US2023287098A1PendingUtilityA1
Polypeptides
Assignee: SORRISO PHARMACEUTICALS INCPriority: Mar 31, 2015Filed: Apr 18, 2023Published: Sep 14, 2023
Est. expiryMar 31, 2035(~8.7 yrs left)· nominal 20-yr term from priority
C07K 16/241A61K 9/0014A61K 2039/542A61K 2039/505C07K 2317/94C07K 2317/92C07K 2317/76C07K 2317/567C07K 2317/565C07K 2317/33C07K 2317/22A61K 9/19A61K 31/606A61K 31/7088A61K 31/713A61K 38/00A61K 45/06A61P 1/04A61P 1/16A61P 3/10A61P 17/00A61P 17/06A61P 29/00A61P 37/02A61P 37/04A61P 43/00C07K 2317/30C07K 2317/54C07K 2317/55C07K 2317/569Y02A50/30C07K 16/24
75
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Claims
Abstract
There is provided inter alia a polypeptide comprising an immunoglobulin chain variable domain which binds to TNF-alpha, wherein the immunoglobulin chain variable domain comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR1-CDR3 and FR1-FR4 are as defined in the specification.
Claims
exact text as granted — not AI-modified1 . A polypeptide comprising an immunoglobulin chain variable domain which binds to TNF-alpha, wherein the immunoglobulin chain variable domain comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR1 comprises a sequence sharing 60% or greater sequence identity with SEQ ID NO: 1, CDR2 comprises a sequence sharing 50% or greater sequence identity with SEQ ID NO: 2 and
(a) CDR3 comprises a sequence sharing 80% or greater sequence identity with SEQ ID NO: 3 or (b) CDR3 comprises a sequence sharing 50% or greater sequence identity with SEQ ID NO: 3 and wherein the residue of CDR3 corresponding to residue number 3 of SEQ ID NO: 3 is R, D, N, C, E, Q, G, H, I, L, K, M, F, P, S, T, W, Y or V.
2 . The polypeptide according to claim 1 , wherein CDR3 comprises a sequence sharing 80% or greater sequence identity with SEQ ID NO: 3.
3 . The polypeptide according to claim 2 , wherein CDR3 consists of a sequence sharing 80% or greater sequence identity with SEQ ID NO: 3.
4 . The polypeptide according to either claim 2 or 3 , wherein any residues of CDR3 differing from their corresponding residues in SEQ ID NO: 3 are conservative substitutions with respect to their corresponding residues.
5 . The polypeptide according to either claim 2 or 3 , wherein the residue of CDR3 corresponding to residue number 3 of SEQ ID NO: 3 is R, H, D, E, N, Q, S, T, Y, G, A, V, L, W, P, M, C, F or I, for example, is R, H, D, E, N, Q, S, T, Y, G, V, L, W, P, M, C, F or I.
6 . The polypeptide according to claim 5 , wherein the residue of CDR3 corresponding to residue number 3 of SEQ ID NO: 3 is H.
7 . The polypeptide according to claim 6 , wherein the residue of CDR3 corresponding to residue number 3 of SEQ ID NO: 3 is H and any other residues of CDR3 differing from their corresponding residues in SEQ ID NO: 3 are conservative substitutions with respect to their corresponding residues.
8 . The polypeptide according to claim 2 , wherein CDR3 comprises SEQ ID NO: 3.
9 . The polypeptide according to claim 3 , wherein CDR3 consists of SEQ ID NO: 3.
10 . The polypeptide according to claim 1 wherein CDR3 comprises a sequence sharing 50% or greater sequence identity with SEQ ID NO: 3 and wherein the residue of CDR3 corresponding to residue number 3 of SEQ ID NO: 3 is R, D, N, C, E, Q, G, H, I, L, K, M, F, P, S, T, W, Y or V, for example, is R, D, N, C, E, Q, G, H, I, L, M, F, P, S, T, W, Y or V.
11 . The polypeptide according to claim 10 , wherein CDR3 comprises a sequence sharing 60% or greater sequence identity, such as sharing 80% or greater sequence identity, with SEQ ID NO: 3 and wherein the residue of CDR3 corresponding to residue number 3 of SEQ ID NO: 3 is R, D, N, C, E, Q, G, H, I, L, K, M, F, P, S, T, W, Y or V, for example, is R, D, N, C, E, Q, G, H, I, L, M, F, P, S, T, W, Y or V.
12 . The polypeptide according to claim 11 , wherein CDR3 consists of a sequence sharing 60% or greater sequence identity, such as sharing 80% or greater sequence identity, with SEQ ID NO: 3 and wherein residue number 3 of SEQ ID NO: 3 is R, D, N, C, E, Q, G, H, I, L, K, M, F, P, S, T, W, Y or V, for example, is R, D, N, C, E, Q, G, H, I, L, M, F, P, S, T, W, Y or V.
13 . The polypeptide according to any one of claims 10 to 12 , wherein residue number 3 of SEQ ID NO: 3 is H or a conservative substitution of H.
14 . The polypeptide according to claim 13 , wherein residue number 3 of SEQ ID NO: 3 is H.
15 . The polypeptide according to any one of claims 10 to 12 , wherein residue number 3 of SEQ ID NO: 3 is H or a conservative substitution of H and any other residues of CDR3 differing from their corresponding residues in SEQ ID NO: 3 are conservative substitutions.
16 . The polypeptide according to claim 15 , wherein residue number 3 of SEQ ID NO: 3 is H and any other residues of CDR3 differing from their corresponding residues in SEQ ID NO: 3 are conservative substitutions.
17 . The polypeptide according to claim 12 , wherein the sequence of CDR3 is SEQ ID NO: 3, SEQ ID NO: 70, SEQ ID NO: 71 or SEQ ID NO: 72.
18 . The polypeptide according to any one of claims 1 to 17 , wherein CDR1 comprises a sequence sharing 80% or greater sequence identity with SEQ ID NO: 1.
19 . The polypeptide according to claim 18 , wherein CDR1 consists of a sequence sharing 80% or greater sequence identity with SEQ ID NO: 1.
20 . The polypeptide according to any one of claims 1 to 19 , wherein any residues of CDR1 differing from their corresponding residues in SEQ ID NO: 1 are conservative substitutions with respect to their corresponding residues.
21 . The polypeptide according to claim 18 , wherein CDR1 comprises SEQ ID NO: 1.
22 . The polypeptide according to claim 19 , wherein CDR1 consists of SEQ ID NO: 1.
23 . The polypeptide according to claim 1 to 17 , wherein the sequence of CDR1 is SEQ ID NO: 1, SEQ ID NO: 59 or SEQ ID NO: 60.
24 . The polypeptide according to any one of claims 1 to 23 , wherein CDR2 comprises a sequence sharing 55% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 2.
25 . The polypeptide according to claim 24 , wherein CDR2 consists of a sequence sharing 55% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 2.
26 . The polypeptide according to any one of claims 1 to 25 , wherein the residue of CDR2 corresponding to residue number 10 of SEQ ID NO: 2 is R, H, D, E, N, Q, S, T, Y, G, A, V, L, W, P, M, C, F or 1.
27 . The polypeptide according to claim 26 , wherein the residue of CDR2 corresponding to residue number 10 of SEQ ID NO: 2 is H.
28 . The polypeptide according to any one of claims 1 to 25 , wherein any residues of CDR2 differing from their corresponding residues in SEQ ID NO: 2 are conservative substitutions with respect to their corresponding residues.
29 . The polypeptide according to claim 24 , wherein CDR2 comprises SEQ ID NO: 2.
30 . The polypeptide according to claim 25 , wherein CDR2 consists of SEQ ID NO: 2.
31 . The polypeptide according to any one of claims 1 to 23 wherein the sequence of CDR2 is SEQ ID NO: 61, SEQ ID NO: 62, SEQ ID NO: 2, SEQ ID NO: 63, SEQ ID NO: 64, SEQ ID NO: 65, SEQ ID NO: 66, SEQ ID NO: 67, SEQ ID NO: 68, SEQ ID NO: 69.
32 . The polypeptide according to any one of claims 1 to 31 , wherein FR1 comprises a sequence sharing 5% or greater sequence identity, such as sharing 12% or greater sequence identity, such as sharing 18% or greater sequence identity, such as sharing 26% or greater sequence identity, such as sharing 32% or greater sequence identity, such as sharing 38% or greater sequence identity, such as sharing 46% or greater sequence identity, such as sharing 52% or greater sequence identity, such as sharing 58% or greater sequence identity, such as sharing 62% or greater sequence identity, such as sharing 66% or greater sequence identity, such as sharing 68% or greater sequence identity, such as sharing 72% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 78% or greater sequence identity, such as sharing 82% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 95% or greater sequence identity, with SEQ ID NO: 4.
33 . The polypeptide according to claim 32 , wherein FR1 consists of a sequence sharing 5% or greater sequence identity, such as sharing 12% or greater sequence identity, such as sharing 18% or greater sequence identity, such as sharing 26% or greater sequence identity, such as sharing 32% or greater sequence identity, such as sharing 38% or greater sequence identity, such as sharing 46% or greater sequence identity, such as sharing 52% or greater sequence identity, such as sharing 58% or greater sequence identity, such as sharing 62% or greater sequence identity, such as sharing 66% or greater sequence identity, such as sharing 68% or greater sequence identity, such as sharing 72% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 78% or greater sequence identity, such as sharing 82% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 95% or greater sequence identity, with SEQ ID NO: 4.
34 . The polypeptide according to any one of claims 1 to 33 , wherein the residue of FR1 corresponding to residue number 1 of SEQ ID NO: 4 is G, A, V, L, I, F, P, S, T, Y, C, M, K, R, H, W, D, E or N.
35 . The polypeptide according to claim 34 , wherein the residue of FR1 corresponding to residue number 1 of SEQ ID NO: 4 is D or E.
36 . The polypeptide according to claim 35 , wherein the residue of FR1 corresponding to residue number 1 of SEQ ID NO: 4 is D.
37 . The polypeptide according to any one of claims 1 to 36 , wherein the residue of FR1 corresponding to residue number 5 of SEQ ID NO: 4 is G, A, V, L, I, F, P, S, T, Y, C, M, K, R, H, W, D, E or N.
38 . The polypeptide according to claim 37 , wherein the residue of FR1 corresponding to residue number 5 of SEQ ID NO: 4 is V.
39 . The polypeptide according to either claim 37 or 38 , wherein the residues of FR1 corresponding to residue numbers 1 to 5 of SEQ ID NO: 4 are DVQLV.
40 . The polypeptide according to any one of claims 1 to 39 , wherein the residue of FR1 corresponding to residue number 20 of SEQ ID NO: 4 is an amino acid which is hydrophobic.
41 . The polypeptide according to claim 40 , wherein the residue of FR1 corresponding to residue number 20 of SEQ ID NO: 4 is L.
42 . The polypeptide according to any one of claims 1 to 41 , wherein the residue of FR1 corresponding to residue number 24 of SEQ ID NO: 4 is an amino acid which is hydrophobic.
43 . The polypeptide according to claim 42 , wherein the residue of FR1 corresponding to residue number 24 of SEQ ID NO: 4 is A.
44 . The polypeptide according to any one of claims 1 to 43 , wherein the residue of FR1 corresponding to residue number 29 of SEQ ID NO: 4 is F.
45 . The polypeptide according to any one of claims 1 to 33 , wherein any residues of FR1 differing from their corresponding residues in SEQ ID NO: 4 are conservative substitutions with respect to their corresponding residues.
46 . The polypeptide according to claim 32 , wherein FR1 comprises SEQ ID NO: 4.
47 . The polypeptide according to claim 33 , wherein FR1 consists of SEQ ID NO: 4.
48 . The polypeptide according to any one of claims 1 to 47 , wherein FR2 comprises a sequence sharing 10% or greater sequence identity, such as sharing 15% or greater sequence identity, such as sharing 25% or greater sequence identity, such as sharing 30% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 45% or greater sequence identity, such as sharing 55% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 5.
49 . The polypeptide according to claim 48 , wherein FR2 consists of a sequence sharing 10% or greater sequence identity, such as sharing 15% or greater sequence identity, such as sharing 25% or greater sequence identity, such as sharing 30% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 45% or greater sequence identity, such as sharing 55% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 5.
50 . The polypeptide according to any one of claims 1 to 49 , wherein the residues of FR2 corresponding to residue numbers 8 to 11 of SEQ ID NO: 5 are KEXE, wherein X is R or L.
51 . The polypeptide according to claim 50 , wherein X is L.
52 . The polypeptide according to claim 50 , wherein X is R.
53 . The polypeptide according to any one of claims 1 to 49 , wherein the residues of FR2 corresponding to residue numbers 9 to 12 of SEQ ID NO: 5 are GLEW.
54 . The polypeptide according to any one of claims 1 to 49 , wherein any residues of FR2 differing from their corresponding residues in SEQ ID NO: 5 are conservative substitutions with respect to their corresponding residues.
55 . The polypeptide according to claim 48 , wherein FR2 comprises SEQ ID NO: 5.
56 . The polypeptide according to claim 49 , wherein FR2 consists of SEQ ID NO: 5.
57 . The polypeptide according to any one of claims 1 to 56 , wherein FR3 comprises a sequence sharing 8% or greater sequence identity, such as sharing 15% or greater sequence identity, such as sharing 20% or greater sequence identity, such as sharing 26% or greater sequence identity, such as sharing 32% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 45% or greater sequence identity, such as sharing 52% or greater sequence identity, such as sharing 58% or greater sequence identity, such as sharing 65% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 76% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 82% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 92% or greater sequence identity, such as sharing 95% or greater sequence identity, with SEQ ID NO: 6.
58 . The polypeptide according to claim 57 , wherein FR3 consists of a sequence sharing 8% or greater sequence identity, such as sharing 15% or greater sequence identity, such as sharing 20% or greater sequence identity, such as sharing 26% or greater sequence identity, such as sharing 32% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 45% or greater sequence identity, such as sharing 52% or greater sequence identity, such as sharing 58% or greater sequence identity, such as sharing 65% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 76% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 82% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 92% or greater sequence identity, such as sharing 95% or greater sequence identity, with SEQ ID NO: 6.
59 . The polypeptide according to any one of claims 1 to 58 , wherein the residue of FR3 corresponding to residue number 26 of SEQ ID NO: 6 is an amino acid which is hydrophobic.
60 . The polypeptide according to claim 59 , wherein the residue of FR3 corresponding to residue number 26 of SEQ ID NO: 6 is A.
61 . The polypeptide according to any one of claims 1 to 60 , wherein any residues of FR3 differing from their corresponding residues in SEQ ID NO: 6 are conservative substitutions with respect to their corresponding residues.
62 . The polypeptide according to claim 57 , wherein FR3 comprises SEQ ID NO: 6.
63 . The polypeptide according to claim 58 , wherein FR3 consists of SEQ ID NO: 6.
64 . The polypeptide according to any one of claims 1 to 63 , wherein FR4 comprises a sequence sharing 5% or greater sequence identity, such as sharing 10% or greater sequence identity, such as sharing 20% or greater sequence identity, such as sharing 30% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 50% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 7.
65 . The polypeptide according to claim 64 , wherein FR4 consists of a sequence sharing 5% or greater sequence identity, such as sharing 10% or greater sequence identity, such as sharing 20% or greater sequence identity, such as sharing 30% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 50% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 7.
66 . The polypeptide according to any one of claims 1 to 65 , wherein any residues of FR4 differing from their corresponding residues in SEQ ID NO: 7 are conservative substitutions with respect to their corresponding residues.
67 . The polypeptide according to claim 64 , wherein FR4 comprises SEQ ID NO: 7.
68 . The polypeptide according to claim 65 wherein FR4 consists of SEQ ID NO: 7.
69 . The polypeptide according to any one of claims 1 to 68 which comprises a sequence sharing 50% or greater sequence identity, such as sharing 55% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 65% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 95% or greater sequence identity, such as sharing 96% or greater sequence identity, such as sharing 97% or greater sequence identity, such as sharing 98% or greater sequence identity, such as sharing 99% or greater sequence identity, with SEQ ID NO: 8.
70 . The polypeptide according to claim 69 which consists of a sequence sharing 50% or greater sequence identity, such as sharing 55% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 65% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 95% or greater sequence identity, such as sharing 96% or greater sequence identity, such as sharing 97% or greater sequence identity, such as sharing 98% or greater sequence identity, such as sharing 99% or greater sequence identity, with SEQ ID NO: 8.
71 . The polypeptide according to any one of claims 1 to 70 , wherein the N-terminus of the polypeptide is D.
72 . The polypeptide according to claim 69 which comprises SEQ ID NO: 8.
73 . The polypeptide according to claim 70 which consists of SEQ ID NO: 8.
74 . A polypeptide comprising an immunoglobulin chain variable domain which binds to TNF-alpha, wherein the immunoglobulin chain variable domain comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR1 comprises a sequence sharing 60% or greater sequence identity with SEQ ID NO: 15 CDR2 comprises a sequence sharing 50% or greater sequence identity with SEQ ID NO: 16 and CDR3 comprises a sequence sharing 50% or greater sequence identity with SEQ ID NO: 17.
75 . The polypeptide according to claim 74 , wherein CDR3 comprises a sequence sharing 60% or greater sequence identity, such as 80% or greater sequence identity, with SEQ ID NO: 17.
76 . The polypeptide according to claim 75 , wherein CDR3 consists of a sequence sharing 60% or greater sequence identity, such as 80% or greater sequence identity, with SEQ ID NO: 17.
77 . The polypeptide according to any one of claims 74 to 76 , wherein any residues of CDR3 differing from their corresponding residues in SEQ ID NO: 17 are conservative substitutions with respect to their corresponding residues.
78 . The polypeptide according to claim 74 , wherein the sequence of CDR3 is SEQ ID NO: 78, SEQ ID NO: 79, SEQ ID NO: 17 or SEQ ID NO: 80.
79 . The polypeptide according to claim 75 , wherein CDR3 comprises SEQ ID NO: 17.
80 . The polypeptide according to claim 76 , wherein CDR3 consists of SEQ ID NO: 17.
81 . The polypeptide according to any one of claims 74 to 80 , wherein CDR1 comprises a sequence sharing 80% or greater sequence identity with SEQ ID NO: 15.
82 . The polypeptide according to any one of claims 74 to 80 , wherein CDR1 consists of a sequence sharing 80% or greater sequence identity with SEQ ID NO: 15.
83 . The polypeptide according to any one of claims 74 to 82 , wherein any residues of CDR1 differing from their corresponding residues in SEQ ID NO: 15 are conservative substitutions with respect to their corresponding residues.
84 . The polypeptide according to claim 81 , wherein CDR1 comprises SEQ ID NO: 15.
85 . The polypeptide according to claim 82 , wherein CDR1 consists of SEQ ID NO: 15.
86 . The polypeptide according to any one of claims 74 to 85 , wherein CDR2 comprises a sequence sharing 55% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 16.
87 . The polypeptide according to claim 86 , wherein CDR2 consists of a sequence sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 16.
88 . The polypeptide according to any one of claims 74 to 87 , wherein the residue of CDR2 corresponding to residue number 10 of SEQ ID NO: 16 is R, H, D, E, N, Q, S, T, Y, G, A, V, L, W, P, M, C, F or I.
89 . The polypeptide according to claim 88 , wherein the residue of CDR2 corresponding to residue number 10 of SEQ ID NO: 16 is H.
90 . The polypeptide according to any one of claims 74 to 89 , wherein the residue of CDR2 corresponding to residue number 16 of SEQ ID NO: 16 is R, H, D, E, N, Q, S, T, Y, G, A, V, L, W, P, M, C, F or I.
91 . The polypeptide according to claim 90 , wherein the residue of CDR2 corresponding to residue number 16 of SEQ ID NO: 16 is H.
92 . The polypeptide according to any one of claims 74 to 87 , wherein any residues of CDR2 differing from their corresponding residues in SEQ ID NO: 16 are conservative substitutions with respect to their corresponding residues.
93 . The polypeptide according to claim 86 , wherein CDR2 comprises SEQ ID NO: 16.
94 . The polypeptide according to claim 87 , wherein CDR2 consists of SEQ ID NO: 16.
95 . The polypeptide according to claim 74 wherein the sequence of CDR2 is SEQ ID NO: 73, SEQ ID NO: 74, SEQ ID NO: 75, SEQ ID NO: 76, SEQ ID NO: 77 or SEQ ID NO: 16.
96 . The polypeptide according to any one of claims 74 to 95 , wherein FR1 comprises a sequence sharing 5% or greater sequence identity, such as sharing 12% or greater sequence identity, such as sharing 18% or greater sequence identity, such as sharing 26% or greater sequence identity, such as sharing 32% or greater sequence identity, such as sharing 38% or greater sequence identity, such as sharing 46% or greater sequence identity, such as sharing 52% or greater sequence identity, such as sharing 58% or greater sequence identity, such as sharing 62% or greater sequence identity, such as sharing 66% or greater sequence identity, such as sharing 68% or greater sequence identity, such as sharing 72% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 78% or greater sequence identity, such as sharing 82% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 95% or greater sequence identity, with SEQ ID NO: 18.
97 . The polypeptide according to claim 96 , wherein FR1 consists of a sequence sharing 5% or greater sequence identity, such as sharing 12% or greater sequence identity, such as sharing 18% or greater sequence identity, such as sharing 26% or greater sequence identity, such as sharing 32% or greater sequence identity, such as sharing 38% or greater sequence identity, such as sharing 46% or greater sequence identity, such as sharing 52% or greater sequence identity, such as sharing 58% or greater sequence identity, such as sharing 62% or greater sequence identity, such as sharing 66% or greater sequence identity, such as sharing 68% or greater sequence identity, such as sharing 72% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 78% or greater sequence identity, such as sharing 82% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 95% or greater sequence identity, with SEQ ID NO: 18.
98 . The polypeptide according to any one of claims 74 to 97 , wherein the residue of FR1 corresponding to residue number 1 of SEQ ID NO: 4 is G, A, V, L, I, F, P, S, T, Y, C, M, K, R, H, W, D, E or N.
99 . The polypeptide according to claim 98 , wherein the residue of FR1 corresponding to residue number 1 of SEQ ID NO: 18 is D or E.
100 . The polypeptide according to claim 99 , wherein the residue of FR1 corresponding to residue number 1 of SEQ ID NO: 18 is D.
101 . The polypeptide according to any one of claims 74 to 100 , wherein the residue of FR1 corresponding to residue number 5 of SEQ ID NO: 18 is G, A, V, L, I, F, P, S, T, Y, C, M, K, R, H, W, D, E or N.
102 . The polypeptide according to claim 101 , wherein the residue of FR1 corresponding to residue number 5 of SEQ ID NO: 4 is V.
103 . The polypeptide according to any one of claims 96 to 102 , wherein the residues of FR1 corresponding to residue numbers 1 to 5 of SEQ ID NO: 18 are DVQLV.
104 . The polypeptide according to any one of claims 74 to 103 , wherein the residue of FR1 corresponding to residue number 20 of SEQ ID NO: 18 is an amino acid which is hydrophobic.
105 . The polypeptide according to claim 104 , wherein the residue of FR1 corresponding to residue number 20 of SEQ ID NO: 18 is L.
106 . The polypeptide according to any one of claims 74 to 105 , wherein the residue of FR1 corresponding to residue number 29 of SEQ ID NO: 18 is F.
107 . The polypeptide according to any one of claims 74 to 97 , wherein any residues of FR1 differing from their corresponding residues in SEQ ID NO: 18 are conservative substitutions with respect to their corresponding residues.
108 . The polypeptide according to claim 96 , wherein FR1 comprises SEQ ID NO: 18.
109 . The polypeptide according to claim 97 , wherein FR1 consists of SEQ ID NO: 18.
110 . The polypeptide according to any one of claims 74 to 109 , wherein FR2 comprises a sequence sharing 10% or greater sequence identity, such as sharing 15% or greater sequence identity, such as sharing 25% or greater sequence identity, such as sharing 30% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 45% or greater sequence identity, such as sharing 55% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 19.
111 . The polypeptide according to claim 110 , wherein FR2 consists of a sequence sharing 10% or greater sequence identity, such as sharing 15% or greater sequence identity, such as sharing 25% or greater sequence identity, such as sharing 30% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 45% or greater sequence identity, such as sharing 55% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 19.
112 . The polypeptide according to any one of claims 74 to 111 , wherein the residues of FR2 corresponding to residue numbers 8 to 11 of SEQ ID NO: 19 are KELE.
113 . The polypeptide according to any one of claims 74 to 111 , wherein any residues of FR2 differing from their corresponding residues in SEQ ID NO: 19 are conservative substitutions with respect to their corresponding residues.
114 . The polypeptide according to claim 110 , wherein FR2 comprises SEQ ID NO: 19.
115 . The polypeptide according to claim 111 , wherein FR2 consists of SEQ ID NO: 19.
116 . The polypeptide according to any one of claims 74 to 115 , wherein FR3 comprises a sequence sharing 8% or greater sequence identity, such as sharing 15% or greater sequence identity, such as sharing 20% or greater sequence identity, such as sharing 26% or greater sequence identity, such as sharing 32% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 45% or greater sequence identity, such as sharing 52% or greater sequence identity, such as sharing 58% or greater sequence identity, such as sharing 65% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 76% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 82% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 92% or greater sequence identity, such as sharing 95% or greater sequence identity, with SEQ ID NO: 20.
117 . The polypeptide according to claim 116 , wherein FR3 consists of a sequence sharing 8% or greater sequence identity, such as sharing 15% or greater sequence identity, such as sharing 20% or greater sequence identity, such as sharing 26% or greater sequence identity, such as sharing 32% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 45% or greater sequence identity, such as sharing 52% or greater sequence identity, such as sharing 58% or greater sequence identity, such as sharing 65% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 76% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 82% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 92% or greater sequence identity, such as sharing 95% or greater sequence identity, with SEQ ID NO: 20.
118 . The polypeptide according to any one of claims 74 to 117 , wherein the residue of FR3 corresponding to residue number 26 of SEQ ID NO: 20 is an amino acid which is hydrophobic.
119 . The polypeptide according to claim 118 , wherein the residue of FR3 corresponding to residue number 26 of SEQ ID NO: 20 is A.
120 . The polypeptide according to any one of claims 74 to 117 , wherein any residues of FR3 differing from their corresponding residues in SEQ ID NO: 20 are conservative substitutions with respect to their corresponding residues.
121 . The polypeptide according to claim 116 , wherein FR3 comprises SEQ ID NO: 20.
122 . The polypeptide according to claim 117 , wherein FR3 consists of SEQ ID NO: 20.
123 . The polypeptide according to any one of claims 74 to 122 , wherein FR4 comprises a sequence sharing 5% or greater sequence identity, such as sharing 10% or greater sequence identity, such as sharing 20% or greater sequence identity, such as sharing 30% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 50% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 21.
124 . The polypeptide according to claim 123 , wherein FR4 consists of a sequence sharing 5% or greater sequence identity, such as sharing 10% or greater sequence identity, such as sharing 20% or greater sequence identity, such as sharing 30% or greater sequence identity, such as sharing 40% or greater sequence identity, such as sharing 50% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 90% or greater sequence identity, with SEQ ID NO: 21.
125 . The polypeptide according to any one of claims 74 to 124 , wherein the residue of FR4 corresponding to residue number 1 of SEQ ID NO: 21 is R, H, D, E, N, Q, S, T, Y, G, A, V, L, W, P, M, C, F or I.
126 . The polypeptide according to claim 125 , wherein the residue of FR4 corresponding to residue number 1 of SEQ ID NO: 21 is H.
127 . The polypeptide according to any one of claims 74 to 126 , wherein any residues of FR4 differing from their corresponding residues in SEQ ID NO: 21 are conservative substitutions with respect to their corresponding residues.
128 . The polypeptide according to claim 123 , wherein FR4 comprises SEQ ID NO: 21.
129 . The polypeptide according to claim 124 wherein FR4 consists of SEQ ID NO: 21.
130 . The polypeptide according to any one of claims 74 to 129 which comprises a sequence sharing 50% or greater sequence identity, such as sharing 55% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 65% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 95% or greater sequence identity, such as sharing 96% or greater sequence identity, such as sharing 97% or greater sequence identity, such as sharing 98% or greater sequence identity, such as sharing 99% or greater sequence identity, with SEQ ID NO: 22.
131 . The polypeptide according to claim 130 which consists of a sequence sharing 50% or greater sequence identity, such as sharing 55% or greater sequence identity, such as sharing 60% or greater sequence identity, such as sharing 65% or greater sequence identity, such as sharing 70% or greater sequence identity, such as sharing 75% or greater sequence identity, such as sharing 80% or greater sequence identity, such as sharing 85% or greater sequence identity, such as sharing 90% or greater sequence identity, such as sharing 95% or greater sequence identity, such as sharing 96% or greater sequence identity, such as sharing 97% or greater sequence identity, such as sharing 98% or greater sequence identity, such as sharing 99% or greater sequence identity, with SEQ ID NO: 22.
132 . The polypeptide according to claim 130 which comprises SEQ ID NO: 22.
133 . The polypeptide according to claim 131 which consists of SEQ ID NO: 22.
134 . The polypeptide according to any one of claims 74 to 133 , wherein the N-terminus of the polypeptide is D.
135 . The polypeptide according to any one of claims 1 to 134 , wherein the polypeptide is an antibody.
136 . The polypeptide according to any one of claims 1 to 135 , wherein the polypeptide is an antibody fragment.
137 . The polypeptide according to claim 136 , which is selected from the list consisting of: a VHH, a VH, a VL, a V-NAR, a Fab fragment and a F(ab′)2 fragment.
138 . The polypeptide according to claim 137 , wherein the polypeptide is a VHH.
139 . The polypeptide according to claim 137 , wherein the polypeptide is a VH.
140 . A construct comprising two or more identical polypeptides according to any one of claims 1 to 139 .
141 . A construct comprising at least one polypeptide according to any one of claims 1 to 139 and at least one different polypeptide, wherein the different polypeptide binds to TNF-alpha.
142 . A construct comprising at least one polypeptide according to any one of claims 1 to 139 and at least one different polypeptide, wherein the different polypeptide binds to a target other than TNF-alpha.
143 . The construct according to any one of claims 140 to 142 wherein the polypeptides are connected by at least one protease-labile linker.
144 . The construct according to claim 143 , wherein the protease-labile linker is of the format
[-(G 4 S) x BJB′-(G 4 S) y -] z
wherein
J is lysine or arginine;
x is 1 to 10;
y is 1 to 10;
z is 1 to 10;
B is 0 to 5 amino acid residues selected from R, H, N, Q, S, T, Y, G, A, V, L, W, P, M, C, F, K or I; and
B′ is 0 to 5 amino acid residues selected from R, H, N, Q, S, T, Y, G, A, V, L, W, M, C, F, K or I.
145 . The construct according to claim 144 wherein J is lysine, B is 0, x is 1, y is 1 and z is 1.
146 . The construct according to any one of claims 140 to 142 wherein the polypeptides are all connected by non-protease-labile linkers.
147 . The construct according to claim 146 , wherein the non-protease-labile linkers are of the format
(G 4 S) x wherein
x is 1 to 10.
148 . The construct according to claim 147 wherein x is 6.
149 . The polypeptide or construct according to any one of claims 1 to 148 , which neutralizes human TNF-alpha cytotoxicity in the normal L929 assay with an EC50 of 1 nM or less, such as 0.9 nM or less, such as 0.8 nM or less, such as 0.7 nM or less, such as 0.6 nM or less, such as 0.5 nM or less, such as 0.4 nM or less, such as 0.3 nM or less, such as 0.2 nM or less, such as 0.1 nM or less, such as 0.09 nM or less, such as 0.08 nM or less, such as 0.07 nM or less, such as 0.06 nM or less, such as 0.05 nM or less, such as 0.04 nM or less.
150 . The polypeptide or construct according to any one of claims 1 to 149 , which neutralizes cynomolgus monkey TNF-alpha cytotoxicity in the normal L929 assay with an EC50 of 1 nM or less, such as 0.9 nM or less, such as 0.8 nM or less, such as 0.7 nM or less, such as 0.6 nM or less, such as 0.5 nM or less, such as 0.4 nM or less, such as 0.3 nM or less, such as 0.2 nM or less, such as 0.1 nM or less, such as 0.09 nM or less, such as 0.08 nM or less, such as 0.07 nM or less, such as 0.06 nM or less, such as 0.05 nM or less, such as 0.04 nM or less, such as 0.03 nM or less, such as 0.02 nM or less, such as 0.01 nM or less.
151 . The polypeptide or construct according to any one of claims 1 to 150 , which is substantially resistant to one or more proteases.
152 . The polypeptide or construct according to claim 151 , wherein the one or more proteases are present in the stomach or the small or large intestine.
153 . The polypeptide or construct according to claim 152 , wherein the one or more proteases are present in the small intestine.
154 . The polypeptide or construct according to claim 151 , wherein the one or more proteases are selected from the group consisting of enteropeptidase, trypsin, chymotrypsin and inflammatory bowel disease inflammatory proteases.
155 . The polypeptide or construct according to claim 154 , wherein the one or more proteases are selected from the group consisting of trypsin, chymotrypsin and inflammatory bowel disease inflammatory proteases.
156 . The polypeptide or construct according to either claim 154 or 155 , wherein the inflammatory bowel disease inflammatory proteases are one or more proteases selected from the group consisting of MMP3, MMP12 and cathepsin.
157 . The polypeptide or construct according to claim 155 , wherein the proteases are trypsin and chymotrypsin.
158 . A pharmaceutical composition comprising the polypeptide or construct according to any one of claims 1 to 157 and one or more pharmaceutically acceptable diluents or carriers.
159 . The pharmaceutical composition according to claim 158 wherein the composition is presented in enterically coated form.
160 . The pharmaceutical composition according to either claim 158 or 159 comprising at least one further active agent.
161 . The pharmaceutical composition according to claim 160 wherein the at least one further active agent is selected from the list consisting of: 5-aminosalicylic acid, or a prodrug thereof (such as sulfasalazine, olsalazine or bisalazide); corticosteroids (e.g. prednisolone, methylprednisolone, or budesonide); immunosuppressants (e.g. cyclosporin, tacrolimus, methotrexate, azathioprine or 6-mercaptopurine); anti-TNF-alpha antibodies (e.g., infliximab, adalimumab, certolizumab pegol or golimumab); anti-IL12/IL23 antibodies (e.g., ustekinumab); anti-IL6R antibodies or small molecule IL12/IL23 inhibitors (e.g., apilimod); Anti-alpha-4-beta-7 antibodies (e.g., vedolizumab); MAdCAM-1 blockers (e.g., PF-00547659); antibodies against the cell adhesion molecule alpha-4-integrin (e.g., natalizumab); antibodies against the IL2 receptor alpha subunit (e.g., daclizumab or basiliximab); JAK3 inhibitors (e.g., tofacitinib or R348); Syk inhibitors and prodrugs thereof (e.g., fostamatinib and R-406); Phosphodiesterase-4 inhibitors (e.g., tetomilast); HMPL-004; probiotics; Dersalazine; semapimod/CPSI-2364; and protein kinase C inhibitors (e.g. AEB-071).
162 . The pharmaceutical composition according to claim 161 wherein the at least one further active agent is 5-aminosalicylic acid.
163 . The polypeptide, pharmaceutical composition or construct according to any one of claims 1 to 162 for use as a medicament.
164 . The polypeptide, pharmaceutical composition or construct according to claim 163 for use in the treatment of an autoimmune and/or inflammatory disease.
165 . The polypeptide, pharmaceutical composition or construct according to claim 164 wherein the autoimmune and/or inflammatory disease is selected from the list consisting of Crohn's disease, ulcerative colitis, irritable bowel disease, diabetes type II, glomerulonephritis, autoimmune hepatitis, Sjogren's syndrome, celiac disease, drug- or radiation-induced mucositis, pemphigus, psoriasis, eczema and scleroderma.
166 . The polypeptide, pharmaceutical composition or construct for use according to claim 165 , wherein the autoimmune and/or inflammatory disease is Crohn's disease.
167 . The polypeptide, pharmaceutical composition or construct for use according to any one of claims 163 to 166 , which is administered orally.
168 . The polypeptide, pharmaceutical composition or construct for use according to any one of claims 163 to 166 , which is administered topically to the skin.
169 . Use of the polypeptide, pharmaceutical composition or construct according to any one of claims 1 to 162 in the manufacture of a medicament for the treatment of autoimmune and/or inflammatory disease.
170 . Use of the polypeptide, pharmaceutical composition or construct according to claim 169 wherein the autoimmune and/or inflammatory disease is selected from the list consisting of Crohn's disease, ulcerative colitis, irritable bowel disease, diabetes type II, glomerulonephritis, autoimmune hepatitis, Sjogren's syndrome, celiac disease, drug- or radiation-induced mucositis, pemphigus, psoriasis, eczema and scleroderma.
171 . The use according to claim 170 wherein the autoimmune and/or inflammatory disease is Crohn's disease.
172 . The use according to any one of claims 169 to 171 wherein the medicament is administered orally.
173 . The use according to any one of claims 169 to 171 wherein the medicament is administered topically to the skin.
174 . A method of treating autoimmune and/or inflammatory disease comprising administering to a person in need thereof a therapeutically effective amount of the polypeptide, pharmaceutical composition or construct according to any one of claims 1 to 162 .
175 . The method of treating autoimmune and/or inflammatory disease according to claim 174 wherein the autoimmune and/or inflammatory disease is selected from the list consisting of Crohn's disease, ulcerative colitis, irritable bowel syndrome, diabetes type II, glomerulonephritis, autoimmune hepatitis, Sjogren's syndrome, celiac disease, drug- or radiation-induced mucositis, pemphigus, psoriasis, eczema and scleroderma.
176 . The method of treating autoimmune disease according to claim 175 wherein the autoimmune disease is Crohn's disease.
177 . The method of treating autoimmune disease according to any one of claims 174 to 176 wherein the polypeptide, pharmaceutical composition or construct is administered orally.
178 . The method of treating autoimmune disease according to any one of claims 174 to 176 wherein the polypeptide, pharmaceutical composition or construct is administered topically to the skin.
179 . The polypeptide, pharmaceutical composition, construct, use or method according to any one of claims 163 to 178 wherein the polypeptide, pharmaceutical composition or construct is administered sequentially, simultaneously or separately with at least one active agent selected from the list consisting of 5-aminosalicylic acid, or a prodrug thereof (such as sulfasalazine, olsalazine or bisalazide); corticosteroids (e.g. prednisolone, methylprednisolone, or budesonide); immunosuppressants (e.g. cyclosporin, tacrolimus, methotrexate, azathioprine or 6-mercaptopurine); anti-TNF-alpha antibodies (e.g., infliximab, adalimumab, certolizumab pegol or golimumab); anti-IL12/IL23 antibodies (e.g., ustekinumab); anti-IL6R antibodies or small molecule IL12/IL23 inhibitors (e.g., apilimod); Anti-alpha-4-beta-7 antibodies (e.g., vedolizumab); MAdCAM-1 blockers (e.g., PF-00547659); antibodies against the cell adhesion molecule alpha-4-integrin (e.g., natalizumab); antibodies against the IL2 receptor alpha subunit (e.g., daclizumab or basiliximab); JAK3 inhibitors (e.g., tofacitinib or R348); Syk inhibitors and prodrugs thereof (e.g., fostamatinib and R-406); Phosphodiesterase-4 inhibitors (e.g., tetomilast); HMPL-004; probiotics; Dersalazine; semapimod/CPSI-2364; and protein kinase C inhibitors (e.g. AEB-071).
180 . The polypeptide, pharmaceutical composition, construct or method according to claim 179 wherein the polypeptide, pharmaceutical composition or construct is administered sequentially, simultaneously or separately with infliximab, adalimumab, certolizumab pegol or golimumab.
181 . A polynucleotide comprising or consisting of a sequence sharing 70% or greater, such as 80% or greater, such as 90% or greater, such as 95% or greater, such as 99% or greater sequence identity with any one of the portions of any one of SEQ ID NOs: 83 to 86 which encode CDR1, CDR2 or CDR3 of the encoded immunoglobulin chain variable domain.
182 . A polynucleotide encoding the polypeptide or construct according to any one of claims 1 to 157 .
183 . The polynucleotide according to claim 182 , wherein the polynucleotide comprises or consists of a sequence sharing 70% or greater, such as 80% or greater, such as 90% or greater, such as 95% or greater, such as 99% or greater sequence identity with any one of SEQ ID NOs: 83 to 88.
184 . The polynucleotide according to claim 183 , wherein the polynucleotide comprises or consists of any one of SEQ ID NOs: 83 to 88.
185 . A cDNA comprising the polynucleotide according to any one of claims 182 to 184 .
186 . A vector comprising the polynucleotide or cDNA according to any one of claims 182 to 185 .
187 . A host cell transformed with a vector according to claim 186 and which is capable of expressing the polypeptide or construct according to any one of claims 1 to 157 .
188 . The host cell transformed with a vector according to claim 187 wherein the host cell is a yeast cell such as S. cerevisiae.
189 . The host cell transformed with a vector according to claim 187 wherein the host cell is a bacterial cell such as E. coli.
190 . A process for the preparation of the polypeptide or construct according to any one of claims 1 to 157 , comprising the following steps:
i) cloning into a vector, such as a plasmid, the polynucleotide according to any one of claims 182 to 184 ,
ii) transforming a cell, such as a bacterial cell or a yeast cell capable of producing the polypeptide or construct according to any one of claims 1 to 157 , with said vector in conditions allowing the production of the polypeptide or construct,
iii) recovering the polypeptide or construct, such as by affinity chromatography.
191 . A polypeptide comprising an immunoglobulin chain variable domain which binds to TNF-alpha, wherein the immunoglobulin chain variable domain comprises three complementarity determining regions (CDR1-CDR3) and four framework regions (FR1-FR4), wherein CDR3 comprises a sequence sharing 80% or greater sequence identity with SEQ ID NO: 3.
192 . The polypeptide according to claim 191 , wherein CDR3 consists of a sequence sharing 80% or greater sequence identity with SEQ ID NO: 3.
193 . The polypeptide according to either claim 191 or 192 , wherein any residues of CDR3 differing from their corresponding residues in SEQ ID NO: 3 are conservative substitutions with respect to their corresponding residues.
194 . The polypeptide according to either claim 191 or 192 , wherein the residue of CDR3 corresponding to residue number 3 of SEQ ID NO: 3 is R, H, D, E, N, Q, S, T, Y, G, A, V, L, W, P, M, C, F or I.
195 . The polypeptide according to claim 194 , wherein the residue of CDR3 corresponding to residue number 3 of SEQ ID NO: 3 is H.
196 . The polypeptide according to claim 191 , wherein CDR3 comprises SEQ ID NO: 3.
197 . The polypeptide according to claim 196 , wherein CDR3 consists of SEQ ID NO: 3.Cited by (0)
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