Methods of treating complement-associated disorders with anti-C5a antibodies

• US 9,469,690 B2
• Filed: 04/01/2016
• Issued: 10/18/2016
• Est. Priority Date: 04/30/2010
• Status: Active Grant

• Current Assignee: Alexion Pharmaceuticals Incorporated (Astrazeneca PLC)
• Original Assignee: Alexion Pharmaceuticals Incorporated (Astrazeneca PLC)
• Inventors: Rother, Russell P., Sheridan, Douglas L., Tamburini, Paul P., Zhang, Yuchun
• Primary Examiner(s): Gambel, Phillip
• Application Number:
  US15/088,421
• Publication Number:
  US 20160207997A1
• Time in Patent Office: 200 Days
• Field of Search: None
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61K 45/06 Mixtures of active ingredients without chemical characterisation, e.g. antiphlogistics and cardiaca
• CPC Class Codes: A61K 47/60 the organic macromolecular compound being a polyoxyalkylene oligomer, polymer or dendrimer, e.g. PEG, PPG, PEO or polyglycerol
• CPC Class Codes: A61P 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• CPC Class Codes: A61P 11/16 Central respiratory analeptics
• CPC Class Codes: A61P 13/02 of urine or of the urinary tract, e.g. urine acidifiers
• CPC Class Codes: A61P 13/12 of the kidneys
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/04 Centrally acting analgesics, e.g. opioids
• CPC Class Codes: A61P 27/02 Ophthalmic agents
• CPC Class Codes: A61P 29/00 Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
• CPC Class Codes: A61P 3/06 Antihyperlipidemics
• CPC Class Codes: A61P 31/04 Antibacterial agents
• CPC Class Codes: A61P 37/00 Drugs for immunological or allergic disorders
• CPC Class Codes: A61P 37/02 Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 7/00 : Drugs for disorders of the blood or the extracellular fluid
• CPC Class Codes: A61P 7/02 : Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors
• CPC Class Codes: A61P 7/04 : Antihaemorrhagics; Procoagulants; Haemostatic agents; Antifibrinolytic agents
• CPC Class Codes: A61P 7/06 : Antianaemics
• CPC Class Codes: C07K 14/472 : Complement proteins, e.g. anaphylatoxin, C3a, C5a
• CPC Class Codes: C07K 16/18 : against material from animals or humans
• CPC Class Codes: C07K 16/28 : against receptors, cell surface antigens or cell surface determinants
• CPC Class Codes: C07K 16/461 : Igs containing Ig-regions, -domains or -residues form different species
• CPC Class Codes: C07K 2317/21 : from primates, e.g. man
• CPC Class Codes: C07K 2317/24 : containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
• CPC Class Codes: C07K 2317/31 : multispecific
• CPC Class Codes: C07K 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/34 : Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/51 : Complete heavy chain or Fd fragment, i.e. VH + CH1
• CPC Class Codes: C07K 2317/515 : Complete light chain, i.e. VL + CL
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/56 : variable (Fv) region, i.e. VH and/or VL
• CPC Class Codes: C07K 2317/565 : Complementarity determining region [CDR]
• CPC Class Codes: C07K 2317/567 : Framework region [FR]
• CPC Class Codes: C07K 2317/71 : Decreased effector function due to an Fc-modification
• CPC Class Codes: C07K 2317/76 : Antagonist effect on antigen, e.g. neutralization or inhibition of binding
• CPC Class Codes: C07K 2317/92 : Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
• CPC Class Codes: C07K 2317/94 : Stability, e.g. half-life, pH, temperature or enzyme-resistance

Abstract

The present disclosure relates to, inter alia, antibodies, or antigen-binding fragments thereof, that bind to C5a and to use of the antibodies in methods for treating or preventing complement-associated disorders such as, but not limited to, atypical hemolytic uremic syndrome, age-related macular degeneration, rheumatoid arthritis, sepsis, severe burn, antiphospholipid syndrome, asthma, lupus nephritis, Goodpasture'"'"'s syndrome, and chronic obstructive pulmonary disease.

Claims

1. A method for treating a complement-associated disorder, the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds C5a, wherein the antibody, or antigen-binding fragment thereof, comprises complementarity determining regions (CDRs) of a heavy chain variable region comprising the amino acid sequence depicted in SEQ ID NO:

45 and CDRs of a light chain variable region comprising the amino acid sequence depicted in SEQ ID NO;

42.

9. The method of any one of claims 1-8, wherein the isolated antibody, or antigen-binding fragment thereof, binds to human C5a with a K_D that is less than 8.0×

10<sup>−

11</sup> M.

10. The method of any one of claims 1-8, wherein the isolated antibody, or antigen-binding fragment thereof, inhibits by at least 90% human C5a-dependent human neutrophil activation at a molar ratio of 1:

1 (antigen-binding site;

C5a).

11. The method of any one of claims 1-8, wherein the isolated antibody, or antigen-binding fragment thereof, inhibits the interaction between C5a and a C5a receptor.

12. The method of any one of claims 1-8, wherein the isolated antibody, or antigen-binding fragment thereof, binds to a free C5a polypeptide, wherein the free C5a is a human polypeptide (hC5a) having the amino acid sequence depicted in SEQ ID NO:

1, and wherein the antibody, or antigen-binding fragment thereof, binds to the free hC5a polypeptide in vitro with a K_D that is less than 1.25×

10<sup>−

9</sup> M in the presence of a molar excess of uncleaved, native human C5.

13. The method of any one of claims 1-8, wherein the isolated antibody, or antigen-binding fragment thereof, is a humanized antibody.

14. The method of any one of claims 1-4, wherein the complement-associated disorder is graft-versus-host disease (GVHD).

2. A method for treating a complement-associated disorder, the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the antibody, or antigen-binding fragment thereof, comprises a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:

20;

a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

21;

a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO;

22;

a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

28;

a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

46; and

a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO;

47.

3. A method for treating a complement-associated disorder, the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the antibody, or antigen-binding fragment thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region comprises the amino acid sequence depicted in SEQ ID NO:

45 and the light chain variable region comprises the amino acid sequence depicted in SEQ ID NO;

42.

4. A method for treating a complement-associated disorder, the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the isolated antibody, or antigen-binding fragment thereof, that binds human C5a, comprises heavy and light chains, wherein the heavy chain comprises the amino acid sequence depicted in SEQ ID NO:

49 and the light chain comprises the amino acid sequence depicted in SEQ ID NO;

40.

5. A method for treating graft-versus-host disease (GVHD), the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds C5a, wherein the antibody, or antigen-binding fragment thereof, comprises complementarity determining regions (CDRs) of a heavy chain variable region comprising the amino acid sequence depicted in SEQ ID NO:

45 and CDRs of a light chain variable region comprising the amino acid sequence depicted in SEQ ID NO;

42.

6. A method for treating graft-versus-host disease (GVHD), the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the antibody, or antigen-binding fragment thereof, comprises a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO:

20;

a light chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

21;

a light chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO;

22;

a heavy chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

28;

a heavy chain CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

46; and

a heavy chain CDR3 comprising the amino acid sequence depicted in SEQ ID NO;

47.

7. A method for treating graft-versus-host disease (GVHD), the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the antibody, or antigen-binding fragment thereof, comprises heavy and light chain variable regions, wherein the heavy chain variable region comprises the amino acid sequence depicted in SEQ ID NO:

45 and the light chain variable region comprises the amino acid sequence depicted in SEQ ID NO;

42.

8. A method for treating graft-versus-host disease (GVHD), the method comprising administering to a human in need thereof, an isolated antibody, or antigen-binding fragment thereof, that binds human C5a, wherein the isolated antibody, or antigen-binding fragment thereof, that binds human C5a, comprises heavy and light chains, wherein the heavy chain comprises the amino acid sequence depicted in SEQ ID NO:

49 and the light chain comprises the amino acid sequence depicted in SEQ ID NO;

40.