Binding molecules for BCMA and CD3

Patent metadata

Field	Value
Publication number	US-10766969-B2
Application number	US-201214358511-A
Country	US
Kind code	B2
Filing date	Nov 15, 2012
Priority date	Nov 15, 2011
Publication date	Sep 8, 2020
Grant date	Sep 8, 2020

Abstract

The present invention relates to a binding molecule which is at least bispecific comprising a first and a second binding domain, wherein the first binding domain is capable of binding to epitope cluster3 of BCMA, and the second binding domain is capable of binding to the Tcell CD3 receptor complex. Moreover, the invention provides a nucleic acid sequence encoding the binding molecule, a vector comprising said nucleic acid sequence and a host cell transformed or transfected with said vector. Furthermore, the invention provides a process for the production of the binding molecule of the invention, a medical use of said binding molecule and a kit comprising said binding molecule.

First claim

The invention claimed is:

1. A binding molecule which is at least bispecific comprising a first and a second binding domain, wherein
(a) the first binding domain comprises a variable heavy chain and a variable light chain and binds to B cell maturation antigen (BCMA), wherein the first binding domain comprises a VH region comprising CDR-H1, CDR-H2, and CDR-H3 and a VL region comprising CDR-L1, CDR-L2, and CDR-L3, and at least five of the six CDRs selected from the group consisting of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 have sequences as follows:
(i) CDR-H1 as depicted in SEQ ID NO: 1, SEQ ID NO: 161, or SEQ ID NO: 311;
(ii) CDR-H2 as depicted in SEQ ID NO: 2, SEQ ID NO: 12, SEQ ID NO: 162, SEQ ID NO: 212, SEQ ID NO: 312, SEQ ID NO: 322, SEQ ID NO: 352, SEQ ID NO: 362, SEQ ID NO: 582, SEQ ID NO: 622, or SEQ OD NO: 752;
(iii) CDR-H3 as depicted in SEQ ID NO: 3, SEQ ID NO: 163, SEQ ID NO: 313, SEQ ID NO: 323, or SEQ ID NO: 623;
(iv) CDR-L1 as depicted in SEQ ID NO: 4, SEQ ID NO: 164, SEQ ID NO: 314, SEQ ID NO: 624, SEQ ID NO: 774, SEQ ID NO: 974, or SEQ ID NO: 994;
(v) CDR-L2 as depicted in SEQ ID NO: 5, SEQ ID NO: 165, SEQ ID NO: 315, or SEQ ID NO: 625; and
(vi) CDR-L3 as depicted in SEQ ID NO: 6, SEQ ID NO: 166, SEQ ID NO: 176, SEQ ID NO: 316, SEQ ID NO: 626, SEQ ID NO: 656, SEQ ID NO: 676, SEQ ID NO: 776, SEQ ID NO: 816, SEQ ID NO: 966, or SEQ ID NO: 996, and
wherein not more than one of CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3 has a sequence as follows:
(i) CDR-H1 comprises amino acid sequence X 1 X 2 X 3 X 4 X 5 which has 80% or greater identity to a sequence selected from the group consisting of NYDMA (SEQ ID NO:1), NFDMA (SEQ ID NO:161), and NHIIH (SEQ ID NO:311), and where X 1 is N; X 2 is Y, F, or H; X 3 is D or I; X 4 is M or I; and X 5 is A or H;
(ii) CDR-H2 comprises amino acid sequence 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 which has 80% or greater identity to a sequence selected from the group consisting of: SIITSGDATYYRDSVKG (SEQ ID NO:2), SIITSGDMTYYRDSVKG (SEQ ID NO:12), SITTGADHAIYADSVKG (SEQ ID NO:162), SITTGADHAIYAESVKG (SEQ ID NO:212), SIITSGGDNYYRDSVKG (SEQ ID NO:582), SITTGGGDTYYADSVKG (SEQ ID NO:732), YINPYPGYHAYNEKFQG (SEQ ID NO:312), YINPYPGYHAYNQKFQG (SEQ ID NO:352), YINPYDGWGDYNEKFQG (SEQ ID NO:322), YINPYDGWGDYNQKFQG (SEQ ID NO:362), and SISTRGDITSYRDSVKG (SEQ ID NO: 622), and where X 6 is S or Y; X 7 is I; X 8 is I, T, N, or S; X 9 is T or P; X 10 is S, Y, R, or G; is G, A, D, or P; X 12 is D or G; X 13 is A, M, H, D, Y, W or I; X 14 is T, A, N, H, or G; X 15 is Y, I, A, D or S; X 16 is Y; X 17 is R, A, or N; X 18 is D, E, or Q; X 19 is S or K; X 20 is V or F; X 21 is K or Q; and X 22 is G;
(iii) CDR-H3 comprises amino acid sequence X 23 X 24 X 25 X 26 X 27 X 28 X 29 X 30 X 31 X 32 X 33 X 34 which has 80% or greater identity to a sequence selected from the group consisting of: HDYYDGSYGFAY (SEQ ID NO:3), HGYYDGYHLFDY (SEQ ID NO:163), QDYYTDYMGFAY (SEQ ID NO:623), DGYYRDTDVLDY (SEQ ID NO:313), and DGYYRDADVLDY (SEQ ID NO:323), and where X 23 is H, Q or D; X 24 is D or G; X 25 is Y; X 26 is Y; X 27 is D, T or R; X 28 is G or D; X 29 is S, Y, T or A; X 30 is Y, H, M or D; X 31 is G, L, or V; X 32 is F or L; X 33 is A or D; and X 34 is Y;
(iv) CDR-L1 comprises amino acid sequence X 35 X 36 X 37 X 38 X 39 X 40 X 41 X 42 X 43 X 44 X 45 which has 80% or greater identity to a sequence selected from the group consisting of: KASQSVGINVD (SEQ ID NO:4), RASQGISNYLN (SEQ ID NO:164), RASEDIYNGLA (SEQ ID NO:624), RASQGISNHLN (SEQ ID NO:774), RANQGISNNLN (SEQ ID NO:974), RASQGISNNLN (SEQ ID NO:994), and QASQDISNYLN (SEQ ID NO:314), and wherein X 35 is K, R or Q; X 36 is A; X 37 is S or N; X 38 is Q or E; X 39 is S, G, or D; X 40 is V or I; X 41 is G, S, or Y; X 42 is I or N; X 43 is N, Y, G, or H; X 44 is V or L; and X 45 is D, N, or A;
(v) CDR-L2 comprises amino acid sequence X 46 X 47 X 48 X 49 X 50 X 51 X 52 which has 80% or greater identity to a sequence selected from the group consisting of: GASNRHT (SEQ ID NO:5), YTSNLQS (SEQ ID NO:165), GASSLQD (SEQ ID NO:625), and YTSRLHT (SEQ ID NO:315), and wherein X 46 is G or Y; X 47 is A or T; X 48 is S; X 49 is N, S, or R; X 50 is R or L; X 51 is H or Q; and X 52 is T, S, or D; or
(vi) CDR-L3 comprises amino acid sequence X 53 X 54 X 55 X 56 X 57 X 58 X 59 X 60 X 61 which has 80% or greater identity to a sequence selected from the group consisting of: LQYGSIPFT (SEQ ID NO:6), QQYDISSYT (SEQ ID NO:166), MGQTISSYT (SEQ ID NO:176), QQGNTLPWT (SEQ ID NO:316), QQSYKYPLT (SEQ ID NO:626), AGPHKYPLT (SEQ ID NO:656), QQSRNYQQT (SEQ ID NO:676), QQYFDRPYT (SEQ ID NO:776), QQYSNLPYT (SEQ ID NO:816), QQFTSLPYT (SEQ ID NO:966), and QQFAHLPYT (SEQ ID NO:996), and wherein X 53 is L, Q, M, or A; X 54 is Q or G; X 55 is G, P, Y, Q, S, or F; X 56 is G, D, T, N, Y, H, R, F, S, or A; X 57 is S, I, T, K, N, D, or H; X 58 is I, S, L, Y, or R; X 59 is P, S, or Q; X 60 is F, Y, W, L, or Q and X 61 is T; and

(b) the second binding domain comprises a variable heavy chain and a variable light chain and binds to the human T cell CD3 receptor complex.

2. The binding molecule according to claim 1 , wherein the first binding domain binds to macaque BCMA.

3. The binding molecule according to claim 1 wherein the second binding domain binds to CD3 epsilon.

4. The binding molecule according to claim 1 , wherein the second binding domain binds to human CD3 and to macaque CD3.

5. The binding molecule according to claim 1 , wherein the binding molecule is selected from the group consisting of (scFv) 2 , diabodies and oligomers thereof.

6. The binding molecule according to claim 1 , wherein the binding molecule has an EC50 (pg/ml) of less than 350 in a cell-based cytotoxicity assay.

7. A pharmaceutical composition comprising any one of the binding molecule according to claim 1 and a pharmaceutically acceptable carrier.

8. The binding molecule according to claim 1 for use in treatment or amelioration of a disease selected from the group consisting of plasma cell disorders, other B cell disorders that correlate with BCMA expression and autoimmune diseases.

9. A kit comprising any one of the binding molecule as defined in claim 1 .

10. The binding molecule according to claim 1 , wherein X 2 is H, X 3 is I, X 4 is I, and X 5 is H.

11. The binding molecule according to claim 1 , wherein X 6 is Y, X 8 is N, X 9 is P, X 10 is Y, X 12 is G, X 17 is N, X 19 is K, X 20 is F, and X 21 is Q.

12. The binding molecule according to claim 11 , wherein X 11 is P, X 13 is Y, X 14 is H, X 15 is A, and X 18 is E.

13. The binding molecule according to claim 1 , wherein X 23 is D, X 24 is G, X 27 is R, X 28 is D, X 30 is D, X 31 is V, X 32 is L, and X 33 is D.

14. The binding molecule according to claim 13 , wherein X 29 is T.

15. The binding molecule according to claim 1 , wherein X 37 is S, X 38 is Q, X 40 is I, X 41 is S, X 42 is N, X 44 is L, and X 45 is N.

16. The binding molecule according to claim 15 , wherein X 35 is Q, X 39 is D, and X 43 is Y.

17. The binding molecule according to claim 1 wherein X 46 is Y, X 47 is T, and X 50 is L.

18. The binding molecule according to claim 17 wherein X 49 is R, X 51 is H, and X 52 is T.

19. The binding molecule according to claim 1 , wherein X 53 is Q, X 54 is Q, and X 59 is P.

20. The binding molecule according to claim 19 , wherein X 55 is G, X 56 is N, X 57 is T, X 58 is L, and X 6

Assignees

• Amgen Res Munich Gmbh
• Boehringer Ingelheim Int
• Amgen Inc

Inventors

• Kufer Peter
• Raum Tobias
• Hoffmann Patrick
• Kischel Roman
• Lutterbuese Ralf
• Rau Doris
• Adam Paul
• Borges Eric
• Hebeis Barbara
• Hipp Susanne

Classifications

• C07K16/2878

  against the NGF-receptor/TNF-receptor superfamily, e.g. CD27, CD30, CD40, CD95 · CPC title

• C07K16/2809 Primary

  against the T-cell receptor (TcR)-CD3 complex · CPC title

• C07K2317/34

  Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues · CPC title

• C07K2317/31

  multispecific · CPC title

• C07K2317/33

  Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity · CPC title