NOVEL ANTI-RNF43 ANTIBODIES AND METHODS OF USE
The invention discloses novel anti-RNF43 antibodies and derivatives thereof, including antibody drug conjugates, and methods of using such anti-RNF43 antibodies and antibody drug conjugates to diagnose and treat cancer.
1 . An antibody drug conjugate of the formula M-[L-D]n, or a pharmaceutically acceptable salt thereof, wherein
M comprises an anti-RNF43 antibody;
L comprises a linker;
D comprises a cytotoxin; and
n is an integer from 1 to 20.
2 . The antibody drug conjugate of claim 1 , wherein the anti-RNF43 antibody is an internalizing antibody.
3 . The antibody drug conjugate of claim 1 , wherein the anti-RNF43 antibody is a chimeric, CDR grafted or humanized antibody, or fragment thereof.
4 . The antibody drug conjugate of claim 1 , wherein the anti-RNF43 antibody binds to tumor initiating cells.
5 . The antibody drug conjugate of claim 1 , wherein the anti-RNF43 antibody binds to human RNF43 (SEQ ID NO: 5) and does not bind to human ZNRF3 (SEQ ID NO: 6).
6 . The antibody drug conjugate of claim 1 , wherein the anti-RNF43 antibody binds to human RNF43 (SEQ ID NO: 5) on the surface of a eukaryotic cell wherein the binding of the antibody decreases WNT signaling.
7 . The antibody drug conjugate of claim 1 , wherein the anti-RNF43 antibody binds to human RNF43 (SEQ ID NO: 5) on the surface of a eukaryotic cell wherein the binding of the antibody increases WNT signaling.
8 . The antibody drug conjugate of claim 1 , wherein the anti-RNF43 antibody binds to human RNF43 (SEQ ID NO: 5) on the surface of a eukaryotic cell wherein the binding of the antibody does not affect WNT signaling.
9 . The antibody drug conjugate of claim 1 wherein the anti-RNF43 antibody binds to human RNF43 (SEQ ID NO: 5) and blocks binding of R-spondin to RNF43.
10 . The antibody drug conjugate of claim 1 wherein the anti-RNF43 antibody binds to human RNF43 (SEQ ID NO: 5) and does not block binding of R-spondin to RNF43.
11 . The antibody drug conjugate of claim 1 , wherein the anti-RNF43 antibody binds to human RNF43 (SEQ ID NO: 5) on the surface of a eukaryotic cell wherein the binding of the antibody does not block R-spondin-stimulated WNT signaling.
12 . The antibody drug conjugate of claim 1 , wherein the anti-RNF43 antibody binds to human RNF43 (SEQ ID NO: 5) on the surface of a eukaryotic cell wherein the binding of the antibody blocks R-spondin-stimulated WNT signaling.
13 . An isolated antibody that binds to human RNF43 (SEQ ID NO: 5) and competes for binding to human RNF43 with an antibody comprising:
(1) a light chain variable region set forth as SEQ ID NO: 78 and a heavy chain variable region set forth as SEQ ID NO: 80; or
(2) a light chain variable region set forth as SEQ ID NO: 110 and a heavy chain variable region set forth as SEQ ID NO: 112.
14 . An isolated antibody that binds to human RNF43 (SEQ ID NO: 5) comprising a light chain comprising the following light chain complimentarity determining regions (CDRL): CDRL1: SEQ ID NO: 288; CDRL2: SEQ ID NO: 289; CDRL3: SEQ ID NO: 290; and a heavy chain comprising the following heavy chain complimentarity determining regions (CDRH): CDRH1: SEQ ID NO: 291; CDRH2: SEQ ID NO: 292; CDRH3: SEQ ID NO: 293.
15 . An isolated antibody that binds to human RNF43 (SEQ ID NO: 5) comprising a light chain comprising the following light chain complimentarity determining regions (CDRL): CDRL1: SEQ ID NO: 294; CDRL2: SEQ ID NO: 295; CDRL3: SEQ ID NO: 296; and a heavy chain comprising the following CDRH: CDRH1: SEQ ID NO: 297; CDRH2: SEQ ID NO: 298; CDRH3: SEQ ID NO: 299.
16 . A humanized antibody that binds to human RNF43 (SEQ ID NO: 5) comprising a light chain set forth as SEQ ID NO: 273; and a heavy chain set forth as SEQ ID NO: 275.
17 . A humanized antibody that binds to human RNF43 (SEQ ID NO: 5) comprising a light chain set forth as SEQ ID NO: 276; and a heavy chain variable region set forth as SEQ ID NO: 278.
18 . A nucleic acid encoding a light chain set forth as SEQ ID NO: 273 or 276, or a heavy chain set forth as SEQ ID NO: 275 or 278.
19 . A vector comprising the nucleic acid of claim 18 .
20 . A host cell comprising the vector of claim 19 .
21 . A pharmaceutical composition comprising an ADC of any one of claims 1 to 11 .
22 . A method of treating cancer comprising administering a pharmaceutical composition of claim 21 to a subject in need thereof.
23 . The method of claim 22 , wherein the cancer is selected from colorectal cancer or lung cancer.