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