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US 2025/0145698 A1Published application
Anti-c5 antibodies having improved pharmacokinetics
AssigneeAlexion Pharmaceuticals, Inc.
InventorsBruce A. Andrien, JR., Douglas L. SHERIDAN, Paul P. TAMBURINI, Yi WANG
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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.
Claims22
1-30. (canceled)
An isolated antibody, or antigen-binding fragment thereof, which inhibits the cleavage of C5 into fragments C5a and C5b and comprises:
- (i) a heavy chain CDR1 comprising the amino acid sequence of SEQ ID NO:1, (ii) a heavy chain CDR2 comprising the amino acid sequence of SEQ ID NO:2, (iii) a heavy chain CDR3 comprising the amino acid sequence of SEQ ID NO:3, (iv) a light chain CDR1 comprising the amino acid sequence of SEQ ID NO:4, (v) a light chain CDR2 comprising the amino acid sequence of SEQ ID NO:5, (vi) a light chain CDR3 comprising the amino acid sequence of SEQ ID NO:6, in which at least one amino acid of (i)-(vi) is substituted with histidine, wherein the substitution is at amino acid position(s) selected from the group consisting of:
- (I) position 8 of SEQ ID NO:4,
- (II) position 2 of SEQ ID NO:1,
- (III) position 9 of SEQ ID NO:1,
- (IV) position 3 of SEQ ID NO:2,
- (V) position 8 of SEQ ID NO:2,
- (VI) position 8 of SEQ ID NO:2 and position 8 of SEQ ID NO:4,
- (VII) position 9 of SEQ ID NO:1, position 8 of SEQ ID NO:2 and position 8 of SEQ ID NO:4,
- (VIII) position 2 of SEQ ID NO:1 and position 3 of SEQ ID NO:2,
- (IX) position 9 of SEQ ID NO:1 and position 8 of SEQ ID NO:2,
- (X) position 2 of SEQ ID NO:1, position 8 of SEQ ID NO:2 and position 8 of SEQ ID NO:4, and
- (XI) position 2 of SEQ ID NO:1 and position 8 of SEQ ID NO:2;
- and
- wherein the antibody, or antigen-binding fragment thereof, has improved pharmacokinetic properties compared to an antibody comprising the heavy chain amino acid sequence of SEQ ID NO:7 and the light chain amino acid sequence of SEQ ID NO:8.
11 more elements
An isolated antibody, 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:1, (ii) a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO:
- 2, (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) further comprises a variant human Fc constant region that binds to human neonatal Fc receptor (FcRn) with greater affinity than that of a native human Fc constant region from which the variant human Fc constant region was derived.
4 more elements
Dependencies are inferred from the claim text.