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
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Publication Number
US-12264203-B2
Publication Date
2025-04-01
Expiration Date
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 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 antibodies and antigen-binding fragments that bind complement component 5a receptor 1 (C5aR1). The antibodies include monospecific Site I and Site II binders and biparatopic or bispecific formats for targeting the C5a/C5aR1-axis dysfunction. The patent describes antibody formats comprising heavy and light chain variable regions with specified complementarity determining regions, including Site I and Site II epitope targeting defined by SEQ ID NOs.
A key aspect is the selection of C5aR1 binders with high specificity and low cross-reactivity to C5aR2 and other GPCRs, together with high C5aR1 binding affinity. The antibodies function as antagonists of C5aR1 signaling pathways including G-protein signaling, calcium signaling, β-arrestin signaling, ROS, CD11b, and neutrophil chemotaxis. The document also references inhibition of C5a-C5aR1 interaction and describes functional behavior associated with blocking these signaling outputs.
The patent further describes enhanced therapeutic behavior via Fc engineering that reduces Fc-mediated effector functions while maintaining FcRn binding. In particular, it states reduction or abolishment of binding to Fcγ receptors and C1q to reduce ADCC, ADCP, and CDC, while preserving FcRn binding. The Fc engineering includes human Fc formats such as modified IgG4 Fc and specific Fc mutations, with optional S228P and control of Fab-arm exchange as described.
The described binding regions are tied to specific sequence definitions for heavy chain and light chain variable regions and complementarity determining regions, including SEQ ID NO:14 for VH and SEQ ID NO:25 for VL. The document identifies lead antibodies and provides examples of epitope targeting using Site I and Site II sequence-defined binders. The antibodies are described in the context of treating autoimmune and inflammatory diseases associated with dysfunction of the C5a/C5aR1 axis, including conditions listed in the partial content.
Claims Coverage
The independent claims are directed to C5aR1-binding antibodies defined by VH and VL sequence specifications, with one independent claim defined by a set of HCDR/LCDR SEQ ID numbers and another independent claim defined by complete VH and VL SEQ ID numbers. Across the claim set, key inventive features include defined C5aR1 binding via specified complementarity determining regions and specified antibody formats including Fc region and IgG subclass selection, plus nucleic-acid encoding.
C5aR1 binding via specified HCDR and LCDR sequences
An antibody or antigen binding fragment thereof that binds complement component 5a receptor 1 (C5aR1), comprising a heavy chain variable (VH) region with three HCDRs wherein the HCDR1, HCDR2, and HCDR3 sequences comprise amino acid sequences of SEQ ID Nos: 6, 7, and 8, respectively, and a light chain variable (VL) region with three LCDRs wherein the LCDR1, LCDR2, and LCDR3 sequences of SEQ ID Nos: 9, 10, and 11, respectively.
C5aR1 binding via a defined VH SEQ ID NO: 14 and VL SEQ ID NO: 25
An antibody or antigen binding fragment thereof that binds complement component 5a receptor 1 (C5aR1) comprising a heavy chain variable region (VH) of SEQ ID NO: 14 and a light chain variable region (VL) of SEQ ID NO: 25.
Fc region inclusion
The antibody or antigen binding fragment further includes an Fc region.
Fc domain selected from IgG1, IgG2, IgG3, or IgG4
The Fc domain independently selected from IgG1, IgG2, IgG3, or IgG4.
Nucleic acid encoding the C5aR1-binding antibody
A nucleic acid is provided that encodes the antibody or antigen binding fragment described in claim 1.
Overall, the claim coverage centers on antibodies that bind C5aR1 using explicitly specified variable-region sequences, with additional refinement by Fc region and IgG subclass selection and by a nucleic acid encoding the C5aR1-binding antibody.
Stated Advantages
High specificity and low cross-reactivity to C5aR2 and other GPCRs.
High C5aR1 binding affinity.
Functional antagonism of C5aR1 signaling pathways, including G-protein signaling, calcium signaling, β-arrestin signaling, ROS, CD11b, and neutrophil chemotaxis.
Reduced Fc-mediated effector functions by abolishing binding to Fcγ receptors and C1q, thereby reducing ADCC, ADCP, and CDC.
Maintaining FcRn binding.
Documented Applications
Treating autoimmune and inflammatory diseases associated with C5a/C5aR1-axis dysfunction.
The partial content specifically lists disease contexts including ANCA-associated vasculitis, lupus, and rheumatoid arthritis.
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