Anti-C5 antibodies having improved pharmacokinetics

• US 9,079,949 B1
• Filed: 03/06/2015
• Issued: 07/14/2015
• 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.
• Primary Examiner(s): Gambel, Phillip
• Application Number:
  US14/641,026
• Time in Patent Office: 130 Days
• Field of Search: None
• 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. 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;

(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; and

(d) comprises a variant human IgG Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the CH3 domain of the variant human Fc constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and Asparagine 434 of a native human IgG Fc constant region, each in EU numbering.

2. 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.

3. The isolated antibody, or antigen-binding fragment thereof, according to claim 1, further comprising a heavy chain constant region depicted in SEQ ID NO:

13.

4. 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.

5. 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.

6. 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°

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

K_D≦

1 nM.

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 6.0 and 25°

C. with a K_D ≧

10 nM.

8. The isolated antibody, or antigen-binding fragment thereof, according to claim 1, 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.

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

16. A therapeutic kit comprising:

(i) the isolated antibody or antigen-binding fragment according to claim 1 and (ii) instructions for administering the antibody or antigen-binding fragment to a human.

17. The therapeutic kit of claim 16, further comprising a syringe.

18. An article of manufacture comprising:

a container comprising a label; and

a composition comprising;

(i) the isolated antibody or antigen-binding fragment according to claim 1, wherein the label indicates that the composition is to be administered to a human having, or suspected of having a complement-associated condition.

9. 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 24,

wherein the antibody comprises a variant human IgG Fc constant region that binds to human neonatal Fc receptor (FcRn), wherein the CH3 domain of the variant human Fc constant region comprises Met-429-Leu and Asn-435-Ser substitutions at residues corresponding to methionine 428 and Asparagine 434 of a native human IgG Fc constant region, each in EU numbering,

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

10. The isolated antibody, or antigen-binding fragment thereof, according to claim 9, 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.

11. The isolated antibody, or antigen-binding fragment thereof, according to claim 9, further comprising a heavy chain constant region depicted in SEQ ID NO:

13.

19. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the antibody or antigen-binding fragment thereof according to claim 9.

12. An isolated antibody, or antigen-binding fragment thereof, that binds to complement component human C5, and comprises 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.

13. The isolated antibody or antigen binding fragment thereof of claim 12, wherein the antibody is manufactured in a CHO cell.

14. The isolated antibody or antigen binding fragment thereof of claim 13, wherein the antibody does not contain detectable sialic acid residues.

20. A pharmaceutical composition comprising a pharmaceutically-acceptable carrier and the antibody or antigen-binding fragment thereof according to claim 12.