FGSGTRLTVLG);

[1010] Or for each FR sequence, comprising an amino acid sequence having the following:

[1011] (i) is at least 50% identical thereto, and / or

[1012] (ii) has one, two, three, four or five amino acid substitutions relative thereto,

[1013] 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. The specific binding molecule comprising a FR having 100% identity to the above FR is referred to herein as "412E10".

[1014] The specific binding molecule may comprise:

[1015] (a) Framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[1016] VHFR1 comprises the sequence set forth in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[1017] VHFR2 comprises the sequence set forth in SEQ ID NO: 460 (WVRQAPGKVPEWLG);

[1018] VHFR3 comprises the sequence set forth in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[1019] VHFR4 comprises the sequence set forth in SEQ ID NO:462 (WGRGLLVTVSS);

[1020] VLFR1 comprises the sequence shown in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC);

[1021] VLFR2 comprises the sequence set forth in SEQ ID NO: 464 (WYQQVPGSAPKLLIY);

[1022] VLFR3 comprises the sequence set forth in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[1023] VLFR4 comprises the sequence set forth in SEQ ID NO: 466 (FGSGTRLTVLG);

[1024] Or for each FR sequence, comprising an amino acid sequence having the following:

[1025] (i) is at least 50% identical thereto, and / or

[1026] (ii) has one, two, three, four or five amino acid substitutions therewith; and

[1027] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1028] VHCDR1 comprises the sequence shown in SEQ ID NO: 128 (SDSVA);

[1029] VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[1030] VHCDR3 comprises the sequence shown in SEQ ID NO: 134 (GIIAGVDV);

[1031] VLCDR1 comprises the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[1032] VLCDR2 comprises the sequence set forth in SEQ ID NO: 139 (GTAIRAS); and

[1033] VLCDR3 comprises the sequence shown in SEQ ID NO: 143 (ASYQSNYAF);

[1034] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1035] (i) is at least 85% identical thereto, and / or

[1036] (ii) has one, two or three amino acid substitutions relative to

[1037] 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 that are 100% identical to the above FRs and CDRs is referred to herein as "412E10."

[1038] The specific binding molecule may comprise:

[1039] (a) Framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[1040] VHFR1 comprises the sequence set forth in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[1041] VHFR2 comprises the sequence set forth in SEQ ID NO: 460 (WVRQAPGKVPEWLG);

[1042] VHFR3 comprises the sequence set forth in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[1043] VHFR4 comprises the sequence set forth in SEQ ID NO:462 (WGRGLLVTVSS);

[1044] VLFR1 comprises the sequence shown in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC);

[1045] VLFR2 comprises the sequence set forth in SEQ ID NO: 464 (WYQQVPGSAPKLLIY);

[1046] VLFR3 comprises the sequence set forth in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[1047] VLFR4 comprises the sequence set forth in SEQ ID NO: 466 (FGSGTRLTVLG);

[1048] Or for each FR sequence, comprising an amino acid sequence having the following:

[1049] (i) is at least 50% identical thereto, and / or

[1050] (ii) has one, two, three, four or five amino acid substitutions therewith; and

[1051] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1052] VHCDR1 comprises the sequence shown in SEQ ID NO: 128 (SDSVA);

[1053] VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[1054] VHCDR3 comprises the sequence shown in SEQ ID NO: 134 (GIIAGVDV);

[1055] VLCDR1 comprises the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[1056] VLCDR2 comprises the sequence set forth in SEQ ID NO: 139 (GTAIRAS); and

[1057] VLCDR3 comprises the sequence shown in SEQ ID NO: 143 (ASYQSNYAF);

[1058] 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 that are 100% identical to the above FRs and CDRs is referred to herein as "412E10."

[1059] The specific binding molecule may comprise the following, or a humanized variant thereof:

[1060] (a) a VH domain comprising SEQ ID NO: 467

[1061] (QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVTVSS); and / or

[1062] (b) a VL domain comprising SEQ ID NO: 468

[1063] The sequence shown in (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLG).

[1064] The specific binding molecule may comprise the following, or a humanized variant thereof:

[1065] (a) a heavy chain comprising SEQ ID NO: 469

[1066] (QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVT VSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKC PAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSV RAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK); the sequence shown, and / or

[1067] (b) a light chain comprising SEQ ID NO: 470

[1068] The sequence shown in (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTI TDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEK SLSRADCS).

[1069] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1070] VHCDR1 comprises the sequence shown in SEQ ID NO: 128 (SDSVA);

[1071] VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[1072] VHCDR3 comprises the sequence shown in SEQ ID NO: 134 (GIIAGVDV);

[1073] VLCDR1 comprises the sequence shown in SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[1074] VLCDR2 comprises the sequence set forth in SEQ ID NO: 140 (GAASRAS); and

[1075] VLCDR3 comprises the sequence shown in SEQ ID NO: 145 (ASYDSSDGGV);

[1076] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1077] (i) is at least 85% identical thereto, and / or

[1078] (ii) has one, two or three amino acid substitutions relative thereto,

[1079] 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 that are 100% identical to the above CDRs is referred to herein as "412B9."

[1080] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1081] VHCDR1 comprises the sequence shown in SEQ ID NO: 128 (SDSVA);

[1082] VHCDR2 comprises the sequence set forth in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[1083] VHCDR3 comprises the sequence shown in SEQ ID NO: 134 (GIIAGVDV);

[1084] VLCDR1 comprises the sequence shown in SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[1085] VLCDR2 comprises the sequence set forth in SEQ ID NO: 140 (GAASRAS); and

[1086] VLCDR3 comprises the sequence shown in SEQ ID NO: 145 (ASYDSSDGGV).

[1087] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1088] VHCDR1 comprises the sequence shown in SEQ ID NO: 129 (NYGVG);

[1089] VHCDR2 comprises the sequence set forth in SEQ ID NO: 133 (NIYSGGSTYYNPALKS);

[1090] VHCDR3 comprises the sequence shown in SEQ ID NO: 135 (GGVGSVDV);

[1091] VLCDR1 comprises the sequence shown in SEQ ID NO: 137 (SGGRNNIGRGTFVD);

[1092] VLCDR2 comprises the sequence set forth in SEQ ID NO: 142 (GTDRRPP); and

[1093] VLCDR3 comprises the sequence shown in SEQ ID NO: 146 (ATYDYSNDMII);

[1094] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1095] (i) is at least 85% identical thereto, and / or

[1096] (ii) has one, two or three amino acid substitutions relative thereto,

[1097] 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 that are 100% identical to the above CDRs is referred to herein as "412E6."

[1098] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1099] VHCDR1 comprises the sequence shown in SEQ ID NO: 129 (NYGVG);

[1100] VHCDR2 comprises the sequence set forth in SEQ ID NO: 133 (NIYSGGSTYYNPALKS);

[1101] VHCDR3 comprises the sequence shown in SEQ ID NO: 135 (GGVGSVDV);

[1102] VLCDR1 comprises the sequence shown in SEQ ID NO: 137 (SGGRNNIGRGTFVD);

[1103] VLCDR2 comprises the sequence set forth in SEQ ID NO: 142 (GTDRRPP); and

[1104] VLCDR3 comprises the sequence shown in SEQ ID NO: 146 (ATYDYSNDMII).

[1105] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1106] VHCDR1 comprises the sequence shown in SEQ ID NO: 130 (SYALG);

[1107] VHCDR2 comprises the sequence shown in SEQ ID NO: 132 (NIWRGGRIEYNPALKS);

[1108] VHCDR3 comprises the sequence shown in SEQ ID NO: 124 (SGGD);

[1109] VLCDR1 comprises the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[1110] VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and

[1111] VLCDR3 comprises the sequence shown in SEQ ID NO: 144 (ASYDRSESVV);

[1112] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1113] (i) is at least 85% identical thereto, and / or

[1114] (ii) has one, two or three amino acid substitutions relative thereto,

[1115] 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 that are 100% identical to the above CDRs is referred to herein as "412G11."

[1116] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1117] VHCDR1 comprises the sequence shown in SEQ ID NO: 130 (SYALG);

[1118] VHCDR2 comprises the sequence shown in SEQ ID NO: 132 (NIWRGGRIEYNPALKS);

[1119] VHCDR3 comprises the sequence shown in SEQ ID NO: 124 (SGGD);

[1120] VLCDR1 comprises the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[1121] VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and

[1122] VLCDR3 comprises the sequence shown in SEQ ID NO: 144 (ASYDRSESVV).

[1123]

[1124] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1125] VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 5;

[1126] VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 5;

[1127] VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 5;

[1128] VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 5;

[1129] VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 5; and

[1130] VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 5;

[1131] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1132] (i) is at least 85% identical thereto, and / or

[1133] (ii) has one, two or three amino acid substitutions relative thereto,

[1134] 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.

[1135] The specific binding molecule can be expressed with a K of less than about 25 nM. D Binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 412 to 441 of SEQ ID NO: 1. D The K may be less than about 20 nM, less than about 15 nM, or less than about 10 nM. D It can be preferably used in combination with SEQ ID NO: 1 or SEQ ID NO: 120. K combined with SEQ ID NO: 1D The K binding to SEQ ID NO: 1 may be from about 1 nM to about 10 nM. D It may be about 3.16 nM or 9.0 nM, wherein the specific binding molecule optionally comprises the CDRs of 412E10.

[1136] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 147, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 147. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 147. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 147, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 147. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 147.

[1137] SEQ ID NO: 147 (412E10 amino acid sequence)

[1138] QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLG

[1139] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 417, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 417. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 417. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 417, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 417. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 417.

[1140] SEQ ID NO:417 (412B9 amino acid sequence)

[1141] QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVSVSSEGKSS GASGESKVDDQAVLTQPSSVSGALGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYGAASRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSSDGGVFGSGTRLTVLG

[1142] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 418, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 418. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 418. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 418, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 418. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 418.

[1143] SEQ ID NO:418 (412E6 amino acid sequence)

[1144] QVQLQESGPSLVKPSETLSLTCTVSGFSLTNYGVGWVRQAPGKALEWLGNIYSGGSTYYNPALKSRLSITRDTSKSQVSLSLNSVTLEDTAVYYCRGGGVGSVDVWGPGLLVTVSSEGKSS GASGESKVDDQAVLTQPPSVSGSPGQRVSITCSGGRNNIGRGTFVDWYQQLPGSGLKTVIYGTDRRPPGVPDRFSGSKTGNAATLTITSLQAEDEADYWCATYDYSNDMIILGSGTRLTVLG

[1145] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 434, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 434. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 434. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 434, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 434. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 434.

[1146] SEQ ID NO:434 (412G11 amino acid sequence)

[1147] QVRLQESGPSLVKPSQTLSLTCTVSGFSLTSYALGWVRQAPGRAPEWIGNIWRGGRIEYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCSRSGGDWGPGLLVTVSSEGKSSGA SGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGATSRASGVPDRFSGSRSENTATLTISSLQAEDEADYYCASYDRSESVVFGSGTRLTVLG

[1148] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 1 to 49 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ). Preferably, the epitope of the specific binding molecule is located within the amino acid sequence comprising residues 1 to 49 of SEQ ID NO: 1, and may be located within the amino acid sequence comprising residues 1 to 15 of SEQ ID NO: 1.

[1149] The epitope may be located within the amino acid sequence comprising residues 1 to 49 of SEQ ID NO: 1. The epitope may bind to a CDR of the specific binding molecule referred to herein as "3aG3."

[1150] The epitope may be located 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. The epitope may bind to the CDRs of the specific binding molecule referred to herein as "3bG4".

[1151] The epitope may comprise the amino acid sequence of SEQ ID NO: 148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ). The epitope may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ).

[1152] The epitope may consist of the amino acid sequence of SEQ ID NO: 148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ). The epitope may consist of an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ).

[1153] The specific binding molecule can 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 can comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1154] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1155] VHCDR2 comprises the sequence shown in SEQ ID NO: 150 (DIS / ASS / V / GGKA / K / VYA / S / GN / HPALKS);

[1156] VHCDR3 comprises the sequence shown in SEQ ID NO: 151 (CRDGGVS / TYGYDI / SDY);

[1157] VLCDR1 comprises the sequence shown in SEQ ID NO: 152 (SGSS / TS / GNI / VGG / S / YGN / DY / DL / VS / G);

[1158] VLCDR2 comprises the sequence shown in SEQ ID NO: 153 (GA / VTS / N / ER / LAS); and

[1159] VLCDR3 comprises the sequence shown in SEQ ID NO: 154 (A / GSF / YDT / S / DS / NSGGI / V);

[1160] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1161] (i) is at least 85% identical thereto, and / or

[1162] (ii) has one, two or three amino acid substitutions relative thereto.

[1163] The sequence identity is at least about 85% sequence identity, and thus 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% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[1164] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1165] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1166] 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);

[1167] VHCDR3 comprises the sequence shown in SEQ ID NO: 159 (CRDGGVSYGYDIDY), SEQ ID NO: 160 (CRDGGVSYGYDSDY), or SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1168] VLCDR1 comprises the sequence shown in SEQ ID NO: 163 (SGSSSNIGGGNYLS), SEQ ID NO: 138 (SGSSSNVGYGDYVG), SEQ ID NO: 165 (SGSSGNVGYGDYVS), or SEQ ID NO: 166 (SGSTSNVGSGNDVS);

[1169] 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

[1170] VLCDR3 comprises 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);

[1171] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1172] (i) is at least 85% identical thereto, and / or

[1173] (ii) has one, two or three amino acid substitutions relative thereto,

[1174] 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.

[1175] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1176] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1177] VHCDR2 comprises the sequence shown in SEQ ID NO: 155 (DISSSGKAYANPALKS);

[1178] VHCDR3 comprises the sequence shown in SEQ ID NO: 159 (CRDGGVSYGYDIDY);

[1179] VLCDR1 comprises the sequence shown in SEQ ID NO: 163 (SGSSSNIGGGNYLS);

[1180] VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and

[1181] VLCDR3 comprises the sequence shown in SEQ ID NO: 171 (ASFDTSSGGI);

[1182] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1183] (i) is at least 85% identical thereto, and / or

[1184] (ii) has one, two or three amino acid substitutions relative thereto,

[1185] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "3aG3".

[1186] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1187] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1188] VHCDR2 comprises the sequence shown in SEQ ID NO: 155 (DISSSGKAYANPALKS);

[1189] VHCDR3 comprises the sequence shown in SEQ ID NO: 159 (CRDGGVSYGYDIDY);

[1190] VLCDR1 comprises the sequence shown in SEQ ID NO: 163 (SGSSSNIGGGNYLS);

[1191] VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and

[1192] VLCDR3 comprises the sequence shown in SEQ ID NO: 171 (ASFDTSSGGI).

[1193] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1194] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1195] VHCDR2 comprises the sequence shown in SEQ ID NO: 156 (DISSGGKVYGHPALKS);

[1196] VHCDR3 comprises the sequence shown in SEQ ID NO: 160 (CRDGGVSYGYDSDY);

[1197] VLCDR1 comprises the sequence shown in SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[1198] VLCDR2 comprises the sequence set forth in SEQ ID NO: 168 (GVTERAS); and

[1199] VLCDR3 comprises the sequence shown in SEQ ID NO: 172 (ASYDDSSGGI);

[1200] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1201] (i) is at least 85% identical thereto, and / or

[1202] (ii) has one, two or three amino acid substitutions relative thereto,

[1203] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "3aD3".

[1204] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1205] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1206] VHCDR2 comprises the sequence shown in SEQ ID NO: 156 (DISSGGKVYGHPALKS);

[1207] VHCDR3 comprises the sequence shown in SEQ ID NO: 160 (CRDGGVSYGYDSDY);

[1208] VLCDR1 comprises the sequence shown in SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[1209] VLCDR2 comprises the sequence set forth in SEQ ID NO: 168 (GVTERAS); and

[1210] VLCDR3 comprises the sequence shown in SEQ ID NO: 172 (ASYDDSSGGI).

[1211] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1212] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1213] VHCDR2 comprises the sequence shown in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1214] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1215] VLCDR1 comprises the sequence shown in SEQ ID NO: 165 (SGSSGNVGYGDYVS);

[1216] VLCDR2 comprises the sequence set forth in SEQ ID NO: 169 (GATNLAS); and

[1217] VLCDR3 comprises the sequence shown in SEQ ID NO: 173 (ASYDSSSGGV);

[1218] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1219] (i) is at least 85% identical thereto, and / or

[1220] (ii) has one, two or three amino acid substitutions relative thereto,

[1221] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "3aH6."

[1222] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1223] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1224] VHCDR2 comprises the sequence shown in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1225] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1226] VLCDR1 comprises the sequence shown in SEQ ID NO: 165 (SGSSGNVGYGDYVS);

[1227] VLCDR2 comprises the sequence set forth in SEQ ID NO: 169 (GATNLAS); and

[1228] VLCDR3 comprises the sequence shown in SEQ ID NO: 173 (ASYDSSSGGV).

[1229] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1230] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1231] VHCDR2 comprises the sequence shown in SEQ ID NO: 158 (DIASSGKAYSNPALKS);

[1232] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1233] VLCDR1 comprises the sequence shown in SEQ ID NO: 166 (SGSTSNVGSGNDVS);

[1234] VLCDR2 comprises the sequence set forth in SEQ ID NO: 170 (GATNRAS); and

[1235] VLCDR3 comprises the sequence shown in SEQ ID NO: 174 (GSYDSNSGGI);

[1236] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1237] (i) is at least 85% identical thereto, and / or

[1238] (ii) has one, two or three amino acid substitutions relative thereto,

[1239] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "3bG4."

[1240] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1241] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1242] VHCDR2 comprises the sequence shown in SEQ ID NO: 158 (DIASSGKAYSNPALKS);

[1243] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1244] VLCDR1 comprises the sequence shown in SEQ ID NO: 166 (SGSTSNVGSGNDVS);

[1245] VLCDR2 comprises the sequence set forth in SEQ ID NO: 170 (GATNRAS); and

[1246] VLCDR3 comprises the sequence shown in SEQ ID NO: 174 (GSYDSNSGGI).

[1247] The specific binding molecule may comprise framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[1248] VHFR1 comprises the sequence set forth in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[1249] VHFR2 comprises the sequence set forth in SEQ ID NO: 472 (WVRQAPGKVPEWVG);

[1250] VHFR3 comprises the sequence set forth in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[1251] VHFR4 comprises the sequence set forth in SEQ ID NO: 474 (WGPGLLVTVSS);

[1252] VLFR1 comprises the sequence shown in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC);

[1253] VLFR2 comprises the sequence set forth in SEQ ID NO: 476 (WFQQVPGSAPKLLFY);

[1254] VLFR3 comprises the sequence set forth in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[1255] VLFR4 comprises the sequence shown in SEQ ID NO: 478 (FGSGTRLTVLG);

[1256] Or for each FR sequence, comprising an amino acid sequence having the following:

[1257] (i) is at least 50% identical thereto, and / or

[1258] (ii) has one, two, three, four or five amino acid substitutions relative thereto.

[1259] The specific binding molecule may comprise framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[1260] VHFR1 comprises the sequence set forth in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[1261] VHFR2 comprises the sequence set forth in SEQ ID NO: 472 (WVRQAPGKVPEWVG);

[1262] VHFR3 comprises the sequence set forth in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[1263] VHFR4 comprises the sequence set forth in SEQ ID NO: 474 (WGPGLLVTVSS);

[1264] VLFR1 comprises the sequence shown in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC);

[1265] VLFR2 comprises the sequence set forth in SEQ ID NO: 476 (WFQQVPGSAPKLLFY);

[1266] VLFR3 comprises the sequence set forth in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[1267] VLFR4 comprises the sequence shown in SEQ ID NO: 478 (FGSGTRLTVLG);

[1268] Or for each FR sequence, comprising an amino acid sequence having the following:

[1269] (i) is at least 50% identical thereto, and / or

[1270] (ii) has one, two, three, four or five amino acid substitutions relative thereto,

[1271] 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. A specific binding molecule comprising FRs that are 100% identical to the above FRs is referred to herein as "3bG4."

[1272] The specific binding molecule may comprise:

[1273] (a) Framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[1274] VHFR1 comprises the sequence set forth in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[1275] VHFR2 comprises the sequence set forth in SEQ ID NO: 472 (WVRQAPGKVPEWVG);

[1276] VHFR3 comprises the sequence set forth in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[1277] VHFR4 comprises the sequence set forth in SEQ ID NO: 474 (WGPGLLVTVSS);

[1278] VLFR1 comprises the sequence shown in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC);

[1279] VLFR2 comprises the sequence set forth in SEQ ID NO: 476 (WFQQVPGSAPKLLFY);

[1280] VLFR3 comprises the sequence set forth in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[1281] VLFR4 comprises the sequence shown in SEQ ID NO: 478 (FGSGTRLTVLG);

[1282] Or for each FR sequence, comprising an amino acid sequence having the following:

[1283] (i) is at least 50% identical thereto, and / or

[1284] (ii) has one, two, three, four or five amino acid substitutions therewith; and

[1285] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1286] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1287] VHCDR2 comprises the sequence shown in SEQ ID NO: 158 (DIASSGKAYSNPALKS);

[1288] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1289] VLCDR1 comprises the sequence shown in SEQ ID NO: 166 (SGSTSNVGSGNDVS);

[1290] VLCDR2 comprises the sequence set forth in SEQ ID NO: 170 (GATNRAS); and

[1291] VLCDR3 comprises the sequence shown in SEQ ID NO: 174 (GSYDSNSGGI);

[1292] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1293] (i) is at least 85% identical thereto, and / or

[1294] (ii) has one, two or three amino acid substitutions relative to

[1295] 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. A specific binding molecule comprising FRs and CDRs that are 100% identical to the above FRs and CDRs is referred to herein as "3bG4."

[1296] The specific binding molecule may comprise:

[1297] (a) Framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[1298] VHFR1 comprises the sequence set forth in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[1299] VHFR2 comprises the sequence set forth in SEQ ID NO: 472 (WVRQAPGKVPEWVG);

[1300] VHFR3 comprises the sequence set forth in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[1301] VHFR4 comprises the sequence set forth in SEQ ID NO: 474 (WGPGLLVTVSS);

[1302] VLFR1 comprises the sequence shown in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC);

[1303] VLFR2 comprises the sequence set forth in SEQ ID NO: 476 (WFQQVPGSAPKLLFY);

[1304] VLFR3 comprises the sequence set forth in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[1305] VLFR4 comprises the sequence shown in SEQ ID NO: 478 (FGSGTRLTVLG);

[1306] Or for each FR sequence, comprising an amino acid sequence having the following:

[1307] (i) is at least 50% identical thereto, and / or

[1308] (ii) has one, two, three, four or five amino acid substitutions therewith; and

[1309] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1310] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1311] VHCDR2 comprises the sequence shown in SEQ ID NO: 158 (DIASSGKAYSNPALKS);

[1312] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1313] VLCDR1 comprises the sequence shown in SEQ ID NO: 166 (SGSTSNVGSGNDVS);

[1314] VLCDR2 comprises the sequence set forth in SEQ ID NO: 170 (GATNRAS); and

[1315] VLCDR3 comprises the sequence shown in SEQ ID NO: 174 (GSYDSNSGGI);

[1316] 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. A specific binding molecule comprising FRs and CDRs that are 100% identical to the above FRs and CDRs is referred to herein as "3bG4."

[1317] The specific binding molecule may comprise the following, or a humanized variant thereof:

[1318] (a) a VH domain comprising SEQ ID NO: 479

[1319] (QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPGLLVTVSS); and / or

[1320] (b) a VL domain comprising SEQ ID NO: 480

[1321] The sequence shown in (QAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLG).

[1322] The specific binding molecule may comprise the following, or a humanized variant thereof:

[1323] (a) a heavy chain comprising SEQ ID NO: 481

[1324] (QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPG LLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPP CKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGS VRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK); the sequence shown, and / or

[1325] (b) a light chain comprising SEQ ID NO: 482

[1326] (QAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVE KSLSRADCS).

[1327]

[1328] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1329] VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 6;

[1330] VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 6;

[1331] VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 6;

[1332] VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 6;

[1333] VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 6; and

[1334] VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 6;

[1335] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1336] (i) is at least 85% identical thereto, and / or

[1337] (ii) has one, two or three amino acid substitutions relative thereto,

[1338] 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.

[1339] The specific binding molecule can be expressed with a K of less than about 25 nM. D Binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1 to 49 of SEQ ID NO: 1. D The K may be less than about 20 nM, less than about 15 nM, or less than about 10 nM. D It can be preferably used in combination with SEQ ID NO: 1 or SEQ ID NO: 148. K combined with SEQ ID NO: 1 D The K binding to SEQ ID NO: 1 may be from about 1 nM to about 20 nM. D The K binding to SEQ ID NO: 1 may be from about 1 nM to about 10 nM. D The specific binding molecule optionally comprises the CDRs of 3aD3. The K binding to SEQ ID NO: 1 may be about 19.1 nM. D Can be about 3.6 nM, wherein optionally the specific binding molecule comprises the CDRs of 3aH6. K binding to SEQ ID NO: 1 D Can be about 6.1 nM, wherein optionally the specific binding molecule comprises the CDRs of 3aG3. K binding to SEQ ID NO: 1 D It may be about 8.9 nM, wherein optionally the specific binding molecule comprises the CDRs of 3bG4.

[1340] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 422, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 422. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 422. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 422, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 422. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 422.

[1341] SEQ ID NO:422 (3aD3 amino acid sequence)

[1342] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNGVGWVRRAPGKVPEWVGDISSGGKVYGHPALKSRLSITRDTSKSQVSLSVSSVTSEDTAVYYCVRCRDGGVSYGYDSDYWGPGLLVTVSSEG KSSGASGESKVDDQAVVTQPSSVSKSLGQSVSITCSGSSSNVGYGDYVGWFQQVPGSAPKLLIYGVTERASGVPDRFSGSRSGNTATLTISSIQAEDEADYYCASYDDSSGGIFGSGTRLTVLG

[1343] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 423, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 423. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 423. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 423, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 423. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 423.

[1344] SEQ ID NO:423 (3aH6 amino acid sequence)

[1345] QVQLQESGPSLVKPSQTLSLTCTVSGGFSLSSNGVGWVRQAPGKVPEWLGDISSVGKKYANPALKSRLSFTRDTSKSQVSLSLSSVTTEDTAVYYCVKCRDGGVTYGYDIDYWGPGLLVTASSEG KSSGASGESKVDDQAVVTQPSSVSGSLGQSVSITCSGSSGNVGYGDYVSWFQQFHGSAPKLLIYGATNLASGVPARFSGSRSGNTATLTISSLHAEDEADYYCASYDSSSGGVFGSGTRLTVLG

[1346] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 424, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 424. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 424. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 424, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 424. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 424.

[1347] SEQ ID NO:424 (3aG3 amino acid sequence)

[1348] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNGVGWVRQAPGKVPEWVGDISSSGKAYANPALKSRLSITRDTAKTQVFLSLSSVTTEDTAVYYCVRCRDGGVSYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPPSVSGSPGQRVSITCGSSSSNIGGGNYLSWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASFDTSSGGIFGAGTRLTVLG

[1349] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 425, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 425. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 425. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 425, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 425. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 425.

[1350] SEQ ID NO:425 (3bG4 amino acid sequence)

[1351] QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLG

[1352] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 49 to 111 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT).

[1353] The epitope may be located within the amino acid sequence comprising residues 49 to 111 of SEQ ID NO: 1. The epitope may bind to a CDR of the specific binding molecule referred to herein as "3bF4."

[1354] The epitope may comprise the amino acid sequence of SEQ ID NO: 175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT). The epitope may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT).

[1355] The epitope may consist of the amino acid sequence of SEQ ID NO: 175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT). The epitope may consist of an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT).

[1356] The specific binding molecule can 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 can comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1357] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1358] VHCDR2 comprises the sequence set forth in SEQ ID NO: 176 (DI / KSSV / AGKK / TYA / GNPALKS);

[1359] VHCDR3 comprises the sequence shown in SEQ ID NO: 177 (CRDGGVTYGYDI / VDY);

[1360] VLCDR1 comprises the sequence shown in SEQ ID NO: 178 (SGSSSNVGL / YR / GN / DY / VT / S);

[1361] VLCDR2 comprises the sequence shown in SEQ ID NO: 179 (GA / TTS / TRAS); and

[1362] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1363] (i) is at least 85% identical thereto, and / or

[1364] (ii) has one, two or three amino acid substitutions relative thereto.

[1365] The sequence identity is at least about 85% sequence identity, and thus 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% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[1366] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1367] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1368] VHCDR2 comprises the sequence shown in SEQ ID NO: 157 (DISSVGKKYANPALKS) or SEQ ID NO: 182 (DKSSAGKTYGNPALKS);

[1369] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY) or SEQ ID NO: 184 (CRDGGVTYGYDVDY);

[1370] VLCDR1 comprises the sequence shown in SEQ ID NO: 185 (SGSSSNVGLRNYVT) or SEQ ID NO: 186 (SGSSSNVGYGDVVS);

[1371] VLCDR2 comprises the sequence shown in SEQ ID NO: 141 (GATSRAS) or SEQ ID NO: 188 (GTTTRAS); and

[1372] VLCDR3 comprises the sequence shown in SEQ ID NO: 189 (ASADTNDGGV) or SEQ ID NO: 190 (ASFDSDSGGI);

[1373] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1374] (i) is at least 85% identical thereto, and / or

[1375] (ii) has one, two or three amino acid substitutions relative thereto,

[1376] 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.

[1377] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1378] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1379] VHCDR2 comprises the sequence shown in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1380] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1381] VLCDR1 comprises the sequence shown in SEQ ID NO: 185 (SGSSSNVGLRNYVT);

[1382] VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and

[1383] VLCDR3 comprises the sequence shown in SEQ ID NO: 189 (ASADTNDGGV);

[1384] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1385] (i) is at least 85% identical thereto, and / or

[1386] (ii) has one, two or three amino acid substitutions relative thereto,

[1387] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "3bF4."

[1388] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1389] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1390] VHCDR2 comprises the sequence shown in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1391] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1392] VLCDR1 comprises the sequence shown in SEQ ID NO: 186 (SGSSSNVGYGDVVS);

[1393] VLCDR2 comprises the sequence set forth in SEQ ID NO: 141 (GATSRAS); and

[1394] VLCDR3 comprises the sequence shown in SEQ ID NO: 189 (ASADTNDGGV).

[1395] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1396] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1397] VHCDR2 comprises the sequence shown in SEQ ID NO: 182 (DKSSAGKTYGNPALKS);

[1398] VHCDR3 comprises the sequence shown in SEQ ID NO: 184 (CRDGGVTYGYDVDY);

[1399] VLCDR1 comprises the sequence shown in SEQ ID NO: 186 (SGSSSNVGYGDVVS);

[1400] VLCDR2 comprises the sequence set forth in SEQ ID NO: 188 (GTTTRAS); and

[1401] VLCDR3 comprises the sequence shown in SEQ ID NO: 190 (ASFDSDSGGI);

[1402] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1403] (i) is at least 85% identical thereto, and / or

[1404] (ii) has one, two or three amino acid substitutions relative thereto,

[1405] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "3aB7."

[1406] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1407] VHCDR1 comprises the sequence shown in SEQ ID NO: 149 (SNGVG);

[1408] VHCDR2 comprises the sequence shown in SEQ ID NO: 182 (DKSSAGKTYGNPALKS);

[1409] VHCDR3 comprises the sequence shown in SEQ ID NO: 184 (CRDGGVTYGYDVDY);

[1410] VLCDR1 comprises the sequence shown in SEQ ID NO: 186 (SGSSSNVGYGDVVS);

[1411] VLCDR2 comprises the sequence set forth in SEQ ID NO: 188 (GTTTRAS); and

[1412] VLCDR3 comprises the sequence shown in SEQ ID NO: 190 (ASFDSDSGGI).

[1413]

[1414] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1415] VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 7;

[1416] VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 7;

[1417] VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 7;

[1418] VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 7;

[1419] VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 7; and

[1420] VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 7;

[1421] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1422] (i) is at least 85% identical thereto, and / or

[1423] (ii) has one, two or three amino acid substitutions relative thereto,

[1424] 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.

[1425] The specific binding molecule can be expressed with a K of less than about 250 nM. D Binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 49 to 111 of SEQ ID NO: 1. D The K may be less than about 200 nM, less than about 150 nM, or less than about 100 nM. D It can be preferably used in combination with SEQ ID NO: 1 or SEQ ID NO: 175. K combined with SEQ ID NO: 1 D The K binding to SEQ ID NO: 1 may be from about 1 nM to about 20 nM. D The K binding to SEQ ID NO: 1 may be from about 50 nM to about 150 nM. D The specific binding molecule optionally comprises the CDRs of 3aB7. The K binding to SEQ ID NO: 1 may be about 69 nM. DIt may be about 140 nM, optionally wherein the specific binding molecule comprises the CDRs of 3bF4.

[1426] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 420, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 420. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 420. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 420, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 420. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 420.

[1427] SEQ ID NO:420 (3aB7 amino acid sequence)

[1428] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNGVGWVRQAPGKVPEWVGDKSSAGKTYGNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCVRCRDGGVTYGYDVDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSLGQSVSITCSGSSSNVGYGDVVSWFQQFPGSAPKLLIFGTTTRASGVPDRFSGSRSGNAATLTINSLQAEDEADYYCASFDSDSGGIAGSGTRLTVLG

[1429] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 421, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 421. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 421. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 421, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 421. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 421.

[1430] SEQ ID NO:421 (3bF4 amino acid sequence)

[1431] QVQLQESGPSLVKPSQTLSLTCTVSGGFSLSSNGVGWVRQAPGKVPEWLGDISSVGKKYANPALKSRLSFTRDTSKSQVSLSLSSVTTEDTAVYYCVKCRDGGVTYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSTGQTVSITCSGSSNVGLRNYVTWFQQVPGSAPKLLIYGATSRASGIPDRFSGSRSGNTATLIISSLQAEDEADYYCASADTNDGGVFGSGTRLTVLG

[1432] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 146 to 157 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 191 (GKTKIATPRGA).

[1433] The epitope may be located within the amino acid sequence comprising residues 147 to 157 of SEQ ID NO: 1. The epitope may bind to a CDR of the specific binding molecule referred to herein as "3aD6."

[1434] The epitope may comprise the amino acid sequence of SEQ ID NO: 191 (GKTKIATPRGA). The epitope may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 191 (GKTKIATPRGA).

[1435] The epitope may consist of the amino acid sequence of SEQ ID NO: 191 (GKTKIATPRGA). The epitope may consist of an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 191 (GKTKIATPRGA).

[1436] The specific binding molecule can 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 can comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1437] VHCDR1 comprises the sequence shown in SEQ ID NO: 192 (SNAVI / G);

[1438] VHCDR2 comprises the sequence shown in SEQ ID NO: 193 (LIDV / IDGDA / TAYD / NPALK / ES);

[1439] VHCDR3 comprises the sequence shown in SEQ ID NO: 194 (D / HYG / DS / KWGYV / AS / DD / SIDY);

[1440] VLCDR1 comprises the sequence shown in SEQ ID NO: 195 (SGSD / S- / S- / N- / VI / GG / YGA / DD / YVG);

[1441] VLCDR2 comprises the sequence shown in SEQ ID NO: 196 (DN / AD / TN / TRP / AS); and

[1442] VLCDR3 comprises the sequence shown in SEQ ID NO: 197 (G / AT / SYS / QG / NA / EN / RY / SGI / V);

[1443] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1444] (i) is at least 85% identical thereto, and / or

[1445] (ii) has one, two or three amino acid substitutions relative thereto.

[1446] The sequence identity is at least about 85% sequence identity, and thus 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% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[1447] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1448] VHCDR1 comprises the sequence shown in SEQ ID NO: 198 (SNAVI) or SEQ ID NO: 17 (SNAVG);

[1449] VHCDR2 comprises the sequence shown in SEQ ID NO: 200 (LIDVDGDAAYDPALKS) or SEQ ID NO: 201 (LIDIDGDTAYNPALES);

[1450] VHCDR3 comprises the sequence shown in SEQ ID NO: 202 (DYGSWGYVSDIDY) or SEQ ID NO: 203 (HYDKWGYADSIDY);

[1451] VLCDR1 comprises the sequence shown in SEQ ID NO: 204 (SGSDIGGADVG) or SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[1452] VLCDR2 comprises the sequence shown in SEQ ID NO: 206 (DNDNRPS) or SEQ ID NO: 207 (DATTRAS); and

[1453] VLCDR3 comprises the sequence shown in SEQ ID NO: 208 (GTYSGANYGI) or SEQ ID NO: 209 (ASYQNERSGV);

[1454] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1455] (i) is at least 85% identical thereto, and / or

[1456] (ii) has one, two or three amino acid substitutions relative thereto,

[1457] 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.

[1458] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1459] VHCDR1 comprises the sequence shown in SEQ ID NO: 198 (SNAVI);

[1460] VHCDR2 comprises the sequence shown in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[1461] VHCDR3 comprises the sequence shown in SEQ ID NO: 202 (DYGSWGYVSDIDY);

[1462] VLCDR1 comprises the sequence shown in SEQ ID NO: 204 (SGSDIGGADVG);

[1463] VLCDR2 comprises the sequence set forth in SEQ ID NO: 206 (DNDNRPS); and

[1464] VLCDR3 comprises the sequence shown in SEQ ID NO: 208 (GTYSGANYGI);

[1465] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1466] (i) is at least 85% identical thereto, and / or

[1467] (ii) has one, two or three amino acid substitutions relative thereto,

[1468] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "3aD6."

[1469] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1470] VHCDR1 comprises the sequence shown in SEQ ID NO: 198 (SNAVI);

[1471] VHCDR2 comprises the sequence shown in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[1472] VHCDR3 comprises the sequence shown in SEQ ID NO: 202 (DYGSWGYVSDIDY);

[1473] VLCDR1 comprises the sequence shown in SEQ ID NO: 204 (SGSDIGGADVG);

[1474] VLCDR2 comprises the sequence set forth in SEQ ID NO: 206 (DNDNRPS); and

[1475] VLCDR3 comprises the sequence shown in SEQ ID NO: 208 (GTYSGANYGI).

[1476] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1477] VHCDR1 comprises the sequence shown in SEQ ID NO: 17 (SNAVG);

[1478] VHCDR2 comprises the sequence shown in SEQ ID NO: 201 (LIDIDGDTAYNPALES);

[1479] VHCDR3 comprises the sequence shown in SEQ ID NO: 203 (HYDKWGYADSIDY);

[1480] VLCDR1 comprises the sequence shown in SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[1481] VLCDR2 comprises the sequence set forth in SEQ ID NO: 207 (DATTRAS); and

[1482] VLCDR3 comprises the sequence shown in SEQ ID NO: 209 (ASYQNERSGV);

[1483] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1484] (i) is at least 85% identical thereto, and / or

[1485] (ii) has one, two or three amino acid substitutions relative thereto,

[1486] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "3aA6".

[1487]

[1488] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1489] VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 8;

[1490] VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 8;

[1491] VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 8;

[1492] VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 8;

[1493] VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 8; and

[1494] VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 8;

[1495] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1496] (i) is at least 85% identical thereto, and / or

[1497] (ii) has one, two or three amino acid substitutions relative thereto,

[1498] 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.

[1499] The specific binding molecule can be expressed with a K of less than about 50 nM. D Binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 147 to 157 of SEQ ID NO: 1. D The K may be less than about 40 nM, less than about 30 nM, or less than about 20 nM. DIt can be preferably used in combination with SEQ ID NO: 1 or SEQ ID NO: 191. K combined with SEQ ID NO: 1 D The K binding to SEQ ID NO: 1 may be from about 10 nM to about 20 nM. D It may be about 16.5 nM, wherein the specific binding molecule optionally comprises the CDRs of 3aD6.

[1500] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 418, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 418. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 418. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 418, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 418. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 418.

[1501] SEQ ID NO:418 (3aA6 amino acid sequence)

[1502] QVRLQESGSSLVKPSQTLSLVCTVSGFPLTSNAVGWVRQAPGKAPEWLGLIDIDGDTAYNPALESRLSITRDTSKSQVSLSLSSVAIEDTAVYYCARHYDKWGYADSIDYWGPGLLVTVSSEG KSSGASGESKVDDQALLTQPSSVFGSLGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYDATTRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYQNERSGVFGSGTRLTVLG

[1503] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 419, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 419. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 419. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 419, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 419. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 419.

[1504] SEQ ID NO:419 (3aD6 amino acid sequence)

[1505] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSDIGGADVGWFQQVPGSGLRTLIYDNDNRPSGVPDRFSGSKSGNTATLTISSLQPEDEADYFCGTYSGANYGIFFSGTRLTVLG

[1506] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 379 to 391 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 221 (RENAKAKTDHGAE).

[1507] 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 located within the amino acid sequence comprising residues 379 to 391 of SEQ ID NO: 1. The epitope may bind to the CDRs of the specific binding molecule referred to herein as "E2E8". The key residue of the epitope may be residue 391 (E) (numbered according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 222 (XXXXXXXXXXXXE, wherein X is any amino acid). The epitope may comprise the amino acid sequence of SEQ ID NO: 8, wherein any one or more residues other than residue number 391 (E) are replaced by non-conservative amino acid substitutions (numbered according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 221, wherein any one or more residues except residue number 391 (E) are substituted with a conservative amino acid substitution (according to SEQ ID NO: 1 numbering). The epitope may comprise the amino acid sequence of SEQ ID NO: 221, wherein any one or more residues except residue number 391 (E) are substituted with a conservative amino acid substitution (according to SEQ ID NO: 1 numbering), and any one or more residues except residue number 391 (E) are substituted with a non-conservative amino acid substitution (according to SEQ ID NO: 1 numbering).

[1508] The epitope may comprise the amino acid sequence of SEQ ID NO: 221 (RENAKAKTDHGAE). The epitope may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 221 (RENAKAKTDHGAE).

[1509] The epitope may consist of the amino acid sequence of SEQ ID NO: 221 (RENAKAKTDHGAE). The epitope may consist of an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identical to SEQ ID NO: 221 (RENAKAKTDHGAE).

[1510] The specific binding molecule can 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 can comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1511] VHCDR1 comprises the sequence shown in SEQ ID NO: 223 (D / SR / WGVA);

[1512] VHCDR2 comprises the sequence shown in SEQ ID NO: 224 (TMRSGGT / GI / TD / EY / DNPALKS);

[1513] VHCDR3 comprises the sequence shown in SEQ ID NO: 225 (GYLSGD / I / VR / HYA);

[1514] VLCDR1 comprises the sequence set forth in SEQ ID NO: 226 (SGSR / SSD / NI / VGY / D / AGN / D / RYVS / G);

[1515] VLCDR2 comprises the sequence set forth in SEQ ID NO: 227 (D / S / GT / AN / R / TT / N / SRAS); and

[1516] VLCDR3 comprises the sequence set forth in SEQ ID NO: 228 (AN / SIDS / TS / GR / NS / NH / LL / I);

[1517] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1518] (i) is at least 85% identical thereto, and / or

[1519] (ii) has one, two or three amino acid substitutions relative thereto.

[1520] The sequence identity is at least about 85% sequence identity, and thus 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% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[1521] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1522] VHCDR1 comprises the sequence shown in SEQ ID NO: 229 (DRGVA), SEQ ID NO: 230 (DWGVA), or SEQ ID NO: 231 (SWGVA);

[1523] VHCDR2 comprises the sequence set forth in SEQ ID NO: 232 (TMRSGGTIDYNPALKS), SEQ ID NO: 233 (TMRSGGGTEYNPALKS), or SEQ ID NO: 234 (TMRSGGTTDDNPALKS);

[1524] VHCDR3 comprises the sequence set forth in SEQ ID NO: 235 (GYLSGDRYA), SEQ ID NO: 236 (GYLSGIHYA), or SEQ ID NO: 237 (GYLSGVHYA);

[1525] 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);

[1526] 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

[1527] VLCDR3 comprises the sequence shown in SEQ ID NO: 245 (ANIDSSRSHL), SEQ ID NO: 246 (ASIDSGNNLL), or SEQ ID NO: 247 (ASIDTSRSHI);

[1528] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1529] (i) is at least 85% identical thereto, and / or

[1530] (ii) has one, two or three amino acid substitutions relative thereto,

[1531] 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.

[1532] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1533] VHCDR1 comprises the sequence shown in SEQ ID NO: 229 (DRGVA);

[1534] VHCDR2 comprises the sequence set forth in SEQ ID NO: 232 (TMRSGGTIDYNPALKS);

[1535] VHCDR3 comprises the sequence set forth in SEQ ID NO: 235 (GYLSGDRYA);

[1536] VLCDR1 comprises the sequence shown in SEQ ID NO: 238 (SGSRSDIGYGNYVS);

[1537] VLCDR2 comprises the sequence set forth in SEQ ID NO: 242 (DTNTRAS); and

[1538] VLCDR3 comprises the sequence set forth in SEQ ID NO: 245 (ANIDSSRSHL);

[1539] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1540] (i) is at least 85% identical thereto, and / or

[1541] (ii) has one, two or three amino acid substitutions relative thereto,

[1542] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "E2E8".

[1543] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1544] VHCDR1 comprises the sequence shown in SEQ ID NO: 229 (DRGVA);

[1545] VHCDR2 comprises the sequence set forth in SEQ ID NO: 232 (TMRSGGTIDYNPALKS);

[1546] VHCDR3 comprises the sequence set forth in SEQ ID NO: 235 (GYLSGDRYA);

[1547] VLCDR1 comprises the sequence shown in SEQ ID NO: 238 (SGSRSDIGYGNYVS);

[1548] VLCDR2 comprises the sequence set forth in SEQ ID NO: 242 (DTNTRAS); and

[1549] VLCDR3 comprises the sequence shown in SEQ ID NO: 245 (ANIDSSRSHL).

[1550] The specific binding molecule may comprise framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[1551] VHFR1 comprises the sequence set forth in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1552] VHFR2 comprises the sequence set forth in SEQ ID NO: 484 (WVRQAPGKALEWVG);

[1553] VHFR3 comprises the sequence set forth in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1554] VHFR4 comprises the sequence set forth in SEQ ID NO: 486 (WGRGLLVTVSS);

[1555] VLFR1 comprises the sequence shown in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC);

[1556] VLFR2 comprises the sequence shown in SEQ ID NO: 488 (WFQQIPGSAPKLLIY);

[1557] VLFR3 comprises the sequence set forth in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1558] VLFR4 comprises the sequence shown in SEQ ID NO: 490 (FGSGTRLTVLG);

[1559] Or for each FR sequence, comprising an amino acid sequence having the following:

[1560] (i) is at least 50% identical thereto, and / or

[1561] (ii) has one, two, three, four or five amino acid substitutions relative thereto.

[1562] The specific binding molecule may comprise framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[1563] VHFR1 comprises the sequence set forth in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1564] VHFR2 comprises the sequence set forth in SEQ ID NO: 484 (WVRQAPGKALEWVG);

[1565] VHFR3 comprises the sequence set forth in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1566] VHFR4 comprises the sequence set forth in SEQ ID NO: 486 (WGRGLLVTVSS);

[1567] VLFR1 comprises the sequence shown in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC);

[1568] VLFR2 comprises the sequence shown in SEQ ID NO: 488 (WFQQIPGSAPKLLIY);

[1569] VLFR3 comprises the sequence set forth in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1570] VLFR4 comprises the sequence shown in SEQ ID NO: 490 (FGSGTRLTVLG);

[1571] Or for each FR sequence, comprising an amino acid sequence having the following:

[1572] (i) is at least 50% identical thereto, and / or

[1573] (ii) has one, two, three, four or five amino acid substitutions relative thereto,

[1574] 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 a FR that is 100% identical to the above FR is referred to herein as "E2E8."

[1575] The specific binding molecule may comprise:

[1576] (a) Framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[1577] VHFR1 comprises the sequence set forth in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1578] VHFR2 comprises the sequence set forth in SEQ ID NO: 484 (WVRQAPGKALEWVG);

[1579] VHFR3 comprises the sequence set forth in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1580] VHFR4 comprises the sequence set forth in SEQ ID NO: 486 (WGRGLLVTVSS);

[1581] VLFR1 comprises the sequence shown in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC);

[1582] VLFR2 comprises the sequence shown in SEQ ID NO: 488 (WFQQIPGSAPKLLIY);

[1583] VLFR3 comprises the sequence set forth in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1584] VLFR4 comprises the sequence shown in SEQ ID NO: 490 (FGSGTRLTVLG);

[1585] Or for each FR sequence, comprising an amino acid sequence having the following:

[1586] (i) is at least 50% identical thereto, and / or

[1587] (ii) has one, two, three, four or five amino acid substitutions therewith; and

[1588] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1589] VHCDR1 comprises the sequence shown in SEQ ID NO: 229 (DRGVA);

[1590] VHCDR2 comprises the sequence set forth in SEQ ID NO: 232 (TMRSGGTIDYNPALKS);

[1591] VHCDR3 comprises the sequence set forth in SEQ ID NO: 235 (GYLSGDRYA);

[1592] VLCDR1 comprises the sequence shown in SEQ ID NO: 238 (SGSRSDIGYGNYVS);

[1593] VLCDR2 comprises the sequence set forth in SEQ ID NO: 242 (DTNTRAS); and

[1594] VLCDR3 comprises the sequence set forth in SEQ ID NO: 245 (ANIDSSRSHL);

[1595] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1596] (i) is at least 85% identical thereto, and / or

[1597] (ii) has one, two or three amino acid substitutions relative to

[1598] 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 that are 100% identical to the above FRs and CDRs is referred to herein as "E2E8."

[1599] The specific binding molecule may comprise:

[1600] (a) Framework regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs comprises the following amino acid sequence:

[1601] VHFR1 comprises the sequence set forth in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1602] VHFR2 comprises the sequence set forth in SEQ ID NO: 484 (WVRQAPGKALEWVG);

[1603] VHFR3 comprises the sequence set forth in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1604] VHFR4 comprises the sequence set forth in SEQ ID NO: 486 (WGRGLLVTVSS);

[1605] VLFR1 comprises the sequence shown in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC);

[1606] VLFR2 comprises the sequence shown in SEQ ID NO: 488 (WFQQIPGSAPKLLIY);

[1607] VLFR3 comprises the sequence set forth in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1608] VLFR4 comprises the sequence shown in SEQ ID NO: 490 (FGSGTRLTVLG);

[1609] Or for each FR sequence, comprising an amino acid sequence having the following:

[1610] (i) is at least 50% identical thereto, and / or

[1611] (ii) has one, two, three, four or five amino acid substitutions therewith; and

[1612] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1613] VHCDR1 comprises the sequence shown in SEQ ID NO: 229 (DRGVA);

[1614] VHCDR2 comprises the sequence set forth in SEQ ID NO: 232 (TMRSGGTIDYNPALKS);

[1615] VHCDR3 comprises the sequence set forth in SEQ ID NO: 235 (GYLSGDRYA);

[1616] VLCDR1 comprises the sequence shown in SEQ ID NO: 238 (SGSRSDIGYGNYVS);

[1617] VLCDR2 comprises the sequence set forth in SEQ ID NO: 242 (DTNTRAS); and

[1618] VLCDR3 comprises the sequence set forth in SEQ ID NO: 245 (ANIDSSRSHL);

[1619] 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 that are 100% identical to the above FRs and CDRs is referred to herein as "E2E8."

[1620] The specific binding molecule may comprise the following, or a humanized variant thereof:

[1621] (a) a VH domain comprising SEQ ID NO: 491

[1622] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLVTVSS); and / or

[1623] (b) a VL domain comprising SEQ ID NO: 492

[1624] The sequence shown in (QAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLG).

[1625] The specific binding molecule may comprise the following, or a humanized variant thereof:

[1626] (a) a heavy chain comprising SEQ ID NO: 493

[1627] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLV TVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCK CPAPNLLGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSV RAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK); the sequence shown, and / or

[1628] (b) a light chain comprising SEQ ID NO: 494

[1629] The sequence shown in (QAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTI TDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEK SLSRADCS).

[1630] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1631] VHCDR1 comprises the sequence shown in SEQ ID NO: 230 (DWGVA);

[1632] VHCDR2 comprises the sequence set forth in SEQ ID NO: 234 (TMRSGGTTDDNPALKS);

[1633] VHCDR3 comprises the sequence set forth in SEQ ID NO: 237 (GYLSGVHYA);

[1634] VLCDR1 comprises the sequence shown in SEQ ID NO: 241 (SGSSSNVGDGRYVS);

[1635] VLCDR2 comprises the sequence set forth in SEQ ID NO: 243 (DTTSRAS); and

[1636] VLCDR3 comprises the sequence shown in SEQ ID NO: 246 (ASIDSGNNLL);

[1637] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1638] (i) is at least 85% identical thereto, and / or

[1639] (ii) has one, two or three amino acid substitutions relative thereto,

[1640] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "E1E8".

[1641] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1642] VHCDR1 comprises the sequence shown in SEQ ID NO: 230 (DWGVA);

[1643] VHCDR2 comprises the sequence set forth in SEQ ID NO: 234 (TMRSGGTTDDNPALKS);

[1644] VHCDR3 comprises the sequence set forth in SEQ ID NO: 237 (GYLSGVHYA);

[1645] VLCDR1 comprises the sequence shown in SEQ ID NO: 241 (SGSSSNVGDGRYVS);

[1646] VLCDR2 comprises the sequence set forth in SEQ ID NO: 243 (DTTSRAS); and

[1647] VLCDR3 comprises the sequence shown in SEQ ID NO: 246 (ASIDSGNNLL).

[1648] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1649] VHCDR1 comprises the sequence shown in SEQ ID NO: 230 (DWGVA);

[1650] VHCDR2 comprises the sequence set forth in SEQ ID NO: 234 (TMRSGGTTDDNPALKS);

[1651] VHCDR3 comprises the sequence set forth in SEQ ID NO: 237 (GYLSGVHYA);

[1652] VLCDR1 comprises the sequence shown in SEQ ID NO: 239 (SGSSSNVGAGNYVG);

[1653] VLCDR2 comprises the sequence set forth in SEQ ID NO:70 (GATNRAS); and

[1654] VLCDR3 comprises the sequence shown in SEQ ID NO: 247 (ASIDTSRSHI);

[1655] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1656] (i) is at least 85% identical thereto, and / or

[1657] (ii) has one, two or three amino acid substitutions relative thereto,

[1658] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "E2A6."

[1659] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1660] VHCDR1 comprises the sequence shown in SEQ ID NO: 230 (DWGVA);

[1661] VHCDR2 comprises the sequence set forth in SEQ ID NO: 234 (TMRSGGTTDDNPALKS);

[1662] VHCDR3 comprises the sequence set forth in SEQ ID NO: 237 (GYLSGVHYA);

[1663] VLCDR1 comprises the sequence shown in SEQ ID NO: 239 (SGSSSNVGAGNYVG);

[1664] VLCDR2 comprises the sequence set forth in SEQ ID NO:70 (GATNRAS); and

[1665] VLCDR3 comprises the sequence shown in SEQ ID NO: 247 (ASIDTSRSHI).

[1666] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1667] VHCDR1 comprises the sequence shown in SEQ ID NO: 231 (SWGVA);

[1668] VHCDR2 comprises the sequence set forth in SEQ ID NO: 233 (TMRSGGGTEYNPALKS);

[1669] VHCDR3 comprises the sequence set forth in SEQ ID NO: 236 (GYLSGIHYA);

[1670] VLCDR1 comprises the sequence shown in SEQ ID NO: 240 (SGSSSNVGDGDYVG);

[1671] VLCDR2 comprises the sequence set forth in SEQ ID NO: 244 (SARNRAS); and

[1672] VLCDR3 comprises the sequence shown in SEQ ID NO: 247 (ASIDTSRSHI);

[1673] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1674] (i) is at least 85% identical thereto, and / or

[1675] (ii) has one, two or three amino acid substitutions relative thereto,

[1676] 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. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "E2B7."

[1677] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1678] VHCDR1 comprises the sequence shown in SEQ ID NO: 231 (SWGVA);

[1679] VHCDR2 comprises the sequence set forth in SEQ ID NO: 233 (TMRSGGGTEYNPALKS);

[1680] VHCDR3 comprises the sequence set forth in SEQ ID NO: 236 (GYLSGIHYA);

[1681] VLCDR1 comprises the sequence shown in SEQ ID NO: 240 (SGSSSNVGDGDYVG);

[1682] VLCDR2 comprises the sequence set forth in SEQ ID NO: 244 (SARNRAS); and

[1683] VLCDR3 comprises the sequence shown in SEQ ID NO: 247 (ASIDTSRSHI).

[1684]

[1685] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1686] VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 9;

[1687] VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 9;

[1688] VHCDR3 comprises the VHCDR3 amino acid sequence shown in Table 9;

[1689] VLCDR1 comprises the VLCDR1 amino acid sequence shown in Table 9;

[1690] VLCDR2 comprises the VLCDR2 amino acid sequence shown in Table 9; and

[1691] VLCDR3 comprises the VLCDR3 amino acid sequence shown in Table 9;

[1692] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1693] (i) is at least 85% identical thereto, and / or

[1694] (ii) has one, two or three amino acid substitutions relative thereto,

[1695] 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.

[1696] The specific binding molecule can be expressed with a K of less than about 25 nM. D Binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 379 to 391 of SEQ ID NO: 1. D The K may be less than about 20 nM, less than about 15 nM, or less than about 10 nM. D It can be preferably used to bind to SEQ ID NO: 4. The binding of the specific binding molecule to SEQ ID NO: 1 may not be detected. D The K binding to SEQ ID NO: 4 may be from about 300 pM to about 10 nM. D It can be from about 300 pM to about 500 pM. K binding to SEQ ID NO: 4 D The K binding to SEQ ID NO: 4 may be from about 1 nM to about 10 nM. D It can be about 401 pM, wherein optionally, the specific binding molecule comprises the CDRs of E1E8. K binding to SEQ ID NO: 4 D It may be about 6.3 nM, wherein optionally, the specific binding molecule comprises the CDRs of E1E8.

[1697] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 248, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 248. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 248. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 248, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 248. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 248.

[1698] SEQ ID NO: 248 (amino acid sequence of E2E8)

[1699] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLG

[1700] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 250, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 250. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 250. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 250, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 250. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 250.

[1701] SEQ ID NO: 250 (E1E8 amino acid sequence)

[1702] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDWGVAWVRQAPGKALEWLGTMRSGGTTDDNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGVHYAWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSGSLGQSVSITCSGSSSNVGDGRYVSWFQQVPGSAPKLLIYDTTSRASGVPDRFSGSRSGNTATLIITSLQAEDEADYYCASIDSGNNLLFGSGTRLTVLG

[1703] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 252, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 252. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 252. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 252, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 252. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 252.

[1704] SEQ ID NO: 252 (E2A6 amino acid sequence)

[1705] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDWGVAWVRQAPGKALEWLGTMRSGGTTDDNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGVHYAWGRGLLVTVSSEGKS SGASGESKVDDRVVRTQPSSVSKSLGQSVSITCSGSSSNVGAGNYVGWFQQVPGSAPKLLIYGATNRASGVPARFSGSKSGVTATLTITSLQAEDEADYYCASIDTSRSHIFGSGTRLTVLG

[1706] The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 254, 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. The CDRs of the specific binding molecule 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% identical to the CDRs of SEQ ID NO: 254. The CDRs may be 100% identical to the CDRs of SEQ ID NO: 254. The specific binding molecule may comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 254, wherein the CDRs are 100% identical to the CDRs of SEQ ID NO: 254. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO: 254.

[1707] SEQ ID NO: 254 (E2B7 amino acid sequence)

[1708] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSWGVAWVRQAPGKALEWLGTMRSGGGTEYNPALKSRLSITRDTSKSQVSLSLSSVTTEDDMAMYYCARGYLSGIHYAWGRGLLVSVSSEGKS SGASGESKVDDQAVLTQLSSVSGSLGQRVSITCSGSSSNVGDGDYVGWFQQLPGSAPKLLIYSARNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCASIDTSRSHIFGSGTRLTVLG

[1709] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 113 to 238 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1710] The epitope may be located within the amino acid sequence comprising residues 113 to 238 of SEQ ID NO: 1. The epitope may bind to a CDR of the specific binding molecule referred to herein as "CB11."

[1711] The epitope may comprise the amino acid sequence of SEQ ID NO: 255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). The epitope may comprise an amino acid sequence at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1712] The epitope may consist of the amino acid sequence of SEQ ID NO: 255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). The epitope may consist of an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1713] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1714] VHCDR1 comprises the sequence shown in SEQ ID NO: 198 (SNAVI);

[1715] VHCDR2 comprises the sequence shown in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[1716] VHCDR3 comprises the sequence shown in SEQ ID NO: 202 (DYGSWGYVSDIDY);

[1717] VLCDR1 comprises the sequence shown in SEQ ID NO: 256 (SGSNIGSNDVG);

[1718] VLCDR2 comprises the sequence set forth in SEQ ID NO: 257 (DNNNRPS); and

[1719] VLCDR3 comprises the sequence shown in SEQ ID NO: 258 (GGYAGSSSNFL);

[1720] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1721] (i) is at least 85% identical thereto, and / or

[1722] (ii) has one, two or three amino acid substitutions relative thereto,

[1723] 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 that are 100% identical to the above CDRs is referred to herein as "CB11."

[1724] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1725] VHCDR1 comprises the sequence shown in SEQ ID NO: 198 (SNAVI);

[1726] VHCDR2 comprises the sequence shown in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[1727] VHCDR3 comprises the sequence shown in SEQ ID NO: 202 (DYGSWGYVSDIDY);

[1728] VLCDR1 comprises the sequence shown in SEQ ID NO: 256 (SGSNIGSNDVG);

[1729] VLCDR2 comprises the sequence set forth in SEQ ID NO: 257 (DNNNRPS); and

[1730] VLCDR3 comprises the sequence shown in SEQ ID NO: 258 (GGYAGSSSNFL).

[1731] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 1 to 155 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPR).

[1732] The epitope may be located within the amino acid sequence comprising residues 1 to 155 of SEQ ID NO: 1. The epitope may be bound by the CDRs of the specific binding molecule referred to herein as "CA2."

[1733] The epitope may comprise the amino acid sequence of SEQ ID NO: 293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPR). The epitope can comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR).

[1734] The epitope may consist of the amino acid sequence of SEQ ID NO: 293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPR). The epitope can consist of an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR).

[1735] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1736] VHCDR1 comprises the sequence shown in SEQ ID NO: 259 (SNGVG);

[1737] VHCDR2 comprises the sequence shown in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1738] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1739] VLCDR1 comprises the sequence shown in SEQ ID NO: 165 (SGSSGNVGYGDYVS);

[1740] VLCDR2 comprises the sequence set forth in SEQ ID NO: 169 (GATNLAS); and

[1741] VLCDR3 comprises the sequence shown in SEQ ID NO: 173 (ASYDSSSGGV);

[1742] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1743] (i) is at least 85% identical thereto, and / or

[1744] (ii) has one, two or three amino acid substitutions relative thereto,

[1745] Wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 1 to 155 of SEQ ID NO: 1. A specific binding molecule comprising CDRs that are 100% identical to the above CDRs is referred to herein as "CA2."

[1746] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1747] VHCDR1 comprises the sequence shown in SEQ ID NO: 259 (SNGVG);

[1748] VHCDR2 comprises the sequence shown in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1749] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1750] VLCDR1 comprises the sequence shown in SEQ ID NO: 165 (SGSSGNVGYGDYVS);

[1751] VLCDR2 comprises the sequence set forth in SEQ ID NO: 169 (GATNLAS); and

[1752] VLCDR3 comprises the sequence shown in SEQ ID NO: 173 (ASYDSSSGGV).

[1753] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 1 to 238 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 260 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1754] The epitope may be located within the amino acid sequence comprising residues 1 to 238 of SEQ ID NO: 1. The epitope may bind to a CDR of the specific binding molecule referred to herein as "CB6."

[1755] The epitope may include SEQ ID NO: 260 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT The amino acid sequence of GSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). The epitope can comprise an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 260 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1756] The epitope may consist of the amino acid sequence of SEQ ID NO: 260 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). The epitope can consist of an amino acid sequence that is at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 260 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1757] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1758] VHCDR1 comprises the sequence shown in SEQ ID NO: 259 (SNGVG);

[1759] VHCDR2 comprises the sequence shown in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1760] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1761] VLCDR1 comprises the sequence shown in SEQ ID NO: 261 (SGSSSNIGTGNYVG);

[1762] VLCDR2 comprises the sequence set forth in SEQ ID NO: 262 (GAVTRAS); and

[1763] VLCDR3 comprises the sequence shown in SEQ ID NO: 263 (ASYDSTSGGV);

[1764] Alternatively, for each CDR sequence, comprising an amino acid sequence having the following:

[1765] (i) is at least 85% identical thereto, and / or

[1766] (ii) has one, two or three amino acid substitutions relative thereto,

[1767] Wherein 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 that are 100% identical to the above CDRs is referred to herein as "CB6".

[1768] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1769] VHCDR1 comprises the sequence shown in SEQ ID NO: 259 (SNGVG);

[1770] VHCDR2 comprises the sequence shown in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1771] VHCDR3 comprises the sequence shown in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1772] VLCDR1 comprises the sequence shown in SEQ ID NO: 261 (SGSSSNIGTGNYVG);

[1773] VLCDR2 comprises the sequence set forth in SEQ ID NO: 262 (GAVTRAS); and

[1774] VLCDR3 comprises the sequence shown in SEQ ID NO: 263 (ASYDSTSGGV).

[1775] The epitope of the specific binding molecule may be located within the amino acid sequence comprising residues 1 to 319 of SEQ ID NO: 1. Thus, the epitope may be located within the amino acid sequence of SEQ ID NO: 264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[1776] The epitope may be located within the amino acid sequence comprising residues 1 to 319 of SEQ ID NO: 1. The epitope may bind to the CDRs of the specific binding molecules referred to herein as "CA7," "CA8," and "CB10."

[1777] The epitope within the amino acid sequence comprising residues 1 to 319 of SEQ ID NO: 1 is preferably located within the amino acid sequence comprising residues 37 to 49 of SEQ ID NO: 1. The epitope may bind to at least a CDR of the specific binding molecule referred to herein as "CA7".

[1778] The epitope may comprise SEQ ID NO: 264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSG YSSPGSPGTPGSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT) amino acid sequence. The epitope can comprise an amino acid sequence at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identical to SEQ ID NO: 264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[1779] The epitope can be composed of the amino acid sequence of SEQ ID NO: 264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT). The epitope can be composed of the amino acid sequence of SEQ ID NO:

[1780] 264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT) has an amino acid sequence composition of at least 70%, at least 75%, at least 80%, at least 90%, at least 95% or at least 99% identity.

[1781] The specific binding molecule may comprise the CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1782] VHCDR1 comprises the sequence shown...

Claims

1. An in vitro method for detecting tau protein fragments in a patient's sample, wherein: The amino acid sequence of the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO:

1.

2. A diagnostic method comprising detecting tau protein fragments in a patient's sample, wherein: The amino acid sequence of the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO:

1.

3. The diagnostic method according to claim 2, wherein: The method is used for diagnosing tauopathy.

4. The diagnostic method according to claim 3, wherein: The tauopathy is selected from the group consisting of: Alzheimer's disease, primary age-related tauopathy (PART), senile dementia with neurofibrillary tangles, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD), behavioral variant frontotemporal dementia (bvFTD), frontotemporal dementia with parkinsonism associated with chromosome 17 (FTDP-17), Pick's disease, disinhibition-dementia-parkinsonism-amyotrophic lateral sclerosis complex (DDPAC), pallidum-pontine-nigral degeneration (PPND), ALS of Guam type. syndrome, globus pallidus-nigral-subthalamic nucleus degeneration (PNLD), argyrophilic granular dementia (AgD), Down syndrome (DS), dementia with Lewy bodies (DLB), postencephalitic parkinsonism (PEP), dementia pugilistica (DP), traumatic brain injury (TBI), stroke, ischemia, Lytico-bodig disease (Guam Parkinsonism complex), ganglioglioma, gangliocytoma, meningioangiomatosis, postencephalitic parkinsonism, subacute sclerosing panencephalitis (SSPE), lead encephalopathy, tuberous sclerosis, pantothenate kinase-related neurodegeneration, lipofuscinosis, and mild cognitive impairment (MCI).

5. The diagnostic method according to any one of claims 2 to 4, wherein: The method is used for diagnosing Alzheimer's disease.

6. A method according to any one of the preceding claims, wherein: The fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO:

1.

7. A method according to any one of the preceding claims, 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 of residues 297 to 391 of SEQ ID NO:

1.

8. A method according to any one of the preceding claims, 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 of residues 151 to 243 of SEQ ID NO:

1.

9. A method according to any one of the preceding claims, wherein: The fragment comprises at least 30 consecutive amino acid residues within residues 113 to 379 of SEQ ID NO: 1, and (a) at least 4 consecutive amino acid residues from residues 297 to 391 of SEQ ID NO: 1; and / or (b) at least 4 consecutive amino acid residues from residues 151 to 243 of SEQ ID NO:

1.

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

1.

11. A method according to any one of the preceding claims, 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.

12. A method according to any one of the preceding claims, 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.

13. A method according to any one of the preceding claims, wherein: The fragment comprises 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 161, at least 162, at least 163, at least 164, at least 165, at least 166, at least 167, at least 168, at least 169, at least 170, at least 171, at least 172, at least 173, at least 174, at least 175 262, at least 263, at least 264, at least 265, at least 266, or 267 consecutive amino acid residues.

14. The method according to any one of claims 1 to 13, wherein: The fragment comprises at least 156 consecutive amino acid residues within residues 113 to 379 of SEQ ID NO: 1, and (a) at least 53 consecutive amino acid residues of 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 of residues 151 to 243 of SEQ ID NO:1, optionally including residues 194 to 198 of SEQ ID NO:

1.

15. The method according to any one of claims 1 to 13, wherein: The fragment comprises at least 181 consecutive amino acid residues within residues 113 to 379 of SEQ ID NO: 1, and (a) at least 78 consecutive amino acid residues of 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 of residues 151 to 243 of SEQ ID NO:1, optionally including residues 194 to 198 of SEQ ID NO:

1.

16. The method according to any one of claims 1 to 13, wherein: The fragment comprises at least 191 consecutive amino acid residues within residues 113 to 379 of SEQ ID NO: 1, and (a) at least 53 consecutive amino acid residues of 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 of residues 151 to 243 of SEQ ID NO:1, optionally including residues 159 to 163 of SEQ ID NO:

1.

17. The method according to any one of claims 1 to 13, wherein: The fragment comprises at least 216 consecutive amino acid residues within residues 113 to 379 of SEQ ID NO: 1, and (a) at least 78 consecutive amino acid residues of 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 of residues 151 to 243 of SEQ ID NO:1, optionally including residues 159 to 163 of SEQ ID NO:

1.

18. A method according to any one of the preceding claims, wherein: The fragment comprises the following amino acid residues: (a) 194 to 349 of SEQ ID NO: 1; (b) 159 to 349 of SEQ ID NO: 1; (c) 194 to 374 of SEQ ID NO: 1; (d) 159 to 374 of SEQ ID NO: 1; (e) 195 to 370 of SEQ ID NO: 1; (f) 159 to 379 of SEQ ID NO: 1; (g) 113 to 224 of SEQ ID NO: 1; (h) 113 to 349 of SEQ ID NO: 1; or (i) 113 to 370 of SEQ ID NO:

1.

19. A method according to any one of the preceding claims, wherein: The amino acid sequence of the fragment consists of the following amino acid residues: (a) 113 to 370 of SEQ ID NO: 1; (b) 113 to 349 of SEQ ID NO: 1; (c) 113 to 224 of SEQ ID NO: 1; (d) 159 to 379 of SEQ ID NO: 1; (e) 195 to 370 of SEQ ID NO: 1; (f) 194 to 349 of SEQ ID NO: 1; (g) 159 to 349 of SEQ ID NO: 1; (h) 194 to 374 of SEQ ID NO: 1; or (i) 159 to 374 of SEQ ID NO:

1.

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

1.

21. A method according to any one of the preceding claims, wherein: The sample is a plasma sample, a whole blood sample, a brain lysate sample or a cerebrospinal fluid (CSF) sample.

22. A method according to any one of the preceding claims, wherein: The sample is a plasma sample.

23. A method according to any one of the preceding claims, wherein: The sample is a plasma sample, and wherein the fragment comprises amino acid residues 194 to 349 of SEQ ID NO:

1.

24. The method according to any one of the preceding claims, comprising contacting the sample with a first specific binding molecule.

25. The method according to claim 24, wherein: The first specific binding molecule binds to an epitope within residues 297 to 391 of SEQ ID NO:

1.

26. The method according to claim 24 or 25, wherein: The first specific binding molecule binds to an epitope within residues 307 to 391 of SEQ ID NO:

1.

27. The method according to any one of claims 24 to 26, wherein: The first specific binding molecule binds to an epitope within residues 337 to 379 of SEQ ID NO:

1.

28. The method according to any one of claims 24 to 27, wherein: The first specific binding molecule binds to an epitope consisting of residues 337 to 349 of SEQ ID NO:

1.

29. The method according to any one of claims 24 to 28, wherein: The first specific binding molecule binds to an epitope consisting of residues 337 to 355 of SEQ ID NO:

1.

30. The method according to any one of claims 24 to 29, wherein: The first specific binding molecule comprises CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence: VHCDR1 comprises the sequence shown in SEQ ID NO:16 (NNAVG); VHCDR2 comprises the sequence shown in SEQ ID NO: 18 (GCSSDGTCYYNSALKS); VHCDR3 comprises the sequence shown in SEQ ID NO:21 (GHYSIYGYDYLGTIDY); VLCDR1 comprises the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG); VLCDR2 comprises the sequence shown in SEQ ID NO:26 (DTNSRPS); VLCDR3 comprises the sequence shown in SEQ ID NO:29 (VTGDSTTHDDL); Alternatively, for each CDR sequence, comprising an amino acid sequence having the following: (i) is at least 85% identical to, and / or (ii) has one, two or three amino acid substitutions relative thereto.

31. The method according to any one of claims 24 to 30, wherein: The first specific binding molecule comprises CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence: VHCDR1 comprises the sequence shown in SEQ ID NO:16 (NNAVG); VHCDR2 comprises the sequence shown in SEQ ID NO: 18 (GCSSDGTCYYNSALKS); VHCDR3 comprises the sequence shown in SEQ ID NO:21 (GHYSIYGYDYLGTIDY); VLCDR1 comprises the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG); VLCDR2 comprises the sequence shown in SEQ ID NO:26 (DTNSRPS); and VLCDR3 comprises the sequence shown in SEQ ID NO: 29 (VTGDSTTHDDL).

32. The method according to any one of claims 24 to 31, wherein: The first specific binding molecule comprises framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence: VHFR1 comprises the sequence shown in SEQ ID NO:435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN); VHFR2 comprises the sequence shown in SEQ ID NO:436 (WVRQAPGKVPESLV); VHFR3 comprises the sequence shown in SEQ ID NO:437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR); VHFR4 comprises the sequence shown in SEQ ID NO:438 (WGPGLLVTVSS); VLFR1 comprises the sequence shown in SEQ ID NO:439 (QAVLTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence shown in SEQ ID NO:440 (WYQHLPGSGLKTIIY); VLFR3 comprises the sequence shown in SEQ ID NO:441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC); VLFR4 comprises the sequence shown in SEQ ID NO:442 (VGSGTRLTVLG); Alternatively, for each FR sequence, comprising an amino acid sequence having the following: (i) is at least 50% identical to, and / or (ii) has one, two, three, four or five amino acid substitutions relative thereto.

33. A method according to any one of claims 24 to 32, wherein: The first specific binding molecule comprises the following, or a humanized variant thereof: (a) a VH domain comprising the sequence shown in SEQ ID NO: 443 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRL DITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSS); and / or (b) A VL domain comprising the sequence shown in SEQ ID NO: 444 (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG).

34. The method according to any one of claims 24 to 33, wherein: The first specific binding molecule has a K of less than about 500 pM. D specifically binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 337 to 355 of SEQ ID NO: 1, optionally wherein the specific binding is measured by surface plasmon resonance (SPR), and optionally wherein i. K combined with SEQ ID NO: 1 D From about 50 pM to about 150 pM, and / or ii. K combined with SEQ ID NO: 5 D From about 300 pM to about 400 pM.

35. The method according to any one of claims 24 to 27, wherein: The first specific binding molecule binds to an epitope consisting of residues 367 to 379 of SEQ ID NO:

1.

36. The method according to any one of claims 24 to 27 or 35, wherein: The first specific binding molecule comprises CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence: VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG); VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence shown in SEQ ID NO:54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG); VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS); VLCDR3 comprises the sequence shown in SEQ ID NO:73 (GSSDRTPYTGV). Alternatively, for each CDR sequence, comprising an amino acid sequence having the following: (i) is at least 85% identical to, and / or (ii) has one, two or three amino acid substitutions relative thereto.

37. A method according to any one of claims 24 to 27, or 35 to 36, wherein The first specific binding molecule comprises CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence: VHCDR1 comprises the sequence shown in SEQ ID NO:42 (SNSVG); VHCDR2 comprises the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS); VHCDR3 comprises the sequence shown in SEQ ID NO:54 (SYRADGLAYGYVQAIDY); VLCDR1 comprises the sequence shown in SEQ ID NO:63 (SGSFIGISSVG); VLCDR2 comprises the sequence shown in SEQ ID NO:70 (ASDGRPS); and VLCDR3 comprises the sequence shown in SEQ ID NO:73 (GSSDRTPYTGV).

38. A method according to any one of claims 24 to 27, or 35 to 37, wherein The first specific binding molecule comprises framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence: VHFR1 comprises the sequence shown in SEQ ID NO:447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence shown in SEQ ID NO:448 (WVRQAPGKAPEWVA); VHFR3 comprises the sequence shown in SEQ ID NO:449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR); VHFR4 comprises the sequence shown in SEQ ID NO:450 (WGPGLLVTVSS); VLFR1 comprises the sequence shown in SEQ ID NO:451 (QAVVTQPSSVSGSLGQRVSITC); VLFR2 comprises the sequence shown in SEQ ID NO:452 (WFQQLPGSGLRTIIV); VLFR3 comprises the sequence shown in SEQ ID NO:453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC); VLFR4 comprises the sequence shown in SEQ ID NO:454 (FGSGTRLTVLG); Alternatively, for each FR sequence, comprising an amino acid sequence having the following: (i) is at least 50% identical to, and / or (ii) has one, two, three, four or five amino acid substitutions relative thereto.

39. A method according to any one of claims 24 to 27, or 35 to 38, wherein The first specific binding molecule comprises the following, or a humanized variant thereof: (a) a VH domain comprising the sequence shown in SEQ ID NO:455 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVSS); and / or (b) A VL domain comprising the sequence shown in SEQ ID NO: 456 (QAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTA TLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG).

40. The method according to any one of claims 24 to 27, or 35 to 39, wherein: The first specific binding molecule has a K of less than about 500 pM. D specifically binds to a polypeptide or protein molecule comprising an amino acid sequence comprising residues 367 to 379 of SEQ ID NO: 1, optionally wherein the specific binding is measured by surface plasmon resonance (SPR), and optionally wherein i. K combined with SEQ ID NO: 1 D is about 100 pM to about 200 pM, and / or ii. K combined with SEQ ID NO: 5 D From about 400 pM to about 500 pM.

41. The method according to any one of claims 24 to 27, wherein: The first specific binding molecule binds to an epitope consisting of residues 355 to 367 of SEQ ID NO:

1.

42. The method according to any one of claims 24 to 27 or 41, wherein: The first specific binding molecule comprises CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence: VHCDR1 comprises the sequence shown in SEQ ID NO:83 (SYSVY); VHCDR2 comprises the sequence shown in SEQ ID NO:84 (IMYASGRVDYNPALKS); VHCDR3 comprises the sequence shown in SEQ ID NO:89 (GIEN); VLCDR1 comprises the sequence shown in SEQ ID NO:91 (RTSQSVNNYLS); VLCDR2 comprises the sequence shown in SEQ ID NO:95 (YATRLYT); and VLCDR3 comprises the sequence shown in SEQ ID NO:97 (LQYDSTPLA); Alternatively, for each CDR sequence, comprising an amino acid sequence having the following: (i) is at least 85% identical to, and / or (ii) has one, two or three amino acid substitutions relative thereto.

43. A method according to any one of claims 24 to 27, or 41 to 42, wherein: The first specific binding molecule comprises CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence: VHCDR1 comprises the sequence shown in SEQ ID NO:83 (SYSVY); VHCDR2 comprises the sequence shown in SEQ ID NO:84 (IMYASGRVDYNPALKS); VHCDR3 comprises the sequence shown in SEQ ID NO:89 (GIEN); VLCDR1 comprises the sequence shown in SEQ ID NO:91 (RTSQSVNNYLS); VLCDR2 comprises the sequence shown in SEQ ID NO:95 (YATRLYT); and VLCDR3 comprises the sequence shown in SEQ ID NO:97 (LQYDSTPLA).

44. A method according to any one of claims 24 to 27, or 41 to 43, wherein The first specific binding molecule comprises framework regions (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3 and VLFR4, wherein each of the FRs comprises the following amino acid sequence: VHFR1 comprises the sequence shown in SEQ ID NO:555 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT); VHFR2 comprises the sequence shown in SEQ ID NO:556 (WVRQAPGQALEWIS); VHFR3 comprises the sequence shown in SEQ ID NO:557 (RLSITRDTSKSQFSLSLSSVTTEDTAVYYCTR); VHFR4 comprises the sequence shown in SEQ ID NO:558 (WGPGLLVTVSS); VLFR1 comprises the sequence shown in SEQ ID NO:559 (DIQVTQSPSSLSASLTERVSITC); VLFR2 comprises the sequence shown in SEQ ID NO:560 (WYQQKPGQAPKLLIY); VLFR3 comprises the sequence shown in SEQ ID NO:561 (DVPSRFSGSGSGTDYTLTITSLEADDTATYYC); VLFR4 comprises the sequence shown in SEQ ID NO:562 (FGGGTNVEIK); Alternatively, for each FR sequence, comprising an amino acid sequence having the following: (i) is at least 50% identical to, and / or (ii) has one, two, three, four or five amino acid substitutions relative thereto.

45. A method according to any one of claims 24 to 27, or 41 to 44, wherein The first specific binding molecule comprises the following, or a humanized variant thereof: (a) a VH domain comprising the sequence shown in SEQ ID NO:563 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSYSVYWVRQAPGQALEWISIMYASGRVDYNPALKSRLSITRTDTSKSQFSLSLSSVTTEDTAVYYCTRGIENWGPGLLVTVSS); and / or (b) a VL domain comprising the sequence shown in SEQ ID NO: 564 (DIQVTQSPSSLSASLTERVSITCRTSQSVNNYLSWYQQKPGQAPKLLIYYATRLYTDVPSRFSGSGSGT DYTLTITSLEADDTATYYCLQYDSTPLAFGGGTNVEIK).

46. ​​The method according to any one of claims 24 to 45, wherein: The first specific binding molecule competes with S1D12, S1G2 or CA4 for binding to SEQ ID NO:

1.

47. The method of any one of claims 24 to 46, further comprising contacting the sample with a second specific binding molecule.

48. The method of claim 47, wherein: The second specific binding molecule binds to an epitope within residues 151 to 243 of SEQ ID NO:

1.

49. The method according to any one of claims 47 to 48, wherein: The second specific binding molecule binds to an epitope consisting of residues 194 to 198 of SEQ ID NO:

1.

50. The method according to any one of claims 47 to 49, wherein: The second specific binding molecule is BT2.

51. The method according to any one of claims 47 to 48, wherein: The second specific binding molecule binds to an epitope consisting of residues 159 to 163 of SEQ ID NO:

1.

52. The method of any one of claims 47, 48 or 51, wherein: The second specific binding molecule is HT7.

53. The method according to any one of claims 47 to 49 or 51, wherein: The second specific binding molecule competes with BT2 or HT7 for binding to SEQ ID NO:

1.

54. The method according to any one of claims 47 to 52, wherein: The first specific binding molecule is S1D12 or S1G2, and the second specific binding molecule is BT2 or HT7.

55. The method of claim 47, wherein: The second specific binding molecule comprises CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence: VHCDR1 comprises the sequence shown in SEQ ID NO:198 (SNAVI); VHCDR2 comprises the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS); VHCDR3 comprises the sequence shown in SEQ ID NO: 202 (DYGSWGYVSDIDY); VLCDR1 comprises the sequence shown in SEQ ID NO: 204 (SGSDIGGADVG); VLCDR2 comprises the sequence shown in SEQ ID NO:206 (DNDNRPS); and VLCDR3 comprises the sequence shown in SEQ ID NO:208 (GTYSGANYGI); Alternatively, for each CDR sequence, comprising an amino acid sequence having the following: (i) is at least 85% identical to, and / or (ii) has one, two or three amino acid substitutions relative thereto, Wherein, the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 147 to 157 of SEQ ID NO:

1.

56. The method of claim 47, wherein: The second specific binding molecule comprises CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, VHCDR1 comprises the sequence shown in SEQ ID NO:17 (SNAVG); VHCDR2 comprises the sequence shown in SEQ ID NO:201 (LIDIDGDTAYNPALES); VHCDR3 comprises the sequence shown in SEQ ID NO: 203 (HYDKWGYADSIDY); VLCDR1 comprises the sequence shown in SEQ ID NO:138 (SGSSSNVGYGDYVG); VLCDR2 comprises the sequence shown in SEQ ID NO:207 (DATTRAS); and VLCDR3 comprises the sequence shown in SEQ ID NO:209 (ASYQNERSGV); Alternatively, for each CDR sequence, comprising an amino acid sequence having the following: (i) is at least 85% identical to, and / or (ii) has one, two or three amino acid substitutions relative thereto, Wherein, the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 147 to 157 of SEQ ID NO:

1.

57. The method of claim 47, wherein: The second specific binding molecule comprises CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2 and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence: VHCDR1 comprises the VHCDR1 amino acid sequence shown in Table 10; VHCDR2 comprises the VHCDR2 amino acid sequence shown in Table 10; VHCDR3 comprises the VHCDR3 amino acid sequence 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; Alternatively, for each CDR sequence, comprising an amino acid sequence having the following: (i) is at least 85% identical to, and / or (ii) has one, two or three amino acid substitutions relative thereto, Wherein, the specific binding molecule binds to the epitope within SEQ ID NO:

1.

58. The method of claim 57, wherein: The second specific binding molecule comprises a cloned CDR selected from the group consisting of 3bD11, CB11, CA2, CB6, CA7, CA8, CB10, CC7, CB12, CC3, CA1, CA3, CD2, CC4, CD1 and CC5.

59. A method according to any one of the preceding claims, wherein: The first specific binding molecule and / or the second specific binding molecule is an immunoglobulin, an immunoglobulin Fab region, Fab', Fv, Fv-Fc, single-chain Fv (scFv), scFv-Fc, (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.

60. The method of any of the preceding claims, further comprising determining the concentration of the tau protein fragments in the sample, and optionally comparing the concentration of the tau protein fragments in the sample to the concentration of the tau protein fragments in a sample of a healthy control or a predetermined concentration of the tau protein fragments indicative of a healthy subject.

61. A method according to any one of the preceding claims, wherein: Tauopathy is diagnosed when a low concentration of said tau protein fragments is detected in a sample from a patient, optionally wherein said low concentration is determined relative to a concentration of said tau protein fragments in a sample from a healthy control or a predetermined concentration of said tau protein fragments indicative of a healthy subject.

62. A method according to any one of the preceding claims, wherein: When the tau protein fragments are detected in plasma at less than about 1300 pg / ml, less than about 1200 pg / ml, less than about 1100 pg / ml, or less than about 1000 pg / ml, tauopathy is diagnosed.

63. A method according to any one of the preceding claims, wherein: When the concentration of the tau protein fragments is detected to be reduced to at least about 1 / 10, at least about 1 / 10.5, at least about 1 / 11, or at least about 1 / 11.5 of the concentration of the tau protein fragments in a sample relative to a healthy control or a predetermined concentration of the tau protein fragments indicative of a healthy subject, tau disease is diagnosed.

64. The method according to any one of claims 60 to 63, wherein: The tauopathy is Alzheimer's disease or frontotemporal dementia, optionally behavioral variant frontotemporal dementia (bvFTD).

65. A diagnostic device for use in a method according to any preceding claim.

66. A kit comprising a specific binding molecule suitable for use in a method according to any one of the preceding claims and a reagent for detecting a tau protein fragment in a patient's sample, wherein the amino acid sequence of the fragment consists of amino acid residues within residues 113 to 379 of SEQ ID NO: 1.

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