ANTI-C5a ANTIBODIES AND METHODS FOR USING THE ANTIBODIES

• US 20130224187A1
• Filed: 04/29/2011
• Published: 08/29/2013
• 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., Tamburini, Paul P., Sheridan, Douglas L., Zhang, Yuchun
• Granted Patent: US 9,011,852 B2
• Time in Patent Office: Days
• 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 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.

2. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the concentration of uncleaved, native human C5 is between 2-fold and 20-fold greater than the concentration of free hC5a.

7. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof binds to free C5a from a non-human mammalian species.

9. The isolated antibody or antigen-binding fragment thereof of claim 7, wherein the non-human mammalian species is a non-human primate.

10. The isolated antibody or antigen-binding fragment thereof of claim 9, wherein the non-human primate is a cynomolgus macaque, rhesus macaque, or baboon.

11. The isolated antibody or antigen-binding fragment thereof of claim 7, wherein the antibody or antigen-binding fragment thereof binds to free hC5a with an affinity no greater than 100-fold its corresponding affinity for free C5a from the non-human mammalian species.

15. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof comprises:

(a) a light chain polypeptide comprising;

(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; and

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

22;

or

(ii) 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; and

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

22; and

(b) a heavy chain polypeptide comprising;

(i) 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;

29; and

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

30;

or

(ii) 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.

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

37 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;

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

33;

(c) 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;

(d) 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;

(e) 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;

(f) 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;

(g) 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;

(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;

or

(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.

42. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the isolated antibody or antigen-binding fragment thereof comprises:

(i) 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;

(ii) 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;

or

(iii) 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 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.

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

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

51. The isolated antibody or antigen-binding fragment thereof of claim 1, wherein the antibody or antigen-binding fragment thereof inhibits the interaction between C5a and a C5a receptor.

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

72. An antibody or antigen-binding fragment thereof that crossblocks the binding of the antibody or antigen-binding fragment thereof of claim 1.

73. A pharmaceutical composition comprising the antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically-acceptable carrier.

74. A nucleic acid encoding the antibody or antigen-binding fragment thereof of claim 1.

90. A method for treating a complement-associated disorder, the method comprising administering to a human in need thereof an antibody or antigen-binding fragment thereof of claim 1 in an amount sufficient to treat a complement-associated disorder afflicting the human.

92. The method of claim 90, wherein the complement-associated disorder is selected from the group consisting of atypical hemolytic uremic syndrome, age-related macular degeneration, severe burn, rheumatoid arthritis, sepsis, lupus nephritis, a complement-associated pulmonary disorder, and antiphospholipid syndrome.

3-4. -4. (canceled)

5. An isolated antibody or antigen-binding fragment thereof that binds to a free C5a polypeptide, wherein the free C5a polypeptide is a human polypeptide (hC5a) having the amino acid sequence depicted in SEQ ID NO:

1, wherein the antibody or antigen-binding fragment thereof binds to the human C5a polypeptide with a K_D that is less than 1.25×

10<sup>−

9</sup> M, wherein the antibody or antigen-binding fragment thereof binds to free hC5a polypeptide with an affinity that is at least 100-fold greater than its corresponding affinity for uncleaved human C5.

6. (canceled)

8. An isolated antibody or antigen-binding fragment thereof that:

(a) binds to a free human C5a polypeptide and (b) binds to a free C5a polypeptide from a non-human species, wherein the antibody or antigen-binding fragment thereof binds to the free hC5a polypeptide with a K_D that is less than 1.25×

10<sup>−

9</sup> M.

12-14. -14. (canceled)

16-20. -20. (canceled)

22-41. -41. (canceled)

43-47. -47. (canceled)

49. (canceled)

52-57. -57. (canceled)

59-71. -71. (canceled)

75-89. -89. (canceled)

91. (canceled)

93-100. -100. (canceled)

101. An isolated antibody or antigen-binding fragment thereof that binds to mouse C5a, the antibody comprising:

(A)

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

54;

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

55; and

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

56;

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

62;

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

63; and

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

64;

or

(B)

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

59; and

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

66.

102-104. -104. (canceled)

105. An isolated antibody, or antigen-binding fragment thereof, comprising;

(A)

a light chain polypeptide comprising;

(i) 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; and

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

142;

(ii) 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; and

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

158;

(iii) 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; and

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

166;

(iv) 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; and

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

174;

(v) 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; and

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

86;

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

92;

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

89; and

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

93;

(vii) 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; and

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

90;

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

95;

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

96; and

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

97;

(ix) 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; and

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

101;

(x) 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; and

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

103;

(xi) 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; and

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

107;

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

92;

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

89; and

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

108;

(xiii) 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; and

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

111;

or

(xiv) 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;

113; and

a heavy chain polypeptide comprising;

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

115;

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

144; and

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

117;

(ii) 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;

67; and

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

30;

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

160;

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

161; and

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

162;

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

168;

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

169; and

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

170;

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

176;

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

177; and

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

178;

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

115;

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

116; and

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

117;

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

119;

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

120; and

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

121;

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

115;

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

123; and

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

117;

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

115;

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

124; and

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

117;

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

119;

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

126; and

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

127;

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

115;

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

129; and

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

117;

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

131;

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

132; and

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

133;

(xiii) 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;

or

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

136;

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

137; and

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

138;

(B)

a paired set of light chain CDR sequences and heavy chain CDR sequences as paired in Table 3 or Table 9;

or

(C)

(i) 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 CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

144; and

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

117;

(ii) 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 CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

67; and

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

30;

(iii) 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 CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

161; and

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

162;

(iv) 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 CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

169; and

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

170;

(v) 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 CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

177; and

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

178;

(vi) 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 CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

120; and

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

121;

(vii) 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 CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

124; and

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

117;

(viii) 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 CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

115;

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

116; and

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

117;

(ix) 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 CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

137; and

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

138;

(x) 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 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;

(xi) 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 CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

126; and

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

127;

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

95;

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;

97;

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

115;

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

144; and

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

117;

(xiii) 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 CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

123; and

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

117;

(xiv) 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 CDR2 comprising the amino acid sequence depicted in SEQ ID NO;

123; and

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

117;

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

92;

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;

108;

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

115;

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

144; and

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

117;

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

92;

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;

93;

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

115;

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

123; and

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

117;

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

92;

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;

93;

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

115;

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

144; and

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

117;

(xviii) 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;

103;

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

115;

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

129; and

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

117;

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

95;

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;

97;

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

115;

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

123; and

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

117;

(xx) 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;

103;

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

115;

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

144; and

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

117;

or

(xxi) 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 CDR1 comprising the amino acid sequence depicted in SEQ ID NO;

131;

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

132; and

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

133.

106-119. -119. (canceled)

120. An isolated antibody comprising two antigen-binding sites, wherein each antigen-binding site independently can bind to free human C5a (hC5a) or uncleaved human C5 (hC5), and wherein, in an aqueous solution comprising:

(i) a plurality of said antibodies and (ii) a molar excess of hC5 as compared to the molar amount of the antigen-binding sites, at equilibrium and under physiological conditions;

(a) at least 95% of said plurality of antibodies bind no more than one hC5 molecule;

(b) at least 95% of said plurality of antibodies retain at least one antigen-binding site available to bind free hC5a;

or

(c) the two antigen-binding sites of no more than 5% of said plurality of antibodies are fully occupied by hC5 molecules.

126. The isolated antibody of claim 120, wherein each antigen-binding site independently can bind to free hC5a with a subnanomolar affinity.

127. The isolated antibody of claim 120, wherein the isolated antibody comprises:

(A)

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

20;

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

21; and

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

22;

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

28;

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

46; and

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

47;

or

(B)

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.

131. A method for treating a human afflicted with a C5a-associated complement disorder, the method comprising administering to the human:

(i) at least 1 mg of the antibody of claim 120 per kg body weight of the human to thereby partially or completely bind and sequester nanogram levels of free C5a for at least 12 days or (ii) the antibody of claim 120 in an amount sufficient to (a) achieve molar Cmax values substantially lower than the molar physiologic concentration of uncleaved hC5 and (b) partially or completely bind and sequester pathophysiologic levels of free C5a.

121-125. -125. (canceled)

128-130. -130. (canceled)

132-140. -140. (canceled)