ANTI-C5 ANTIBODIES HAVING IMPROVED PHARMACOKINETICS

• US 20160108115A1
• Filed: 10/27/2015
• Published: 04/21/2016
• Est. Priority Date: 03/07/2014
• Status: Active Grant

• Current Assignee: Alexion Pharmaceuticals Incorporated (Astrazeneca PLC)
• Original Assignee: Alexion Pharmaceuticals Incorporated (Astrazeneca PLC)
• Inventors: ANDRIEN, Bruce A. Jr., SHERIDAN, Douglas L., TAMBURINI, Paul P.
• Granted Patent: US 9,371,377 B2
• Time in Patent Office: Days
• US Class Current: 1/1
• CPC Class Codes: A61K 2039/505 comprising antibodies
• CPC Class Codes: A61K 2039/54 characterised by the route of administration
• CPC Class Codes: A61K 2039/545 characterised by the dose, timing or administration schedule
• CPC Class Codes: A61K 38/00 Medicinal preparations containing peptides peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00
• CPC Class Codes: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/04 for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 11/06 Antiasthmatics
• 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 15/06 Antiabortive agents; Labour repressants
• CPC Class Codes: A61P 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/06 Antipsoriatics
• CPC Class Codes: A61P 19/02 for joint disorders, e.g. arthritis, arthrosis
• CPC Class Codes: A61P 21/00 Drugs for disorders of the muscular or neuromuscular system
• CPC Class Codes: A61P 21/04 for myasthenia gravis
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/02 for peripheral neuropathies
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• 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 3/00 : Drugs for disorders of the metabolism of the blood or the extracellular fluid A61P7/00
• CPC Class Codes: A61P 3/06 : Antihyperlipidemics
• CPC Class Codes: A61P 3/10 : for hyperglycaemia, e.g. antidiabetics
• 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 39/02 : Antidotes
• CPC Class Codes: A61P 43/00 : Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
• CPC Class Codes: A61P 5/14 : of the thyroid hormones, e.g. T3, T4
• CPC Class Codes: A61P 5/16 : for decreasing, blocking or antagonising the activity of the thyroid hormones
• CPC Class Codes: A61P 5/48 : of the pancreatic hormones
• 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: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: A61P 9/04 : Inotropic agents, i.e. stimulants of cardiac contraction; Drugs for heart failure
• CPC Class Codes: A61P 9/10 : for treating ischaemic or atherosclerotic diseases, e.g. antianginal drugs, coronary vasodilators, drugs for myocardial infarction, retinopathy, cerebrovascula insufficiency, renal arteriosclerosis
• CPC Class Codes: A61P 9/12 : Antihypertensives
• 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 16/40 : against enzymes
• CPC Class Codes: C07K 2317/14 : Specific host cells or culture conditions, e.g. components, pH or temperature
• 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 2317/33 : Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
• CPC Class Codes: C07K 2317/35 : Valency
• CPC Class Codes: C07K 2317/41 : Glycosylation, sialylation, or fucosylation
• CPC Class Codes: C07K 2317/52 : Constant or Fc region; Isotype
• CPC Class Codes: C07K 2317/526 : CH3 domain
• 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 2317/64 : comprising a combination of variable region and constant region components
• CPC Class Codes: C07K 2317/72 : Increased 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 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.

Claims

1-36. -36. (canceled)

37. 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.

38. The isolated antibody, or antigen-binding fragment thereof, according to claim 37, 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.

39. The isolated antibody, or antigen-binding fragment thereof, according to claim 37, comprising a heavy chain variable region depicted in SEQ ID NO:

12 and a light chain variable region depicted in SEQ ID NO;

8.

40. The isolated antibody, or antigen-binding fragment thereof, according to claim 37, comprising a heavy chain constant region depicted in SEQ ID NO:

13.

41. The isolated antibody, or antigen-binding fragment thereof, according to claim 37, 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.

42. The isolated antibody, or antigen-binding fragment thereof, according to claim 37, wherein the antibody has a serum half-life in humans of at least 25 days.

43. The isolated antibody, or antigen-binding fragment thereof, according to claim 37, wherein the antibody or antigen-binding fragment thereof binds to human C5 at pH 7.4 and 25°

C. with an affinity dissociation constant (K_D) that is in the range 0.1 nM≦

K_D≦

1 nM.

44. The isolated antibody, or antigen-binding fragment thereof, according to claim 37, wherein the antibody or antigen-binding fragment thereof binds to human C5 at pH 6.0 and 25°

C. with a K_D≧

10 nM.

45. The isolated antibody, or antigen-binding fragment thereof, according to claim 37, wherein the [(K_D of the antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and at 25°

C.)/(K_D of the antibody or antigen-binding fragment thereof for human C5 at pH 7.4 and at 25°

C.)] is greater than 25.

46. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the antibody, or antigen-binding fragment thereof, of claim 37.

47. A therapeutic kit comprising:

(i) the isolated antibody, or antigen-binding fragment thereof, of claim 37 and (ii) instructions for administering the antibody, or antigen-binding fragment thereof to a human.

54. A method for treating a patient afflicted with a C5 mediated complement-associated condition, the method comprising administering to the subject the antibody, or antigen-binding fragment thereof, of claim 37 in an amount effective to treat the complement-associated condition.

55. The method of claim 54, wherein the C5 mediated complement-associated condition is paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS).

48. 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_D of the antibody or antigen-binding fragment thereof for human C5 at pH 6.0 and at 25°

C.)/(K_D of the antibody or antigen-binding fragment thereof for human C5 at pH 7.4 and at 25°

C.)] is greater than 25, and

and wherein the antibody has a serum half-life in humans that is at least 25 days.

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

50. The isolated antibody, or antigen-binding fragment thereof, according to claim 48, 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.

51. The isolated antibody, or antigen-binding fragment thereof, according to claim 48, comprising a heavy chain constant region depicted in SEQ ID NO:

13.

52. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the antibody, or antigen-binding fragment thereof, of claim 48.

53. A therapeutic kit comprising:

(i) the isolated antibody, or antigen-binding fragment thereof, of claim 48 and (ii) instructions for administering the antibody, or antigen-binding fragment thereof to a human.

56. A method for treating a patient afflicted with a complement-associated condition, the method comprising administering to the subject the antibody, or antigen-binding fragment thereof, of claim 48 in an amount effective to treat the C5 mediated complement-associated condition.

57. The method of claim 56, wherein the C5 mediated complement-associated condition is paroxysmal nocturnal hemoglobinuria (PNH) or atypical hemolytic uremic syndrome (aHUS).