Cannabinoid receptor-1 (CB1) monoclonal antibodies
This disclosure relates to CB1 receptor antigen-binding proteins, e.g. antibodies and methods of using the CB1 receptor antibodies. The CB1 receptor antibodies may comprise an antagonistic antibody to CB1 receptors and may be used to treat various health conditions. The health conditions can comprise obesity or diabetes or any disease that benefits from antagonism of the CB1 receptor.
1. A monoclonal antibody or antigen-binding fragment wherein the antibody or antigen-binding fragment thereof comprises a heavy chain variable region comprising complementarity determining regions (CDRs) designated H1, H2, and H3 and a light chain variable region comprising CDRs designated L1, L2, and L3, wherein H1, H2, and H3 have the sequence of SEQ ID NO: 17, 18, and 19, respectively, and L1, L2, and L3 have the sequence of SEQ ID NO: 20, 21, and 22, respectively.
2. A monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein:
(a) the heavy chain comprises the sequence of SEQ ID NO: 4 and the light chain comprises the sequence of SEQ ID NO: 5;
(b) the heavy chain comprises the sequence of SEQ ID NO: 4 and the light chain comprises the sequence of SEQ ID NO: 14;
(c) the heavy chain comprises the sequence of SEQ ID NO: 4 and the light chain comprises the sequence of SEQ ID NO: 8;
(d) the heavy chain comprises the sequence of SEQ ID NO: 7 and the light chain comprises the sequence of SEQ ID NO: 8;
(e) the heavy chain comprises the sequence of SEQ ID NO: 7 and the light chain comprises the sequence of SEQ ID NO: 10;
(f) the heavy chain comprises the sequence of SEQ ID NO: 7 and the light chain comprises the sequence of SEQ ID NO: 12;
(g) the heavy chain comprises the sequence of SEQ ID NO: 6 and the light chain comprises the sequence of SEQ ID NO: 16;
(h) the heavy chain comprises the sequence of SEQ ID NO: 37 and the light chain comprises the sequence of SEQ ID NO: 36; or
(i) the heavy chain comprises the sequence of SEQ ID NO: 38 and the light chain comprises the sequence of SEQ ID NO: 36.
3. The monoclonal antibody or antigen binding fragment thereof of claim 1 wherein the antibody or antigen-binding fragment thereof antagonizes G-protein signaling of the cannabinoid receptor-1 (“CB1”) receptor.
4. The monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody or antigen-binding fragment thereof has an EC50 between 69 nm-100 nM in a cAMP assay.
5. The monoclonal antibody or antigen-binding fragment thereof of claim 2 , wherein the antibody or antigen-binding fragment thereof has an EC50 less than 100 nM in a cAMP assay.
6. The monoclonal antibody or antigen-binding fragment thereof of claim 1 , wherein the antibody is a human antibody.
7. The monoclonal antibody or antigen-binding fragment thereof of claim 2 , wherein the antibody is a human antibody.
8. A composition comprising the antibody or antigen-binding fragment thereof of claim 2 and a pharmaceutically acceptable carrier, diluent or excipient.
9. A nucleic acid encoding the antibody of claim 2 .
10. An expression vector comprising the nucleic acid of claim 9 .
11. An isolated host cell comprising the expression vector of claim 10 .
12. A method of producing an antibody comprising culturing the host cell of claim 11 under suitable conditions such that antibody encoded by the expression vector is produced, and recovering the antibody from the host cell culture.
13. A method for inhibiting the activity of the human CB1 receptor in a subject in need thereof comprising administering to the subject an antibody or antigen-binding fragment thereof of claim 2 .
14. The method of claim 13 , wherein the subject has a metabolic disorder.
15. The method of claim 14 , wherein the metabolic disorder is diabetes or obesity.
16. A method for improving a metabolic parameter in a subject in need thereof comprising administering to the subject an antibody or antigen-binding fragment thereof of claim wherein one or more metabolic parameters is improved in the subject following administration of the antibody or antigen-binding fragment thereof.
17. The method of claim 16 , wherein the improved metabolic parameter is reduced plasma glucose, reduced insulin levels, reduced triglyceride levels, reduced HbA1c, reduced intraabdominal liver fat, reduced blood pressure, increased adiponectin, increased HDL, increased cholesterol or increased energy expenditure.