US2016009796A9PendingUtilityA9
Heparin-Binding Epidermal Growth Factor-like Growth Factor Binding Proteins
Est. expirySep 26, 2027(~1.2 yrs left)· nominal 20-yr term from priority
A61P 35/04A61P 37/06A61P 9/10A61P 35/00A61P 35/02A61P 3/10A61P 27/02A61P 3/00A61P 29/00A61P 1/04A61P 13/12A61P 17/06A61P 19/02A61P 11/00C07K 2317/76C07K 2317/565C07K 16/22C07K 2317/56A61K 39/39558C07K 2317/73A61K 2039/505C07K 2317/92C07K 16/2863A61K 45/06C07K 2317/34A61K 2300/00A61K 2039/507C07K 2317/567C07K 2317/21C07K 2317/54C07K 2317/55C07K 16/36
45
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Claims
Abstract
Provided herein are antigen binding proteins, e.g., human and/or monoclonal antibodies that have affinity for heparin-binding epidermal growth factor-like growth factor (HB-EGF) and neutralize the biological functions of this growth factor.
Claims
exact text as granted — not AI-modified1 . An isolated antigen binding protein that binds HB-EGF, comprising:
A) one or more light chain complementary determining regions (CDRLs) selected from the group consisting of:
(i) a CDRL1 selected from the group consisting of SEQ ID NOs:189-217;
(ii) a CDRL2 selected from the group consisting of SEQ ID NOs:218-233;
(iii) a CDRL3 selected from the group consisting of SEQ ID NOs:234-274; and
(iv) a CDRL of (i), (ii) or (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than four amino acids; or
B) one or more heavy chain complementary determining regions (CDRHs) selected from the group consisting of:
(i) a CDRH1 selected from the group consisting of SEQ ID NOs:275-299;
(ii) a CDRH2 selected from the group consisting of SEQ ID NOs:300-331;
(iii) a CDRH3 selected from the group consisting of SEQ ID NOs:332-372; and
(iv) a CDRH of (i), (ii) or (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than four amino acids.
2 . The isolated antigen binding protein of claim 1 , comprising one or more light chain CDRLs of A), and one or more heavy chain CDRHs of B).
3 . The isolated antigen binding protein of claim 1 that comprises at least two CDRLs of A) and at least two CDRHs of B).
4 . The isolated antigen binding protein of claim 1 that comprises said CDRH1, CDRH2, CDRH3, CDRL1, CDRL2 and CDRL3.
5 . The isolated antigen binding protein of claim 1 , wherein
said CDRL of A) is selected from the group consisting of:
(i) a CDRL1 selected from the group consisting of SEQ ID NOs:189-217;
(ii) a CDRL2 selected from the group consisting of SEQ ID NOs:218-233;
(iii) a CDRL3 selected from the group consisting of SEQ ID NOs:234-274; and
(iv) a CDRL of (i), (ii) or (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than two amino acids;
said CDRH of B) is selected from the group consisting of:
(i) a CDRH1 selected from the group consisting of SEQ ID NOs:275-299;
(ii) a CDRH2 selected from the group consisting of SEQ ID NOs:300-331;
(iii) a CDRH3 selected from the group consisting of SEQ ID NOs:332-372; and
(iv) a CDRH of (i), (ii) or (iii) that contains one or more amino acid substitutions, deletions or insertions of no more than two amino acids;
or C) one or more light chain CDRLs of A) and one or more heavy chain CDRHs of B).
6 . The isolated antigen binding protein of claim 1 , wherein said antigen binding protein comprises
A) a CDRL selected from the group consisting of
(i) a CDRL1 selected from the group consisting of SEQ ID NOs:189-217;
(ii) a CDRL2 selected from the group consisting of SEQ ID NOs:218-233; and
(iii) a CDRL3 selected from the group consisting of SEQ ID NOs:234-274;
B) a CDRH selected from the group consisting of
(i) a CDRH1 selected from the group consisting of SEQ ID NOs:275-299;
(ii) a CDRH2 selected from the group consisting of SEQ ID NOs:300-331; and
(iii) a CDRH3 selected from the group consisting of SEQ ID NOs:332-372;
or C) one or more light chain CDRLs of A) and one or more heavy chain CDRHs of B).
7 . The isolated antigen binding protein of claim 6 , wherein said antigen binding protein comprises
A) a CDRL1 of SEQ ID NOs:189-217, a CDRL2 of SEQ ID NOs:218-233, and a CDRL3 of SEQ ID NOs:234-274, and/or B) a CDRH1 of SEQ ID NOs:275-299, a CDRH2 of SEQ ID NOs:300-331, and a CDRH3 of SEQ ID NOs:332-372.
8 . The isolated antigen binding protein of claim 1 , wherein said antigen binding protein comprises a light chain variable region (V L ) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs:94-141, and/or a heavy chain variable region (V H ) having at least 80% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs:142-186.
9 . The isolated antigen binding protein of claim 8 , wherein the V L has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs:94-141, and/or the V H has at least 90% sequence identity with an amino acid sequence selected from the group consisting of SEQ ID NOs:142-186.
10 . The isolated antigen binding protein of claim 8 , wherein the V L is selected from the group consisting of SEQ ID NOs:94-141, and/or the V H is selected from the group consisting of SEQ ID NOs:142-186.
11 . An isolated antigen binding protein that specifically recognizes at least an IHGE-containing epitope and/or an EGF-like domain of HB-EGF.
12 . An isolated antigen binding protein that competes for binding with the antigen binding protein of claim 1 .
13 . An isolated antigen binding protein that binds HB-EGF, wherein said antigen binding protein comprises:
A) one or more light chain CDRs (CDRLs) selected from the group consisting of:
(i) a CDRL1 with at least 80% sequence identity to SEQ ID NOs:189-217;
(ii) a CDRL2 with at least 80% sequence identity to SEQ ID NOs:218-233; and
(iii) a CDRL3 with at least 80% sequence identity to SEQ ID NOs:234-274;
B) one or more heavy chain CDRs (CDRHs) selected from the group consisting of:
(i) a CDRH1 with at least 80% sequence identity to SEQ ID NOs:275-299;
(ii) a CDRH2 with at least 80% sequence identity to SEQ ID NOs:300-331; and
(iii) a CDRH3 with at least 80% sequence identity to SEQ ID NOs:332-372;
or C) one or more light chain CDRLs of A) and one or more heavy chain CDRHs of B).
14 . The isolated antigen binding protein of claim 13 , wherein said antigen binding protein comprises:
A) one or more CDRLs selected from the group consisting of:
(i) a CDRL1 with at least 90% sequence identity to SEQ ID NOs:189-217;
(ii) a CDRL2 with at least 90% sequence identity to SEQ ID NOs:218-233; and
(iii) a CDRL3 with at least 90% sequence identity to SEQ ID NOs:234-274;
B) one or more CDRHs selected from the group consisting of:
(i) a CDRH1 with at least 90% sequence identity to SEQ ID NOs:275-299;
(ii) a CDRH2 with at least 90% sequence identity to SEQ ID NOs:300-331; and
(iii) a CDRH3 with at least 90% sequence identity to SEQ ID NOs:332-372;
or
C) one or more light chain CDRLs of A) and one or more heavy chain CDRHs of B).
15 . An isolated antigen binding protein that binds HB-EGF, the antigen binding protein comprising:
A) a light chain complementary determining region (CDRL) selected from the group consisting of
(i) a CDRL3 selected from the group consisting of SEQ ID NOs:234-274,
(ii) a CDRL3 that differs in amino acid sequence from the CDRL3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and
(iii) a CDRL3 amino acid sequence selected from the group consisting of
X 1 QX 2 X 3 X 4 X 5 PX 6 X 7 ,
(SEQ ID NO: 1046)
wherein
X 1 is selected from the group consisting of I and M,
X 2 is selected from the group consisting of A, G and S,
X 3 is selected from the group consisting of I and T,
X 4 is selected from the group consisting of H and Q,
X 5 is selected from the group consisting of F, L and W,
7X 6 is selected from the group consisting of C, I, H, L and T,
X 7 is selected from the group consisting of S and T;
QQX 1 X 2 X 3 X 4 X 5 IT,
(SEQ ID NO: 1047)
wherein
X 1 is selected from the group consisting of I and S,
X 2 is selected from the group consisting of F and Y,
X 3 is selected from the group consisting of F, I, S and Y,
X 4 is selected from the group consisting of A, S and T,
X 5 is selected from the group consisting of P and S;
X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 T,
(SEQ ID NO: 1048)
wherein
X 1 is selected from the group consisting of L and Q,
X 2 is selected from the group consisting of K, N and Q,
X 3 is selected from the group consisting of A, H, S and Y,
X 4 is selected from the group consisting of H, N and Y,
X 5 is selected from the group consisting of N, S and T,
X 6 is selected from the group consisting of A, F, I, T, V and Y,
X 7 is selected from the group consisting of P and no amino acid,
X 8 is selected from the group consisting of F, L and P;
QX 1 X 2 DX 3 LPX 4 X 5 ,
(SEQ ID NO: 1049)
wherein
X 1 is selected from the group consisting of H and Q,
X 2 is selected from the group consisting of C and Y,
X 3 is selected from the group consisting of D, I, N, S and Y,
X 4 is selected from the group consisting of F, I and L,
X 5 is selected from the group consisting of A, S and T;
QQX 1 X 2 X 3 X 4 PX 5 X 6 X 7 ,
(SEQ ID NO: 1050)
wherein
X 1 is selected from the group consisting of H and Y,
X 2 is selected from the group consisting of G and N,
X 3 is selected from the group consisting of N and S,
X 4 is selected from the group consisting of S and W,
X 5 is selected from the group consisting of P and no amino acid,
X 6 is selected from the group consisting of R and W,
X 7 is selected from the group consisting of S and T; and
X 1 QYX 2 X 3 X 4 X 5 X 6 X 7 F,
(SEQ ID NO: 1051)
wherein
X 1 is selected from the group consisting of H and Q,
X 2 is selected from the group consisting of F and Y,
X 3 is selected from the group consisting of G, I and S,
X 4 is selected from the group consisting of F, I and T,
X 5 is selected from the group consisting of M, P, S and T,
X 6 is selected from the group consisting of F, L, R and W,
X 7 is selected from the group consisting of S and T; and/or
B) a heavy chain complementary determining region (CDRH) selected from the group consisting of
(i) a CDRH3 selected from the group consisting of SEQ ID NOs:332-372,
(ii) a CDRH3 that differs in amino acid sequence from the CDRH3 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids; and
(iii) a CDRH3 amino acid sequence selected from the group consisting of
X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 DX 12 ,
(SEQ ID NO: 1065)
wherein
X 1 is selected from the group consisting of E and S,
X 2 is selected from the group consisting of D, G and no amino acid,
X 3 is selected from the group consisting of D, N and no amino acid,
X 4 is selected from the group consisting of G and no amino acid,
X 5 is selected from the group consisting of G and no amino acid,
X 6 is selected from the group consisting of W, Y and no amino acid,
X 7 is selected from the group consisting of I, N and Y,
X 8 is selected from the group consisting of A and Y,
X 9 is selected from the group consisting of G, V and Y,
X 10 is selected from the group consisting of A, F and G,
X 11 is selected from the group consisting of F, L and M,
X 12 is selected from the group consisting of V and Y;
(SEQ ID NO: 1066)
QX 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 YX 12 X 13 X 14 DX 15 ,
wherein
X 1 is selected from the group consisting of G and no amino acid,
X 2 is selected from the group consisting of K, L and Y,
X 3 is selected from the group consisting of A, G and S,
X 4 is selected from the group consisting of S, V and Y,
X 5 is selected from the group consisting of A and G,
X 6 is selected from the group consisting of G and no amino acid,
X 7 is selected from the group consisting of T and no amino acid,
X 8 is selected from the group consisting of S and no amino acid,
X 9 is selected from the group consisting of Y and no amino acid,
X 10 is selected from the group consisting of W and Y,
X 11 is selected from the group consisting of G, S and Y,
X 12 is selected from the group consisting of F and Y,
X 13 is selected from the group consisting of G and no amino acid,
X 14 is selected from the group consisting of M and no amino acid,
X 15 is selected from the group consisting of V and Y;
(SEQ ID NO: 1067)
X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 ,
wherein
X 1 is selected from the group consisting of D, G, L, S and no amino acid,
X 2 is selected from the group consisting of G, H, W, Y and no amino acid,
X 3 is selected from the group consisting of A, F, W, Y and no amino acid,
X 4 is selected from the group consisting of D, G, Q, T and no amino acid,
X 5 is selected from the group consisting of G, I, Q, S and no amino acid,
X 6 is selected from the group consisting of A, D, N, Q, S and no amino acid,
X 7 is selected from the group consisting of G, Y and no amino acid,
X 8 is selected from the group consisting of D, Y and no amino acid,
X 9 is selected from the group consisting of Y and no amino acid,
X 10 is selected from the group consisting of A, E, N and Y,
X 11 is selected from the group consisting of G, P, T, V and Y,
X 12 is selected from the group consisting of F and I,
X 13 is selected from the group consisting of D and Q,
X 14 is selected from the group consisting of C, H, V and Y;
(SEQ ID NO: 1068)
X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 DX 18 ,
wherein
X 1 is selected from the group consisting of E, D and no amino acid,
X 2 is selected from the group consisting of G, R and no amino acid,
X 3 is selected from the group consisting of I, V, Y and no amino acid,
X 4 is selected from the group consisting of A, G, L and N,
X 5 is selected from the group consisting of A, G, V and W,
X 6 is selected from the group consisting of A, N, R and T,
X 7 is selected from the group consisting of G, N, P and no amino acid,
X 8 is selected from the group consisting of G, T and no amino acid,
X 9 is selected from the group consisting of A and no amino acid,
X 10 is selected from the group consisting of D, E and no amino acid,
X 11 is selected from the group consisting of S, Y and no amino acid,
X 12 is selected from the group consisting of G, Y and no amino acid,
X 13 is selected from the group consisting of N, Y and no amino acid,
X 14 is selected from the group consisting of Y and no amino acid,
X 15 is selected from the group consisting of D, Y and no amino acid,
X 16 is selected from the group consisting of A, G and no amino acid,
X 17 is selected from the group consisting of F and M,
X 18 is selected from the group consisting of I, V and Y:
(SEQ ID NO: 1069)
X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 X 19 X 20 X 21
X 22 X 23 ,
wherein
X 1 is selected from the group consisting of A, D, G, S and T,
X 2 is selected from the group consisting of A, E, G, L, N, R, Y and no amino acid,
X 3 is selected from the group consisting of A, G, L, N, R, T, Y and no amino acid,
X 4 is selected from the group consisting of D, G, R, S, V, Y and no amino acid,
X 5 is selected from the group consisting of A, G, I, S, V, Y and no amino acid,
X 6 is selected from the group consisting of F, G, L, R, V and no amino acid,
X 7 is selected from the group consisting of L, T, Y and no amino acid,
X 8 is selected from the group consisting of Y and no amino acid,
X 9 is selected from the group consisting of Y and no amino acid,
X 10 is selected from the group consisting of D and no amino acid,
X 11 is selected from the group consisting of S and no amino acid,
X 12 is selected from the group consisting of S and no amino acid,
X 13 is selected from the group consisting of G and no amino acid,
X 14 is selected from the group consisting of D, L, M, S, Y and no amino acid,
X 15 is selected from the group consisting of H, I, P, V, W and no amino acid,
X 16 is selected from the group consisting of F, G, L, R, S, Y and no amino acid,
X 17 is selected from the group consisting of D, F, V, W, Y and no amino acid,
X 18 is selected from the group consisting of C, F, L, P, S and Y,
X 19 is selected from the group consisting of D, F, G and Y,
X 20 is selected from the group consisting of A, C, G, P, R, V and Y,
X 21 is selected from the group consisting of F, L, M, S and no amino acid,
X 22 is selected from the group consisting of A, D and no amino acid,
X 23 is selected from the group consisting of I, L, V, Y and no amino acid;
X 1 YSSGWX 2 X 3 YGX 4 X 5 DX 6 ,
(SEQ ID NO: 1070)
wherein
X 1 is selected from the group consisting of M and V,
X 2 is selected from the group consisting of S and no amino acid,
X 3 is selected from the group consisting of F and no amino acid,
X 4 is selected from the group consisting of V and no amino acid,
X 5 is selected from the group consisting of F and M,
X 6 is selected from the group consisting of V and Y; and
RX 1 X 2 X 3 PFX 4 Y,
(SEQ ID NO: 1071)
wherein
X 1 is selected from the group consisting of G, H, L, N and R,
X 2 is selected from the group consisting of E, T and W,
X 3 is selected from the group consisting of L, N, T and V,
X 4 is selected from the group consisting of D and E.
16 . The isolated antigen binding protein of claim 15 , said antigen binding protein further comprising:
A) a CDRL selected from the group consisting of:
(i) a CDRL1 selected from the group consisting of SEQ ID NOs:189-217;
(ii) a CDRL1 that differs in amino acid sequence from the CDRL1 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids;
(iii) a CDRL1 amino acid sequence selected from the group consisting of
X 1 SSQSLX 2 X 3 SDGX 4 TYLX 5 ,
(SEQ ID NO: 1035)
wherein
X 1 is selected from the group consisting of K and R,
X 2 is selected from the group consisting of L and V,
X 3 is selected from the group consisting of H and Y,
X 4 is selected from the group consisting of K and N,
X 5 is selected from the group consisting of N, S and Y;
RASQX 1 ISX 2 YLN,
(SEQ ID NO: 1036)
wherein
X 1 is selected from the group consisting of R, S and T,
X 2 is selected from the group consisting of R and S;
RASQX 1 IX 2 X 3 X 4 LX 5 ,
(SEQ ID NO: 1037)
wherein
X 1 is selected from the group consisting of D, G, S and T,
X 2 is selected from the group consisting of A, R and S,
X 3 is selected from the group consisting of H, I, N, R, S and T,
X 4 is selected from the group consisting of D, W and Y,
X 5 is selected from the group consisting of A, G and N;
QASQDIX 1 X 2 X 3 LN,
(SEQ ID NO: 1038)
wherein
X 1 is selected from the group consisting of S and T,
X 2 is selected from the group consisting of D and N,
X 3 is selected from the group consisting of S and Y;
RASQX 1 VX 2 X 3 X 4 X 5 LA,
(SEQ ID NO: 1039)
wherein
X 1 is selected from the group consisting of S and T,
X 2 is selected from the group consisting of I and S,
X 3 is selected from the group consisting of R and S,
X 4 is selected from the group consisting of S, N and no amino acid,
X 5 is selected from the group consisting of Y and no amino acid; and
KSSQX 1 X 2 LX 3 X 4 SNNKNYLX 5 ,
(SEQ ID NO: 1040)
wherein
X 1 is selected from the group consisting of N and S,
X 2 is selected from the group consisting of I and V,
X 3 is selected from the group consisting of D and Y,
X 4 is selected from the group consisting of N, R and S,
X 5 is selected from the group consisting of A and V;
(iv) a CDRL2 selected from the group consisting of SEQ ID NOs:218-233;
(v) a CDRL2 that differs in amino acid sequence from the CDRL2 of (iv) by an amino acid addition, deletion or substitution of not more than two amino acids; and
(vi) a CDRL2 amino acid sequence selected from the group consisting of
X 1 X 2 SNX 3 X 4 S,
(SEQ ID NO: 1041)
wherein
X 1 is selected from the group consisting of E and K,
X 2 is selected from the group consisting of I and V,
X 3 is selected from the group consisting of R and W,
X 4 is selected from the group consisting of D and F;
X 1 X 2 SX 3 LQS,
(SEQ ID NO: 1042)
wherein
X 1 is selected from the group consisting of A and T,
X 2 is selected from the group consisting of A, E and V,
X 3 is selected from the group consisting of S and T;
X 1 ASX 2 LQS,
(SEQ ID NO: 1043)
wherein
X 1 is selected from the group consisting of A and V,
X 2 is selected from the group consisting of S and T;
DASX 1 LET,
(SEQ ID NO: 1044)
wherein
X 1 is selected from the group consisting of I and N;
GASSRAT;
(SEQ ID NO: 223)
and
WASX 1 RES,
(SEQ ID NO: 1045)
wherein
X 1 is selected from the group consisting of A and T; or
B) a CDRH selected from the group consisting of:
(i) a CDRH1 selected from the group consisting of SEQ ID NOs:275-299;
(ii) a CDRH1 that differs in amino acid sequence from the CDRH1 of (i) by an amino acid addition, deletion or substitution of not more than two amino acids;
(iii) a CDRH1 amino acid sequence selected from the group consisting of
GYTX 1 TX 2 X 3 X 4 X 5 X 6 ,
(SEQ ID NO: 1052)
wherein
X 1 is selected from the group consisting of F and L,
X 2 is selected from the group consisting of E, G and S,
X 3 is selected from the group consisting of H, L and Y,
X 4 is selected from the group consisting of G, S and Y,
X 5 is selected from the group consisting of I and M,
X 6 is selected from the group consisting of H and S;
GYX 1 FTSYWIG,
(SEQ ID NO: 1053)
wherein
X 1 is selected from the group consisting of R and S;
GFTFX 1 SX 2 X 3 MH,
(SEQ ID NO: 1054)
wherein
X 1 is selected from the group consisting of R and S,
X 2 is selected from the group consisting of H and Y,
X 3 is selected from the group consisting of D and G;
GFX 1 FSX 2 YX 3 MX 4 ,
(SEQ ID NO: 1055)
wherein
X 1 is selected from the group consisting of P and T,
X 2 is selected from the group consisting of A, R and S,
X 3 is selected from the group consisting of A and S,
X 4 is selected from the group consisting of N and S;
GX 1 SX 2 SX 3 X 4 X 5 X 6 X 7 WX 8 ,
(SEQ ID NO: 1056)
wherein
X 1 is selected from the group consisting of D and G,
X 2 is selected from the group consisting of F, I and V,
X 3 is selected from the group consisting of R, S and no amino acid,
X 4 is selected from the group consisting of G, Y and no amino acid,
X 5 is selected from the group consisting of D, G, S and no amino acid,
X 6 is selected from the group consisting of A, S and Y,
X 7 is selected from the group consisting of A and Y,
X 8 is selected from the group consisting of N and S;
GFSLSNARMGVS;
(SEQ ID NO: 279)
and
GFSLX 1 TGGVGVG,
(SEQ ID NO: 1057)
wherein
X 1 is selected from the group consisting of S and N;
(iv) a CDRH2 selected from the group consisting of SEQ ID NOs:300-331;
(v) a CDRH2 that differs in amino acid sequence from the CDRH2 of (iv) by an amino acid addition, deletion or substitution of not more than two amino acids; and
(vi) a CDRH2 amino acid sequence selected from the group consisting of
(SEQ ID NO: 1058)
X 1 X 2 X 3 X 4 X 5 X 6 GX 7 TX 8 X 9 X 10 QKX 11 X 12 ,
wherein
X 1 is selected from the group consisting of S and W,
X 2 is selected from the group consisting of F and I,
X 3 is selected from the group consisting of D, N and S,
X 4 is selected from the group consisting of A and P,
X 5 is selected from the group consisting of E, N and S,
X 6 is selected from the group consisting of D, N and S,
X 7 is selected from the group consisting of E, G and N,
X 8 is selected from the group consisting of I and N,
X 9 is selected from the group consisting of C, H and Y,
X 10 is selected from the group consisting of A and T,
X 11 is selected from the group consisting of F and L,
X 12 is selected from the group consisting of D and G;
IIYPX 1 DSDX 2 RYSPSFQG,
(SEQ ID NO: 1059)
wherein
X 1 is selected from the group consisting of D and G,
X 2 is selected from the group consisting of A, I and T;
X 1 IX 2 X 3 DGSX 4 X 5 X 6 YX 7 DSVX 8 G,
(SEQ ID NO: 1060)
wherein
X 1 is selected from the group consisting of F and V,
X 2 is selected from the group consisting of S and W,
X 3 is selected from the group consisting of D, S and Y,
X 4 is selected from the group consisting of I, N and T,
X 5 is selected from the group consisting of K and Q,
X 6 is selected from the group consisting of N, R and Y,
X 7 is selected from the group consisting of A, T and V,
X 8 is selected from the group consisting of K and R;
X 1 ISX 2 SX 3 X 4 X 5 X 6 YYADSVKG,
(SEQ ID NO: 1061)
wherein
X 1 is selected from the group consisting of A, H and Y,
X 2 is selected from the group consisting of G, R and S,
X 3 is selected from the group consisting of G and S,
X 4 is selected from the group consisting of G, R and S,
X 5 is selected from the group consisting of S, T and Y,
X 6 is selected from the group consisting of I and T;
(SEQ ID NO: 1062)
X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 YX 12 X 13 SX 14 KS,
wherein
X 1 is selected from the group consisting of E, R and Y,
X 2 is selected from the group consisting of I and T,
X 3 is selected from the group consisting of H, N and Y,
X 4 is selected from the group consisting of C, H, S, T and Y,
X 5 is selected from the group consisting of S and R,
X 6 is selected from the group consisting of G and S,
X 7 is selected from the group consisting of G, K, S and T,
X 8 is selected from the group consisting of T and W,
X 9 is selected from the group consisting of N and Y,
X 10 is selected from the group consisting of N and no amino acid,
X 11 is selected from the group consisting of D and no amino acid,
X 12 is selected from the group consisting of A and N,
X 13 is selected from the group consisting of P and V,
X 14 is selected from the group consisting of L and V;
X 1 IFSNDEKSYSTSLKS,
(SEQ ID NO: 1063)
wherein
X 1 is selected from the group consisting of H and L1; and
LIYWNX 1 X 2 KRYSPSLX 3 S,
(SEQ ID NO: 1064)
wherein
X 1 is selected from the group consisting of D and V,
X 2 is selected from the group consisting of D and E,
X 3 is selected from the group consisting of K and R.
17 . The isolated antigen binding protein of claim 16 , wherein said antigen binding protein comprises said first amino acid sequence and said second amino acid sequence.
18 . The isolated antigen binding protein of claim 17 , wherein said first amino acid sequence is covalently bonded to said second amino acid sequence.
19 . The isolated antigen binding protein of claim 17 , wherein said first amino acid sequence comprises said CDRL3 of SEQ ID NOs:234-274, CDRL2 of SEQ ID NOs:218-233, and CDRL1 of SEQ ID NOs: 189-217, and said second amino acid sequence comprises said CDRH3 of SEQ ID NOs:332-372, CDRH2 of SEQ ID NOs:300-331, and CDRH1 of SEQ ID NOs:275-299.
20 . The isolated antigen binding protein of any of claim 1 - 19 , wherein said antigen binding protein is a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or an antibody fragment thereof.
21 . The isolated antigen binding protein of claim 20 , wherein said antibody fragment is a Fab fragment, a Fab′ fragment, a F(ab′) 2 fragment, a Fv fragment, a diabody, or a single chain antibody molecule.
22 . The isolated antigen binding protein of claim 20 , wherein said antigen binding protein is a human antibody.
23 . The isolated antigen binding protein of claim 20 , wherein said antigen binding protein is a monoclonal antibody.
24 . The isolated antigen binding protein of any of claims 1 - 19 wherein said antigen binding protein is of the IgG1-, IgG2-IgG3- or IgG4-type.
25 . The isolated antigen binding protein of claim 24 , wherein said antigen binding protein is of the IgG2- or IgG4-type.
26 . The isolated antigen binding protein of any of claims 1 - 19 , wherein said antigen binding protein is coupled to a labeling group.
27 . The isolate antigen binding protein of claim 26 , wherein the labeling group is a radioisotope, radionuclide, a fluorescent group, an enzymatic group, a chemiluminescent group, a biotinyl group, or a predetermined polypeptide group.
28 . The isolated antigen binding protein of any of claims 1 - 19 , wherein said antigen binding protein is coupled to an effector group.
29 . The isolated antigen binding protein of claim 28 , wherein said effector group is a radioisotope, a radionuclide, a toxin, a therapeutic group, or a chemotherapeutic group.
30 . The isolated antigen binding protein of claim 29 , wherein said therapeutic group or chemotherapeutic group is calicheamicin, auristatin-PE, geldanamycin, maytanasine, or derivatives thereof.
31 . An isolated antigen binding protein that competes for binding to human HB-EGF with an antigen binding protein of one of claims 1 - 19 .
32 . The isolated antigen binding protein of claim 31 , wherein said antigen binding protein is a monoclonal antibody, a polyclonal antibody, a recombinant antibody, a human antibody, a humanized antibody, a chimeric antibody, a multispecific antibody, or an antibody fragment thereof.
33 . The isolated antigen binding protein of claim 32 , wherein said antibody fragment is a Fab fragment, a Fab′ fragment, a F(ab′) 2 fragment, a Fv fragment, a diabody, or a single chain antibody molecule.
34 . The isolated antigen binding protein of claim 32 , wherein said antigen binding protein is a human antibody.
35 . The isolated antigen binding protein of claim 32 , wherein said antigen binding protein is a monoclonal antibody.
36 . The isolated antigen binding protein of any of claim 31 , wherein said antigen binding protein is of the IgG1-, IgG2-IgG3- or IgG4-type.
37 . The isolated antigen binding protein of claim 36 , wherein said antigen binding protein is of the IgG2- or the IgG4-type.
38 . The isolated antigen binding protein of any of claim 31 , wherein said antigen binding protein is coupled to a labeling group.
39 . The isolate antigen binding protein of claim 38 , wherein the labeling group is a radioisotope, radionuclide, a fluorescent group, an enzymatic group, a chemiluminescent group, a biotinyl group, or a predetermined polypeptide group.
40 . The isolated antigen binding protein of claim 31 , wherein said antigen binding protein is coupled to an effector group.
41 . The isolated antigen binding protein of claim 40 , wherein said effector group is a radioisotope, a radionuclide, a toxin, a therapeutic group, or a chemotherapeutic group.
42 . The isolated antigen binding protein of claim 41 , wherein said therapeutic group or chemotherapeutic group is calicheamicin, auristatin-PE, geldanamycin, maytanasine, or derivatives thereof.
43 . The isolated antigen binding protein of one of claims 1 - 19 , wherein said antigen binding protein reduces at least partially HB-EGF-mediated signal transduction.
44 . A nucleic acid molecule encoding the antigen binding protein according to any one of claims 1 - 19 .
45 . The nucleic acid molecule according to claim 44 , wherein said nucleic acid molecule is operably linked to a control sequence.
46 . A vector comprising a nucleic acid molecule according to claim 44 .
47 . A vector comprising a nucleic acid molecule according to claim 45 .
48 . A host cell comprising the nucleic acid molecule according to claim 45 .
49 . A host cell comprising the vector according to one of claim 46 or 47 .
50 . A method of making the antigen binding protein according to any one of claims 1 - 19 , comprising the step of preparing said antigen binding protein from a host cell that secretes said antigen binding protein.
51 . A pharmaceutical composition comprising at least one antigen binding protein according to any one of claims 1 - 19 , and pharmaceutically acceptable carrier, diluents and/or adjuvants.
52 . The pharmaceutical composition of claim 51 , further comprises an additional active agent.
53 . The pharmaceutical composition according to claim 52 , wherein the at least one further active agent is an anti-neoplastic agent.
54 . The pharmaceutical composition of claim 53 , wherein the anti-neoplastic agent is an anti-tumor antibody.
55 . The pharmaceutical composition of claim 54 , wherein the anti-tumor antibody is an antibody directed against a receptor tyrosine kinase.
56 . The pharmaceutical composition of claim 53 , wherein the anti-tumor antibody is directed against EGFR.
57 . The pharmaceutical composition of claim 51 , for the diagnosis, prevention or treatment of a hyperproliferative disease.
58 . The pharmaceutical composition to claim 57 , wherein said hyperproliferative disease is associated with HB-EGF expression.
59 . The pharmaceutical composition according to claim 57 , wherein said hyperproliferative disease is associated with or accompanied by a disturbed, e.g., pathologically enhanced growth factor receptor activation.
60 . The pharmaceutical composition of claim 59 , wherein said pathologically enhanced growth factor receptor activation is associated with or caused by a pathological increase in the activity of a G protein and/or a G protein coupled receptor.
61 . The pharmaceutical composition of claim 51 for the diagnosis, prevention or treatment of cancer.
62 . The pharmaceutical composition claim 61 , wherein said cancer is selected from the group consisting of breast cancer, gastrointestinal cancer, pancreas cancer, prostate cancer, ovarian cancer, stomach cancer, endometrial cancer, salivary gland cancer, lung cancer, kidney cancer, colon cancer, colorectal cancer, thyroid cancer, bladder cancer, glioma, melanoma, carcinoma, in particular epithelial or squamous carcinoma, other HB-EGF expressing or overexpressing cancers, and formation of tumor metastases.
63 . Use of at least one antigen binding protein of claims 1 - 19 , for the manufacture of a pharmaceutical composition for the diagnosis, prevention or treatment of a hyperproliferative disease.
64 . The use according to claim 63 , wherein said hyperproliferative disease is a hyperproliferative disease as defined in claim 58 .
65 . A method for diagnosing a condition associated with the expression of HB-EGF, comprising contacting a sample with an antigen binding protein of claims 1 - 19 , and determining the presence of HB-EGF in said sample.
66 . The method according to claim 65 , wherein the condition is a hyperproliferative disease as defined in claim 58 .
67 . A method for preventing or treating a condition associated with the expression of HB-EGF in a patient, comprising administering to a patient in need thereof an effective amount of at least one antigen binding protein of claims 1 - 19 .
68 . The method according to claim 62 , wherein the condition is a hyperproliferative disease as defined in any one of claims 57 - 60 .
69 . The method of claim 57 , wherein the patient is a mammalian patient.
70 . A kit comprising a antigen binding protein of claims 1 - 19 , a nucleic acid molecule of claim 44 or 45 or a vector according to claim 46 or 47 .
71 . The kit of claim 70 comprising at least one further active agent.
72 . The kit of claim 71 , wherein the further active agent is an anti-neoplastic agent.
73 . The pharmaceutical composition according to claim 53 , wherein the anti-neoplastic agent id Cisplatin or Avastin.
74 . The pharmaceutical composition according to any of the claims 51 to 62 which is to be administered as a monotherapy or in combination with a further pharmaceutical composition preferably comprising an anti-neoplastic agent such as cisplatin or Avastin.Cited by (0)
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