Method for detecting TAU protein in saliva sample

Abstract

The present invention relates to in vitro methods for detecting tau protein or fragments thereof in a saliva sample using specific binding molecules (e.g., antibodies) directed against tau key epitopes. The invention can be used for diagnosing tauopathy.

Description

Technical Field

[0001] This invention relates to an in vitro method for detecting tau protein or fragments thereof in saliva samples using a specific binding molecule (e.g., an antibody) targeting a key tau epitope. This invention can be used for the diagnosis of tau protein disorders. Background Technology

[0002] Diseases associated with tau are collectively known as neurodegenerative tau protein diseases. Alzheimer's disease (AD) belongs to this category of neurodegenerative diseases. A common feature of dementias such as Alzheimer's disease (AD) is the gradual accumulation of intracellular and / or extracellular deposits of protein structures composed of tau, such as β-amyloid plaques and neurofibrillary tangles (NFTs), in the brains of affected patients. The occurrence of tau aggregation lesions 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. The misfolding of proteins to form amyloid fibrils is characteristic of many different diseases collectively known as amyloidosis, each characterized by a specific precursor protein.

[0003] Long-term research into the etiology of Alzheimer's disease (AD) and other protein conformational disorders has not yielded the expected significant advances in diagnosis or treatment. One reason for the limited progress is believed to be the lack of high-affinity specific binding molecules targeting key tau epitopes. This deficiency is addressed by the specific binding molecule disclosed in PCT application PCT / EP2021 / 069160 (the entire contents of which are incorporated herein by reference), filed in the name of WisTa Laboratories Ltd. The disclosed specific binding molecule is derived from antibodies isolated from sheep immunized with full-length tau protein and a truncated tau fragment from the PHF core. The use of sheep as the source of the specific binding molecule is considered to contribute to the high affinity of the specific binding molecule of the present invention. PCT application PCT / EP2021 / 069160 describes the use of the specific binding molecule in a sample, which may be a plasma sample, whole blood sample, brain lysate, or cerebrospinal fluid (CSF) sample.

[0004] H. Pekeles et al., *Alzheimer's & Dementia: Diagnosis, Assessment & Disease Monitoring* 11 (2019) 53-6054, described the development and validation of a salivary tau biomarker in Alzheimer's disease. The authors reported a significantly elevated ratio of phosphorylated tau to total tau (p-tau / t-tau) at the S396 phosphorylation site. However, the authors acknowledged that the large variability in salivary tau levels in AD limits the applicability of this test as a clinical biomarker.

[0005] The inventors have developed an assay for detecting tau protein or fragments thereof in saliva samples, comprising contacting the sample with a first specific binding molecule, wherein the first specific binding molecule binds to a major fragment (residues 297 to 391 of SEQ ID NO: 1) isolated from the proteolytically stable core of a paired helical filament (PHF). These assays may use one or more specific binding molecules described in PCT application PCT / EP2021 / 069160, which may provide advantages including increased sensitivity due to high affinity. The inventors unexpectedly discovered that using a first specific binding molecule that binds to residues 297 to 391 of SEQ ID NO:1 enabled a second specific binding molecule to robustly detect salivary tau. However, reverse use (external binding of the first specific binding molecule to residues 297 to 391 of SEQ ID NO:1 and internal binding of the second specific binding molecule to residues 297 to 391 of SEQ ID NO:1) may fail to detect salivary tau, even when using a high-affinity specific binding molecule that binds to residues 297 to 391 of SEQ ID NO:1. Summary of the Invention

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

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

[0008] According to a third aspect, the present invention provides a kit comprising a specific binding molecule suitable for use with the method according to the first aspect and reagents for detecting tau protein or fragments thereof in a saliva sample, wherein the first specific binding molecule binds to epitopes within residues 297 to 391 of SEQ ID NO:1. Attached Figure Description

[0009] Please refer to the following attached images:

[0010] Figure 1 According to the definition of alternative CDRs in S1D12 by Kabat, Chothia and Martin.

[0011] Figure 2 The sequence of the major fragment isolated from the proteolytically stable core of the paired helical filament (PHF; Wischik et al., 1988). This fragment (called "dGAE") contains full-length tau residues 296-391 and contains fragments (residues 308-378) that constitute the PHF core (Fitzpatrick et al., 2017), as identified by cryo-electron microscopy. Figure 3 The image shows the location of the epitopes for the selected antibody / scAb.

[0012] Figure 3 The PHF core is shown against the background of PHF.

[0013] Figure 4 The same core sequence and corresponding epitope locations are associated with the basic C-shaped subunit structure of the core. The 1D12 epitope forms the key fold or "hairpin" of the C-shaped subunit.

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

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

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

[0017] Figure 8Cross-reactivity of scAbs in group "E" was characterized using ELISA with hT40, dGA, and dGAE antigens. (A) E1E8 scAb, (B) E2B7 scAb, (C) E2C5 scAb, (D) E2E8 scAb, (E) E1B8 scAb. Except for E1B8, all these scAbs exhibited specific dGAE binding and therefore required an accessible C-terminal "391E" epitope to generate an immune response. E1B8 cross-reacted with dGA, and a detailed map of its binding region is shown in […]. Figure 9 As shown in the image.

[0018] Figure 9 Detailed plot of .E1B8scAb shows specific binding to the tau peptide, which represents amino acids 313-336 of the hT40 protein.

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

[0020] Figure 11 Cross-reactivity of “S” group scAbs was characterized 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 binding to these shorter antigens is shown in Table 16.

[0021] Figure 12 Cross-reactivity of "C" group scAbs was characterized 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 binding to these shorter antigens is shown in Table 17.

[0022] Figure 13 Cross-reactivity of scAbs in group "412" with hT40. (A) shows the binding of scAbs to biotinylated 412-441 peptides, which are used as antigens for selective binding of C-terminal antibodies. (B) shows the binding profiles of four scAbs exhibiting cross-reactivity in an hT40 binding ELISA.

[0023] Figure 14 Cross-reactivity of '3a' & '3b' group scAbs was characterized 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 the specific '3a' & '3b' group scAbs that bind to these shorter antigens is shown in Table 18.

[0024] Figure 15 (A) Immunoreactivity of CE2scAb against the parent peptide and a series of alanine substitution residues located at the positions shown in Table 19. (B) Percentage of binding of 500 nM scAb to any 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 substitution residues located at the positions shown in Table 20. (C) Percentage of binding of 500 nM scAb to any of these ASM peptides relative to the parent peptide.

[0026] Figure 17 (AB) Immunoreactivity of ME12scAb against the parent peptide and a series of alanine substitution residues located at the positions shown in Table 20. (C) Percentage of binding of 100 nM scAb to any of these ASM peptides relative to the parent peptide.

[0027] Figure 18 (A) Immunoreactivity of CA4scAb against the parent peptide and a series of alanine substitution residues located at the positions shown in Table 21. (B) Percentage of binding of 500 nM scAb to any of these ASM peptides relative to the parent peptide.

[0028] Figure 19 (AB) Immunoreactivity of S1G2scAb against the parent peptide and a series of alanine substitution residues located at the positions shown in Table 22. (C) Percentage of binding of 500 nM scAb to any of these ASM peptides relative to the parent peptide.

[0029] Figure 20The percentage of binding between various scAbs in regions 367-379 and the ASM peptide relative to the parent peptide. 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, where alanine substitutions at positions 370, 373, 374, 377, or 378 result in decreased antibody binding.

[0030] Figure 21 Sort using hT40 against the binding affinity of TauscAb. Those with known k... D The values ​​of scAbs (e.g., NS2A1 and S1D12) were used to rank the relative binding affinity of the tested scAbs, and scAbs with similar binding characteristics were shortlisted and selected for Biacore analysis. (A) "S" group clone, (BC) "C" clone, (D) "412" clone, (E) "3a" clone.

[0031] Figure 22 A schematic diagram of a sandwich ELISA method used to calculate the detection limit (LoD) for various antibody pairs.

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

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

[0034] Figure 25 The generated ELISA #1hT40 standard curve was obtained using S1D12mAb capture and CB7scAb 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 substance with N-terminal regions in this mixture. The concentrations and types of tau substances inferred from this assay are shown in Table 29.

[0035] Figure 26The generated ELISA#2 dGAE standard curve was captured using S1D12mAb and detected using E2E8scAb. 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 signals, thus confirming the absence of dGAE in these mixtures. The concentrations and types of tau inferred from this assay are shown in Table 29.

[0036] Figure 27 The average standard curve for ELISA #3 was generated using S1D12mAb capture and S1G2scAb 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 inferred from this assay are shown in Table 29.

[0037] Figure 28 This study compares the binding properties of dGAE monomers or aggregates treated with various SDS (+ / - Triton X-100) in a sandwich ELISA system. S1D12 mAb 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, mAb paired with scAb could detect approximately 2 ng / ml of dGAE aggregates.

[0038] Figure 29 A) L66 cDNA, containing human tau (hT40) and 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 by Melis et al., 2015.

[0039] Figure 30 (a) Tau protein was detected in 50 μg brain homogenates isolated from WT, L1, L66+ / -, and L66+ / + mice using S1D12mAb capture and S-1G2scAb detection. All four samples showed similar tau levels when detected using core region-specific antibody pairings. (b) Tau protein was detected in 50 μg brain homogenates isolated from WT, L1, L66+ / -, and L66+ / + mice using S1D12mAb capture and CB7scAb detection. The N'-terminal oriented CB7scAb specifically detected human tau in both Line66 homozygous and heterozygous samples and was able to distinguish expression levels between the two groups.

[0040] Figure 31Plasma tau levels were measured at the following rates: 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 assays. Tau concentrations were determined using standard curves for hT40 (for WT and L66) and dGA (296–390) (for L1).

[0041] Figure 32 Plasma tau levels in 1.5-month-old Line66+ / + mouse samples (number: 23) were detected using two different sandwich ELISA pairs and compared with plasma from age-matched wild-type mice. (A) Chemiluminescent signal readings for Line66+ / + and wild-type mice are shown using S1D12mAb capture and CB7scAb detection. (B) Signal readings for the same samples using S1D12mAb capture and S1G2scAb detection. When paired with CB7scAb, which specifically detects N-terminal hT40 in the samples, 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, age-matched AD samples and controls were detected using S1D12-S1G12 (for the core region) and S1D12-CB7 (for the N-terminus).

[0043] Figure 34 This shows a sandwich ELISA plot illustrating increased immunoreactivity of scAbs and dGAE in the core region of aggregation-inhibiting samples (“total,” “supernatant,” and “precipitate”) prepared in the presence of LMTM. The dGAE monomer was included as an assay control to indicate the binding characteristics of each test scAb to its corresponding epitope in the non-aggregating sample. (AC)CA4scAb, (DF)CA9, (GI)CB3scAb, (JL)CE2scAb, (MO)CE3, (PR)S1D12 scAb. As confirmed by SDS gel electrophoresis (data not included), the lack of antibody binding in some dGAE+LMTM precipitate samples corresponds to the absence of the protein in that group.

[0044] Figure 35.mAbs capture dGAE aggregates. The various antibodies shown are coated onto a solid-phase ELISA plate and used to capture dGAE aggregates. Except for S1G2 mAb, all capture antibodies were detected using S1G2 scAb. For S1G2 mAb capture, S1D12 scAb was used as the detection antibody.

[0045] Figure 36 Western blot analysis revealed brain-derived tau labeled with a human-specific CB7 antibody that binds to an N-terminal epitope (residues 13-25) absent in mouse tau. This was observed in L66 cells from 5-month-old mice. + / + Bands were present in the lanes of a 20 μg homogenate of mouse brain protein, but not in lanes containing WT or L1. + / + No bands were found in the lanes of the brain sample. The protein standard molecular weights added to the left side of the blot provide an approximation of the relative size of the proteins in the gel, but it is well known that the apparent size of tau is much larger than its actual molecular weight.

[0046] Figure 37 Western blot analysis revealed tau labeled with a human-specific CC7 antibody, which recognizes epitopes located at residues 145-157. Human-specific tau is only present at L66. + / + Detected in mouse brains, but not in WT or L1 + / + Not detected in the sample. Protein standard molecular weight is as follows: Figure 36 As shown.

[0047] Figure 38 Western blot labeled with S1D12tau core antibody. Containing L66 cells from 5-month-old infants. + / + Bands were present in lanes of 20 μg protein homogenates from L1 and WT mouse brains. Mouse tau (indicated by the arrow below) in each sample is shown as a band of approximately 55 kDa. Only present in L66. + / + The human tau in the sample (indicated by the arrow above) is shown as a protein of 68 kDa. Protein standard molecular weight is as follows: Figure 36 As shown.

[0048] Figure 39 Western blots labeled with S1D12 core antibody. Containing L66 cells from 5-month-old infants. + / + L1 + / + Bands were present in the lanes of a 20 μg protein homogenate from WT mouse brains. Mouse tau (indicated by the arrow below) in each sample is shown as a band of approximately 55 kDa. It was present only in L66. + / + The human tau in the sample (indicated by the arrow above) is shown as approximately 68 kDa. Using this antibody, in L1 + / +A band of approximately 10 kDa was visible in the sample. The protein standard molecular weight is as follows: Figure 36 As shown.

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

[0050] Figure 41 A) A paired antibody ELISA using S1D12 capture and CB7 detection showed that at L66 + / + In mouse brain homogenate samples, the signal gradually weakens with age. B) When the direction of the assay was reversed, using CB7 as the capture agent and S1D12 as the detection agent in the brain homogenate sample, a similar pattern of signal weakening with age was observed.

[0051] Figure 42 A paired antibody ELISA using CB7 capture and HT7 detection showed that, against L66... + / + In mice, the signal gradually increases with age. This suggests that truncation between the core and N-terminal regions of the tau protein or protein fragment results in the accumulation of smaller, intact N-terminal fragments.

[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 assay reagent 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) NT1 assay data (Chen et al., 2019) reported that, using the Tau12-BT2 antibody, slightly increased plasma NT-1 tau levels were detected 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 were measured 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 assay reagent HT7, was significantly higher in healthy controls than in AD / MCI samples. The assay was performed on a total of 4 healthy control plasma samples and 34 AD / MCI samples. ****p<0.0001.

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

[0055] Figure 46 The assay of various antibody combinations used in human plasma experiments to generate Calibration curve.

[0056] Figure 47 Immunoprecipitation and trypsin digestion LC-MS revealed core-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 in samples doped with htau40 without immunoprecipitation were also used for comparison.

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

[0058] According to a first aspect, the present invention provides an in vitro method for detecting tau protein or fragments thereof in a saliva sample, comprising contacting the sample with a first specific binding molecule, wherein the first specific binding molecule binds to an epitope within residues 297 to 391 of SEQ ID NO:1.

[0059] All residues of the sequence and structure of the Tau protein in this disclosure are numbered with reference to the residues of SEQ ID NO:1, which is the sequence of human Tau protein tetrad repeat isoform 2N4R (Uniprot ID P10636-8), or a homologous position in other species or variants thereof. Human Tau isoform 2N4R (Uniprot ID P10636-8) corresponds to amino acids 1-124, 376-394, and 461-758 of full-length Tau (Uniprot ID P10636 or P10636-1, provided as SEQ ID NO:2). SEQ ID NO:2 relates to the 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 for the CNS) and not SEQ ID NO:2 (which is unrelated to the CNS).

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

[0061] >sp|P10636-8|TAU_HUMAN microtubule-associated protein tau isotype 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 described 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 a homologous position in other species (the mentioned residues refer to human or mouse Tau sequences, which are identical in this region). It will be apparent to those skilled in the art that dGAE97 also corresponds to a fragment of isotype 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 described in SEQ ID NO:4, wherein the N-terminus is located at residue Ile-297 and the C-terminus at residue Glu-391, or at a homologous position in other species (the mentioned residues refer 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 isotype PNS-Tau(P10636-1), wherein the N-terminus is located at Ile-614 and the C-terminus 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 isolated from the proteolytically stable core of the paired helical filament (PHF). Therefore, references herein to “residues 297 to 391 of SEQ ID NO:1” may replace references to SEQ ID NO:4.

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

[0098] IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAE

[0099] “dGA” refers to a 94-residue fragment of Tau(2N4R), as described in SEQ ID NO:5, wherein the N-terminus is located at residue Ile-297 and the C-terminus is located at residue Ala-390, or at a homologous position in other species (the residues mentioned refer to human or mouse Tau sequences, 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 at residue Phe-378, or at a homologous position in other species (the residues mentioned refer to human or mouse Tau sequences, which are identical in this region). This fragment corresponds to residues 306-378 of this sequence, which was identified by cryo-electron microscopy as the PHF core isolated from AD brain tissue (Fitzpatrick et al., 2017; Nature). This core may extend beyond these residues, but this is limited by the resolution of cryo-electron microscopy. It will be apparent to those skilled in the art that dGAE73 also corresponds to a fragment of the isotype PNS-Tau (P10636-1) with the N-terminus at Val-623 and the C-terminus 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 at a homologous position in other species (the residues mentioned refer to human or mouse Tau sequences, which are identical in this region).

[0106] Another segment of the PHF core is residues 308-378 of Tau(2N4R), as described in SEQ ID NO:7, where the N-terminus is located at residue Ile-308 and the C-terminus is located at residue Phe-378, or at a homologous position in other species (the residues mentioned refer to the human or mouse Tau sequences, 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] First specific binding molecule

[0110] The method includes contacting a sample with a first specific binding molecule, wherein the first specific binding molecule binds to epitopes from residues 297 to 391 of SEQ ID NO:1. The first specific binding molecule can be any specific binding molecule disclosed herein that binds to epitopes from residues 297 to 391 of SEQ ID NO:1, preferably to epitopes from residues 307 to 391 of SEQ ID NO:1, and more preferably to epitopes from residues 337 to 379 of SEQ ID NO:1. The first specific binding molecule is described below. Any reference to specific binding molecules under this subheading refers to the first specific binding molecule.

[0111] The epitope of the first specific binding molecule may be located in SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6 or SEQ ID NO:7.

[0112] 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 the full-length Tau are also referred to as the major fragment isolated from the proteolytic stability core of the paired helical filament (PHF) or the PHF core fragment. Therefore, the epitope of the specific binding molecule can be located within the PHF core or the dGAE fragment. Therefore, the epitope of the specific binding molecule can be located within SEQ ID NO:4.

[0113] The epitope of the specifically binding molecule can be located within residues 297 to 390 of SEQ ID NO:1. Residues 297 to 390 of the full-length Tau are also referred to as the dGA fragment. Therefore, the epitope of the specifically binding molecule can be located within the dGA fragment. Therefore, the epitope of the specifically binding molecule can be located within SEQ ID NO:5. The epitope of the specifically binding molecule can be located within dGAE73 and / or dGAE71. Therefore, the epitope of the specifically binding molecule can be located within SEQ ID NO:6 and / or SEQ ID NO:7.

[0114] The epitope of the specifically binding molecule can be located within residues 308 to 378 of SEQ ID NO:1. Residues 308 to 378 of the full-length Tau are also referred to as the PHF core. Therefore, the epitope of the specifically binding molecule can be located within the PHF core. Therefore, the epitope of the specifically binding molecule can be located within SEQ ID NO:7.

[0115] Typically, specific binding molecules bind to polypeptide or protein molecules containing their epitopes. Therefore, specific binding molecules can bind to SEQ ID NO:1 or fragments thereof containing residues 297 to 391 of SEQ ID NO:1. Specific binding molecules 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. Specific binding molecules can bind to PHF or dGAE fragments. Specific binding molecules can bind to dGA fragments. Specific binding molecules can bind to the PHF core. The specific binding molecule can bind to polypeptide or protein molecules containing amino acid sequences 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.

[0116] The first specific binding molecule can bind to epitopes from residues 307 to 391 of SEQ ID NO:1. The first specific binding molecule can bind to epitopes from residues 337 to 379 of SEQ ID NO:1. The first specific binding molecule can bind to epitopes composed of residues 337 to 349 of SEQ ID NO:1. The first specific binding molecule can bind to epitopes composed of residues 337 to 355 of SEQ ID NO:1. This epitope can bind to the CDR of the specific binding molecule (referred to herein as "S1D12").

[0117] 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:

[0118] VHCDR1 contains the sequence shown in SEQ ID NO:16 (NNAVG);

[0119] VHCDR2 contains the sequence shown in SEQ ID NO:18 (GCSSDGTCYYNSALKS);

[0120] VHCDR3 contains the sequence shown in SEQ ID NO:21 (GHYSIYGYDYLGTIDY);

[0121] VLCDR1 contains the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0122] VLCDR2 contains the sequence shown in SEQ ID NO:26 (DTNSRPS);

[0123] VLCDR3 contains the sequence shown in SEQ ID NO:29 (VTGDSTTHDDL);

[0124] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0125] (i) having at least 85% identity with it, and / or

[0126] (ii) relative to having one, two or three amino acid substitutions.

[0127] 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:

[0128] VHCDR1 contains the sequence shown in SEQ ID NO:16 (NNAVG);

[0129] VHCDR2 contains the sequence shown in SEQ ID NO:18 (GCSSDGTCYYNSALKS);

[0130] VHCDR3 contains the sequence shown in SEQ ID NO:21 (GHYSIYGYDYLGTIDY);

[0131] VLCDR1 contains the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0132] VLCDR2 contains the sequence shown in SEQ ID NO:26 (DTNSRPS); and

[0133] VLCDR3 contains the sequence shown in SEQ ID NO:29 (VTGDSTTHDDL).

[0134] The first specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0135] VHFR1 contains the sequence shown in SEQ ID NO:435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0136] VHFR2 contains the sequence shown in SEQ ID NO:436 (WVRQAPGKVPESLV);

[0137] VHFR3 contains the sequence shown in SEQ ID NO:437(RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0138] VHFR4 contains the sequence shown in SEQ ID NO:438 (WGPGLLVTVSS);

[0139] VLFR1 contains the sequence shown in SEQ ID NO:439 (QAVLTQPSSVSGSLGQRVSITC);

[0140] VLFR2 contains the sequence shown in SEQ ID NO:440(WYQHLPGSGLKTIIY);

[0141] VLFR3 contains the sequence shown in SEQ ID NO:441(GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0142] VLFR4 contains the sequence shown in SEQ ID NO:442 (VGSGTRLTVLG);

[0143] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0144] (i) having at least 50% similarity to it, and / or

[0145] (ii) relative to having one, two, three, four or five amino acid substitutions.

[0146] The first-specific binding molecule may include the following, or humanized variants thereof:

[0147] (a) The VH domain, which contains SEQ ID NO:443

[0148] The sequence shown in (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSS); and / or

[0149] (b) The VL domain, which contains SEQ ID NO:444

[0150] The sequence shown is (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG).

[0151] The first specific binding molecule can bind at a Kc of less than approximately 500 pM. D Specifically binds to polypeptide or protein molecules containing the amino acid sequence of residues 337 to 355 of SEQ ID NO:1, optionally wherein the specific binding is measured by surface plasmon resonance (SPR), and optionally wherein...

[0152] iii. K in combination with SEQ ID NO:1 D From approximately 50 pM to approximately 150 pM, and / or

[0153] iv. K binding to SEQ ID NO:5 D It ranges from approximately 300pM to approximately 400pM.

[0154] The first specific binding molecule can bind to the epitope consisting of residues 367 to 379 of SEQ ID NO:1. This epitope can bind to the CDR of the specific binding molecule (referred to herein as "S1G2").

[0155] 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:

[0156] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0157] VHCDR2 contains the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0158] VHCDR3 contains the sequence shown in SEQ ID NO:54 (SYRADGLAYGYVQAIDY);

[0159] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0160] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0161] VLCDR3 contains the sequence shown in SEQ ID NO:73 (GSSDRTPYTGV);

[0162] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0163] (i) having at least 85% identity with it, and / or

[0164] (ii) relative to having one, two or three amino acid substitutions.

[0165] 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:

[0166] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0167] VHCDR2 contains the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0168] VHCDR3 contains the sequence shown in SEQ ID NO:54 (SYRADGLAYGYVQAIDY);

[0169] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0170] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS); and

[0171] VLCDR3 contains the sequence shown in SEQ ID NO:73 (GSSDRTPYTGV).

[0172] The first specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0173] VHFR1 contains the sequence shown in SEQ ID NO:447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0174] VHFR2 contains the sequence shown in SEQ ID NO:448 (WVRQAPGKAPEWVA);

[0175] VHFR3 contains the sequence shown in SEQ ID NO:449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0176] VHFR4 contains the sequence shown in SEQ ID NO:450 (WGPGLLVTVSS);

[0177] VLFR1 contains the sequence shown in SEQ ID NO:451 (QAVVTQPSSVSGSLGQRVSITC);

[0178] VLFR2 contains the sequence shown in SEQ ID NO:452 (WFQQLPGSGLRTIIV);

[0179] VLFR3 contains the sequence shown in SEQ ID NO:453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0180] VLFR4 contains the sequence shown in SEQ ID NO:454 (FGSGTRLTVLG);

[0181] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0182] (i) having at least 50% similarity to it, and / or

[0183] (ii) relative to having one, two, three, four or five amino acid substitutions.

[0184] The first-specific binding molecule may include the following, or humanized variants thereof:

[0185] (a) The VH domain, which contains SEQ ID NO:455

[0186] The sequences shown in (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVSS) are: and / or

[0187] (b) The VL domain, which contains SEQ ID NO:456

[0188] The sequence shown is (QAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNT ATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG).

[0189] The first specific binding molecule can bind at a Kc of less than approximately 500 pM. D Specifically binds to polypeptide or protein molecules containing the amino acid sequence of residues 367 to 379 of SEQ ID NO:1, optionally wherein the specific binding is measured by surface plasmon resonance (SPR), and optionally wherein...

[0190] iii. K in combination with SEQ ID NO:1 D From approximately 100 pM to approximately 200 pM, and / or

[0191] iv. K binding to SEQ ID NO:5 D It ranges from approximately 400pM to approximately 500pM.

[0192] The first specific binding molecule can compete with any specific binding molecule disclosed herein that binds to epitopes 297 to 391 of SEQ ID NO:1 for binding to SEQ ID NO:1. The first specific binding molecule can also compete with S1D12 or S1G2 for binding to SEQ ID NO:1.

[0193] Competitive antibodies can be identified by those skilled in the art without extensive experimentation or creative inventiveness (e.g., by using conventional competitive binding assays). As used herein, a specific binding molecule competing with another specific binding molecule is achieved by including competition with molecules that specifically bind to the same target.

[0194] In a preferred embodiment, the first specific binding molecule may comprise a CDR of a specific binding molecule selected from the group consisting of S1D12, S1G2 and CA4, and optionally further comprise a framework region, and optionally comprise a VH domain and / or a VL domain.

[0195] The first specific binding molecule can bind to the epitope consisting of residues 355 to 367 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:330 (GSLDNITHVPGGG). This epitope can bind to the CDR of the specific binding molecule (referred to herein as "CA4").

[0196] 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:

[0197] VHCDR1 contains the sequence shown in SEQ ID NO:83 (SYSVY);

[0198] VHCDR2 contains the sequence shown in SEQ ID NO:84 (IMYASGRVDYNPALKS);

[0199] VHCDR3 contains the sequence shown in SEQ ID NO:89(GIEN);

[0200] VLCDR1 contains the sequence shown in SEQ ID NO:91 (RTSQSVNNYLS);

[0201] VLCDR2 contains the sequence shown in SEQ ID NO:95 (YATRLYT); and

[0202] VLCDR3 contains the sequence shown in SEQ ID NO:97 (LQYDSTPLA);

[0203] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0204] (i) having at least 85% identity with it, and / or

[0205] (ii) relative to having one, two or three amino acid substitutions.

[0206] 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:

[0207] VHCDR1 contains the sequence shown in SEQ ID NO:83 (SYSVY);

[0208] VHCDR2 contains the sequence shown in SEQ ID NO:84 (IMYASGRVDYNPALKS);

[0209] VHCDR3 contains the sequence shown in SEQ ID NO:89(GIEN);

[0210] VLCDR1 contains the sequence shown in SEQ ID NO:91 (RTSQSVNNYLS);

[0211] VLCDR2 contains the sequence shown in SEQ ID NO:95 (YATRLYT); and

[0212] VLCDR3 contains the sequence shown in SEQ ID NO:97 (LQYDSTPLA).

[0213] The first specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0214] VHFR1 contains the sequence shown in SEQ ID NO:555 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0215] VHFR2 contains the sequence shown in SEQ ID NO:556 (WVRQAPGQALEWIS);

[0216] VHFR3 contains the sequence shown in SEQ ID NO:557(RLSITRDTSKSQFSLSLSSVTTEDTAVYYCTR);

[0217] VHFR4 contains the sequence shown in SEQ ID NO:558 (WGPGLLVTVSS);

[0218] VLFR1 contains the sequence shown in SEQ ID NO:559 (DIQVTQSPSSLSASLTERVSITC);

[0219] VLFR2 contains the sequence shown in SEQ ID NO:560(WYQQKPGQAPKLLIY);

[0220] VLFR3 contains the sequence shown in SEQ ID NO:561(DVPSRFSGSGSGTDYTLTITSLEADDTATYYC);

[0221] VLFR4 contains the sequence shown in SEQ ID NO:562 (FGGGTNVEIK);

[0222] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0223] (i) having at least 50% similarity to it, and / or

[0224] (ii) relative to having one, two, three, four or five amino acid substitutions.

[0225] The first-specific binding molecule may include the following, or humanized variants thereof:

[0226] (a) The VH domain, which contains SEQ ID NO:563

[0227] The sequence shown is (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSYSVYWVRQAPGQALEWISIMYASGRVDYNPALKSRLSITRDTSKSQFSLSLSSVTTEDTAVYYCTRGIENWGPGLLVTVSS); and / or

[0228] (b) The VL domain, which contains SEQ ID NO:564

[0229] The sequence shown is (DIQVTQSPSSLSASLTERVSITCRTSQSVNNYLSWYQQKPGQAPKLLIYYATRLYTDVPSRFSGSGSGT DYTLTITSLEADDTATYYCLQYDSTPLAFGGGTNVEIK).

[0230] The first specific binding molecule can compete with CA4 for binding to SEQ ID NO:1.

[0231] The first specific binding molecule can compete with S1D12, S1G2 or CA4 for binding to SEQ ID NO:1.

[0232] In a preferred embodiment, the first specific binding molecule may comprise a CDR of a specific binding molecule selected from the group consisting of S1D12 and S1G2, and optionally further comprise a framework region, and optionally comprise a VH domain and / or a VL domain.

[0233] The first specific binding molecule may comprise a CDR of S1D12, S1G2, or CA4, or an alternative specific binding molecule having a neighboring or overlapping epitope relative to any one or more of S1D12, S1G2, or CA4. For example, the first specific binding molecule may be any specific binding molecule disclosed herein that binds to epitopes located within or overlapping with residues 307 to 391 of SEQ ID NO:1. The first specific binding molecule may be any specific binding molecule disclosed herein that binds to epitopes located within or overlapping with residues 337 to 379 of SEQ ID NO:1. The first specific binding molecule may comprise a CDR sequence of a clone listed in Tables 1, 2, 3, 4, 9, 10 (where the epitope is located within or overlapping with residues 307 to 391 of SEQ ID NO:1) or Table 11.

[0234] Second specific binding molecule

[0235] The method may also include contacting the sample with a second specific binding molecule. The second specific binding molecule binds to the epitope in SEQ ID NO:1. Contacting the sample with the second specific binding molecule may be a separate step from contacting the sample with the first specific binding molecule. Contacting the sample with the second specific binding molecule is performed after contacting the sample with the first specific binding molecule. The second specific binding molecule is described below. Any reference to specific binding molecules (not limited to those relating to the first specific binding molecule) under this subheading refers to the first specific binding molecule.

[0236] The second specific binding molecule can be any specific binding molecule disclosed herein, such as the specific binding molecule described in PCT application 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, and its binding affinity is greater than that of antibody mAb423 to the epitope in SEQ ID NO:1.

[0237] The epitope of the second specific binding molecule may be located in SEQ ID NO:3, SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6 or SEQ ID NO:7.

[0238] Provided that the second specific binding molecule differs from the first specific binding molecule, the second specific binding molecule may have any combination of the features described for the first specific binding molecule. For example, the epitopes and / or any one or more sequences of the second specific binding molecule may be as described above for the first specific binding molecule. Alternatively, the epitopes and / or any one or more sequences of the second specific binding molecule may differ from those described above for the first specific binding molecule. The epitopes of the second specific binding molecule may not be found in SEQ ID NO:4, SEQ ID NO:5, SEQ ID NO:6, or SEQ ID NO:7.

[0239] The second specific binding molecule can be a known specific binding molecule, such as HT7, BT2, Tau12, or Tau146. The second specific binding molecule can be HT7 or BT2. BT2 and HT7 are described in US6010913A and 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.

[0240] The second specific binding molecule can bind to epitopes within residues 151 to 243 of SEQ ID NO:1.

[0241] The second specific binding molecule can bind to the epitope consisting of residues 194 to 198 of SEQ ID NO:1. The second specific binding molecule can be BT2.

[0242] The second specific binding molecule can bind to the epitope consisting of residues 159 to 163 of SEQ ID NO:1. The second specific binding molecule can be HT7.

[0243] The second specific binding molecule can compete with BT2 or HT7 for binding to SEQ ID NO:1.

[0244] The second specific binding molecule may comprise HT7 or a CDR of an alternative specific binding molecule disclosed herein, having adjacent or overlapping epitopes, such as 3aA6 and 3aD6, which bind to adjacent epitopes within residues 147 to 157 of SEQ ID NO:1.

[0245] Alternative second specific binding molecules for HT7 and / or BT2 may comprise the CDR of the cloned specific binding molecules listed in Table 8 (optionally also comprising an FW region and optional VH and / or VL domains). For example, a second specific binding molecule may comprise a CDR of 3aA6 or 3aD6. A second specific binding molecule may comprise a CDR and an FW region of 3aA6 or 3aD6. A second specific binding molecule may comprise a VH and / or VL domain of 3aA6 or 3aD6.

[0246] The second specific binding molecule may comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0247] VHCDR1 contains the sequence shown in SEQ ID NO:198 (SNAVI);

[0248] VHCDR2 contains the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS);

[0249] VHCDR3 contains the sequence shown in SEQ ID NO:202 (DYGSWGYVSDIDY);

[0250] VLCDR1 contains the sequence shown in SEQ ID NO:204 (SGSDIGGADVG);

[0251] VLCDR2 contains the sequence shown in SEQ ID NO:206 (DNDNRPS); and

[0252] VLCDR3 contains the sequence shown in SEQ ID NO:208 (GTYSGANYGI);

[0253] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0254] (i) having at least 85% identity with it, and / or

[0255] (ii) relative to having one, two, or three amino acid substitutions.

[0256] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 147 to 157 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "3aD6".

[0257] The second specific binding molecule may comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0258] VHCDR1 contains the sequence shown in SEQ ID NO:198 (SNAVI);

[0259] VHCDR2 contains the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS);

[0260] VHCDR3 contains the sequence shown in SEQ ID NO:202 (DYGSWGYVSDIDY);

[0261] VLCDR1 contains the sequence shown in SEQ ID NO:204 (SGSDIGGADVG);

[0262] VLCDR2 contains the sequence shown in SEQ ID NO:206 (DNDNRPS); and

[0263] VLCDR3 contains the sequence shown in SEQ ID NO:208 (GTYSGANYGI).

[0264] The second specific binding molecule may comprise CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0265] VHCDR1 contains the sequence shown in SEQ ID NO:17 (SNAVG);

[0266] VHCDR2 contains the sequence shown in SEQ ID NO:201 (LIDIDGDTAYNPALES);

[0267] VHCDR3 contains the sequence shown in SEQ ID NO:203 (HYDKWGYADSIDY);

[0268] VLCDR1 contains the sequence shown in SEQ ID NO:138 (SGSSSNVGYGDYVG);

[0269] VLCDR2 contains the sequence shown in SEQ ID NO:207 (DATTRAS); and

[0270] VLCDR3 contains the sequence shown in SEQ ID NO:209 (ASYQNERSGV);

[0271] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0272] (i) having at least 85% identity with it, and / or

[0273] (ii) relative to having one, two, or three amino acid substitutions.

[0274] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 147 to 157 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "3aA6".

[0275] The second specific binding molecule can bind at a Kc of less than approximately 50 nM. D It binds to polypeptide or protein molecules containing the amino acid sequence of residues 147 to 157 of SEQ ID NO:1. D It can be less than approximately 40 nM, less than approximately 30 nM, or less than approximately 20 nM. This K D It can preferably be used in conjunction with SEQ ID NO:1 or SEQ ID NO:191. K in conjunction with SEQ ID NO:1 D It can be from about 10 nM to about 20 nM. K bound to SEQ ID NO:1 D It can be about 16.5 nM, optionally wherein the specific binding molecule contains a CDR of 3aD6.

[0276] The second specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:418, 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. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:418. The CDR may have 100% identity with the CDR of SEQ ID NO:418. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:418, wherein the CDR has 100% identity with the CDR of SEQ ID NO:418. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:418.

[0277] SEQ ID NO:418 (3aA6 amino acid sequence)

[0278] QVRLQESGSSLVKPSQTLSLVCTVSGFPLTSNAVGWVRQAPGKAPEWLGLIDIDGDTAYNPALESRLSITRDTSKSQVSLSLSSVAIEDTAVYYCARHYDKWGYADSIDYWGPGLLVTVSSEG KSSGASGESKVDDQALLTQPSSVFGSLGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYDATTRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYQNERSGVFGSGTRLTVLG

[0279] The second specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:419, 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. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:419. The CDR may have 100% identity with the CDR of SEQ ID NO:419. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:419, wherein the CDR has 100% identity with the CDR of SEQ ID NO:419. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:419.

[0280] SEQ ID NO:419 (3aD6 amino acid sequence)

[0281] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSDIGGADVGWFQQVPGSGLRTLIYDNDNRPSGVPDRFSGSKSGNTATLTISSLQPEDEADYFCGTYSGANYGIFFSGTRLTVLG

[0282] The second specific binding molecule may include a CDR of BT2, or a CDR of an alternative specific binding molecule with adjacent or overlapping epitopes as disclosed herein.

[0283] Alternative second specific binding molecules for HT7 and / or BT2 may include the CDR of the specific binding molecules listed in Table 10 (optionally also including an FW region and optional VH and / or VL domains). For example, the second specific binding molecule may include the CDR of 3bD11, CB11, CA2, CB6, CA7, CA8, CB10, CC7, CB12, CC3, CA1, CA3, CD2, CC4, CD1, or CC5. The second specific binding molecule may include the CDR 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 contain a VH domain and / or a VL domain of 3bD11, CB11, CA2, CB6, CA7, CA8, CB10, CC7, CB12, CC3, CA1, CA3, CD2, CC4, CD1, or CC5.

[0284] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0285] VHCDR1 contains the VHCDR1 amino acid sequence shown in Table 10;

[0286] VHCDR2 contains the VHCDR2 amino acid sequence shown in Table 10;

[0287] VHCDR3 contains the VHCDR3 amino acid sequence shown in Table 10;

[0288] VLCDR1 contains the VLCDR1 amino acid sequence shown in Table 10;

[0289] VLCDR2 contains the VLCDR2 amino acid sequence shown in Table 10; and

[0290] VLCDR3 contains the VLCDR3 amino acid sequence shown in Table 10;

[0291] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0292] (i) having at least 85% identity with it, and / or

[0293] (ii) relative to having one, two, or three amino acid substitutions.

[0294] The specific binding molecule binds to the epitope in SEQ ID NO:1. VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3 can be derived from a single clone listed in Table 10. This clone can be selected from the group consisting of 3bD11, CB11, CA2, CB6, CA7, CA8, CB10, CC7, CB12, CC3, CA1, CA3, CD2, CC4, CD1, and CC5.

[0295] General characteristics of first and / or second specific binding molecules

[0296] The following describes the general characteristics of a specific binding molecule and includes details of the specific binding molecule described in PCT application PCT / EP2021 / 069160. Any reference to a specific binding molecule under this subheading (not limited to being specifically associated with a first or second specific binding molecule) refers to a specific binding molecule in general and is expressly considered to be binding to any characteristic of a first or second specific binding molecule, provided that the first specific binding molecule binds to the epitopes within residues 297 to 391 of SEQ ID NO:1 (therefore, the specific binding molecule disclosed herein that does not bind to the epitopes within residues 297 to 391 of SEQ ID NO:1 refers only to the second specific binding molecule).

[0297] 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 the full-length Tau are also referred to as the major fragment isolated from the proteolytically stable core of the paired helical filament (PHF) or the PHF core fragment. Therefore, the epitope of the specific binding molecule can be located within the PHF or the dGAE fragment. Therefore, the epitope of the specific binding molecule can be located within SEQ ID NO:4.

[0298] The epitope of the specifically binding molecule may be located within residues 297 to 390 of SEQ ID NO:1. Residues 297 to 390 of the full-length Tau are also referred to as the dGA fragment. Therefore, the epitope of the specifically binding molecule may be located within the dGA fragment. Therefore, the epitope of the specifically binding molecule may be located within SEQ ID NO:5. The epitope of the specifically binding molecule may be located within dGAE73 and / or dGAE71. Therefore, the epitope of the specifically binding molecule may be located within SEQ ID NO:6 and / or SEQ ID NO:7.

[0299] The epitope of the specifically binding molecule can be located within residues 308 to 378 of SEQ ID NO:1. Residues 308 to 378 of the full-length Tau are also referred to as the PHF core. Therefore, the epitope of the specifically binding molecule can be located within the PHF core. Therefore, the epitope of the specifically binding molecule can be located within SEQ ID NO:7.

[0300] The epitope of the specifically binding molecule may be located within residues 297 to 386 of SEQ ID NO:1. The epitope of the specifically binding molecule may be located within residues 306 to 391 of SEQ ID NO:1. The epitope of the specifically binding molecule may be located within residues 306 to 386 of SEQ ID NO:1.

[0301] The epitope of the specific binding molecule may 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 1 to 49 ... 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, 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 26 Residues 348 to 441 of NO:1, residues 359 to 391 of SEQ ID NO:1, and residues 360 to 390 of SEQ ID NO:1.

[0302] 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, 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.

[0303] 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.

[0304] The epitope that specifically binds to the molecule may be located within the amino acid sequence selected from residues 341 to 353 of SEQ ID NO:1.

[0305] 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 by ELISA or alanine scanning mutagenesis to contain key binding residues, as described in Examples 5 to 12.

[0306] The epitopes described herein may be referred to as "containing" a certain amino acid sequence, or by the phrase "specifically binding molecule binds to a polypeptide or protein molecule containing an amino acid sequence having residues...". As will be apparent to those skilled in the art, when a specific binding molecule binds to a polypeptide or protein molecule containing its epitope, the specific binding molecule will also bind to polypeptide or protein molecules composed of its epitope. Therefore, as used herein, the phrase "specifically binding molecule binds to a polypeptide or protein molecule containing an amino acid sequence having residues..." wherever it appears may alternatively be replaced by the phrase "specifically binding molecule binds to a polypeptide or protein molecule containing an amino acid sequence consisting of residues..."; or the phrase "specifically binding molecule binds to a polypeptide or protein molecule consisting of an amino acid sequence having residues..."; or the phrase "specifically binding molecule binds to a polypeptide or protein molecule consisting of an amino acid sequence consisting of residues...".

[0307] Those skilled in the art will understand that not all residues within an epitope are essential. Specific binding molecules can maintain binding to an amino acid sequence that has at least 70% identity with the epitope. Specific binding molecules can bind to any epitope disclosed herein or an amino acid sequence that has at least 70% identity with it.

[0308] The specific binding molecule can maintain binding to an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with an epitope. The specific binding molecule can bind to any epitope disclosed herein or an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with it.

[0309] In embodiments of the invention, the specific binding molecule maintains binding with an amino acid sequence having less than 100% sequence identity with the amino acid sequence SEQ ID NO:1 (or any of SEQ ID NO:3 to SEQ ID NO:7, or any other epitope as defined herein), the epitope sequence of which can be altered by substitution, insertion, or deletion of an appropriate number of amino acids in sequence SEQ ID NO:1 (or any of SEQ ID NO:3 to SEQ ID NO:7, or any other epitope as defined herein). In another embodiment of the invention, the epitope can be modified by substitution, insertion, or deletion of up to two amino acids relative to SEQ ID NO:1 (or any of SEQ ID NO:3 to SEQ ID NO:7, or any other epitope as defined herein), provided that the resulting epitope sequence has at least 85% or 90% sequence identity with SEQ ID NO:1 (or any of SEQ ID NO:3 to SEQ ID NO:7, or any other epitope as defined herein), as described above. “Substitution, insertion, or deletion” includes combinations of substitution, insertion, and deletion.

[0310] When an epitope sequence is modified by replacing a specific amino acid residue, the substitution can be a conserved amino acid substitution. As used herein, the term "conserved amino acid substitution" refers to an amino acid substitution in which one amino acid residue is replaced by another amino acid residue with a similar side chain. Amino acids with similar side chains tend to have similar properties, and therefore it can be expected that a conserved substitution of an amino acid important for the structure or function of a polypeptide will have a smaller impact on the polypeptide structure / function than a non-conserved amino acid substitution 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), nonpolar side chains (e.g., glycine, cysteine, alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine, tryptophan), and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine). Therefore, a conserved amino acid substitution can be considered as a substitution in which a specific amino acid residue is replaced by a different amino acid from the same family. However, the substitution of epitope residues can also be a non-conservative substitution, in which one amino acid is replaced by another amino acid with a side chain belonging to a different family.

[0311] Epitopes can be at least five, six, seven, eight, nine, ten, eleven, twelve, thirteen, fourteen, fifteen, sixteen, seventeen, eighteen, nineteen, or twenty amino acids long. Epitopes can be 5 to 20 amino acids long. Epitopes can be 5 to 15 amino acids long. Epitopes can be 5 to 12 amino acids long. Epitopes can be 6 to 12 amino acids long. Epitopes can be 7 to 12 amino acids long.

[0312] As used herein, the term "located within" means "included within" or "completely located within". None of the residues considered essential for the binding of the specifically binding molecule to its target are outside the epitope. Residues outside the epitope do not significantly contribute to binding. For example, when the epitope of the specifically binding molecule is within residues 337 to 355 of SEQ ID NO:1, residues outside 337 to 355 do not significantly contribute to binding.

[0313] Epitopes may contain any residue in SEQ ID NO:1 that binds to a specifically binding molecule. Epitopes may be continuous or non-continuous.

[0314] A continuous epitope can be any consecutive residue within SEQ ID NO:1 that binds to a specific binding molecule. The consecutive residues are adjacent to each other in the primary structure of the polypeptide.

[0315] Discontinuous epitopes can be any non-continuous residue within SEQ ID NO:1 that binds to a specifically binding molecule. Discontinuous epitopes are typically formed by non-continuous residues that occupy adjacent positions in three-dimensional space due to polypeptide folding.

[0316] Typically, specific binding molecules bind to polypeptide or protein molecules containing their epitopes. Therefore, specific binding molecules can bind to SEQ ID NO:1 or fragments thereof. Specific binding molecules 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. Specific binding molecules can bind to PHF or dGAE fragments. Specific binding molecules can bind to dGA fragments. Specific binding molecules can bind to the PHF core. The specific binding molecule can bind to polypeptide or protein molecules containing amino acid sequences 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, and ...337 to 355 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 348 to 441 of SEQ ID NO:1, residues 359 to 391 of SEQ ID NO:1, and SEQ ID NO:1 Residues 360 to 390 of NO:1.

[0317] The specific binding molecule can bind to polypeptide or protein molecules containing amino acid sequences of residues 341 to 353 of SEQ ID NO:1.

[0318] In the sequence described herein, " / " indicates "or" and signifies that the residues shown by the inventors can be varied as specified. In this case, "-" indicates an empty position or absence of an amino acid. X is any amino acid. For example, "N / S" indicates that the residue can be N or S. Similarly, "G / -" indicates that the residue can be G or absent. Likewise, "H / F / Y" indicates that the residue can be H, F, or Y. When specifying sequence identity values, sequence identity can be calculated starting from any residue separated by " / ".

[0319] The epitope of a specific binding molecule may be located within the amino acid sequence containing residues 337 to 355 of SEQ ID NO:1. The epitope of a specific binding molecule located within the amino acid sequence containing residues 337 to 355 of SEQ ID NO:1 may be located within the amino acid sequence containing residues 341 to 353 of SEQ ID NO:1. Therefore, the epitope may be located within the amino acid sequence of SEQ ID NO:8 (VEVKSEKLDFKDR).

[0320] The epitope may 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. This epitope can bind to the CDR of a specific binding molecule referred to herein as “S1D12”. The epitope may comprise the amino acid sequence of SEQ ID NO:8 (VEVKSEKLDFKDR). The epitope may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:8 (VEVKSEKLDFKDR). The key residues of the epitope may be residues 343 (K), 346 (F), and / or 349 (R) (as numbered according to SEQ ID NO:1). The epitope may comprise the amino acid sequence of SEQ ID NO:9 (XXXXXXXKXXFXXR, where X is any amino acid). The epitope may comprise the amino acid sequence SEQ ID NO:8, wherein any one or more residues other than residues numbered 343(K), 346(F), and / or 349(R) are replaced by non-conservative amino acid substitutions (according to SEQ ID NO:1). The epitope may comprise the amino acid sequence SEQ ID NO:8, wherein any one or more residues other than residues numbered 343(K), 346(F), and / or 349(R) are replaced by conserved amino acid substitutions (according to SEQ ID NO:1), and any one or more residues other than residues numbered 343(K), 346(F), and / or 349(R) are replaced by non-conservative amino acid substitutions (according to SEQ ID NO:1).

[0321] The epitope may consist of residues 337 to 349 of SEQ ID NO:1, preferably residues 337 to 355 of SEQ ID NO:1. The epitope may consist of the amino acid sequence of SEQ ID NO:8 (VEVKSEKLDFKDR). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:8 (VEVKSEKLDFKDR).

[0322] The specific binding molecule can bind to polypeptide or protein molecules containing amino acid sequences of residues 337 to 355 of SEQ ID NO:1. The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each CDR contains the following amino acid sequence:

[0323] VHCDR1 contains the sequence shown in SEQ ID NO:10 (N / SNAVG);

[0324] VHCDR2 contains the sequence shown in SEQ ID NO:11 (GCSSDGT / KCYY / HNSALKS);

[0325] VHCDR3 contains the sequence shown in SEQ ID NO:12 (GH / F / YYS / PI / VYGYDYL / SGTIDY);

[0326] VLCDR1 contains the sequence shown in SEQ ID NO:13 (SGSSSNVG / -GG / RNS / DVG / A);

[0327] VLCDR2 contains the sequence shown in SEQ ID NO:14 (D / N / GTN / TSRPS);

[0328] VLCDR3 contains the sequence shown in SEQ ID NO:15 (V / AT / SGDST / ST / AH / ID / NDL / I);

[0329] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0330] (i) having at least 85% identity with it, and / or

[0331] (ii) relative to having one, two or three amino acid substitutions.

[0332] The sequence identity is at least about 85% sequence identity, and therefore 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%.

[0333] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0334] VHCDR1 contains the sequence shown in SEQ ID NO:16 (NNAVG) or SEQ ID NO:17 (SNAVG);

[0335] VHCDR2 contains the sequences shown in SEQ ID NO:18 (GCSSDGTCYYNSALKS), SEQ ID NO:19 (GCSSDGKCYHNSALKS), or SEQ ID NO:20 (GCSSDGKCYYNSALKS);

[0336] VHCDR3 includes the sequence shown in SEQ ID NO:21 (GHYSIYGYDYLGTIDY), SEQ ID NO:22 (GFYSIYGYDYSGTIDY) or SEQ ID NO:23 (GYYPVYGYDYLGTIDY);

[0337] VLCDR1 contains the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG) or SEQ ID NO:25 (SGSSSNVGRNDVA);

[0338] VLCDR2 contains the sequences shown in SEQ ID NO:26 (DTNSRPS), SEQ ID NO:27 (NTNSRPS), or SEQ ID NO:28 (GTTSRPS);

[0339] VLCDR3 contains the sequence shown in SEQ ID NO:29 (VTGDSTTHDDL), SEQ ID NO:30 (VTGDSSTHDDL), or SEQ ID NO:31 (ASGDSSAINDI);

[0340] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0341] (i) having at least 85% identity with it, and / or

[0342] (ii) relative to having one, two, or three amino acid substitutions.

[0343] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 337 to 355 of SEQ ID NO:1.

[0344] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0345] VHCDR1 contains the sequence shown in SEQ ID NO:16 (NNAVG);

[0346] VHCDR2 contains the sequence shown in SEQ ID NO:18 (GCSSDGTCYYNSALKS);

[0347] VHCDR3 contains the sequence shown in SEQ ID NO:21 (GHYSIYGYDYLGTIDY);

[0348] VLCDR1 contains the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0349] VLCDR2 contains the sequence shown in SEQ ID NO:26 (DTNSRPS);

[0350] VLCDR3 contains the sequence shown in SEQ ID NO:29 (VTGDSTTHDDL);

[0351] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0352] (i) having at least 85% identity with it, and / or

[0353] (ii) relative to having one, two, or three amino acid substitutions.

[0354] Specifically, the binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 337 to 355 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the one described above is referred to herein as “S1D12” (or abbreviated as “1D12”).

[0355] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0356] VHCDR1 contains the sequence shown in SEQ ID NO:16 (NNAVG);

[0357] VHCDR2 contains the sequence shown in SEQ ID NO:18 (GCSSDGTCYYNSALKS);

[0358] VHCDR3 contains the sequence shown in SEQ ID NO:21 (GHYSIYGYDYLGTIDY);

[0359] VLCDR1 contains the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0360] VLCDR2 contains the sequence shown in SEQ ID NO:26 (DTNSRPS); and

[0361] VLCDR3 contains the sequence shown in SEQ ID NO:29 (VTGDSTTHDDL).

[0362] The specific binding molecules disclosed herein can be further defined with reference to one or more frame regions (FRs). Frame regions (FRs) are non-CDR sequences that, together with CDR sequences, form variable domains.

[0363] The VH domain can have the following structure: VHFR1-VHCDR1-VHFR2–VHCDR2-VHFR3–VHCDR3-VHFR4.

[0364] The VL domain can have the following structure: VLFR1-VLCDR1-VLFR2–VLCDR2-VLFR3–VLCDR3-VLFR4.

[0365] Those skilled in the art can identify CDRs and framework regions within the amino acid sequence of variable domains using known methods described elsewhere herein. Therefore, any specific binding molecule disclosed herein can be defined by reference to its CDR and FR. In some cases, certain FR residues can contribute to the affinity of a specific binding molecule for its target. However, without being bound by theory, substituting FR residues is more likely to preserve function than substituting CDR residues. For example, during humanization, FR residues can often be substituted with corresponding residues from human sequences. Therefore, FR sequences can be more tolerant of amino acid substitutions than CDR sequences.

[0366] Specific binding molecules may include:

[0367] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains an amino acid sequence from any of the specific binding molecules disclosed herein; or for each FR sequence, it contains an amino acid sequence having the following:

[0368] (i) having at least 50% similarity to it, and / or

[0369] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0370] (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:

[0371] (i) having at least 85% identity with it, and / or

[0372] (ii) relative to having one, two or three amino acid substitutions.

[0373] The sequence identity in the CDR sequence is at least about 85% sequence identity, and therefore 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%.

[0374] The sequence identity in the FR sequence is at least about 50% sequence identity, and therefore can be at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 86%, at least 87%, at least 88%, at least 89%, at least 90%, at least 91%, at least 92%, at least 93%, at least 94%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity. Preferably, the sequence identity is at least 90% or at least 95%.

[0375] The FR sequence can be a humanized sequence when it shares at least 50% (but less than 100%) identity with a disclosed FR sequence of a subset of the specific binding molecules disclosed herein. In other words, the change in amino acid sequence can be simply the change required for sequence humanization.

[0376] The FR sequence can be a humanized sequence when it has one, two, three, four, or five amino acid substitutions relative to a portion of the FR sequence disclosed in the specific binding molecules herein. In other words, the substitutions can be simply those required for sequence humanization.

[0377] Specific binding molecules may include:

[0378] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains an amino acid sequence from any of the specifically binding molecules disclosed herein; and

[0379] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains an amino acid sequence from any specific binding molecule disclosed herein.

[0380] Typically, each of the FRs originates from the same specific binding molecule disclosed herein. Typically, each of the CDRs originates from the same specific binding molecule disclosed herein. Typically, no additional amino acid residues are inserted between the defined FRs and CDRs; therefore, it can be said that each of the FRs and each of the CDRs consists of an amino acid sequence from any specific binding molecule disclosed herein.

[0381] As used herein, the phrase "containing a CDR" also encompasses specific binding molecules containing the CDR and FR (which contain FR variants, FR variants described above, such as humanized FR) of the specific binding molecules disclosed herein. It also encompasses specific binding molecules containing the VH and / or VL domains (which contain FR variants, FR variants described above, such as humanized FR) of the specific binding molecules disclosed herein. Furthermore, it encompasses specific binding molecules containing the heavy chain and / or light chain (which contain FR variants and constant regions, FR variants described above and constant regions, such as humanized FR and humanized constant regions) of the specific binding molecules disclosed herein.

[0382] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0383] VHFR1 contains the sequence shown in SEQ ID NO:435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0384] VHFR2 contains the sequence shown in SEQ ID NO:436 (WVRQAPGKVPESLV);

[0385] VHFR3 contains the sequence shown in SEQ ID NO:437(RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0386] VHFR4 contains the sequence shown in SEQ ID NO:438 (WGPGLLVTVSS);

[0387] VLFR1 contains the sequence shown in SEQ ID NO:439 (QAVLTQPSSVSGSLGQRVSITC);

[0388] VLFR2 contains the sequence shown in SEQ ID NO:440(WYQHLPGSGLKTIIY);

[0389] VLFR3 contains the sequence shown in SEQ ID NO:441(GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0390] VLFR4 contains the sequence shown in SEQ ID NO:442 (VGSGTRLTVLG);

[0391] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0392] (i) having at least 50% similarity to it, and / or

[0393] (ii) relative to having one, two, three, four or five amino acid substitutions.

[0394] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0395] VHFR1 contains the sequence shown in SEQ ID NO:435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0396] VHFR2 contains the sequence shown in SEQ ID NO:436 (WVRQAPGKVPESLV);

[0397] VHFR3 contains the sequence shown in SEQ ID NO:437(RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0398] VHFR4 contains the sequence shown in SEQ ID NO:438 (WGPGLLVTVSS);

[0399] VLFR1 contains the sequence shown in SEQ ID NO:439 (QAVLTQPSSVSGSLGQRVSITC);

[0400] VLFR2 contains the sequence shown in SEQ ID NO:440(WYQHLPGSGLKTIIY);

[0401] VLFR3 contains the sequence shown in SEQ ID NO:441(GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0402] VLFR4 contains the sequence shown in SEQ ID NO:442 (VGSGTRLTVLG);

[0403] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0404] (i) having at least 50% similarity to it, and / or

[0405] (ii) relative to having one, two, three, four or five amino acid substitutions,

[0406] Specifically, the 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. The specific binding molecule comprising FR having 100% identity with the above is referred to herein as “S1D12” (or abbreviated as “1D12”).

[0407] Specific binding molecules may include:

[0408] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0409] VHFR1 contains the sequence shown in SEQ ID NO:435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0410] VHFR2 contains the sequence shown in SEQ ID NO:436 (WVRQAPGKVPESLV);

[0411] VHFR3 contains the sequence shown in SEQ ID NO:437(RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0412] VHFR4 contains the sequence shown in SEQ ID NO:438 (WGPGLLVTVSS);

[0413] VLFR1 contains the sequence shown in SEQ ID NO:439 (QAVLTQPSSVSGSLGQRVSITC);

[0414] VLFR2 contains the sequence shown in SEQ ID NO:440(WYQHLPGSGLKTIIY);

[0415] VLFR3 contains the sequence shown in SEQ ID NO:441(GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0416] VLFR4 contains the sequence shown in SEQ ID NO:442 (VGSGTRLTVLG);

[0417] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0418] (i) having at least 50% similarity to it, and / or

[0419] (ii) relative to having one, two, three, four or five amino acid substitutions, and

[0420] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0421] VHCDR1 contains the sequence shown in SEQ ID NO:16 (NNAVG);

[0422] VHCDR2 contains the sequence shown in SEQ ID NO:18 (GCSSDGTCYYNSALKS);

[0423] VHCDR3 contains the sequence shown in SEQ ID NO:21 (GHYSIYGYDYLGTIDY);

[0424] VLCDR1 contains the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0425] VLCDR2 contains the sequence shown in SEQ ID NO:26 (DTNSRPS);

[0426] VLCDR3 contains the sequence shown in SEQ ID NO:29 (VTGDSTTHDDL);

[0427] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0428] (i) having at least 85% identity with it, and / or

[0429] (ii) relative to having one, two, or three amino acid substitutions.

[0430] Specifically, the binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 337 to 355 of SEQ ID NO:1. The specific binding molecule containing FR and CDR that are 100% identical to those described above is referred to herein as “S1D12” (or abbreviated as “1D12”).

[0431] Specific binding molecules may include:

[0432] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0433] VHFR1 contains the sequence shown in SEQ ID NO:435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0434] VHFR2 contains the sequence shown in SEQ ID NO:436 (WVRQAPGKVPESLV);

[0435] VHFR3 contains the sequence shown in SEQ ID NO:437(RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0436] VHFR4 contains the sequence shown in SEQ ID NO:438 (WGPGLLVTVSS);

[0437] VLFR1 contains the sequence shown in SEQ ID NO:439 (QAVLTQPSSVSGSLGQRVSITC);

[0438] VLFR2 contains the sequence shown in SEQ ID NO:440(WYQHLPGSGLKTIIY);

[0439] VLFR3 contains the sequence shown in SEQ ID NO:441(GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0440] VLFR4 contains the sequence shown in SEQ ID NO:442 (VGSGTRLTVLG);

[0441] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0442] (i) having at least 50% similarity to it, and / or

[0443] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0444] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0445] VHCDR1 contains the sequence shown in SEQ ID NO:16 (NNAVG);

[0446] VHCDR2 contains the sequence shown in SEQ ID NO:18 (GCSSDGTCYYNSALKS);

[0447] VHCDR3 contains the sequence shown in SEQ ID NO:21 (GHYSIYGYDYLGTIDY);

[0448] VLCDR1 contains the sequence shown in SEQ ID NO:24 (SGSSSNVGGGNSVG);

[0449] VLCDR2 contains the sequence shown in SEQ ID NO:26 (DTNSRPS);

[0450] VLCDR3 contains the sequence shown in SEQ ID NO:29 (VTGDSTTHDDL);

[0451] Specifically, the binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 337 to 355 of SEQ ID NO:1. The specific binding molecule containing FR and CDR that are 100% identical to those described above is referred to herein as “S1D12” (or abbreviated as “1D12”).

[0452] Specific binding molecules may include the following or their humanized variants:

[0453] (a) The VH domain, which contains SEQ ID NO:443

[0454] The sequence shown in (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSS); and / or

[0455] (b) The VL domain, which contains SEQ ID NO:444

[0456] The sequence shown is (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG).

[0457] Specific binding molecules may include the following or their humanized variants:

[0458] (a) Heavy chain, which contains SEQ ID NO:445

[0459] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWG PGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPC PPCKCPAPNLLGGPSVFIFPPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPK and / or

[0460] (b) A light chain containing SEQ ID NO:446

[0461] The sequence shown is (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVC TITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTV EKSLSRADCS).

[0462]

[0463] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0464] VHCDR1 contains the VHCDR1 amino acid sequence shown in Table 1;

[0465] VHCDR2 contains the VHCDR2 amino acid sequence shown in Table 1;

[0466] VHCDR3 contains the VHCDR3 amino acid sequence shown in Table 1;

[0467] VLCDR1 contains the VLCDR1 amino acid sequence shown in Table 1;

[0468] VLCDR2 contains the VLCDR2 amino acid sequence shown in Table 1; and

[0469] VLCDR3 contains the VLCDR3 amino acid sequence shown in Table 1;

[0470] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0471] (i) having at least 85% identity with it, and / or

[0472] (ii) relative to having one, two, or three amino acid substitutions.

[0473] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 337 to 355 of SEQ ID NO:1.

[0474] Specific binding molecules can be at a Kc of less than approximately 500 pM. DIt binds to polypeptide or protein molecules containing the amino acid sequence of residues 337 to 355 of SEQ ID NO:1. D It can be less than approximately 400 pM, less than approximately 300 pM, less than approximately 200 pM, or less than approximately 150 pM. This K D It can be preferably used in combination with SEQ ID NO:1 or SEQ ID NO:5. K in combination with SEQ ID NO:1 D It can be from approximately 50 pM to approximately 150 pM. K bound to SEQ ID NO:1 D It can be approximately 101 pM or 122 pM, optionally wherein the specifically binding molecule comprises a CDR of S1D12. K binds to SEQ ID NO:5 D It can be from approximately 300 pM to approximately 400 pM. K bound to SEQ ID NO:5 D It can be about 344 pM, optionally wherein the specific binding molecule contains the CDR of S1D12.

[0475] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:32, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 337 to 355 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:30. The CDR may have 100% identity with the CDR of SEQ ID NO:32. The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:30, wherein the CDR has 100% identity with the CDR of SEQ ID NO:32. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:32.

[0476] SEQ ID NO:32 (S1D12 amino acid sequence)

[0477] QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG

[0478] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 367 to 379 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:33 (GNKKIETHKLTFR).

[0479] This epitope may be located within the amino acid sequence containing residues 367 to 379 of SEQ ID NO:1. This epitope may be bound by the CDR of a specific binding molecule referred to herein as “S1G2”.

[0480] 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 with SEQ ID NO:33 (GNKKIETHKLTFR). The key residues of the epitope may be residues 370(K) and / or 374(H) (as per SEQ ID NO:1). The epitope may comprise the amino acid sequence of SEQ ID NO:34 (XXXKXXXHXXXXX, where X is any amino acid). The epitope may comprise the amino acid sequence of SEQ ID NO:33, wherein any one or more residues other than residues 370(K) and / or 374(H) are replaced by non-conservative amino acid substitutions (as per 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 residues 370(K) and / or 374(H) are replaced by conserved amino acid substitutions (as per SEQ ID NO:1). Epitopes may contain the amino acid sequence of SEQ ID NO:33, wherein any one or more residues other than residue number 370(K) and / or 374(H) are replaced by conserved amino acid substitutions (according to SEQ ID NO:1), and any one or more residues other than residue number 370(K) and / or 374(H) are replaced by non-conserved amino acid substitutions (according to SEQ ID NO:1).

[0481] The epitope may consist of the amino acid sequence of SEQ ID NO:33 (GNKKIETHKLTFR). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:33 (GNKKIETHKLTFR).

[0482] The specific binding molecule can bind to polypeptide or protein molecules containing amino acid sequences of residues 367 to 379 of SEQ ID NO:1. The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0483] VHCDR1 contains the sequence shown in SEQ ID NO:35 (S / TN / YS / A / YVG);

[0484] VHCDR2 contains the sequence shown in SEQ ID NO:36 (G / S / NI / VD / YT / SD / TGE / Y / D / RE / T / AG / Y / FY / FNPA / VLN / KS);

[0485] VHCDR3 contains the sequence shown 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);

[0486] VLCDR1 contains 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);

[0487] VLCDR2 contains the sequence shown in SEQ ID NO:40 (A / DS / AD / S / TG / SRP / AS);

[0488] VLCDR3 contains 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);

[0489] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0490] (i) having at least 85% identity with it, and / or

[0491] (ii) relative to having one, two or three amino acid substitutions.

[0492] The sequence identity is at least about 85% sequence identity, and therefore 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%.

[0493] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0494] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG), SEQ ID NO:17 (SNAVG), SEQ ID NO:44 (SYYVG), or SEQ ID NO:45 (TNSVG);

[0495] 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);

[0496] 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);

[0497] VLCDR1 contains the sequences shown 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);

[0498] VLCDR2 contains the sequences shown in SEQ ID NO:70 (ASDGRPS); SEQ ID NO:71 (DSSSRPS); or SEQ ID NO:72 (AATSRAS);

[0499] VLCDR3 contains the sequences shown 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).

[0500] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0501] (i) having at least 85% identity with it, and / or

[0502] (ii) relative to having one, two, or three amino acid substitutions.

[0503] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO:1.

[0504] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0505] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0506] VHCDR2 contains the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0507] VHCDR3 contains the sequence shown in SEQ ID NO:54 (SYRADGLAYGYVQAIDY);

[0508] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0509] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0510] VLCDR3 contains the sequence shown in SEQ ID NO:73 (GSSDRTPYTGV);

[0511] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0512] (i) having at least 85% identity with it, and / or

[0513] (ii) relative to having one, two, or three amino acid substitutions.

[0514] The specific binding molecule binds to polypeptide or protein molecules containing amino acid sequences of residues 367 to 379 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the one described above is referred to herein as "S1G2".

[0515] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0516] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0517] VHCDR2 contains the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0518] VHCDR3 contains the sequence shown in SEQ ID NO:54 (SYRADGLAYGYVQAIDY);

[0519] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0520] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS); and

[0521] VLCDR3 contains the sequence shown in SEQ ID NO:73 (GSSDRTPYTGV).

[0522] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0523] VHFR1 contains the sequence shown in SEQ ID NO:447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0524] VHFR2 contains the sequence shown in SEQ ID NO:448 (WVRQAPGKAPEWVA);

[0525] VHFR3 contains the sequence shown in SEQ ID NO:449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0526] VHFR4 contains the sequence shown in SEQ ID NO:450 (WGPGLLVTVSS);

[0527] VLFR1 contains the sequence shown in SEQ ID NO:451 (QAVVTQPSSVSGSLGQRVSITC);

[0528] VLFR2 contains the sequence shown in SEQ ID NO:452 (WFQQLPGSGLRTIIV);

[0529] VLFR3 contains the sequence shown in SEQ ID NO:453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0530] VLFR4 contains the sequence shown in SEQ ID NO:454 (FGSGTRLTVLG);

[0531] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0532] (i) having at least 50% similarity to it, and / or

[0533] (ii) relative to having one, two, three, four or five amino acid substitutions.

[0534] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0535] VHFR1 contains the sequence shown in SEQ ID NO:447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0536] VHFR2 contains the sequence shown in SEQ ID NO:448 (WVRQAPGKAPEWVA);

[0537] VHFR3 contains the sequence shown in SEQ ID NO:449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0538] VHFR4 contains the sequence shown in SEQ ID NO:450 (WGPGLLVTVSS);

[0539] VLFR1 contains the sequence shown in SEQ ID NO:451 (QAVVTQPSSVSGSLGQRVSITC);

[0540] VLFR2 contains the sequence shown in SEQ ID NO:452 (WFQQLPGSGLRTIIV);

[0541] VLFR3 contains the sequence shown in SEQ ID NO:453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0542] VLFR4 contains the sequence shown in SEQ ID NO:454 (FGSGTRLTVLG);

[0543] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0544] (i) having at least 50% similarity to it, and / or

[0545] (ii) relative to having one, two, three, four or five amino acid substitutions,

[0546] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 367 to 379 of SEQ ID NO:1. The specific binding molecule containing a FR that is 100% identical to the above-mentioned FR is referred to herein as "S1G2".

[0547] Specific binding molecules may include:

[0548] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0549] VHFR1 contains the sequence shown in SEQ ID NO:447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0550] VHFR2 contains the sequence shown in SEQ ID NO:448 (WVRQAPGKAPEWVA);

[0551] VHFR3 contains the sequence shown in SEQ ID NO:449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0552] VHFR4 contains the sequence shown in SEQ ID NO:450 (WGPGLLVTVSS);

[0553] VLFR1 contains the sequence shown in SEQ ID NO:451 (QAVVTQPSSVSGSLGQRVSITC);

[0554] VLFR2 contains the sequence shown in SEQ ID NO:452 (WFQQLPGSGLRTIIV);

[0555] VLFR3 contains the sequence shown in SEQ ID NO:453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0556] VLFR4 contains the sequence shown in SEQ ID NO:454 (FGSGTRLTVLG);

[0557] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0558] (i) having at least 50% similarity to it, and / or

[0559] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0560] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0561] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0562] VHCDR2 contains the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0563] VHCDR3 contains the sequence shown in SEQ ID NO:54 (SYRADGLAYGYVQAIDY);

[0564] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0565] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS); and

[0566] VLCDR3 contains the sequence shown in SEQ ID NO:73 (GSSDRTPYTGV).

[0567] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0568] (i) having at least 85% identity with it, and / or

[0569] (ii) relative to having one, two, or three amino acid substitutions.

[0570] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 367 to 379 of SEQ ID NO:1. The specific binding molecule containing FRs and CDRs that are 100% identical to the above-mentioned FRs and CDRs is referred to herein as "S1G2".

[0571] Specific binding molecules may include:

[0572] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0573] VHFR1 contains the sequence shown in SEQ ID NO:447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0574] VHFR2 contains the sequence shown in SEQ ID NO:448 (WVRQAPGKAPEWVA);

[0575] VHFR3 contains the sequence shown in SEQ ID NO:449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0576] VHFR4 contains the sequence shown in SEQ ID NO:450 (WGPGLLVTVSS);

[0577] VLFR1 contains the sequence shown in SEQ ID NO:451 (QAVVTQPSSVSGSLGQRVSITC);

[0578] VLFR2 contains the sequence shown in SEQ ID NO:452 (WFQQLPGSGLRTIIV);

[0579] VLFR3 contains the sequence shown in SEQ ID NO:453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0580] VLFR4 contains the sequence shown in SEQ ID NO:454 (FGSGTRLTVLG);

[0581] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0582] (i) having at least 50% similarity to it, and / or

[0583] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0584] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0585] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0586] VHCDR2 contains the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0587] VHCDR3 contains the sequence shown in SEQ ID NO:54 (SYRADGLAYGYVQAIDY);

[0588] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0589] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS); and

[0590] VLCDR3 contains the sequence shown in SEQ ID NO:73 (GSSDRTPYTGV).

[0591] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 367 to 379 of SEQ ID NO:1. The specific binding molecule containing FRs and CDRs that are 100% identical to the above-mentioned FRs and CDRs is referred to herein as "S1G2".

[0592] Specific binding molecules may include the following or their humanized variants:

[0593] (a) The VH domain, which contains SEQ ID NO:455

[0594] The sequences shown in (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVSS) are: and / or

[0595] (b) The VL domain, which contains SEQ ID NO:456

[0596] The sequence shown is (QAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNT ATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG).

[0597] Specific binding molecules may include the following or their humanized variants:

[0598] (a) Heavy chain, which contains SEQ ID NO:457

[0599] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYW GPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPC PPCKCPAPNLLGGPSVFIFPPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPK and / or

[0600] (b) A light chain containing SEQ ID NO:458

[0601] The sequence shown is (QAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNT ATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLS RADCS).

[0602] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0603] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0604] VHCDR2 contains the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0605] VHCDR3 contains the sequence shown in SEQ ID NO:55 (SYRTDGLAYGYVQAIDY);

[0606] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0607] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0608] VLCDR3 contains the sequence shown in SEQ ID NO:74 (GSSDRTQYTGV);

[0609] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0610] (i) having at least 85% identity with it, and / or

[0611] (ii) relative to having one, two, or three amino acid substitutions.

[0612] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 367 to 379 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "S1B1".

[0613] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0614] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0615] VHCDR2 contains the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0616] VHCDR3 contains the sequence shown in SEQ ID NO:55 (SYRTDGLAYGYVQAIDY);

[0617] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0618] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0619] VLCDR3 contains the sequence shown in SEQ ID NO:74 (GSSDRTQYTGV).

[0620] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0621] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0622] VHCDR2 contains the sequence shown in SEQ ID NO:48 (GIDSDGEEGYNPALNS);

[0623] VHCDR3 contains the sequence shown in SEQ ID NO:57 (TYRTDGYAYGYVQAIDY);

[0624] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0625] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0626] VLCDR3 contains the sequence shown in SEQ ID NO:74 (GSSDRTQYTGV);

[0627] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0628] (i) having at least 85% identity with it, and / or

[0629] (ii) relative to having one, two, or three amino acid substitutions.

[0630] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 367 to 379 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "S1D9".

[0631] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0632] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0633] VHCDR2 contains the sequence shown in SEQ ID NO:48 (GIDSDGEEGYNPALNS);

[0634] VHCDR3 contains the sequence shown in SEQ ID NO:57 (TYRTDGYAYGYVQAIDY);

[0635] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0636] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0637] VLCDR3 contains the sequence shown in SEQ ID NO:74 (GSSDRTQYTGV).

[0638] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0639] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0640] VHCDR2 contains the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0641] VHCDR3 contains the sequence shown in SEQ ID NO:54 (SYRADGLAYGYVQAIDY);

[0642] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0643] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0644] VLCDR3 contains the sequence shown in SEQ ID NO:74 (GSSDRTQYTGV);

[0645] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0646] (i) having at least 85% identity with it, and / or

[0647] (ii) relative to having one, two, or three amino acid substitutions.

[0648] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 367 to 379 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "S1F4".

[0649] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0650] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0651] VHCDR2 contains the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0652] VHCDR3 contains the sequence shown in SEQ ID NO:54 (SYRADGLAYGYVQAIDY);

[0653] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0654] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0655] VLCDR3 contains the sequence shown in SEQ ID NO:74 (GSSDRTQYTGV).

[0656] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0657] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0658] VHCDR2 contains the sequence shown in SEQ ID NO:46 (GIDTDGEEGYNPALNS);

[0659] VHCDR3 contains the sequence shown in SEQ ID NO:54 (SYRADGLAYGYVQAIDY);

[0660] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0661] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0662] VLCDR3 contains the sequence shown in SEQ ID NO:74 (GSSDRTQYTGV);

[0663] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0664] (i) having at least 85% identity with it, and / or

[0665] (ii) relative to having one, two, or three amino acid substitutions.

[0666] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 367 to 379 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "S1G10".

[0667] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

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

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

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

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

[0672] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0673] VLCDR3 contains the sequence shown in SEQ ID NO:74 (GSSDRTQYTGV).

[0674] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0675] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0676] VHCDR2 contains the sequence shown in SEQ ID NO:51 (GIDTDGEEGYNPALKS);

[0677] VHCDR3 contains the sequence shown in SEQ ID NO:60 (TYRTDGFAYGYVQAIDY);

[0678] VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0679] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0680] VLCDR3 contains the sequence shown in SEQ ID NO:74 (GSSDRTQYTGV);

[0681] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0682] (i) having at least 85% identity with it, and / or

[0683] (ii) relative to having one, two, or three amino acid substitutions.

[0684] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 367 to 379 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "S2C6".

[0685] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0686] VHCDR1 contains the sequence shown in SEQ ID NO:42 (SNSVG);

[0687] VHCDR2 contains the sequence shown in SEQ ID NO:51 (GIDTDGEEGYNPALKS);

[0688] VHCDR3 contains the sequence shown in SEQ ID NO:60 (TYRTDGFAYGYVQAIDY); VLCDR1 contains the sequence shown in SEQ ID NO:63 (SGSFIGISSVG);

[0689] VLCDR2 contains the sequence shown in SEQ ID NO:70 (ASDGRPS);

[0690] VLCDR3 contains the sequence shown in SEQ ID NO:74 (GSSDRTQYTGV).

[0691]

[0692]

[0693]

[0694] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0695] VHCDR1 includes the VHCDR1 amino acid sequence shown in Table 2;

[0696] VHCDR2 includes the VHCDR2 amino acid sequence shown in Table 2;

[0697] VHCDR3 includes the VHCDR3 amino acid sequence shown in Table 2;

[0698] VLCDR1 contains the VLCDR1 amino acid sequence shown in Table 2;

[0699] VLCDR2 contains the VLCDR2 amino acid sequence shown in Table 2; and

[0700] VLCDR3 contains the VLCDR3 amino acid sequence shown in Table 2;

[0701] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0702] (i) having at least 85% identity with it, and / or

[0703] (ii) relative to having one, two, or three amino acid substitutions.

[0704] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO:1.

[0705] Specific binding molecules can be at a Kc of less than approximately 500 pM. D It binds to polypeptide or protein molecules containing the amino acid sequence of residues 367 to 379 of SEQ ID NO:1. This K DIt can be less than approximately 400 pM, less than approximately 300 pM, or less than approximately 200 pM. This K D Preferably, it can be used in conjunction with SEQ ID NO:1 or SEQ ID NO:5. K in conjunction with SEQ ID NO:1 D It can be from approximately 100 pM to approximately 200 pM. K combined with SEQ ID NO:1 D It can be approximately 140 pM or 170 pM, optionally wherein the specifically binding molecule comprises a CDR of S1G2. K binds to SEQ ID NO:5 D It can be approximately 400 pM to approximately 500 pM. K bound to SEQ ID NO:5 D It can be approximately 447 pM, optionally wherein the specifically binding molecule comprises the CDR of S1G2.

[0706] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:81, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 367 to 379 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:81. The CDR may have 100% identity with the CDR of SEQ ID NO:81. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:81, wherein the CDR is 100% identical to the CDR of SEQ ID NO:81. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:81.

[0707] SEQ ID NO:81 (S1G2 amino acid sequence)

[0708] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG

[0709] The specific binding molecule may contain an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:412, wherein the specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:412. The CDR may have 100% identity with the CDR of SEQ ID NO:412. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:412, wherein the CDR has 100% identity with the CDR of SEQ ID NO:412. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:412.

[0710] SEQ ID NO:412 (S1B1 amino acid sequence)

[0711] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCVRSYRTDGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTVIVASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0712] The specific binding molecule may contain an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:413, wherein the specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:413. The CDR may have 100% identity with the CDR of SEQ ID NO:413. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:413, wherein the CDR has 100% identity with the CDR of SEQ ID NO:413. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:413.

[0713] SEQ ID NO:413 (S1D9 amino acid sequence)

[0714] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDSDGEEGYNPALNSRLSITRDTSKNQVSLSLSRVTSEDTAVYYCGRTYRTDGYAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDRVMLTQPPSVSGSPGQTVSITCSGSFIGISSVGWFQQLPGSGLRTVIFASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLS

[0715] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:414, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 367 to 379 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:414. The CDR may have 100% identity with the CDR of SEQ ID NO:414. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:414, wherein the CDR has 100% identity with the CDR of SEQ ID NO:414. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:414.

[0716] SEQ ID NO:414 (S1F4 amino acid sequence)

[0717] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCVRSYRADGLAYGYVQAIDYWGPGLLLTIS SEGKSSGASGESKVDDQAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTVIVASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0718] The specific binding molecule may contain an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:415, wherein the specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:415. The CDR may have 100% identity with the CDR of SEQ ID NO:415. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:415, wherein the CDR has 100% identity with the CDR of SEQ ID NO:415. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:415.

[0719] SEQ ID NO:415 (S1G10 amino acid sequence)

[0720] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVLTQPSSMSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0721] The specific binding molecule may contain an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:416, wherein the specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:416. The CDR may have 100% identity with the CDR of SEQ ID NO:416. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:416, wherein the CDR has 100% identity with the CDR of SEQ ID NO:416. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:416.

[0722] SEQ ID NO:416 (S2C6 amino acid sequence)

[0723] QVQLQESGPSLVKPSQTLSLTCTVSGFSLISNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALKSQYAASDPDTSKSQVSLSLSSVTSEDTAVYYCGRTYRTDGFAYGYVQAIDYWGPGLLLTIS SEGKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0724] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 337 to 368 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN).

[0725] The epitope may be located within the amino acid sequence containing residues 337 to 368 of SEQ ID NO:1. This epitope can bind to the CDR of a specific binding molecule referred to herein as "NS2A3".

[0726] The epitope may contain the amino acid sequence of SEQ ID NO:82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN). The epitope may contain 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 with SEQ ID NO:82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN).

[0727] The epitope may consist of the amino acid sequence of SEQ ID NO:82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN). The epitope may also consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with the sequence of SEQ ID NO:82 (VEVKSEKLDFKDRVQSKIGSLDNITHVPGGGN).

[0728] The specific binding molecule can bind to polypeptide or protein molecules containing the amino acid sequence of residues 337 to 368 of SEQ ID NO:1. The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0729] VHCDR1 contains the sequence shown in SEQ ID NO:83 (SYSVY);

[0730] VHCDR2 contains the sequence shown in SEQ ID NO:84 (IMYASGRVDYNPALKS);

[0731] VHCDR3 contains the sequence shown in SEQ ID NO:85 (GIEN / D);

[0732] VLCDR1 contains the sequence shown in SEQ ID NO:86 (RTS / NQ / ES / NV / IN / G / DN / SY / GLS / A);

[0733] VLCDR2 contains the sequence shown in SEQ ID NO:87 (YATYLY / HT);

[0734] VLCDR3 contains the sequence shown in SEQ ID NO:88 (LQYD / G / ES / TTPLA / T);

[0735] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0736] (i) having at least 85% identity with it, and / or

[0737] (ii) relative to having one, two or three amino acid substitutions.

[0738] The sequence identity is at least about 85% sequence identity, and therefore 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%.

[0739] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0740] VHCDR1 contains the sequence shown in SEQ ID NO:83 (SYSVY);

[0741] VHCDR2 contains the sequence shown in SEQ ID NO:84 (IMYASGRVDYNPALKS);

[0742] VHCDR3 contains the sequence shown in SEQ ID NO:89 (GIEN) or SEQ ID NO:90 (GIED);

[0743] VLCDR1 contains the sequences shown in SEQ ID NO:91 (RTSQSVNNYLS), SEQ ID NO:92 (RTNESVGNYLS), SEQ ID NO:93 (RTSQNIDNGLA), or SEQ ID NO:94 (RTSQSVGSYLS);

[0744] VLCDR2 contains the sequence shown in SEQ ID NO:95 (YATRLYT) or SEQ ID NO:96 (YATRLHT);

[0745] VLCDR3 contains the sequence shown in SEQ ID NO:97 (LQYDSTPLA), SEQ ID NO:98 (LQYDSTPLT), SEQ ID NO:99 (LQYESTPLA), or SEQ ID NO:100 (LQYGTTPLA);

[0746] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0747] (i) having at least 85% identity with it, and / or

[0748] (ii) relative to having one, two, or three amino acid substitutions.

[0749] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 337 to 368 of SEQ ID NO:1.

[0750] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0751] VHCDR1 contains the sequence shown in SEQ ID NO:83 (SYSVY);

[0752] VHCDR2 contains the sequence shown in SEQ ID NO:84 (IMYASGRVDYNPALKS);

[0753] VHCDR3 contains the sequence shown in SEQ ID NO:89(GIEN);

[0754] VLCDR1 contains the sequence shown in SEQ ID NO:91 (RTSQSVNNYLS);

[0755] VLCDR2 contains the sequence shown in SEQ ID NO:95 (YATRLYT);

[0756] VLCDR3 contains the sequence shown in SEQ ID NO:97 (LQYDSTPLA);

[0757] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0758] (i) having at least 85% identity with it, and / or

[0759] (ii) relative to having one, two, or three amino acid substitutions.

[0760] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 337 to 368 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "NS2A3".

[0761] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0762] VHCDR1 contains the sequence shown in SEQ ID NO:83 (SYSVY);

[0763] VHCDR2 contains the sequence shown in SEQ ID NO:84 (IMYASGRVDYNPALKS);

[0764] VHCDR3 contains the sequence shown in SEQ ID NO:89(GIEN);

[0765] VLCDR1 contains the sequence shown in SEQ ID NO:91 (RTSQSVNNYLS);

[0766] VLCDR2 contains the sequence shown in SEQ ID NO:95 (YATRLYT); and

[0767] VLCDR3 contains the sequence shown in SEQ ID NO:97 (LQYDSTPLA).

[0768]

[0769] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0770] VHCDR1 includes the VHCDR1 amino acid sequence shown in Table 3;

[0771] VHCDR2 includes the VHCDR2 amino acid sequence shown in Table 3;

[0772] VHCDR3 includes the VHCDR3 amino acid sequence shown in Table 3;

[0773] VLCDR1 contains the VLCDR1 amino acid sequence shown in Table 3;

[0774] VLCDR2 contains the VLCDR2 amino acid sequence shown in Table 3; and

[0775] VLCDR3 contains the VLCDR3 amino acid sequence shown in Table 3;

[0776] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0777] (i) having at least 85% identity with it, and / or

[0778] (ii) relative to having one, two, or three amino acid substitutions.

[0779] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 337 to 368 of SEQ ID NO:1.

[0780] The specific binding molecule can bind to polypeptide or protein molecules containing amino acid sequences of residues 337 to 368 of SEQ ID NO:1, and its K D Less than 25 nM, preferably less than 20 nM, 15 nM, or 10 nM. This K D It can be preferably used in combination with SEQ ID NO:1 or SEQ ID NO:5.

[0781] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 369 to 390 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:101 (KKIETHKLTFRENAKAKTDHGA).

[0782] The epitope may be located within the amino acid sequence containing residues 369 to 390 of SEQ ID NO:1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “NS4E3”.

[0783] The epitope may contain the amino acid sequence of SEQ ID NO:101 (KKIETHKLTFRENAKAKTDHGA). The epitope may contain 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 with SEQ ID NO:101 (KKIETHKLTFRENAKAKTDHGA).

[0784] The epitope may consist of the amino acid sequence of SEQ ID NO:101 (KKIETHKLTFRENAKAKTDHGA). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:101 (KKIETHKLTFRENAKAKTDHGA).

[0785] The specific binding molecule can bind to polypeptide or protein molecules containing amino acid sequences of residues 369 to 390 of SEQ ID NO:1. The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0786] VHCDR1 contains the sequence shown in SEQ ID NO:102 (RESIA);

[0787] VHCDR2 contains the sequence shown in SEQ ID NO:103 (GVGIDGTSYYSPALKS);

[0788] VHCDR3 contains the sequence shown in SEQ ID NO:104 (NYIDFEY);

[0789] VLCDR1 contains 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);

[0790] VLCDR2 contains the sequence shown in SEQ ID NO:106 (G / RT / N / ST / SN / T / RRP / AS); and

[0791] VLCDR3 contains the sequence shown in SEQ ID NO:107 (L / A / GSYDR / T / G / SS / TG / NS / R / -N / G / S / IF / I / V);

[0792] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0793] (i) having at least 85% identity with it, and / or

[0794] (ii) relative to having one, two or three amino acid substitutions.

[0795] The sequence identity is at least about 85% sequence identity, and therefore 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%.

[0796] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0797] VHCDR1 contains the sequence shown in SEQ ID NO:102 (RESIA);

[0798] VHCDR2 contains the sequence shown in SEQ ID NO:103 (GVGIDGTSYYSPALKS);

[0799] VHCDR3 contains the sequence shown in SEQ ID NO:104 (NYIDFEY);

[0800] VLCDR1 contains the sequences shown in SEQ ID NO:108 (SGSSSNVGYEDYVN), SEQ ID NO:109 (SGSNIAGNGVG), SEQ ID NO:110 (SGSSNNVGSGDYVS), or SEQ ID NO:111 (SGSYIGSTDVG);

[0801] VLCDR2 contains the sequences shown in SEQ ID NO:112 (GTTNRPS), SEQ ID NO:113 (GSTRRPS), SEQ ID NO:114 (RNSNRPS), or SEQ ID NO:115 (RTTTRAS); and

[0802] VLCDR3 contains the sequences shown in SEQ ID NO:116 (LSYDRSGSNF), SEQ ID NO:117 (ASYDTSNRGI), SEQ ID NO:118 (GSYDGTNSF), or SEQ ID NO:119 (ASYDSNNSIV);

[0803] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0804] (i) having at least 85% identity with it, and / or

[0805] (ii) relative to having one, two, or three amino acid substitutions.

[0806] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 369 to 390 of SEQ ID NO:1.

[0807] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0808] VHCDR1 contains the sequence shown in SEQ ID NO:102 (RESIA);

[0809] VHCDR2 contains the sequence shown in SEQ ID NO:103 (GVGIDGTSYYSPALKS);

[0810] VHCDR3 contains the sequence shown in SEQ ID NO:104 (NYIDFEY);

[0811] VLCDR1 contains the sequence shown in SEQ ID NO:108 (SGSSSNVGYEDYVN);

[0812] VLCDR2 contains the sequence shown in SEQ ID NO:112 (GTTNRPS); and

[0813] VLCDR3 contains the sequence shown in SEQ ID NO:116 (LSYDRSGSNF);

[0814] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0815] (i) having at least 85% identity with it, and / or

[0816] (ii) relative to having one, two, or three amino acid substitutions.

[0817] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 369 to 390 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "NS4E4".

[0818] This specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0819] VHCDR1 contains the sequence shown in SEQ ID NO:102 (RESIA);

[0820] VHCDR2 contains the sequence shown in SEQ ID NO:103 (GVGIDGTSYYSPALKS);

[0821] VHCDR3 contains the sequence shown in SEQ ID NO:104 (NYIDFEY);

[0822] VLCDR1 contains the sequence shown in SEQ ID NO:108 (SGSSSNVGYEDYVN);

[0823] VLCDR2 contains the sequence shown in SEQ ID NO:112 (GTTNRPS); and

[0824] VLCDR3 contains the sequence shown in SEQ ID NO:116(LSYDRSGSNF).

[0825]

[0826] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0827] VHCDR1 contains the VHCDR1 amino acid sequence shown in Table 4;

[0828] VHCDR2 contains the VHCDR2 amino acid sequence shown in Table 4;

[0829] VHCDR3 contains the VHCDR3 amino acid sequence shown in Table 4;

[0830] VLCDR1 contains the VLCDR1 amino acid sequence shown in Table 4;

[0831] VLCDR2 contains the VLCDR2 amino acid sequence shown in Table 4; and

[0832] VLCDR3 contains the VLCDR3 amino acid sequence shown in Table 4;

[0833] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0834] (i) having at least 85% identity with it, and / or

[0835] (ii) relative to having one, two, or three amino acid substitutions.

[0836] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 369 to 390 of SEQ ID NO:1.

[0837] The specific binding molecule can bind to polypeptide or protein molecules containing amino acid sequences of residues 369 to 390 of SEQ ID NO:1, and its K D Less than 25 nM, preferably less than 20 nM, 15 nM, or 10 nM. This K D It can be preferably used in combination with SEQ ID NO:1 or SEQ ID NO:5.

[0838] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 412 to 441 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL).

[0839] This epitope may be located within the amino acid sequence containing residues 412 to 441 of SEQ ID NO:1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “412E10”.

[0840] The epitope may contain the amino acid sequence of SEQ ID NO:120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL). The epitope may contain 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 with SEQ ID NO:120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL).

[0841] The epitope may consist of the amino acid sequence of SEQ ID NO:120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:120 (SSTGSIDMVDSPQLATLADEVSASLAKQGL).

[0842] The specific binding molecule can bind to polypeptide or protein molecules containing the amino acid sequence of residues 412 to 441 of SEQ ID NO:1. The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0843] VHCDR1 contains the sequence shown in SEQ ID NO:121 (S / ND / YS / G / AV / LA / G);

[0844] VHCDR2 contains the sequence shown in SEQ ID NO:122 (A / NS / IG / Y / WS / RS / GGN / S / RK / T / IY / EYNPALKS);

[0845] VHCDR3 contains the sequence shown in SEQ ID NO:123 (GI / GI / VA / GG / SVDV) or SEQ ID NO:124 (SGGD);

[0846] VLCDR1 contains the sequence shown in SEQ ID NO:125 (SGS / GS / NNV / IGY / RGN / D / TY / FVG / D);

[0847] VLCDR2 contains the sequence shown in SEQ ID NO:126 (GT / AA / D / TI / S / RRA / PS / P); and

[0848] VLCDR3 contains 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);

[0849] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0850] (i) having at least 85% identity with it, and / or

[0851] (ii) relative to having one, two or three amino acid substitutions.

[0852] The sequence identity is at least about 85% sequence identity, and therefore 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%.

[0853] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0854] VHCDR1 contains the sequence shown in SEQ ID NO:128 (SDSVA), SEQ ID NO:129 (NYGVG), or SEQ ID NO:130 (SYALG);

[0855] VHCDR2 contains the sequences shown in SEQ ID NO:131 (ASGSSGNKYYNPALKS), SEQ ID NO:132 (NIWRGGRIEYNPALKS), or SEQ ID NO:133 (NIYSGGSTYYNPALKS);

[0856] VHCDR3 includes the sequences shown in SEQ ID NO:134 (GIIAGVDV), SEQ ID NO:135 (GGVGSVDV), or SEQ ID NO:124 (SGGD);

[0857] VLCDR1 contains the sequences shown in SEQ ID NO:39 (SGSSSNVGYGNYVG), SEQ ID NO:137 (SGGRNNIGRGTFVD), and SEQ ID NO:138 (SGSSSNVGYGDYVG);

[0858] VLCDR2 contains the sequence shown in SEQ ID NO:139 (GTAIRAS), SEQ ID NO:140 (GAASRAS), SEQ ID NO:141 (GATSRAS), or SEQ ID NO:142 (GTDRRPP); and

[0859] VLCDR3 contains the sequences shown in SEQ ID NO:143 (ASYQSNYAF), SEQ ID NO:144 (ASYDRSESVV), SEQ ID NO:145 (ASYDSSDGGV), or SEQ ID NO:146 (ATYDYSNDMII);

[0860] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0861] (i) having at least 85% identity with it, and / or

[0862] (ii) relative to having one, two, or three amino acid substitutions.

[0863] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO:1.

[0864] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0865] VHCDR1 contains the sequence shown in SEQ ID NO:128 (SDSVA);

[0866] VHCDR2 contains the sequence shown in SEQ ID NO:131(ASGSSGNKYYNPALKS);

[0867] VHCDR3 contains the sequence shown in SEQ ID NO:134 (GIIAGVDV);

[0868] VLCDR1 contains the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[0869] VLCDR2 contains the sequence shown in SEQ ID NO:139 (GTAIRAS); and

[0870] VLCDR3 contains the sequence shown in SEQ ID NO:143 (ASYQSNYAF);

[0871] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0872] (i) having at least 85% identity with it, and / or

[0873] (ii) relative to having one, two, or three amino acid substitutions.

[0874] Specifically, the 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. The specific binding molecule comprising a CDR that is 100% identical to the aforementioned CDR is referred to herein as "412E10".

[0875] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0876] VHCDR1 contains the sequence shown in SEQ ID NO:128 (SDSVA);

[0877] VHCDR2 contains the sequence shown in SEQ ID NO:131(ASGSSGNKYYNPALKS);

[0878] VHCDR3 contains the sequence shown in SEQ ID NO:134 (GIIAGVDV);

[0879] VLCDR1 contains the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[0880] VLCDR2 contains the sequence shown in SEQ ID NO:139 (GTAIRAS); and

[0881] VLCDR3 contains the sequence shown in SEQ ID NO:143 (ASYQSNYAF).

[0882] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0883] VHFR1 contains the sequence shown in SEQ ID NO:459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[0884] VHFR2 contains the sequence shown in SEQ ID NO:460 (WVRQAPGKVPEWLG);

[0885] VHFR3 contains the sequence shown in SEQ ID NO:461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[0886] VHFR4 contains the sequence shown in SEQ ID NO:462 (WGRGLLVTVSS);

[0887] VLFR1 contains the sequence shown in SEQ ID NO:463 (QAVLTQPSSVSGSLGQRVSITC);

[0888] VLFR2 contains the sequence shown in SEQ ID NO:464 (WYQQVPGSAPKLLIY);

[0889] VLFR3 contains the sequence shown in SEQ ID NO:465(GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[0890] VLFR4 contains the sequence shown in SEQ ID NO:466 (FGSGTRLTVLG);

[0891] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0892] (i) having at least 50% similarity to it, and / or

[0893] (ii) relative to having one, two, three, four or five amino acid substitutions.

[0894] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0895] VHFR1 contains the sequence shown in SEQ ID NO:459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[0896] VHFR2 contains the sequence shown in SEQ ID NO:460 (WVRQAPGKVPEWLG);

[0897] VHFR3 contains the sequence shown in SEQ ID NO:461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[0898] VHFR4 contains the sequence shown in SEQ ID NO:462 (WGRGLLVTVSS);

[0899] VLFR1 contains the sequence shown in SEQ ID NO:463 (QAVLTQPSSVSGSLGQRVSITC);

[0900] VLFR2 contains the sequence shown in SEQ ID NO:464 (WYQQVPGSAPKLLIY);

[0901] VLFR3 contains the sequence shown in SEQ ID NO:465(GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[0902] VLFR4 contains the sequence shown in SEQ ID NO:466 (FGSGTRLTVLG);

[0903] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0904] (i) having at least 50% similarity to it, and / or

[0905] (ii) relative to having one, two, three, four or five amino acid substitutions,

[0906] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 412 to 441 of SEQ ID NO:1. The specific binding molecule containing a FR that is 100% identical to the above-mentioned FR is referred to herein as "412E10".

[0907] Specific binding molecules may include:

[0908] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0909] VHFR1 contains the sequence shown in SEQ ID NO:459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[0910] VHFR2 contains the sequence shown in SEQ ID NO:460 (WVRQAPGKVPEWLG);

[0911] VHFR3 contains the sequence shown in SEQ ID NO:461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[0912] VHFR4 contains the sequence shown in SEQ ID NO:462 (WGRGLLVTVSS);

[0913] VLFR1 contains the sequence shown in SEQ ID NO:463 (QAVLTQPSSVSGSLGQRVSITC);

[0914] VLFR2 contains the sequence shown in SEQ ID NO:464 (WYQQVPGSAPKLLIY);

[0915] VLFR3 contains the sequence shown in SEQ ID NO:465(GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[0916] VLFR4 contains the sequence shown in SEQ ID NO:466 (FGSGTRLTVLG);

[0917] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0918] (i) having at least 50% similarity to it, and / or

[0919] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0920] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0921] VHCDR1 contains the sequence shown in SEQ ID NO:128 (SDSVA);

[0922] VHCDR2 contains the sequence shown in SEQ ID NO:131(ASGSSGNKYYNPALKS);

[0923] VHCDR3 contains the sequence shown in SEQ ID NO:134 (GIIAGVDV);

[0924] VLCDR1 contains the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[0925] VLCDR2 contains the sequence shown in SEQ ID NO:139 (GTAIRAS); and

[0926] VLCDR3 contains the sequence shown in SEQ ID NO:143 (ASYQSNYAF);

[0927] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0928] (i) having at least 85% identity with it, and / or

[0929] (ii) relative to having one, two or three amino acid substitutions

[0930] Specifically, the binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO:1. The specific binding molecule containing FR and CDR that are 100% identical to the above-mentioned FR and CDR is referred to herein as "412E10".

[0931] Specific binding molecules may include:

[0932] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0933] VHFR1 contains the sequence shown in SEQ ID NO:459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[0934] VHFR2 contains the sequence shown in SEQ ID NO:460 (WVRQAPGKVPEWLG);

[0935] VHFR3 contains the sequence shown in SEQ ID NO:461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[0936] VHFR4 contains the sequence shown in SEQ ID NO:462 (WGRGLLVTVSS);

[0937] VLFR1 contains the sequence shown in SEQ ID NO:463 (QAVLTQPSSVSGSLGQRVSITC);

[0938] VLFR2 contains the sequence shown in SEQ ID NO:464 (WYQQVPGSAPKLLIY);

[0939] VLFR3 contains the sequence shown in SEQ ID NO:465(GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[0940] VLFR4 contains the sequence shown in SEQ ID NO:466 (FGSGTRLTVLG);

[0941] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[0942] (i) having at least 50% similarity to it, and / or

[0943] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0944] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0945] VHCDR1 contains the sequence shown in SEQ ID NO:128 (SDSVA);

[0946] VHCDR2 contains the sequence shown in SEQ ID NO:131(ASGSSGNKYYNPALKS);

[0947] VHCDR3 contains the sequence shown in SEQ ID NO:134 (GIIAGVDV);

[0948] VLCDR1 contains the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[0949] VLCDR2 contains the sequence shown in SEQ ID NO:139 (GTAIRAS); and

[0950] VLCDR3 contains the sequence shown in SEQ ID NO:143 (ASYQSNYAF);

[0951] Specifically, the binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO:1. The specific binding molecule containing FR and CDR that are 100% identical to the above-mentioned FR and CDR is referred to herein as "412E10".

[0952] Specific binding molecules may include the following or their humanized variants:

[0953] (a) The VH domain, which contains SEQ ID NO:467

[0954] The sequence shown in (QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVTVSS) is shown; and / or

[0955] (b) The VL domain, which contains SEQ ID NO:468

[0956] The sequence shown is (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLG).

[0957] Specific binding molecules may include the following or their humanized variants:

[0958] (a) Heavy chain, which contains SEQ ID NO:469

[0959] (QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVT VSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKC PAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSV RAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK); the sequence shown, and / or

[0960] (b) A light chain containing SEQ ID NO:470

[0961] The sequence shown is (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTI TDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEK SLSRADCS).

[0962] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0963] VHCDR1 contains the sequence shown in SEQ ID NO:128 (SDSVA);

[0964] VHCDR2 contains the sequence shown in SEQ ID NO:131(ASGSSGNKYYNPALKS);

[0965] VHCDR3 contains the sequence shown in SEQ ID NO:134 (GIIAGVDV);

[0966] VLCDR1 contains the sequence shown in SEQ ID NO:138 (SGSSSNVGYGDYVG);

[0967] VLCDR2 contains the sequence shown in SEQ ID NO:140 (GAASRAS); and

[0968] VLCDR3 contains the sequence shown in SEQ ID NO:145 (ASYDSSDGGV);

[0969] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0970] (i) having at least 85% identity with it, and / or

[0971] (ii) relative to having one, two, or three amino acid substitutions.

[0972] Specifically, the binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the aforementioned CDR is referred to herein as "412B9".

[0973] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0974] VHCDR1 contains the sequence shown in SEQ ID NO:128 (SDSVA);

[0975] VHCDR2 contains the sequence shown in SEQ ID NO:131(ASGSSGNKYYNPALKS);

[0976] VHCDR3 contains the sequence shown in SEQ ID NO:134 (GIIAGVDV);

[0977] VLCDR1 contains the sequence shown in SEQ ID NO:138 (SGSSSNVGYGDYVG);

[0978] VLCDR2 contains the sequence shown in SEQ ID NO:140 (GAASRAS); and

[0979] VLCDR3 contains the sequence shown in SEQ ID NO:145 (ASYDSSDGGV).

[0980] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0981] VHCDR1 contains the sequence shown in SEQ ID NO:129 (NYGVG);

[0982] VHCDR2 contains the sequence shown in SEQ ID NO:133(NIYSGGSTYYNPALKS);

[0983] VHCDR3 contains the sequence shown in SEQ ID NO:135 (GGVGSVDV);

[0984] VLCDR1 contains the sequence shown in SEQ ID NO:137 (SGGRNNIGRGTFVD);

[0985] VLCDR2 contains the sequence shown in SEQ ID NO:142 (GTDRRPP); and

[0986] VLCDR3 contains the sequence shown in SEQ ID NO:146 (ATYDYSNDMII);

[0987] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[0988] (i) having at least 85% identity with it, and / or

[0989] (ii) relative to having one, two, or three amino acid substitutions.

[0990] Specifically, the binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "412E6".

[0991] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0992] VHCDR1 contains the sequence shown in SEQ ID NO:129 (NYGVG);

[0993] VHCDR2 contains the sequence shown in SEQ ID NO:133(NIYSGGSTYYNPALKS);

[0994] VHCDR3 contains the sequence shown in SEQ ID NO:135 (GGVGSVDV);

[0995] VLCDR1 contains the sequence shown in SEQ ID NO:137 (SGGRNNIGRGTFVD);

[0996] VLCDR2 contains the sequence shown in SEQ ID NO:142 (GTDRRPP); and

[0997] VLCDR3 contains the sequence shown in SEQ ID NO:146 (ATYDYSNDMII).

[0998] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0999] VHCDR1 contains the sequence shown in SEQ ID NO:130 (SYALG);

[1000] VHCDR2 contains the sequence shown in SEQ ID NO:132 (NIWRGGRIEYNPALKS);

[1001] VHCDR3 contains the sequence shown in SEQ ID NO:124 (SGGD);

[1002] VLCDR1 contains the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[1003] VLCDR2 contains the sequence shown in SEQ ID NO:141 (GATSRAS); and

[1004] VLCDR3 contains the sequence shown in SEQ ID NO:144 (ASYDRSESVV);

[1005] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1006] (i) having at least 85% identity with it, and / or

[1007] (ii) relative to having one, two, or three amino acid substitutions.

[1008] Specifically, the binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "412G11".

[1009] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1010] VHCDR1 contains the sequence shown in SEQ ID NO:130 (SYALG);

[1011] VHCDR2 contains the sequence shown in SEQ ID NO:132 (NIWRGGRIEYNPALKS);

[1012] VHCDR3 contains the sequence shown in SEQ ID NO:124 (SGGD);

[1013] VLCDR1 contains the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[1014] VLCDR2 contains the sequence shown in SEQ ID NO:141 (GATSRAS); and

[1015] VLCDR3 contains the sequence shown in SEQ ID NO:144 (ASYDRSESVV).

[1016]

[1017] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1018] VHCDR1 contains the VHCDR1 amino acid sequence shown in Table 5;

[1019] VHCDR2 contains the VHCDR2 amino acid sequence shown in Table 5;

[1020] VHCDR3 contains the VHCDR3 amino acid sequence shown in Table 5;

[1021] VLCDR1 contains the VLCDR1 amino acid sequence shown in Table 5;

[1022] VLCDR2 contains the VLCDR2 amino acid sequence shown in Table 5; and

[1023] VLCDR3 contains the VLCDR3 amino acid sequence shown in Table 5;

[1024] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1025] (i) having at least 85% identity with it, and / or

[1026] (ii) relative to having one, two, or three amino acid substitutions.

[1027] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO:1.

[1028] Specific binding molecules can be achieved at Kc values ​​less than approximately 25 nM. D It binds to polypeptide or protein molecules containing the amino acid sequence of residues 412 to 441 of SEQ ID NO:1. D It can be less than about 20 nM, less than about 15 nM, or less than about 10 nM. This K D It can be preferably used in conjunction with SEQ ID NO:1 or SEQ ID NO:120. K in conjunction with SEQ ID NO:1D It can be from about 1 nM to about 10 nM. K bound to SEQ ID NO:1 D It can be about 3.16 nM or 9.0 nM, wherein the specific binding molecule optionally contains a CDR of 412E10.

[1029] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:147, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 412 to 441 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:147. The CDR may have 100% identity with the CDR of SEQ ID NO:147. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:147, wherein the CDR has 100% identity with the CDR of SEQ ID NO:147. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:147.

[1030] SEQ ID NO:147 (412E10 amino acid sequence)

[1031] QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLG

[1032] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:417, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 412 to 441 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:417. The CDR may have 100% identity with the CDR of SEQ ID NO:417. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:417, wherein the CDR has 100% identity with the CDR of SEQ ID NO:417. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:417.

[1033] SEQ ID NO:417 (412B9 amino acid sequence)

[1034] QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVSVSSEGKSS GASGESKVDDQAVLTQPSSVSGALGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYGAASRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSSDGGVFGSGTRLTVLG

[1035] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:418, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 412 to 441 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:418. The CDR may have 100% identity with the CDR of SEQ ID NO:418. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:418, wherein the CDR has 100% identity with the CDR of SEQ ID NO:418. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:418.

[1036] SEQ ID NO:418 (412E6 amino acid sequence)

[1037] QVQLQESGPSLVKPSETLSLTCTVSGFSLTNYGVGWVRQAPGKALEWLGNIYSGGSTYYNPALKSRLSITRDTSKSQVSLSLNSVTLEDTAVYYCRGGGVGSVDVWGPGLLVTVSSEGKSS GASGESKVDDQAVLTQPPSVSGSPGQRVSITCSGGRNNIGRGTFVDWYQQLPGSGLKTVIYGTDRRPPGVPDRFSGSKTGNAATLTITSLQAEDEADYWCATYDYSNDMIILGSGTRLTVLG

[1038] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:434, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 412 to 441 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:434. The CDR may have 100% identity with the CDR of SEQ ID NO:434. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:434, wherein the CDR has 100% identity with the CDR of SEQ ID NO:434. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:434.

[1039] SEQ ID NO:434 (412G11 amino acid sequence)

[1040] QVRLQESGPSLVKPSQTLSLTCTVSGFSLTSYALGWVRQAPGRAPEWIGNIWRGGRIEYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCSRSGGDWGPGLLVTVSSEGKSSGA SGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGATSRASGVPDRFSGSRSENTATLTISSLQAEDEADYYCASYDRSESVVFGSGTRLTVLG

[1041] The epitope of the specifically binding molecule may be located within the amino acid sequence containing residues 1 to 49 of SEQ ID NO:1. Therefore, the epitope may be located within the amino acid sequence of SEQ ID NO:148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ). Preferably, the epitope of the specifically binding molecule is located within the amino acid sequence containing residues 1 to 49 of SEQ ID NO:1, and may be located within the amino acid sequence containing residues 1 to 15 of SEQ ID NO:1.

[1042] This epitope can be located within the amino acid sequence containing residues 1 to 49 of SEQ ID NO:1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “3aG3”.

[1043] The epitope may be located within the amino acid sequence containing residues 1 to 49 of SEQ ID NO:1, preferably within the amino acid sequence containing residues 1 to 15 of SEQ ID NO:1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “3bG4”.

[1044] The epitope may contain the amino acid sequence of SEQ ID NO:148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ). The epitope may contain 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 with SEQ ID NO:148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ).

[1045] The epitope may consist of the amino acid sequence of SEQ ID NO:148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ). The epitope may also consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with the sequence of SEQ ID NO:148 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQ).

[1046] The specific binding molecule can bind to polypeptide or protein molecules containing the amino acid sequence of residues 1 to 49 of SEQ ID NO:1. The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1047] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1048] VHCDR2 contains the sequence shown in SEQ ID NO:150 (DIS / ASS / V / GGKA / K / VYA / S / GN / HPALKS);

[1049] VHCDR3 contains the sequence shown in SEQ ID NO:151 (CRDGGVS / TYGYDI / SDY);

[1050] VLCDR1 contains the sequence shown in SEQ ID NO:152 (SGSS / TS / GNI / VGG / S / YGN / DY / DL / VS / G);

[1051] VLCDR2 contains the sequence shown in SEQ ID NO:153 (GA / VTS / N / ER / LAS); and

[1052] VLCDR3 contains the sequence shown in SEQ ID NO:154 (A / GSF / YDT / S / DS / NSGGI / V);

[1053] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1054] (i) having at least 85% identity with it, and / or

[1055] (ii) relative to having one, two or three amino acid substitutions.

[1056] The sequence identity is at least about 85% sequence identity, and therefore 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%.

[1057] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1058] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1059] VHCDR2 contains the sequences shown in SEQ ID NO:155 (DISSSGKAYANPALKS), SEQ ID NO:156 (DISSGGKVYGHPALKS), SEQ ID NO:157 (DISSVGKKYANPALKS), or SEQ ID NO:158 (DIASSGKAYSNPALKS);

[1060] VHCDR3 contains the sequences shown in SEQ ID NO:159 (CRDGGVSYGYDIDY), SEQ ID NO:160 (CRDGGVSYGYDSDY), or SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1061] VLCDR1 contains the sequences shown in SEQ ID NO:163 (SGSSSNIGGGNYLS), SEQ ID NO:138 (SGSSSNVGYGDYVG), SEQ ID NO:165 (SGSSGNVGYGDYVS), or SEQ ID NO:166 (SGSTSNVGSGNDVS);

[1062] VLCDR2 contains the sequences shown in SEQ ID NO:141 (GATSRAS), SEQ ID NO:168 (GVTERAS), SEQ ID NO:169 (GATNLAS), or SEQ ID NO:170 (GATNRAS); and

[1063] VLCDR3 contains the sequences shown in SEQ ID NO:171 (ASFDTSSGGI), SEQ ID NO:172 (ASYDDSSGGI), SEQ ID NO:173 (ASYDSSSGGV), or SEQ ID NO:174 (GSYDSNSGGI);

[1064] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1065] (i) having at least 85% identity with it, and / or

[1066] (ii) relative to having one, two, or three amino acid substitutions.

[1067] The specific binding molecule binds to a polypeptide or protein molecule containing an amino acid sequence of residues 1 to 49 of SEQ ID NO:1.

[1068] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1069] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1070] VHCDR2 contains the sequence shown in SEQ ID NO:155 (DISSSGKAYANPALKS);

[1071] VHCDR3 contains the sequence shown in SEQ ID NO:159 (CRDGGVSYGYDIDY);

[1072] VLCDR1 contains the sequence shown in SEQ ID NO:163 (SGSSSNIGGGNYLS);

[1073] VLCDR2 contains the sequence shown in SEQ ID NO:141 (GATSRAS); and

[1074] VLCDR3 contains the sequence shown in SEQ ID NO:171 (ASFDTSSGGI);

[1075] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1076] (i) having at least 85% identity with it, and / or

[1077] (ii) relative to having one, two, or three amino acid substitutions.

[1078] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 49 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "3aG3".

[1079] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1080] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1081] VHCDR2 contains the sequence shown in SEQ ID NO:155 (DISSSGKAYANPALKS);

[1082] VHCDR3 contains the sequence shown in SEQ ID NO:159 (CRDGGVSYGYDIDY);

[1083] VLCDR1 contains the sequence shown in SEQ ID NO:163 (SGSSSNIGGGNYLS);

[1084] VLCDR2 contains the sequence shown in SEQ ID NO:141 (GATSRAS); and

[1085] VLCDR3 contains the sequence shown in SEQ ID NO:171 (ASFDTSSGGI).

[1086] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1087] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1088] VHCDR2 contains the sequence shown in SEQ ID NO:156(DISSGGKVYGHPALKS);

[1089] VHCDR3 contains the sequence shown in SEQ ID NO:160 (CRDGGVSYGYDSDY);

[1090] VLCDR1 contains the sequence shown in SEQ ID NO:138 (SGSSSNVGYGDYVG);

[1091] VLCDR2 contains the sequence shown in SEQ ID NO:168 (GVTERAS); and

[1092] VLCDR3 contains the sequence shown in SEQ ID NO:172 (ASYDDSSGGI);

[1093] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1094] (i) having at least 85% identity with it, and / or

[1095] (ii) relative to having one, two, or three amino acid substitutions.

[1096] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 49 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "3aD3".

[1097] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1098] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1099] VHCDR2 contains the sequence shown in SEQ ID NO:156(DISSGGKVYGHPALKS);

[1100] VHCDR3 contains the sequence shown in SEQ ID NO:160 (CRDGGVSYGYDSDY);

[1101] VLCDR1 contains the sequence shown in SEQ ID NO:138 (SGSSSNVGYGDYVG);

[1102] VLCDR2 contains the sequence shown in SEQ ID NO:168 (GVTERAS); and

[1103] VLCDR3 contains the sequence shown in SEQ ID NO:172 (ASYDDSSGGI).

[1104] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1105] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1106] VHCDR2 contains the sequence shown in SEQ ID NO:157 (DISSVGKKYANPALKS);

[1107] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1108] VLCDR1 contains the sequence shown in SEQ ID NO:165 (SGSSGNVGYGDYVS);

[1109] VLCDR2 contains the sequence shown in SEQ ID NO:169 (GATNLAS); and

[1110] VLCDR3 contains the sequence shown in SEQ ID NO:173 (ASYDSSSGGV);

[1111] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1112] (i) having at least 85% identity with it, and / or

[1113] (ii) relative to having one, two, or three amino acid substitutions.

[1114] The specific binding molecule binds to polypeptide or protein molecules containing amino acid sequences of residues 1 to 49 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "3aH6".

[1115] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1116] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1117] VHCDR2 contains the sequence shown in SEQ ID NO:157 (DISSVGKKYANPALKS);

[1118] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1119] VLCDR1 contains the sequence shown in SEQ ID NO:165 (SGSSGNVGYGDYVS);

[1120] VLCDR2 contains the sequence shown in SEQ ID NO:169 (GATNLAS); and

[1121] VLCDR3 contains the sequence shown in SEQ ID NO:173 (ASYDSSSGGV).

[1122] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1123] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1124] VHCDR2 contains the sequence shown in SEQ ID NO:158 (DIASSGKAYSNPALKS);

[1125] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1126] VLCDR1 contains the sequence shown in SEQ ID NO:166 (SGSTSNVGSGNDVS);

[1127] VLCDR2 contains the sequence shown in SEQ ID NO:170 (GATNRAS); and

[1128] VLCDR3 contains the sequence shown in SEQ ID NO:174 (GSYDSNSGGI);

[1129] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1130] (i) having at least 85% identity with it, and / or

[1131] (ii) relative to having one, two, or three amino acid substitutions.

[1132] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 49 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "3bG4".

[1133] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1134] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1135] VHCDR2 contains the sequence shown in SEQ ID NO:158 (DIASSGKAYSNPALKS);

[1136] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1137] VLCDR1 contains the sequence shown in SEQ ID NO:166 (SGSTSNVGSGNDVS);

[1138] VLCDR2 contains the sequence shown in SEQ ID NO:170 (GATNRAS); and

[1139] VLCDR3 contains the sequence shown in SEQ ID NO:174(GSYDSNSGGI).

[1140] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1141] VHFR1 contains the sequence shown in SEQ ID NO:471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[1142] VHFR2 contains the sequence shown in SEQ ID NO:472 (WVRQAPGKVPEWVG);

[1143] VHFR3 contains the sequence shown in SEQ ID NO:473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[1144] VHFR4 contains the sequence shown in SEQ ID NO:474 (WGPGLLVTVSS);

[1145] VLFR1 contains the sequence shown in SEQ ID NO:475 (QAVLTQPSSVSKSLGQSVSITC);

[1146] VLFR2 contains the sequence shown in SEQ ID NO:476(WFQQVPGSAPKLLFY);

[1147] VLFR3 contains the sequence shown in SEQ ID NO:477(GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[1148] VLFR4 contains the sequence shown in SEQ ID NO:478 (FGSGTRLTVLG);

[1149] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1150] (i) having at least 50% similarity to it, and / or

[1151] (ii) relative to having one, two, three, four or five amino acid substitutions.

[1152] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1153] VHFR1 contains the sequence shown in SEQ ID NO:471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[1154] VHFR2 contains the sequence shown in SEQ ID NO:472 (WVRQAPGKVPEWVG);

[1155] VHFR3 contains the sequence shown in SEQ ID NO:473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[1156] VHFR4 contains the sequence shown in SEQ ID NO:474 (WGPGLLVTVSS);

[1157] VLFR1 contains the sequence shown in SEQ ID NO:475 (QAVLTQPSSVSKSLGQSVSITC);

[1158] VLFR2 contains the sequence shown in SEQ ID NO:476(WFQQVPGSAPKLLFY);

[1159] VLFR3 contains the sequence shown in SEQ ID NO:477(GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[1160] VLFR4 contains the sequence shown in SEQ ID NO:478 (FGSGTRLTVLG);

[1161] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1162] (i) having at least 50% similarity to it, and / or

[1163] (ii) relative to having one, two, three, four or five amino acid substitutions,

[1164] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 49 of SEQ ID NO:1. The specific binding molecule containing a FR that is 100% identical to the above-mentioned FR is referred to herein as "3bG4".

[1165] Specific binding molecules may include:

[1166] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1167] VHFR1 contains the sequence shown in SEQ ID NO:471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[1168] VHFR2 contains the sequence shown in SEQ ID NO:472 (WVRQAPGKVPEWVG);

[1169] VHFR3 contains the sequence shown in SEQ ID NO:473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[1170] VHFR4 contains the sequence shown in SEQ ID NO:474 (WGPGLLVTVSS);

[1171] VLFR1 contains the sequence shown in SEQ ID NO:475 (QAVLTQPSSVSKSLGQSVSITC);

[1172] VLFR2 contains the sequence shown in SEQ ID NO:476(WFQQVPGSAPKLLFY);

[1173] VLFR3 contains the sequence shown in SEQ ID NO:477(GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[1174] VLFR4 contains the sequence shown in SEQ ID NO:478 (FGSGTRLTVLG);

[1175] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1176] (i) having at least 50% similarity to it, and / or

[1177] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1178] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1179] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1180] VHCDR2 contains the sequence shown in SEQ ID NO:158 (DIASSGKAYSNPALKS);

[1181] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1182] VLCDR1 contains the sequence shown in SEQ ID NO:166 (SGSTSNVGSGNDVS);

[1183] VLCDR2 contains the sequence shown in SEQ ID NO:170 (GATNRAS); and

[1184] VLCDR3 contains the sequence shown in SEQ ID NO:174 (GSYDSNSGGI);

[1185] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1186] (i) having at least 85% identity with it, and / or

[1187] (ii) relative to having one, two or three amino acid substitutions

[1188] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 49 of SEQ ID NO:1. The specific binding molecule containing FRs and CDRs that are 100% identical to the above-mentioned FRs and CDRs is referred to herein as "3bG4".

[1189] Specific binding molecules may include:

[1190] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1191] VHFR1 contains the sequence shown in SEQ ID NO:471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[1192] VHFR2 contains the sequence shown in SEQ ID NO:472 (WVRQAPGKVPEWVG);

[1193] VHFR3 contains the sequence shown in SEQ ID NO:473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[1194] VHFR4 contains the sequence shown in SEQ ID NO:474 (WGPGLLVTVSS);

[1195] VLFR1 contains the sequence shown in SEQ ID NO:475 (QAVLTQPSSVSKSLGQSVSITC);

[1196] VLFR2 contains the sequence shown in SEQ ID NO:476(WFQQVPGSAPKLLFY);

[1197] VLFR3 contains the sequence shown in SEQ ID NO:477(GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[1198] VLFR4 contains the sequence shown in SEQ ID NO:478 (FGSGTRLTVLG);

[1199] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1200] (i) having at least 50% similarity to it, and / or

[1201] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1202] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1203] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1204] VHCDR2 contains the sequence shown in SEQ ID NO:158 (DIASSGKAYSNPALKS);

[1205] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1206] VLCDR1 contains the sequence shown in SEQ ID NO:166 (SGSTSNVGSGNDVS);

[1207] VLCDR2 contains the sequence shown in SEQ ID NO:170 (GATNRAS); and

[1208] VLCDR3 contains the sequence shown in SEQ ID NO:174 (GSYDSNSGGI);

[1209] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 49 of SEQ ID NO:1. The specific binding molecule containing FRs and CDRs that are 100% identical to the above-mentioned FRs and CDRs is referred to herein as "3bG4".

[1210] Specific binding molecules may include the following or their humanized variants:

[1211] (a) The VH domain, which contains SEQ ID NO:479

[1212] The sequence shown in (QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPGLLVTVSS) is shown; and / or

[1213] (b) The VL domain, which contains SEQ ID NO:480

[1214] The sequence shown is (QAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLG).

[1215] Specific binding molecules may include the following or their humanized variants:

[1216] (a) Heavy chain, which contains SEQ ID NO:481

[1217] (QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPG LLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPP CKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGS VRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK); the sequence shown, and / or

[1218] (b) A light chain containing SEQ ID NO:482

[1219] The sequence shown is (QAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCT ITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVE KSLSRADCS).

[1220]

[1221] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1222] VHCDR1 contains the VHCDR1 amino acid sequence shown in Table 6;

[1223] VHCDR2 contains the VHCDR2 amino acid sequence shown in Table 6;

[1224] VHCDR3 contains the VHCDR3 amino acid sequence shown in Table 6;

[1225] VLCDR1 contains the VLCDR1 amino acid sequence shown in Table 6;

[1226] VLCDR2 contains the VLCDR2 amino acid sequence shown in Table 6; and

[1227] VLCDR3 contains the VLCDR3 amino acid sequence shown in Table 6;

[1228] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1229] (i) having at least 85% identity with it, and / or

[1230] (ii) relative to having one, two, or three amino acid substitutions.

[1231] The specific binding molecule binds to a polypeptide or protein molecule containing an amino acid sequence of residues 1 to 49 of SEQ ID NO:1.

[1232] Specific binding molecules can be achieved at Kc values ​​less than approximately 25 nM. D It binds to polypeptide or protein molecules containing the amino acid sequence of residues 1 to 49 of SEQ ID NO:1. D It can be less than about 20 nM, less than about 15 nM, or less than about 10 nM. This K D It can be preferably used in conjunction with SEQ ID NO:1 or SEQ ID NO:148. K in conjunction with SEQ ID NO:1 D It can be from about 1 nM to about 20 nM. K bound to SEQ ID NO:1 D It can be from about 1 nM to about 10 nM. K bound to SEQ ID NO:1 D It can be approximately 19.1 nM, wherein the specifically binding molecule optionally contains a CDR of 3aD3. K binding to SEQ ID NO:1 D It can be approximately 3.6 nM, wherein the optionally specifically binding molecule contains a CDR of 3aH6. K binding to SEQ ID NO:1 D It can be approximately 6.1 nM, wherein the optionally specifically binding molecule comprises a CDR of 3aG3. K binding to SEQ ID NO:1 D It can be about 8.9 nM, wherein the selectively specific binding molecule contains a CDR of 3bG4.

[1233] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:422, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 49 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:422. The CDR may have 100% identity with the CDR of SEQ ID NO:422. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:422, wherein the CDR is 100% identical to the CDR of SEQ ID NO:422. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:422.

[1234] SEQ ID NO:422 (3aD3 amino acid sequence)

[1235] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNGVGWVRRAPGKVPEWVGDISSGGKVYGHPALKSRLSITRDTSKSQVSLSVSSVTSEDTAVYYCVRCRDGGVSYGYDSDYWGPGLLVTVSSEG KSSGASGESKVDDQAVVTQPSSVSKSLGQSVSITCSGSSSNVGYGDYVGWFQQVPGSAPKLLIYGVTERASGVPDRFSGSRSGNTATLTISSIQAEDEADYYCASYDDSSGGIFGSGTRLTVLG

[1236] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:423, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 49 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:423. The CDR may have 100% identity with the CDR of SEQ ID NO:423. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:423, wherein the CDR is 100% identical to the CDR of SEQ ID NO:423. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:423.

[1237] SEQ ID NO:423 (3aH6 amino acid sequence)

[1238] QVQLQESGPSLVKPSQTLSLTCTVSGGFSLSSNGVGWVRQAPGKVPEWLGDISSVGKKYANPALKSRLSFTRDTSKSQVSLSLSSVTTEDTAVYYCVKCRDGGVTYGYDIDYWGPGLLVTASSEG KSSGASGESKVDDQAVVTQPSSVSGSLGQSVSITCSGSSGNVGYGDYVSWFQQFHGSAPKLLIYGATNLASGVPARFSGSRSGNTATLTISSLHAEDEADYYCASYDSSSGGVFGSGTRLTVLG

[1239] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:424, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 49 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:424. The CDR may have 100% identity with the CDR of SEQ ID NO:424. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:424, wherein the CDR is 100% identical to the CDR of SEQ ID NO:424. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:424.

[1240] SEQ ID NO:424 (3aG3 amino acid sequence)

[1241] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNGVGWVRQAPGKVPEWVGDISSSGKAYANPALKSRLSITRDTAKTQVFLSLSSVTTEDTAVYYCVRCRDGGVSYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPPSVSGSPGQRVSITCGSSSSNIGGGNYLSWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASFDTSSGGIFGAGTRLTVLG

[1242] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:425, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 49 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:425. The CDR may have 100% identity with the CDR of SEQ ID NO:425. The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:425, wherein the CDR is 100% identical to the CDR of SEQ ID NO:425. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:425.

[1243] SEQ ID NO:425 (3bG4 amino acid sequence)

[1244] QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLG

[1245] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 49 to 111 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT).

[1246] This epitope can be located within the amino acid sequence containing residues 49 to 111 of SEQ ID NO:1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “3bF4”.

[1247] The epitope may contain the amino acid sequence of SEQ ID NO:175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT). The epitope may contain 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 with SEQ ID NO:175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT).

[1248] The epitope may consist of the amino acid sequence of SEQ ID NO:175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT). The epitope may also consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with the sequence of SEQ ID NO:175 (QTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDT).

[1249] The specific binding molecule can bind to polypeptide or protein molecules containing the amino acid sequence of residues 49 to 111 of SEQ ID NO:1. The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1250] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1251] VHCDR2 contains the sequence shown in SEQ ID NO:176 (DI / KSSV / AGKK / TYA / GNPALKS);

[1252] VHCDR3 contains the sequence shown in SEQ ID NO:177 (CRDGGVTYGYDI / VDY);

[1253] VLCDR1 contains the sequence shown in SEQ ID NO:178 (SGSSSNVGL / YR / GN / DY / VT / S);

[1254] VLCDR2 contains the sequence shown in SEQ ID NO:179 (GA / TTS / TRAS); and

[1255] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1256] (i) having at least 85% identity with it, and / or

[1257] (ii) relative to having one, two or three amino acid substitutions.

[1258] The sequence identity is at least about 85% sequence identity, and therefore 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%.

[1259] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1260] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1261] VHCDR2 contains the sequence shown in SEQ ID NO:157 (DISSVGKKYANPALKS) or SEQ ID NO:182 (DKSSAGKTYGNPALKS);

[1262] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY) or SEQ ID NO:184 (CRDGGVTYGYDVDY);

[1263] VLCDR1 contains the sequence shown in SEQ ID NO:185 (SGSSSNVGLRNYVT) or SEQ ID NO:186 (SGSSSNVGYGDVVS);

[1264] VLCDR2 contains the sequence shown in SEQ ID NO:141 (GATSRAS) or SEQ ID NO:188 (GTTTRAS); and

[1265] VLCDR3 contains the sequence shown in SEQ ID NO:189 (ASADTNDGGV) or SEQ ID NO:190 (ASFDSDSGGI);

[1266] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1267] (i) having at least 85% identity with it, and / or

[1268] (ii) relative to having one, two, or three amino acid substitutions.

[1269] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 49 to 111 of SEQ ID NO:1.

[1270] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1271] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1272] VHCDR2 contains the sequence shown in SEQ ID NO:157 (DISSVGKKYANPALKS);

[1273] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1274] VLCDR1 contains the sequence shown in SEQ ID NO:185 (SGSSSNVGLRNYVT);

[1275] VLCDR2 contains the sequence shown in SEQ ID NO:141 (GATSRAS); and

[1276] VLCDR3 contains the sequence shown in SEQ ID NO:189 (ASADTNDGGV);

[1277] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1278] (i) having at least 85% identity with it, and / or

[1279] (ii) relative to having one, two, or three amino acid substitutions.

[1280] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 49 to 111 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "3bF4".

[1281] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1282] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1283] VHCDR2 contains the sequence shown in SEQ ID NO:157 (DISSVGKKYANPALKS);

[1284] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1285] VLCDR1 contains the sequence shown in SEQ ID NO:186 (SGSSSNVGYGDVVS);

[1286] VLCDR2 contains the sequence shown in SEQ ID NO:141 (GATSRAS); and

[1287] VLCDR3 contains the sequence shown in SEQ ID NO:189 (ASADTNDGGV).

[1288] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1289] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1290] VHCDR2 contains the sequence shown in SEQ ID NO:182(DKSSAGKTYGNPALKS);

[1291] VHCDR3 contains the sequence shown in SEQ ID NO:184 (CRDGGVTYGYDVDY);

[1292] VLCDR1 contains the sequence shown in SEQ ID NO:186 (SGSSSNVGYGDVVS);

[1293] VLCDR2 contains the sequence shown in SEQ ID NO:188 (GTTTRAS); and

[1294] VLCDR3 contains the sequence shown in SEQ ID NO:190 (ASFDSDSGGI);

[1295] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1296] (i) having at least 85% identity with it, and / or

[1297] (ii) relative to having one, two, or three amino acid substitutions.

[1298] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 49 to 111 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "3aB7".

[1299] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1300] VHCDR1 contains the sequence shown in SEQ ID NO:149 (SNGVG);

[1301] VHCDR2 contains the sequence shown in SEQ ID NO:182(DKSSAGKTYGNPALKS);

[1302] VHCDR3 contains the sequence shown in SEQ ID NO:184 (CRDGGVTYGYDVDY);

[1303] VLCDR1 contains the sequence shown in SEQ ID NO:186 (SGSSSNVGYGDVVS);

[1304] VLCDR2 contains the sequence shown in SEQ ID NO:188 (GTTTRAS); and

[1305] VLCDR3 contains the sequence shown in SEQ ID NO:190(ASFDSDSGGI).

[1306]

[1307] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1308] VHCDR1 contains the VHCDR1 amino acid sequence shown in Table 7;

[1309] VHCDR2 contains the VHCDR2 amino acid sequence shown in Table 7;

[1310] VHCDR3 contains the VHCDR3 amino acid sequence shown in Table 7;

[1311] VLCDR1 contains the VLCDR1 amino acid sequence shown in Table 7;

[1312] VLCDR2 contains the VLCDR2 amino acid sequence shown in Table 7; and

[1313] VLCDR3 contains the VLCDR3 amino acid sequence shown in Table 7;

[1314] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1315] (i) having at least 85% identity with it, and / or

[1316] (ii) relative to having one, two, or three amino acid substitutions.

[1317] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 49 to 111 of SEQ ID NO:1.

[1318] Specific binding molecules can be achieved at Kc values ​​less than approximately 250 nM. D It binds to polypeptide or protein molecules containing the amino acid sequence of residues 49 to 111 of SEQ ID NO:1. K D It can be less than approximately 200 nM, less than approximately 150 nM, or less than approximately 100 nM. This K D It can be preferably used in conjunction with SEQ ID NO:1 or SEQ ID NO:175. K in conjunction with SEQ ID NO:1 D It can be from about 1 nM to about 20 nM. K bound to SEQ ID NO:1 D It can be from about 50 nM to about 150 nM. K bound to SEQ ID NO:1 D It can be approximately 69 nM, wherein the specifically binding molecule optionally contains a CDR of 3aB7. K binding to SEQ ID NO:1 DIt can be about 140 nM, optionally wherein the specific binding molecule contains a CDR of 3bF4.

[1319] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:420, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 49 to 111 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:420. The CDR may have 100% identity with the CDR of SEQ ID NO:420. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:420, wherein the CDR is 100% identical to the CDR of SEQ ID NO:420. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:420.

[1320] SEQ ID NO:420 (3aB7 amino acid sequence)

[1321] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNGVGWVRQAPGKVPEWVGDKSSAGKTYGNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCVRCRDGGVTYGYDVDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSLGQSVSITCSGSSSNVGYGDVVSWFQQFPGSAPKLLIFGTTTRASGVPDRFSGSRSGNAATLTINSLQAEDEADYYCASFDSDSGGIAGSGTRLTVLG

[1322] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:421, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 49 to 111 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:421. The CDR may have 100% identity with the CDR of SEQ ID NO:421. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:421, wherein the CDR is 100% identical to the CDR of SEQ ID NO:421. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:421.

[1323] SEQ ID NO:421 (3bF4 amino acid sequence)

[1324] QVQLQESGPSLVKPSQTLSLTCTVSGGFSLSSNGVGWVRQAPGKVPEWLGDISSVGKKYANPALKSRLSFTRDTSKSQVSLSLSSVTTEDTAVYYCVKCRDGGVTYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSTGQTVSITCSGSSNVGLRNYVTWFQQVPGSAPKLLIYGATSRASGIPDRFSGSRSGNTATLIISSLQAEDEADYYCASADTNDGGVFGSGTRLTVLG

[1325] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 146 to 157 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:191 (GKTKIATPRGA).

[1326] The epitope may be located within the amino acid sequence containing residues 147 to 157 of SEQ ID NO:1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “3aD6”.

[1327] The epitope may contain the amino acid sequence of SEQ ID NO:191 (GKTKIATPRGA). The epitope may contain 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 with SEQ ID NO:191 (GKTKIATPRGA).

[1328] The epitope may consist of the amino acid sequence of SEQ ID NO:191 (GKTKIATPRGA). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:191 (GKTKIATPRGA).

[1329] The specific binding molecule can bind to polypeptide or protein molecules containing amino acid sequences of residues 147 to 157 of SEQ ID NO:1. The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1330] VHCDR1 contains the sequence shown in SEQ ID NO:192 (SNAVI / G);

[1331] VHCDR2 contains the sequence shown in SEQ ID NO:193 (LIDV / IDGDA / TAYD / NPALK / ES);

[1332] VHCDR3 contains the sequence shown in SEQ ID NO:194 (D / HYG / DS / KWGYV / AS / DD / SIDY);

[1333] VLCDR1 contains the sequence shown in SEQ ID NO:195 (SGSD / S- / S- / N- / VI / GG / YGA / DD / YVG);

[1334] VLCDR2 contains the sequence shown in SEQ ID NO:196 (DN / AD / TN / TRP / AS); and

[1335] VLCDR3 contains the sequence shown in SEQ ID NO:197 (G / AT / SYS / QG / NA / EN / RY / SGI / V);

[1336] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1337] (i) having at least 85% identity with it, and / or

[1338] (ii) relative to having one, two or three amino acid substitutions.

[1339] The sequence identity is at least about 85% sequence identity, and therefore 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%.

[1340] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1341] VHCDR1 contains the sequence shown in SEQ ID NO:198 (SNAVI) or SEQ ID NO:17 (SNAVG);

[1342] VHCDR2 contains the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS) or SEQ ID NO:201 (LIDIDGDTAYNPALES);

[1343] VHCDR3 contains the sequence shown in SEQ ID NO:202 (DYGSWGYVSDIDY) or SEQ ID NO:203 (HYDKWGYADSIDY);

[1344] VLCDR1 contains the sequence shown in SEQ ID NO:204 (SGSDIGGADVG) or SEQ ID NO:138 (SGSSSNVGYGDYVG);

[1345] VLCDR2 contains the sequence shown in SEQ ID NO:206 (DNDNRPS) or SEQ ID NO:207 (DATTRAS); and

[1346] VLCDR3 contains the sequence shown in SEQ ID NO:208 (GTYSGANYGI) or SEQ ID NO:209 (ASYQNERSGV);

[1347] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1348] (i) having at least 85% identity with it, and / or

[1349] (ii) relative to having one, two, or three amino acid substitutions.

[1350] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 147 to 157 of SEQ ID NO:1.

[1351] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1352] VHCDR1 contains the sequence shown in SEQ ID NO:198 (SNAVI);

[1353] VHCDR2 contains the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS);

[1354] VHCDR3 contains the sequence shown in SEQ ID NO:202 (DYGSWGYVSDIDY);

[1355] VLCDR1 contains the sequence shown in SEQ ID NO:204 (SGSDIGGADVG);

[1356] VLCDR2 contains the sequence shown in SEQ ID NO:206 (DNDNRPS); and

[1357] VLCDR3 contains the sequence shown in SEQ ID NO:208 (GTYSGANYGI);

[1358] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1359] (i) having at least 85% identity with it, and / or

[1360] (ii) relative to having one, two, or three amino acid substitutions.

[1361] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 147 to 157 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "3aD6".

[1362] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1363] VHCDR1 contains the sequence shown in SEQ ID NO:198 (SNAVI);

[1364] VHCDR2 contains the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS);

[1365] VHCDR3 contains the sequence shown in SEQ ID NO:202 (DYGSWGYVSDIDY);

[1366] VLCDR1 contains the sequence shown in SEQ ID NO:204 (SGSDIGGADVG);

[1367] VLCDR2 contains the sequence shown in SEQ ID NO:206 (DNDNRPS); and

[1368] VLCDR3 contains the sequence shown in SEQ ID NO:208 (GTYSGANYGI).

[1369] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1370] VHCDR1 contains the sequence shown in SEQ ID NO:17 (SNAVG);

[1371] VHCDR2 contains the sequence shown in SEQ ID NO:201 (LIDIDGDTAYNPALES);

[1372] VHCDR3 contains the sequence shown in SEQ ID NO:203 (HYDKWGYADSIDY);

[1373] VLCDR1 contains the sequence shown in SEQ ID NO:138 (SGSSSNVGYGDYVG);

[1374] VLCDR2 contains the sequence shown in SEQ ID NO:207 (DATTRAS); and

[1375] VLCDR3 contains the sequence shown in SEQ ID NO:209 (ASYQNERSGV);

[1376] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1377] (i) having at least 85% identity with it, and / or

[1378] (ii) relative to having one, two, or three amino acid substitutions.

[1379] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 147 to 157 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "3aA6".

[1380]

[1381] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1382] VHCDR1 contains the VHCDR1 amino acid sequence shown in Table 8;

[1383] VHCDR2 contains the VHCDR2 amino acid sequence shown in Table 8;

[1384] VHCDR3 contains the VHCDR3 amino acid sequence shown in Table 8;

[1385] VLCDR1 contains the VLCDR1 amino acid sequence shown in Table 8;

[1386] VLCDR2 contains the VLCDR2 amino acid sequence shown in Table 8; and

[1387] VLCDR3 contains the VLCDR3 amino acid sequence shown in Table 8;

[1388] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1389] (i) having at least 85% identity with it, and / or

[1390] (ii) relative to having one, two, or three amino acid substitutions.

[1391] The specific binding molecule binds to a polypeptide or protein molecule containing an amino acid sequence of residues 147 to 157 of SEQ ID NO:1.

[1392] Specific binding molecules can be achieved at Kc values ​​less than approximately 50 nM. D It binds to polypeptide or protein molecules containing the amino acid sequence of residues 147 to 157 of SEQ ID NO:1. D It can be less than approximately 40 nM, less than approximately 30 nM, or less than approximately 20 nM. This K DIt can be preferably used in conjunction with SEQ ID NO:1 or SEQ ID NO:191. K in conjunction with SEQ ID NO:1 D It can be from about 10 nM to about 20 nM. K bound to SEQ ID NO:1 D It can be about 16.5 nM, wherein the specific binding molecule optionally includes a CDR of 3aD6.

[1393] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:418, 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. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:418. The CDR may have 100% identity with the CDR of SEQ ID NO:418. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:418, wherein the CDR is 100% identical to the CDR of SEQ ID NO:418. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:418.

[1394] SEQ ID NO:418 (3aA6 amino acid sequence)

[1395] QVRLQESGSSLVKPSQTLSLVCTVSGFPLTSNAVGWVRQAPGKAPEWLGLIDIDGDTAYNPALESRLSITRDTSKSQVSLSLSSVAIEDTAVYYCARHYDKWGYADSIDYWGPGLLVTVSSEG KSSGASGESKVDDQALLTQPSSVFGSLGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYDATTRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYQNERSGVFGSGTRLTVLG

[1396] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:419, 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. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:419. The CDR may have 100% identity with the CDR of SEQ ID NO:419. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:419, wherein the CDR is 100% identical to the CDR of SEQ ID NO:419. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:419.

[1397] SEQ ID NO:419 (3aD6 amino acid sequence)

[1398] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSDIGGADVGWFQQVPGSGLRTLIYDNDNRPSGVPDRFSGSKSGNTATLTISSLQPEDEADYFCGTYSGANYGIFFSGTRLTVLG

[1399] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 379 to 391 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:221 (RENAKAKTDHGAE).

[1400] 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 with 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. This epitope may bind to the CDR of a specific binding molecule referred to herein as “E2E8”. The key residue of the epitope may be residue 391(E) (as numbered according to SEQ ID NO:1). The epitope may comprise the amino acid sequence of SEQ ID NO:222 (XXXXXXXXXXXXE, where X is any amino acid). The epitope may comprise the amino acid sequence of SEQ ID NO:8, wherein any one or more residues other than residue number 391(E) are replaced by non-conservative amino acid substitutions (as 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 other than residue number 391(E) are replaced by conserved amino acid substitutions (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 other than residue number 391(E) are replaced by conserved amino acid substitutions (according to SEQ ID NO:1), and any one or more residues other than residue number 391(E) are replaced by non-conserved amino acid substitutions (according to SEQ ID NO:1).

[1401] The epitope may contain the amino acid sequence of SEQ ID NO:221 (RENAKAKTDHGAE). The epitope may contain 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 with SEQ ID NO:221 (RENAKAKTDHGAE).

[1402] The epitope may consist of the amino acid sequence of SEQ ID NO:221 (RENAKAKTDHGAE). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:221 (RENAKAKTDHGAE).

[1403] The specific binding molecule can bind to polypeptide or protein molecules containing the amino acid sequence of residues 379 to 391 of SEQ ID NO:1. The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1404] VHCDR1 contains the sequence shown in SEQ ID NO:223 (D / SR / WGVA);

[1405] VHCDR2 contains the sequence shown in SEQ ID NO:224 (TMRSGGT / GI / TD / EY / DNPALKS);

[1406] VHCDR3 contains the sequence shown in SEQ ID NO:225 (GYLSGD / I / VR / HYA);

[1407] VLCDR1 contains the sequence shown in SEQ ID NO:226 (SGSR / SSD / NI / VGY / D / AGN / D / RYVS / G);

[1408] VLCDR2 contains the sequence shown in SEQ ID NO:227 (D / S / GT / AN / R / TT / N / SRAS); and

[1409] VLCDR3 contains the sequence shown in SEQ ID NO:228 (AN / SIDS / TS / GR / NS / NH / LL / I);

[1410] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1411] (i) having at least 85% identity with it, and / or

[1412] (ii) relative to having one, two or three amino acid substitutions.

[1413] The sequence identity is at least about 85% sequence identity, and therefore 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%.

[1414] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1415] VHCDR1 contains the sequence shown in SEQ ID NO:229 (DRGVA), SEQ ID NO:230 (DWGVA), or SEQ ID NO:231 (SWGVA);

[1416] VHCDR2 contains the sequences shown in SEQ ID NO:232 (TMRSGGTIDYNPALKS), SEQ ID NO:233 (TMRSGGGTEYNPALKS), or SEQ ID NO:234 ​​(TMRSGGTTDDNPALKS);

[1417] VHCDR3 contains the sequences shown in SEQ ID NO:235 (GYLSGDRYA), SEQ ID NO:236 (GYLSGIHYA), or SEQ ID NO:237 (GYLSGVHYA);

[1418] VLCDR1 contains the sequences shown in SEQ ID NO:238 (SGSRSDIGYGNYVS), SEQ ID NO:239 (SGSSSNVGAGNYVG), SEQ ID NO:240 (SGSSSNVGDGDYVG), or SEQ ID NO:241 (SGSSSNVGDGRYVS);

[1419] VLCDR2 contains the sequences shown in SEQ ID NO:242 (DTNTRAS), SEQ ID NO:243 (DTTSRAS), SEQ ID NO:170 (GATNRAS), or SEQ ID NO:244 (SARNRAS); and

[1420] VLCDR3 contains the sequences shown in SEQ ID NO:245 (ANIDSSRSHL), SEQ ID NO:246 (ASIDSGNNLL), or SEQ ID NO:247 (ASIDTSRSHI);

[1421] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1422] (i) having at least 85% identity with it, and / or

[1423] (ii) relative to having one, two, or three amino acid substitutions.

[1424] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 379 to 391 of SEQ ID NO:1.

[1425] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1426] VHCDR1 contains the sequence shown in SEQ ID NO:229 (DRGVA);

[1427] VHCDR2 contains the sequence shown in SEQ ID NO:232 (TMRSGGTIDYNPALKS);

[1428] VHCDR3 contains the sequence shown in SEQ ID NO:235 (GYLSGDRYA);

[1429] VLCDR1 contains the sequence shown in SEQ ID NO:238 (SGSRSDIGYGNYVS);

[1430] VLCDR2 contains the sequence shown in SEQ ID NO:242 (DTNTRAS); and

[1431] VLCDR3 contains the sequence shown in SEQ ID NO:245 (ANIDSSRSHL);

[1432] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1433] (i) having at least 85% identity with it, and / or

[1434] (ii) relative to having one, two, or three amino acid substitutions.

[1435] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 379 to 391 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "E2E8".

[1436] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1437] VHCDR1 contains the sequence shown in SEQ ID NO:229 (DRGVA);

[1438] VHCDR2 contains the sequence shown in SEQ ID NO:232 (TMRSGGTIDYNPALKS);

[1439] VHCDR3 contains the sequence shown in SEQ ID NO:235 (GYLSGDRYA);

[1440] VLCDR1 contains the sequence shown in SEQ ID NO:238 (SGSRSDIGYGNYVS);

[1441] VLCDR2 contains the sequence shown in SEQ ID NO:242 (DTNTRAS); and

[1442] VLCDR3 contains the sequence shown in SEQ ID NO:245 (ANIDSSRSHL).

[1443] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1444] VHFR1 contains the sequence shown in SEQ ID NO:483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1445] VHFR2 contains the sequence shown in SEQ ID NO:484 (WVRQAPGKALEWVG);

[1446] VHFR3 contains the sequence shown in SEQ ID NO:485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1447] VHFR4 contains the sequence shown in SEQ ID NO:486 (WGRGLLVTVSS);

[1448] VLFR1 contains the sequence shown in SEQ ID NO:487 (QAVLTQPSSVSKSLGQSVSIAC);

[1449] VLFR2 contains the sequence shown in SEQ ID NO:488(WFQQIPGSAPKLLIY);

[1450] VLFR3 contains the sequence shown in SEQ ID NO:489(GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1451] VLFR4 contains the sequence shown in SEQ ID NO:490 (FGSGTRLTVLG);

[1452] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1453] (i) having at least 50% similarity to it, and / or

[1454] (ii) relative to having one, two, three, four or five amino acid substitutions.

[1455] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1456] VHFR1 contains the sequence shown in SEQ ID NO:483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1457] VHFR2 contains the sequence shown in SEQ ID NO:484 (WVRQAPGKALEWVG);

[1458] VHFR3 contains the sequence shown in SEQ ID NO:485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1459] VHFR4 contains the sequence shown in SEQ ID NO:486 (WGRGLLVTVSS);

[1460] VLFR1 contains the sequence shown in SEQ ID NO:487 (QAVLTQPSSVSKSLGQSVSIAC);

[1461] VLFR2 contains the sequence shown in SEQ ID NO:488(WFQQIPGSAPKLLIY);

[1462] VLFR3 contains the sequence shown in SEQ ID NO:489(GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1463] VLFR4 contains the sequence shown in SEQ ID NO:490 (FGSGTRLTVLG);

[1464] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1465] (i) having at least 50% similarity to it, and / or

[1466] (ii) relative to having one, two, three, four or five amino acid substitutions,

[1467] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 379 to 391 of SEQ ID NO:1. The specific binding molecule containing a FR that is 100% identical to the above-mentioned FR is referred to herein as "E2E8".

[1468] Specific binding molecules may include:

[1469] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1470] VHFR1 contains the sequence shown in SEQ ID NO:483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1471] VHFR2 contains the sequence shown in SEQ ID NO:484 (WVRQAPGKALEWVG);

[1472] VHFR3 contains the sequence shown in SEQ ID NO:485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1473] VHFR4 contains the sequence shown in SEQ ID NO:486 (WGRGLLVTVSS);

[1474] VLFR1 contains the sequence shown in SEQ ID NO:487 (QAVLTQPSSVSKSLGQSVSIAC);

[1475] VLFR2 contains the sequence shown in SEQ ID NO:488(WFQQIPGSAPKLLIY);

[1476] VLFR3 contains the sequence shown in SEQ ID NO:489(GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1477] VLFR4 contains the sequence shown in SEQ ID NO:490 (FGSGTRLTVLG);

[1478] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1479] (i) having at least 50% similarity to it, and / or

[1480] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1481] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1482] VHCDR1 contains the sequence shown in SEQ ID NO:229 (DRGVA);

[1483] VHCDR2 contains the sequence shown in SEQ ID NO:232 (TMRSGGTIDYNPALKS);

[1484] VHCDR3 contains the sequence shown in SEQ ID NO:235 (GYLSGDRYA);

[1485] VLCDR1 contains the sequence shown in SEQ ID NO:238 (SGSRSDIGYGNYVS);

[1486] VLCDR2 contains the sequence shown in SEQ ID NO:242 (DTNTRAS); and

[1487] VLCDR3 contains the sequence shown in SEQ ID NO:245 (ANIDSSRSHL);

[1488] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1489] (i) having at least 85% identity with it, and / or

[1490] (ii) relative to having one, two or three amino acid substitutions

[1491] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 379 to 391 of SEQ ID NO:1. The specific binding molecule containing FRs and CDRs that are 100% identical to the above-mentioned FRs and CDRs is referred to herein as "E2E8".

[1492] Specific binding molecules may include:

[1493] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1494] VHFR1 contains the sequence shown in SEQ ID NO:483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1495] VHFR2 contains the sequence shown in SEQ ID NO:484 (WVRQAPGKALEWVG);

[1496] VHFR3 contains the sequence shown in SEQ ID NO:485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1497] VHFR4 contains the sequence shown in SEQ ID NO:486 (WGRGLLVTVSS);

[1498] VLFR1 contains the sequence shown in SEQ ID NO:487 (QAVLTQPSSVSKSLGQSVSIAC);

[1499] VLFR2 contains the sequence shown in SEQ ID NO:488(WFQQIPGSAPKLLIY);

[1500] VLFR3 contains the sequence shown in SEQ ID NO:489(GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1501] VLFR4 contains the sequence shown in SEQ ID NO:490 (FGSGTRLTVLG);

[1502] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1503] (i) having at least 50% similarity to it, and / or

[1504] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1505] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1506] VHCDR1 contains the sequence shown in SEQ ID NO:229 (DRGVA);

[1507] VHCDR2 contains the sequence shown in SEQ ID NO:232 (TMRSGGTIDYNPALKS);

[1508] VHCDR3 contains the sequence shown in SEQ ID NO:235 (GYLSGDRYA);

[1509] VLCDR1 contains the sequence shown in SEQ ID NO:238 (SGSRSDIGYGNYVS);

[1510] VLCDR2 contains the sequence shown in SEQ ID NO:242 (DTNTRAS); and

[1511] VLCDR3 contains the sequence shown in SEQ ID NO:245 (ANIDSSRSHL);

[1512] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 379 to 391 of SEQ ID NO:1. The specific binding molecule containing FRs and CDRs that are 100% identical to the above-mentioned FRs and CDRs is referred to herein as "E2E8".

[1513] Specific binding molecules may include the following or their humanized variants:

[1514] (a) The VH domain, which contains SEQ ID NO:491

[1515] The sequence shown is (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLVTVSS); and / or

[1516] (b) The VL domain, which contains SEQ ID NO:492

[1517] The sequence shown is (QAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLG).

[1518] Specific binding molecules may include the following or their humanized variants:

[1519] (a) Heavy chain, which contains SEQ ID NO:493

[1520] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLV TVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCK CPAPNLLGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSV RAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK); the sequence shown, and / or

[1521] (b) A light chain containing SEQ ID NO:494

[1522] The sequence shown is (QAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTI TDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEK SLSRADCS).

[1523] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1524] VHCDR1 contains the sequence shown in SEQ ID NO:230 (DWGVA);

[1525] VHCDR2 contains the sequence shown in SEQ ID NO:234 ​​(TMRSGGTTDDNPALKS);

[1526] VHCDR3 contains the sequence shown in SEQ ID NO:237 (GYLSGVHYA);

[1527] VLCDR1 contains the sequence shown in SEQ ID NO:241 (SGSSSNVGDGRYVS);

[1528] VLCDR2 contains the sequence shown in SEQ ID NO:243 (DTTSRAS); and

[1529] VLCDR3 contains the sequence shown in SEQ ID NO:246 (ASIDSGNNLL);

[1530] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1531] (i) having at least 85% identity with it, and / or

[1532] (ii) relative to having one, two, or three amino acid substitutions.

[1533] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 379 to 391 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "E1E8".

[1534] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1535] VHCDR1 contains the sequence shown in SEQ ID NO:230 (DWGVA);

[1536] VHCDR2 contains the sequence shown in SEQ ID NO:234 ​​(TMRSGGTTDDNPALKS);

[1537] VHCDR3 contains the sequence shown in SEQ ID NO:237 (GYLSGVHYA);

[1538] VLCDR1 contains the sequence shown in SEQ ID NO:241 (SGSSSNVGDGRYVS);

[1539] VLCDR2 contains the sequence shown in SEQ ID NO:243 (DTTSRAS); and

[1540] VLCDR3 contains the sequence shown in SEQ ID NO:246 (ASIDSGNNLL).

[1541] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1542] VHCDR1 contains the sequence shown in SEQ ID NO:230 (DWGVA);

[1543] VHCDR2 contains the sequence shown in SEQ ID NO:234 ​​(TMRSGGTTDDNPALKS);

[1544] VHCDR3 contains the sequence shown in SEQ ID NO:237 (GYLSGVHYA);

[1545] VLCDR1 contains the sequence shown in SEQ ID NO:239 (SGSSSNVGAGNYVG);

[1546] VLCDR2 contains the sequence shown in SEQ ID NO:70 (GATNRAS); and

[1547] VLCDR3 contains the sequence shown in SEQ ID NO:247 (ASIDTSRSHI);

[1548] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1549] (i) having at least 85% identity with it, and / or

[1550] (ii) relative to having one, two, or three amino acid substitutions.

[1551] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 379 to 391 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "E2A6".

[1552] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1553] VHCDR1 contains the sequence shown in SEQ ID NO:230 (DWGVA);

[1554] VHCDR2 contains the sequence shown in SEQ ID NO:234 ​​(TMRSGGTTDDNPALKS);

[1555] VHCDR3 contains the sequence shown in SEQ ID NO:237 (GYLSGVHYA);

[1556] VLCDR1 contains the sequence shown in SEQ ID NO:239 (SGSSSNVGAGNYVG);

[1557] VLCDR2 contains the sequence shown in SEQ ID NO:70 (GATNRAS); and

[1558] VLCDR3 contains the sequence shown in SEQ ID NO:247 (ASIDTSRSHI).

[1559] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1560] VHCDR1 contains the sequence shown in SEQ ID NO:231 (SWGVA);

[1561] VHCDR2 contains the sequence shown in SEQ ID NO:233 (TMRSGGGTEYNPALKS);

[1562] VHCDR3 contains the sequence shown in SEQ ID NO:236 (GYLSGIHYA);

[1563] VLCDR1 contains the sequence shown in SEQ ID NO:240 (SGSSSNVGDGDYVG);

[1564] VLCDR2 contains the sequence shown in SEQ ID NO:244 (SARNRAS); and

[1565] VLCDR3 contains the sequence shown in SEQ ID NO:247 (ASIDTSRSHI);

[1566] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1567] (i) having at least 85% identity with it, and / or

[1568] (ii) relative to having one, two, or three amino acid substitutions.

[1569] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 379 to 391 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "E2B7".

[1570] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1571] VHCDR1 contains the sequence shown in SEQ ID NO:231 (SWGVA);

[1572] VHCDR2 contains the sequence shown in SEQ ID NO:233 (TMRSGGGTEYNPALKS);

[1573] VHCDR3 contains the sequence shown in SEQ ID NO:236 (GYLSGIHYA);

[1574] VLCDR1 contains the sequence shown in SEQ ID NO:240 (SGSSSNVGDGDYVG);

[1575] VLCDR2 contains the sequence shown in SEQ ID NO:244 (SARNRAS); and

[1576] VLCDR3 contains the sequence shown in SEQ ID NO:247 (ASIDTSRSHI).

[1577]

[1578] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1579] VHCDR1 contains the VHCDR1 amino acid sequence shown in Table 9;

[1580] VHCDR2 contains the VHCDR2 amino acid sequence shown in Table 9;

[1581] VHCDR3 contains the VHCDR3 amino acid sequence shown in Table 9;

[1582] VLCDR1 contains the VLCDR1 amino acid sequence shown in Table 9;

[1583] VLCDR2 contains the VLCDR2 amino acid sequence shown in Table 9; and

[1584] VLCDR3 contains the VLCDR3 amino acid sequence shown in Table 9;

[1585] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1586] (i) having at least 85% identity with it, and / or

[1587] (ii) relative to having one, two, or three amino acid substitutions.

[1588] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 379 to 391 of SEQ ID NO:1.

[1589] Specific binding molecules can be achieved at Kc values ​​less than approximately 25 nM. D It binds to polypeptide or protein molecules containing the amino acid sequence of residues 379 to 391 of SEQ ID NO:1. D It can be less than about 20 nM, less than about 15 nM, or less than about 10 nM. This K D This can be preferably used for binding to SEQ ID NO:4. The binding of a specifically binding molecule to SEQ ID NO:1 may be undetectable. K binding to SEQ ID NO:4... D It can be from approximately 300 pM to approximately 10 nM. K bound to SEQ ID NO:4 D It can be from approximately 300 pM to approximately 500 pM. K bound to SEQ ID NO:4 D It can be from about 1 nM to about 10 nM. K bound to SEQ ID NO:4 D It can be approximately 401 pM, wherein optionally, the specifically binding molecule comprises a CDR of E1E8. K binds to SEQ ID NO:4 D It can be about 6.3 nM, wherein optionally, the specific binding molecule contains the CDR of E1E8.

[1590] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:248, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 379 to 391 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:248. The CDR may have 100% identity with the CDR of SEQ ID NO:248. The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:248, wherein the CDR is 100% identical to the CDR of SEQ ID NO:248. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:248.

[1591] SEQ ID NO:248 (amino acid sequence of E2E8)

[1592] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLG

[1593] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:250, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 379 to 391 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:250. The CDR may have 100% identity with the CDR of SEQ ID NO:250. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:250, wherein the CDR is 100% identical to the CDR of SEQ ID NO:250. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:250.

[1594] SEQ ID NO:250 (E1E8 amino acid sequence)

[1595] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDWGVAWVRQAPGKALEWLGTMRSGGTTDDNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGVHYAWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSGSLGQSVSITCSGSSSNVGDGRYVSWFQQVPGSAPKLLIYDTTSRASGVPDRFSGSRSGNTATLIITSLQAEDEADYYCASIDSGNNLLFGSGTRLTVLG

[1596] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:252, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 379 to 391 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:252. The CDR may have 100% identity with the CDR of SEQ ID NO:252. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:252, wherein the CDR is 100% identical to the CDR of SEQ ID NO:252. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:252.

[1597] SEQ ID NO:252 (E2A6 amino acid sequence)

[1598] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDWGVAWVRQAPGKALEWLGTMRSGGTTDDNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGVHYAWGRGLLVTVSSEGKS SGASGESKVDDRVVRTQPSSVSKSLGQSVSITCSGSSSNVGAGNYVGWFQQVPGSAPKLLIYGATNRASGVPARFSGSKSGVTATLTITSLQAEDEADYYCASIDTSRSHIFGSGTRLTVLG

[1599] The specific binding molecule may comprise an amino acid sequence having at least 70%, 75%, 80%, 90%, 95%, or 99% identity with SEQ ID NO:254, wherein the specific binding molecule binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 379 to 391 of SEQ ID NO:1. The CDR of the specific binding molecule may have at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identity with the CDR of SEQ ID NO:254. The CDR may have 100% identity with the CDR of SEQ ID NO:254. The specific binding molecule may comprise an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:254, wherein the CDR is 100% identical to the CDR of SEQ ID NO:254. The specific binding molecule may comprise the amino acid sequence of SEQ ID NO:254.

[1600] SEQ ID NO:254 (E2B7 amino acid sequence)

[1601] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSWGVAWVRQAPGKALEWLGTMRSGGGTEYNPALKSRLSITRDTSKSQVSLSLSSVTTEDDMAMYYCARGYLSGIHYAWGRGLLVSVSSEGKS SGASGESKVDDQAVLTQLSSVSGSLGQRVSITCSGSSSNVGDGDYVGWFQQLPGSAPKLLIYSARNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCASIDTSRSHIFGSGTRLTVLG

[1602] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 113 to 238 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPA PKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1603] The epitope may be located within the amino acid sequence containing residues 113 to 238 of SEQ ID NO:1. The epitope may bind to the CDR of a specific binding molecule referred to herein as “CB11”.

[1604] The epitope may contain the amino acid sequence of SEQ ID NO:255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPA PKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). The epitope may contain 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 with SEQ ID NO:255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPA PKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1605] Epitopes can be composed of the amino acid sequence SEQ ID NO:255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPA PKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). Epitopes can also be composed of amino acid sequences having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPA PKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1606] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1607] VHCDR1 contains the sequence shown in SEQ ID NO:198 (SNAVI);

[1608] VHCDR2 contains the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS);

[1609] VHCDR3 contains the sequence shown in SEQ ID NO:202 (DYGSWGYVSDIDY);

[1610] VLCDR1 contains the sequence shown in SEQ ID NO:256 (SGSNIGSNDVG);

[1611] VLCDR2 contains the sequence shown in SEQ ID NO:257 (DNNNRPS); and

[1612] VLCDR3 contains the sequence shown in SEQ ID NO:258 (GGYAGSSSNFL);

[1613] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1614] (i) having at least 85% identity with it, and / or

[1615] (ii) relative to having one, two, or three amino acid substitutions.

[1616] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 113 to 238 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "CB11".

[1617] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1618] VHCDR1 contains the sequence shown in SEQ ID NO:198 (SNAVI);

[1619] VHCDR2 contains the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS);

[1620] VHCDR3 contains the sequence shown in SEQ ID NO:202 (DYGSWGYVSDIDY);

[1621] VLCDR1 contains the sequence shown in SEQ ID NO:256 (SGSNIGSNDVG);

[1622] VLCDR2 contains the sequence shown in SEQ ID NO:257 (DNNNRPS); and

[1623] VLCDR3 contains the sequence shown in SEQ ID NO:258 (GGYAGSSSNFL).

[1624] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 1 to 155 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPR).

[1625] Epitopes can be located within the amino acid sequence containing residues 1 to 155 of SEQ ID NO:1. Epitopes can be bound by the CDR of a specific binding molecule referred to herein as “CA2”.

[1626] Epitopes may contain the amino acid sequence of SEQ ID NO:293(MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPR). Epitopes may contain amino acid sequences that are 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 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR).

[1627] Epitopes can be composed of the amino acid sequence of SEQ ID NO:293(MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPR). Epitopes may consist of amino acid sequences having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR).

[1628] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1629] VHCDR1 contains the sequence shown in SEQ ID NO:259 (SNGVG);

[1630] VHCDR2 contains the sequence shown in SEQ ID NO:157 (DISSVGKKYANPALKS);

[1631] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1632] VLCDR1 contains the sequence shown in SEQ ID NO:165 (SGSSGNVGYGDYVS);

[1633] VLCDR2 contains the sequence shown in SEQ ID NO:169 (GATNLAS); and

[1634] VLCDR3 contains the sequence shown in SEQ ID NO:173 (ASYDSSSGGV);

[1635] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1636] (i) having at least 85% identity with it, and / or

[1637] (ii) relative to having one, two, or three amino acid substitutions.

[1638] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 155 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "CA2".

[1639] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1640] VHCDR1 contains the sequence shown in SEQ ID NO:259 (SNGVG);

[1641] VHCDR2 contains the sequence shown in SEQ ID NO:157 (DISSVGKKYANPALKS);

[1642] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1643] VLCDR1 contains the sequence shown in SEQ ID NO:165 (SGSSGNVGYGDYVS);

[1644] VLCDR2 contains the sequence shown in SEQ ID NO:169 (GATNLAS); and

[1645] VLCDR3 contains the sequence shown in SEQ ID NO:173 (ASYDSSSGGV).

[1646] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 1 to 238 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:260 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1647] The epitope may be located within the amino acid sequence containing residues 1 to 238 of SEQ ID NO:1. The epitope may bind to the CDR of a specific binding molecule referred to herein as “CB6”.

[1648] The epitope may include SEQ ID NO: 260 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT The amino acid sequence of GSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). Epitopes may contain amino acid sequences that are 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 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1649] Epitopes can be composed of the amino acid sequence of SEQ ID NO:260(MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). Epitopes may consist of amino acid sequences having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:260 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGT GSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTP GSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1650] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1651] VHCDR1 contains the sequence shown in SEQ ID NO:259 (SNGVG);

[1652] VHCDR2 contains the sequence shown in SEQ ID NO:157 (DISSVGKKYANPALKS);

[1653] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1654] VLCDR1 contains the sequence shown in SEQ ID NO:261 (SGSSSNIGTGNYVG);

[1655] VLCDR2 contains the sequence shown in SEQ ID NO:262 (GAVTRAS); and

[1656] VLCDR3 contains the sequence shown in SEQ ID NO:263 (ASYDSTSGGV);

[1657] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1658] (i) having at least 85% identity with it, and / or

[1659] (ii) relative to having one, two, or three amino acid substitutions.

[1660] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 238 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "CB6".

[1661] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1662] VHCDR1 contains the sequence shown in SEQ ID NO:259 (SNGVG);

[1663] VHCDR2 contains the sequence shown in SEQ ID NO:157 (DISSVGKKYANPALKS);

[1664] VHCDR3 contains the sequence shown in SEQ ID NO:161 (CRDGGVTYGYDIDY);

[1665] VLCDR1 contains the sequence shown in SEQ ID NO:261 (SGSSSNIGTGNYVG);

[1666] VLCDR2 contains the sequence shown in SEQ ID NO:262 (GAVTRAS); and

[1667] VLCDR3 contains the sequence shown in SEQ ID NO:263 (ASYDSTSGGV).

[1668] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 1 to 319 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[1669] Epitopes may be located within the amino acid sequence containing residues 1 to 319 of SEQ ID NO:1. Epitopes may bind to the CDRs of specific binding molecules referred to herein as “CA7”, “CA8”, and “CB10”.

[1670] The epitope within the amino acid sequence containing residues 1 to 319 of SEQ ID NO:1 is preferably located within the amino acid sequence containing residues 37 to 49 of SEQ ID NO:1. The epitope can bind at least to the CDR of a specific binding molecule referred to herein as “CA7”.

[1671] The epitope may comprise SEQ ID NO: 264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSG The amino acid sequence of YSSPGSPGTPGSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT). Epitopes may contain amino acid sequences that are 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 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[1672] Epitopes can be composed of the amino acid sequence of SEQ ID NO: 264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSD AKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT). Epitopes can be composed of the amino acid sequence of SEQ ID NO:

[1673] 264(MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT) has an amino acid sequence composition with at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity.

[1674] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1675] VHCDR1 contains the sequence shown in SEQ ID NO:44 (SYYVG);

[1676] VHCDR2 contains the sequence shown in SEQ ID NO:52 (NIYSTGRAFYNPALKS);

[1677] VHCDR3 contains the sequence shown in SEQ ID NO:265(GSYYHGGGNGMVDFFDY);

[1678] VLCDR1 contains the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[1679] VLCDR2 contains the sequence shown in SEQ ID NO:72 (AATSRAS); and

[1680] VLCDR3 contains the sequence shown in SEQ ID NO:78 (SSYQRGNTGV);

[1681] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1682] (i) having at least 85% identity with it, and / or

[1683] (ii) relative to having one, two, or three amino acid substitutions.

[1684] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 319 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "CA7".

[1685] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1686] VHCDR1 contains the sequence shown in SEQ ID NO:44 (SYYVG);

[1687] VHCDR2 contains the sequence shown in SEQ ID NO:52 (NIYSTGRAFYNPALKS);

[1688] VHCDR3 contains the sequence shown in SEQ ID NO:265(GSYYHGGGNGMVDFFDY);

[1689] VLCDR1 contains the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[1690] VLCDR2 contains the sequence shown in SEQ ID NO:72 (AATSRAS); and

[1691] VLCDR3 contains the sequence shown in SEQ ID NO:78 (SSYQRGNTGV).

[1692] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1693] VHFR1 contains the sequence shown in SEQ ID NO:495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD);

[1694] VHFR2 contains the sequence shown in SEQ ID NO:496 (WVRQAPGKALEWLG);

[1695] VHFR3 contains the sequence shown in SEQ ID NO:497(RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR);

[1696] VHFR4 contains the sequence shown in SEQ ID NO:498 (WSPGLLVTVSS);

[1697] VLFR1 contains the sequence shown in SEQ ID NO:499 (QVVRTQPSSVSGSLGQRVSITC);

[1698] VLFR2 contains the sequence shown in SEQ ID NO:500(WFQQVPGSAPKLLIY);

[1699] VLFR3 contains the sequence shown in SEQ ID NO:501(GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC);

[1700] VLFR4 contains the sequence shown in SEQ ID NO:502 (FGSGTRLTVLG);

[1701] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1702] (i) having at least 50% similarity to it, and / or

[1703] (ii) relative to having one, two, three, four or five amino acid substitutions.

[1704] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1705] VHFR1 contains the sequence shown in SEQ ID NO:495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD);

[1706] VHFR2 contains the sequence shown in SEQ ID NO:496 (WVRQAPGKALEWLG);

[1707] VHFR3 contains the sequence shown in SEQ ID NO:497(RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR);

[1708] VHFR4 contains the sequence shown in SEQ ID NO:498 (WSPGLLVTVSS);

[1709] VLFR1 contains the sequence shown in SEQ ID NO:499 (QVVRTQPSSVSGSLGQRVSITC);

[1710] VLFR2 contains the sequence shown in SEQ ID NO:500(WFQQVPGSAPKLLIY);

[1711] VLFR3 contains the sequence shown in SEQ ID NO:501(GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC);

[1712] VLFR4 contains the sequence shown in SEQ ID NO:502 (FGSGTRLTVLG);

[1713] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1714] (i) having at least 50% similarity to it, and / or

[1715] (ii) relative to having one, two, three, four or five amino acid substitutions,

[1716] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 319 of SEQ ID NO:1. The specific binding molecule containing a FR that is 100% identical to the above-mentioned FR is referred to herein as "CA7".

[1717] Specific binding molecules may include:

[1718] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1719] VHFR1 contains the sequence shown in SEQ ID NO:495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD);

[1720] VHFR2 contains the sequence shown in SEQ ID NO:496 (WVRQAPGKALEWLG);

[1721] VHFR3 contains the sequence shown in SEQ ID NO:497(RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR);

[1722] VHFR4 contains the sequence shown in SEQ ID NO:498 (WSPGLLVTVSS);

[1723] VLFR1 contains the sequence shown in SEQ ID NO:499 (QVVRTQPSSVSGSLGQRVSITC);

[1724] VLFR2 contains the sequence shown in SEQ ID NO:500(WFQQVPGSAPKLLIY);

[1725] VLFR3 contains the sequence shown in SEQ ID NO:501(GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC);

[1726] VLFR4 contains the sequence shown in SEQ ID NO:502 (FGSGTRLTVLG);

[1727] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1728] (i) having at least 50% similarity to it, and / or

[1729] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1730] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1731] VHCDR1 contains the sequence shown in SEQ ID NO:44 (SYYVG);

[1732] VHCDR2 contains the sequence shown in SEQ ID NO:52 (NIYSTGRAFYNPALKS);

[1733] VHCDR3 contains the sequence shown in SEQ ID NO:265(GSYYHGGGNGMVDFFDY);

[1734] VLCDR1 contains the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[1735] VLCDR2 contains the sequence shown in SEQ ID NO:72 (AATSRAS); and

[1736] VLCDR3 contains the sequence shown in SEQ ID NO:78 (SSYQRGNTGV).

[1737] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1738] (i) having at least 85% identity with it, and / or

[1739] (ii) relative to having one, two or three amino acid substitutions

[1740] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 319 of SEQ ID NO:1. The specific binding molecule containing FRs and CDRs that are 100% identical to the above-mentioned FRs and CDRs is referred to herein as "CA7".

[1741] Specific binding molecules may include:

[1742] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1743] VHFR1 contains the sequence shown in SEQ ID NO:495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD);

[1744] VHFR2 contains the sequence shown in SEQ ID NO:496 (WVRQAPGKALEWLG);

[1745] VHFR3 contains the sequence shown in SEQ ID NO:497(RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR);

[1746] VHFR4 contains the sequence shown in SEQ ID NO:498 (WSPGLLVTVSS);

[1747] VLFR1 contains the sequence shown in SEQ ID NO:499 (QVVRTQPSSVSGSLGQRVSITC);

[1748] VLFR2 contains the sequence shown in SEQ ID NO:500(WFQQVPGSAPKLLIY);

[1749] VLFR3 contains the sequence shown in SEQ ID NO:501(GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC);

[1750] VLFR4 contains the sequence shown in SEQ ID NO:502 (FGSGTRLTVLG);

[1751] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1752] (i) having at least 50% similarity to it, and / or

[1753] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1754] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1755] VHCDR1 contains the sequence shown in SEQ ID NO:44 (SYYVG);

[1756] VHCDR2 contains the sequence shown in SEQ ID NO:52 (NIYSTGRAFYNPALKS);

[1757] VHCDR3 contains the sequence shown in SEQ ID NO:265(GSYYHGGGNGMVDFFDY);

[1758] VLCDR1 contains the sequence shown in SEQ ID NO:39 (SGSSSNVGYGNYVG);

[1759] VLCDR2 contains the sequence shown in SEQ ID NO:72 (AATSRAS); and

[1760] VLCDR3 contains the sequence shown in SEQ ID NO:78 (SSYQRGNTGV).

[1761] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 319 of SEQ ID NO:1. The specific binding molecule containing FRs and CDRs that are 100% identical to the above-mentioned FRs and CDRs is referred to herein as "CA7".

[1762] Specific binding molecules may include the following or their humanized variants:

[1763] (a) The VH domain, which contains SEQ ID NO:503

[1764] The sequence shown in (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFDSYYVGWVRQAPGKALEWLGNIYSTGRAFYNPALKSRLSITRDTSKSQVSLSVSSVTIEDTALYYCVRGSYYHGGGNGMVDFFDYWSPGLLVTVSS) is shown; and / or

[1765] (b) The VL domain, which contains SEQ ID NO:504

[1766] The sequence shown is (QVVRTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWFQQVPGSAPKLLIYAATSRASGVPDRFSGSRSGNTATLTIDSLQAEDEADYYCSSYQRGNTGVFGSGTRLTVLG).

[1767] Specific binding molecules may include the following or their humanized variants:

[1768] (a) Heavy chain, which contains SEQ ID NO:505

[1769] (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFDSYYVGWVRQAPGKALEWLGNIYSTGRAFYNPALKSRLSITRDTSKSQVSLSVSSVTIEDTALYYCVRGSYYHGGGNGMVDFFDYW SPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPC PPCKCPAPNLLGGPSVFIFPPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPK and / or

[1770] (b) A light chain containing SEQ ID NO:506

[1771] The sequence shown is (QVVRTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWFQQVPGSAPKLLIYAATSRASGVPDRFSGSRSGNTATLTIDSLQAEDEADYYCSSYQRGNTGVFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVC TITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTV EKSLSRADCS).

[1772] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1773] VHCDR1 contains the sequence shown in SEQ ID NO:266 (SNAVV);

[1774] VHCDR2 contains the sequence shown in SEQ ID NO:267 (AIDKDGDTIYNPALKS);

[1775] VHCDR3 contains the sequence shown in SEQ ID NO:268 (DPSGWGYPDVDY);

[1776] VLCDR1 contains the sequence shown in SEQ ID NO:269 (SGTYIGSSDVG);

[1777] VLCDR2 contains the sequence shown in SEQ ID NO:270 (GTSSRPS); and

[1778] VLCDR3 contains the sequence shown in SEQ ID NO:271 (ATYESSYHNSV);

[1779] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1780] (i) having at least 85% identity with it, and / or

[1781] (ii) relative to having one, two, or three amino acid substitutions.

[1782] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 319 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "CA8".

[1783] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1784] VHCDR1 contains the sequence shown in SEQ ID NO:266 (SNAVV);

[1785] VHCDR2 contains the sequence shown in SEQ ID NO:267 (AIDKDGDTIYNPALKS);

[1786] VHCDR3 contains the sequence shown in SEQ ID NO:268 (DPSGWGYPDVDY);

[1787] VLCDR1 contains the sequence shown in SEQ ID NO:269 (SGTYIGSSDVG);

[1788] VLCDR2 contains the sequence shown in SEQ ID NO:270 (GTSSRPS); and

[1789] VLCDR3 contains the sequence shown in SEQ ID NO:271 (ATYESSYHNSV).

[1790] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1791] VHCDR1 contains the sequence shown in SEQ ID NO:272 (SNTVA);

[1792] VHCDR2 contains the sequence shown in SEQ ID NO:273 (EINSGGSTYYNPALKS);

[1793] VHCDR3 contains the sequence shown in SEQ ID NO:274 (GARSTYAAY);

[1794] VLCDR1 contains the sequence shown in SEQ ID NO:275 (SGSSSDVGYSTWVY);

[1795] VLCDR2 contains the sequence shown in SEQ ID NO:276 (HISNRAS); and

[1796] VLCDR3 contains the sequence shown in SEQ ID NO:277 (AAYDSSNNVWI);

[1797] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1798] (i) having at least 85% identity with it, and / or

[1799] (ii) relative to having one, two, or three amino acid substitutions.

[1800] The specific binding molecule binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 319 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "CB10".

[1801] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1802] VHCDR1 contains the sequence shown in SEQ ID NO:272 (SNTVA);

[1803] VHCDR2 contains the sequence shown in SEQ ID NO:273 (EINSGGSTYYNPALKS);

[1804] VHCDR3 contains the sequence shown in SEQ ID NO:274 (GARSTYAAY);

[1805] VLCDR1 contains the sequence shown in SEQ ID NO:275 (SGSSSDVGYSTWVY);

[1806] VLCDR2 contains the sequence shown in SEQ ID NO:276 (HISNRAS); and

[1807] VLCDR3 contains the sequence shown in SEQ ID NO:277 (AAYDSSNNVWI).

[1808] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 13 to 25 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:278 (DHAGTYGLGDRKD).

[1809] The epitope may be located within the amino acid sequence containing residues 13 to 25 of SEQ ID NO:1. The epitope may bind to the CDR of a specific binding molecule referred to herein as “CB7”.

[1810] The epitope may contain the amino acid sequence of SEQ ID NO:278 (DHAGTYGLGDRKD). The epitope may contain 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 with SEQ ID NO:278 (DHAGTYGLGDRKD).

[1811] The epitope may consist of the amino acid sequence of SEQ ID NO:278 (DHAGTYGLGDRKD). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:278 (DHAGTYGLGDRKD).

[1812] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1813] VHCDR1 contains the sequence shown in SEQ ID NO:279 (NYRVG);

[1814] VHCDR2 contains the sequence shown in SEQ ID NO:280 (NIRSGGTTWYNPALKS);

[1815] VHCDR3 contains the sequence shown in SEQ ID NO:281 (DSSGDLYAYDY);

[1816] VLCDR1 contains the sequence shown in SEQ ID NO:282 (SGSSSNVGYGNYMA);

[1817] VLCDR2 contains the sequence shown in SEQ ID NO:141 (GATSRAS); and

[1818] VLCDR3 contains the sequence shown in SEQ ID NO:263 (ASYDSTSGGV);

[1819] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1820] (i) having at least 85% identity with it, and / or

[1821] (ii) relative to having one, two, or three amino acid substitutions.

[1822] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 13 to 25 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "CB7".

[1823] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1824] VHCDR1 contains the sequence shown in SEQ ID NO:279 (NYRVG);

[1825] VHCDR2 contains the sequence shown in SEQ ID NO:280 (NIRSGGTTWYNPALKS);

[1826] VHCDR3 contains the sequence shown in SEQ ID NO:281 (DSSGDLYAYDY);

[1827] VLCDR1 contains the sequence shown in SEQ ID NO:282 (SGSSSNVGYGNYMA);

[1828] VLCDR2 contains the sequence shown in SEQ ID NO:141 (GATSRAS); and

[1829] VLCDR3 contains the sequence shown in SEQ ID NO:263 (ASYDSTSGGV).

[1830] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1831] VHFR1 contains the sequence shown in SEQ ID NO:507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1832] VHFR2 contains the sequence shown in SEQ ID NO:508 (WVRQAPGKALEWVS);

[1833] VHFR3 contains the sequence shown in SEQ ID NO:509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR);

[1834] VHFR4 contains the sequence shown in SEQ ID NO:510 (WGPGLLVTVSS);

[1835] VLFR1 contains the sequence shown in SEQ ID NO:511 (QAVLTQPSSVSRSLGQSVSMTC);

[1836] VLFR2 contains the sequence shown in SEQ ID NO:512(WFQQVPGSAPKLLIY);

[1837] VLFR3 contains the sequence shown in SEQ ID NO:513(GVPDRFSGSRSGNTATLTISSLQAEDEADYYC);

[1838] VLFR4 contains the sequence shown in SEQ ID NO:514 (FGSGTRLTVLG);

[1839] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1840] (i) having at least 50% similarity to it, and / or

[1841] (ii) relative to having one, two, three, four or five amino acid substitutions.

[1842] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1843] VHFR1 contains the sequence shown in SEQ ID NO:507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1844] VHFR2 contains the sequence shown in SEQ ID NO:508 (WVRQAPGKALEWVS);

[1845] VHFR3 contains the sequence shown in SEQ ID NO:509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR);

[1846] VHFR4 contains the sequence shown in SEQ ID NO:510 (WGPGLLVTVSS);

[1847] VLFR1 contains the sequence shown in SEQ ID NO:511 (QAVLTQPSSVSRSLGQSVSMTC);

[1848] VLFR2 contains the sequence shown in SEQ ID NO:512(WFQQVPGSAPKLLIY);

[1849] VLFR3 contains the sequence shown in SEQ ID NO:513(GVPDRFSGSRSGNTATLTISSLQAEDEADYYC);

[1850] VLFR4 contains the sequence shown in SEQ ID NO:514 (FGSGTRLTVLG);

[1851] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1852] (i) having at least 50% similarity to it, and / or

[1853] (ii) relative to having one, two, three, four or five amino acid substitutions,

[1854] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 13 to 25 of SEQ ID NO:1. The specific binding molecule containing a FR that is 100% identical to the above-described FR is referred to herein as "CB7".

[1855] Specific binding molecules may include:

[1856] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1857] VHFR1 contains the sequence shown in SEQ ID NO:507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1858] VHFR2 contains the sequence shown in SEQ ID NO:508 (WVRQAPGKALEWVS);

[1859] VHFR3 contains the sequence shown in SEQ ID NO:509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR);

[1860] VHFR4 contains the sequence shown in SEQ ID NO:510 (WGPGLLVTVSS);

[1861] VLFR1 contains the sequence shown in SEQ ID NO:511 (QAVLTQPSSVSRSLGQSVSMTC);

[1862] VLFR2 contains the sequence shown in SEQ ID NO:512(WFQQVPGSAPKLLIY);

[1863] VLFR3 contains the sequence shown in SEQ ID NO:513(GVPDRFSGSRSGNTATLTISSLQAEDEADYYC);

[1864] VLFR4 contains the sequence shown in SEQ ID NO:514 (FGSGTRLTVLG);

[1865] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1866] (i) having at least 50% similarity to it, and / or

[1867] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1868] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1869] VHCDR1 contains the sequence shown in SEQ ID NO:279 (NYRVG);

[1870] VHCDR2 contains the sequence shown in SEQ ID NO:280 (NIRSGGTTWYNPALKS);

[1871] VHCDR3 contains the sequence shown in SEQ ID NO:281 (DSSGDLYAYDY);

[1872] VLCDR1 contains the sequence shown in SEQ ID NO:282 (SGSSSNVGYGNYMA);

[1873] VLCDR2 contains the sequence shown in SEQ ID NO:141 (GATSRAS); and

[1874] VLCDR3 contains the sequence shown in SEQ ID NO:263 (ASYDSTSGGV);

[1875] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1876] (i) having at least 85% identity with it, and / or

[1877] (ii) relative to having one, two or three amino acid substitutions

[1878] The specific binding molecule binds to polypeptide or protein molecules containing amino acid sequences of residues 13 to 25 of SEQ ID NO:1. The specific binding molecule containing FR and CDR that are 100% identical to those described above is referred to herein as "CB7".

[1879] Specific binding molecules may include:

[1880] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1881] VHFR1 contains the sequence shown in SEQ ID NO:507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1882] VHFR2 contains the sequence shown in SEQ ID NO:508 (WVRQAPGKALEWVS);

[1883] VHFR3 contains the sequence shown in SEQ ID NO:509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR);

[1884] VHFR4 contains the sequence shown in SEQ ID NO:510 (WGPGLLVTVSS);

[1885] VLFR1 contains the sequence shown in SEQ ID NO:511 (QAVLTQPSSVSRSLGQSVSMTC);

[1886] VLFR2 contains the sequence shown in SEQ ID NO:512(WFQQVPGSAPKLLIY);

[1887] VLFR3 contains the sequence shown in SEQ ID NO:513(GVPDRFSGSRSGNTATLTISSLQAEDEADYYC);

[1888] VLFR4 contains the sequence shown in SEQ ID NO:514 (FGSGTRLTVLG);

[1889] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1890] (i) having at least 50% similarity to it, and / or

[1891] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1892] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1893] VHCDR1 contains the sequence shown in SEQ ID NO:279 (NYRVG);

[1894] VHCDR2 contains the sequence shown in SEQ ID NO:280 (NIRSGGTTWYNPALKS);

[1895] VHCDR3 contains the sequence shown in SEQ ID NO:281 (DSSGDLYAYDY);

[1896] VLCDR1 contains the sequence shown in SEQ ID NO:282 (SGSSSNVGYGNYMA);

[1897] VLCDR2 contains the sequence shown in SEQ ID NO:141 (GATSRAS); and

[1898] VLCDR3 contains the sequence shown in SEQ ID NO:263 (ASYDSTSGGV);

[1899] The specific binding molecule binds to polypeptide or protein molecules containing amino acid sequences of residues 13 to 25 of SEQ ID NO:1. The specific binding molecule containing FR and CDR that are 100% identical to those described above is referred to herein as "CB7".

[1900] Specific binding molecules may include the following or their humanized variants:

[1901] (a) The VH domain, which contains SEQ ID NO:515

[1902] The sequences shown in (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTNYRVGWVRQAPGKALEWVSNIRSGGTTWYNPALKSRLSITADTSKSQVSLSLSSVTTEDTAVYYCARDSSGDLYAYDYWGPGLLVTVSS) are: and / or

[1903] (b) The VL domain, which contains SEQ ID NO:516

[1904] The sequence shown is (QAVLTQPSSVSRSLGQSVSMTCSGSSSNVGYGNYMAWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSTSGGVFGSGTRLTVLG).

[1905] Specific binding molecules may include the following or their humanized variants:

[1906] (a) Heavy chain, which contains SEQ ID NO:517

[1907] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTNYRVGWVRQAPGKALEWVSNIRSGGTTWYNPALKSRLSITADTSKSQVSLSLSSVTTEDTAVYYCARDSSGDLYAYDYWGPGLL VTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPC KCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGS and / or

[1908] (b) A light chain containing SEQ ID NO:518

[1909] The sequence shown is (QAVLTQPSSVSRSLGQSVSMTCSGSSSNVGYGNYMAWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSTSGGVFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLV CTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS).

[1910] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 145 to 157 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:283 (ADGKTKIATPRGA).

[1911] The epitope may be located within the amino acid sequence containing residues 145 to 157 of SEQ ID NO:1. The epitope may bind to the CDR of a specific binding molecule referred to herein as “CC7”.

[1912] The epitope may contain the amino acid sequence of SEQ ID NO:283 (ADGKTKIATPRGA). The epitope may contain 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 with SEQ ID NO:283 (ADGKTKIATPRGA).

[1913] The epitope may consist of the amino acid sequence of SEQ ID NO:283 (ADGKTKIATPRGA). The epitope may consist of an amino acid sequence having at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with SEQ ID NO:283 (ADGKTKIATPRGA).

[1914] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1915] VHCDR1 contains the sequence shown in SEQ ID NO:198 (SNAVI);

[1916] VHCDR2 contains the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS);

[1917] VHCDR3 contains the sequence shown in SEQ ID NO:202 (DYGSWGYVSDIDY);

[1918] VLCDR1 contains the sequence shown in SEQ ID NO:292 (SGSYITGSSVG);

[1919] VLCDR2 contains the sequence shown in SEQ ID NO:284 (DNNDRPS); and

[1920] VLCDR3 contains the sequence shown in SEQ ID NO:285 (ASYDTSNIGL);

[1921] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1922] (i) having at least 85% identity with it, and / or

[1923] (ii) relative to having one, two, or three amino acid substitutions.

[1924] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 145 to 157 of SEQ ID NO:1. The specific binding molecule containing a CDR that is 100% identical to the above-mentioned CDR is referred to herein as "CC7".

[1925] The specific binding molecule may contain CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1926] VHCDR1 contains the sequence shown in SEQ ID NO:198 (SNAVI);

[1927] VHCDR2 contains the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS);

[1928] VHCDR3 contains the sequence shown in SEQ ID NO:202 (DYGSWGYVSDIDY);

[1929] VLCDR1 contains the sequence shown in SEQ ID NO:292 (SGSYITGSSVG);

[1930] VLCDR2 contains the sequence shown in SEQ ID NO:284 (DNNDRPS); and

[1931] VLCDR3 contains the sequence shown in SEQ ID NO:285 (ASYDTSNIGL).

[1932] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1933] VHFR1 contains the sequence shown in SEQ ID NO:519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1934] VHFR2 contains the sequence shown in SEQ ID NO:520 (WVRQAPGKAPEWVA);

[1935] VHFR3 contains the sequence shown in SEQ ID NO:521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR);

[1936] VHFR4 contains the sequence shown in SEQ ID NO:522 (WGPGLLVTVSS);

[1937] VLFR1 contains the sequence shown in SEQ ID NO:523 (RVVRTQPSSVSGSLGQRVSITC);

[1938] VLFR2 contains the sequence shown in SEQ ID NO:524(WFQQVPGSGLKTVIY);

[1939] VLFR3 contains the sequence shown in SEQ ID NO:525(GVPDRFSGSKSGDTATLTISSLQAEDEADYYC);

[1940] VLFR4 contains the sequence shown in SEQ ID NO:526 (FGSGTRLTVLG);

[1941] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1942] (i) having at least 50% similarity to it, and / or

[1943] (ii) relative to having one, two, three, four or five amino acid substitutions.

[1944] The specific binding molecule may contain a framework region (FR): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1945] VHFR1 contains the sequence shown in SEQ ID NO:519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1946] VHFR2 contains the sequence shown in SEQ ID NO:520 (WVRQAPGKAPEWVA);

[1947] VHFR3 contains the sequence shown in SEQ ID NO:521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR);

[1948] VHFR4 contains the sequence shown in SEQ ID NO:522 (WGPGLLVTVSS);

[1949] VLFR1 contains the sequence shown in SEQ ID NO:523 (RVVRTQPSSVSGSLGQRVSITC);

[1950] VLFR2 contains the sequence shown in SEQ ID NO:524(WFQQVPGSGLKTVIY);

[1951] VLFR3 contains the sequence shown in SEQ ID NO:525(GVPDRFSGSKSGDTATLTISSLQAEDEADYYC);

[1952] VLFR4 contains the sequence shown in SEQ ID NO:526 (FGSGTRLTVLG);

[1953] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1954] (i) having at least 50% similarity to it, and / or

[1955] (ii) relative to having one, two, three, four or five amino acid substitutions,

[1956] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 145 to 157 of SEQ ID NO:1. The specific binding molecule containing a FR that is 100% identical to the above-mentioned FR is referred to herein as "CC7".

[1957] Specific binding molecules may include:

[1958] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1959] VHFR1 contains the sequence shown in SEQ ID NO:519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1960] VHFR2 contains the sequence shown in SEQ ID NO:520 (WVRQAPGKAPEWVA);

[1961] VHFR3 contains the sequence shown in SEQ ID NO:521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR);

[1962] VHFR4 contains the sequence shown in SEQ ID NO:522 (WGPGLLVTVSS);

[1963] VLFR1 contains the sequence shown in SEQ ID NO:523 (RVVRTQPSSVSGSLGQRVSITC);

[1964] VLFR2 contains the sequence shown in SEQ ID NO:524(WFQQVPGSGLKTVIY);

[1965] VLFR3 contains the sequence shown in SEQ ID NO:525(GVPDRFSGSKSGDTATLTISSLQAEDEADYYC);

[1966] VLFR4 contains the sequence shown in SEQ ID NO:526 (FGSGTRLTVLG);

[1967] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1968] (i) having at least 50% similarity to it, and / or

[1969] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1970] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1971] VHCDR1 contains the sequence shown in SEQ ID NO:198 (SNAVI);

[1972] VHCDR2 contains the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS);

[1973] VHCDR3 contains the sequence shown in SEQ ID NO:202 (DYGSWGYVSDIDY);

[1974] VLCDR1 contains the sequence shown in SEQ ID NO:292 (SGSYITGSSVG);

[1975] VLCDR2 contains the sequence shown in SEQ ID NO:284 (DNNDRPS); and

[1976] VLCDR3 contains the sequence shown in SEQ ID NO:285 (ASYDTSNIGL);

[1977] Alternatively, each CDR sequence may contain an amino acid sequence with the following characteristics:

[1978] (i) having at least 85% identity with it, and / or

[1979] (ii) relative to having one, two or three amino acid substitutions

[1980] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 145 to 157 of SEQ ID NO:1. The specific binding molecule containing FRs and CDRs that are 100% identical to the above-mentioned FRs and CDRs is referred to herein as "CC7".

[1981] Specific binding molecules may include:

[1982] (a) Frame regions (FRs): VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1983] VHFR1 contains the sequence shown in SEQ ID NO:519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1984] VHFR2 contains the sequence shown in SEQ ID NO:520 (WVRQAPGKAPEWVA);

[1985] VHFR3 contains the sequence shown in SEQ ID NO:521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR);

[1986] VHFR4 contains the sequence shown in SEQ ID NO:522 (WGPGLLVTVSS);

[1987] VLFR1 contains the sequence shown in SEQ ID NO:523 (RVVRTQPSSVSGSLGQRVSITC);

[1988] VLFR2 contains the sequence shown in SEQ ID NO:524(WFQQVPGSGLKTVIY);

[1989] VLFR3 contains the sequence shown in SEQ ID NO:525(GVPDRFSGSKSGDTATLTISSLQAEDEADYYC);

[1990] VLFR4 contains the sequence shown in SEQ ID NO:526 (FGSGTRLTVLG);

[1991] Alternatively, for each FR sequence, it may contain an amino acid sequence with the following:

[1992] (i) having at least 50% similarity to it, and / or

[1993] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1994] (b) CDRs: VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1995] VHCDR1 contains the sequence shown in SEQ ID NO:198 (SNAVI);

[1996] VHCDR2 contains the sequence shown in SEQ ID NO:200 (LIDVDGDAAYDPALKS);

[1997] VHCDR3 contains the sequence shown in SEQ ID NO:202 (DYGSWGYVSDIDY);

[1998] VLCDR1 contains the sequence shown in SEQ ID NO:292 (SGSYITGSSVG);

[1999] VLCDR2 contains the sequence shown in SEQ ID NO:284 (DNNDRPS); and

[2000] VLCDR3 contains the sequence shown in SEQ ID NO:285 (ASYDTSNIGL);

[2001] The specific binding molecule binds to a polypeptide or protein molecule containing amino acid sequences of residues 145 to 157 of SEQ ID NO:1. The specific binding molecule containing FRs and CDRs that are 100% identical to the above-mentioned FRs and CDRs is referred to herein as "CC7".

[2002] Specific binding molecules may include the following or their humanized variants:

[2003] (a) The VH domain, which contains SEQ ID NO:527

[2004] The sequence shown is (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSS); and / or

[2005] (b) The VL domain, which contains SEQ ID NO:528

[2006] The sequence shown is (RVVRTQPSSVSGSLGQRVSITCSGSYITGSSVGWFQQVPGSGLKTVIYDNNDRPSGVPDRFSGSKSGDTATLTISSLQAEDEADYYCASYDTSNIGLFGSGTRLTVLG).

[2007] Specific binding molecules may include the following or their humanized variants:

[2008] (a) Heavy chain, containing SEQ ID NO:529

[2009] (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPG LLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPP CKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKG and / or

[2010] (b) A light chain containing SEQ ID NO:530

[2011] The sequence shown is (RVVRTQPSSVSGSLGQRVSITCSGSYITGSSVGWFQQVPGSGLKTVIYDNNDRPSGVPDRFSGSKSGDTATLTISSLQAEDEADYYCASYDTSNIGLFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTITD FYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSL SRADCS).

[2012] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 155 to 227 of SEQ ID NO:1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO:294 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTRE...

Claims

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

1.

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

1.

3. The method according to any one of claims 1 to 2, wherein: The first specific binding molecule binds to an epitope within residues 337 to 379 of SEQ ID NO:

1.

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

1.

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

1.

6. The method according to any one of claims 1 to 5, 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.

7. The method according to any one of claims 1 to 6, 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).

8. The method according to any one of claims 1 to 7, wherein: The first specific binding molecule comprises framework regions (FRs): 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.

9. The method according to any one of claims 1 to 8, 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).

10. The method according to any one of claims 1 to 9, 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.

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

1.

12. The method according to any one of claims 1 to 3 or 11, 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.

13. The method according to any one of claims 1 to 3, or 11 to 12, 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).

14. The method according to any one of claims 1 to 3, or 11 to 13, 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.

15. The method according to any one of claims 1 to 3, or 11 to 14, 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).

16. The method according to any one of claims 1 to 3, or 11 to 15, 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.

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

1.

18. The method according to any one of claims 1 to 3 or 17, 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.

19. The method according to any one of claims 1 to 3, or 17 to 18, 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).

20. The method according to any one of claims 1 to 3, or 17 to 19, wherein The first specific binding molecule comprises framework regions (FRs): 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.

21. The method according to any one of claims 1 to 3, or 17 to 20, 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).

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

1.

23. The method of any preceding claim, further comprising contacting the sample with a second specific binding molecule.

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

1.

25. The method according to any one of claims 23 to 24, wherein: The second specific binding molecule binds to an epitope consisting of residues 194 to 198 of SEQ ID NO:

1.

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

27. The method according to any one of claims 23 to 24, wherein: The second specific binding molecule binds to an epitope consisting of residues 159 to 163 of SEQ ID NO:

1.

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

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

1.

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

31. The method of claim 23, 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.

32. The method of claim 23, 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.

33. The method of claim 23, 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.

34. The method of claim 33, 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.

35. 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.

36. 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.

37. 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.

38. 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.

39. 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.

40. 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.

41. 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.

42. 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.

43. 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.

44. The method according to any one of claims 1 to 43, 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.

45. The method according to any one of claims 1 to 43, 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.

46. ​​The method according to any one of claims 1 to 43, 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.

47. The method according to any one of claims 1 to 43, 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.

48. 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.

49. 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.

50. 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.

51. The method of any of the preceding claims, further comprising determining the concentration of the tau protein fragments in the sample.

52. An apparatus for use in a method according to any preceding claim.

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

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