Humanized complement 5A receptor 1 antibodies and methods of use thereof
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.
1. A method of treating a C5a/C5aR1 mediated autoimmune disease, comprising administering an antibody or an antigen binding fragment thereof to a subject in need of the treatment, wherein the antibody or the antigen binding fragment thereof binds complement component 5a receptor 1 (C5aR1) and comprises a heavy chain variable region (VH) and a light chain variable region (VL), wherein the VH comprises three heavy chain complementarity determining regions (HCDRs), wherein the HCDR1, HCDR2 and HCDR3 comprise SEQ ID NO: 6 (NYWMH), SEQ ID NO: 7 (YLNPSSGYTKYAQKFQG), and SEQ ID NO: 8 (SGGDNYGNPY YFDR), respectively, wherein the VL comprises three light chain complementary determining regions (LCDRs), wherein the LCDR1, LCDR2, and LCDR3 comprise SEQ ID NO: 9 (RASQSIVHSNGNTYLH), SEQ ID NO: 10 (KVSNRES), SEQ ID NO: 11 (AQYTLVPLT), respectively.
2. The method of claim 1 , wherein the VH comprises SEQ ID NO: 14, and the VL comprises SEQ ID NO: 25.
3. The method of claim 1 , wherein the disease is anti-neutrophilic cytoplasmic antibody vasculitis (ANCA vasculitis) or lupus.
4. The method of claim 1 , wherein the disease is stroke.
5. The method of claim 1 , wherein the antibody comprises an Fc domain selected from IgG1, IgG2, IgG2 and IgG4.
6. The method of claim 1 , wherein the antibody binds to C5aR1 and inhibits C5a mediated Gα signaling.
7. The method of claim 1 , wherein the antibody binds to C5aR1 and inhibits calcium signaling.
8. The method of claim 1 , wherein the antibody binds to C5aR1 and inhibits CD11b expression.
9. The method of claim 1 , wherein the antibody binds to C5aR1 and inhibits neutropenia.
10. The method of claim 1 , wherein the antibody binds to C5aR1 and inhibits β-arrestin signaling.