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-11773179-B2
Publication Date
2023-10-03
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-complement component 5a receptor 1 (C5aR1) antibody molecules that are capable of binding C5aR1. The antibody molecule comprises a VH and a VL, wherein the VH comprises HCDR1, HCDR2, and HCDR3 defined by SEQ ID NO: 612, SEQ ID NO: 732, and SEQ ID NO: 852, and wherein the VL comprises LCDR1, LCDR2, and LCDR3 defined by SEQ ID NO: 672, SEQ ID NO: 792, and SEQ ID NO: 912, with LCDR1 and LCDR3 subject to identity-or-no-more-than-2-residue-difference constraints in some embodiments.
The disclosure further describes extensive variants of anti-C5aR1 antibodies defined by allowed amino-acid differences and homology thresholds for VH, HCDRs, and VL, including multiple antibody variable-region variants and VH/VL pairings. It also includes antibodies in diverse molecular architectures, including monospecific/monoparatopic or multispecific/multiparatopic formats, including bispecific/biparatopic formats.
The invention is directed to anti-C5aR1 antibodies that compete for or overlap with epitopes on C5aR1, including Site I and Site II, and that may inhibit C5aR1 signaling. The disclosure also describes epitope characteristics that distinguish linear versus conformational epitopes and addresses conserved epitopes between human and mouse, along with evaluation of efficacy in animal models and use in treating C5aR1-associated disorders.
Claims Coverage
The claim coverage centers on an anti-C5aR1 antibody molecule defined by VH and VL CDR amino-acid sequence requirements using SEQ ID NOs, with limited allowable sequence differences in certain CDR regions. The independent claim covers one inventive feature, and dependent claims extend coverage to pharmaceutical composition and combination formats while one dependent narrows the LCDR1 and LCDR3 variability to exact sequences.
C5aR1-binding antibody with defined VH and VL CDR sequences
An antibody molecule capable of binding to complement component 5a receptor 1 (C5aR1), comprising a VH and a VL, wherein the VH comprises HCDR1 comprising SEQ ID NO: 612, HCDR2 comprising SEQ ID NO: 732, and HCDR3 comprising SEQ ID NO: 852, and wherein the VL comprises LCDR1 identical to or differing by no more than 2 amino acid residues from SEQ ID NO: 672, LCDR2 comprising SEQ ID NO: 792, and LCDR3 identical to or differing by no more than 2 amino acid residues from SEQ ID NO: 912.
Pharmaceutical composition with pharmaceutically acceptable carrier or excipient
A pharmaceutical composition that includes the antibody molecule capable of binding to C5aR1 and further contains a pharmaceutically acceptable carrier or excipient.
Combination with a second therapeutic agent
A combination including the antibody molecule capable of binding to C5aR1 together with a second therapeutic agent.
Antibody with exact LCDR1 and LCDR3 sequences
A specified antibody molecule comprising a VH and a VL, where the VH includes HCDR1, HCDR2, and HCDR3 with the given SEQ ID NO amino acid sequences, and the VL includes LCDR1 and LCDR3 with specified exact SEQ ID NO amino acid sequences while LCDR2 comprises SEQ ID NO: 792.
Claim coverage is anchored on a C5aR1-binding antibody defined by VH and VL CDR sequence requirements using SEQ ID NOs, including limited residue differences for LCDR1 and LCDR3 in the independent claim. Dependent claims extend the construct to a pharmaceutical composition with a pharmaceutically acceptable carrier or excipient and to a combination that includes a second therapeutic agent, and one dependent claim narrows the construct by specifying exact LCDR1 and LCDR3 sequences.
Stated Advantages
Modulate effector and complement-related functions via alteration of antibody constant regions associated with Fc receptors (FcR) and complement component C1.
Improved specificity, including reduced cross-reactivity to C5aR2 and other GPCRs.
Potent functional inhibition of C5aR1 signaling.
Lack of substantial C5aR2 binding.
Reduced reliance on high-dose glucocorticoids.
Documented Applications
Use in treating C5aR1-associated disorders.
Evaluation of efficacy in animal models.
Clinical, therapeutic, and/or diagnostic use concepts for anti-C5aR1 antibodies in diseases explicitly listed in the disclosure, including ANCA-vasculitis, COVID-19, ARDS, Influenza A, typical hemolytic uremic syndrome, age-related macular degeneration, rheumatoid arthritis, sepsis, severe burn, antiphospho lipid syndrome, asthma, lupus nephritis, Goodpasture's syndrome, chronic obstructive pulmonary disease, Henoch-Schönlein purpura, and acute proliferative and/or post-streptococcal glomerulonephritis.
Diagnostic methods for detecting C5aR1 using the disclosed anti-C5aR1 antibodies.
Therapeutic use of antagonistic anti-C5aR1 antibody molecules for broad autoimmune disorders and cancers.
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