Anti-tau antibodies

Abstract

The present invention relates to specific binding molecules, e.g. antibodies, directed against key epitopes of tau. The specific binding molecules of the present invention are useful for the diagnosis and treatment of tauopathies, including Alzheimer's disease.

Description

[0001] This invention relates to specific binding molecules, such as antibodies, targeting key epitopes of tau. The specific binding molecules of this invention can be used for the diagnosis and treatment of tau diseases, including Alzheimer's disease.

[0002] Diseases associated with tau are collectively known as neurodegenerative tau diseases. Alzheimer's disease (AD) is part of this group of neurodegenerative diseases. Dementias such as Alzheimer's disease (AD) are typically characterized by the progressive accumulation of intracellular and / or extracellular deposits of protein structures in the brain of affected patients, such as β-amyloid plaques and neurofibrillary tangles (NFTs) composed of tau. The occurrence of tau aggregation lesions is largely 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, constituting neurofibrillary tangles within neurons and dystrophic neurites in the brain. The misfolding of proteins to form amyloid fibrils is a hallmark of many different diseases collectively known as amyloidosis, each characterized by a specific precursor protein.

[0003] Long-term research into the etiology of Alzheimer's disease (AD) and other protein conformational disorders has not yielded the desired significant advances in diagnosis or treatment. One reason for this limited progress is believed to be the lack of high-affinity specific binding molecules targeting key tau epitopes. The inventors have addressed this shortcoming by creating the specific binding molecule disclosed herein. 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 believed to contribute to the high affinity of the specific binding molecule of this invention. Summary of the Invention

[0004] According to a first aspect, the present invention provides a specific binding molecule whose binding affinity to the epitope in SEQ ID NO: 1 is greater than the binding affinity of antibody mAb423 to the epitope in SEQ ID NO: 1.

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

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

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

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

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

[0010] According to a seventh aspect, the present invention provides a method for preparing a specific binding molecule according to a first aspect of the present invention, comprising:

[0011] i) Introducing the nucleic acid molecule of the third aspect of the present invention, the construct of the fourth aspect of the present invention, or the vector of the fifth aspect of the present invention into a host cell;

[0012] ii) Expressing nucleic acid molecules to produce specific binding molecules; and

[0013] iii) Collect the specific binding molecules, preferably by purification.

[0014] According to the eighth aspect, the present invention provides a specific binding molecule that can be obtained by the method according to the seventh aspect of the present invention.

[0015] According to a ninth aspect, the present invention provides a pharmaceutical composition comprising a specific binding molecule according to a first aspect of the invention or a composition according to a second aspect of the invention, and one or more pharmaceutically acceptable diluents, carriers, or excipients.

[0016] According to a tenth aspect, the present invention provides a specific binding molecule according to a first aspect of the invention, a composition according to a second aspect of the invention, or a pharmaceutical composition according to a ninth aspect of the invention for treatment.

[0017] According to the eleventh aspect, the present invention provides a specific binding molecule according to the first aspect of the invention, a composition according to the second aspect of the invention, or a pharmaceutical composition according to the ninth aspect of the invention for treating tau disease.

[0018] According to a twelfth aspect, the present invention provides a method for treating tau disease, comprising administering to a subject in need a specific binding molecule according to a first aspect of the invention, a composition according to a second aspect of the invention, or a pharmaceutical composition according to a ninth aspect of the invention.

[0019] According to a thirteenth aspect, the present invention provides an in vitro method for inhibiting the aggregation of tau protein or fragments thereof, comprising contacting tau protein or fragments thereof with a specific binding molecule according to a first aspect of the present invention.

[0020] According to the fourteenth aspect, the present invention provides an in vitro method for detecting tau protein or fragments thereof in a sample, comprising contacting the sample with a specific binding molecule of the first aspect of the invention.

[0021] According to the fifteenth aspect, the present invention provides a diagnostic method comprising contacting a sample with a specific binding molecule of the first aspect of the invention.

[0022] According to the sixteenth aspect, the present invention provides a diagnostic apparatus for use in the method according to the fifteenth aspect of the present invention.

[0023] According to the seventeenth aspect, the present invention provides a kit comprising a specific binding molecule according to the first aspect of the invention and reagents for detecting tau protein or fragments thereof in a sample.

[0024] Please refer to the following attached figures:

[0025] Figure 1 Based on the different CDR definitions of S1D12 by Kabat, Chothia, and Martin.

[0026] 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 to 391 and includes the fragments constituting the PHF core (residues 308 to 378) identified by cryo-electron microscopy (Fitzpatrick et al., 2017), as shown below. Figure 3 As shown. The location of the epitopes for the selected antibody / scAb is also displayed.

[0027] Figure 3 The PHF core displayed against a PHF background.

[0028] Figure 4 The location of the corresponding epitopes associated with the same core sequence and the basic C-shaped subunit structure of the core. The 1D12 epitope forms the key fold or "hairpin" of the C-shaped subunit.

[0029] Figure 5 Molecular modeling was used to show how the new dGAE units gradually unfolded and aligned with the structure of the existing oligomers.

[0030] Figure 6 The connection sequence is shown based on the three stages of gradual binding of key segments and epitopes corresponding to dGAE into the oligomer. It can be seen that the hinge region identified by 1D12 is the primary connection site, followed by the gradual symmetrical binding of other domains.

[0031] 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 were included as negative controls.

[0032] Figure 8 Cross-reactivity of scAbs in group "E" was characterized using ELISA using hT40, dGA, and dGAE antigens: (A) E1E8 scAb, (B) E2B7 scAb, (C) E2C5 scAb, (D) E2E8 scAb, and (E) E1B8 scAb. Except for E1B8, all these scAbs showed specific dGAE binding, therefore their immunoreactivity requires the '391E' epitope accessible at the C-terminus. E1B8 cross-reacts with dGA, and a detailed map of its binding region is shown below. Figure 9 As shown.

[0033] Figure 9 Detailed map of .E1B8 scAb, showing specific binding to tau peptide representing amino acids 313 to 336 on the hT40 protein.

[0034] Figure 10 The cross-reactivity of 'NS' group scAbs was characterized using ELISA using various short tau fragments numbered corresponding 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. Table 16 shows a summary of the specific NS scAbs that bind to these shorter antigens.

[0035] Figure 11 The cross-reactivity of 'S' group scAbs was characterized using ELISA based on 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. Table 16 shows a summary of the specific 'S' scAbs that bind to these shorter antigens.

[0036] Figure 12The cross-reactivity of group 'C' scAbs was characterized using ELISA based on 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. Table 17 shows a summary of the specific 'C' scAbs that bind to these shorter antigens.

[0037] Figure 13 Cross-reactivity of scAbs in group '412' with hT40. (A) Showing the binding of scAbs to biotinylated peptides 412-441, which are used as antigens to select C-terminal conjugates. (B) Binding profiles of the four cross-reactive scAbs in hT40 binding ELISA.

[0038] Figure 14 The cross-reactivity of scAbs in groups "3a" and "3b" was characterized using ELISA based on various short tau fragments numbered according to their corresponding amino acid residues on the hT40 molecule. (A) 1-49, (B) 1-111, (CD) 1-155, (E) 113-251. Table 18 shows a summary of the specific '3a' and '3b' group scAbs that bind to these shorter antigens.

[0039] Figure 15 (A) Immunoreactivity of CE2 scAb to the parent peptide and a series of alanine-substituted residues at the positions shown in Table 19. (B) The percentage of binding of 500 nM scAb to each of these ASM peptides compared to binding to the parent peptide.

[0040] Figure 16 (AB) Immunoreactivity of S1D12 scAb to the parent peptide and a series of alanine-substituted residues at the positions shown in Table 20. (C) The percentage of binding of 500 nM scAb to each of these ASM peptides compared to binding to the parent peptide.

[0041] Figure 17 (AB) Immunoreactivity of ME12 scAb to the parent peptide and a series of alanine-substituted residues at the positions shown in Table 20. (C) The percentage of binding of 100 nM scAb to each of these ASM peptides compared to binding to the parent peptide.

[0042] Figure 18(A) Immunoreactivity of CA4 scAb to the parent peptide and a series of alanine-substituted residues at the positions shown in Table 21. (B) The percentage of binding of 500 nM scAb to each of these ASM peptides compared to binding to the parent peptide.

[0043] Figure 19 (AB) Immunoreactivity of S1G2 scAb to the parent peptide and a series of alanine-substituted residues at the positions shown in Table 22. (C) The percentage of binding of 500 nM scAb to each of these ASM peptides compared to binding to the parent peptide.

[0044] Figure 20 The percentage of binding of each scAb in regions 367-379 to the ASM peptide compared to binding 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 reduced antibody binding.

[0045] Figure 21 The binding affinity of hT40 against Tau scAbs was used for ranking. The relative binding affinity of the tested scAbs was ranked using scAbs with known kD values ​​(e.g., NS2A1 and S1D12), and those with similar binding spectra were shortlisted and selected for Biacore analysis: (A) 'S' clones, (BC) 'C' clones, (D) '412' clones, and (E) '3a' clones.

[0046] Figure 22 A schematic diagram of a sandwich ELISA format used to calculate the LoD of various antibody pairs.

[0047] Figure 23 A schematic diagram of a sandwich ELISA form used to calculate LoD, where S1G2 mAb is used as the capture antibody and HRP-conjugated S1D12 mAb is used for detection.

[0048] Figure 24 The sandwich ELISA plot shows the LoD obtained using S1G2 mAb as the capture antibody and HRP-labeled S1D12 mAb as the assay. Antibody binding was measured using chemiluminescence; for this assay setup, the LOD of hT40 was approximately 1 ng / ml.

[0049] Figure 25The generated ELISA #1hT40 standard curve was obtained using S1D12 mAb capture and CB7 scAb detection. The concentrations of the four spiked samples (samples A, B, C, and D) were determined by plotting their respective absorbance values ​​on the standard curve. Sample C did not produce a binding signal, thus confirming the absence of any tau species with N-terminal regions in the mixture. Table 29 shows the concentrations and types of tau species derived from this assay.

[0050] Figure 26 The generated ELISA#2 dGAE standard curve was obtained using S1D12 mAb capture and E2E8 scAb detection. The concentrations of the four spiked samples (samples A, B, C, and D) were determined by plotting their respective absorbance values ​​on the standard curve. Samples A, C, and D did not produce any binding signal, thus confirming the absence of dGAE species in these mixtures. Table 29 shows the concentrations and types of tau species derived from this assay.

[0051] Figure 27 The ELISA#3 average standard curve was generated using S1G2 mAb capture and E2E8 scAb detection. The concentrations of the four spiked samples (samples A, B, C, and D) were determined by plotting their respective absorbance values ​​on this standard curve. Table 29 shows the concentrations and types of tau derived from this assay.

[0052] Figure 28 A comparison of binding profiles 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 role of SDS+Triton X-100 in restoring immunoreactivity is noted here. This mAb-scAb pairing allows for the detection of approximately 2 ng / ml dGAE aggregates in a simple sandwich ELISA.

[0053] Figure 29 A) L66 cDNA, containing human tau (hT40) and point mutations P301S and G335D (2N4R Tau, 441 amino acids); B) L1 cDNA encoding human tau amino acid residues 296 to 390 with a signal sequence and a mouse Thy1 expression sequence as described in Melis et al., 2015.

[0054] Figure 30(A) Tau protein was detected in 50 μg brain homogenates isolated from WT, L1, L66+ / -, and L66+ / + mice using S1D12 mAb capture and S-1G2 scAb 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 S1D12 mAb capture and CB7 scAb detection. The N'-terminal oriented CB7 scAb specifically detected human tau in Line66 homozygous and heterozygous samples and was able to distinguish expression levels between the two groups.

[0055] Figure 31 Plasma tau levels were as follows: 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. Standard curves using hT40 were used for WT and L66, and standard curves using dGA (296 to 390) were used for L1 to determine tau class concentrations.

[0056] Figure 32 Plasma tau levels in Line66+ / + mice (sample number 23) were detected at 1.5 months of age and compared with plasma from age-matched wild-type mice using two different sandwich ELISA pairs. (A) Chemiluminescent signal readings for Line66+ / + and wild-type mice are shown using S1D12 mAb capture and CB7 scAb detection. (b) Signal readings for the same sample were shown using S1D12 mAb capture and S1G2 scAb detection. When using the S1D12 mAb-CB7 scAb pair (which specifically detects N-terminal hT40 in this sample), the signal intensity was at least 1000-fold increased compared to wild-type mice.

[0057] Figure 33 Plasma tau levels in AD samples were compared with those in age-matched controls using S1D12-S1G12 (core region) and S1D12-CB7 (N-terminus) paired detection.

[0058] Figure 34Sandwich ELISA plots show increased immunoreactivity of the core region scAbs in dGAE "total", "supernatant", and "precipitate" aggregate-inhibiting samples prepared in the presence of LMTM. dGAE monomers are included as assay controls to indicate the binding profile of each test scAb to its corresponding epitope in non-aggregated samples. (AC)CA4 scAb, (DF)CA9, (GI)CB3 scAb, (JL)CE2 scAb, (MO)CE3, (PR)S1D12 scAb. Lack of antibody binding in some dGAE+LMTM precipitate samples corresponds to the presence of protein deficiencies in that group, as confirmed by SDS gels (data not included).

[0059] Figure 35 Example data plot of .S1D12 scAb-mediated dGAE aggregation inhibition.

[0060] Figure 36 The aggregation-inhibiting properties of antagonistic tau scAbs were ranked by thioflavin T assay. Aggregation inhibition (dGAE) was quantified by calculating the percentage change in aggregates compared to the absence of scAbs. scAbs 3bA3, 3aD6, and 3aD3 were used as negative controls and showed no cross-reactivity with dGAE (data not shown). n=3, error bars represent SD, NS=not significant, *=P<0.05, **=P<0.01, ***=P<0.001 (one-way ANOVA and post-hoc Dunnett test compared to scAb 3aD3).

[0061] Figure 37 A schematic diagram of a tau-tau immunoassay that ranks the inhibitory effects of anti-tau scAbs during truncated tau aggregation containing a core repeat domain. (a) Tau-tau aggregation occurs when dGAE is added to wells pre-coated with dGA, and the presence of dGAE is detected using a 391E epitope-specific E2E8 scAb. (b) When dGAE is pre-incubated with a scAb binding to the core region, this binding event inhibits the dGAE-dGA interaction, as measured by the loss of antibody detected by E2E8 scAb.

[0062] Figure 38 The aggregation-inhibiting properties of anti-tau scAbs were ranked by tau-tau immunoassay (B50). A: Example of B50 quantification for NS2A1 and 3aD6 (negative control). Aggregation-inhibiting properties were quantified by calculating the B50 value (the concentration of scAb at which 50% of dGAE binds significantly to dGA). Error bars = SD, n = 4, -ve = negative control. b: Summary of B50 rankings for scAb groups.

[0063] Figure 39 mAb capture of .dGAE aggregates.

[0064] Figure 40 Experimental design to investigate the effects of intraperitoneal administration of S1D12 on line 1, line 66, and WT mice. Animals were injected intraperitoneally (ip) with either the solvent or S1D12 (10- or 50- mg / kg) once a week (Tuesdays) for twelve consecutive weeks (Group 1), eight consecutive weeks (Group 2), or four consecutive weeks (Group 3). Mice in all three groups were the same age (i.e., 6 months) at the end of the experiment.

[0065] Figure 41 Western blot analysis revealed tau labeled with a human-specific CB7 antibody. A band was present in L66 cells from 5-month-old infants. + / + The protein homogenate from a 20µg mouse brain was found in the lanes of a homogenate, but not in the WT or L1 glutamate. + / + In the lane. The protein ladder superimposed on the left side of the blot provides an approximation of the relative size of proteins on the gel, but it is well known that the apparent size of tau is much larger than its actual molecular weight.

[0066] Figure 42 Western blot analysis revealed tau labeled with human-specific CC7. Results and tiers... Figure 41 As described in [the text].

[0067] Figure 43 Western blot was labeled with S1D12 tau core antibody. Bands appeared in L66 cells from 5-month-old pharmacokinetic cells. + / + Protein homogenates from L66, L1, and WT mouse brains were homogenized in lanes. Mouse tau (indicated by the arrow below) appeared as a band of approximately 55 kDa in each sample. Human tau (indicated by the arrow above) appeared as a 68 kDa protein, present only in L66. + / + In the sample. Protein gradient. Figure 41 .

[0068] Figure 44 Western blot was used with S1G2 core antibody. Bands appeared in samples containing L66 cells from 5-month-old pharmacokinetic cells. + / + L1 + / + Protein homogenates from WT mouse brains were homogenized in lanes. Mouse tau (indicated by the arrow below) appeared as a band of approximately 55 kDa in each sample. Human tau (indicated by the arrow above) appeared as approximately 68 kDa, but was only present in L66. + / + In the sample. Using this antibody, in L1 + / + A band of approximately 10 kDa was visible in the sample. Protein gradient. Figure 41 .

[0069] Figure 45 Sequence comparison of human and mouse tau. The sequence shown consists of SEQ ID NO: 1 of human tau (with two gaps introduced to allow sequence alignment) and SEQ ID NO: 589 of mouse tau. Protein regions containing candidate antibody epitopes are superimposed. The CB7 and CC7 binding regions in human tau are absent in mouse tau. Conversely, protein regions containing epitopes of antibodies S1D12 and S1G2 show 100% homology between the two species.

[0070] Figure 46 A) Paired antibody ELISA with S1D12 capture and CB7 detection showed L66 + / + In mice, the signal gradually decreases with age. B) A similar pattern was observed when the measurement direction was reversed and CB7 was used as the capture and S1G2 as the detection substance.

[0071] Figure 47 Paired antibody ELISA with CB7 capture and HT7 detection shows L66 + / + The signal increased with age in mice. This indicates the accumulation of small, intact N-terminal fragments resulting from some form of tau protein or protein fragment truncated between the core and N'-terminal regions.

[0072] Figure 48 (A) Plasma tau levels in healthy controls (HC) and patients diagnosed with Alzheimer's disease (AD / MCI). The concentration of the core proline region, measured in paired measurements using S1D12 capture beads with BT2 as the analyte, was significantly higher in healthy controls than in AD samples. A total of 12 healthy control plasma samples and 42 AD / MCI samples were analyzed. ****p<0.0001(B) NT-1 assay data (Chen et al 2019) reported a slight increase in plasma tau levels of NT-1 in patients with AD-MCI (AD biomarker positive – mild cognitive impairment) and AD (AD biomarker positive – clinical AD) compared to NC (normal controls) using Tau12-BT2 antibody.

[0073] Figure 49 Plasma tau levels were measured in healthy controls (HC) and patients diagnosed with Alzheimer's disease (AD / MCI). The concentration of the core proline region, measured using S1D12 capture beads paired with HT7 as the analyte, was significantly higher in healthy controls than in AD samples. A total of 4 healthy control plasma samples and 34 AD / MCI samples were analyzed. ****p<0.0001.

[0074] Figure 50 .L66 + / - LMTM treatment in mice increased plasma tau levels. (A) NT1 assay using BT2 and HT7 antibodies detected L66 mice treated with LMTM (15 mg / kg). + / - (B) Human-specific N-terminal tau levels were slightly elevated in mouse plasma; similarly, higher levels of tau were also measured in LMTM-treated mouse plasma using core-proline assays with S1D2 and BT2 antibodies, at concentrations significantly higher than those seen using human-specific NT1 assays. The elevated levels in treated mice suggest an improved clearance of pathological tau from the brain into the bloodstream.

[0075] Figure 51 Concentrations of S1D12 mAb in mouse plasma at different time points. The plotted values ​​are the mean concentrations in the mouse groups analyzed at 24, 48, and 72 hours and 7, 14, and 31 days after administration of a single dose of 30 mg / kg S1D12 mAb.

[0076] Figure 52 Comparison of free S1D12 mAb concentrations in WT mouse plasma 7 days after a single or repeated administration of 30 mg / kg. The plotted values ​​are the mean concentrations (+standard error) of the mouse groups, n = 6.

[0077] Figure 53 Received S1D12 mAb at a weekly dose of 30 mg / kg for 6 weeks, wild-type, L1, and L66. + / + Detection of S1D12 in the brain of mice. Values ​​are expressed as the percentage of S1D12 concentration in the brain compared to plasma in the treated mouse group (mean + standard error; n = 6).

[0078] Figure 54 .L66 + / + Comparison of the ratio of human tau to mouse tau in brain homogenates from the solvent-treated and S1D12 mAb-treated groups. Decreased human tau levels were observed in the brains of mAb-treated mice when detected using the core region antibody S1G2 in Western blot analysis. Plotted values ​​represent the ratio of human to mouse tau protein band densities for each group (mean + standard error; n = 6). *p < 0.05.

[0079] Figure 55 L66 treated with S1D12 mAb were treated with a core-proline region-specific antibody pair (S1G2-BT2) in solvent. + / +Levels of creatine amide-insoluble tau were detected in mouse brain homogenates. Core proline fragment levels were reduced to 1 / 6 to 1 / 5 in mAb-treated mice compared to the solvent group. Individual mouse samples were analyzed in duplicate; values ​​represent the mean of relative luminescence readings for each group. (Mean + standard error; n = 6).

[0080] Figure 56 Plasma tau levels increased in mice after treatment with S1D12 mAb. Human-specific core-proline tau levels were elevated in S1D12 mAb-treated mice compared to the solvent group, using S1G2 (367–379) and BT2 (194–198) antibodies. Individual mouse samples were analyzed in duplicate; values ​​represent the mean concentration of the tau fragment detected by S1G2-BT2 antibody pairing. In L66 mice, the treatment group showed an increase of more than three-fold, while in L1 and wild-type mice, the difference was not statistically significant (n = 6, mean + standard error). Unpaired t-tests were performed between the solvent and treatment groups; **P ≤ 0.01, ns: not significant.

[0081] Figure 57 S1D12 treatment in L66 mice increased plasma tau levels of N-terminal tau. Human-specific N-terminal tau levels were elevated in S1D12 mAb-treated mice compared to the solvent group, using BT2 (194–198) and Tau12 (6–18) antibodies. Individual mouse samples were analyzed in duplicate, and values ​​represent the mean concentration of the tau fragment detected by BT2-Tau12 antibody pairing (n = 6, standard error bars); unpaired t-tests were performed between the solvent and treatment groups, ***P ≤ 0.001.

[0082] Figure 58 S1D12 treatment in L66 mice increased plasma tau levels of N-terminal tau. Human-specific proline tau levels were increased in S1D12 mAb-treated mice compared to the solvent group using BT2 (194–198) and HT7 (159–163) antibodies, but the difference was not statistically significant. Individual mouse samples were analyzed in duplicate; values ​​represent the mean concentration of the tau fragment detected by BT2-HT7 antibody pairing (n = 6; standard error bars).

[0083] Figure 59Transmission electron microscopy images of dGAE assembled in the presence and absence of antibodies. (A) dGAE (100 μM); (B) dGAE (25 μM); (C) dGAE (10 μM); (D) dGAE (100 μM) + s1D12 (25 μM; 4:1); (E) dGAE (25 μM) + s1D12 (25 μM; 1:1); (F) dGAE (10 μM) + s1D12 (2.5 μM; 4:1); (G) dGAE (10 μM) + anti-ovalbumin (2.5 μM; 4:1); (H) s1D12 (25 μM); (I) anti-ovalbumin (2.5 μM). Fibrillars were observed only in the formulation without s1D12 (AC) or in the dGAE control (G) prepared in the presence of non-tau IgG antibody and anti-ovalbumin. No fibrillation was observed when s1D12 was added to the assembly mixture at a dGAE protein:antibody ratio of 1:1 or 4:1 (D, E, and F). Fibrillars were also absent in the antibody controls in the absence of dGAE (H and I). Scale bar (scale bar on I applies to all figures), 200 nm.

[0084] Figure 60 The following CD spectra (in millidisenduration, mdeg): (A) 100 μM dGAE with 25 μM s1D12 (dashed line) (ratio 4:1) or without 25 μM s1D12 (solid line), and antibody only (dashed dotted line); (B) antibody subtracted spectrum. dGAE (solid line) shows a β-sheet conformation (positive at approximately 200 nm, negative at approximately 220 nm), but shows random coils (negative at approximately 200 nm, positive at approximately 220 nm) when the s1D12 spectrum is subtracted (B; dashed dotted line), indicating that dGAE has not yet assembled into protofibrils.

[0085] Figure 61 Fluorescence of samples incubated with ThS. An emission peak at 483 nm can be clearly observed using dGAE (solid line) at 25 μM (A, 1:1) and 100 μM (B, 4:1). This emission peak is eliminated when s1D12 is included in the assembly mixture (dashed line), indicating that only samples without s1D12 contain self-assembled amyloid fibrils. The dashed line indicates that s1D12 alone does not contribute to the fluorescence. Detailed Implementation

[0086] According to a first aspect, the present invention provides a specific binding molecule whose binding affinity to the epitope in SEQ ID NO: 1 is greater than the binding affinity of antibody mAb423 to the epitope in SEQ ID NO: 1.

[0087] In this disclosure, all residue numbers of the Tau protein sequence and structure refer to residues of SEQ ID NO: 1, namely the sequence of the quadruple repeat isoform 2N4R of human Tau protein (Uniprot ID P10636-8), or homologous positions or variants thereof in other species. 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, as shown in SEQ ID NO: 2). SEQ ID NO: 2 relates to a longer form of Tau found in the peripheral nervous system (PNS) rather than the central nervous system (CNS). As used herein, references to “full-length” tau refer to SEQ ID NO: 1 (the relevant sequence for the CNS) and not SEQ ID NO: 2 (which is unrelated to the CNS).

[0088] SEQ ID NO: 1 (Isotype Tau-F, also known as Tau-4, 2N4R, 441 amino acids):

[0089] >sp|P10636-8|TAU_HUMAN microtubule-associated protein tau isotype Tau-F OS=Homo sapiens OX=9606GN=MAPTMAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSR TPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLG NIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL

[0090] SEQ ID NO: 2 (Full-length human Tau, isotype PNS-Tau, 758 amino acids);

[0091] >sp|P10636-1|TAU_HUMAN Microtubule-associated protein tau OS=Homo sapiens OX=9606 GN=MAPT PE=1 SV=5 MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQEPESGKVVQEGFLREPGPPGLSHQLMSGMPGAPLLPEGPREATRQPSGTGPEDTEGGRHAPELLKHQLLGDLHQEGPPLKGAGGKERPGSKEEVDEDRDVDESSPQDSPPSKASPAQDGRPPQTAAREATSIPGFPAEGAIPLPVDFLSKVSTEIPASEPDGPSVGRAKGQDAPLEFTFHVEITPNVQKEQAHSEEHLGRAAFPGAPGEGPEARGPSLGEDTKEADLPEPSEKQPAAAPRGKPVSRVPQLKARMVSKSKDGTGSDDKKAKTSTRSSAKTLKNRPCLSPKHPTPGSSDPLIQPSSPAVCPEPPSSPKYVSSVTSRTGSSGAKEMKLKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSGDTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL

[0092] As used herein, "mouse tau" refers to isoform Tau-A, which has the sequence Uniprot ID P10637-2, as provided in SEQ ID NO: 589:

[0093] MADPRQEFDTMEDHAGDYTLLQDQEGDMDHGLKESPPQPPADDGAEEPGSETSDAKSTPTAEDVTAPLVDERAPDKQAAAQPHTEIPEGITAEEAGIGDTPNQEDQAAGHVTQARVASKDRTGNDEKKAKGADGKTGAKIATPRGAASPAQKGTSNATRIPAKTTPSPKTPPGS GEPPKSGERSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSAKSRLQTAPVPMPDLKNVRSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNI

[0094] THVPGGGNKKIETHKLTFRENAKAKTDHGAEIVYKSPVVSG

[0095] DTSPRHLSNVSSTGSIDMVDSPQLATLADEVSASLAKQGL

[0096] dGAE97 refers to a 97-residue fragment of Tau(2N4R) with its N-terminus at residue Asp-295 and its C-terminus at residue Glu-391 (as described in SEQ ID NO: 3), or a fragment at a homologous position in other species (the residues mentioned 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) with its N-terminus at Asp-612 and its C-terminus at Glu-708.

[0097] SEQ ID NO: 3 (dGAE97, human / mouse, 97 amino acids):

[0098] DNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAE

[0099] dGAE95 refers to a 95-residue fragment of Tau(2N4R) with its N-terminus at residue Ile-297 and its C-terminus at residue Glu-391 (as described in SEQ ID NO: 4), or a fragment at a homologous position in other species (the residues mentioned 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) with its N-terminus at Ile-614 and its C-terminus at Glu-708. This sequence is sometimes 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).

[0100] SEQ ID NO: 4 (dGAE95 or "dGAE", human / mouse, 95 amino acids):

[0101] IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGAE

[0102] “dGA” refers to a 94-residue fragment of Tau(2N4R) with its N-terminus at residue Ile-297 and its C-terminus at residue Ala-390 (as described in SEQ ID NO: 5), or a fragment at a homologous position in other species (the residues mentioned refer to human or mouse Tau sequences, which are identical in this region).

[0103] SEQ ID NO: 5 (dGA, human / mouse, 94 amino acids):

[0104] IKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTFRENAKAKTDHGA

[0105] dGAE73 refers to a fragment of Tau(2N4R) with its N-terminus at residue Val-306 and its C-terminus at residue Phe-378 (as described in SEQ ID NO: 6), or a fragment 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 the sequence identified by cryo-electron microscopy (cryo-EM) as the core sequence of PHF isolated from AD brain tissue (Fitzpatrick et al., 2017; Nature). The core can extend beyond these residues, but is limited by the resolution of cryo-EM. It will be apparent to those skilled in the art that dGAE73 also corresponds to a fragment of isoform PNS-Tau (P10636-1) with its N-terminus at Val-623 and its C-terminus at Phe-695.

[0106] SEQ ID NO: 6 (dGAE73, human / mouse, 73 amino acids):

[0107] VQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTF

[0108] The PHF core refers to residues 296 to 391 of Tau(2N4R) as described in SEQ ID NO: 3, or fragments at homologous positions in other species (the residues mentioned refer to human or mouse Tau sequences that are identical in this region).

[0109] Another segment of the PHF core is residues 308 to 378 of Tau(2N4R), with its N-terminus at residue Ile-308 and its C-terminus at residue Phe-378 (as described in SEQ ID NO: 7), or a segment at a homologous position in other species (the residues mentioned refer to the human or mouse Tau sequence, which are identical in this region).

[0110] SEQ ID NO: 7 (dGAE71, residues 308 to 378 of 2N4R, human / mouse, 71 amino acids):

[0111] IVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDNITHVPGGGNKKIETHKLTF

[0112] The epitopes that specifically bind to the molecule may be in SEQ ID NO: 3, SEQ ID NO: 4, SEQ ID NO: 5, SEQ ID NO: 6 or SEQ ID NO: 7.

[0113] The epitope of the specific binding molecule may 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 may be located within the PHF or within the dGAE fragment. Therefore, the epitope of the specific binding molecule may be located within SEQ ID NO: 4.

[0114] The epitope of the specific binding molecule may be 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 specific binding molecule may be within the dGA fragment. Therefore, the epitope of the specific binding molecule may be within SEQ ID NO: 5. The epitope of the specific binding molecule may be within dGAE73 and / or dGAE71. Therefore, the epitope of the specific binding molecule may be within SEQ ID NO: 6 and / or SEQ ID NO: 7.

[0115] 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.

[0116] The epitopes of the specifically binding molecules can be found in residues 297 to 386 of SEQ ID NO: 1. The epitopes of the specifically binding molecules can be found in residues 306 to 391 of SEQ ID NO: 1. The epitopes of the specifically binding molecules can be found in residues 306 to 386 of SEQ ID NO: 1.

[0117] The epitope that specifically binds to the molecule may be 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, 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 ... 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. NO: 1 residues 360 to 390.

[0118] The epitope that specifically binds to the molecule may be 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.

[0119] The epitope that specifically binds to the molecule may be within the 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.

[0120] The epitope that specifically binds to the molecule can be within the amino acid sequence selected from residues 341 to 353 of SEQ ID NO: 1.

[0121] The epitope of the specific binding molecule of the present invention can be any amino acid sequence of SEQ ID NO: 1 that, as indicated by ELISA or alanine scanning mutagenesis, contains a key binding residue, for example, as described in Examples 5 to 12.

[0122] The epitopes described herein can be identified as “containing” a particular amino acid sequence, or by the phrase “specifically binding molecule binds to a polypeptide or protein molecule containing an amino acid sequence with residues…”. It will be apparent to those skilled in the art that when a specific binding molecule binds to a polypeptide or protein molecule containing its epitope, it will also bind to the polypeptide or protein molecule composed of its epitope. As used herein, the phrase “specifically binding molecule binds to a polypeptide or protein molecule containing an amino acid sequence with residues…” can therefore alternatively replace, wherever it appears, the phrases: “specifically binding molecule binds to a polypeptide or protein molecule containing an amino acid sequence composed of residues…”; “specifically binding molecule binds to a polypeptide or protein molecule composed of an amino acid sequence containing residues…”; or “specifically binding molecule binds to a polypeptide or protein molecule composed of an amino acid sequence composed of residues…”.

[0123] Those skilled in the art know that not all residues within an epitope are always necessary. 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.

[0124] The specific binding molecule can maintain binding to an amino acid sequence that has at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with an epitope. The specific binding molecule can bind to any epitope disclosed herein or an amino acid sequence that has at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity with it.

[0125] In embodiments of the invention, the specifically binding molecule maintains binding to an amino acid sequence having less than 100% sequence identity with the amino acid sequence of SEQ ID NO: 1 (or any of SEQ ID NO: 3 to 7 or any other epitope defined herein), and the epitope sequence can be modified by substituting, adding, or deleting an appropriate number of amino acids in the sequence of SEQ ID NO: 1 (or any of SEQ ID NO: 3 to 7 or any other epitope defined herein). In another embodiment of the invention, the epitope can be modified by substituting, adding, or deleting up to two amino acids relative to SEQ ID NO: 1 (or any of SEQ ID NO: 3 to 7 or any other epitope defined herein), provided that the resulting epitope sequence has at least 85% or 90% sequence identity with SEQ ID NO: 1 (or any of SEQ ID NO: 3 to 7 or any other epitope defined herein), as listed above. “Substituting, adding, or deleting” includes combinations of substitution, addition, and deletion.

[0126] When an epitope sequence is modified by substituting 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 an amino acid residue is replaced by an amino acid residue with a similar side chain. Amino acids with similar side chains tend to have similar properties, and therefore, a conserved substitution of an amino acid important for the structure or function of a polypeptide may be expected to have less impact on the polypeptide's 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 non-conservative substitution, where one amino acid is replaced by another amino acid with a side chain belonging to a different family.

[0127] The length of an epitope can be at least 5, at least 6, at least 7, at least 8, at least 9, at least 10, at least 11, at least 12, at least 13, at least 14, at least 15, at least 16, at least 17, at least 18, at least 19, or at least 20 amino acids. The length of an epitope can be 5 to 20 amino acids. The length of an epitope can be 5 to 15 amino acids. The length of an epitope can be 5 to 12 amino acids. The length of an epitope can be 6 to 12 amino acids. The length of an epitope can be 7 to 12 amino acids.

[0128] As used herein, the term "within" means "included in" or "completely within". Outside the epitope, there are no residues considered essential for the binding of a specifically binding molecule to its target. 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.

[0129] Epitopes may contain any residue within SEQ ID NO: 1 that is bound by a specific binding molecule. Epitopes may be continuous or discontinuous.

[0130] A continuous epitope can be any consecutive residue within SEQ ID NO: 1 that is bound by a specific binding molecule. The consecutive residues are adjacent to each other in the primary structure of the polypeptide.

[0131] Discontinuous epitopes can be any non-continuous residue within SEQ ID NO: 1 that is specifically bound by a binding molecule. Discontinuous epitopes are typically formed by non-continuous residues located in adjacent positions in three-dimensional space due to polypeptide folding.

[0132] 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 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. NO: 1 residues 360 to 390.

[0133] The specific binding molecule can bind to a polypeptide or protein molecule containing the amino acid sequence of residues 341 to 353 of SEQ ID NO: 1.

[0134] In the following sequence, " / " indicates "or" and indicates that the inventor has indicated that a residue can vary as specified. In the context, "-" indicates an empty or absent amino acid. X is any amino acid. For example, "N / S" means it can be residue N or S. Similarly, "G / -" means it can be residue G or absent. Likewise, "H / F / Y" means it can be residue H, F, or Y. When specifying sequence identity values, sequence identity can be calculated based on any one of the residues separated by " / ".

[0135] The epitope of the specifically binding molecule may be located within the amino acid sequence containing residues 337 to 355 of SEQ ID NO: 1. The epitope of the specifically binding molecule located within the amino acid sequence containing residues 337 to 355 of SEQ ID NO: 1 may also 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).

[0136] 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 of SEQ ID NO: 8, wherein any one or more residues other than residues numbered 343(K), 346(F), and / or 349(R) are substituted with non-conservative amino acids (according to SEQ ID NO: 1). The epitope may comprise the amino acid sequence of SEQ ID NO: 8, wherein any one or more residues other than residues numbered 343(K), 346(F), and / or 349(R) are substituted with conserved amino acids (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 substituted with non-conservative amino acids (according to SEQ ID NO: 1).

[0137] The epitope may consist of residues 337 to 349, preferably residues 337 to 355, of SEQ ID NO: 1. The epitope may also consist of the amino acid sequence of SEQ ID NO: 8 (VEVKSEKLDFKDR). 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 SEQ ID NO: 8 (VEVKSEKLDFKDR).

[0138] The specific binding molecule can bind to polypeptide or protein molecules containing the amino acid sequence 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 of the CDRs contains the following amino acid sequence:

[0139] VHCDR1 contains the sequence listed in SEQ ID NO: 10 (N / SN AV G);

[0140] VHCDR2 contains the sequence listed in SEQ ID NO: 11 (GCSSDGT / KCYY / HNSALKS);

[0141] VHCDR3 contains the sequence listed in SEQ ID NO: 12 (GH / F / YYS / PI / VYGYDYL / SGTIDY);

[0142] VLCDR1 contains the sequence listed in SEQ ID NO: 13 (SGSSSNVG / -GG / RNS / DVG / A);

[0143] VLCDR2 contains the sequence listed in SEQ ID NO: 14 (D / N / GTN / TSRPS);

[0144] VLCDR3 contains the sequence listed in SEQ ID NO: 15 (V / AT / SGDST / ST / AH / ID / NDL / I);

[0145] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0146] (i) having at least 85% identity with it, and / or

[0147] (ii) relative to having one, two or three amino acid substitutions.

[0148] 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%.

[0149] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0150] VHCDR1 contains the sequence listed in SEQ ID NO: 16 (NNAVG) or SEQ ID NO: 17 (SNAVG);

[0151] VHCDR2 contains the sequences listed in SEQ ID NO: 18 (GCSSDGTCYYNSALKS), SEQ ID NO: 19 (GCSSDGKCYHNSALKS), or SEQ ID NO: 20 (GCSSDGKCYYNSALKS);

[0152] VHCDR3 contains the sequence listed in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY), SEQ ID NO: 22 (GFYSIYGYDYSGTIDY) or SEQ ID NO: 23 (GYYPVYGYDYLGTIDY);

[0153] VLCDR1 contains the sequence listed in SEQ ID NO: 24 (SGSSSNVGGGNSVG) or SEQ ID NO: 25 (SGSSSNVGRNDVA);

[0154] VLCDR2 contains the sequences listed in SEQ ID NO: 26 (DTNSRPS), SEQ ID NO: 27 (NTNSRPS), or SEQ ID NO: 28 (GTTSRPS);

[0155] VLCDR3 contains the sequence listed in SEQ ID NO: 29 (VTGDSTTHDDL), SEQ ID NO: 30 (VTGDSSTHDDL), or SEQ ID NO: 31 (ASGDSSAINDI);

[0156] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0157] (i) having at least 85% identity with it, and / or

[0158] (ii) relative to having one, two, or three amino acid substitutions.

[0159] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 337 to 355 of SEQ ID NO: 1.

[0160] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0161] VHCDR1 contains the sequence listed in SEQ ID NO: 16 (NNAVG);

[0162] VHCDR2 contains the sequence listed in SEQ ID NO: 18 (GCSSDGTCYYNSALKS);

[0163] VHCDR3 contains the sequence listed in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY);

[0164] VLCDR1 contains the sequence listed in SEQ ID NO: 24 (SGSSSNVGGGNSVG);

[0165] VLCDR2 contains the sequence listed in SEQ ID NO: 26 (DTNSRPS);

[0166] VLCDR3 contains the sequence listed in SEQ ID NO: 29 (VTGDSTTHDDL);

[0167] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0168] (i) having at least 85% identity with it, and / or

[0169] (ii) relative to having one, two, or three amino acid substitutions.

[0170] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 337 to 355 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to those given above is referred to herein as “S1D12” (or abbreviated as “1D12”).

[0171] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0172] VHCDR1 contains the sequence listed in SEQ ID NO: 16 (NNAVG);

[0173] VHCDR2 contains the sequence listed in SEQ ID NO: 18 (GCSSDGTCYYNSALKS);

[0174] VHCDR3 contains the sequence listed in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY);

[0175] VLCDR1 contains the sequence listed in SEQ ID NO: 24 (SGSSSNVGGGNSVG);

[0176] VLCDR2 contains the sequence listed in SEQ ID NO: 26 (DTNSRPS); and

[0177] VLCDR3 contains the sequence listed in SEQ ID NO: 29 (VTGDSTTHDDL).

[0178] Any specific binding molecules disclosed herein can be further defined by reference to one or more framework regions (FRs). Framework regions (FRs) are non-CDR sequences that, together with CDR sequences, form variable domains.

[0179] The VH structural domain can have the following formula: VHFR1-VHCDR1-VHFR2-VHCDR2-VHFR3-VHCDR3-VHFR4.

[0180] The VL structural domain can have the following formula: VLFR1-VLCDR1-VLFR2-VLCDR2-VLFR3-VLCDR3-VLFR4.

[0181] Those skilled in the art can identify the CDR and backbone regions within the amino acid sequence of the variable domain 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 may 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 may typically be replaced by corresponding residues from the human sequence. Therefore, FR sequences may be more tolerant of amino acid substitutions than CDR sequences.

[0182] Specific binding molecules may include:

[0183] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains an amino acid sequence from any specific binding molecule disclosed herein; or for each FR sequence, an amino acid sequence having the following characteristics:

[0184] (i) having at least 50% similarity with it, and / or

[0185] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0186] (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, or for each CDR sequence, an amino acid sequence having the following characteristics:

[0187] (i) having at least 85% identity with it, and / or

[0188] (ii) relative to having one, two or three amino acid substitutions.

[0189] 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%.

[0190] 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%. Preferably, the sequence identity is at least 90% or at least 95%.

[0191] An FR sequence can be a humanized sequence when it shares at least 50% (but less than 100%) identity with an FR sequence disclosed as part of a specific binding molecule disclosed herein. In other words, the change in amino acid sequence can be simply the change required for sequence humanization.

[0192] The FR sequence can be a humanized sequence when it has one, two, three, four, or five amino acid substitutions relative to the FR sequence disclosed as part of the specific binding molecule disclosed herein. In other words, the substitutions can be simply those required for sequence humanization.

[0193] Specific binding molecules may include:

[0194] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains an amino acid sequence from any specific binding molecule disclosed herein; and

[0195] (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.

[0196] Typically, each FR will come from the same specific binding molecule disclosed herein. Typically, each CDR will come from the same specific binding molecule disclosed herein. Typically, no additional amino acid residues are inserted between the identified 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.

[0197] As used herein, the phrase “containing a CDR” also encompasses specific binding molecules containing the CDR and FR of the specific binding molecules disclosed herein, including variants of the FR (including those FRs mentioned above), such as humanized FRs. It also encompasses specific binding molecules containing the VH and / or VL domains of the specific binding molecules disclosed herein, including variants of the FR (including those FRs mentioned above), such as humanized FRs. Furthermore, it encompasses specific binding molecules containing the heavy chain and / or light chain of the specific binding molecules disclosed herein, including variants of the FR and constant region (including those FRs and constant regions mentioned above), such as humanized FRs and humanized constant regions.

[0198] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0199] VHFR1 contains the sequence listed in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0200] VHFR2 contains the sequence listed in SEQ ID NO: 436 (WVRQAPGKVPESLV);

[0201] VHFR3 contains the sequence listed in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0202] VHFR4 contains the sequence listed in SEQ ID NO: 438 (WGPGLLVTVSS);

[0203] VLFR1 contains the sequence listed in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC);

[0204] VLFR2 contains the sequence listed in SEQ ID NO: 440 (WYQHLPGSGLKTIIY);

[0205] VLFR3 contains the sequence listed in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0206] VLFR4 contains the sequence listed in SEQ ID NO: 442 (VGSGTRLTVLG);

[0207] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0208] (i) having at least 50% similarity with it, and / or

[0209] (ii) relative to having one, two, three, four or five amino acid substitutions.

[0210] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0211] VHFR1 contains the sequence listed in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0212] VHFR2 contains the sequence listed in SEQ ID NO: 436 (WVRQAPGKVPESLV);

[0213] VHFR3 contains the sequence listed in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0214] VHFR4 contains the sequence listed in SEQ ID NO: 438 (WGPGLLVTVSS);

[0215] VLFR1 contains the sequence listed in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC);

[0216] VLFR2 contains the sequence listed in SEQ ID NO: 440 (WYQHLPGSGLKTIIY);

[0217] VLFR3 contains the sequence listed in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0218] VLFR4 contains the sequence listed in SEQ ID NO: 442 (VGSGTRLTVLG);

[0219] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0220] (i) having at least 50% similarity with it, and / or

[0221] (ii) relative to having one, two, three, four, or five amino acid substitutions,

[0222] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 337 to 355 of SEQ ID NO: 1. A specific binding molecule containing a FR that is 100% identical to the given FRs described above is referred to herein as “S1D12” (or abbreviated as “1D12”).

[0223] Specific binding molecules may include:

[0224] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0225] VHFR1 contains the sequence listed in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0226] VHFR2 contains the sequence listed in SEQ ID NO: 436 (WVRQAPGKVPESLV);

[0227] VHFR3 contains the sequence listed in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0228] VHFR4 contains the sequence listed in SEQ ID NO: 438 (WGPGLLVTVSS);

[0229] VLFR1 contains the sequence listed in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC);

[0230] VLFR2 contains the sequence listed in SEQ ID NO: 440 (WYQHLPGSGLKTIIY);

[0231] VLFR3 contains the sequence listed in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0232] VLFR4 contains the sequence listed in SEQ ID NO: 442 (VGSGTRLTVLG);

[0233] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0234] (i) having at least 50% similarity with it, and / or

[0235] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0236] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0237] VHCDR1 contains the sequence listed in SEQ ID NO: 16 (NNAVG);

[0238] VHCDR2 contains the sequence listed in SEQ ID NO: 18 (GCSSDGTCYYNSALKS);

[0239] VHCDR3 contains the sequence listed in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY);

[0240] VLCDR1 contains the sequence listed in SEQ ID NO: 24 (SGSSSNVGGGNSVG);

[0241] VLCDR2 contains the sequence listed in SEQ ID NO: 26 (DTNSRPS);

[0242] VLCDR3 contains the sequence listed in SEQ ID NO: 29 (VTGDSTTHDDL);

[0243] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0244] (i) having at least 85% identity with it, and / or

[0245] (ii) relative to having one, two, or three amino acid substitutions.

[0246] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 337 to 355 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “S1D12” (or abbreviated as “1D12”).

[0247] Specific binding molecules may include:

[0248] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0249] VHFR1 contains the sequence listed in SEQ ID NO: 435 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLN);

[0250] VHFR2 contains the sequence listed in SEQ ID NO: 436 (WVRQAPGKVPESLV);

[0251] VHFR3 contains the sequence listed in SEQ ID NO: 437 (RLDITRDTSKNQISLSLSSVTTDDAAVYYCTR);

[0252] VHFR4 contains the sequence listed in SEQ ID NO: 438 (WGPGLLVTVSS);

[0253] VLFR1 contains the sequence listed in SEQ ID NO: 439 (QAVLTQPSSVSGSLGQRVSITC);

[0254] VLFR2 contains the sequence listed in SEQ ID NO: 440 (WYQHLPGSGLKTIIY);

[0255] VLFR3 contains the sequence listed in SEQ ID NO: 441 (GVPDRFSGSRSGNTATLTINSLQAEDEGDYYC);

[0256] VLFR4 contains the sequence listed in SEQ ID NO: 442 (VGSGTRLTVLG);

[0257] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0258] (i) having at least 50% similarity with it, and / or

[0259] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0260] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0261] VHCDR1 contains the sequence listed in SEQ ID NO: 16 (NNAVG);

[0262] VHCDR2 contains the sequence listed in SEQ ID NO: 18 (GCSSDGTCYYNSALKS);

[0263] VHCDR3 contains the sequence listed in SEQ ID NO: 21 (GHYSIYGYDYLGTIDY);

[0264] VLCDR1 contains the sequence listed in SEQ ID NO: 24 (SGSSSNVGGGNSVG);

[0265] VLCDR2 contains the sequence listed in SEQ ID NO: 26 (DTNSRPS);

[0266] VLCDR3 contains the sequence listed in SEQ ID NO: 29 (VTGDSTTHDDL);

[0267] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 337 to 355 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “S1D12” (or abbreviated as “1D12”).

[0268] Specific binding molecules may include:

[0269] (a) A VH domain containing the sequence listed in SEQ ID NO: 443 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDI TRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSS); and / or

[0270] (b) A VL domain containing the sequence listed in SEQ ID NO: 444 (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSG NTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG);

[0271] Or its humanized variants.

[0272] Specific binding molecules may include:

[0273] (a) A heavy chain containing SEQ ID NO: 445(QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDI) TRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVT CVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMT and / or

[0274] (b) A light chain containing the sequences listed in SEQ ID NO: 446 (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSG NTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTI TDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEK SLSRADCS);

[0275] Or its humanized variants.

[0276]

[0277] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0278] VHCDR1 contains the VHCDR1 amino acid sequence listed in Table 1;

[0279] VHCDR2 contains the VHCDR2 amino acid sequence listed in Table 1;

[0280] VHCDR3 contains the VHCDR3 amino acid sequence listed in Table 1;

[0281] VLCDR1 contains the VLCDR1 amino acid sequence listed in Table 1;

[0282] VLCDR2 contains the VLCDR2 amino acid sequence listed in Table 1; and

[0283] VLCDR3 contains the VLCDR3 amino acid sequence listed in Table 1;

[0284] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0285] (i) having at least 85% identity with it, and / or

[0286] (ii) relative to having one, two, or three amino acid substitutions.

[0287] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 337 to 355 of SEQ ID NO: 1.

[0288] 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 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. K D K may preferably be combined with SEQ ID NO: 1 or SEQ ID NO: 5. D K combined 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 binding to SEQ ID NO: 5 D It can be approximately 300 pM to approximately 400 pM. K bound to SEQ ID NO: 5 D It can be approximately 344 pM, and optionally the specific binding molecule includes the CDR of S1D12.

[0289] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 30. The CDR may be 100% identical to the CDR of SEQ ID NO: 32. 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: 30, wherein the CDR is 100% identical to the CDR of SEQ ID NO: 32. The specific binding molecule may include the amino acid sequence of SEQ ID NO: 32.

[0290] SEQ ID NO: 32 (S1D12 amino acid sequence)

[0291] QVQLQESGPSLVKPSQTLSLTCTVSGFSLNNNAVGWVRQAPGKVPESLVGCSSDGTCYYNSALKSRLDITRDTSKNQISLSLSSVTTDDAAVYYCTRGHYSIYGYDYLGTIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSSSNVGGGNSVGWYQHLPGSGLKTIIYDTNSRPSGVPDRFSGSRSGNTATLTINSLQAEDEGDYYCVTGDSTTHDDLVGSGTRLTVLG

[0292] 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).

[0293] The epitope may be located within the amino acid sequence containing residues 367 to 379 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “S1G2”.

[0294] Epitopes may comprise the amino acid sequence of SEQ ID NO: 33 (GNKKIETHKLTFR). Epitopes may comprise 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: 33 (GNKKIETHKLTFR). Key residues of the epitope may be residues 370(K) and / or 374(H) (according to SEQ ID NO: 1). Epitopes may comprise the amino acid sequence of SEQ ID NO: 34 (XXXKXXXHXXXXX, where X is any amino acid). Epitopes 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 substituted with non-conservative amino acid substitutions (according to SEQ ID NO: 1). Epitopes 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 substituted with conserved amino acid substitutions (according to SEQ ID NO: 1). The epitope 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 a conserved amino acid (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 a non-conserved amino acid (according to SEQ ID NO: 1).

[0295] 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).

[0296] 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:

[0297] VHCDR1 contains the sequence listed in SEQ ID NO: 35 (S / TN / YS / A / YVG);

[0298] VHCDR2 contains the sequence listed in SEQ ID NO: 36 (G / S / NI / VD / YT / SD / TGE / Y / D / RE / T / AG / Y / FY / FNPA / VLN / KS);

[0299] VHCDR3 contains the sequence listed 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);

[0300] VLCDR1 contains the sequence listed in SEQ ID NO: 38 (SGS / RF / Y / DI / L / VG / SI / S / RSS / R / A / GVG) or SEQ ID NO: 39 (SGSSSNVGYGNYVG);

[0301] VLCDR2 contains the sequence listed in SEQ ID NO: 40 (A / DS / AD / S / TG / SRP / AS);

[0302] VLCDR3 contains the sequence listed 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);

[0303] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0304] (i) having at least 85% identity with it, and / or

[0305] (ii) relative to having one, two or three amino acid substitutions.

[0306] 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%.

[0307] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0308] VHCDR1 contains the sequences listed in SEQ ID NO: 42 (SNSVG), SEQ ID NO: 17 (SNAVG), SEQ ID NO: 44 (SYYVG), or SEQ ID NO: 45 (TNSVG);

[0309] 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 Sequences listed in NO: 51 (GIDTGEEGYNPALKS), SEQ ID NO: 52 (NIYSTGRAFYNPALKS) or SEQ ID NO: 53 (GIDTDGEEGFNPVLKS);

[0310] 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 Sequences listed in NO: 59 (SANGHPDVYYIDK), SEQ ID NO: 60 (TYRTDGFAYGYVQAIDY), SEQ ID NO: 61 (SYRTDGLAYGYVQAIEY) or SEQ ID NO: 265 (GSYYHGGGNGMVDFFDY);

[0311] VLCDR1 contains the sequences listed 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);

[0312] VLCDR2 contains the sequences listed in SEQ ID NO: 70 (ASDGRPS), SEQ ID NO: 71 (DSSSRPS), or SEQ ID NO: 72 (AATSRAS);

[0313] VLCDR3 contains the sequences listed 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);

[0314] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0315] (i) having at least 85% identity with it, and / or

[0316] (ii) relative to having one, two, or three amino acid substitutions.

[0317] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 367 to 379 of SEQ ID NO: 1.

[0318] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0319] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0320] VHCDR2 contains the sequence listed in SEQ ID NO: 46 (GIDTDGEEGYNPALNS);

[0321] VHCDR3 contains the sequence listed in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0322] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0323] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS);

[0324] VLCDR3 contains the sequence listed in SEQ ID NO: 73 (GSSDRTPYTGV);

[0325] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0326] (i) having at least 85% identity with it, and / or

[0327] (ii) relative to having one, two, or three amino acid substitutions.

[0328] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “S1G2”.

[0329] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0330] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0331] VHCDR2 contains the sequence listed in SEQ ID NO: 46 (GIDTDGEEGYNPALNS);

[0332] VHCDR3 contains the sequence listed in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0333] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0334] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS); and

[0335] VLCDR3 contains the sequence listed in SEQ ID NO: 73 (GSSDRTPYTGV).

[0336] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0337] VHFR1 contains the sequence listed in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0338] VHFR2 contains the sequence listed in SEQ ID NO: 448 (WVRQAPGKAPEWVA);

[0339] VHFR3 contains the sequence listed in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0340] VHFR4 contains the sequence listed in SEQ ID NO: 450 (WGPGLLVTVSS);

[0341] VLFR1 contains the sequence listed in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC);

[0342] VLFR2 contains the sequence listed in SEQ ID NO: 452 (WFQQLPGSGLRTIIV);

[0343] VLFR3 contains the sequence listed in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0344] VLFR4 contains the sequence listed in SEQ ID NO: 454 (FGSGTRLTVLG);

[0345] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0346] (i) having at least 50% similarity with it, and / or

[0347] (ii) relative to having one, two, three, four or five amino acid substitutions.

[0348] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0349] VHFR1 contains the sequence listed in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0350] VHFR2 contains the sequence listed in SEQ ID NO: 448 (WVRQAPGKAPEWVA);

[0351] VHFR3 contains the sequence listed in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0352] VHFR4 contains the sequence listed in SEQ ID NO: 450 (WGPGLLVTVSS);

[0353] VLFR1 contains the sequence listed in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC);

[0354] VLFR2 contains the sequence listed in SEQ ID NO: 452 (WFQQLPGSGLRTIIV);

[0355] VLFR3 contains the sequence listed in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0356] VLFR4 contains the sequence listed in SEQ ID NO: 454 (FGSGTRLTVLG);

[0357] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0358] (i) having at least 50% similarity with it, and / or

[0359] (ii) relative to having one, two, three, four, or five amino acid substitutions,

[0360] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO: 1. A specific binding molecule containing a FR that is 100% identical to the given FRs described above is referred to herein as “S1G2”.

[0361] Specific binding molecules may include:

[0362] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0363] VHFR1 contains the sequence listed in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0364] VHFR2 contains the sequence listed in SEQ ID NO: 448 (WVRQAPGKAPEWVA);

[0365] VHFR3 contains the sequence listed in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0366] VHFR4 contains the sequence listed in SEQ ID NO: 450 (WGPGLLVTVSS);

[0367] VLFR1 contains the sequence listed in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC);

[0368] VLFR2 contains the sequence listed in SEQ ID NO: 452 (WFQQLPGSGLRTIIV);

[0369] VLFR3 contains the sequence listed in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0370] VLFR4 contains the sequence listed in SEQ ID NO: 454 (FGSGTRLTVLG);

[0371] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0372] (i) having at least 50% similarity with it, and / or

[0373] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0374] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0375] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0376] VHCDR2 contains the sequence listed in SEQ ID NO: 46 (GIDTDGEEGYNPALNS);

[0377] VHCDR3 contains the sequence listed in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0378] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0379] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS); and

[0380] VLCDR3 contains the sequence listed in SEQ ID NO: 73 (GSSDRTPYTGV).

[0381] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0382] (i) having at least 85% identity with it, and / or

[0383] (ii) relative to having one, two, or three amino acid substitutions.

[0384] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “S1G2”.

[0385] Specific binding molecules may include:

[0386] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0387] VHFR1 contains the sequence listed in SEQ ID NO: 447 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[0388] VHFR2 contains the sequence listed in SEQ ID NO: 448 (WVRQAPGKAPEWVA);

[0389] VHFR3 contains the sequence listed in SEQ ID NO: 449 (RLSITRDTSKSQVSLSLSSVTSEDTAVYYCGR);

[0390] VHFR4 contains the sequence listed in SEQ ID NO: 450 (WGPGLLVTVSS);

[0391] VLFR1 contains the sequence listed in SEQ ID NO: 451 (QAVVTQPSSVSGSLGQRVSITC);

[0392] VLFR2 contains the sequence listed in SEQ ID NO: 452 (WFQQLPGSGLRTIIV);

[0393] VLFR3 contains the sequence listed in SEQ ID NO: 453 (GVPDRFSMSKSGNTATLTISSLQAEDEADYFC);

[0394] VLFR4 contains the sequence listed in SEQ ID NO: 454 (FGSGTRLTVLG);

[0395] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0396] (i) having at least 50% similarity with it, and / or

[0397] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0398] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0399] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0400] VHCDR2 contains the sequence listed in SEQ ID NO: 46 (GIDTDGEEGYNPALNS);

[0401] VHCDR3 contains the sequence listed in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0402] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0403] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS); and

[0404] VLCDR3 contains the sequence listed in SEQ ID NO: 73 (GSSDRTPYTGV).

[0405] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “S1G2”.

[0406] Specific binding molecules may include:

[0407] (a) A VH domain containing the sequences listed in SEQ ID NO: 455 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSI TRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVSS); and / or

[0408] (b) A VL domain containing the sequence listed in SEQ ID NO: 456 (QAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATL TISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG);

[0409] Or its humanized variants.

[0410] Specific binding molecules may include:

[0411] (a) A heavy chain containing SEQ ID NO: 457(QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSI) TRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGSLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIV TCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEM and / or

[0412] (b) A light chain containing the sequences listed in SEQ ID NO: 458 (QAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATL TISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPG VVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRAD CS);

[0413] Or its humanized variants.

[0414] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0415] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0416] VHCDR2 contains the sequence listed in SEQ ID NO: 46 (GIDTDGEEGYNPALNS);

[0417] VHCDR3 contains the sequence listed in SEQ ID NO: 55 (SYRTDGLAYGYVQAIDY);

[0418] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0419] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS);

[0420] VLCDR3 contains the sequence listed in SEQ ID NO: 74 (GSSDRTQYTGV);

[0421] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0422] (i) having at least 85% identity with it, and / or

[0423] (ii) relative to having one, two, or three amino acid substitutions.

[0424] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “S1B1”.

[0425] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0426] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0427] VHCDR2 contains the sequence listed in SEQ ID NO: 46 (GIDTDGEEGYNPALNS);

[0428] VHCDR3 contains the sequence listed in SEQ ID NO: 55 (SYRTDGLAYGYVQAIDY);

[0429] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0430] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS);

[0431] VLCDR3 contains the sequence listed in SEQ ID NO: 74 (GSSDRTQYTGV).

[0432] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0433] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0434] VHCDR2 contains the sequence listed in SEQ ID NO: 48 (GIDSDGEEGYNPALNS);

[0435] VHCDR3 contains the sequence listed in SEQ ID NO: 57 (TYRTDGYAYGYVQAIDY);

[0436] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0437] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS);

[0438] VLCDR3 contains the sequence listed in SEQ ID NO: 74 (GSSDRTQYTGV);

[0439] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0440] (i) having at least 85% identity with it, and / or

[0441] (ii) relative to having one, two, or three amino acid substitutions.

[0442] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “S1D9”.

[0443] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0444] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0445] VHCDR2 contains the sequence listed in SEQ ID NO: 48 (GIDSDGEEGYNPALNS);

[0446] VHCDR3 contains the sequence listed in SEQ ID NO: 57 (TYRTDGYAYGYVQAIDY);

[0447] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0448] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS);

[0449] VLCDR3 contains the sequence listed in SEQ ID NO: 74 (GSSDRTQYTGV).

[0450] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0451] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0452] VHCDR2 contains the sequence listed in SEQ ID NO: 46 (GIDTDGEEGYNPALNS);

[0453] VHCDR3 contains the sequence listed in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0454] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0455] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS);

[0456] VLCDR3 contains the sequence listed in SEQ ID NO: 74 (GSSDRTQYTGV);

[0457] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0458] (i) having at least 85% identity with it, and / or

[0459] (ii) relative to having one, two, or three amino acid substitutions.

[0460] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO: 1. The specific binding molecule containing a CDR that is 100% identical to those given above is referred to herein as “S1F4”.

[0461] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0462] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0463] VHCDR2 contains the sequence listed in SEQ ID NO: 46 (GIDTDGEEGYNPALNS);

[0464] VHCDR3 contains the sequence listed in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0465] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0466] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS);

[0467] VLCDR3 contains the sequence listed in SEQ ID NO: 74 (GSSDRTQYTGV).

[0468] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0469] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0470] VHCDR2 contains the sequence listed in SEQ ID NO: 46 (GIDTDGEEGYNPALNS);

[0471] VHCDR3 contains the sequence listed in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0472] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0473] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS);

[0474] VLCDR3 contains the sequence listed in SEQ ID NO: 74 (GSSDRTQYTGV);

[0475] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0476] (i) having at least 85% identity with it, and / or

[0477] (ii) relative to having one, two, or three amino acid substitutions.

[0478] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “S1G10”.

[0479] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0480] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0481] VHCDR2 contains the sequence listed in SEQ ID NO: 46 (GIDTDGEEGYNPALNS);

[0482] VHCDR3 contains the sequence listed in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[0483] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0484] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS);

[0485] VLCDR3 contains the sequence listed in SEQ ID NO: 74 (GSSDRTQYTGV).

[0486] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0487] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0488] VHCDR2 contains the sequence listed in SEQ ID NO: 51 (GIDTDGEEGYNPALKS);

[0489] VHCDR3 contains the sequence listed in SEQ ID NO: 60 (TYRTDGFAYGYVQAIDY);

[0490] VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0491] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS);

[0492] VLCDR3 contains the sequence listed in SEQ ID NO: 74 (GSSDRTQYTGV);

[0493] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0494] (i) having at least 85% identity with it, and / or

[0495] (ii) relative to having one, two, or three amino acid substitutions.

[0496] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 367 to 379 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “S2C6”.

[0497] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0498] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[0499] VHCDR2 contains the sequence listed in SEQ ID NO: 51 (GIDTDGEEGYNPALKS);

[0500] VHCDR3 contains the sequence listed in SEQ ID NO: 60 (TYRTDGFAYGYVQAIDY); VLCDR1 contains the sequence listed in SEQ ID NO: 63 (SGSFIGISSVG);

[0501] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS);

[0502] VLCDR3 contains the sequence listed in SEQ ID NO: 74 (GSSDRTQYTGV).

[0503]

[0504]

[0505]

[0506] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0507] VHCDR1 contains the VHCDR1 amino acid sequence listed in Table 2;

[0508] VHCDR2 contains the VHCDR2 amino acid sequence listed in Table 2;

[0509] VHCDR3 contains the VHCDR3 amino acid sequence listed in Table 2;

[0510] VLCDR1 contains the VLCDR1 amino acid sequence listed in Table 2;

[0511] VLCDR2 contains the VLCDR2 amino acid sequence listed in Table 2; and

[0512] VLCDR3 contains the VLCDR3 amino acid sequence listed in Table 2;

[0513] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0514] (i) having at least 85% identity with it, and / or

[0515] (ii) relative to having one, two, or three amino acid substitutions.

[0516] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 367 to 379 of SEQ ID NO: 1.

[0517] 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. K D It can be less than approximately 400 pM, less than approximately 300 pM, or less than approximately 200 pM. K D K may preferably be combined with SEQ ID NO: 1 or SEQ ID NO: 5. D K combined with SEQ ID NO: 1 D It can be from approximately 100 pM to approximately 200 pM. K bound to 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 binding 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, and optionally the specific binding molecule includes the CDR of S1G2.

[0518] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 81. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 81.

[0519] SEQ ID NO: 81 (S1G2 amino acid sequence)

[0520] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKSGNTATLTISSLQAEDEADYFCGSSDRTPYTGVFGSGTRLTVLG

[0521] 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: 412, 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 412. The CDR may be 100% identical to 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 is 100% identical to the CDR of SEQ ID NO: 412. The specific binding molecule may include the amino acid sequence of SEQ ID NO: 412.

[0522] SEQ ID NO: 412 (S1B1 amino acid sequence)

[0523] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCVRSYRTDGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTVIVASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0524] 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: 413, 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 413. The CDR may be 100% identical to 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 is 100% identical to the CDR of SEQ ID NO: 413. The specific binding molecule may include the amino acid sequence of SEQ ID NO: 413.

[0525] SEQ ID NO: 413 (S1D9 amino acid sequence)

[0526] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDSDGEEGYNPALNSRLSITRDTSKNQVSLSLSRVTSEDTAVYYCGRTYRTDGYAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDRVMLTQPPSVSGSPGQTVSITCSGSFIGISSVGWFQQLPGSGLRTVIFASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLS

[0527] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 414. The CDR may be 100% identical to 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 is 100% identical to the CDR of SEQ ID NO: 414. The specific binding molecule may include the amino acid sequence of SEQ ID NO: 414.

[0528] SEQ ID NO: 414 (S1F4 amino acid sequence)

[0529] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCVRSYRADGLAYGYVQAIDYWGPGLLLTIS SEGKSSGASGESKVDDQAVVTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTVIVASDGRPSGVPDRFSNSKSGNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0530] 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: 415, 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 415. The CDR may be 100% identical to 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 is 100% identical to the CDR of SEQ ID NO: 415. The specific binding molecule may include the amino acid sequence of SEQ ID NO: 415.

[0531] SEQ ID NO: 415 (S1G10 amino acid sequence)

[0532] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALNSRLSITRDTSKSQVSLSLSSVTSEDTAVYYCGRSYRADGLAYGYVQAIDYWGPGLLVTVS SEGKSSGASGESKVDDQAVLTQPSSMSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0533] 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: 416, 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 416. The CDR may be 100% identical to 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 is 100% identical to the CDR of SEQ ID NO: 416. The specific binding molecule may include the amino acid sequence of SEQ ID NO: 416.

[0534] SEQ ID NO: 416 (S2C6 amino acid sequence)

[0535] QVQLQESGPSLVKPSQTLSLTCTVSGFSLISNSVGWVRQAPGKAPEWVAGIDTDGEEGYNPALKSQYAASDPDTSKSQVSLSLSSVTSEDTAVYYCGRTYRTDGFAYGYVQAIDYWGPGLLLTIS SEGKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSFIGISSVGWFQQLPGSGLRTIIVASDGRPSGVPDRFSMSKNTATLTISSLQAEDEADYFCGSSDRTQYTGVFGSGTRLTVLG

[0536] 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).

[0537] 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”.

[0538] 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).

[0539] 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).

[0540] 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:

[0541] VHCDR1 contains the sequence listed in SEQ ID NO: 83 (SYSVY);

[0542] VHCDR2 contains the sequence listed in SEQ ID NO: 84 (IMYASGRVDYNPALKS);

[0543] VHCDR3 contains the sequence listed in SEQ ID NO: 85 (GIEN / D);

[0544] VLCDR1 contains the sequence listed in SEQ ID NO: 86 (RTS / NQ / ES / NV / IN / G / DN / SY / GLS / A);

[0545] VLCDR2 contains the sequence listed in SEQ ID NO: 87 (YATYLY / HT);

[0546] VLCDR3 contains the sequence listed in SEQ ID NO: 88 (LQYD / G / ES / TTPLA / T);

[0547] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0548] (i) having at least 85% identity with it, and / or

[0549] (ii) relative to having one, two or three amino acid substitutions.

[0550] 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%.

[0551] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0552] VHCDR1 contains the sequence listed in SEQ ID NO: 83 (SYSVY);

[0553] VHCDR2 contains the sequence listed in SEQ ID NO: 84 (IMYASGRVDYNPALKS);

[0554] VHCDR3 contains the sequence listed in SEQ ID NO: 89 (GIEN) or SEQ ID NO: 90 (GIED);

[0555] VLCDR1 contains the sequences listed in SEQ ID NO: 91 (RTSQSVNNYLS), SEQ ID NO: 92 (RTNESVGNYLS), SEQ ID NO: 93 (RTSQNIDNGLA), or SEQ ID NO: 94 (RTSQSVGSYLS);

[0556] VLCDR2 contains the sequence listed in SEQ ID NO: 95 (YATRLYT) or SEQ ID NO: 96 (YATRLHT);

[0557] VLCDR3 contains the sequences listed in SEQ ID NO: 97 (LQYDSTPLA), SEQ ID NO: 98 (LQYDSTPLT), SEQ ID NO: 99 (LQYESTPLA), or SEQ ID NO: 100 (LQYGTTPLA);

[0558] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0559] (i) having at least 85% identity with it, and / or

[0560] (ii) relative to having one, two, or three amino acid substitutions.

[0561] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 337 to 368 of SEQ ID NO: 1.

[0562] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0563] VHCDR1 contains the sequence listed in SEQ ID NO: 83 (SYSVY);

[0564] VHCDR2 contains the sequence listed in SEQ ID NO: 84 (IMYASGRVDYNPALKS);

[0565] VHCDR3 contains the sequence listed in SEQ ID NO: 89(GIEN);

[0566] VLCDR1 contains the sequence listed in SEQ ID NO: 91 (RTSQSVNNYLS);

[0567] VLCDR2 contains the sequence listed in SEQ ID NO: 95 (YATRLYT);

[0568] VLCDR3 contains the sequence listed in SEQ ID NO: 97 (LQYDSTPLA);

[0569] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0570] (i) having at least 85% identity with it, and / or

[0571] (ii) relative to having one, two, or three amino acid substitutions.

[0572] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 337 to 368 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “NS2A3”.

[0573] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0574] VHCDR1 contains the sequence listed in SEQ ID NO: 83 (SYSVY);

[0575] VHCDR2 contains the sequence listed in SEQ ID NO: 84 (IMYASGRVDYNPALKS);

[0576] VHCDR3 contains the sequence listed in SEQ ID NO: 89(GIEN);

[0577] VLCDR1 contains the sequence listed in SEQ ID NO: 91 (RTSQSVNNYLS);

[0578] VLCDR2 contains the sequence listed in SEQ ID NO: 95 (YATRLYT); and

[0579] VLCDR3 contains the sequence listed in SEQ ID NO: 97 (LQYDSTPLA);

[0580]

[0581] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0582] VHCDR1 contains the VHCDR1 amino acid sequence listed in Table 3;

[0583] VHCDR2 contains the VHCDR2 amino acid sequence listed in Table 3;

[0584] VHCDR3 contains the VHCDR3 amino acid sequence listed in Table 3;

[0585] VLCDR1 contains the VLCDR1 amino acid sequence listed in Table 3;

[0586] VLCDR2 contains the VLCDR2 amino acid sequence listed in Table 3; and

[0587] VLCDR3 contains the VLCDR3 amino acid sequence listed in Table 3;

[0588] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0589] (i) having at least 85% identity with it, and / or

[0590] (ii) relative to having one, two, or three amino acid substitutions.

[0591] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 337 to 368 of SEQ ID NO: 1.

[0592] The specific binding molecule can be in the form of Kc at a concentration of less than 25 pM, preferably less than 20 nM, 15 nM or 10 nM. D It binds to polypeptide or protein molecules containing the amino acid sequence of residues 337 to 368 of SEQ ID NO: 1. DK may preferably be combined with SEQ ID NO: 1 or SEQ ID NO: 5. D .

[0593] 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).

[0594] 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”.

[0595] The epitope may contain the amino acid sequence of SEQ ID NO: 101 (KKIETHKLTFRENAKAKTDHGA). The epitope may contain an amino acid sequence that has 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).

[0596] 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).

[0597] The specific binding molecule can bind to polypeptide or protein molecules containing the amino acid sequence 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:

[0598] VHCDR1 contains the sequence listed in SEQ ID NO: 102 (RESIA);

[0599] VHCDR2 contains the sequence listed in SEQ ID NO: 103 (GVGIDGTSYYSPALKS);

[0600] VHCDR3 contains the sequence listed in SEQ ID NO: 104 (NYIDFEY);

[0601] VLCDR1 contains the sequence listed in SEQ ID NO: 105 (SGSS / N / YS / N / -N / -V / -G / IY / S / A / GE / G / SD / N / TY / G / DVN / S / G);

[0602] VLCDR2 contains the sequence listed in SEQ ID NO: 106 (G / RT / N / ST / SN / T / RRP / AS);

[0603] VLCDR3 contains the sequence listed in SEQ ID NO: 107 (L / A / GSYDR / T / G / SS / TG / NS / R / -N / G / S / IF / I / V);

[0604] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0605] (i) having at least 85% identity with it, and / or

[0606] (ii) relative to having one, two or three amino acid substitutions.

[0607] 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%.

[0608] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0609] VHCDR1 contains the sequence listed in SEQ ID NO: 102 (RESIA);

[0610] VHCDR2 contains the sequence listed in SEQ ID NO: 103 (GVGIDGTSYYSPALKS);

[0611] VHCDR3 contains the sequence listed in SEQ ID NO: 104 (NYIDFEY);

[0612] VLCDR1 contains the sequences listed in SEQ ID NO: 108 (SGSSSNVGYEDYVN), SEQ ID NO: 109 (SGSNIAGNGVG), SEQ ID NO: 110 (SGSSNNVGSGDYVS), or SEQ ID NO: 111 (SGSYIGSTDVG);

[0613] VLCDR2 contains the sequences listed in SEQ ID NO: 112 (GTTNRPS), SEQ ID NO: 113 (GSTRRPS), SEQ ID NO: 114 (RNSNRPS), or SEQ ID NO: 115 (RTTTRAS); and

[0614] VLCDR3 contains the sequences listed in SEQ ID NO: 116 (LSYDRSGSNF), SEQ ID NO: 117 (ASYDTSNRGI), SEQ ID NO: 118 (GSYDGTNSF), or SEQ ID NO: 119 (ASYDSNNSIV);

[0615] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0616] (i) having at least 85% identity with it, and / or

[0617] (ii) relative to having one, two, or three amino acid substitutions.

[0618] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 369 to 390 of SEQ ID NO: 1.

[0619] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0620] VHCDR1 contains the sequence listed in SEQ ID NO: 102 (RESIA);

[0621] VHCDR2 contains the sequence listed in SEQ ID NO: 103 (GVGIDGTSYYSPALKS);

[0622] VHCDR3 contains the sequence listed in SEQ ID NO: 104 (NYIDFEY);

[0623] VLCDR1 contains the sequence listed in SEQ ID NO: 108 (SGSSSNVGYEDYVN);

[0624] VLCDR2 contains the sequence listed in SEQ ID NO: 112 (GTTNRPS); and

[0625] VLCDR3 contains the sequence listed in SEQ ID NO: 116 (LSYDRSGSNF);

[0626] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0627] (i) having at least 85% identity with it, and / or

[0628] (ii) relative to having one, two, or three amino acid substitutions.

[0629] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 369 to 390 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “NS4E4”.

[0630] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0631] VHCDR1 contains the sequence listed in SEQ ID NO: 102 (RESIA);

[0632] VHCDR2 contains the sequence listed in SEQ ID NO: 103 (GVGIDGTSYYSPALKS);

[0633] VHCDR3 contains the sequence listed in SEQ ID NO: 104 (NYIDFEY);

[0634] VLCDR1 contains the sequence listed in SEQ ID NO: 108 (SGSSSNVGYEDYVN);

[0635] VLCDR2 contains the sequence listed in SEQ ID NO: 112 (GTTNRPS); and

[0636] VLCDR3 contains the sequence listed in SEQ ID NO: 116 (LSYDRSGSNF).

[0637]

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

[0639] VHCDR1 contains the VHCDR1 amino acid sequence listed in Table 4;

[0640] VHCDR2 contains the VHCDR2 amino acid sequence listed in Table 4;

[0641] VHCDR3 contains the VHCDR3 amino acid sequence listed in Table 4;

[0642] VLCDR1 contains the VLCDR1 amino acid sequence listed in Table 4;

[0643] VLCDR2 contains the VLCDR2 amino acid sequence listed in Table 4; and

[0644] VLCDR3 contains the VLCDR3 amino acid sequence listed in Table 4;

[0645] Alternatively, for each CDR sequence, there is 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 thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 369 to 390 of SEQ ID NO: 1.

[0649] The specific binding molecule can be in the form of Kc at a concentration of less than 25 pM, preferably less than 20 nM, 15 nM or 10 nM. D It binds to polypeptide or protein molecules containing the amino acid sequence of residues 369 to 390 of SEQ ID NO: 1. D K may preferably be combined with SEQ ID NO: 1 or SEQ ID NO: 5. D .

[0650] 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).

[0651] The 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”.

[0652] 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).

[0653] 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).

[0654] 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:

[0655] VHCDR1 contains the sequence listed in SEQ ID NO: 121 (S / ND / YS / G / AV / LA / G);

[0656] VHCDR2 contains the sequence listed in SEQ ID NO: 122 (A / NS / IG / Y / WS / RS / GGN / S / RK / T / IY / EYN PA LKS);

[0657] VHCDR3 contains the sequence listed in SEQ ID NO: 123 (GI / GI / VA / GG / SVDV) or SEQ ID NO: 124 (SGGD);

[0658] VLCDR1 contains the sequence listed in SEQ ID NO: 125 (SGS / GS / NNV / IGY / RGN / D / TY / FVG / D);

[0659] VLCDR2 contains the sequence listed in SEQ ID NO: 126 (GT / AA / D / TI / S / RRA / PS / P); and

[0660] VLCDR3 contains the sequence listed in SEQ ID NO: 127 (AS / TYQ / DS / Y / RN / SY / D / N / EA / G / D / S- / G / M / V- / IF / V / I);

[0661] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0662] (i) having at least 85% identity with it, and / or

[0663] (ii) relative to having one, two or three amino acid substitutions.

[0664] 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%.

[0665] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0666] VHCDR1 contains the sequence listed in SEQ ID NO: 128 (SDSVA), SEQ ID NO: 129 (NYGVG), or SEQ ID NO: 130 (SYALG);

[0667] VHCDR2 contains the sequences listed in SEQ ID NO: 131 (ASGSSGNKYYNPALKS), SEQ ID NO: 132 (NIWRGGRIEYNPALKS), or SEQ ID NO: 133 (NIYSGGSTYYNPALKS);

[0668] VHCDR3 includes the sequences listed in SEQ ID NO: 134 (GILAGVDV), SEQ ID NO: 135 (GGVGSVDV), or SEQ ID NO: 124 (SGGD);

[0669] VLCDR1 contains the sequences listed in SEQ ID NO: 39 (SGSSSNVGYGNYVG), SEQ ID NO: 137 (SGGRNNIGRGTFVD), and SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[0670] VLCDR2 contains the sequences listed in SEQ ID NO: 139 (GTAIRAS), SEQ ID NO: 140 (GAASRAS), SEQ ID NO: 141 (GATSRAS), or SEQ ID NO: 142 (GTDRRPP); and

[0671] VLCDR3 contains the sequences listed in SEQ ID NO: 143 (ASYQSNYAF), SEQ ID NO: 144 (ASYDRSESVV), SEQ ID NO: 145 (ASYDSSDGGV), or SEQ ID NO: 146 (ATYDYSNDMII);

[0672] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0673] (i) having at least 85% identity with it, and / or

[0674] (ii) relative to having one, two, or three amino acid substitutions.

[0675] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 412 to 441 of SEQ ID NO: 1.

[0676] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0677] VHCDR1 contains the sequence listed in SEQ ID NO: 128 (SDSVA);

[0678] VHCDR2 contains the sequence listed in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[0679] VHCDR3 contains the sequence listed in SEQ ID NO: 134 (GIIAGVDV);

[0680] VLCDR1 contains the sequence listed in SEQ ID NO: 39 (SGSSSNVGYGNYVG);

[0681] VLCDR2 contains the sequence listed in SEQ ID NO: 139 (GTAIRAS); and

[0682] VLCDR3 contains the sequence listed in SEQ ID NO: 143 (ASYQSNYAF);

[0683] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0684] (i) having at least 85% identity with it, and / or

[0685] (ii) relative to having one, two, or three amino acid substitutions.

[0686] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the CDRs given above is referred to herein as “412E10”.

[0687] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0688] VHCDR1 contains the sequence listed in SEQ ID NO: 128 (SDSVA);

[0689] VHCDR2 contains the sequence listed in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[0690] VHCDR3 contains the sequence listed in SEQ ID NO: 134 (GIIAGVDV);

[0691] VLCDR1 contains the sequence listed in SEQ ID NO: 39 (SGSSSNVGYGNYVG);

[0692] VLCDR2 contains the sequence listed in SEQ ID NO: 139 (GTAIRAS); and

[0693] VLCDR3 contains the sequence listed in SEQ ID NO: 143 (ASYQSNYAF).

[0694] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0695] VHFR1 contains the sequence listed in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[0696] VHFR2 contains the sequence listed in SEQ ID NO: 460 (WVRQAPGKVPEWLG);

[0697] VHFR3 contains the sequence listed in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[0698] VHFR4 contains the sequence listed in SEQ ID NO: 462 (WGRGLLVTVSS);

[0699] VLFR1 contains the sequence listed in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC);

[0700] VLFR2 contains the sequence listed in SEQ ID NO: 464 (WYQQVPGSAPKLLIY);

[0701] VLFR3 contains the sequence listed in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[0702] VLFR4 contains the sequence listed in SEQ ID NO: 466 (FGSGTRLTVLG);

[0703] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0704] (i) having at least 50% similarity with it, and / or

[0705] (ii) relative to having one, two, three, four or five amino acid substitutions.

[0706] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0707] VHFR1 contains the sequence listed in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[0708] VHFR2 contains the sequence listed in SEQ ID NO: 460 (WVRQAPGKVPEWLG);

[0709] VHFR3 contains the sequence listed in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[0710] VHFR4 contains the sequence listed in SEQ ID NO: 462 (WGRGLLVTVSS);

[0711] VLFR1 contains the sequence listed in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC);

[0712] VLFR2 contains the sequence listed in SEQ ID NO: 464 (WYQQVPGSAPKLLIY);

[0713] VLFR3 contains the sequence listed in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[0714] VLFR4 contains the sequence listed in SEQ ID NO: 466 (FGSGTRLTVLG);

[0715] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0716] (i) having at least 50% similarity with it, and / or

[0717] (ii) relative to having one, two, three, four, or five amino acid substitutions,

[0718] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO: 1. A specific binding molecule containing a FR that is 100% identical to the given FRs described above is referred to herein as “412E10”.

[0719] Specific binding molecules may include:

[0720] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0721] VHFR1 contains the sequence listed in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[0722] VHFR2 contains the sequence listed in SEQ ID NO: 460 (WVRQAPGKVPEWLG);

[0723] VHFR3 contains the sequence listed in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[0724] VHFR4 contains the sequence listed in SEQ ID NO: 462 (WGRGLLVTVSS);

[0725] VLFR1 contains the sequence listed in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC);

[0726] VLFR2 contains the sequence listed in SEQ ID NO: 464 (WYQQVPGSAPKLLIY);

[0727] VLFR3 contains the sequence listed in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[0728] VLFR4 contains the sequence listed in SEQ ID NO: 466 (FGSGTRLTVLG);

[0729] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0730] (i) having at least 50% similarity with it, and / or

[0731] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0732] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0733] VHCDR1 contains the sequence listed in SEQ ID NO: 128 (SDSVA);

[0734] VHCDR2 contains the sequence listed in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[0735] VHCDR3 contains the sequence listed in SEQ ID NO: 134 (GIIAGVDV);

[0736] VLCDR1 contains the sequence listed in SEQ ID NO: 39 (SGSSSNVGYGNYVG);

[0737] VLCDR2 contains the sequence listed in SEQ ID NO: 139 (GTAIRAS); and

[0738] VLCDR3 contains the sequence listed in SEQ ID NO: 143 (ASYQSNYAF);

[0739] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0740] (i) having at least 85% identity with it, and / or

[0741] (ii) relative to having one, two, or three amino acid substitutions.

[0742] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “412E10”.

[0743] Specific binding molecules may include:

[0744] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0745] VHFR1 contains the sequence listed in SEQ ID NO: 459 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVI);

[0746] VHFR2 contains the sequence listed in SEQ ID NO: 460 (WVRQAPGKVPEWLG);

[0747] VHFR3 contains the sequence listed in SEQ ID NO: 461 (RLSITRDTSKSQVSLSLSSVTTEDTAVYYCAR);

[0748] VHFR4 contains the sequence listed in SEQ ID NO: 462 (WGRGLLVTVSS);

[0749] VLFR1 contains the sequence listed in SEQ ID NO: 463 (QAVLTQPSSVSGSLGQRVSITC);

[0750] VLFR2 contains the sequence listed in SEQ ID NO: 464 (WYQQVPGSAPKLLIY);

[0751] VLFR3 contains the sequence listed in SEQ ID NO: 465 (GVPDRFSGSRSGDTATLTITSLQAEDEADYYC);

[0752] VLFR4 contains the sequence listed in SEQ ID NO: 466 (FGSGTRLTVLG);

[0753] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0754] (i) having at least 50% similarity with it, and / or

[0755] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0756] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0757] VHCDR1 contains the sequence listed in SEQ ID NO: 128 (SDSVA);

[0758] VHCDR2 contains the sequence listed in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[0759] VHCDR3 contains the sequence listed in SEQ ID NO: 134 (GIIAGVDV);

[0760] VLCDR1 contains the sequence listed in SEQ ID NO: 39 (SGSSSNVGYGNYVG);

[0761] VLCDR2 contains the sequence listed in SEQ ID NO: 139 (GTAIRAS); and

[0762] VLCDR3 contains the sequence listed in SEQ ID NO: 143 (ASYQSNYAF);

[0763] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “412E10”.

[0764] Specific binding molecules may include:

[0765] (a) A VH domain containing the sequence listed in SEQ ID NO: 467 (QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVTVSS); and / or

[0766] (b) A VL domain containing the sequence listed in SEQ ID NO: 468 (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLG);

[0767] Or its humanized variants.

[0768] Specific binding molecules may include:

[0769] (a) Heavy chain, the heavy chain comprising SEQ ID NO:469(QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRG LLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCPP The sequences listed in CKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) are listed; and / or

[0770] (b) A light chain containing the sequences listed in SEQ ID NO: 470 (QAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS);

[0771] Or its humanized variants.

[0772] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0773] VHCDR1 contains the sequence listed in SEQ ID NO: 128 (SDSVA);

[0774] VHCDR2 contains the sequence listed in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[0775] VHCDR3 contains the sequence listed in SEQ ID NO: 134 (GIIAGVDV);

[0776] VLCDR1 contains the sequence listed in SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[0777] VLCDR2 contains the sequence listed in SEQ ID NO: 140 (GAASRAS); and

[0778] VLCDR3 contains the sequence listed in SEQ ID NO: 145 (ASYDSSDGGV);

[0779] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0780] (i) having at least 85% identity with it, and / or

[0781] (ii) relative to having one, two, or three amino acid substitutions.

[0782] The specific binding molecule thereunder 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 given CDRs is referred to herein as “412B9”.

[0783] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0784] VHCDR1 contains the sequence listed in SEQ ID NO: 128 (SDSVA);

[0785] VHCDR2 contains the sequence listed in SEQ ID NO: 131 (ASGSSGNKYYNPALKS);

[0786] VHCDR3 contains the sequence listed in SEQ ID NO: 134 (GIIAGVDV);

[0787] VLCDR1 contains the sequence listed in SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[0788] VLCDR2 contains the sequence listed in SEQ ID NO: 140 (GAASRAS); and

[0789] VLCDR3 contains the sequence listed in SEQ ID NO: 145 (ASYDSSDGGV).

[0790] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0791] VHCDR1 contains the sequence listed in SEQ ID NO: 129 (NYGVG);

[0792] VHCDR2 contains the sequence listed in SEQ ID NO: 133 (NIYSGGSTYYNPALKS);

[0793] VHCDR3 contains the sequence listed in SEQ ID NO: 135 (GGVGSVDV);

[0794] VLCDR1 contains the sequence listed in SEQ ID NO: 137 (SGGRNNIGRGTFVD);

[0795] VLCDR2 contains the sequence listed in SEQ ID NO: 142 (GTDRRPP); and

[0796] VLCDR3 contains the sequence listed in SEQ ID NO: 146 (ATYDYSNDMII);

[0797] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0798] (i) having at least 85% identity with it, and / or

[0799] (ii) relative to having one, two, or three amino acid substitutions.

[0800] The specific binding molecule thereunder 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 CDRs given above is referred to herein as “412E6”.

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

[0802] VHCDR1 contains the sequence listed in SEQ ID NO: 129 (NYGVG);

[0803] VHCDR2 contains the sequence listed in SEQ ID NO: 133 (NIYSGGSTYYNPALKS);

[0804] VHCDR3 contains the sequence listed in SEQ ID NO: 135 (GGVGSVDV);

[0805] VLCDR1 contains the sequence listed in SEQ ID NO: 137 (SGGRNNIGRGTFVD);

[0806] VLCDR2 contains the sequence listed in SEQ ID NO: 142 (GTDRRPP); and

[0807] VLCDR3 contains the sequence listed in SEQ ID NO: 146 (ATYDYSNDMII).

[0808] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0809] VHCDR1 contains the sequence listed in SEQ ID NO: 130 (SYALG);

[0810] VHCDR2 contains the sequence listed in SEQ ID NO: 132 (NIWRGGRIEYNPALKS);

[0811] VHCDR3 contains the sequence listed in SEQ ID NO: 124 (SGGD);

[0812] VLCDR1 contains the sequence listed in SEQ ID NO: 39 (SGSSSNVGYGNYVG);

[0813] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS); and

[0814] VLCDR3 contains the sequence listed in SEQ ID NO: 144 (ASYDRSESVV);

[0815] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0816] (i) having at least 85% identity with it, and / or

[0817] (ii) relative to having one, two, or three amino acid substitutions.

[0818] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 412 to 441 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the CDRs given above is referred to herein as “412G11”.

[0819] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0820] VHCDR1 contains the sequence listed in SEQ ID NO: 130 (SYALG);

[0821] VHCDR2 contains the sequence listed in SEQ ID NO: 132 (NIWRGGRIEYNPALKS);

[0822] VHCDR3 contains the sequence listed in SEQ ID NO: 124 (SGGD);

[0823] VLCDR1 contains the sequence listed in SEQ ID NO: 39 (SGSSSNVGYGNYVG);

[0824] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS); and

[0825] VLCDR3 contains the sequence listed in SEQ ID NO: 144 (ASYDRSESVV).

[0826]

[0827] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0828] VHCDR1 contains the VHCDR1 amino acid sequence listed in Table 5;

[0829] VHCDR2 contains the VHCDR2 amino acid sequence listed in Table 5;

[0830] VHCDR3 contains the VHCDR3 amino acid sequence listed in Table 5;

[0831] VLCDR1 contains the VLCDR1 amino acid sequence listed in Table 5;

[0832] VLCDR2 contains the VLCDR2 amino acid sequence listed in Table 5; and

[0833] VLCDR3 contains the VLCDR3 amino acid sequence listed in Table 5;

[0834] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0835] (i) having at least 85% identity with it, and / or

[0836] (ii) relative to having one, two, or three amino acid substitutions.

[0837] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 412 to 441 of SEQ ID NO: 1.

[0838] 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. K D K may preferably be combined with SEQ ID NO: 1 or SEQ ID NO: 120 D K combined with 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 about 3.16 nM or 9.0 nM, and optionally the specific binding molecule contains a CDR of 412E10.

[0839] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 147. The CDR may be 100% identical to 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 is 100% identical to the CDR of SEQ ID NO: 147. The specific binding molecule may include the amino acid sequence of SEQ ID NO: 147.

[0840] SEQ ID NO: 147 (412E10 amino acid sequence)

[0841] QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGTAIRASGVPDRFSGSRSGDTATLTITSLQAEDEADYYCASYQSNYAFFGSGTRLTVLG

[0842] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 417. The CDR may be 100% identical to 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 is 100% identical to the CDR of SEQ ID NO: 417. The specific binding molecule may include the amino acid sequence of SEQ ID NO: 417.

[0843] SEQ ID NO: 417 (412B9 amino acid sequence)

[0844] QVQLQESGPSLVKPSQTLSLTCTVSGFSVISDSVAWVRQAPGKVPEWLGASGSSGNKYYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCARGIIAGVDVWGRGLLVSVSSEGKSS GASGESKVDDQAVLTQPSSVSGALGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYGAASRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSSDGGVFGSGTRLTVLG

[0845] 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 the amino acid sequence containing residues 412 to 441 of SEQ ID NO: 1. The CDR of the specific binding molecule may be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 418. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 418.

[0846] SEQ ID NO: 418 (412E6 amino acid sequence)

[0847] QVQLQESGPSLVKPSETLSLTCTVSGFSLTNYGVGWVRQAPGKALEWLGNIYSGGSTYYNPALKSRLSITRDTSKSQVSLSLNSVTLEDTAVYYCRGGGVGSVDVWGPGLLVTVSSEGKSS GASGESKVDDQAVLTQPPSVSGSPGQRVSITCSGGRNNIGRGTFVDWYQQLPGSGLKTVIYGTDRRPPGVPDRFSGSKTGNAATLTITSLQAEDEADYWCATYDYSNDMIILGSGTRLTVLG

[0848] 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 the amino acid sequence containing residues 412 to 441 of SEQ ID NO: 1. The CDR of the specific binding molecule may be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 434. The CDR may be 100% identical to 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 is 100% identical to the CDR of SEQ ID NO: 434. The specific binding molecule may include the amino acid sequence of SEQ ID NO: 434.

[0849] SEQ ID NO: 434 (412G11 amino acid sequence)

[0850] QVRLQESGPSLVKPSQTLSLTCTVSGFSLTSYALGWVRQAPGRAPEWIGNIWRGGRIEYNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCSRSGGDWGPGLLVTVSSEGKSSGA SGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWYQQVPGSAPKLLIYGATSRASGVPDRFSGSRSENTATLTISSLQAEDEADYYCASYDRSESVVFGSGTRLTVLG

[0851] 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 located within the amino acid sequence containing residues 1 to 49 of SEQ ID NO: 1 may be located within the amino acid sequence containing residues 1 to 15 of SEQ ID NO: 1.

[0852] The epitope may 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”.

[0853] 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 may bind to the CDR of a specific binding molecule referred to herein as “3bG4”.

[0854] 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).

[0855] 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).

[0856] 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:

[0857] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[0858] VHCDR2 contains the sequence listed in SEQ ID NO: 150 (DIS / AS S / V / GGKA / K / VYA / S / GN / HPAL KS);

[0859] VHCDR3 contains the sequence listed in SEQ ID NO: 151 (CRDGGVS / TYGYDI / SDY);

[0860] VLCDR1 contains the sequence listed in SEQ ID NO: 152 (SGSS / TS / GNI / VGG / S / YGN / DY / DL / VS / G);

[0861] VLCDR2 contains the sequence listed in SEQ ID NO: 153 (GA / VTS / N / ER / L AS); and

[0862] VLCDR3 contains the sequence listed in SEQ ID NO: 154 (A / GSF / YDT / S / DS / NSGGI / V);

[0863] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0864] (i) having at least 85% identity with it, and / or

[0865] (ii) relative to having one, two or three amino acid substitutions.

[0866] 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%.

[0867] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0868] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[0869] VHCDR2 contains the sequences listed in SEQ ID NO: 155 (DISSSGKAYANPALKS), SEQ ID NO: 156 (DISSGGKVYGHPALKS), SEQ ID NO: 157 (DISSVGKKYANPALKS), or SEQ ID NO: 158 (DIASSGKAYSNPALKS);

[0870] VHCDR3 contains the sequences listed in SEQ ID NO: 159 (CRDGGVSYGYDIDY), SEQ ID NO: 160 (CRDGGVSYGYDSDY), or SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[0871] VLCDR1 contains the sequences listed in SEQ ID NO: 163 (SGSSSNIGGGNYLS), SEQ ID NO: 138 (SGSSSNVGYGDYVG), SEQ ID NO: 165 (SGSSGNVGYGDYVS), or SEQ ID NO: 166 (SGSTSNVGSGNDVS);

[0872] VLCDR2 contains the sequences listed in SEQ ID NO: 141 (GATSRAS), SEQ ID NO: 168 (GVTERAS), SEQ ID NO: 169 (GATNLAS), or SEQ ID NO: 170 (GATNRAS); and

[0873] VLCDR3 contains the sequences listed in SEQ ID NO: 171 (ASFDTSSGGI), SEQ ID NO: 172 (ASYDDSSGGI), SEQ ID NO: 173 (ASYDSSSGGV), or SEQ ID NO: 174 (GSYDSNSGGI);

[0874] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0875] (i) having at least 85% identity with it, and / or

[0876] (ii) relative to having one, two, or three amino acid substitutions.

[0877] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 1 to 49 of SEQ ID NO: 1.

[0878] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0879] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[0880] VHCDR2 contains the sequence listed in SEQ ID NO: 155 (DISSSGKAYANPALKS);

[0881] VHCDR3 contains the sequence listed in SEQ ID NO: 159 (CRDGGVSYGYDIDY);

[0882] VLCDR1 contains the sequence listed in SEQ ID NO: 163 (SGSSSNIGGGNYLS);

[0883] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS); and

[0884] VLCDR3 contains the sequence listed in SEQ ID NO: 171 (ASFDTSSGGI);

[0885] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0886] (i) having at least 85% identity with it, and / or

[0887] (ii) relative to having one, two, or three amino acid substitutions.

[0888] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 49 of SEQ ID NO: 1. A specific binding molecule comprising a CDR having 100% identity with the CDRs given above is referred to herein as “3aG3”.

[0889] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0890] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[0891] VHCDR2 contains the sequence listed in SEQ ID NO: 155 (DISSSGKAYANPALKS);

[0892] VHCDR3 contains the sequence listed in SEQ ID NO: 159 (CRDGGVSYGYDIDY);

[0893] VLCDR1 contains the sequence listed in SEQ ID NO: 163 (SGSSSNIGGGNYLS);

[0894] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS); and

[0895] VLCDR3 contains the sequence listed in SEQ ID NO: 171 (ASFDTSSGGI).

[0896] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0897] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[0898] VHCDR2 contains the sequence listed in SEQ ID NO: 156 (DISSGGKVYGHPALKS).

[0899] VHCDR3 contains the sequence listed in SEQ ID NO: 160 (CRDGGVSYGYDSDY);

[0900] VLCDR1 contains the sequence listed in SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[0901] VLCDR2 contains the sequence listed in SEQ ID NO: 168 (GVTERAS); and

[0902] VLCDR3 contains the sequence listed in SEQ ID NO: 172 (ASYDDSSGGI);

[0903] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0904] (i) having at least 85% identity with it, and / or

[0905] (ii) relative to having one, two, or three amino acid substitutions.

[0906] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 49 of SEQ ID NO: 1. A specific binding molecule comprising a CDR having 100% identity with the CDRs given above is referred to herein as “3aD3”.

[0907] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0908] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[0909] VHCDR2 contains the sequence listed in SEQ ID NO: 156 (DISSGGKVYGHPALKS).

[0910] VHCDR3 contains the sequence listed in SEQ ID NO: 160 (CRDGGVSYGYDSDY);

[0911] VLCDR1 contains the sequence listed in SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[0912] VLCDR2 contains the sequence listed in SEQ ID NO: 168 (GVTERAS); and

[0913] VLCDR3 contains the sequence listed in SEQ ID NO: 172 (ASYDDSSGGI).

[0914] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0915] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[0916] VHCDR2 contains the sequence listed in SEQ ID NO: 157 (DISSVGKKYANPALKS).

[0917] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[0918] VLCDR1 contains the sequence listed in SEQ ID NO: 165 (SGSSGNVGYGDYVS);

[0919] VLCDR2 contains the sequence listed in SEQ ID NO: 169 (GATNLAS); and

[0920] VLCDR3 contains the sequence listed in SEQ ID NO: 173 (ASYDSSSGGV);

[0921] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0922] (i) having at least 85% identity with it, and / or

[0923] (ii) relative to having one, two, or three amino acid substitutions.

[0924] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 49 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “3aH6”.

[0925] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0926] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[0927] VHCDR2 contains the sequence listed in SEQ ID NO: 157 (DISSVGKKYANPALKS).

[0928] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[0929] VLCDR1 contains the sequence listed in SEQ ID NO: 165 (SGSSGNVGYGDYVS);

[0930] VLCDR2 contains the sequence listed in SEQ ID NO: 169 (GATNLAS); and

[0931] VLCDR3 contains the sequence listed in SEQ ID NO: 173 (ASYDSSSGGV).

[0932] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0933] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[0934] VHCDR2 contains the sequence listed in SEQ ID NO: 158 (DIASSGKAYSNPALKS).

[0935] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[0936] VLCDR1 contains the sequence listed in SEQ ID NO: 166 (SGSTSNVGSGNDVS);

[0937] VLCDR2 contains the sequence listed in SEQ ID NO: 170 (GATNRAS); and

[0938] VLCDR3 contains the sequence listed in SEQ ID NO: 174 (GSYDSNSGGI);

[0939] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0940] (i) having at least 85% identity with it, and / or

[0941] (ii) relative to having one, two, or three amino acid substitutions.

[0942] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 49 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to those given above is referred to herein as “3bG4”.

[0943] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[0944] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[0945] VHCDR2 contains the sequence listed in SEQ ID NO: 158 (DIASSGKAYSNPALKS).

[0946] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[0947] VLCDR1 contains the sequence listed in SEQ ID NO: 166 (SGSTSNVGSGNDVS);

[0948] VLCDR2 contains the sequence listed in SEQ ID NO: 170 (GATNRAS); and

[0949] VLCDR3 contains the sequence listed in SEQ ID NO: 174 (GSYDSNSGGI).

[0950] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0951] VHFR1 contains the sequence listed in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[0952] VHFR2 contains the sequence listed in SEQ ID NO: 472 (WVRQAPGKVPEWVG);

[0953] VHFR3 contains the sequence listed in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[0954] VHFR4 contains the sequence listed in SEQ ID NO: 474 (WGPGLLVTVSS);

[0955] VLFR1 contains the sequence listed in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC);

[0956] VLFR2 contains the sequence listed in SEQ ID NO: 476 (WFQQVPGSAPKLLFY);

[0957] VLFR3 contains the sequence listed in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[0958] VLFR4 contains the sequence listed in SEQ ID NO: 478 (FGSGTRLTVLG);

[0959] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0960] (i) having at least 50% similarity with it, and / or

[0961] (ii) relative to having one, two, three, four or five amino acid substitutions.

[0962] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0963] VHFR1 contains the sequence listed in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[0964] VHFR2 contains the sequence listed in SEQ ID NO: 472 (WVRQAPGKVPEWVG);

[0965] VHFR3 contains the sequence listed in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[0966] VHFR4 contains the sequence listed in SEQ ID NO: 474 (WGPGLLVTVSS);

[0967] VLFR1 contains the sequence listed in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC);

[0968] VLFR2 contains the sequence listed in SEQ ID NO: 476 (WFQQVPGSAPKLLFY);

[0969] VLFR3 contains the sequence listed in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[0970] VLFR4 contains the sequence listed in SEQ ID NO: 478 (FGSGTRLTVLG);

[0971] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0972] (i) having at least 50% similarity with it, and / or

[0973] (ii) relative to having one, two, three, four, or five amino acid substitutions,

[0974] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 49 of SEQ ID NO: 1. A specific binding molecule comprising a FR having 100% identity with the given FRs described above is referred to herein as “3bG4”.

[0975] Specific binding molecules may include:

[0976] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[0977] VHFR1 contains the sequence listed in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[0978] VHFR2 contains the sequence listed in SEQ ID NO: 472 (WVRQAPGKVPEWVG);

[0979] VHFR3 contains the sequence listed in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[0980] VHFR4 contains the sequence listed in SEQ ID NO: 474 (WGPGLLVTVSS);

[0981] VLFR1 contains the sequence listed in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC);

[0982] VLFR2 contains the sequence listed in SEQ ID NO: 476 (WFQQVPGSAPKLLFY);

[0983] VLFR3 contains the sequence listed in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[0984] VLFR4 contains the sequence listed in SEQ ID NO: 478 (FGSGTRLTVLG);

[0985] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[0986] (i) having at least 50% similarity with it, and / or

[0987] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[0988] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[0989] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[0990] VHCDR2 contains the sequence listed in SEQ ID NO: 158 (DIASSGKAYSNPALKS).

[0991] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[0992] VLCDR1 contains the sequence listed in SEQ ID NO: 166 (SGSTSNVGSGNDVS);

[0993] VLCDR2 contains the sequence listed in SEQ ID NO: 170 (GATNRAS); and

[0994] VLCDR3 contains the sequence listed in SEQ ID NO: 174 (GSYDSNSGGI);

[0995] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[0996] (i) having at least 85% identity with it, and / or

[0997] (ii) relative to having one, two, or three amino acid substitutions.

[0998] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 49 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “3bG4”.

[0999] Specific binding molecules may include:

[1000] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1001] VHFR1 contains the sequence listed in SEQ ID NO: 471 (QVQLQESGPSLVKPSQTLSLTCTISGFSLI);

[1002] VHFR2 contains the sequence listed in SEQ ID NO: 472 (WVRQAPGKVPEWVG);

[1003] VHFR3 contains the sequence listed in SEQ ID NO: 473 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCVR);

[1004] VHFR4 contains the sequence listed in SEQ ID NO: 474 (WGPGLLVTVSS);

[1005] VLFR1 contains the sequence listed in SEQ ID NO: 475 (QAVLTQPSSVSKSLGQSVSITC);

[1006] VLFR2 contains the sequence listed in SEQ ID NO: 476 (WFQQVPGSAPKLLFY);

[1007] VLFR3 contains the sequence listed in SEQ ID NO: 477 (GVPDRFSGSRSGNTATLTITSLQAEDEADYYC);

[1008] VLFR4 contains the sequence listed in SEQ ID NO: 478 (FGSGTRLTVLG);

[1009] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1010] (i) having at least 50% similarity with it, and / or

[1011] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1012] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1013] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[1014] VHCDR2 contains the sequence listed in SEQ ID NO: 158 (DIASSGKAYSNPALKS).

[1015] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1016] VLCDR1 contains the sequence listed in SEQ ID NO: 166 (SGSTSNVGSGNDVS);

[1017] VLCDR2 contains the sequence listed in SEQ ID NO: 170 (GATNRAS); and

[1018] VLCDR3 contains the sequence listed in SEQ ID NO: 174 (GSYDSNSGGI);

[1019] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 49 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “3bG4”.

[1020] Specific binding molecules may include:

[1021] (a) A VH domain containing the sequence listed in SEQ ID NO: 479 (QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPGLLVTVSS); and / or

[1022] (b) A VL domain containing the sequence listed in SEQ ID NO: 480 (QAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLG);

[1023] Or its humanized variants.

[1024] Specific binding molecules may include:

[1025] (a) Heavy chain, the heavy chain comprising SEQ ID NO:481(QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDID YWGPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKP The sequences listed in CPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) are listed; and / or

[1026] (b) A light chain containing the sequences listed in SEQ ID NO: 482 (QAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS);

[1027] Or its humanized variants.

[1028]

[1029] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1030] VHCDR1 contains the VHCDR1 amino acid sequence listed in Table 6;

[1031] VHCDR2 contains the VHCDR2 amino acid sequence listed in Table 6;

[1032] VHCDR3 contains the VHCDR3 amino acid sequence listed in Table 6;

[1033] VLCDR1 contains the VLCDR1 amino acid sequence listed in Table 6;

[1034] VLCDR2 contains the VLCDR2 amino acid sequence listed in Table 6; and

[1035] VLCDR3 contains the VLCDR3 amino acid sequence listed in Table 6;

[1036] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1037] (i) having at least 85% identity with it, and / or

[1038] (ii) relative to having one, two, or three amino acid substitutions.

[1039] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 1 to 49 of SEQ ID NO: 1.

[1040] 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. K D K may preferably be combined with SEQ ID NO: 1 or SEQ ID NO: 148 D K combined 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, optionally wherein the specifically binding molecule comprises a CDR of 3aD3. K binding to SEQ ID NO: 1 D It can be approximately 3.6 nM, optionally wherein the specifically binding molecule comprises a CDR of 3aH6. K binding to SEQ ID NO: 1 D It can be approximately 6.1 nM, optionally wherein the specifically binding molecule comprises a CDR of 3aG3. K binds to SEQ ID NO: 1. DIt can be approximately 8.9 nM, and optionally the specific binding molecule contains a 3bG4 CDR.

[1041] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 422. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 422.

[1042] SEQ ID NO: 422 (3aD3 amino acid sequence)

[1043] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNGVGWVRRAPGKVPEWVGDISSGGKVYGHPALKSRLSITRDTSKSQVSLSVSSVTSEDTAVYYCVRCRDGGVSYGYDSDYWGPGLLVTVSSEG KSSGASGESKVDDQAVVTQPSSVSKSLGQSVSITCSGSSSNVGYGDYVGWFQQVPGSAPKLLIYGVTERASGVPDRFSGSRSGNTATLTISSIQAEDEADYYCASYDDSSGGIFGSGTRLTVLG

[1044] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 423. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 423.

[1045] SEQ ID NO: 423 (3aH6 amino acid sequence)

[1046] QVQLQESGPSLVKPSQTLSLTCTVSGGFSLSSNGVGWVRQAPGKVPEWLGDISSVGKKYANPALKSRLSFTRDTSKSQVSLSLSSVTTEDTAVYYCVKCRDGGVTYGYDIDYWGPGLLVTASSEG KSSGASGESKVDDQAVVTQPSSVSGSLGQSVSITCSGSSGNVGYGDYVSWFQQFHGSAPKLLIYGATNLASGVPARFSGSRSGNTATLTISSLHAEDEADYYCASYDSSSGGVFGSGTRLTVLG

[1047] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 424. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 424.

[1048] SEQ ID NO: 424 (3aG3 amino acid sequence)

[1049] QVQLQESGPSLVKPSQTLSLTCTVSGFSLSSNGVGWVRQAPGKVPEWVGDISSSGKAYANPALKSRLSITRDTAKTQVFLSLSSVTTEDTAVYYCVRCRDGGVSYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPPSVSGSPGQRVSITCGSSSSNIGGGNYLSWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASFDTSSGGIFGAGTRLTVLG

[1050] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 425. The CDR may be 100% identical to the CDR of SEQ ID NO: 425. 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: 425, wherein the CDR is 100% identical to the CDR of SEQ ID NO: 425. The specific binding molecule may include the amino acid sequence of SEQ ID NO: 425.

[1051] SEQ ID NO: 425 (3bG4 amino acid sequence)

[1052] QVQLQESGPSLVKPSQTLSLTCTISGFSLISNGVGWVRQAPGKVPEWVGDIASSGKAYSNPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCVRCRDGGVTYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSLGQSVSITCSGSTSNVGSGNDVSWFQQVPGSAPKLLFYGATNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCGSYDSNSGGIFGSGTRLTVLG

[1053] 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).

[1054] The epitope may 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”.

[1055] 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).

[1056] 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).

[1057] 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:

[1058] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[1059] VHCDR2 contains the sequence listed in SEQ ID NO: 176 (DI / KSSV / AG KK / TYA / GNPALKS);

[1060] VHCDR3 contains the sequence listed in SEQ ID NO: 177 (CRDGGVTYGYDI / VDY);

[1061] VLCDR1 contains the sequence listed in SEQ ID NO: 178 (SGSSSNVGL / YR / GN / DY / VVT / S);

[1062] VLCDR2 contains the sequence listed in SEQ ID NO: 179 (GA / TTS / TRAS); and

[1063] VLCDR3 contains the sequence listed in SEQ ID NO: 180 (ASA / FDT / SN / DD / SGGV / I);

[1064] Alternatively, for each CDR sequence, there is 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 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%.

[1068] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1069] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[1070] VHCDR2 contains the sequence listed in SEQ ID NO: 157 (DISSVGKKYANPALKS) or SEQ ID NO: 182 (DKSSAGKTYGNPALKS);

[1071] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY) or SEQ ID NO: 184 (CRDGGVTYGYDVDY);

[1072] VLCDR1 contains the sequence listed in SEQ ID NO: 185 (SGSSSNVGLRNYVT) or SEQ ID NO: 186 (SGSSSNVGYGDVVS);

[1073] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS) or SEQ ID NO: 188 (GTTTRAS); and

[1074] VLCDR3 contains the sequence listed in SEQ ID NO: 189 (ASADTNDGGV) or SEQ ID NO: 190 (ASFDSDSGGI);

[1075] Alternatively, for each CDR sequence, there is 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 thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 49 to 111 of SEQ ID NO: 1.

[1079] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1080] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[1081] VHCDR2 contains the sequence listed in SEQ ID NO: 157 (DISSVGKKYANPALKS).

[1082] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1083] VLCDR1 contains the sequence listed in SEQ ID NO: 185 (SGSSSNVGLRNYVT);

[1084] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS); and

[1085] VLCDR3 contains the sequence listed in SEQ ID NO: 189 (ASADTNDGGV);

[1086] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1087] (i) having at least 85% identity with it, and / or

[1088] (ii) relative to having one, two, or three amino acid substitutions.

[1089] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 49 to 111 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the CDRs given above is referred to herein as “3bF4”.

[1090] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1091] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[1092] VHCDR2 contains the sequence listed in SEQ ID NO: 157 (DISSVGKKYANPALKS).

[1093] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1094] VLCDR1 contains the sequence listed in SEQ ID NO: 186 (SGSSSNVGYGDVVS);

[1095] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS); and

[1096] VLCDR3 contains the sequence listed in SEQ ID NO: 189 (ASADTNDGGV).

[1097] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1098] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[1099] VHCDR2 contains the sequence listed in SEQ ID NO: 182 (DKSSAGKTYGNPALKS).

[1100] VHCDR3 contains the sequence listed in SEQ ID NO: 184 (CRDGGVTYGYDVDY).

[1101] VLCDR1 contains the sequence listed in SEQ ID NO: 186 (SGSSSNVGYGDVVS);

[1102] VLCDR2 contains the sequence listed in SEQ ID NO: 188 (GTTTRAS); and

[1103] VLCDR3 contains the sequence listed in SEQ ID NO: 190 (ASFDSDSGGI);

[1104] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1105] (i) having at least 85% identity with it, and / or

[1106] (ii) relative to having one, two, or three amino acid substitutions.

[1107] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 49 to 111 of SEQ ID NO: 1. A specific binding molecule comprising a CDR having 100% identity with the CDRs given above is referred to herein as “3aB7”.

[1108] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1109] VHCDR1 contains the sequence listed in SEQ ID NO: 149 (SNGVG);

[1110] VHCDR2 contains the sequence listed in SEQ ID NO: 182 (DKSSAGKTYGNPALKS).

[1111] VHCDR3 contains the sequence listed in SEQ ID NO: 184 (CRDGGVTYGYDVDY).

[1112] VLCDR1 contains the sequence listed in SEQ ID NO: 186 (SGSSSNVGYGDVVS);

[1113] VLCDR2 contains the sequence listed in SEQ ID NO: 188 (GTTTRAS); and

[1114] VLCDR3 contains the sequence listed in SEQ ID NO: 190 (ASFDSDSGGI).

[1115]

[1116] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1117] VHCDR1 contains the VHCDR1 amino acid sequence listed in Table 7;

[1118] VHCDR2 contains the VHCDR2 amino acid sequence listed in Table 7;

[1119] VHCDR3 contains the VHCDR3 amino acid sequence listed in Table 7;

[1120] VLCDR1 contains the VLCDR1 amino acid sequence listed in Table 7;

[1121] VLCDR2 contains the VLCDR2 amino acid sequence listed in Table 7; and

[1122] VLCDR3 contains the VLCDR3 amino acid sequence listed in Table 7;

[1123] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1124] (i) having at least 85% identity with it, and / or

[1125] (ii) relative to having one, two, or three amino acid substitutions.

[1126] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 49 to 111 of SEQ ID NO: 1.

[1127] 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. D It can be less than approximately 200 nM, less than approximately 150 nM, or less than approximately 100 nM. K D K may preferably be combined with SEQ ID NO: 1 or SEQ ID NO: 175. D K combined 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 DIt can be approximately 69 nM, optionally wherein the specifically binding molecule comprises a CDR of 3aB7. K binding to SEQ ID NO: 1 D It can be approximately 140 nM, and optionally the specific binding molecule contains a CDR of 3bF4.

[1128] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 420. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 420.

[1129] SEQ ID NO: 420 (3aB7 amino acid sequence)

[1130] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNGVGWVRQAPGKVPEWVGDKSSAGKTYGNPALKSRLSITRDTSKSQVSLSLSSVTTEDTAVYYCVRCRDGGVTYGYDVDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSLGQSVSITCSGSSSNVGYGDVVSWFQQFPGSAPKLLIFGTTTRASGVPDRFSGSRSGNAATLTINSLQAEDEADYYCASFDSDSGGIAGSGTRLTVLG

[1131] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 421. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 421.

[1132] SEQ ID NO: 421 (3bF4 amino acid sequence)

[1133] QVQLQESGPSLVKPSQTLSLTCTVSGGFSLSSNGVGWVRQAPGKVPEWLGDISSVGKKYANPALKSRLSFTRDTSKSQVSLSLSSVTTEDTAVYYCVKCRDGGVTYGYDIDYWGPGLLVTVSSEG KSSGASGESKVDDQAVLTQPSSVSKSTGQTVSITCSGSSNVGLRNYVTWFQQVPGSAPKLLIYGATSRASGIPDRFSGSRSGNTATLIISSLQAEDEADYYCASADTNDGGVFGSGTRLTVLG

[1134] 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).

[1135] 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”.

[1136] 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).

[1137] 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).

[1138] The specific binding molecule can bind to polypeptide or protein molecules containing the amino acid sequence 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:

[1139] VHCDR1 contains the sequence listed in SEQ ID NO: 192 (SNAVI / G);

[1140] VHCDR2 contains the sequence listed in SEQ ID NO: 193 (LIDV / IDGDA / TAYD / NPALK / ES);

[1141] VHCDR3 contains the sequence listed in SEQ ID NO: 194 (D / HYG / DS / KWGYV / AS / DD / SIDY);

[1142] VLCDR1 contains the sequence listed in SEQ ID NO: 195 (SGSD / S- / S- / N- / VI / GG / YGA / DD / YVG);

[1143] VLCDR2 contains the sequence listed in SEQ ID NO: 196 (DN / AD / TN / TRP / AS);

[1144] VLCDR2 contains the sequence listed in SEQ ID NO: 197 (G / AT / SYS / QG / NA / EN / RY / SGI / V);

[1145] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1146] (i) having at least 85% identity with it, and / or

[1147] (ii) relative to having one, two or three amino acid substitutions.

[1148] 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%.

[1149] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1150] VHCDR1 contains the sequence listed in SEQ ID NO: 198 (SNAVI) or SEQ ID NO: 17 (SNAVG);

[1151] VHCDR2 contains the sequence listed in SEQ ID NO: 200 (LIDVDGDAAYDPALKS) or SEQ ID NO: 201 (LIDIDGDTAYNPALES);

[1152] VHCDR3 contains the sequence listed in SEQ ID NO: 202 (DYGSWGYVSDIDY) or SEQ ID NO: 203 (HYDKWGYADSIDY);

[1153] VLCDR1 contains the sequence listed in SEQ ID NO: 204 (SGSDIGGADVG) or SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[1154] VLCDR2 contains the sequence listed in SEQ ID NO: 206 (DNDNRPS) or SEQ ID NO: 207 (DATTRAS); and

[1155] VLCDR3 contains the sequence listed in SEQ ID NO: 208 (GTYSGANYGI) or SEQ ID NO: 209 (ASYQNERSGV);

[1156] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1157] (i) having at least 85% identity with it, and / or

[1158] (ii) relative to having one, two, or three amino acid substitutions.

[1159] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 147 to 157 of SEQ ID NO: 1.

[1160] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1161] VHCDR1 contains the sequence listed in SEQ ID NO: 198 (SNAVI).

[1162] VHCDR2 contains the sequence listed in SEQ ID NO: 200 (LIDVDGDAAYDPALKS).

[1163] VHCDR3 contains the sequence listed in SEQ ID NO: 202 (DYGSWGYVSDIDY).

[1164] VLCDR1 contains the sequence listed in SEQ ID NO: 204 (SGSDIGGADVG);

[1165] VLCDR2 contains the sequence listed in SEQ ID NO: 206 (DNDNRPS); and

[1166] VLCDR3 contains the sequence listed in SEQ ID NO: 208 (GTYSGANYGI);

[1167] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1168] (i) having at least 85% identity with it, and / or

[1169] (ii) relative to having one, two, or three amino acid substitutions.

[1170] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 147 to 157 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to those given above is referred to herein as “3aD6”.

[1171] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1172] VHCDR1 contains the sequence listed in SEQ ID NO: 198 (SNAVI).

[1173] VHCDR2 contains the sequence listed in SEQ ID NO: 200 (LIDVDGDAAYDPALKS).

[1174] VHCDR3 contains the sequence listed in SEQ ID NO: 202 (DYGSWGYVSDIDY).

[1175] VLCDR1 contains the sequence listed in SEQ ID NO: 204 (SGSDIGGADVG);

[1176] VLCDR2 contains the sequence listed in SEQ ID NO: 206 (DNDNRPS); and

[1177] VLCDR3 contains the sequence listed in SEQ ID NO: 208 (GTYSGANYGI).

[1178] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1179] VHCDR1 contains the sequence listed in SEQ ID NO: 17 (SNAVG).

[1180] VHCDR2 contains the sequence listed in SEQ ID NO: 201 (LIDIDGDTAYNPALES).

[1181] VHCDR3 contains the sequence listed in SEQ ID NO: 203 (HYDKWGYADSIDY).

[1182] VLCDR1 contains the sequence listed in SEQ ID NO: 138 (SGSSSNVGYGDYVG);

[1183] VLCDR2 contains the sequence listed in SEQ ID NO: 207 (DATTRAS); and

[1184] VLCDR3 contains the sequence listed in SEQ ID NO: 209 (ASYQNERSGV);

[1185] Alternatively, for each CDR sequence, there is 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 described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 147 to 157 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “3aA6”.

[1189]

[1190] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1191] VHCDR1 contains the VHCDR1 amino acid sequence listed in Table 8;

[1192] VHCDR2 contains the VHCDR2 amino acid sequence listed in Table 8;

[1193] VHCDR3 contains the VHCDR3 amino acid sequence listed in Table 8;

[1194] VLCDR1 contains the VLCDR1 amino acid sequence listed in Table 8;

[1195] VLCDR2 contains the VLCDR2 amino acid sequence listed in Table 8; and

[1196] VLCDR3 contains the VLCDR3 amino acid sequence listed in Table 8;

[1197] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1198] (i) having at least 85% identity with it, and / or

[1199] (ii) relative to having one, two, or three amino acid substitutions.

[1200] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 147 to 157 of SEQ ID NO: 1.

[1201] 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. K D K may preferably be combined with SEQ ID NO: 1 or SEQ ID NO: 191. D K combined with SEQ ID NO: 1 D It can be from about 10 nM to about 20 nM. The KD binding to SEQ ID NO: 1 can be about 16.5 nM, optionally wherein the specifically binding molecule comprises a CDR of 3aD6.

[1202] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 418. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 418.

[1203] SEQ ID NO: 418 (3aA6 amino acid sequence)

[1204] QVRLQESGSSLVKPSQTLSLVCTVSGFPLTSNAVGWVRQAPGKAPEWLGLIDIDGDTAYNPALESRLSITRDTSKSQVSLSLSSVAIEDTAVYYCARHYDKWGYADSIDYWGPGLLVTVSSEG KSSGASGESKVDDQALLTQPSSVFGSLGQRVSITCSGSSSNVGYGDYVGWYQQVPGSAPKLLIYDATTRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYQNERSGVFGSGTRLTVLG

[1205] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 419. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 419.

[1206] SEQ ID NO: 419 (3aD6 amino acid sequence)

[1207] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSSE GKSSGASGESKVDDQAVLTQPSSVSGSLGQRVSITCSGSDIGGADVGWFQQVPGSGLRTLIYDNDNRPSGVPDRFSGSKSGNTATLTISSLQPEDEADYFCGTYSGANYGIFFSGTRLTVLG

[1208] 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).

[1209] 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 contained 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 substituted with 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 substituted with conserved amino acids (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 substituted with conserved amino acids (according to SEQ ID NO: 1), and any one or more residues other than residue number 391(E) are substituted with non-conserved amino acids (according to SEQ ID NO: 1).

[1210] 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).

[1211] 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).

[1212] 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:

[1213] VHCDR1 contains the sequence listed in SEQ ID NO: 223 (D / SR / WGVA);

[1214] VHCDR2 contains the sequence listed in SEQ ID NO: 224 (TMRSGGT / GI / TD / EY / DNPALKS);

[1215] VHCDR3 contains the sequence listed in SEQ ID NO: 225 (GYLSGD / I / VR / HYA);

[1216] VLCDR1 contains the sequence listed in SEQ ID NO: 226 (SGSR / SSD / NI / VGY / D / AGN / D / RYVS / G);

[1217] VLCDR2 contains the sequence listed in SEQ ID NO: 227 (D / S / GT / AN / R / TT / N / SRAS);

[1218] VLCDR3 contains the sequence listed in SEQ ID NO: 228 (AN / SIDS / TS / GR / NS / NH / LL / I);

[1219] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1220] (i) having at least 85% identity with it, and / or

[1221] (ii) relative to having one, two or three amino acid substitutions.

[1222] 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%.

[1223] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1224] VHCDR1 contains the sequence listed in SEQ ID NO: 229 (DRGVA), SEQ ID NO: 230 (DWGVA), or SEQ ID NO: 231 (SWGVA);

[1225] VHCDR2 contains the sequences listed in SEQ ID NO: 232 (TMRSGGTIDYNPALKS), SEQ ID NO: 233 (TMRSGGGTEYNPALKS), or SEQ ID NO: 234 (TMRSGGTTDDNPALKS);

[1226] VHCDR3 contains the sequences listed in SEQ ID NO: 235 (GYLSGDRYA), SEQ ID NO: 236 (GYLSGIHYA), or SEQ ID NO: 237 (GYLSGVHYA);

[1227] VLCDR1 contains the sequences listed in SEQ ID NO: 238 (SGSRSDIGYGNYVS), SEQ ID NO: 239 (SGSSSNVGAGNYVG), SEQ ID NO: 240 (SGSSSNVGDGDYVG), or SEQ ID NO: 241 (SGSSSNVGDGRYVS);

[1228] VLCDR2 contains the sequences listed in SEQ ID NO: 242 (DTNTRAS), SEQ ID NO: 243 (DTTSRAS), SEQ ID NO: 170 (GATNRAS), or SEQ ID NO: 244 (SARNRAS); and

[1229] VLCDR3 contains the sequences listed in SEQ ID NO: 245 (ANIDSSRSHL), SEQ ID NO: 246 (ASIDSGNNLL), or SEQ ID NO: 247 (ASIDTSRSHI);

[1230] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1231] (i) having at least 85% identity with it, and / or

[1232] (ii) relative to having one, two, or three amino acid substitutions.

[1233] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 379 to 391 of SEQ ID NO: 1.

[1234] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1235] VHCDR1 contains the sequence listed in SEQ ID NO: 229 (DRGVA);

[1236] VHCDR2 contains the sequence listed in SEQ ID NO: 232 (TMRSGGTIDYNPALKS);

[1237] VHCDR3 contains the sequence listed in SEQ ID NO: 235 (GYLSGDRYA);

[1238] VLCDR1 contains the sequence listed in SEQ ID NO: 238 (SGSRSDIGYGNYVS);

[1239] VLCDR2 contains the sequence listed in SEQ ID NO: 242 (DTNTRAS); and

[1240] VLCDR3 contains the sequence listed in SEQ ID NO: 245 (ANIDSSRSHL);

[1241] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1242] (i) having at least 85% identity with it, and / or

[1243] (ii) relative to having one, two, or three amino acid substitutions.

[1244] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 379 to 391 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “E2E8”.

[1245] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1246] VHCDR1 contains the sequence listed in SEQ ID NO: 229 (DRGVA);

[1247] VHCDR2 contains the sequence listed in SEQ ID NO: 232 (TMRSGGTIDYNPALKS);

[1248] VHCDR3 contains the sequence listed in SEQ ID NO: 235 (GYLSGDRYA);

[1249] VLCDR1 contains the sequence listed in SEQ ID NO: 238 (SGSRSDIGYGNYVS);

[1250] VLCDR2 contains the sequence listed in SEQ ID NO: 242 (DTNTRAS); and

[1251] VLCDR3 contains the sequence listed in SEQ ID NO: 245 (ANIDSSRSHL).

[1252] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1253] VHFR1 contains the sequence listed in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1254] VHFR2 contains the sequence listed in SEQ ID NO: 484 (WVRQAPGKALEWVG);

[1255] VHFR3 contains the sequence listed in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1256] VHFR4 contains the sequence listed in SEQ ID NO: 486 (WGRGLLVTVSS);

[1257] VLFR1 contains the sequence listed in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC);

[1258] VLFR2 contains the sequence listed in SEQ ID NO: 488 (WFQQIPGSAPKLLIY);

[1259] VLFR3 contains the sequence listed in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1260] VLFR4 contains the sequence listed in SEQ ID NO: 490 (FGSGTRLTVLG);

[1261] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1262] (i) having at least 50% similarity with it, and / or

[1263] (ii) relative to having one, two, three, four or five amino acid substitutions.

[1264] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1265] VHFR1 contains the sequence listed in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1266] VHFR2 contains the sequence listed in SEQ ID NO: 484 (WVRQAPGKALEWVG);

[1267] VHFR3 contains the sequence listed in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1268] VHFR4 contains the sequence listed in SEQ ID NO: 486 (WGRGLLVTVSS);

[1269] VLFR1 contains the sequence listed in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC);

[1270] VLFR2 contains the sequence listed in SEQ ID NO: 488 (WFQQIPGSAPKLLIY);

[1271] VLFR3 contains the sequence listed in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1272] VLFR4 contains the sequence listed in SEQ ID NO: 490 (FGSGTRLTVLG);

[1273] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1274] (i) having at least 50% similarity with it, and / or

[1275] (ii) relative to having one, two, three, four, or five amino acid substitutions,

[1276] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 379 to 391 of SEQ ID NO: 1. A specific binding molecule containing a FR that is 100% identical to the given FRs described above is referred to herein as “E2E8”.

[1277] Specific binding molecules may include:

[1278] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1279] VHFR1 contains the sequence listed in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1280] VHFR2 contains the sequence listed in SEQ ID NO: 484 (WVRQAPGKALEWVG);

[1281] VHFR3 contains the sequence listed in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1282] VHFR4 contains the sequence listed in SEQ ID NO: 486 (WGRGLLVTVSS);

[1283] VLFR1 contains the sequence listed in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC);

[1284] VLFR2 contains the sequence listed in SEQ ID NO: 488 (WFQQIPGSAPKLLIY);

[1285] VLFR3 contains the sequence listed in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1286] VLFR4 contains the sequence listed in SEQ ID NO: 490 (FGSGTRLTVLG);

[1287] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1288] (i) having at least 50% similarity with it, and / or

[1289] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1290] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1291] VHCDR1 contains the sequence listed in SEQ ID NO: 229 (DRGVA);

[1292] VHCDR2 contains the sequence listed in SEQ ID NO: 232 (TMRSGGTIDYNPALKS);

[1293] VHCDR3 contains the sequence listed in SEQ ID NO: 235 (GYLSGDRYA);

[1294] VLCDR1 contains the sequence listed in SEQ ID NO: 238 (SGSRSDIGYGNYVS);

[1295] VLCDR2 contains the sequence listed in SEQ ID NO: 242 (DTNTRAS); and

[1296] VLCDR3 contains the sequence listed in SEQ ID NO: 245 (ANIDSSRSHL);

[1297] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1298] (i) having at least 85% identity with it, and / or

[1299] (ii) relative to having one, two, or three amino acid substitutions.

[1300] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 379 to 391 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “E2E8”.

[1301] Specific binding molecules may include:

[1302] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1303] VHFR1 contains the sequence listed in SEQ ID NO: 483 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1304] VHFR2 contains the sequence listed in SEQ ID NO: 484 (WVRQAPGKALEWVG);

[1305] VHFR3 contains the sequence listed in SEQ ID NO: 485 (RLSITRDTSKSQVFLSLSSVTTEDMAMYYCAR);

[1306] VHFR4 contains the sequence listed in SEQ ID NO: 486 (WGRGLLVTVSS);

[1307] VLFR1 contains the sequence listed in SEQ ID NO: 487 (QAVLTQPSSVSKSLGQSVSIAC);

[1308] VLFR2 contains the sequence listed in SEQ ID NO: 488 (WFQQIPGSAPKLLIY);

[1309] VLFR3 contains the sequence listed in SEQ ID NO: 489 (GVPDRFSGARSGNTATLTINSLQAEDEADYYC);

[1310] VLFR4 contains the sequence listed in SEQ ID NO: 490 (FGSGTRLTVLG);

[1311] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1312] (i) having at least 50% similarity with it, and / or

[1313] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1314] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1315] VHCDR1 contains the sequence listed in SEQ ID NO: 229 (DRGVA);

[1316] VHCDR2 contains the sequence listed in SEQ ID NO: 232 (TMRSGGTIDYNPALKS);

[1317] VHCDR3 contains the sequence listed in SEQ ID NO: 235 (GYLSGDRYA);

[1318] VLCDR1 contains the sequence listed in SEQ ID NO: 238 (SGSRSDIGYGNYVS);

[1319] VLCDR2 contains the sequence listed in SEQ ID NO: 242 (DTNTRAS); and

[1320] VLCDR3 contains the sequence listed in SEQ ID NO: 245 (ANIDSSRSHL);

[1321] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 379 to 391 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “E2E8”.

[1322] Specific binding molecules may include:

[1323] (a) A VH domain containing the sequence listed in SEQ ID NO: 491 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLVTVSS); and / or

[1324] (b) A VL domain containing the sequence listed in SEQ ID NO: 492 (QAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLG);

[1325] Or its humanized variants.

[1326] Specific binding molecules may include:

[1327] (a) Heavy chain, the heavy chain comprising SEQ ID NO:493(QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDDMAMYYCARGYLSGDRYAWGR GLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPCP The sequences listed in PCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) are listed; and / or

[1328] (b) A light chain containing the sequences listed in SEQ ID NO: 494 (QAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS);

[1329] Or its humanized variants.

[1330] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1331] VHCDR1 contains the sequence listed in SEQ ID NO: 230 (DWGVA);

[1332] VHCDR2 contains the sequence listed in SEQ ID NO: 234 (TMRSGGTTDDNPALKS);

[1333] VHCDR3 contains the sequence listed in SEQ ID NO: 237 (GYLSGVHYA);

[1334] VLCDR1 contains the sequence listed in SEQ ID NO: 241 (SGSSSNVGDGRYVS);

[1335] VLCDR2 contains the sequence listed in SEQ ID NO: 243 (DTTSRAS); and

[1336] VLCDR3 contains the sequence listed in SEQ ID NO: 246 (ASIDSGNNLL);

[1337] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1338] (i) having at least 85% identity with it, and / or

[1339] (ii) relative to having one, two, or three amino acid substitutions.

[1340] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 379 to 391 of SEQ ID NO: 1. Specific binding molecules containing CDRs that are 100% identical to those given above are referred to herein as “E1E8”.

[1341] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1342] VHCDR1 contains the sequence listed in SEQ ID NO: 230 (DWGVA);

[1343] VHCDR2 contains the sequence listed in SEQ ID NO: 234 (TMRSGGTTDDNPALKS);

[1344] VHCDR3 contains the sequence listed in SEQ ID NO: 237 (GYLSGVHYA);

[1345] VLCDR1 contains the sequence listed in SEQ ID NO: 241 (SGSSSNVGDGRYVS);

[1346] VLCDR2 contains the sequence listed in SEQ ID NO: 243 (DTTSRAS); and

[1347] VLCDR3 contains the sequence listed in SEQ ID NO: 246 (ASIDSGNNLL).

[1348] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1349] VHCDR1 contains the sequence listed in SEQ ID NO: 230 (DWGVA);

[1350] VHCDR2 contains the sequence listed in SEQ ID NO: 234 (TMRSGGTTDDNPALKS);

[1351] VHCDR3 contains the sequence listed in SEQ ID NO: 237 (GYLSGVHYA);

[1352] VLCDR1 contains the sequence listed in SEQ ID NO: 239 (SGSSSNVGAGNYVG);

[1353] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (GATNRAS); and

[1354] VLCDR3 contains the sequence listed in SEQ ID NO: 247 (ASIDTSRSHI);

[1355] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1356] (i) having at least 85% identity with it, and / or

[1357] (ii) relative to having one, two, or three amino acid substitutions.

[1358] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 379 to 391 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to those given above is referred to herein as “E2A6”.

[1359] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1360] VHCDR1 contains the sequence listed in SEQ ID NO: 230 (DWGVA);

[1361] VHCDR2 contains the sequence listed in SEQ ID NO: 234 (TMRSGGTTDDNPALKS);

[1362] VHCDR3 contains the sequence listed in SEQ ID NO: 237 (GYLSGVHYA);

[1363] VLCDR1 contains the sequence listed in SEQ ID NO: 239 (SGSSSNVGAGNYVG);

[1364] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (GATNRAS); and

[1365] VLCDR3 contains the sequence listed in SEQ ID NO: 247 (ASIDTSRSHI).

[1366] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1367] VHCDR1 contains the sequence listed in SEQ ID NO: 231 (SWGVA);

[1368] VHCDR2 contains the sequence listed in SEQ ID NO: 233 (TMRSGGGTEYNPALKS);

[1369] VHCDR3 contains the sequence listed in SEQ ID NO: 236 (GYLSGIHYA);

[1370] VLCDR1 contains the sequence listed in SEQ ID NO: 240 (SGSSSNVGDGDYVG);

[1371] VLCDR2 contains the sequence listed in SEQ ID NO: 244 (SARNRAS); and

[1372] VLCDR3 contains the sequence listed in SEQ ID NO: 247 (ASIDTSRSHI);

[1373] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1374] (i) having at least 85% identity with it, and / or

[1375] (ii) relative to having one, two, or three amino acid substitutions.

[1376] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 379 to 391 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “E2B7”.

[1377] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1378] VHCDR1 contains the sequence listed in SEQ ID NO: 231 (SWGVA);

[1379] VHCDR2 contains the sequence listed in SEQ ID NO: 233 (TMRSGGGTEYNPALKS);

[1380] VHCDR3 contains the sequence listed in SEQ ID NO: 236 (GYLSGIHYA);

[1381] VLCDR1 contains the sequence listed in SEQ ID NO: 240 (SGSSSNVGDGDYVG);

[1382] VLCDR2 contains the sequence listed in SEQ ID NO: 244 (SARNRAS); and

[1383] VLCDR3 contains the sequence listed in SEQ ID NO: 247 (ASIDTSRSHI).

[1384]

[1385] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1386] VHCDR1 contains the VHCDR1 amino acid sequence listed in Table 9;

[1387] VHCDR2 contains the VHCDR2 amino acid sequence listed in Table 9;

[1388] VHCDR3 contains the VHCDR3 amino acid sequence listed in Table 9;

[1389] VLCDR1 contains the VLCDR1 amino acid sequence listed in Table 9;

[1390] VLCDR2 contains the VLCDR2 amino acid sequence listed in Table 9; and

[1391] VLCDR3 contains the VLCDR3 amino acid sequence listed in Table 9;

[1392] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1393] (i) having at least 85% identity with it, and / or

[1394] (ii) relative to having one, two, or three amino acid substitutions.

[1395] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing an amino acid sequence of residues 379 to 391 of SEQ ID NO: 1.

[1396] 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. K D K is preferably combined with SEQ ID NO: 4 D The specifically binding molecule may not bind to SEQ ID NO: 1 as detectable. K binds to SEQ ID NO: 4. D It can range from approximately 300 pM to approximately 10 nM. K binds to SEQ ID NO: 4. D It can be 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, optionally wherein the specifically binding molecule comprises an E1E8 CDR. K binding to SEQ ID NO: 1 D It can be approximately 6.3 nM, and optionally the specific binding molecule contains the CDR of E1E8.

[1397] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 248. The CDR may be 100% identical to the CDR of SEQ ID NO: 248. 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: 248, wherein the CDR is 100% identical to the CDR of SEQ ID NO: 248. The specific binding molecule may include the amino acid sequence of SEQ ID NO: 248.

[1398] SEQ ID NO: 248 (E2E8 amino acid sequence)

[1399] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDRGVAWVRQAPGKALEWVGTMRSGGTIDYNPALKSRLSITRDTSKSQVFLSLSSVTTEDMAMYYCARGYLSGDRYAWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSKSLGQSVSIACSGSRSDIGYGNYVSWFQQIPGSAPKLLIYDTNTRASGVPDRFSGARSGNTATLTINSLQAEDEADYYCANIDSSRSHLFGSGTRLTVLG

[1400] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 250. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 250.

[1401] SEQ ID NO: 250 (E1E8 amino acid sequence)

[1402] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDWGVAWVRQAPGKALEWLGTMRSGGTTDDNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGVHYAWGRGLLVTVSSEGKS SGASGESKVDDQAVLTQPSSVSGSLGQSVSITCSGSSSNVGDGRYVSWFQQVPGSAPKLLIYDTTSRASGVPDRFSGSRSGNTATLIITSLQAEDEADYYCASIDSGNNLLFGSGTRLTVLG

[1403] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 252. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 252.

[1404] SEQ ID NO: 252 (E2A6 amino acid sequence)

[1405] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTDWGVAWVRQAPGKALEWLGTMRSGGTTDDNPALKSRLSITRDTSKSQVSLSLSSVTTEDMAMYYCARGYLSGVHYAWGRGLLVTVSSEGKS SGASGESKVDDRVVRTQPSSVSKSLGQSVSITCSGSSSNVGAGNYVGWFQQVPGSAPKLLIYGATNRASGVPARFSGSKSGVTATLTITSLQAEDEADYYCASIDTSRSHIFGSGTRLTVLG

[1406] 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 be at least 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, or 99% identical to the CDR of SEQ ID NO: 254. The CDR may be 100% identical to 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 include the amino acid sequence of SEQ ID NO: 254.

[1407] SEQ ID NO: 254 (E2B7 amino acid sequence)

[1408] QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSWGVAWVRQAPGKALEWLGTMRSGGGTEYNPALKSRLSITRDTSKSQVSLSLSSVTTEDDMAMYYCARGYLSGIHYAWGRGLLVSVSSEGKS SGASGESKVDDQAVLTQLSSVSGSLGQRVSITCSGSSSNVGDGDYVGWFQQLPGSAPKLLIYSARNRASGVPDRFSGSRSGNTATLTITSLQAEDEADYYCASIDTSRSHIFGSGTRLTVLG

[1409] 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 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1410] The epitope may be located within the amino acid sequence containing residues 113 to 238 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CB11”.

[1411] The epitope may contain the amino acid sequence of SEQ ID NO: 255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). 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 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1412] The epitope may consist of an amino acid sequence of SEQ ID NO: 255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). 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 SEQ ID NO: 255 (SLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1413] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1414] VHCDR1 contains the sequence listed in SEQ ID NO: 198 (SNAVI);

[1415] VHCDR2 contains the sequence listed in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[1416] VHCDR3 contains the sequence listed in SEQ ID NO: 202(DYGSWGYVSDIDY);

[1417] VLCDR1 contains the sequence listed in SEQ ID NO: 256 (SGSNIGSNDVG);

[1418] VLCDR2 contains the sequence listed in SEQ ID NO: 257 (DNNNRPS); and

[1419] VLCDR3 contains the sequence listed in SEQ ID NO: 258 (GGYAGSSSNFL);

[1420] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1421] (i) having at least 85% identity with it, and / or

[1422] (ii) relative to having one, two, or three amino acid substitutions.

[1423] The specific binding molecule described herein binds to a polypeptide or protein molecule containing an amino acid sequence containing residues 113 to 238 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the given CDRs is referred to herein as “CB11”.

[1424] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1425] VHCDR1 contains the sequence listed in SEQ ID NO: 198 (SNAVI);

[1426] VHCDR2 contains the sequence listed in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[1427] VHCDR3 contains the sequence listed in SEQ ID NO: 202(DYGSWGYVSDIDY);

[1428] VLCDR1 contains the sequence listed in SEQ ID NO: 256 (SGSNIGSNDVG);

[1429] VLCDR2 contains the sequence listed in SEQ ID NO: 257 (DNNNRPS); and

[1430] VLCDR3 contains the sequence listed in SEQ ID NO: 258 (GGYAGSSSNFL).

[1431] The epitope that specifically binds to the molecule can be within the amino acid sequence containing residues 1 to 155 of SEQ ID NO: 1. Therefore, the epitope can be within the amino acid sequence of SEQ ID NO: 293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR).

[1432] The epitope may be located within the amino acid sequence containing residues 1 to 155 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CA2”.

[1433] Epitopes may contain the amino acid sequence of SEQ ID NO: 293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR). 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 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR).

[1434] Epitopes can be composed of the amino acid sequence of SEQ ID NO: 293 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR). 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 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPR).

[1435] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1436] VHCDR1 contains the sequence listed in SEQ ID NO: 259 (SNGVG);

[1437] VHCDR2 contains the sequence listed in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1438] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1439] VLCDR1 contains the sequence listed in SEQ ID NO: 165 (SGSSGNVGYGDYVS);

[1440] VLCDR2 contains the sequence listed in SEQ ID NO: 169 (GATNLAS); and

[1441] VLCDR3 contains the sequence listed in SEQ ID NO: 173 (ASYDSSSGGV);

[1442] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1443] (i) having at least 85% identity with it, and / or

[1444] (ii) relative to having one, two, or three amino acid substitutions.

[1445] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 155 of SEQ ID NO: 1. A specific binding molecule comprising a CDR having 100% identity with those given above is referred to herein as “CA2”.

[1446] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1447] VHCDR1 contains the sequence listed in SEQ ID NO: 259 (SNGVG);

[1448] VHCDR2 contains the sequence listed in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1449] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1450] VLCDR1 contains the sequence listed in SEQ ID NO: 165 (SGSSGNVGYGDYVS);

[1451] VLCDR2 contains the sequence listed in SEQ ID NO: 169 (GATNLAS); and

[1452] VLCDR3 contains the sequence listed in SEQ ID NO: 173 (ASYDSSSGGV).

[1453] 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 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1454] The epitope may be located within the amino acid sequence containing residues 1 to 238 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CB6”.

[1455] The epitope may contain SEQ ID NO:260(MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAA The amino acid sequence of GHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). 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 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1456] The epitope can be identified by SEQ ID NO:260(MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAG The amino acid sequence composition of HVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). 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 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1457] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1458] VHCDR1 contains the sequence listed in SEQ ID NO: 259 (SNGVG);

[1459] VHCDR2 contains the sequence listed in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1460] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1461] VLCDR1 contains the sequence listed in SEQ ID NO: 261 (SGSSSNIGTGNYVG);

[1462] VLCDR2 contains the sequence listed in SEQ ID NO: 262 (GAVTRAS); and

[1463] VLCDR3 contains the sequence listed in SEQ ID NO: 263 (ASYDSTSGGV);

[1464] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1465] (i) having at least 85% identity with it, and / or

[1466] (ii) relative to having one, two, or three amino acid substitutions.

[1467] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 238 of SEQ ID NO: 1. A specific binding molecule comprising a CDR having 100% identity with the CDRs given above is referred to herein as “CB6”.

[1468] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1469] VHCDR1 contains the sequence listed in SEQ ID NO: 259 (SNGVG);

[1470] VHCDR2 contains the sequence listed in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1471] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1472] VLCDR1 contains the sequence listed in SEQ ID NO: 261 (SGSSSNIGTGNYVG);

[1473] VLCDR2 contains the sequence listed in SEQ ID NO: 262 (GAVTRAS); and

[1474] VLCDR3 contains the sequence listed in SEQ ID NO: 263 (ASYDSTSGGV).

[1475] 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 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[1476] The epitope may be located within the amino acid sequence containing residues 1 to 319 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CA7”, “CA8”, and “CB10”.

[1477] The epitope, preferably located within the amino acid sequence containing residues 1 to 319 of SEQ ID NO: 1, is located within the amino acid sequence containing residues 37 to 49 of SEQ ID NO: 1. This epitope can bind at least to the CDR of a specific binding molecule referred to herein as “CA7”.

[1478] Epitopes may contain the amino acid sequence of SEQ ID NO: 264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT). Epitopes may contain the amino acid sequence of SEQ ID NO: 264.

[1479] (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT) has an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity.

[1480] The epitope may be composed of the amino acid sequence of SEQ ID NO: 264 (MAEPRQEFEVMEDHAGTYGLGDRKDQGGYTMHQDQEGDTDAGLKESPLQTPTEDGSEEPGSETSDAKSTPTAEDVTAPLVDEGAPGKQAAAQPHTEIPEGTTAEEAGIGDTPSLEDEAAGHVTQARMVSKSKDGTGSDDKKAKGADGKTKIATPRGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[1481] (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.

[1482] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1483] VHCDR1 contains the sequence listed in SEQ ID NO: 44 (SYYVG);

[1484] VHCDR2 contains the sequence listed in SEQ ID NO: 52 (NIYSTGRAFYNPALKS);

[1485] VHCDR3 contains the sequence listed in SEQ ID NO: 265 (GSYYHGGGNGMVDFFDY);

[1486] VLCDR1 contains the sequence listed in SEQ ID NO: 39 (SGSSSNVGYGNYVG);

[1487] VLCDR2 contains the sequence listed in SEQ ID NO: 72 (AATSRAS); and

[1488] VLCDR3 contains the sequence listed in SEQ ID NO: 78 (SSYQRGNTGV);

[1489] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1490] (i) having at least 85% identity with it, and / or

[1491] (ii) relative to having one, two, or three amino acid substitutions.

[1492] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 319 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to the CDRs given above is referred to herein as “CA7”.

[1493] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1494] VHCDR1 contains the sequence listed in SEQ ID NO: 44 (SYYVG);

[1495] VHCDR2 contains the sequence listed in SEQ ID NO: 52 (NIYSTGRAFYNPALKS);

[1496] VHCDR3 contains the sequence listed in SEQ ID NO: 265 (GSYYHGGGNGMVDFFDY);

[1497] VLCDR1 contains the sequence listed in SEQ ID NO: 39 (SGSSSNVGYGNYVG);

[1498] VLCDR2 contains the sequence listed in SEQ ID NO: 72 (AATSRAS); and

[1499] VLCDR3 contains the sequence listed in SEQ ID NO: 78 (SSYQRGNTGV).

[1500] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1501] VHFR1 contains the sequence listed in SEQ ID NO: 495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD);

[1502] VHFR2 contains the sequence listed in SEQ ID NO: 496 (WVRQAPGKALEWLG);

[1503] VHFR3 contains the sequence listed in SEQ ID NO: 497 (RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR);

[1504] VHFR4 contains the sequence listed in SEQ ID NO: 498 (WSPGLLVTVSS);

[1505] VLFR1 contains the sequence listed in SEQ ID NO: 499 (QVVRTQPSSVSGSLGQRVSITC);

[1506] VLFR2 contains the sequence listed in SEQ ID NO: 500 (WFQQVPGSAPKLLIY);

[1507] VLFR3 contains the sequence listed in SEQ ID NO: 501 (GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC);

[1508] VLFR4 contains the sequence listed in SEQ ID NO: 502 (FGSGTRLTVLG);

[1509] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1510] (i) having at least 50% similarity with it, and / or

[1511] (ii) relative to having one, two, three, four or five amino acid substitutions.

[1512] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1513] VHFR1 contains the sequence listed in SEQ ID NO: 495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD);

[1514] VHFR2 contains the sequence listed in SEQ ID NO: 496 (WVRQAPGKALEWLG);

[1515] VHFR3 contains the sequence listed in SEQ ID NO: 497 (RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR);

[1516] VHFR4 contains the sequence listed in SEQ ID NO: 498 (WSPGLLVTVSS);

[1517] VLFR1 contains the sequence listed in SEQ ID NO: 499 (QVVRTQPSSVSGSLGQRVSITC);

[1518] VLFR2 contains the sequence listed in SEQ ID NO: 500 (WFQQVPGSAPKLLIY);

[1519] VLFR3 contains the sequence listed in SEQ ID NO: 501 (GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC);

[1520] VLFR4 contains the sequence listed in SEQ ID NO: 502 (FGSGTRLTVLG);

[1521] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1522] (i) having at least 50% similarity with it, and / or

[1523] (ii) relative to having one, two, three, four, or five amino acid substitutions,

[1524] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 319 of SEQ ID NO: 1. Specific binding molecules comprising FRs having 100% identity with those given above are referred to herein as “CA7”.

[1525] Specific binding molecules may include:

[1526] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1527] VHFR1 contains the sequence listed in SEQ ID NO: 495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD);

[1528] VHFR2 contains the sequence listed in SEQ ID NO: 496 (WVRQAPGKALEWLG);

[1529] VHFR3 contains the sequence listed in SEQ ID NO: 497 (RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR);

[1530] VHFR4 contains the sequence listed in SEQ ID NO: 498 (WSPGLLVTVSS);

[1531] VLFR1 contains the sequence listed in SEQ ID NO: 499 (QVVRTQPSSVSGSLGQRVSITC);

[1532] VLFR2 contains the sequence listed in SEQ ID NO: 500 (WFQQVPGSAPKLLIY);

[1533] VLFR3 contains the sequence listed in SEQ ID NO: 501 (GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC);

[1534] VLFR4 contains the sequence listed in SEQ ID NO: 502 (FGSGTRLTVLG);

[1535] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1536] (i) having at least 50% similarity with it, and / or

[1537] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1538] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1539] VHCDR1 contains the sequence listed in SEQ ID NO: 44 (SYYVG);

[1540] VHCDR2 contains the sequence listed in SEQ ID NO: 52 (NIYSTGRAFYNPALKS);

[1541] VHCDR3 contains the sequence listed in SEQ ID NO: 265 (GSYYHGGGNGMVDFFDY);

[1542] VLCDR1 contains the sequence listed in SEQ ID NO: 39 (SGSSSNVGYGNYVG);

[1543] VLCDR2 contains the sequence listed in SEQ ID NO: 72 (AATSRAS); and

[1544] VLCDR3 contains the sequence listed in SEQ ID NO: 78 (SSYQRGNTGV).

[1545] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1546] (i) having at least 85% identity with it, and / or

[1547] (ii) relative to having one, two, or three amino acid substitutions.

[1548] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 319 of SEQ ID NO: 1. Specific binding molecules comprising FRs and CDRs that are 100% identical to those given above are referred to herein as “CA7”.

[1549] Specific binding molecules may include:

[1550] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1551] VHFR1 contains the sequence listed in SEQ ID NO: 495 (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFD);

[1552] VHFR2 contains the sequence listed in SEQ ID NO: 496 (WVRQAPGKALEWLG);

[1553] VHFR3 contains the sequence listed in SEQ ID NO: 497 (RLSITRDTSKSQVSLSVSSVTIEDTALYYCVR);

[1554] VHFR4 contains the sequence listed in SEQ ID NO: 498 (WSPGLLVTVSS);

[1555] VLFR1 contains the sequence listed in SEQ ID NO: 499 (QVVRTQPSSVSGSLGQRVSITC);

[1556] VLFR2 contains the sequence listed in SEQ ID NO: 500 (WFQQVPGSAPKLLIY);

[1557] VLFR3 contains the sequence listed in SEQ ID NO: 501 (GVPDRFSGSRSGNTATLTIDSLQAEDEADYYC);

[1558] VLFR4 contains the sequence listed in SEQ ID NO: 502 (FGSGTRLTVLG);

[1559] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1560] (i) having at least 50% similarity with it, and / or

[1561] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1562] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1563] VHCDR1 contains the sequence listed in SEQ ID NO: 44 (SYYVG);

[1564] VHCDR2 contains the sequence listed in SEQ ID NO: 52 (NIYSTGRAFYNPALKS);

[1565] VHCDR3 contains the sequence listed in SEQ ID NO: 265 (GSYYHGGGNGMVDFFDY);

[1566] VLCDR1 contains the sequence listed in SEQ ID NO: 39 (SGSSSNVGYGNYVG);

[1567] VLCDR2 contains the sequence listed in SEQ ID NO: 72 (AATSRAS); and

[1568] VLCDR3 contains the sequence listed in SEQ ID NO: 78 (SSYQRGNTGV).

[1569] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 1 to 319 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “CA7”.

[1570] Specific binding molecules may include:

[1571] (a) A VH domain containing SEQ ID NO: 503

[1572] The sequences listed in (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFDSYYVGWVRQAPGKALEWLGNIYSTGRAFYNPALKSRLSITRDTSKSQVSLSVSSVTIEDTALYYCVRGSYYHGGGNGMVDFFDYWSPGLLVTVSS); and / or the sequences listed in (RVRLQGSGPSLVKPSQTLSLTCTVSGFSFDSYYVGWVRQAPGKALEWLGNIYSTGRAFYNPALKSRLSITRDTSKSQVSLSVSSVTIEDTALYYCVRGSYYHGGGNGMVDFFDYWSPGLLVTVSS); and / or

[1573] (b) A VL domain containing SEQ ID NO: 504

[1574] The sequences listed in (QVVRTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWFQQVPGSAPKLLIYAATSRASGVPDRFSGSRSGNTATLTIDSLQAEDEADYYCSSYQRGNTGVFGSGTRLTVLG) are as follows;

[1575] Or its humanized variants.

[1576] Specific binding molecules may include:

[1577] (a) Heavy chain, the heavy chain comprising SEQ ID NO: 505(RVRLQGSGPSLVKPSQTLSLTCTVSGFSFDSYYVGWVRQAPGKALEWLGNIYSTGRAFYNPALKSRLSITRDTSKSQVSLSVSSVTIEDTALYYCVRGSYYHGGGNGMVDF FDYWSPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTI The sequences listed in KPCPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) are listed; and / or

[1578] (b) A light chain containing the sequences listed in SEQ ID NO: 506 (QVVRTQPSSVSGSLGQRVSITCSGSSSNVGYGNYVGWFQQVPGSAPKLLIYAATSRASGVPDRFSGSRSGNTATLTIDSLQAEDEADYYCSSYQRGNTGVFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS);

[1579] Or its humanized variants.

[1580] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1581] VHCDR1 contains the sequence listed in SEQ ID NO: 266 (SNAVV);

[1582] VHCDR2 contains the sequence listed in SEQ ID NO: 267 (AIDKDGDTIYNPALKS);

[1583] VHCDR3 contains the sequence listed in SEQ ID NO: 268 (DPSGWGYPDVDY);

[1584] VLCDR1 contains the sequence listed in SEQ ID NO: 269 (SGTYIGSSDVG);

[1585] VLCDR2 contains the sequence listed in SEQ ID NO: 270 (GTSSRPS); and

[1586] VLCDR3 contains the sequence listed in SEQ ID NO: 271 (ATYESSYHNSV);

[1587] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1588] (i) having at least 85% identity with it, and / or

[1589] (ii) relative to having one, two, or three amino acid substitutions.

[1590] The specific binding molecule described herein binds to a polypeptide or protein molecule containing an amino acid sequence containing residues 1 to 319 of SEQ ID NO: 1. Specific binding molecules containing CDRs that are 100% identical to the given CDRs described above are referred to herein as “CA8”.

[1591] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1592] VHCDR1 contains the sequence listed in SEQ ID NO: 266 (SNAVV);

[1593] VHCDR2 contains the sequence listed in SEQ ID NO: 267 (AIDKDGDTIYNPALKS);

[1594] VHCDR3 contains the sequence listed in SEQ ID NO: 268 (DPSGWGYPDVDY);

[1595] VLCDR1 contains the sequence listed in SEQ ID NO: 269 (SGTYIGSSDVG);

[1596] VLCDR2 contains the sequence listed in SEQ ID NO: 270 (GTSSRPS); and

[1597] VLCDR3 contains the sequence listed in SEQ ID NO: 271 (ATYESSYHNSV).

[1598] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1599] VHCDR1 contains the sequence listed in SEQ ID NO: 272 (SNTVA);

[1600] VHCDR2 contains the sequence listed in SEQ ID NO: 273 (EINSGGSTYYNPALKS);

[1601] VHCDR3 contains the sequence listed in SEQ ID NO: 274 (GARSTYAAY);

[1602] VLCDR1 contains the sequence listed in SEQ ID NO: 275 (SGSSSDVGYSTWVY);

[1603] VLCDR2 contains the sequence listed in SEQ ID NO: 276 (HISNRAS); and

[1604] VLCDR3 contains the sequence listed in SEQ ID NO: 277 (AAYDSSNNVWI);

[1605] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1606] (i) having at least 85% identity with it, and / or

[1607] (ii) relative to having one, two, or three amino acid substitutions.

[1608] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 1 to 319 of SEQ ID NO: 1. A specific binding molecule comprising a CDR having 100% identity with the CDRs given above is referred to herein as “CB10”.

[1609] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1610] VHCDR1 contains the sequence listed in SEQ ID NO: 272 (SNTVA);

[1611] VHCDR2 contains the sequence listed in SEQ ID NO: 273 (EINSGGSTYYNPALKS);

[1612] VHCDR3 contains the sequence listed in SEQ ID NO: 274 (GARSTYAAY);

[1613] VLCDR1 contains the sequence listed in SEQ ID NO: 275 (SGSSSDVGYSTWVY);

[1614] VLCDR2 contains the sequence listed in SEQ ID NO: 276 (HISNRAS); and

[1615] VLCDR3 contains the sequence listed in SEQ ID NO: 277 (AAYDSSNNVWI).

[1616] 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).

[1617] The epitope may be located within the amino acid sequence containing residues 13 to 25 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CB7”.

[1618] 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).

[1619] 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).

[1620] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1621] VHCDR1 contains the sequence listed in SEQ ID NO: 279 (NYRVG);

[1622] VHCDR2 contains the sequence listed in SEQ ID NO: 280 (NIRSGGTTWYNPALKS);

[1623] VHCDR3 contains the sequence listed in SEQ ID NO: 281 (DSSGDLYAYDY);

[1624] VLCDR1 contains the sequence listed in SEQ ID NO: 282 (SGSSSNVGYGNYMA);

[1625] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS); and

[1626] VLCDR3 contains the sequence listed in SEQ ID NO: 263 (ASYDSTSGGV);

[1627] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1628] (i) having at least 85% identity with it, and / or

[1629] (ii) relative to having one, two, or three amino acid substitutions.

[1630] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 13 to 25 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to those given above is referred to herein as “CB7”.

[1631] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1632] VHCDR1 contains the sequence listed in SEQ ID NO: 279 (NYRVG);

[1633] VHCDR2 contains the sequence listed in SEQ ID NO: 280 (NIRSGGTTWYNPALKS);

[1634] VHCDR3 contains the sequence listed in SEQ ID NO: 281 (DSSGDLYAYDY);

[1635] VLCDR1 contains the sequence listed in SEQ ID NO: 282 (SGSSSNVGYGNYMA);

[1636] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS); and

[1637] VLCDR3 contains the sequence listed in SEQ ID NO: 263 (ASYDSTSGGV).

[1638] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1639] VHFR1 contains the sequence listed in SEQ ID NO: 507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1640] VHFR2 contains the sequence listed in SEQ ID NO: 508 (WVRQAPGKALEWVS);

[1641] VHFR3 contains the sequence listed in SEQ ID NO: 509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR);

[1642] VHFR4 contains the sequence listed in SEQ ID NO: 510 (WGPGLLVTVSS);

[1643] VLFR1 contains the sequence listed in SEQ ID NO: 511 (QAVLTQPSSVSRSLGQSVSMTC);

[1644] VLFR2 contains the sequence listed in SEQ ID NO: 512 (WFQQVPGSAPKLLIY);

[1645] VLFR3 contains the sequence listed in SEQ ID NO: 513 (GVPDRFSGSRSGNTATLTISSLQAEDEADYYC);

[1646] VLFR4 contains the sequence listed in SEQ ID NO: 514 (FGSGTRLTVLG);

[1647] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1648] (i) having at least 50% similarity with it, and / or

[1649] (ii) relative to having one, two, three, four or five amino acid substitutions.

[1650] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1651] VHFR1 contains the sequence listed in SEQ ID NO: 507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1652] VHFR2 contains the sequence listed in SEQ ID NO: 508 (WVRQAPGKALEWVS);

[1653] VHFR3 contains the sequence listed in SEQ ID NO: 509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR);

[1654] VHFR4 contains the sequence listed in SEQ ID NO: 510 (WGPGLLVTVSS);

[1655] VLFR1 contains the sequence listed in SEQ ID NO: 511 (QAVLTQPSSVSRSLGQSVSMTC);

[1656] VLFR2 contains the sequence listed in SEQ ID NO: 512 (WFQQVPGSAPKLLIY);

[1657] VLFR3 contains the sequence listed in SEQ ID NO: 513 (GVPDRFSGSRSGNTATLTISSLQAEDEADYYC);

[1658] VLFR4 contains the sequence listed in SEQ ID NO: 514 (FGSGTRLTVLG);

[1659] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1660] (i) having at least 50% similarity with it, and / or

[1661] (ii) relative to having one, two, three, four, or five amino acid substitutions,

[1662] The specific binding molecule thereunder binds to a polypeptide or protein molecule containing the amino acid sequence of residues 13 to 25 of SEQ ID NO: 1. A specific binding molecule containing a FR that is 100% identical to the given FRs described above is referred to herein as “CB7”.

[1663] Specific binding molecules may include:

[1664] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1665] VHFR1 contains the sequence listed in SEQ ID NO: 507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1666] VHFR2 contains the sequence listed in SEQ ID NO: 508 (WVRQAPGKALEWVS);

[1667] VHFR3 contains the sequence listed in SEQ ID NO: 509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR);

[1668] VHFR4 contains the sequence listed in SEQ ID NO: 510 (WGPGLLVTVSS);

[1669] VLFR1 contains the sequence listed in SEQ ID NO: 511 (QAVLTQPSSVSRSLGQSVSMTC);

[1670] VLFR2 contains the sequence listed in SEQ ID NO: 512 (WFQQVPGSAPKLLIY);

[1671] VLFR3 contains the sequence listed in SEQ ID NO: 513 (GVPDRFSGSRSGNTATLTISSLQAEDEADYYC);

[1672] VLFR4 contains the sequence listed in SEQ ID NO: 514 (FGSGTRLTVLG);

[1673] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1674] (i) having at least 50% similarity with it, and / or

[1675] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1676] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1677] VHCDR1 contains the sequence listed in SEQ ID NO: 279 (NYRVG);

[1678] VHCDR2 contains the sequence listed in SEQ ID NO: 280 (NIRSGGTTWYNPALKS);

[1679] VHCDR3 contains the sequence listed in SEQ ID NO: 281 (DSSGDLYAYDY).

[1680] VLCDR1 contains the sequence listed in SEQ ID NO: 282 (SGSSSNVGYGNYMA);

[1681] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS); and

[1682] VLCDR3 contains the sequence listed in SEQ ID NO: 263 (ASYDSTSGGV);

[1683] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1684] (i) having at least 85% identity with it, and / or

[1685] (ii) relative to having one, two, or three amino acid substitutions.

[1686] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 13 to 25 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “CB7”.

[1687] Specific binding molecules may include:

[1688] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1689] VHFR1 contains the sequence listed in SEQ ID NO: 507 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1690] VHFR2 contains the sequence listed in SEQ ID NO: 508 (WVRQAPGKALEWVS);

[1691] VHFR3 contains the sequence listed in SEQ ID NO: 509 (RLSITADTSKSQVSLSLSSVTTEDTAVYYCAR);

[1692] VHFR4 contains the sequence listed in SEQ ID NO: 510 (WGPGLLVTVSS);

[1693] VLFR1 contains the sequence listed in SEQ ID NO: 511 (QAVLTQPSSVSRSLGQSVSMTC);

[1694] VLFR2 contains the sequence listed in SEQ ID NO: 512 (WFQQVPGSAPKLLIY);

[1695] VLFR3 contains the sequence listed in SEQ ID NO: 513 (GVPDRFSGSRSGNTATLTISSLQAEDEADYYC);

[1696] VLFR4 contains the sequence listed in SEQ ID NO: 514 (FGSGTRLTVLG);

[1697] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1698] (i) having at least 50% similarity with it, and / or

[1699] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1700] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1701] VHCDR1 contains the sequence listed in SEQ ID NO: 279 (NYRVG);

[1702] VHCDR2 contains the sequence listed in SEQ ID NO: 280 (NIRSGGTTWYNPALKS);

[1703] VHCDR3 contains the sequence listed in SEQ ID NO: 281 (DSSGDLYAYDY);

[1704] VLCDR1 contains the sequence listed in SEQ ID NO: 282 (SGSSSNVGYGNYMA);

[1705] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS); and

[1706] VLCDR3 contains the sequence listed in SEQ ID NO: 263 (ASYDSTSGGV);

[1707] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 13 to 25 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “CB7”.

[1708] Specific binding molecules may include:

[1709] (a) A VH domain containing the sequence listed in SEQ ID NO: 515 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTNYRVGWVRQAPGKALEWVSNIRSGGTTWYNPALKSRLSITADTSKSQVSLSLSSVTTEDTAVYYCARDSSGDLYAYDYWGPGLLVTVSS); and / or

[1710] (b) A VL domain containing the sequence listed in SEQ ID NO: 516 (QAVLTQPSSVSRSLGQSVSMTCSGSSSNVGYGNYMAWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSTSGGVFGSGTRLTVLG);

[1711] Or its humanized variants.

[1712] Specific binding molecules may include:

[1713] (a) Heavy chain, the heavy chain comprising SEQ ID NO:517(QVQLQESGPSLVKPSQTLSLTCTVSGFSLTNYRVGWVRQAPGKALEWVSNIRSGGTTWYNPALKSRLSITADTSKSQVSLSLSSVTTEDTAVYYCARDSSGDLYAYDYW GPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKPC The sequences listed in PPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) are listed; and / or

[1714] (b) A light chain containing the sequences listed in SEQ ID NO: 518 (QAVLTQPSSVSRSLGQSVSMTCSGSSSNVGYGNYMAWFQQVPGSAPKLLIYGATSRASGVPDRFSGSRSGNTATLTISSLQAEDEADYYCASYDSTSGGVFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS);

[1715] Or its humanized variants.

[1716] 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).

[1717] The epitope may be located within the amino acid sequence containing residues 145 to 157 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CC7”.

[1718] 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).

[1719] 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).

[1720] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1721] VHCDR1 contains the sequence listed in SEQ ID NO: 198 (SNAVI);

[1722] VHCDR2 contains the sequence listed in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[1723] VHCDR3 contains the sequence listed in SEQ ID NO: 202(DYGSWGYVSDIDY);

[1724] VLCDR1 contains the sequence listed in SEQ ID NO: 292 (SGSYITGSSVG);

[1725] VLCDR2 contains the sequence listed in SEQ ID NO: 284 (DNNDRPS); and

[1726] VLCDR3 contains the sequence listed in SEQ ID NO: 285 (ASYDTSNIGL);

[1727] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1728] (i) having at least 85% identity with it, and / or

[1729] (ii) relative to having one, two, or three amino acid substitutions.

[1730] The specific binding molecule described herein binds to a polypeptide or protein molecule containing an amino acid sequence of residues 145 to 157 of SEQ ID NO: 1. Specific binding molecules containing CDRs that are 100% identical to those given above are referred to herein as “CC7”.

[1731] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1732] VHCDR1 contains the sequence listed in SEQ ID NO: 198 (SNAVI);

[1733] VHCDR2 contains the sequence listed in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[1734] VHCDR3 contains the sequence listed in SEQ ID NO: 202(DYGSWGYVSDIDY);

[1735] VLCDR1 contains the sequence listed in SEQ ID NO: 292 (SGSYITGSSVG);

[1736] VLCDR2 contains the sequence listed in SEQ ID NO: 284 (DNNDRPS); and

[1737] VLCDR3 contains the sequence listed in SEQ ID NO: 285 (ASYDTSNIGL).

[1738] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1739] VHFR1 contains the sequence listed in SEQ ID NO: 519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1740] VHFR2 contains the sequence listed in SEQ ID NO: 520 (WVRQAPGKAPEWVA);

[1741] VHFR3 contains the sequence listed in SEQ ID NO: 521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR);

[1742] VHFR4 contains the sequence listed in SEQ ID NO: 522 (WGPGLLVTVSS);

[1743] VLFR1 contains the sequence listed in SEQ ID NO: 523 (RVVRTQPSSVSGSLGQRVSITC);

[1744] VLFR2 contains the sequence listed in SEQ ID NO: 524 (WFQQVPGSGLKTVIY);

[1745] VLFR3 contains the sequence listed in SEQ ID NO: 525 (GVPDRFSGSKSGDTATLTISSLQAEDEADYYC);

[1746] VLFR4 contains the sequence listed in SEQ ID NO: 526 (FGSGTRLTVLG);

[1747] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1748] (i) having at least 50% similarity with it, and / or

[1749] (ii) relative to having one, two, three, four or five amino acid substitutions.

[1750] The specific binding molecule may contain backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1751] VHFR1 contains the sequence listed in SEQ ID NO: 519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1752] VHFR2 contains the sequence listed in SEQ ID NO: 520 (WVRQAPGKAPEWVA);

[1753] VHFR3 contains the sequence listed in SEQ ID NO: 521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR);

[1754] VHFR4 contains the sequence listed in SEQ ID NO: 522 (WGPGLLVTVSS);

[1755] VLFR1 contains the sequence listed in SEQ ID NO: 523 (RVVRTQPSSVSGSLGQRVSITC);

[1756] VLFR2 contains the sequence listed in SEQ ID NO: 524 (WFQQVPGSGLKTVIY);

[1757] VLFR3 contains the sequence listed in SEQ ID NO: 525 (GVPDRFSGSKSGDTATLTISSLQAEDEADYYC);

[1758] VLFR4 contains the sequence listed in SEQ ID NO: 526 (FGSGTRLTVLG);

[1759] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1760] (i) having at least 50% similarity with it, and / or

[1761] (ii) relative to having one, two, three, four, or five amino acid substitutions,

[1762] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 145 to 157 of SEQ ID NO: 1. A specific binding molecule containing a FR that is 100% identical to the given FRs described above is referred to herein as “CC7”.

[1763] Specific binding molecules may include:

[1764] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1765] VHFR1 contains the sequence listed in SEQ ID NO: 519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1766] VHFR2 contains the sequence listed in SEQ ID NO: 520 (WVRQAPGKAPEWVA);

[1767] VHFR3 contains the sequence listed in SEQ ID NO: 521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR);

[1768] VHFR4 contains the sequence listed in SEQ ID NO: 522 (WGPGLLVTVSS);

[1769] VLFR1 contains the sequence listed in SEQ ID NO: 523 (RVVRTQPSSVSGSLGQRVSITC);

[1770] VLFR2 contains the sequence listed in SEQ ID NO: 524 (WFQQVPGSGLKTVIY);

[1771] VLFR3 contains the sequence listed in SEQ ID NO: 525 (GVPDRFSGSKSGDTATLTISSLQAEDEADYYC);

[1772] VLFR4 contains the sequence listed in SEQ ID NO: 526 (FGSGTRLTVLG);

[1773] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1774] (i) having at least 50% similarity with it, and / or

[1775] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1776] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1777] VHCDR1 contains the sequence listed in SEQ ID NO: 198 (SNAVI);

[1778] VHCDR2 contains the sequence listed in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[1779] VHCDR3 contains the sequence listed in SEQ ID NO: 202(DYGSWGYVSDIDY);

[1780] VLCDR1 contains the sequence listed in SEQ ID NO: 292 (SGSYITGSSVG);

[1781] VLCDR2 contains the sequence listed in SEQ ID NO: 284 (DNNDRPS); and

[1782] VLCDR3 contains the sequence listed in SEQ ID NO: 285 (ASYDTSNIGL);

[1783] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1784] (i) having at least 85% identity with it, and / or

[1785] (ii) relative to having one, two, or three amino acid substitutions.

[1786] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 145 to 157 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “CC7”.

[1787] Specific binding molecules may include:

[1788] (a) Backbone regions (FRs) VHFR1, VHFR2, VHFR3, VHFR4, VLFR1, VLFR2, VLFR3, and VLFR4, wherein each of the FRs contains the following amino acid sequence:

[1789] VHFR1 contains the sequence listed in SEQ ID NO: 519 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLT);

[1790] VHFR2 contains the sequence listed in SEQ ID NO: 520 (WVRQAPGKAPEWVA);

[1791] VHFR3 contains the sequence listed in SEQ ID NO: 521 (RLSITRDTSKSQVSLSLRSVTTEDTAVYYCAR);

[1792] VHFR4 contains the sequence listed in SEQ ID NO: 522 (WGPGLLVTVSS);

[1793] VLFR1 contains the sequence listed in SEQ ID NO: 523 (RVVRTQPSSVSGSLGQRVSITC);

[1794] VLFR2 contains the sequence listed in SEQ ID NO: 524 (WFQQVPGSGLKTVIY);

[1795] VLFR3 contains the sequence listed in SEQ ID NO: 525 (GVPDRFSGSKSGDTATLTISSLQAEDEADYYC);

[1796] VLFR4 contains the sequence listed in SEQ ID NO: 526 (FGSGTRLTVLG);

[1797] Alternatively, for each FR sequence, there is an amino acid sequence with the following characteristics:

[1798] (i) having at least 50% similarity with it, and / or

[1799] (ii) relative to having one, two, three, four, or five amino acid substitutions; and

[1800] (b) CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs contains the following amino acid sequence:

[1801] VHCDR1 contains the sequence listed in SEQ ID NO: 198 (SNAVI);

[1802] VHCDR2 contains the sequence listed in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[1803] VHCDR3 contains the sequence listed in SEQ ID NO: 202(DYGSWGYVSDIDY);

[1804] VLCDR1 contains the sequence listed in SEQ ID NO: 292 (SGSYITGSSVG);

[1805] VLCDR2 contains the sequence listed in SEQ ID NO: 284 (DNNDRPS); and

[1806] VLCDR3 contains the sequence listed in SEQ ID NO: 285 (ASYDTSNIGL);

[1807] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 145 to 157 of SEQ ID NO: 1. Specific binding molecules containing FRs and CDRs that are 100% identical to those given above are referred to herein as “CC7”.

[1808] Specific binding molecules may include:

[1809] (a) A VH domain containing the sequence listed in SEQ ID NO: 527 (QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDYWGPGLLVTVSS); and / or

[1810] (b) A VL domain containing the sequence listed in SEQ ID NO: 528 (RVVRTQPSSVSGSLGQRVSITCSGSYITGSSVGWFQQVPGSGLKTVIYDNNDRPSGVPDRFSGSKSGDTATLTISSLQAEDEADYYCASYDTSNIGLFGSGTRLTVLG);

[1811] Or its humanized variants.

[1812] Specific binding molecules may include:

[1813] (a) Heavy chain, the heavy chain comprising SEQ ID NO:529(QVQLQESGPSLVKPSQTLSLTCTVSGFSLTSNAVIWVRQAPGKAPEWVALIDVDGDAAYDPALKSRLSITRDTSKSQVSLSLRSVTTEDTAVYYCARDYGSWGYVSDIDY WGPGLLVTVSSAKTTAPSVYPLAPVCGDTTGSSVTLGCLVKGYFPEPVTLTWNSGLSSGVHTFPAVLQSDLYTLSSSVTVTSSTWPSQSITCNVAHPASSTKVDKKIEPRGPTIKP The sequences listed in CPPCKCPAPNLLGGPSVFIFPPKIKDVLMISLSPIVTCVVVDVSEDDPDVQISWFVNNVEVHTAQTQTHREDYNSTLRVVSALPIQHQDWMSGKEFKCKVNNKDLPAPIERTISKPKGSVRAPQVYVLPPPEEEMTKKQVTLTCMVTDFMPEDIYVEWTNNGKTELNYKNTEPVLDSDGSYFMYSKLRVEKKNWVERNSYSCSVVHEGLHNHHTTKSFSRTPGK) are listed; and / or

[1814] (b) A light chain containing the sequences listed in SEQ ID NO: 530 (RVVRTQPSSVSGSLGQRVSITCSGSYITGSSVGWFQQVPGSGLKTVIYDNNDRPSGVPDRFSGSKSGDTATLTISSLQAEDEADYYCASYDTSNIGLFGSGTRLTVLGGQPKSSPSVTLFPPSSEELETNKATLVCTITDFYPGVVTVDWKVDGTPVTQGMETTQPSKQSNNKYMASSYLTLTARAWERHSSYSCQVTHEGHTVEKSLSRADCS);

[1815] Or its humanized variants.

[1816] 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 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA).

[1817] The epitope may be located within the amino acid sequence containing residues 155 to 227 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CB12” and “CC3”.

[1818] The epitope may contain the amino acid sequence of SEQ ID NO: 294 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA). 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: 294 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA).

[1819] The epitope may consist of an amino acid sequence of SEQ ID NO: 294 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA). 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: 294 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVA).

[1820] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1821] VHCDR1 contains the sequence listed in SEQ ID NO: 259 (SNGVG);

[1822] VHCDR2 contains the sequence listed in SEQ ID NO: 182 (DKSSAGKTYGNPALKS);

[1823] VHCDR3 contains the sequence listed in SEQ ID NO: 286 (CRDGGVSYGYDVDY);

[1824] VLCDR1 contains the sequence listed in SEQ ID NO: 287 (SGSSSNVGGDYVG);

[1825] VLCDR2 contains the sequence listed in SEQ ID NO: 288 (DTTSRPS); and

[1826] VLCDR3 contains the sequence listed in SEQ ID NO: 289 (ASVDKTTGGV);

[1827] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1828] (i) having at least 85% identity with it, and / or

[1829] (ii) relative to having one, two, or three amino acid substitutions.

[1830] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 155 to 227 of SEQ ID NO: 1. A specific binding molecule comprising a CDR having 100% identity with the CDRs given above is referred to herein as “CB12”.

[1831] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1832] VHCDR1 contains the sequence listed in SEQ ID NO: 259 (SNGVG);

[1833] VHCDR2 contains the sequence listed in SEQ ID NO: 182 (DKSSAGKTYGNPALKS);

[1834] VHCDR3 contains the sequence listed in SEQ ID NO: 286 (CRDGGVSYGYDVDY);

[1835] VLCDR1 contains the sequence listed in SEQ ID NO: 287 (SGSSSNVGGDYVG);

[1836] VLCDR2 contains the sequence listed in SEQ ID NO: 288 (DTTSRPS); and

[1837] VLCDR3 contains the sequence listed in SEQ ID NO: 289 (ASVDKTTGGV).

[1838] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1839] VHCDR1 contains the sequence listed in SEQ ID NO: 259 (SNGVG);

[1840] VHCDR2 contains the sequence listed in SEQ ID NO: 182 (DKSSAGKTYGNPALKS);

[1841] VHCDR3 contains the sequence listed in SEQ ID NO: 286 (CRDGGVSYGYDVDY);

[1842] VLCDR1 contains the sequence listed in SEQ ID NO: 290 (SGSSSNVGYGTYVS);

[1843] VLCDR2 contains the sequence listed in SEQ ID NO: 188 (GTTTRAS); and

[1844] VLCDR3 contains the sequence listed in SEQ ID NO: 291 (ASYDTGSGGV);

[1845] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1846] (i) having at least 85% identity with it, and / or

[1847] (ii) relative to having one, two, or three amino acid substitutions.

[1848] The specific binding molecule described herein binds to a polypeptide or protein molecule containing an amino acid sequence of residues 155 to 227 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to those given above is referred to herein as “CC3”.

[1849] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1850] VHCDR1 contains the sequence listed in SEQ ID NO: 259 (SNGVG);

[1851] VHCDR2 contains the sequence listed in SEQ ID NO: 182 (DKSSAGKTYGNPALKS);

[1852] VHCDR3 contains the sequence listed in SEQ ID NO: 286 (CRDGGVSYGYDVDY);

[1853] VLCDR1 contains the sequence listed in SEQ ID NO: 290 (SGSSSNVGYGTYVS);

[1854] VLCDR2 contains the sequence listed in SEQ ID NO: 188 (GTTTRAS); and

[1855] VLCDR3 contains the sequence listed in SEQ ID NO: 291 (ASYDTGSGGV).

[1856] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 155 to 238 of SEQ ID NO: 1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO: 295 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1857] The epitope may be located within the amino acid sequence containing residues 155 to 238 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CA1”.

[1858] The epitope may contain the amino acid sequence of SEQ ID NO: 295 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). 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 the sequence of SEQ ID NO: 295 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1859] The epitope may consist of an amino acid sequence of SEQ ID NO: 295 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS). 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: 295 (RGAAPPGQKGQANATRIPAKTPPAPKTPPSSGEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSS).

[1860] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1861] VHCDR1 contains the sequence listed in SEQ ID NO: 198 (SNAVI);

[1862] VHCDR2 contains the sequence listed in SEQ ID NO: 296 (DIRADGATNYNAALKS);

[1863] VHCDR3 contains the sequence listed in SEQ ID NO: 297 (PGNYYYGAGRDVARLAD);

[1864] VLCDR1 contains the sequence listed in SEQ ID NO: 298 (SGSSSNIGGGNAVG);

[1865] VLCDR2 contains the sequence listed in SEQ ID NO: 288 (DTTSRPS); and

[1866] VLCDR3 contains the sequence listed in SEQ ID NO: 299 (AAMDSSSLIGV);

[1867] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1868] (i) having at least 85% identity with it, and / or

[1869] (ii) relative to having one, two, or three amino acid substitutions.

[1870] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 155 to 238 of SEQ ID NO: 1. A specific binding molecule comprising a CDR having 100% identity with the CDRs given above is referred to herein as “CA1”.

[1871] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 186 to 263 of SEQ ID NO: 1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO: 300 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGST).

[1872] The epitope may be located within the amino acid sequence containing residues 186 to 263 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CA3”.

[1873] The epitope may contain the amino acid sequence of SEQ ID NO: 300 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGST). 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: 300 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGST).

[1874] The epitope may consist of an amino acid sequence of SEQ ID NO: 300 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGST). 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: 300 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGST).

[1875] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1876] VHCDR1 contains the sequence listed in SEQ ID NO: 259 (SNGVG);

[1877] VHCDR2 contains the sequence listed in SEQ ID NO: 182 (DKSSAGKTYGNPALKS);

[1878] VHCDR3 contains the sequence listed in SEQ ID NO: 184 (CRDGGVTYGYDVDY);

[1879] VLCDR1 contains the sequence listed in SEQ ID NO: 301 (SGSSGNIGYDDYVS);

[1880] VLCDR2 contains the sequence listed in SEQ ID NO: 302 (GATRRSS); and

[1881] VLCDR3 contains the sequence listed in SEQ ID NO: 303 (ASYDSSGGGV);

[1882] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1883] (i) having at least 85% identity with it, and / or

[1884] (ii) relative to having one, two, or three amino acid substitutions.

[1885] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 186 to 263 of SEQ ID NO: 1. A specific binding molecule comprising a CDR that is 100% identical to the CDRs given above is referred to herein as “CA3”.

[1886] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 186 to 350 of SEQ ID NO: 1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO: 304 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRV).

[1887] The epitope may be located within the amino acid sequence containing residues 186 to 350 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as "CD2".

[1888] Epitopes may contain the amino acid sequence of SEQ ID NO: 304 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRV). 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: 304 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRV).

[1889] Epitopes can be composed of the amino acid sequence of SEQ ID NO: 304 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRV). 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: 304 (GEPPKSGDRSGYSSPGSPGTPGSRSRTPSLPTPPTREPKKVAVVRTPPKSPSSAKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRV).

[1890] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1891] VHCDR1 contains the sequence listed in SEQ ID NO: 198 (SNAVI);

[1892] VHCDR2 contains the sequence listed in SEQ ID NO: 200 (LIDVDGDAAYDPALKS);

[1893] VHCDR3 contains the sequence listed in SEQ ID NO: 202(DYGSWGYVSDIDY);

[1894] VLCDR1 contains the sequence listed in SEQ ID NO: 305 (SGSNIGDADVG);

[1895] VLCDR2 contains the sequence listed in SEQ ID NO: 306 (YNENRPS); and

[1896] VLCDR3 contains the sequence listed in SEQ ID NO: 307 (GSYAGDTYNHGV);

[1897] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1898] (i) having at least 85% identity with it, and / or

[1899] (ii) relative to having one, two, or three amino acid substitutions.

[1900] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 186 to 350 of SEQ ID NO: 1. A specific binding molecule comprising a CDR having 100% identity with the CDRs given above is referred to herein as “CD2”.

[1901] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 239 to 348 of SEQ ID NO: 1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO: 308 (AKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKD).

[1902] The epitope may be located within the amino acid sequence containing residues 239 to 348 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CB9”.

[1903] The epitope may contain the amino acid sequence of SEQ ID NO: 308 (AKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKD).

[1904] (AKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKD) has an amino acid sequence with at least 70%, at least 75%, at least 80%, at least 90%, at least 95%, or at least 99% identity.

[1905] 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: 308 (AKSRLQTAPVPMPDLKNVKSKIGSTENLKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKD).

[1906] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1907] VHCDR1 contains the sequence listed in SEQ ID NO: 42 (SNSVG);

[1908] VHCDR2 contains the sequence listed in SEQ ID NO: 48 (GIDSDGEEGYNPALNS);

[1909] VHCDR3 contains the sequence listed in SEQ ID NO: 54 (SYRADGLAYGYVQAIDY);

[1910] VLCDR1 contains the sequence listed in SEQ ID NO: 67 (SGRFIGISSVG);

[1911] VLCDR2 contains the sequence listed in SEQ ID NO: 70 (ASDGRPS); and

[1912] VLCDR3 contains the sequence listed in SEQ ID NO: 74 (GSSDRTQYTGV);

[1913] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1914] (i) having at least 85% identity with it, and / or

[1915] (ii) relative to having one, two, or three amino acid substitutions.

[1916] The specific binding molecule described herein binds to a polypeptide or protein molecule containing the amino acid sequence of residues 239 to 348 of SEQ ID NO: 1. A specific binding molecule containing a CDR that is 100% identical to those given above is referred to herein as “CB9”.

[1917] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 266 to 359 of SEQ ID NO: 1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO: 309 (LKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDN).

[1918] The epitope may be located within the amino acid sequence containing residues 266 to 359 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CG11”.

[1919] 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: 309 (LKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDN).

[1920] 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 the amino acid sequence of SEQ ID NO: 309 (LKHQPGGGKVQIINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVTSKCGSLGNIHHKPGGGQVEVKSEKLDFKDRVQSKIGSLDN).

[1921] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1922] VHCDR1 contains the sequence listed in SEQ ID NO: 310 (NYPVG);

[1923] VHCDR2 contains the sequence listed in SEQ ID NO: 311 (NIENDGSANYASALKS);

[1924] VHCDR3 contains the sequence listed in SEQ ID NO: 312 (EFGGSDGYTYFVDIDY);

[1925] VLCDR1 contains the sequence listed in SEQ ID NO: 313 (SGSSSNVGYGNYVS);

[1926] VLCDR2 contains the sequence listed in SEQ ID NO: 141 (GATSRAS); and

[1927] VLCDR3 contains the sequence listed in SEQ ID NO: 314 (ASYDGSSSGV);

[1928] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1929] (i) having at least 85% identity with it, and / or

[1930] (ii) relative to having one, two, or three amino acid substitutions.

[1931] The specific binding molecule described herein binds to a polypeptide or protein molecule comprising an amino acid sequence containing residues 266 to 359 of SEQ ID NO: 1. A specific binding molecule comprising a CDR having 100% identity with the CDRs given above is referred to herein as “CG11”.

[1932] The epitope that specifically binds to the molecule can be located within the amino acid sequence containing residues 277 to 319 of SEQ ID NO: 1. Therefore, the epitope can be located within the amino acid sequence of SEQ ID NO: 315 (IINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[1933] The epitope may be located within the amino acid sequence containing residues 277 to 319 of SEQ ID NO: 1. This epitope can bind to the CDR of a specific binding molecule referred to herein as “CA10”.

[1934] The epitope may contain the amino acid sequence of SEQ ID NO: 315 (IINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT). 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: 315 (IINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[1935] The epitope may consist of the amino acid sequence of SEQ ID NO: 315 (IINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT). 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: 315 (IINKKLDLSNVQSKCGSKDNIKHVPGGGSVQIVYKPVDLSKVT).

[1936] The specific binding molecule may comprise CDRs VHCDR1, VHCDR2, VHCDR3, VLCDR1, VLCDR2, and VLCDR3, wherein each of the CDRs comprises the following amino acid sequence:

[1937] VHCDR1 contains the sequence listed in SEQ ID NO: 259 (SNGVG);

[1938] VHCDR2 contains the sequence listed in SEQ ID NO: 157 (DISSVGKKYANPALKS);

[1939] VHCDR3 contains the sequence listed in SEQ ID NO: 161 (CRDGGVTYGYDIDY);

[1940] VLCDR1 contains the sequence listed in SEQ ID NO: 316 (SGSSSNVGYGNYVT);

[1941] VLCDR2 contains the sequence listed in SEQ ID NO: 317 (DATTRVS); and

[1942] VLCDR3 contains the sequence listed in SEQ ID NO: 318 (AAHDSSSGGV);

[1943] Alternatively, for each CDR sequence, there is an amino acid sequence with the following characteristics:

[1944] (i) having at least 85% identity with it, and / or

[1945] (ii) relative to having one, two, or three amino acid substitutions.

[1946] The specific binding molecule described herein binds to a polypeptide or protein molecule contain...

Claims

1. An anti-Tau antibody or an antibody fragment thereof, comprising a VH domain and a VL domain, wherein the VH domain comprises the sequence shown in SEQ ID NO: 443, and the VL domain comprises the sequence shown in SEQ ID NO: 444, wherein the antibody fragment is a Fab or F(ab')2 antibody fragment, or an scFv molecule.

2. The anti-Tau antibody or antibody fragment thereof according to claim 1, wherein, (a) The antibody or its antibody fragment is humanized; and / or (b) The antibody is a monoclonal antibody.

3. A composition comprising the anti-Tau antibody or an antibody fragment thereof according to claim 1 or 2, wherein at least 90% of the anti-Tau antibody or antibody fragment thereof binds to the epitope in SEQ ID NO: 1 at a Kc concentration of less than 25 nM. D Combine.

4. A nucleic acid molecule comprising a nucleic acid sequence encoding an anti-Tau antibody or an antibody fragment thereof as claimed in claim 1 or 2.

5. The nucleic acid molecule according to claim 4, wherein, The nucleic acid sequence includes the nucleic acid sequence shown in SEQ ID NO:

380.

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

7. A delivery vector comprising a nucleic acid molecule according to claim 4 or 5 or a construct according to claim 6.

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

9. A method for preparing the anti-Tau antibody or an antibody fragment thereof according to claim 1 or 2, comprising: i) Introducing the nucleic acid molecule according to claim 4 or 5, the construct according to claim 6, or the vector according to claim 7 into a host cell; ii) Expressing the nucleic acid molecule to produce the anti-Tau antibody or an antibody fragment thereof; as well as iii) Collect the anti-Tau antibody or its antibody fragment.

10. The method according to claim 9, wherein, The anti-Tau antibody or its antibody fragments are collected through purification.

11. An anti-Tau antibody or an antibody fragment thereof that can be obtained by the method according to claim 9.

12. A pharmaceutical composition comprising an anti-Tau antibody or an antibody fragment thereof as claimed in claim 1 or 2, or a composition as claimed in claim 3, and one or more pharmaceutically acceptable carriers.

13. Use of the anti-Tau antibody or antibody fragment thereof according to claim 1 or 2, the composition according to claim 3, or the pharmaceutical composition according to claim 12 in the preparation of a medicament for treating Tau disease.

14. The use according to claim 13, wherein, The tau diseases selected are from the following groups: Alzheimer's disease, primary age-related tau disease (PART), senile dementia with neurofibrillary tangles, chronic traumatic encephalopathy (CTE), progressive supranuclear palsy (PSP), corticobasal degeneration (CBD), frontotemporal dementia (FTD), frontotemporal dementia and Parkinson's syndrome associated with chromosome 17 (FTDP-17), Pick's disease, disinhibition-dementia-Parkinson's syndrome-amyotrophic lateral sclerosis (DDPAC), globus pallidus-pons-substantia nigra degeneration (PPND), Guam-ALS syndrome, globus pallidus-substantia nigra - Subthalamic nucleus degeneration (PNLD), aurophilic dementia (AgD), Down syndrome (DS), Lewy body dementia (DLB), post-encephalitis Parkinson's syndrome (PEP), boxing dementia (DP), traumatic brain injury (TBI), stroke, ischemia, Lytico-bodig disease (Guam Parkinson's dementia syndrome), ganglioglioma, gangliocytoma, meningioma, post-encephalitis Parkinson's syndrome, subacute sclerosing panencephalitis (SSPE), lead poisoning encephalopathy, tuberous sclerosis, pantothenic kinase-related neurodegeneration, lipofuscinosis, and mild cognitive impairment (MCI).

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

16. A diagnostic apparatus for an in vitro method of detecting tau protein or a fragment thereof in a sample, wherein the diagnostic apparatus comprises an anti-Tau antibody or an antibody fragment thereof as claimed in claim 1 or 2.

17. A kit comprising an anti-Tau antibody or an antibody fragment thereof as claimed in claim 1 or 2 and reagents for detecting tau protein or a fragment thereof in a sample.

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