Therapeutic antibodies that bind to the serine protease domain of MASP-2 and uses thereof

Inventors

Dudler, Thomas • Nollert von Specht, Peter Kurt • Yabuki, Munehisa • Yaseen, Sadam

Assignees

Omeros Corp

Abstract

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.

Core Innovation

The invention relates to therapeutic isolated antibodies or antigen-binding fragments that specifically bind to human MASP-2. The antibodies are defined by heavy chain variable region CDR sequences and light chain variable region CDR sequences set forth as SEQ ID NO:57, SEQ ID NO:53, SEQ ID NO:18, SEQ ID NO:32, SEQ ID NO:34, and SEQ ID NO:36.

The disclosed antibodies are characterized as chimeric anti-MASP-2 monoclonal antibodies and include candidate clones OMS850, OMS860, and OMS870, together with humanization variants OMS852, OMS854, OMS856, and OMS858. Binding and lectin-pathway functional screening identifies high-inhibitory clones and supports affinity characterization and molecular definitions for antibody and epitope targeting.

The antibodies are directed to an epitope in the serine protease domain of human MASP-2 and exhibit functional selectivity in the complement system. The disclosure describes inhibition selective for lectin-pathway complement activation, with decreased C3b/C4/MAC deposition and avoidance of classical pathway inhibition in mammalian blood, together with epitope mapping and Fab crystallography for the MASP-2-Fab complex.

The background problem addressed is selective inhibition of lectin-pathway complement activation mediated by human MASP-2 without inhibiting the classical pathway in mammalian blood. The disclosed antibodies therefore aim to achieve therapeutic lectin-pathway complement inhibition through binding to MASP-2 serine protease domain epitopes.

Claims Coverage

Two independent claim themes are presented: one defines an isolated antibody or antigen-binding fragment by specific heavy- and light-chain CDR sequence identities for human MASP-2 binding, and another includes a pharmaceutical composition formulation aspect. The dependent claim set adds binding-affinity constraints, lectin-pathway inhibitory function readouts such as decreased C3b deposition, and a negative functional constraint of not inhibiting the classical pathway.

Overall claim coverage is anchored in antibodies with specific HC-CDR and LC-CDR sequence identities that specifically bind human MASP-2, and is further limited in dependents by binding-affinity, lectin-pathway inhibitory effects characterized by decreased C3b deposition, and an explicit lack of classical pathway inhibition in mammalian blood, with at least one dependent specifying subcutaneous administration formulation.

Stated Advantages

Documented Applications