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Last Updated: March 29, 2024

Claims for Patent: 9,371,377


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Summary for Patent: 9,371,377
Title:Anti-C5 antibodies having improved pharmacokinetics
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.
Inventor(s): Andrien, Jr.; Bruce A. (Guilford, CT), Sheridan; Douglas L. (Branford, CT), Tamburini; Paul P. (Kensington, CT)
Assignee: Alexion Pharmaceuticals, Inc. (New Haven, CT)
Application Number:14/923,879
Patent Claims: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.degree. C. with an affinity dissociation constant (K.sub.D) that is in the range 0.1 nM.ltoreq.K.sub.D.ltoreq.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.degree. C. with a K.sub.D.gtoreq.10 nM.

9. The isolated antibody, or antigen-binding fragment thereof, according to claim 1, wherein the [(K.sub.D of the antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and at 25.degree. C.)/(K.sub.D of the antibody or antigen-binding fragment thereof for human C5 at pH 7.4 and at 25.degree. 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.sub.D of the antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and at 25.degree. C.)/(K.sub.D of the antibody or antigen-binding fragment thereof for human C5 at pH 7.4 and at 25.degree. 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.

Details for Patent 9,371,377

Applicant Tradename Biologic Ingredient Dosage Form BLA Approval Date Patent No. Expiredate
Alexion Pharmaceuticals, Inc. ULTOMIRIS ravulizumab-cwvz Injection 761108 12/21/2018 ⤷  Try a Trial 2034-03-07
Alexion Pharmaceuticals, Inc. ULTOMIRIS ravulizumab-cwvz Injection 761108 10/09/2020 ⤷  Try a Trial 2034-03-07
>Applicant >Tradename >Biologic Ingredient >Dosage Form >BLA >Approval Date >Patent No. >Expiredate

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