IP Library › Granted Patent US 8,981,072
Granted Patent B2
US 8,981,072 · App. 14/101,441 · Granted Mar 17, 2015

Nucleic acids encoding antibody polypeptides that antagonize CD40L

Inventors: Steven G. Nadler (Princeton, NJ); James K. Tamura (Yardley, PA); Laura Price (Langhorne, PA); Robert P. Rehfuss (North Wales, PA); Suzanne J. Suchard (Wilmington, DE); Anish Suri (Yardley, PA); James William Bryson (Langhorne, PA); Aaron Yamniuk (Lawrenceville, NJ); Steven Grant (Swaffham Prior, GB); Olga Ignatovich (Cambridge, GB); Philip Drew (Histon, GB)
Assignees: Bristol-Myers Squibb Company; Domantis Limited
C07K16/2878A61K39/3955A61K45/06C07K16/46C07K16/468C07K16/2875C07K16/283C07K2317/565C07K2317/569A61K2039/505A61K2039/545C07K2317/21C07K2317/52C07K2317/76C07K2317/92C07K2319/00C07K2319/30A61K38/00
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Quick Facts
Patent No.
US 8,981,072
App. No.
14/101,441
Granted
Mar 17, 2015
Kind
B2
Abstract

Antibody polypeptides that specifically bind human CD40L are provided. The antibody polypeptides do not activate platelets. The antibody polypeptides are useful in the treatment of diseases involving CD40L activation, such as graft-related diseases and autoimmune diseases. The antibody polypeptides may be domain antibodies (dAbs) comprising a single V H or V K domain. The half-life of the antibody polypeptides may be increased by modifying the antibody polypeptides to be dual specific reagents that can also bind human serum albumin (HSA) or another antigen.

Claims (50)

1. A nucleic acid encoding an antibody polypeptide comprising a first variable domain that specifically binds human CD40L, wherein the amino acid sequence of the first variable domain comprises the amino acid sequence of BMS2h-572-633 (SEQ ID NO: 274) or differs from the ammo acid sequence of BMS2h-572-633 (SEQ ID NO: 274) by up to 5 amino acids.

2. A vector comprising the nucleic acid of claim 1 .

3. An isolated host cell comprising the vector of claim 2 .

4. The nucleic acid of claim 1 , wherein the amino acid sequence of the first variable domain differs from the amino acid sequence of BMS2h-572-633 by up to 2 amino acids.

5. The nucleic acid of claim 4 , wherein the first variable domain differs from the amino acid sequence of BMS2h-572-633 by one amino acid.

6. The nucleic acid of claim 1 wherein the antibody polypeptide is selected from the lineage group of BMS2h-572, and wherein the amino acid sequence of the first variable domain comprises:

(a) a CDRI region having a sequence Trp-X1-Leu-Met-Gly (SEQ :ID NO: 2), wherein X1is Glu or Gln;

(b) a CDR2 region having a sequence Gly-Ile-Glu-Gly-Pro-Gly-Asp-Val-Thr-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly (SEQ ID NO: 3); and

(c) a CDR3 region having a sequence Lys-X2-Y2- Z2-Ser-Asp-Tyr (SEQ ID NO: 4), wherein X2is Asp or Glu, Y2 is Ala or Ser, and Z2is Lys, Asn, or Arg.

7. The nucleic acid of claim 6 , wherein the amino acid sequence of the first variable domain comprises:

(a) a FR1 region having a sequence Glu-Val-Gln-Leu-Leu-Glu-Ser-Gly-Gly-Gly-Leu-Val-Gin-Pro-Gly-Gly-Ser-Leu-Arg-Leu-Ser-Cys-Ala-Ala-Ser-Gly-Phe-Thr-Phe-Asn (SEQ ID NO: 5);

(b) a FR2 region having a sequence Trp-X1-Arg-Gln-Ala-Pro-Gly-Lys-Gly-Leu-Glu-Trp-Val-Ser (SEQ ID NO: 6), wherein X1is Ala or Val;

(c) a FR3 region having a sequence Arg-Thr-Phe-lle-Ser-Arg-Asp-Asn-Ser-Lys-Asn-Thr-Leu-Tyr-Leu-Gln-Met-Asn-Ser-Leu-Arg-Ala-Glu-Asp-Thr-Ala-Val-Tyr-Tyr-Cys-Val-Lys-Val-Gly (SEQ ID NO: 7); and

(d) a FR4 region having a sequence Arg-Gly-Gln-Gly-Thr-Len-Val-Thr-Val-Ser-Ser (SEQ ID NO: 8).

8. The nucleic acid of claim 1 , wherein the first variable domain comprises the amino acid sequence of BMS2h-572-633 (SEQ ID NO: 274).

9. The nucleic acid of claim 1 , wherein the amino acid sequence of the first variable domain comprises:

(a) a CDR1 region of BMS2h-572-633 comprising SEQ ID NO: 2,

(b) a CDR2 region of BMS2h-572-633 comprising SEQ ID NO: 3,

(c) a CDR3 region of BMS2h-572-633 comprising SEQ ID NO: 4,

(d) a FR1 region of BMS2h-572-633 comprising SEQ ID NO: 5,

(e) a FR2 region of BMS2h-572-633 comprising SEQ ID NO: 6,

(f) a FR3 region of BMS2h-572-633 comprising SEQ ID NO: 7, and

(g) a FR4 region of BMS2h-572-633 comprising SEQ ID NO: 8.

10. The nucleic acid of claim 9 , wherein the antibody polypeptide is selected from the lineage group of BMS2h-572, and wherein the amino acid sequence of the first variable domain comprises:

(a) a CDR1 region having a sequence Trp-X1-Leu-Met-Gly (SEQ ID NO: 2), wherein X1 is Glu;

(b) a CDR2 region having a sequence Gly-Ile-Glu-Gly-Pro-Gly-Asp-Val-Thr-Tyr-Tyr-Ala-Asp-Ser-Val-Lys-Gly (SEQ ID) NO: 3); and

(c) a CDR3 region having a sequence Lys-X2-Y2- Z2-Ser-Asp-Tyr (SEQ ID NO: 4), wherein X2 is Asp, Y2 is Ala, and Z2 is Lys.

11. The nucleic acid of claim 10 , wherein the amino acid sequence of the first variable domain comprises:

(a) a FR1 region having a sequence Glu-Val-Gln-Leu-Leu-Glu-Ser-Gly-Gly-Gly-Leu-Val-Gln-Pro-Gly-Gly-Ser-Leu-Arg-Leu-Ser-Cys-Ala-Ala-Ser-Gly-Phe-Thr-Phe-Asn (SEQ ID NO: 5);

(b) a FR2 region having a sequence Trp-X1-Arg-Gln-Ala-Pro-Gly-Lys-Gly-Leu-Glu-Trp-Val-Ser (SEQ ID NO: 6), wherein X1 is Ala;

(c) a FR3 region having a sequence Arg-Thr-Phe-Ile-Ser-Arg-Asp-Asn-Ser-Lys-Asn-Thr-Leu-Tyr-Leu-Gln-Met-Asn-Ser-Leu-Arg-Ala-Glu-Asp-Thr-Ala-Val-Tyr-Tyr-Cys-Val-Lys-Val-Gly (SEQ ID NO: 7); and

(d) a FR4 region having a sequence Arg-Gly-Gln-Gly-Thr-Leu-Val-Thr-Val-Ser-Ser (SEQ ID NO: 8).

12. The nucleic acid of claim 1 , wherein the antibody polypeptide is a domain antibody (dAb).

13. The nucleic acid of claim 1 , wherein the antibody polypeptide is a fusion polypeptide comprising the first variable domain and an Fc domain.

14. The nucleic acid of claim 13 , wherein the fusion polypeptide comprises an IgG4 Fc domain.

15. The nucleic acid of claim 13 , wherein the fusion polypeptide comprises an IgG1 Fc domain.

16. The nucleic acid of claim 13 , wherein the fusion polypeptide comprises a CT-Long domain.

17. The nucleic acid of claim 13 wherein the fusion polypeptide comprises a CT-Short domain.

18. The nucleic acid of claim 13 , wherein the fusion polypeptide comprises a N297Q Long Fc domain.

19. The nucleic acid of claim 13 , wherein the fusion polypeptide comprises a N297Q Short Fc domain.

20. The nucleic acid of claim 13 , wherein the antibody polypeptide further comprises a second variable domain that specifically binds a second antigen, wherein the second antigen is an antigen other than human CD40L.

21. The nucleic acid of claim 20 , wherein the second antigen is a cluster of differentiation (CD) molecule or a Major Histocompatibility Complex (MHC) Class II molecule.

22. The nucleic acid of claim 20 , wherein the second antigen is serum albumin (SA).

23. A nucleic acid encoding an antibody polypeptide comprising a first variable domain, wherein said antibody polypeptide specifically binds human CD40L, wherein the first variable domain comprises:

a) an amino acid sequence at least 95% identical to BMS2h-572-6 (SEQ ID NO: 243), BMS2h-572-608 (SEQ ID NO: 251),BMS2h-572-614(SEQ ID NO:257), BMS2h-572-619 (SEQ ID NO: 262) BMS2h-572-633 (SEQ ID NO:274),BMS2h-572-634 (SEQ ID NO:275), BMS2h-572-635(SEQ ID NO: 276),BMS2h-719-2(SEQ ID NO: 352),BMS2h-719-202(SEQ ID NO:354),BMS2h-719-203(SEQ ID NO:355),BMS2h-719-213 (SEQ ID NO:357), BMS2h-719-214 (SEQ ID NO:358),BMS2h-719-215(SEQ ID NO: 359),BMS2h-719-218 (SEQ ID NO: 360),BMS2h-719-225(SEQ ID NO:361),BMS2h-116-1312 (SEQ ID NO: 970), BMS2h-116-1313(SEQ ID NO: 971), or BMS2h-116-1320(SEQ ID NO: 974); or

b) the amino acid sequence of BMS2h-503-1 (SEQ ID NO: 1087)or BMS2h-503-2 (SEQ ID NO: 1088).

24. The nucleic acid of claim 23 , wherein the first variable domain comprises the amino acid of BMS2h-572-6 (SEQ ID NO: 243), BMS2h-572-608(SEQ ID NO: 251),BMS2h-572 -614 (SEQ ID NO:257),BMS2h-572-619 (SEQ ID NO:262),BMS2h-572-633 (SEQ ID NO:274),BMS2h-572-634(SEQ ID NO:275), BMS2h-572-635(SEQ ID NO: 276),BMS2h-719-2 (SEQ ID NO: 352),BMS2h-719-202(SEQ ID NO:354),BMS2h-719-203 (SEQ ID NO: 355),BMS2h-719-213 (SEQ ID NO: 357), BMS2h-719-214 (SEQ ID NO: 358),BMS2h-719-215 (SEQ ID NO: 359),BMS2h-719-218 (SEQ ID NO: 360),BMS2h-719-225 (SEQ ID NO: 361),BMS2h-503-1 (SEQ ID NO: 1087), BMS2h-503-2 (SEQ ID NO: 1088),BMS2h-116-1312 (SEQ ID NO: 970), BMS2h-116-1313 (SEQ ID NO: 971) or BMS2h-116-1320 (SEQ ID NO: 974).

25. The nucleic acid of claim 24 wherein the first variable domain is selected from the group of consisting of the amino acid sequence of BMS2h-572-6 (SEQ ID NO: 243),BMS2h-572-608 (SEQ ID NO: 251), BMS2h-572-614 (SEQ ID NO: 257), BMS2h-572-619 (SEQ ID NO: 262), BMS2h-572-633 (SEQ ID NO: 274), BMS2h-572-634(SEQ ID NO: 275), and BMS2h-572-635(SEQ ID NO: 276).

26. The nucleic acid of claim 25 , wherein said nucleic acid encodes a polypeptide comprising SEQ ID NO: 1355.

27. A nucleic acid encoding an antibody polypeptide comprising a first variable domain of BMS2h-572 (SEQ ID NO: 223).

Assignments (1)
CHANGE OF ADDRESS Recorded Oct 1, 2025
From: DOMANTIS LIMITED
To: DOMANTIS LIMITED
Reel/Frame 072987/0472 →
Continuity (4)
Division 13650493 · Oct 12, 2012
Provisional Application 61546800 · Oct 13, 2011
Provisional Application 61655110 · Jun 4, 2012
Related Publication 20140099707A1 · Apr 10, 2014