Anti-C5a antibodies

• US 9,011,852 B2
• Filed: 04/29/2011
• Issued: 04/21/2015
• 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:
  US13/695,277
• Publication Number:
  US 20130224187A1
• Time in Patent Office: 1,453 Days
• Field of Search: None
• US Class Current: 424/133.1
• 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, antiphospho lipid syndrome, asthma, lupus nephritis, Goodpasture'"'"'s syndrome, and chronic obstructive pulmonary disease.

Claims

1. An isolated antibody, or antigen-binding fragment thereof, that binds C5a, wherein the antibody, or antigen-binding fragment thereof, comprises:

(a) a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

140;

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

96;

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

142;

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

115;

a heavy chain CDR2comprising the amino acid sequence depicted in SEQ ID NO;

144; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

117;

(b) 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; and

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 CDR2comprising the amino acid sequence depicted in SEQ ID NO;

67; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

30;

(c) a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

156;

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

157;

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

158;

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

160;

a heavy chain CDR2comprising the amino acid sequence depicted in SEQ ID NO;

161; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

162;

(d) a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

164;

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

165;

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

166;

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

168;

a heavy chain CDR2comprising the amino acid sequence depicted in SEQ ID NO;

169; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

170;

(e) a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

172;

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

173;

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

174;

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

176;

a heavy chain CDR2comprising the amino acid sequence depicted in SEQ ID NO;

177; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

178;

(f) a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

84;

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

85;

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

86;

a heavy chain CDR1comprising the amino acid sequence depicted in SEQ ID NO;

115;

a heavy chain CDR2comprising the amino acid sequence depicted in SEQ ID NO;

116; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

117;

(g) a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

88;

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

89;

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

90;

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

119;

a heavy chain CDR2comprising the amino acid sequence depicted in SEQ ID NO;

120; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

121;

(h) a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

99;

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

100;

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

101;

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

119;

a heavy chain CDR2comprising the amino acid sequence depicted in SEQ ID NO;

126; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

127;

(i) 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;

113;

a heavy chain CDR1comprising the amino acid sequence depicted in SEQ ID NO;

28;

a heavy chain CDR2comprising the amino acid sequence depicted in SEQ ID NO;

46; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

47;

(j) 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;

110;

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

111;

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

136;

a heavy chain CDR2comprising the amino acid sequence depicted in SEQ ID NO;

137; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

138;

(k) a light chain CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

105;

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

106;

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

107;

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

115;

a heavy chain CDR2comprising the amino acid sequence depicted in SEQ ID NO;

124; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

117;

(l) 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 CDR1comprising the amino acid sequence depicted in SEQ ID NO;

28;

a heavy chain CDR2comprising the amino acid sequence depicted in SEQ ID NO;

29; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

30;

(m) 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;

38;

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 CDR2comprising the amino acid sequence depicted in SEQ ID NO;

29; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

30;

(n) 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 CDR2comprising the amino acid sequence depicted in SEQ ID NO;

46; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

47;

or

(o) 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;

38;

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 CDR2comprising the amino acid sequence depicted in SEQ ID NO;

46; and

a heavy chain CDR3comprising the amino acid sequence depicted in SEQ ID NO;

47.

7. The isolated antibody, or antigen-binding fragment thereof, of claim 1, 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.

14. The isolated antibody or antigen-binding fragment thereof of any one of claims 1-6, wherein the antibody or antigen-binding fragment thereof binds to hC5a with a K_D that is less than 8.0×

10<sup>−

11</sup> M.

15. The isolated antibody or antigen-binding fragment thereof of any one of claims 1-6, wherein the antibody inhibits by at least 90% human C5a-dependent human neutrophil activation at a molar ratio of 1:

1 (antigen-binding site;

C5a).

16. The isolated antibody, or antigen-binding fragment thereof, of any one of claims 1-6, wherein the antibody or antigen-binding fragment thereof inhibits the interaction between C5a and a C5a receptor.

17. The isolated antibody, or antigen-binding fragment, of any one of claims 1-6, wherein the antibody, or antigen-binding fragment, is selected from the group consisting of a monoclonal antibody, a humanized antibody, a fully human antibody, a recombinant antibody, a bispecific antibody, a single chain antibody, a diabody, an intrabody, a chimerized or chimeric antibody, a deimmunized human antibody, an Fv fragment, an Fd fragment, an Fab fragment, an Fab′

fragment, and an F(ab′

)₂ fragment.

18. A pharmaceutical composition comprising the antibody, or antigen-binding fragment thereof, of any one of claims 1-3 and a pharmaceutically-acceptable carrier.

2. An isolated antibody, or antigen-binding fragment thereof, that binds C5a, wherein the isolated antibody, or antigen-binding fragment thereof, comprises heavy and light chains, wherein the light chain comprises the amino acid sequence depicted in SEQ ID NO:

17, 36, or 40.

8. The isolated antibody, or antigen-binding fragment thereof, of claim 2, wherein the isolated antibody, or antigen-binding fragment thereof, comprises heavy and light chains, wherein the light chain comprises the amino acid sequence depicted in SEQ ID NO:

40.

3. An isolated antibody, or antigen-binding fragment thereof, that binds C5a, wherein the isolated antibody, or antigen-binding fragment thereof, comprises heavy and light chains, wherein the heavy chain comprises the amino acid sequence depicted in SEQ ID NO:

25, 33, 44, or 49.

9. The isolated antibody, or antigen-binding fragment thereof, of claim 3, wherein the isolated antibody, or antigen-binding fragment thereof, comprises heavy and light chains, wherein the heavy chain comprises the amino acid sequence depicted in SEQ ID NO:

49.

4. An isolated antibody, or antigen-binding fragment thereof, that binds C5a, wherein the isolated antibody, or antigen-binding fragment thereof, comprises heavy and light chain variable regions, wherein the light chain variable region comprises the amino acid sequence depicted in SEQ ID NO:

19, 37, or 42.

10. The isolated antibody, or antigen-binding fragment thereof, of claim 4, wherein the isolated antibody, or antigen-binding fragment thereof, comprises heavy and light chain variable regions, wherein the light chain variable region comprises the amino acid sequence depicted in SEQ ID NO:

42.

5. An isolated antibody, or antigen-binding fragment thereof, that binds C5a, wherein the isolated 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:

27 or 45.

11. The isolated antibody, or antigen-binding fragment thereof, of claim 5, wherein the isolated 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.

6. An isolated antibody, or antigen-binding fragment thereof, that binds C5a, wherein the isolated antibody, or antigen-binding fragment thereof, comprises:

(a) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

19 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

27;

(b) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

17 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

25;

(c) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

17 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

33;

(d) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

37 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

27;

(e) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

36 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

33;

(f) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

42 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

27;

(g) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

40 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

33;

(h) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

19 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

45;

(i) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

17 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

44;

(j) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

17 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

49;

(k) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

37 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

45;

(l) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

36 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

49;

(m) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

42 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

45;

or

(n) a light chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

40 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

49.

12. The isolated antibody, or antigen-binding fragment thereof, of claim 6, wherein the isolated antibody, or antigen-binding fragment thereof, comprises:

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

42 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

45.

13. The isolated antibody, or antigen-binding fragment thereof, of claim 6, wherein the isolated antibody, or antigen-binding fragment thereof, comprises:

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

40 and a heavy chain polypeptide comprising the amino acid sequence depicted in SEQ ID NO;

49.