Therapeutic antibodies that bind to the serine protease domain of MASP-2 and uses thereof
Isolated monoclonal antibodies and antigen-binding fragments thereof are provided that specifically bind to an epitope within the serine protease domain of human MASP-2. In some embodiments, the antibodies or antigen-binding fragments thereof inhibit lectin pathway complement activation. Also provided are polynucleotides encoding the disclosed monoclonal antibodies or antigen-binding fragments thereof, and cloning vectors or expression cassettes comprising such polynucleotides. Further provided are methods of inhibiting lectin pathway complement activation and methods of treating lectin pathway diseases and disorders.
1. An isolated antibody or antigen-binding fragment thereof that specifically binds to human MASP-2, wherein the antibody or antigen-binding fragment thereof comprises:
a heavy chain variable region comprising a HC-CDR1 set forth as SEQ ID NO:57, a HC-CDR2 set forth as SEQ ID NO:53, and a HC-CDR3 set forth as SEQ ID NO:18; and a light chain variable region comprising a LC-CDR1 set forth as SEQ ID NO:32; a LC-CDR2 set forth as SEQ ID NO:34 and a LC-CDR3 set forth as SEQ ID NO:36.
2. The isolated antibody or antigen-binding fragment of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain comprising a heavy chain variable region set forth as SEQ ID NO:50 and a light chain comprising a light chain variable region set forth as SEQ ID NO:47.
3. The isolated antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment is selected from the group consisting of a human antibody, a humanized antibody, a chimeric antibody, a murine antibody, and an antigen-binding fragment of any of the foregoing.
4. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen binding fragment thereof is selected from the group consisting of a single chain antibody, an ScFv, a Fab fragment, an Fab′ fragment, an F(ab′)2 fragment, a univalent antibody lacking a hinge region and a whole antibody.
5. The isolated antibody or antigen-binding fragment thereof of claim 1 , further comprising an immunoglobulin constant region.
6. The isolated antibody or antigen binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is humanized.
7. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof is an IgG immunoglobulin selected from the group consisting of IgG1, IgG2, and IgG4.
8. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises one or more mutations in the Fc region.
9. The isolated antibody or antigen-binding fragment thereof of claim 8 , wherein the Fc region comprises an S228P amino acid substitution.
10. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof binds to the serine protease domain of human MASP-2 with an affinity of less than 20 nM.
11. The isolated antibody or antigen-binding fragment thereof of claim 10 , wherein the antibody or antigen-binding fragment thereof binds to the serine protease domain of human MASP-2 with an affinity of less than 10 nM.
12. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof inhibits the lectin pathway in mammalian blood.
13. The isolated antibody or antigen-binding fragment thereof of claim 12 , wherein lectin pathway inhibition comprises a decrease in C3b deposition under lectin pathway-specific assay conditions.
14. The isolated antibody or antigen-binding fragment thereof of claim 12 , wherein lectin pathway inhibition comprises a decrease in C4 deposition under lectin pathway-specific assay conditions.
15. The isolated antibody or antigen-binding fragment thereof of claim 12 , wherein lectin pathway inhibition comprises a decrease in MAC deposition under lectin pathway-specific assay conditions.
16. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof does not inhibit the classical pathway in mammalian blood.
17. A composition comprising the antibody or antigen-binding fragment thereof of claim 1 and a pharmaceutically acceptable excipient.
18. The composition of claim 17 , wherein said composition is formulated for subcutaneous administration.