Anti-C5a receptor antibodies
The present invention concerns human antibodies recognizing the human C5a receptor. By binding to C5aR the antibodies inhibit C5a signalling, whereby the pro-inflammatory signal is inhibited. Based on the role of C5a and its receptor in stimulation of inflammation the invention further relates to therapeutic use of said human anti-C5aR antibodies and in particular in relation to treatment of immunological disorders.
1. An antibody that specifically binds C5aR, wherein the antibody comprises a heavy chain variable region comprising:
a CDR1 sequence selected from the sequences set forth in SEQ ID NO: 1, 9, 17 or 25;
a CDR2 sequence selected from the sequences set forth in SEQ ID NO: 2, 10, 18 or 26; and a CDR3 sequence selected from the sequences set forth in SEQ ID NO: 3, 11, 19 or 27.
2. The antibody according to claim 1 , wherein the antibody comprises a light chain variable region comprising:
a CDR1 sequence selected from the sequences set forth in SEQ ID NO: 5, 13, 21 or 29; a CDR2 sequence selected from the sequences set forth in SEQ ID NO: 6, 14, 22 or 30; and a CDR3 sequence comprising the sequence set forth in SEQ ID NO: 7, 15, 23 or 31.
3. The antibody according to claim 2 , wherein the variable region of the heavy chain of said antibody comprises a sequence selected from the sequences set forth in SEQ ID NO: 4, 12, 20 or 28 and/or wherein the variable region of the light chain of said antibody comprises a sequence SEQ ID NO: 8, 16, 24 or 32.
4. The antibody according to claim 1 , wherein the antibody is a human antibody.
5. The antibody according to claim 1 , wherein said antibody binds the 2nd extracellular loop of human C5aR.
6. The antibody according to claim 1 wherein the affinity of the antibody as measured by competition ligand binding assay on neutrophils is below 0.80 nM.
7. The antibody according to claim 1 wherein the antibody significantly inhibits or reduces binding of C5a to C5aR.
8. The antibody according to claim 1 wherein the antibody significantly inhibits migration of human neutrophils in vitro.
9. The antibody according to claim 1 wherein the antibody binds human C5aR, wherein the Fc region has decreased binding affinity to one or more Fcγ receptors, compared to IgG1, IgG2, IgG4 or IgG4/G2 Fc reference having the sequences set forth in SEQ ID NO 33, 34, 35 and 36, respectively.
10. The antibody according to claim 1 wherein the antibody does not significantly induce ADCC, CDC and/or phagocytosis of neutrophils in vitro.
11. The antibody according to claim 1 wherein the Fc region is IgG1 (SEQ ID NO: 33), IgG2 (SEQ ID NO: 34), IgG2/4 (SEQ ID NO: 35), or IgG4 (SEQ ID NO: 36), with one or more of the following point mutations:
a. E233P;
b. L234A or V234A or F234L or F234V;
c. L235E or L235A;
d. G236R or G236A;
e. G237A;
f. N297Q;
g. L328R;
h. A330S;
i. P331S.
12. A method of inhibiting binding of C5a to C5aR in subject in need thereof comprising administering the antibody of claim 1 to said subject.
13. The method of claim 12 , wherein the subject has an immunological disease or disorder that is selected from the group consisting of rheumatoid arthritis (RA), psoriatic arthritis, systemic lupus erythematosus (SLE), lupus nephritis, Inflammatory bowel disease (IBD), and irritable bowel syndrome.