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. An isolated antibody, or antigen-binding fragment thereof, that:
(a) binds to complement component human C5;
(b) inhibits the cleavage of C5 into fragments C5a and C5b; and
(c) comprises: (i) a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:23, (ii) a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:19, (iii) a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:3, (iv) a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:4, (v) a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:5, and (vi) a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:6.
2. The isolated antibody, or antigen-binding fragment thereof, according to claim 1 , further comprising a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, each in EU numbering.
3. The isolated antibody, or antigen-binding fragment thereof, according to claim 1 , comprising a heavy chain variable region depicted in SEQ ID NO:12 and a light chain variable region depicted in SEQ ID NO:8.
4. The isolated antibody, or antigen-binding fragment thereof, according to claim 1 , comprising a heavy chain constant region depicted in SEQ ID NO:13.
5. The isolated antibody, or antigen-binding fragment thereof, according to claim 1 , comprising 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.
6. The isolated antibody, or antigen-binding fragment thereof, according to claim 1 , wherein the antibody has a serum half-life in humans of at least 25 days.
7. The isolated antibody, or antigen-binding fragment thereof, according to claim 1 , wherein the 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.
8. The isolated antibody, or antigen-binding fragment thereof, according to 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.
9. The isolated antibody, or antigen-binding fragment thereof, according to 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.
10. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the antibody, or antigen-binding fragment thereof, of claim 1 .
11. A therapeutic kit comprising: (i) the isolated antibody, or antigen-binding fragment thereof, of claim 1 and (ii) instructions for administering the antibody, or antigen-binding fragment thereof to a human.
12. An isolated antibody, or antigen-binding fragment thereof, that:
(a) binds to complement component human C5;
(b) inhibits the cleavage of human C5 into fragments C5a and C5b; and
(c) comprises: (i) a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:23, (ii) a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:19, (iii) a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO:3, (iv) a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:4, (v) a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:5, and (vi) 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 than 25, and
and wherein the antibody has a serum half-life in humans that is at least 25 days.
13. The isolated antibody, or antigen-binding fragment thereof, of claim 12 , further comprising a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the variant human Fc CH3 constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and asparagine 434, each in EU numbering.
14. The isolated antibody, or antigen-binding fragment thereof, according to claim 12 , 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.
15. The isolated antibody, or antigen-binding fragment thereof, according to claim 12 , comprising a heavy chain constant region depicted in SEQ ID NO:13.
16. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the antibody, or antigen-binding fragment thereof, of claim 12 .
17. A therapeutic kit comprising: (i) the isolated antibody, or antigen-binding fragment thereof, of claim 12 and (ii) instructions for administering the antibody, or antigen-binding fragment thereof to a human.