Methods of inhibiting MASP-2-dependent complement activation in a subject suffering from catastrophic antiphospholipid syndrome

Patent metadata

Field	Value
Publication number	US-11525011-B2
Application number	US-201916509336-A
Country	US
Kind code	B2
Filing date	Jul 11, 2019
Priority date	Oct 17, 2013
Publication date	Dec 13, 2022
Grant date	Dec 13, 2022

Abstract

In one aspect, the invention provides methods of inhibiting the effects of MASP-2-dependent complement activation in a living subject suffering from, or at risk for developing a thrombotic microangiopathy (TMA). 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.

First claim

The embodiments of the invention in which an exclusive property or privilege is claimed are defined as follows:

1. A method of inhibiting MASP-2-dependent complement activation in a subject suffering from Catastrophic Antiphospholipid Syndrome (CAPS), comprising administering to the subject a composition comprising an amount of a MASP-2 inhibitory monoclonal antibody or antigen-binding fragment thereof that specifically binds to a portion of SEQ ID NO:6 and is effective to inhibit MASP-2-dependent complement activation, wherein the MASP-2 inhibitory monoclonal antibody, or antigen-binding fragment thereof, comprises:
(a) a heavy-chain variable region comprising: i) a heavy chain CDR-H1 comprising the amino acid sequence from 31-35 of SEQ ID NO:67; and ii) a heavy-chain CDR-H2 comprising the amino acid sequence from 50-65 of SEQ ID NO:67; and iii) a heavy-chain CDR-H3 comprising the amino acid sequence from 95-102 of SEQ ID NO:67 and
(b) a light-chain variable region comprising: i) a light-chain CDR-L1 comprising the amino acid sequence from 24-34 of SEQ ID NO:70; and ii) a light-chain CDR-L2 comprising the amino acid sequence from 50-56 of SEQ ID NO:70; and iii) a light-chain CDR-L3 comprising the amino acid sequence from 89-97 of SEQ ID NO:70, and wherein said MASP-2 inhibitory antibody does not substantially inhibit the classical pathway.

2. The method of claim 1 , wherein the antibody or fragment thereof is selected from the group consisting of a recombinant antibody, an antibody having reduced effector function, a chimeric antibody, a humanized antibody and a human antibody.

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

4. The method of claim 1 , wherein said MASP-2 inhibitory antibody binds human MASP-2 with a K D of 10 nM or less.

5. The method of claim 1 , wherein said MASP-2 inhibitory antibody binds an epitope in the CCP1 domain of MASP-2.

6. The method of claim 1 , wherein said MASP-2 inhibitory antibody inhibits C3b deposition in an in vitro assay in 1% human serum at an IC 50 of 10 nM or less.

7. The method of claim 1 , wherein said MASP-2 inhibitory antibody inhibits C3b deposition in 90% human serum with an IC 50 of 30 nM or less.

8. The method of claim 1 , wherein said MASP-2 inhibitory antibody is an antibody fragment selected from the group consisting of Fv, Fab, Fab′, F(ab) 2 and F(ab′) 2 .

9. The method of claim 1 , wherein said MASP-2 inhibitory antibody is a single-chain molecule.

10. The method of claim 1 , wherein said MASP-2 inhibitory antibody is selected from the group consisting of an IgG1 molecule, an IgG2 and an IgG4 molecule.

11. The method of claim 1 , wherein the IgG4 molecule comprises a S228P mutation.

12. The method of claim 1 , wherein the MASP-2 inhibitory monoclonal antibody comprises a heavy-chain variable region set forth as SEQ ID NO:67 and a light-chain variable region set forth as SEQ ID NO:70.

Assignees

• Omeros Corp
• Univ Leicester

Inventors

• Demopulos Gregory A
• Dudler Thomas
• Schwaeble Hans-Wilhelm

Classifications

• A61K2039/507

  Comprising a combination of two or more separate antibodies · CPC title

• A61K2039/505

  comprising antibodies · CPC title

• C07K2317/21

  from primates, e.g. man · CPC title

• C07K2317/76

  Antagonist effect on antigen, e.g. neutralization or inhibition of binding · CPC title

• A61P7/02

  Antithrombotic agents; Anticoagulants; Platelet aggregation inhibitors · CPC title