Humanized complement 5A receptor 1 antibodies and methods of use thereof

Inventors

Viswanathan, Karthik • Booth, Brian • Ramakrishnan, Boopathy • Wollacott, Andrew • Babcock, Gregory • Shriver, Zachary • Olinski, Lauren

Assignees

Visterra Inc

Abstract

The present disclosure provides, among other things, two different formats of humanized antibodies against human complement component 5a receptor I. The disclosure also provides a method of treating a subject having dysfunctions of C5a/C5aR1 axis pathway, including but not limited to ANCA-associated vasculitis, comprising administering to the subject in need thereof a an effective amount of antibody or a nucleic encoding an antibodies binding to C5aR1 described herein, and wherein administering results in a decrease in symptoms associated with C5a/C5aR1 associated dysfunction in the subject.

Core Innovation

The invention relates to humanized C5aR1 antagonist antibodies and antigen binding fragments that bind complement component 5a receptor 1 (C5aR1) and are used for treating C5a/C5aR1 mediated autoimmune disease. The disclosure also describes thermal-stability engineering of monospecific or biparatopic C5aR1 antibodies, including cysteine residue substitutions to increase thermal stability (Tm), and construction of biparatopic and crosslinked bispecific antibody formats comprising Site I and Site II binding domains.

The antibodies are defined by specific heavy chain variable region (VH) and light chain variable region (VL) structures, including three heavy chain complementarity determining regions (HCDRs) and three light chain complementarity determining regions (LCDRs) with SEQ ID NOs provided for the HCDRs and LCDRs. The disclosure further describes Fc-domain engineering to prevent Fab arm exchange and to reduce effector functions, including IgG4 Fc mutations such as S228P and additional Fc-silencing substitutions.

The antibodies are characterized by increased specificity, including low cross-reactivity to C5aR2 and other GPCRs, and are reported to have high binding affinity to C5aR1. Functional characterization includes inhibition of C5aR1 signaling and cellular responses, including inhibition of neutrophil chemotaxis, G and calcium signaling, CD11b expression, β-arrestin signaling, and ROS production.

Claims Coverage

The independent claim centers on treating a C5a/C5aR1 mediated autoimmune disease using a C5aR1-binding antibody or antigen binding fragment with specified VH and VL CDR SEQ ID NOs. Dependent and related features add signaling inhibition, disease selection, and Fc domain isotype selection, yielding multiple inventive-feature combinations built around the same C5aR1-binding antibody architecture.

Claim coverage centers on administering a C5aR1-binding antibody or antigen binding fragment defined by particular VH and VL CDR SEQ ID NOs, with dependent claim refinements directed to downstream signaling inhibition, specific disease indications, and selection of an Fc domain isotype.

Stated Advantages

Documented Applications