IP Library › Granted Patent US 9,000,131
Granted Patent B2
US 9,000,131 · App. 13/055,436 · Granted Apr 7, 2015

Antibodies that neutralize botulinum neurotoxins

Inventors: James D. Marks (Kensington, CA); Isin N. Geren (San Francisco, CA)
Assignee: The Regents of the University of California
C07K16/1282A61K2039/505C07K2316/96C07K2317/21C07K2317/622C07K2317/92C07K2319/00C07K2317/52
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Quick Facts
Patent No.
US 9,000,131
App. No.
13/055,436
Granted
Apr 7, 2015
Kind
B2
Abstract

This disclosure provides antibodies that specifically bind to and typically neutralize botulinum neurotoxins (e.g., BoNT/A, BoNT/B, BoNT/E, etc.) and the epitopes bound by those antibodies. The antibodies and derivatives thereof and/or other antibodies that specifically bind to the neutralizing epitopes provided herein can be used to neutralize botulinum neurotoxin and are therefore also useful in the treatment of botulism.

Claims (151)

1. An isolated antibody that specifically binds an epitope of a Botulinum neurotoxin that is specifically bound by an antibody comprising:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:492;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:494;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:496;

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:742;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:744; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:746; or

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:1309;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:1310;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:1311;

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1312;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:1313; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:1314.

2. The isolated antibody of claim 1 , wherein said antibody is a human antibody or a humanized antibody.

3. The isolated antibody of claim 1 , wherein said antibody is a single chain Fv (scFv).

4. The isolated antibody of claim 1 , wherein said antibody is an IgG.

5. The isolated antibody of claim 1 , wherein said antibody is a Fab.

6. The isolated antibody of claim 1 , wherein said antibody is a (Fab′) 2 .

7. The isolated antibody of claim 1 , wherein said antibody is a (scFv′) 2 .

8. A composition comprising:

a pharmaceutically acceptable carrier; and

the antibody of claim 1 .

9. The composition of claim 8 , comprising a second antibody that specifically binds an epitope of a Botulinum neurotoxin that is specifically bound by an antibody comprising:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:463;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:465;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:467;

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:714;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:716; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:718.

10. A method of specifically binding a botulinum neurotoxin in a mammal comprising:

administering to said mammal an effective amount of the antibody of claim 1 ;

wherein said administering provides for binding of the antibody to the botulinum neurotoxin present in the mammal.

11. A method of specifically binding a botulinum neurotoxin in a mammal, comprising:

administering to said mammal an effective amount of the composition of claim 8 ;

wherein said administering provides for binding of the antibody to the botulinum neurotoxin present in the mammal.

12. A kit comprising the composition of claim 8 .

13. The isolated antibody of claim 1 , wherein said antibody competes for binding to a Botulinum neurotoxin with an antibody comprising:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:492;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:494; and

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:496;

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:742;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:744; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:746.

14. The isolated antibody of claim 1 , wherein said antibody competes for binding to a Botulinum neurotoxin with an antibody comprising:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:1309;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:1310;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:1311;

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1312;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:1313; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:1314.

15. The isolated antibody of claim 1 , wherein the antibody comprises:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:492;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:494;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:496;

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:742;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:744; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:746.

16. The isolated antibody of claim 1 , wherein the antibody comprises:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:1309;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:1310;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:1311;

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1312;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:1313; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:1314.

17. The composition of claim 8 , wherein the antibody comprises:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:492;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:494;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:496;

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:742;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:744; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:746.

18. The composition of claim 8 , wherein the antibody comprises:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:1309;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:1310;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:1311;

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1312;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:1313; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:1314.

19. The kit of claim 12 , wherein the antibody comprises:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:492;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:494;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:496;

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:742;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:744; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:746.

20. The kit of claim 12 , wherein the antibody comprises:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:1309;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:1310;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:1311;

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1312;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:1313; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:1314.

21. An isolated antibody that specifically binds an epitope of a Botulinum neurotoxin, comprising:

a variable heavy chain (V H ) comprising the amino acid sequence of SEQ ID NO:19; and

a variable light chain (V L ) comprising:

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:742;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:744; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:746; or

a variable light chain (V L ) comprising:

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1312;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:1313; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:1314; or

a variable light chain (V L ) comprising:

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:735;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:737; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:739.

22. The isolated antibody of claim 21 , wherein the variable light chain comprises:

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:742;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:744; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:746.

23. The isolated antibody of claim 21 , wherein the variable light chain comprises the amino acid sequence of SEQ ID NO:55.

24. The isolated antibody of claim 21 , wherein the variable light chain comprises:

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:735;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:737; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:739.

25. The isolated antibody of claim 21 , wherein the variable light chain comprises the amino acid sequence of SEQ ID NO:54.

26. An isolated antibody that specifically binds an epitope of a Botulinum neurotoxin, comprising:

a variable light chain (V L ) comprising the amino acid sequence of SEQ ID NO:55; and

a variable heavy chain (V H ) comprising:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:492;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:494;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:496; or

a variable heavy chain (V H ) comprising:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:1309;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:1310;

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:1311.

27. The isolated antibody of claim 26 , wherein the variable heavy chain comprises the amino acid sequence of SEQ ID NO:19.

28. A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier; and

the antibody of claim 21 .

29. A kit comprising the pharmaceutical composition of claim 28 .

30. A method of specifically binding a botulinum neurotoxin in a mammal comprising:

administering to said mammal an effective amount of the antibody of claim 21 ; wherein said administering provides for binding of the antibody to the botulinum neurotoxin present in the mammal.

31. A pharmaceutical composition comprising:

a pharmaceutically acceptable carrier; and

the antibody of claim 26 .

32. A kit comprising the pharmaceutical composition of claim 31 .

33. A method of specifically binding a botulinum neurotoxin in a mammal comprising:

administering to said mammal an effective amount of the antibody of claim 26 ; wherein said administering provides for binding of the antibody to the botulinum neurotoxin present in the mammal.

34. The isolated antibody of claim 21 , wherein the variable light chain comprises:

a V L CDR1 comprising the amino acid sequence of SEQ ID NO:1312;

a V L CDR2 comprising the amino acid sequence of SEQ ID NO:1313; and

a V L CDR3 comprising the amino acid sequence of SEQ ID NO:1314.

35. The isolated antibody of claim 26 , wherein the variable heavy chain comprises:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:492;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:494; and

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:496.

36. The isolated antibody of claim 26 , wherein the variable heavy chain comprises:

a V H CDR1 comprising the amino acid sequence of SEQ ID NO:1309;

a V H CDR2 comprising the amino acid sequence of SEQ ID NO:1310; and

a V H CDR3 comprising the amino acid sequence of SEQ ID NO:1311.

Assignments (2)
CONFIRMATORY LICENSE Recorded Dec 16, 2011
From: UNIVERSITY OF CALIFORNIA SAN FRANCISCO
To: NATIONAL INSTITUTES OF HEALTH (NIH), U.S. DEPT. OF HEALTH AND HUMAN SERVICES (DHHS), U.S. GOVERNMENT
Reel/Frame 027399/0488 →
ASSIGNMENT OF ASSIGNOR'S INTEREST Recorded Apr 5, 2011
From: MARKS, JAMES D.; LOU, JIANLONG; RODRIGUEZ, MARIA CONSUELO G.; GEREN, ISIN N.
To: THE REGENTS OF THE UNIVERSITY OF CALIFORNIA
Reel/Frame 026079/0026 →
Continuity (2)
Provisional Application 61085328 · Jul 31, 2008
Related Publication 20110200615A1 · Aug 18, 2011