Antibody molecules to C5AR1 and uses thereof
Inventors
Viswanathan, Karthik • Booth, Brian • Ramakrishnan, Boopathy • Wollacott, Andrew • Babcock, Gregory • Shriver, Zachary
Assignees
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Publication Number
US-12187807-B2
Publication Date
2025-01-07
Expiration Date
Abstract
Antibody molecules that specifically bind to C5aR1 are disclosed. The antibody molecules can be used to treat, prevent, and/or diagnose disorders, such as ANCA-vasculitis.
Core Innovation
The invention provides anti-C5aR1 antibodies that bind to complement component 5a receptor 1 (C5aR1) and are defined by specific antibody variable regions. The antibodies include a VH and a VL, with the VH comprising an HCDR1, an HCDR2, and an HCDR3, and the VL comprising an LCDR1, an LCDR2, and an LCDR3. The document describes exemplary C5aR1-binding antibody variable-region amino-acid sequences, CDR mapping, and VH/VL sequence similarity or minor substitutions relative to reference antibodies.
The disclosed antibodies are characterized by specific binding and epitope features on C5aR1, including Site I and Site II targeting, epitope overlap, and linear and/or conformational epitopes. Functional effects include inhibition of C5a binding and signaling, orthosteric inhibition, inhibition of G signaling, neutrophil chemotaxis, calcium release, calcium flux, CD11b expression, chemotaxis priming, and neutrophil activation.
The disclosure also covers monospecific/monoparatopic and multispecific/multiparatopic antibodies, including bispecific/biparatopic embodiments that target both Site I and Site II. Pharmaceutical compositions, combination strategies with a second therapeutic agent, and therapeutic and prophylactic treatment and prevention of C5aR1-associated disorders are described, including ANCA-vasculitis and other complement/inflammation-driven diseases.
Claims Coverage
The claims support protection for a C5aR1-binding antibody defined by specific VH and VL CDR amino-acid sequence identifiers. The inventive scope is further extended to a pharmaceutical composition and to a combination with a second therapeutic agent, with dependent coverage also referring to alternative VH and VL sequence identifiers.
C5aR1-binding antibody with defined VH and VL CDR sequence identities
An antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising a VH and a VL, wherein the VH comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 602, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 722, and an HCDR3 comprising an amino acid sequence of SEQ ID NO: 842, and wherein the VL comprises an LCDR1 comprising an amino acid sequence of SEQ ID NO: 662, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 782, and an LCDR3 comprising an amino acid sequence of SEQ ID NO: 902.
Alternative VH and VL specified by SEQ ID NO: 482 and SEQ ID NO: 542
The antibody according to claim 1, wherein the VH region corresponds to SEQ ID NO: 482 and the VL region corresponds to SEQ ID NO: 542.
Pharmaceutical composition including the antibody
A pharmaceutical composition comprising the antibody molecule of claim 1 and a pharmaceutically acceptable carrier or excipient.
Combination with a second therapeutic agent
A combination comprising the antibody molecule of claim 1 and a second therapeutic agent.
Overall, the claims cover anti-C5aR1 antibodies defined by specific VH and VL CDR sequence content, with dependent claims further specifying alternative VH and VL identifiers and including the antibody in a pharmaceutical composition and in combination with a second therapeutic agent.
Stated Advantages
High-affinity binding to human C5aR1, with K_D ranges and slower K_off characteristics.
Inhibition of C5a binding and C5aR1 activity.
Increased specificity, including reduced cross-reactivity to C5aR2 and other GPCRs.
Functional blockade of C5aR1 signaling, including reduced chemotaxis, calcium flux, CD11b expression, chemotaxis priming, and neutrophil activation.
Decreased endothelium injury.
Epitope characteristics that are conserved between human and mouse and involve ECL2 and sulfated/non-sulfated N-terminal (Site I) features.
Therapeutic and prophylactic treatment and prevention of C5aR1-associated disorders, including ANCA-vasculitis and other complement/inflammation-driven diseases.
Documented Applications
Therapeutic treatment and prophylactic prevention of C5aR1-associated disorders, including ANCA-vasculitis.
Diagnosis/detecting C5aR1 using labeled antibodies and complex-formation detection, including detection of an antibody–C5aR1 complex.
Use in disease models described in the document for complement/inflammation-driven diseases, including crescentic glomerulonephritis, acute proliferative glomerulonephritis/post-streptococcal glomerulonephritis, Henoch-Schönlein purpura (HSP), and an anti-MPO IgG passive transfer context.
Pharmaceutical composition including the antibody molecule and a pharmaceutically acceptable carrier or excipient.
Combination therapy including the antibody molecule together with a second therapeutic agent, including avacopan (CCX168) as a second therapeutic agent.
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