COMPOSITIONS AND METHODS FOR THE THERAPY AND DIAGNOSIS OF INFLUENZA

• US 20090226433A1
• Filed: 11/12/2008
• Published: 09/10/2009
• Est. Priority Date: 11/12/2007
• Status: Active Grant

• Current Assignee: Spaltudaq Corporation
• Original Assignee: Spaltudaq Corporation
• Inventors: Mitcham, Jennifer, Moyle, Matthew, Olsen, Ole, King, Gordon, Cox, Thomas, Grandea, Andres III
• Granted Patent: US 8,057,796 B2
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61P 31/16 for influenza or rhinoviruses
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 43/00 Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: C07K 14/005 from viruses
• CPC Class Codes: C07K 16/1018 Orthomyxoviridae, e.g. influenza virus
• CPC Class Codes: C07K 2317/21 from primates, e.g. man
• CPC Class Codes: C07K 2317/32 specific for a neo-epitope on a complex, e.g. antibody-antigen or ligand-receptor
• CPC Class Codes: C07K 2317/34 Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C12N 2760/16122 New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
• CPC Class Codes: G01N 33/56983 Viruses

Abstract

The present invention provides novel human anti-influenza antibodies and related compositions and methods. These antibodies are used in the diagnosis and treatment of influenza infection.

Claims

1. An isolated fully human monoclonal antibody, wherein said monoclonal antibody has the following characteristics

a) binds to an epitope in the extracellular domain of the matrix 2 ectodomain (M2e) polypeptide of an influenza virus;

b) binds to influenza A infected cells; and

c) binds to influenza A virus.

2. The antibody of claim 1, wherein said antibody is isolated from a B-cell from a human donor.

3. The antibody of claim 1, wherein said epitope is non-linear.

4. The antibody of claim 1, wherein said epitope comprises the amino-terminal region of the M2e polypeptide.

5. The antibody of claim 1, wherein said epitope comprises the amino acid at position 2, 5, and 6 of the M2e polypeptide, wherein amino acid position numbers are in accordance with SEQ ID NO:

1.

6. The antibody of claim 4, wherein the amino acid at

a) position 2 is a serine;

b) position 5 is a threonine; and

c) position 6 is a glutamic acid.

7. The antibody of claim 1, wherein said epitope wholly of partially includes the amino acid sequence SLLTEV (SEQ ID NO:

42)

8. The antibody of claim 1, wherein said antibody is 8I10, 21B15 or 23K12.

24. A composition comprising the antibody of claim 1.

25. The composition of claim 24, further comprising an anti-viral drug, a viral entry inhibitor or a viral attachment inhibitor.

26. The composition of claim 25, wherein said anti-viral drug is a neuraminidase inhibitor, a HA inhibitor, a sialic acid inhibitor or an M2 ion channel inhibitor.

27. The method of claim 26, wherein said M2 ion channel inhibitor is amantadine or rimantadine.

28. The method of claim 26, wherein said neuraminidase inhibitor zanamivir, or oseltamivir phosphate.

29. The composition of claim 24, further comprising a second anti-influenza A antibody.

30. The antibody of claim 1, wherein said antibody is operably-linked to a therapeutic agent or a detectable label.

31. A method for stimulating an immune response in a subject, comprising administering to the patient the composition of claim 24.

32. A method for the treatment or prevention of an influenza virus infection in a subject, comprising administering to the subject the composition of claim 24.

33. The method of claim 32, wherein the method further comprises administering an anti-viral drug, a viral entry inhibitor or a viral attachment inhibitor.

34. The method of claim 33, wherein said anti-viral drug is a neuraminidase inhibitor, a HA inhibitor, a sialic acid inhibitor or an M2 ion channel.

35. The method of claim 34, wherein said M2 ion channel inhibitor is amantadine or rimantadine.

36. The method of claim 34, wherein said neuraminidase inhibitor zanamivir, or oseltamivir phosphate.

37. The composition of claim 32, further comprising a second anti-influenza A antibody.

38. The method of claim 32, wherein said antibody is administered prior to or after exposure to influenza virus.

39. The method of claim 32, wherein said antibody is administered at a dose sufficient to promote viral clearance or eliminate influenza A infected cells.

40. A method for determining the presence of a influenza virus infection in a patient, comprising the steps of:

(a) contacting a biological sample obtained from the patient with the antibody according to claim 1;

(b) detecting an amount of the antibody that binds to the biological sample; and

(c) comparing the amount of antibody that binds to the biological sample to a control value, and therefrom determining the presence of the influenza virus in the patient.

41. A diagnostic kit comprising the antibody according to claim 1.

9. An antibody that binds the same epitope as 8I10, 21B15 or 23K12.

10. An isolated fully human monoclonal anti-M2e antibody or fragment thereof, wherein said antibody comprises a variable heavy chain (V_H) region comprising CDR1 and CDR2, wherein said region is encoded by a human IGHV4 or IGHV3 V_H germline sequence, or a nucleic acid sequence that is homologous to the said V_H germline gene sequence.

11. The antibody of claim 10, wherein said nucleic acid sequence that is homologous to the germline sequence is at least 90% homologous to said germline sequence.

12. The antibody of claim 10, wherein said antibody further comprises a variable light chain (VL) region encoded by a human IGHK1 V_L germline gene sequence, or a nucleotide acid sequence that is homologous to the said V_L germline gene sequence.

13. The antibody of claim 12, wherein said nucleic acid sequence that is homologous to the IGHV1 V_L germline sequence is at least 90% homologous to the said IGHV1 V_L germline sequence.

14. An isolated anti-matrix 2 ectodomain (M2e) antibody, wherein said antibody has a heavy chain with three CDRs comprising an amino acid sequence selected from the group consisting of the amino acid sequences of NYYWS (SEQ ID NO:

72), FIYYGGNTKYNPSLKS (SEQ ID NO;

     74), ASCSGGYCILD (SEQ ID NO;

     76), SNYMS (SEQ ID NO;

     103), VIYSGGSTYYAD SVK (SEQ ID NO;

     105), and CLSRMRGYGLDV (SEQ ID NO;

     107) and a light chain with three CDRs that include an amino acid sequence selected from the group consisting of the amino acid sequences of RASQNIYKYLN (SEQ ID NO;

     59), AASGLQS (SEQ ID NO;

     61), QQSYSPPLT (SEQ ID NO;

     63), RTSQSISSYLN (SEQ ID NO;

     92), AASSLQSGVPSRF (SEQ ID NO;

     94), and QQSYSMPA (SEQ ID NO;

     96).

15. An isolated anti-matrix 2 ectodomain (M2e) antibody, wherein said antibody has a heavy chain with three CDRs comprising an amino acid sequence selected from the group consisting of the amino acid sequences of NYYWS (SEQ ID NO:

72), FIYYGGNTKYNPSLKS (SEQ ID NO;

     74), ASCSGGYCILD (SEQ ID NO;

     76), SNYMS (SEQ ID NO;

     103), VIYSGGSTYYADSVK (SEQ ID NO;

     105), and CLSRMRGYGLDV (SEQ ID NO;

     107), wherein said antibody binds M2e.

16. An isolated anti-matrix 2 ectodomain (M2e) antibody, wherein said antibody has a light chain with three CDRs that include an amino acid sequence selected from the group consisting of the amino acid sequences of RASQNIYKYLN (SEQ ID NO:

59), AASGLQS (SEQ ID NO;

     61), QQSYSPPLT (SEQ ID NO;

     63), RTSQSISSYLN (SEQ ID NO;

     92), AASSLQSGVPSRF (SEQ ID NO;

     94), and QQSYSMPA (SEQ ID NO;

     96), wherein said antibody binds M2e.

17. An isolated anti-matrix 2 ectodomain (M2e) antibody, wherein said antibody has a heavy chain with three CDRs comprising an amino acid sequence selected from the group consisting of the amino acid sequences of NYYWS (SEQ ID NO:

72), FIYYGGNTKYNPSLKS (SEQ ID NO;

     74), and ASCSGGYCILD (SEQ ID NO;

     76), and a light chain with three CDRs that include an amino acid sequence selected from the group consisting of the amino acid sequences of RASQNIYKYLN (SEQ ID NO;

     59), AASGLQS (SEQ ID NO;

     61), and QQSYSPPLT (SEQ ID NO;

     63).

18. An isolated anti-matrix 2 ectodomain (M2e) antibody, wherein said antibody comprises a V_H CDR1 region comprising the amino acid sequence of NYYWS (SEQ ID NO:

72);

a V_H CDR2 region comprising the amino acid sequence of FIYYGGNTKYNPSLKS (SEQ ID NO;

     74);

a V_H CDR3 region comprising the amino acid sequence of ASCSGGYCILD (SEQ ID NO;

     76);

a V_L CDR1 region comprising the amino acid sequence of RASQNIYKYLN (SEQ ID NO;

59);

a V_L CDR2 region comprising the amino acid sequence of AASGLQS (SEQ ID NO;

     61);

a V_L CDR3 region comprising the amino acid sequence of and QQSYSPPLT (SEQ ID NO;

     63).

19. An isolated anti-matrix 2 ectodomain (M2e) antibody, wherein said antibody has a heavy chain with three CDRs comprising an amino acid sequence selected from the group consisting of the amino acid sequences of SNYMS (SEQ ID NO:

103), VIYSGGSTYYADSVK (SEQ ID NO;

     105), and CLSRMRGYGLDV (SEQ ID NO;

     107) and a light chain with three CDRs that include an amino acid sequence selected from the group consisting of the amino acid sequences of RTSQSISSYLN (SEQ ID NO;

     92), AASSLQSGVPSRF (SEQ ID NO;

     94), and QQSYSMPA (SEQ ID NO;

     96).

20. An isolated anti-matrix 2 ectodomain (M2e) antibody, wherein said antibody comprises a V_H CDR1 region comprising the amino acid sequence of SNYMS (SEQ ID NO:

103);

a V_H CDR2 region comprising the amino acid sequence of VIYSGGSTYYADSVK (SEQ ID NO;

     105), a V_H CDR1 region comprising the amino acid sequence of CLSRMRGYGLDV (SEQ ID NO;

     107);

a V_L CDR1 region comprising the amino acid sequence of RTSQSISSYLN (SEQ ID NO;

     92);

a V_L CDR2 region comprising the amino acid sequence of AASSLQSGVPSRF (SEQ ID NO;

     94); and

a V_L CDR3 region comprising the amino acid sequence of QQSYSMPA (SEQ ID NO;

     96).

21. An isolated anti-matrix 2 ectodomain (M2e) antibody or fragment thereof, wherein said antibody comprises:

(a) a V_H CDR1 region comprising the amino acid sequence of SEQ ID NO;

72 or 103;

(b) a V_H CDR2 region comprising the amino acid sequence of SEQ ID NO;

74 or 105; and

(c) a V_H CDR3 region comprising the amino acid sequence of SEQ ID NO;

76 or 107, wherein said antibody binds M2e.

22. The antibody of claim 21, wherein said antibody further comprises:

(a) a V_L CDR1 region comprising the amino acid sequence of SEQ ID NO;

59 or 92;

(b) a V_L CDR2 region comprising the amino acid sequence of SEQ ID NO;

61 or 94; and

(c) a V_L CDR3 region comprising the amino acid sequence of SEQ ID NO;

63 or 96.

23. An isolated fully human monoclonal anti-matrix 2 ectodomain (M2e) antibody comprising:

a) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO;

44 and a light chain sequence comprising amino acid sequence SEQ ID NO;

46 or

b) a heavy chain sequence comprising the amino acid sequence of SEQ ID NO;

50 and a light chain sequence comprising amino acid sequence SEQ ID NO;

52.