JCV NEUTRALIZING ANTIBODIES

• US 20150056188A1
• Filed: 03/15/2013
• Published: 02/26/2015
• Est. Priority Date: 03/20/2012
• Status: Active Grant

• Current Assignee: Biogen MA Inc. (Biogen, Inc.)
• Original Assignee: Biogen Idec MA Inc. (Biogen, Inc.)
• Inventors: Simon, Kenneth, Cameron, Thomas, Rushe, Mia, Caravella, Justin, Kaynor, George Campbell
• Granted Patent: US 9,567,391 B2
• Time in Patent Office: Days
• US Class Current: 424/133.1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: C07K 16/084 Papovaviridae, e.g. papillomavirus, polyomavirus, SV40, BK virus, JC virus
• CPC Class Codes: C07K 2317/00 Immunoglobulins specific features
• CPC Class Codes: C07K 2317/24 containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/40 characterized by post-translational modification
• CPC Class Codes: C07K 2317/76 Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: Y02A 50/30 Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change

Abstract

In one aspect, the disclosure provides neutralizing antibodies against JCV and methods for the treatment of PML. In some embodiments, aspects of the invention relate to an isolated JC-virus neutralizing monoclonal antibody against JCV capsid protein VPI (JCV-VP1). In some embodiments, the antibody suppresses infectivity of the JC-virus. In some embodiments, the antibody binds the sialic acid binding pocket of JCV-VPI. In some embodiments, the antibody binds JCV-VP 1 comprising one or more of the following mutations: S269F, S269Y, S267F, N265D, Q271 H, D66H, K60E, K60N and L55F.

Claims

1. An isolated JC-virus neutralizing monoclonal antibody against JCV capsid protein VP1 (JCV-VP1).

2. The antibody of claim 1, wherein the antibody suppresses infectivity of the JC-virus.

3. The antibody of claim 1 or claim 2, wherein the antibody binds the sialic acid binding pocket of JCV-VP1.

4. The antibody of any one of claims 1-3, wherein the antibody binds JCV-VP1 comprising one or more of the following mutations:

S269F, S269Y, S267F, N265D, Q271H, D66H, K60E, K60N, and L55F.

5. The antibody of any one of claims 1-3, wherein the antibody binds JCV-VP1 comprising mutation S269F, JCV-VP1 comprising mutation S269Y, JCV-VP1 comprising mutation S267F, JCV-VP1 comprising mutation N265D, JCV-VP1 comprising mutation Q271H, JCV-VP1 comprising mutation D66H, JCV-VP1 comprising mutation K60E, JCV-VP1 comprising mutation K60N, and JCV-VP1 comprising mutation L55F.

6. The antibody of any one of claims 1-5, wherein the JCV-VP1 is from JCV strain type 1a, 1b, 2a, 2b, 3, 4, or 7.

7. The antibody of any one of claims 1-6, wherein the antibody comprises one or more of the following CDRs:

CDR1;

GYTLT (SEQ ID NO;

48, h-18C9), CDR1;

KASQDVGTAVA (SEQ ID NO;

64, 1-18C9), CDR2;

LINPYXXGTRYNQKFKG (SEQ ID NO;

62, h-18C9 N55X N56X), CDR2;

WASTRHT (SEQ ID NO;

65, 1-18C9), CDR3;

LGYYATGDEYFDY (SEQ ID NO;

63, h-18C9), CDR3;

QQYSSYPXT (SEQ ID NO;

70, 1-18C9 C96X), and CDR sequences with up to two amino acid mutations as compared to SEQ ID NOs;

48, 64, 62, 65, 63 and 70.

8. The antibody of any one of claims 1-6, wherein the antibody comprises one or more of the following CDRs:

CDR1;

GYTLT (SEQ ID NO;

48, h-18C9), CDR1;

KASQDVGTAVA (SEQ ID NO;

64, 1-18C9), CDR2;

LINPYHGGTRYNQKFKG (SEQ ID NO;

53, h-18C9 N55H), CDR2;

WASTRHT (SEQ ID NO;

65, 1-18C9), CDR3;

LGYYATGDEYFDY (SEQ ID NO;

63, h-18C9), CDR3;

QQYSSYPST (SEQ ID NO;

68, 1-18C9 C96S), and CDR sequences with up to two amino acid mutations as compared to SEQ ID NOs;

48, 64, 53, 65, 63 and 68.

9. The antibody of any one of claims 1-6, wherein the antibody comprises one or more of the following CDRs:

CDR1;

GYTLT (SEQ ID NO;

48, h-18C9), CDR1;

KASQDVGTAVA (SEQ ID NO;

64, 1-18C9), CDR2;

LINPYHGGTRYNQKFKG (SEQ ID NO;

53, h-18C9 N55H), CDR2;

WASTRHT (SEQ ID NO;

65, 1-18C9), CDR3;

LGYYATGDEYFDY (SEQ ID NO;

63, h-18C9), CDR3;

QQYSSYPST (SEQ ID NO;

68, 1-18C9 C96S).

10. The antibody of any one of claims 1-6, wherein the antibody comprises one or more of the following CDRs:

CDR3;

LGYYATGDEYFDY (SEQ ID NO;

63, h-18C9), CDR3;

QQYSSYPST (SEQ ID NO;

68, 1-18C9 C96S), and CDR sequences with up to two amino acid mutations as compared to SEQ ID NOs;

63 and 68.

11. The antibody of any one of claims 1-6, wherein the antibody comprises one or more of the following CDRs:

CDR3;

LGYYATGDEYFDY (SEQ ID NO;

63, h-18C9), and CDR3;

QQYSSYPST (SEQ ID NO;

68, 1-18C9 C96S).

12. The antibody of any one of claims 1-6, wherein the antibody comprises the following CDRs:

CDR1;

GYTLT (SEQ ID NO;

48, h-18C9), CDR2;

LINPYHGGTRYNQKFKG (SEQ ID NO;

53, h-18C9 N55H), and CDR3;

LGYYATGDEYFDY (SEQ ID NO;

63, h-18C9).

13. The antibody of any one of claims 1-6, wherein the antibody comprises the following CDRs:

CDR1;

KASQDVGTAVA (SEQ ID NO;

64, 1-18C9), CDR2;

WASTRHT (SEQ ID NO;

65, 1-18C9), and CDR3;

QQYSSYPST (SEQ ID NO;

68, 1-18C9 C96S).

14. The antibody of any one of claims 1-6, wherein the antibody comprises the following CDRs:

CDR1;

GYTLT (SEQ ID NO;

48, h-18C9), CDR1;

KASQDVGTAVA (SEQ ID NO;

64, 1-18C9), CDR2;

LINPYHGGTRYNQKFKG (SEQ ID NO;

53, h-18C9 N55H), CDR2;

WASTRHT (SEQ ID NO;

65, 1-18C9), CDR3;

LGYYATGDEYFDY (SEQ ID NO;

63, h-18C9), and CDR3;

QQYSSYPST (SEQ ID NO;

68, 1-18C9 C96S).

15. The antibody of any of the preceding claims, wherein the antibody is a chimeric antibody.

16. The antibody of any of the preceding claims, wherein the antibody comprises an IgG1 Fc-region.

17. The antibody of any of the preceding claims, wherein the antibody has effector function.

24. A method of treating a subject having one or more signs or symptoms of progressive multifocal leukoencephalopathy (PML), or having PML, the method comprising

administering the antibody of any of the preceding claims to a subject having one or more signs or symptoms of PML, or of having PML, in a therapeutically effective amount to treat PML.

25. The method of claim 24, wherein the antibody crosses the blood-brain barrier.

26. The method of claim 24-25, wherein treatment results in a reduction in viral load, an improved EDSS score, an improved Karnofsky score, an improved MRI scan, or an improvement in cognition.

27. The method of any one of claims 24-26, wherein the subject is undergoing, or has been undergoing, immunotherapy treatment.

28. The method of any one of claims 24-27, wherein the subject is immunocompromised.

18. An isolated antibody comprising SEQ ID NO:

23 (h-18C9 N55H) and SEQ ID NO;

43 (1-18C9 C96S).

19. An isolated antibody comprising a sequence that has at least 80% homology to SEQ ID NO:

23 (h-18C9 N55H) and a sequence that has at least 80% homology to SEQ ID NO;

43 (1-18C9 C96S).

20. An isolated antibody comprising a sequence that has at least 90% homology to SEQ ID NO:

23 (h-18C9 N55H) and a sequence that has at least 90% homology to SEQ ID NO;

43 (1-18C9 C96S).

21. An isolated antibody comprising a sequence that has at least 95% homology to SEQ ID NO:

23 (h-18C9 N55H) and a sequence that has at least 95% homology to SEQ ID NO;

43 (1-18C9 C96S).

22. An isolated antibody comprising a sequence that has up to 10 mutations compared to SEQ ID NO:

23 (h-18C9 N55H) and a sequence that has up to 10 mutations compared to SEQ ID NO;

43 (1-18C9 C96S).

23. An isolated antibody having heavy chain sequence