Therapeutic Antibodies
The present invention concerns human antibodies recognising 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 - 15 . (canceled)
16 . An antibody that specifically binds C5aR, comprising an Fc region, wherein the Fc region has been modified to include one or more point mutations compared to a reference Fc region.
17 . The antibody of claim 16 , wherein the reference Fc region comprises IgG1 (SEQ ID NO:33), IgG2 (SEQ ID NO:34), IgG4 (SEQ ID NO:35) or IgG4/G2 (SEQ ID NO:36) isotypes.
18 . The antibody of claim 17 , wherein the antibody has a decreased binding affinity to one or more Fc gamma receptors (FcγR) compared to the binding affinity of IgG1, IgG2, IgG3 or IgG4/G2 Fc reference sequences.
19 . The antibody of claim 16 , wherein the antibody binds the 2nd extracellular loop of C5aR.
20 . The antibody of claim 16 , wherein the antibody has an Fc hinge region of the IgG1 isotype.
21 . The antibody of claim 16 , wherein the antibody has an Fc region of the IgG1 isotype.
22 . The antibody of claim 16 , wherein the Fc region of the antibody 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.
23 . The antibody of claim 16 , wherein the antibody is a human antibody.
24 . The antibody of claim 16 , wherein said antibody binds human C5aR and preferably the 2nd extracellular loop of human C5aR.
25 . The antibody of claim 16 , wherein the affinity of the antibody as measured by competition ligand binding assay on neutrophils is below 0.80 nM.
26 . The antibody of claim 16 , wherein the antibody significantly inhibits or reduces binding of C5a to C5aR.
27 . The antibody of claim 16 , wherein the antibody significantly inhibits migration of human neutrophils in vitro.
28 . The antibody of claim 16 , wherein the antibody does not significantly induce ADCC, CDC and/or phagocytosis of neutrophils in vitro.