Antibodies to NKP46 and constructs thereof for treatment of cancers and infections
The present invention provides monoclonal antibodies that recognize human NKp46 with high affinity and specificity and do not block NKp46 binding to its natural ligands. The present invention further provides multi-specific antibodies, chimeric antigen receptors (CAR) and uses thereof in treating diseases, particularly malignancies and infections.
1 . An antibody that binds to NKp46, or an antibody fragment thereof comprising at least an antigen binding portion, wherein the antibody or antibody fragment comprises a heavy chain (HC) complementarity determining region (CDR) 1 amino acid sequence of SEQ ID NO: 1, a HC CDR2 amino acid sequence of SEQ ID NO: 2, a HC CDR3 amino acid sequence of SEQ ID NO: 3; and a light chain (LC) CDR1 amino acid sequence of SEQ ID NO: 4, a LC CDR2 amino acid sequence of SEQ ID No: 5, and a LC CDR3 amino acid sequence of SEQ ID NO: 6.
2 . The antibody or the antibody fragment according to claim 1 , comprising a heavy chain variable region set forth in amino acid sequence of SEQ ID NO: 7, or an analog having at least 95% sequence similarity with said heavy chain variable region sequence.
3 . The antibody or the antibody fragment according to claim 1 , comprising a light chain variable sequence set forth in SEQ ID NO: 8, or an analog having at least 95% sequence similarity with said slight chain variable region sequence.
4 . The antibody or the antibody fragment according to claim 1 , comprising a heavy chain and a light chain, wherein the heavy chain comprises SEQ ID NO: 7 and the light chain comprises SEQ ID NO: 8.
5 . The antibody fragment according to claim 1 , wherein the antibody fragment is a single chain Fv (scFv).
6 . The antibody or antibody fragment according to claim 1 , wherein the antibody binds to human NKp46 with an affinity of 10 −11 M to 10 −16 M.
7 . The antibody or the antibody fragment according to claim 1 , wherein the antibody is a humanized antibody.
8 . The antibody or the antibody fragment according to claim 7 , wherein the humanized antibody comprises a heavy chain comprising SEQ ID NO: 14, and a light chain comprising a sequence selected from the group consisting of SEQ ID NOs: 15 and 16.
9 . A multi-specific antibody comprising a binding site of an antibody according to claim 1 .
10 . The multi-specific antibody of claim 9 , wherein the multi-specific antibody is a bi-specific antibody further comprising a binding site having specificity to a tumor antigen.
11 . The multi-specific antibody of claim 9 , wherein the multi-specific antibody is a bi-specific antibody further comprising a binding site having specificity to a viral, bacterial, or fungal antigen.
12 . The multi-specific antibody of claim 9 , wherein the multi-specific antibody is a tri-specific antibody further comprising a binding site specific to CD160 or CD16.
13 . The multi-specific antibody of claim 9 , wherein the multi-specific antibody is fused or conjugated to a cytokine.
14 . A pharmaceutical composition comprising as an active ingredient, at least one antibody or fragment thereof according to claim 1 , and a pharmaceutical acceptable excipient, diluent, salt, or carrier.
15 . A method of treating cancer, comprising administering to a subject in need thereof, a pharmaceutical composition according to claim 14 .
16 . A method of treating an infection in a subject, comprising administering a pharmaceutical composition according to claim 15 to a subject in need thereof.
17 . A chimeric antigen receptor (CAR) comprising at least one antibody or antibody fragment according to claim 1 .
18 . A method of treating cancer comprising administering to a subject in need thereof, at least one cell expressing the CAR according to claim 17 .