NKp46 binding agents
The present invention provides antigen-binding proteins capable of binding to NKp46 polypeptides. The antigen-binding proteins have increased activity in the treatment of disorders characterized by NKp46-expressing cells, particularly tumor cells.
1. An antibody or antibody fragment selected from the group consisting of:
(a) an antibody or antibody fragment comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 3 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 4;
(b) an antibody or antibody fragment comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 3 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 21;
(c) an antibody or antibody fragment comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 29 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 30;
(d) an antibody or antibody fragment comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 29 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 47; and
(e) an antibody or antibody fragment comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 55 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 56.
2. The antibody or antibody fragment of claim 1 , comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 3 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 4.
3. The antibody or antibody fragment of claim 1 , comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 3 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 21.
4. The antibody or antibody fragment of claim 1 , comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 29 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 30.
5. The antibody or antibody fragment of claim 1 , comprising (i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 29 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 47.
6. The antibody or antibody fragment of claim 1 , comprising(i) a heavy chain comprising CDR 1, 2 and 3 of the heavy chain variable region of SEQ ID NO: 55 and (ii) a light chain comprising CDR 1, 2 and 3 of the light chain variable region of SEQ ID NO: 56.
7. The antibody or antibody fragment of claim 1 , wherein said antibody is conjugated to a cytotoxic agent.
8. The antibody or antibody fragment of claim 1 , wherein the antibody or antibody fragment comprises a functionalized acceptor glutamine residue (Q) comprising the structure:
(Q)-L″-Y-Z
or a pharmaceutically acceptable salt or solvate thereof,
wherein:
Q is a glutamine residue present within or appended to a constant region of the antibody or antibody fragment;
L″ is a lysine-based linker in which the nitrogen atom is covalently bonded to the γ carbon of Q as a secondary amine;
Y is a spacer system; and
Z is a cytotoxic agent.
9. The antibody or antibody fragment of claim 7 , wherein the cytotoxic agent is a DNA minor groove binding agent.
10. The antibody or antibody fragment of claim 1 , wherein said antibody comprises a human heavy chain constant region that binds a human FcγIIIA receptor polypeptide.
11. The antibody or antibody fragment of claim 1 , wherein said antibody binds to a non-human primate NKp46 polypeptide of SEQ ID NO: 2.
12. The antibody or antibody fragment of claim 1 , wherein said antibody fragment is selected from the group consisting of Fab, Fab′, Fab′-SH, F(ab′) 2, Fv, a diabody, a single-chain antibody fragment, and a multispecific antibody comprising multiple different antibody fragments.
13. A protein comprising an antibody fragment of claim 1 .
14. The protein of claim 13 , wherein the protein is a chimeric cell surface receptor protein.
15. A pharmaceutical composition comprising an antibody or antibody fragment, of claim 1 , and a pharmaceutically acceptable carrier.
16. A method for the treatment of lymphoma or celiac disease in an individual in need thereof, the method comprising administering to said individual an effective amount of an antibody or antibody fragment of claim 1 .