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-12415865-B2
Publication Date
2025-09-16
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 relates to anti-C5aR1 antibody molecules and nucleic acid molecules encoding antibody molecules that bind to complement component 5a receptor 1 (C5aR1). The antibody molecule is characterized by a heavy chain variable region (VH) and a light chain variable region (VL), with defined complementarity-determining regions (CDRs) and matched VH/VL pairings.
The disclosure includes antibodies defined by specific heavy-chain and light-chain variable region CDR variants, including HCDR1 with SEQ ID NO: 612, HCDR2 with SEQ ID NO: 732, HCDR3 with SEQ ID NO: 852, LCDR2 with SEQ ID NO: 792, and LCDR1 and LCDR3 that are identical to or differ by no more than 2 amino acid residues from SEQ ID NO: 672 and SEQ ID NO: 912, respectively. The antibodies target C5aR1 epitopes, including Site I and Site II, with binding site concepts discussed using competition and epitope overlap.
The document further describes functional characterization in terms of binding and inhibitory effects, including inhibition of C5aR1-C5a binding and inhibition of signaling endpoints such as Gα signaling, neutrophil chemotaxis, calcium release, calcium flux, and CD11b. It also describes altered constant regions, post-translationally modified forms, structural variations, antibody conjugates and labeled antibody molecules, and multispecific and multiparatopic formats including bispecific and biparatopic formats.
Claims Coverage
The claim coverage identifies one independent claim centered on a nucleic acid encoding a C5aR1-binding antibody with tightly defined VH and VL CDR sequences, and a dependent host cell claim containing the nucleic acid molecule.
Nucleic acid encoding a C5aR1-binding antibody with defined VH and VL CDR sequences
A nucleic acid molecule comprising a nucleotide sequence encoding an antibody molecule that binds to complement component 5a receptor 1 (C5aR1), wherein the antibody molecule comprises a heavy chain variable region (VH) and a light chain variable region (VL); wherein the VH comprises an HCDR1 comprising an amino acid sequence of SEQ ID NO: 612, an HCDR2 comprising an amino acid sequence of SEQ ID NO: 732, and an HCDR3 comprising an amino acid sequence of SEQ ID NO: 852; and wherein the VL comprises an LCDR1 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acid residues from SEQ ID NO: 672, an LCDR2 comprising an amino acid sequence of SEQ ID NO: 792, and an LCDR3 comprising an amino acid sequence that is identical to or differs by no more than 2 amino acid residues from SEQ ID NO: 912.
Host cell comprising the nucleic acid molecule
A host cell comprising the nucleic acid molecule encoding the antibody molecule that binds C5aR1 and comprises the specified VH and VL CDR sequence constraints.
The claim coverage is limited to nucleic acids encoding anti-C5aR1 antibodies defined by specific VH and VL CDR sequence assignments, together with a host cell embodiment containing that nucleic acid.
Stated Advantages
High-affinity binding to human C5aR1 is described, with Kd values down to ~0.001 nM and thresholds below 50 nM.
The document describes slower off-rate/on-rate ranges.
The described antibodies inhibit C5aR1-C5a binding, reported as inhibition of C5aR1-C5a binding of 50% to 100%.
Epitope binding is described as linear/conformational and conserved between human and mouse.
Competitive binding/overlapping epitopes are described.
Epitope sites are described as involving ECL2 and sulfated/non-sulfated N-termini.
Minimal cross-reactivity to C5aR2 and other GPCRs is described as reduced cross-reactivity.
Reduced C5a-induced chemotaxis and signaling effects, including calcium flux and CD11b, are described.
Enhanced inhibition is described when simultaneously targeting C5aR1 Site I and Site II via combinations or multispecific/biparatopic antibodies.
Inhibits Gα signaling.
Inhibits neutrophil chemotaxis.
Inhibits calcium release.
Documented Applications
Treating, preventing, and/or diagnosing complement-mediated disorders, including ANCA-vasculitis (ANCA-associated vasculitis).
Use in connection with COVID-19, as described in the document summary.
Multispecific and multiparatopic, including bispecific and biparatopic, antibody formats for C5aR1 targeting.
Therapeutic relevance in ANCA-vasculitis and other inflammatory or immune disorders where C5a-C5aR1 signaling is described as critical.
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