Cannabinoid receptor type 1 (CB1) binding proteins and uses thereof
The present disclosure provides isolated, engineered, non-naturally occurring CB1 binding proteins, including anti-CB1 antibodies or antigen-binding fragment thereof. The CB1 binding proteins find utility in the treatment and diagnosis of CB1 mediated conditions, diseases and disorders.
1. An isolated antibody or antigen-binding fragment thereof that binds human cannabinoid type 1 receptor (CB1) set forth in SEQ ID NO:1, wherein the antibody or antigen-binding fragment comprises a variable heavy (VH) domain sequence and a variable light (VL) domain sequence, and wherein the antibody or antigen-binding fragment comprises six complementarity determining regions (CDRs): CDR-H1, CDR-H2, CDR-H3, CDR-L1, CDR-L2, and CDR-L3, wherein
CDR-H1 has the amino acid sequence S-Y-T-F-T-R-Y-W (SEQ ID NO: 92);
CDR-H2 has the amino acid sequence I-D-P-Y-D-S-E-T (SEQ ID NO: 93);
CDR-H3 has the amino acid sequence A-R-S-Q-P-R-Y-Y-A-M-D-Y (SEQ ID NO: 94);
CDR-L1 has the amino acid sequence Q-E-I-S-G-F (SEQ ID NO: 98);
CDR-L2 has the amino acid sequence: A-A-S(SEQ ID NO: 99); and
CDR-L3 has the amino acid sequence: L-Q-Y-S-S-Y-P-Y-T (SEQ ID NO: 100).
2. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a heavy chain/light chain pair selected from the group consisting of SEQ ID NOs: 89/95, 113/119, 125/131, 137/143, 149/155, 161/167, 185/191, 197/203, 209/215, 221/227, 233/239, 245/251, 257/263, 269/275, 281/287, and 293/299.
3. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the VH domain sequence has at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 90, 114, 126, 138, 150, 162, 186, 198, 210, 222, 234, 246, 258, 270, 282, and 294, and the VL domain sequence has at least 95% identity to an amino acid sequence selected from the group consisting of SEQ ID NOs: 96, 120, 132, 144, 156, 168, 192, 204, 216, 228, 240, 252, 264, 276, 288, and 300.
4. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 114 and the VL domain sequence is set forth in SEQ ID NO: 120.
5. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 126 and the VL domain sequence is set forth in SEQ ID NO: 132.
6. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 138 and the VL domain sequence is set forth in SEQ ID NO: 144.
7. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 150 and the VL domain sequence is set forth in SEQ ID NO: 156.
8. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 162 and the VL domain sequence is set forth in SEQ ID NO: 168.
9. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 90 and the VL domain sequence is set forth in SEQ ID NO: 96.
10. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 186 and the VL domain sequence is set forth in SEQ ID NO: 192.
11. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 198 and the VL domain sequence is set forth in SEQ ID NO: 204.
12. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 210 and the VL domain sequence is set forth in SEQ ID NO: 216.
13. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 222 and the VL domain sequence is set forth in SEQ ID NO: 228.
14. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 234 and the VL domain sequence is set forth in SEQ ID NO: 240.
15. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 246 and the VL domain sequence is set forth in SEQ ID NO: 252.
16. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 258 and the VL domain sequence is set forth in SEQ ID NO: 264.
17. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 270 and the VL domain sequence is set forth in SEQ ID NO: 276.
18. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 282 and the VL domain sequence is set forth in SEQ ID NO: 288.
19. The isolated antibody or antigen-binding fragment thereof of claim 3 , wherein the VH domain sequence is set forth in SEQ ID NO: 294 and the VL domain sequence is set forth in SEQ ID NO: 300.
20. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the fragment comprises a Fab fragment, a Fab′ fragment, a F(ab) 2 fragment or a scFv fragment.
21. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a human Fc region selected from the group consisting of an IgG1, IgG2, IgG3, IgG4, IgA, IgD, IgE, and IgM Fc.
22. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof comprises a modified human Fc region.
23. The isolated antibody or antigen-binding fragment thereof of claim 22 , wherein the modified human Fc region comprises a mutation selected from the group consisting of L234A/L235A, S228P, A330S, P331S, E233P/L234V/L235A, A327G/A330S/P331S, L234F/L235E/P331S, and N297Q.
24. A multispecific binding protein comprising an antigen-binding fragment of claim 1 .
25. The isolated antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment is a humanized antibody.