Methods for treating conditions associated with MASP-2 dependent complement activation

• US 8,951,522 B2
• Filed: 04/06/2012
• Issued: 02/10/2015
• Est. Priority Date: 04/08/2011
• Status: Active Grant

• Current Assignee: Omeros Corporation, University of Leicester
• Original Assignee: Omeros Corporation, University of Leicester
• Inventors: Demopulos, Gregory A., Dudler, Thomas, Schwaeble, Hans-Wilhelm
• Primary Examiner(s): SKELDING, ZACHARY S
• Application Number:
  US13/441,827
• Publication Number:
  US 20120258095A1
• Time in Patent Office: 1,040 Days
• Field of Search: None
• US Class Current: 424/145.1
• 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 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: A61P 1/00 Drugs for disorders of the alimentary tract or the digestive system
• CPC Class Codes: A61P 1/08 for nausea, cinetosis or vertigo; Antiemetics
• CPC Class Codes: A61P 1/12 Antidiarrhoeals
• CPC Class Codes: A61P 11/00 Drugs for disorders of the respiratory system
• CPC Class Codes: A61P 13/00 Drugs for disorders of the urinary 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 15/00 Drugs for genital or sexual disorders for disorders of sex hormones A61P5/24; Contraceptives
• CPC Class Codes: A61P 17/02 for treating wounds, ulcers, burns, scars, keloids, or the like
• CPC Class Codes: A61P 17/14 for baldness or alopecia
• 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 25/30 for treating abuse or dependence
• CPC Class Codes: A61P 27/06 Antiglaucoma agents or miotics
• 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 31/00 Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
• CPC Class Codes: A61P 31/04 : Antibacterial agents
• CPC Class Codes: A61P 35/00 : Antineoplastic agents
• CPC Class Codes: A61P 37/02 : Immunomodulators
• CPC Class Codes: A61P 37/06 : Immunosuppressants, e.g. drugs for graft rejection
• CPC Class Codes: A61P 39/00 : General protective or antinoxious agents
• 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 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: 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 2317/34 : 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 2317/54 : F(ab')2
• CPC Class Codes: C07K 2317/55 : Fab or Fab'
• 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

In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a living subject. The methods comprise the step of administering, to a subject in need thereof, an amount of a MASP-2 inhibitory agent effective to inhibit MASP-2-dependent complement activation. In some embodiments, the MASP-2 inhibitory agent inhibits cellular injury associated with MASP-2-mediated alternative complement pathway activation, while leaving the classical (C1q-dependent) pathway component of the immune system intact. In another aspect, the invention provides compositions for inhibiting the effects of lectin-dependent complement activation, comprising a therapeutically effective amount of a MASP-2 inhibitory agent and a pharmaceutically acceptable carrier.

Claims

1. A method of inhibiting MASP-2-dependent complement activation in a subject suffering from paroxysmal nocturnal hemoglobinuria (PNH), comprising administering to the subject a composition comprising an amount of a monoclonal MASP-2 inhibitory antibody, or antigen-binding fragment thereof, that specifically binds to a portion of SEQ ID NO:

6 and selectively inhibits MASP-2-dependent complement activation without substantially inhibiting the C1q-dependent complement pathway.

2. The method of claim 1, wherein the composition increases the survival of red blood cells in the subject.

3. The method of claim 1, wherein the subject exhibits one or more symptoms selected from the group consisting of (i) below normal levels of hemoglobin, (ii) below normal levels of platelets;

(iii) above normal levels of reticulocytes, and (iv) above normal levels of bilirubin.

4. The method of claim 1, wherein the subject has previously undergone, or is currently undergoing, treatment with an anti-C5 antibody or antigen binding fragment thereof that inhibits cleavage of complement protein C5.

5. The method of claim 1, wherein the method further comprises administering to the subject an anti-C5 antibody or antigen binding fragment thereof that inhibits cleavage of complement protein C5.

6. The method of claim 5, wherein the anti-C5 antibody or antigen binding fragment thereof is humanized.

7. The method of claim 6, wherein the anti-C5 antibody is eculizumab.

8. The method of claim 1, wherein the monoclonal antibody or antigen-binding fragment thereof is a recombinant antibody.

9. The method of claim 1, wherein the composition is administered subcutaneously, intra-muscularly, intra-arterially, intravenously, or as an inhalant.

10. The method of claim 1, wherein the composition is administered subcutaneously.

11. The method of claim 1, wherein the monoclonal antibody or antigen-binding fragment thereof is an antibody having reduced effector function.

12. The method of claim 1, wherein the monoclonal antibody or antigen-binding fragment thereof is a chimeric antibody.

13. The method of claim 1, wherein the monoclonal antibody or antigen-binding fragment thereof is a humanized antibody.

14. The method of claim 1, wherein the monoclonal antibody or antigen-binding fragment thereof is a human antibody.