ANTI-COMPLEMENT C1S ANTIBODIES AND USES THEREOF

• US 20140140933A1
• Filed: 11/01/2013
• Published: 05/22/2014
• Est. Priority Date: 11/02/2012
• Status: Active Grant

• Current Assignee: Bioverativ USA Inc.
• Original Assignee: True North Therapeutics, Inc. (Sanofi )
• Inventors: Van Vlasselaer, Peter, Parry, Graham, Stagliano, Nancy E., Panicker, Sandip
• Granted Patent: US 8,945,562 B2
• Time in Patent Office: Days
• US Class Current: 424/9.34
• CPC Class Codes: A01N 1/021 Preservation or perfusion media, liquids, solids or gases used in the preservation of cells, tissue, organs or bodily fluids
• 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 49/00 Preparations for testing in vivo
• CPC Class Codes: A61K 49/16 Antibodies; Immunoglobulins; Fragments thereof
• CPC Class Codes: A61K 51/10 Antibodies or immunoglobulins; Fragments thereof , the carrier being an antibody, an immunoglobulin or a fragment thereof, e.g. a camelised human single domain antibody or the Fc fragment of an antibody
• 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 1/16 for liver or gallbladder disorders, e.g. hepatoprotective agents, cholagogues, litholytics
• CPC Class Codes: A61P 1/18 for pancreatic disorders, e.g. pancreatic enzymes
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• 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 17/00 Drugs for dermatological disorders
• CPC Class Codes: A61P 17/04 Antipruritics
• CPC Class Codes: A61P 17/08 Antiseborrheics
• CPC Class Codes: A61P 19/00 Drugs for skeletal disorders
• CPC Class Codes: A61P 19/08 for bone diseases, e.g. rachitism, Paget's disease
• 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 27/10 : for accommodation disorders, e.g. myopia
• 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 7/06 : Antianaemics
• CPC Class Codes: A61P 7/08 : Plasma substitutes; Perfusion solutions; Dialytics or haemodialytics; Drugs for electrolytic or acid-base disorders, e.g. hypovolemic shock artificial tears A61P27/04
• CPC Class Codes: A61P 7/10 : Antioedematous agents; Diuretics
• CPC Class Codes: A61P 9/00 : Drugs for disorders of the cardiovascular system
• CPC Class Codes: C07K 16/18 : against material from animals or humans
• CPC Class Codes: C07K 16/40 : against enzymes
• 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 2317/34 : 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 2317/35 : Valency
• CPC Class Codes: C07K 2317/54 : F(ab')2
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• 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 2317/76 : 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 2319/00 : Fusion polypeptide
• CPC Class Codes: C12Y 304/21042 : Complement subcomponent C1s (3.4.21.42)
• CPC Class Codes: G01N 2800/52 : Predicting or monitoring the response to treatment, e.g. for selection of therapy based on assay results in personalised medicine; Prognosis
• CPC Class Codes: G01N 33/6893 : related to diseases not provided for elsewhere

Abstract

The present disclosure provides antibodies that bind complement C1s protein; and nucleic acid molecules that encode such antibodies. The present disclosure also provides compositions comprising such antibodies, and methods to produce and use such antibodies, nucleic acid molecules, and compositions.

Claims

1. An antibody that binds a complement C1s protein, wherein the antibody comprises a complementarity-determining region (CDR) having an amino acid sequence selected from the group consisting of SEQ ID NO:

1, SEQ ID NO;

2, SEQ ID NO;

3, SEQ ID NO;

4, SEQ ID NO;

5, and SEQ ID NO;

6.

2. The antibody of claim 1, wherein the antibody comprises a light chain variable region comprising amino acid sequences SEQ ID NO:

1, SEQ ID NO;

2, and SEQ ID NO;

3.

3. The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising amino acid sequences SEQ ID NO:

4, SEQ ID NO;

5, and SEQ ID NO;

6.

4. The antibody of claim 1, wherein the antibody comprises a CDR-L1 having amino acid sequence SEQ ID NO:

1, a CDR-L2 having amino acid sequence SEQ ID NO;

2, a CDR-L3 having amino acid sequence SEQ ID NO;

3, a CDR-H1 having amino acid sequence SEQ ID NO;

4, a CDR-H2 having amino acid sequence SEQ ID NO;

5, and a CDR-H3 having amino acid sequence SEQ ID NO;

6.

5. The antibody of claim 1, wherein the antibody comprises a light chain variable region comprising an amino acid sequence that is 90% identical to amino acid sequence SEQ ID NO:

7.

6. The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising an amino acid sequence that is 90% identical to amino acid sequence SEQ ID NO:

8.

7. The antibody of claim 1, wherein the antibody comprises a light chain variable region comprising amino acid sequence SEQ ID NO:

7.

8. The antibody of claim 1, wherein the antibody comprises a heavy chain variable region comprising amino acid sequence SEQ ID NO:

8.

9. The antibody of claim 1, wherein the antibody comprises a light chain variable region comprising an amino acid sequence that is 90% identical to amino acid sequence SEQ ID NO:

7 and a heavy chain variable region comprising an amino acid sequence that is 90% identical to amino acid sequence SEQ ID NO;

8.

10. The antibody of claim 1, wherein the antibody comprises a light chain variable region comprising amino acid sequence SEQ ID NO:

7 and a heavy chain variable region comprising amino acid sequence SEQ ID NO;

8.

11. An antibody that binds a complement C1s protein, wherein the antibody specifically binds an epitope within the complement C1s protein, wherein the antibody competes for binding the epitope with an antibody that comprises light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO:

7 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

8.

12. The antibody of claim 11, wherein the antibody comprises light chain CDRs of an antibody light chain variable region comprising amino acid sequence SEQ ID NO:

7 and heavy chain CDRs of an antibody heavy chain variable region comprising amino acid sequence SEQ ID NO;

8.

13. The antibody of claim 11, wherein the antibody binds a human complement C1s protein.

14. The antibody of claim 11, wherein the antibody binds a rat complement C1s protein or a monkey complement C1s protein.

15. The antibody of claim 11, wherein the antibody inhibits cleavage of at least one substrate cleaved by complement C1s protein.

16. The antibody of claim 15, wherein the substrate is selected from the group consisting of complement C2 and complement C4.

17. The antibody of claim 11, wherein the antibody comprises a humanized light chain framework region.

18. The antibody of claim 11, wherein the antibody comprises a humanized heavy chain framework region.

19. The antibody of claim 11, wherein the antibody is selected from the group consisting of an Ig monomer and an antigen-binding fragment thereof that binds complement C1s protein.

20. The antibody of claim 11, wherein the antibody is an antigen binding fragment that binds complement C1s protein.

21. The antibody of claim 11, wherein the antibody is selected from the group consisting of an Ig monomer, a Fab fragment, a F(ab′

)₂ fragment, a Fd fragment, a scFv, a scAb, a dAb, a Fv, a single domain heavy chain antibody, and a single domain light chain antibody.

22. The antibody of claim 11, wherein the antibody is selected from the group consisting of a mono-specific antibody, a bi-specific antibody, and a multi-specific antibody.

23. The antibody of claim 11, wherein the antibody comprises a light chain region and a heavy chain region that are present in separate polypeptides.

24. The antibody of claim 11, wherein the antibody comprises a light chain region and a heavy chain region that are present in a single polypeptide.

25. The antibody of claim 11, wherein the antibody comprises a Fc region.

29. The antibody of claim 11, wherein the antibody is encapsulated in a liposome.

30. The antibody of claim 11, wherein the antibody comprises a covalently linked non-peptide synthetic polymer.

31. The antibody of claim 30, where in the synthetic polymer is a poly(ethylene glycol) polymer.

32. The antibody of claim 11, wherein the antibody is formulated with an agent that facilitates crossing the blood-brain barrier.

33. The antibody of claim 11, wherein the antibody is fused, directly or through a linker, to a compound that promotes the crossing of the blood-brain barrier, wherein the compound is selected from the group consisting of a carrier molecule, a peptide, or a protein.

35. A nucleic acid comprising a nucleotide sequence encoding an antibody of claim 11.

36. A recombinant vector comprising a nucleic acid molecule of claim 35.

38. A recombinant cell comprising the recombinant vector of claim 36.

39. A pharmaceutical composition comprising an antibody of claim 11 and a pharmaceutically acceptable excipient.

40. A sterile container comprising the pharmaceutical composition of claim 39.

41. The container of claim 40, wherein the container is selected from the group consisting of a bottle and a syringe.

42. A method to treat an individual having a complement-mediated disease or disorder, the method comprising administering to the individual an antibody of claim 11.

43. A method to inhibit complement activation in an individual having a complement-mediated disease or disorder, the method comprising administering to the individual an antibody of claim 11.

44. The method of claim 42, wherein the individual is a mammal.

45. The method of claim 42, wherein the individual is a human.

46. The method of claim 42, wherein the administering is intravenous.

47. The method of claim 42, wherein the administering is intrathecal.

48. The method of claim 42, wherein the administering results in an outcome selected from the group consisting of:

(a) a reduction in complement activation;

(b) an improvement in cognitive function;

(c) a reduction in neuron loss;

(d) a reduction in phospho-Tau levels in neurons;

(e) a reduction in glial cell activation;

(f) a reduction in lymphocyte infiltration;

(g) a reduction in macrophage infiltration;

(h) a reduction in antibody deposition;

(i) a reduction in glial cell loss;

(i) a reduction in oligodendrocyte loss;

(k) a reduction in dendritic cell infiltration;

(l) a reduction in neutrophil infiltration;

(m) a reduction in red blood cell lysis;

(n) a reduction in red blood cell phagocytosis;

(o) a reduction in platelet phagocytosis;

(p) a reduction in platelet lysis;

(q) an improvement in transplant graft survival;

(r) a reduction in macrophage mediated phagocytosis;

(s) an improvement in vision;

(t) an improvement in motor control;

(u) an improvement in thrombus formation;

(v) an improvement in clotting;

(w) an improvement in kidney function;

(x) a reduction in antibody mediated complement activation;

(y) a reduction in autoantibody mediated complement activation;

(z) an improvement in anemia;

(aa) reduction in demyelination; and

(ab) reduction in eosinophilia.

49. The method of claim 48, wherein the glial cells are selected from the group consisting of astrocytes and microglia.

57. A method to diagnose a complement-mediated disease or disorder in an individual, the method comprising:

(a) determining the amount of a complement C1s protein in a biological sample obtained from the individual, wherein the step of determining comprises;

(i) contacting the biological sample with an antibody of claim 11; and

(ii) quantitating binding of the antibody to complement C1s protein present in the biological sample; and

(b) comparing the amount of the complement C1s protein present in the biological sample to a normal control value that indicates the amount of complement C1s protein in a normal control individual, wherein a significant difference between the amount of C1s protein in the biological sample and the normal control value indicates that the individual has a complement-mediated disease or disorder.

58. A method to monitor progression of a complement-mediated disease or disorder in an individual, the method comprising:

(a) determining a first amount of complement a C1s protein in a biological sample obtained from the individual at a first time point;

(b) determining a second amount of complement a C1s protein in a biological sample obtained from the individual at a second time point; and

(c) comparing the second amount of complement C1s protein with the first amount of complement C1s protein,

wherein the steps of determining comprise;

(iii) contacting the biological sample with an antibody of claim 11; and

(iv) quantitating binding of the antibody to complement C1s protein present in the biological sample.

59. The method of claim 58, wherein the first time point is a time point before initiation of a treatment regimen, and wherein the second time point is a time point after initiation of a treatment regimen.

60. An in vitro method to detect complement C1s protein in a biological sample obtained from an individual, the method comprising:

(a) contacting the biological sample with an antibody of claim 11; and

(b) detecting binding of the antibody to complement C1s protein present in the biological sample.

61. A method to detect complement C1s protein in a living individual in vivo, the method comprising:

(a) administering to the individual an antibody of claim 11; and

(b) detecting binding of the antibody to complement C1s protein in the individual using an imaging method.

62. The method of claim 61, wherein the binding is detected in the individual at a site altered by a complement-mediated disease or disorder.

63. The method of claim 62, wherein the binding is detected in the brain of the individual.

64. The method of claim 61, wherein the antibody comprises a contrast agent suitable for use in the imaging method.

65. The method of any one of claim 61, wherein the imaging method is selected from the group consisting of magnetic resonance imaging, positron emission tomography, and IVIS instrumentation.

66. The method of claim 57, wherein the biological sample is selected from the group consisting of blood, serum, plasma, urine, saliva, cerebrospinal fluid, interstitial fluid, ocular fluid, synovial fluid, solid tissue sample, tissue culture sample, and cellular sample.

67. The method of claim 60, wherein the method is quantitative.

68. The method of claim 57, wherein the individual is suspected of having a complement-mediated disease or disorder, has been diagnosed as having a complement-mediated disease or disorder, or has a genetic predisposition to developing a complement-mediated disease or disorder.

69. A composition comprising:

(a) an anti-C1s antibody of claim 11; and

(b) a solution comprising one or more agents that maintain an organ or a tissue intended for transplantation into a recipient individual.

70. The composition of claim 69, wherein the solution is an organ preservation solution or a tissue preservation solution.

71. The composition of claim 69, wherein the solution is an organ perfusion solution or a tissue perfusion solution.

72. The composition of claim 69, wherein the solution comprises:

(i) a salt;

(ii) an agent that reduces edema;

(iii) an oxygen free-radical scavenger; and

(iv) an energy supply system component.

73. The composition of claim 69, wherein the composition comprises potassium lactobionate, KH₂PO₄, MgSO₄, raffinose, adenosine, glutathione, allopurinol, and hydroxyethyl starch.

74. An organ or tissue preservation solution comprising an anti-C1s antibody of claim 11.

75. An organ or tissue perfusion solution comprising an anti-C1s antibody of claim 11.

76. A method for maintaining an organ or tissue for transplant, the method comprising contacting the organ or the tissue with a composition of claim 66.

77. An isolated organ or tissue maintained in a composition of claim 69.

78. The organ of claim 77, wherein the organ is selected from the group consisting of an eye, a heart, an intestine, a kidney, a liver, a lung, a pancreas, a stomach, and a thymus.

79. The tissue of claim 77, wherein the tissue is selected from the group consisting of bone, bone marrow, cornea, heart valve, islet of Langerhans, tendon, skin, and vein.

80. An in vitro method for inhibiting complement activation in an organ or a tissue, the method comprising contacting the organ or the tissue with an antibody of claim 11.

26-28. -28. (canceled)

34. (canceled)

37. (canceled)

50-56. -56. (canceled)