Anti-C5 antibodies having improved pharmacokinetics
AssigneeAlexion Pharmaceuticals, Inc.
InventorsBruce A. Andrien, Jr., Douglas L. Sheridan, Paul P. Tamburini
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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.
Claims20
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;
- (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;
- and
- (d) comprises 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.
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 [(KD of the antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and at 25° C.)/(KD 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 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,
- and wherein the antibody has a serum half-life in humans that is at least 25 days.
An isolated antibody, or antigen-binding fragment thereof, that binds to complement component human C5, 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.
Dependencies are inferred from the claim text.