Methods of treating C5 mediated complement-associated conditions with anti-C5 antibodies having improved pharmacokinetics

Patent metadata

Field	Value
Publication number	US-9107861-B1
Application number	US-201514727313-A
Country	US
Kind code	B1
Filing date	Jun 1, 2015
Priority date	Mar 7, 2014
Publication date	Aug 18, 2015
Grant date	Aug 18, 2015

Abstract

The disclosure provides antibodies that are useful for, among other things, inhibiting terminal complement (e.g., the assembly and/or activity of the C5b-9 TCC) and C5a anaphylatoxin-mediated inflammation and, thus, treating complement-associated disorders. The antibodies have a number of improved properties relative to eculizumab, including, e.g., increased serum half-life in a human.

First claim

What is claimed is:

1. A method for treating a patient afflicted with a C5 mediated complement-associated condition, the method comprising administering to the subject an antibody, or antigen-binding fragment, thereof in an amount effective to treat the C5 mediated complement-associated condition, wherein the antibody, or antigen-binding fragment thereof, binds to complement component human C5, inhibits the cleavage of C5 into fragments C5a and C5b, and comprises:
(i) a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:23, a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 19, a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:3, a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:4, a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:5, and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:6; and
(ii) a variant human IgG Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the CH3 domain of the variant human Fc constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering.

2. The method of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region depicted in SEQ ID NO: 12 and a light chain variable region depicted in SEQ ID NO:8.

3. The method of claim 1 , wherein the antibody, or antigen-binding fragment thereof, further comprises a heavy chain constant region depicted in SEQ ID NO: 13.

4. The method of claim 1 , wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 11.

5. The method of claim 1 , wherein the antibody, or antigen-binding fragment thereof, has a serum half-life in humans of at least 25 days.

6. The method of claim 1 , wherein the isolated antibody, or antigen-binding fragment thereof, binds to human C5 at pH 7.4 and 25° C. with an affinity dissociation constant (K D ) that is in the range 0.1 nM≦K D ≦1 nM.

7. The method of claim 1 , wherein the antibody, or antigen-binding fragment thereof, binds to human C5 at pH 6.0 and 25° C. with a K D ≧10 nM.

8. The method of claim 1 , wherein the [(K D of the antibody, or antigen-binding fragment thereof, for human C5 at pH 6.0 and at 25° C.)/(K D of the antibody, or antigen-binding fragment thereof, for human C5 at pH 7.4 and at 25° C.)] is greater than 25.

9. The method of claim 1 , wherein the C5 mediated complement-associated condition is paroxysmal nocturnal hemoglobinuria (PNH).

10. The method of claim 1 , wherein the C5 mediated complement-associated condition is atypical hemolytic uremic syndrome (aHUS).

11. A method for treating a patient afflicted with a C5 mediated complement-associated condition, the method comprising administering to the subject an antibody, or antigen-binding fragment, thereof in an amount effective to treat the C5 mediated complement-associated condition, wherein the antibody, or antigen-binding fragment thereof, binds to complement component human C5, inhibits the cleavage of C5 into fragments C5a and C5b, and comprises:
a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:23, a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO: 19, a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:3, a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:4, a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:5, and a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:6,
wherein the [(K D of the antibody, or antigen-binding fragment thereof, for human C5 at pH 6.0 and at 25° C.)/(K D of the antibody, or antigen-binding fragment thereof, for human C5 at pH 7.4 and at 25° C.)] is greater 24,
wherein the antibody comprises a variant human IgG Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the C113 domain of the variant human Fc constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434 of a native human IgG Fc constant region, each in EU numbering,
and wherein the antibody, or antigen-binding fragment thereof, has a serum half-life in humans that is at least 25 days.

12. The method of claim 11 , wherein the antibody, or antigen-binding fragment thereof, comprises a heavy chain variable region polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 12 and a light chain variable region comprising the amino acid sequence depicted in SEQ ID NO: 8.

13. The method of claim 11 , further comprising a heavy chain constant region depicted in SEQ ID NO:13.

14. The method of claim 11 , wherein the C5 mediated complement-associated condition is paroxysmal nocturnal hemoglobinuria (PNH).

15. The method of claim 11 , wherein the C5 mediated complement-associated condition is atypical hemolytic uremic syndrome (aHUS).

16. A method for treating a patient afflicted with a C5 mediated complement-associated condition, the method comprising administering to the subject an antibody, or antigen-binding fragment, thereof in an amount effective to treat the C5 mediated complement-associated condition, wherein the antibody, or antigen-binding fragment thereof, binds to complement component human C5, inhibits the cleavage of C5 into fragments C5a and C5b, and comprises:
a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 14 and a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO: 11.

17. The method of claim 16 , wherein the C5 mediated complement-associated condition is paroxysmal nocturnal hemoglobinuria (PNH).

18. The method of claim 16 , wherein the C5 mediated complement-associated condition is atypical hemolytic uremic syndrome (aHUS).

Assignees

• Alexion Pharma Inc

Inventors

• Andrien Jr Bruce A
• Sheridan Douglas L
• Tamburini Paul P

Classifications

• A61P31/04

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• A61P5/14

  of the thyroid hormones, e.g. T3, T4 · CPC title

• A61P9/04

  Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure · CPC title

• A61P37/02

  Immunomodulators · CPC title

• A61P17/06

  Antipsoriatics · CPC title