Inverse agonist monoclonal antibody that suppresses thyrotropin receptor constitutive activity
This invention describes monoclonal antibodies that suppress thyrotropin receptor constitutive activity and methods of using the antibodies to treat thyroid related diseases; particularly hyperthyroidism and thyroid cancer.
1. A purified antibody that binds specifically to a thyrotropin receptor (“TSHR’) and has inverse agonist activity on the TSHR.
2. The purified antibody of claim 1 , wherein the purified antibody is a monoclonal antibody produced by hybridoma CS-17, ATCC accession number PTA-8174.
3. The purified antibody of claim 1 , having the same epitope specificity as a monoclonal antibody produced by hybridoma CS-17, ATCC accession number PTA-8174.
4. The purified antibody of claim 1 , wherein the TSHR is a mutant TSHR comprising a mutation at C24, C29, C31, C41, S281, I486, I568, A623, or V656, or a combination thereof.
5. The purified antibody of claim 1 that binds specifically to the A-subunit of the TSHR.
6. The purified antibody of claim 1 , wherein the TSHR is a polypeptide as disclosed by SEQ ID NO: 1.
7. The purified antibody of claim 1 that binds specifically to a conformational epitope of TSHR, wherein at least a substantial portion of the conformational epitope is located between amino acid residues 171 and 260 of the TSHR.
8. The purified antibody of claim 7 , wherein the amino acid residues 171 through 260 are as disclosed by SEQ ID NO: 2.
9. The purified antibody of claim 1 , wherein the TSHR is human TSHR.
10. The purified antibody of claim 1 that is humanized or a human antibody.
11. A purified antibody that binds specifically to a polypeptide that is encoded by a polynucleotide as disclosed by SEQ ID NO: 3 and has inverse agonist activity on the polypeptide.
12. The purified antibody of claim 11 that binds specifically to a conformational epitope on the polypeptide.
13. The purified antibody of claim 12 , wherein a substantial portion of the conformational epitope is on a polypeptide that is encoded by a polynucleotide as disclosed by SEQ ID NO: 4.
14. The purified antibody of claim 11 that is humanized or is a human antibody.
15. A cell of hybridoma CS-17, ATCC accession number PTA-8174.
16. A kit for the treatment of a thyroid or thyroid or thyroid-related disease or disease condition in a subject in need thereof, comprising:
a purified antibody that binds specifically to thyrotropin receptor (“TSHR”) and has inverse agonist activity on TSHR; and
instructions for using the purified antibody to treat the thyroid or thyroid-related disease or disease condition.
17. The kit of claim 16 , wherein the purified antibody is a monoclonal antibody produced by hybridoma CS-17, ATCC accession number PTA-8174.
18. The purified antibody of claim 1 , wherein the purified antibody is a Fab, Fab′ or F(ab′)2 fragment.
19. The purified antibody of claim 11 , wherein the purified antibody is a Fab, Fab′ or F(ab′)2 fragment.
20. The kit of claim 16 , wherein the purified antibody is a Fab, Fab′ or F(ab′)2 fragment.
21. The purified antibody of claim 1 that binds specifically to a conformational epitope of TSHR, wherein at least a substantial portion of the conformational epitope is located between amino acid residues 170 and 289 of the TSHR.
22. The purified antibody of claim 12 , wherein at least a substantial portion of the conformational epitope is on a polypeptide that is encoded by nucleotides 508 through 867 of SEQ ID NO: 3.
23. The purified antibody of claim 4 , wherein the mutation comprises (C29, 31S), (C24, 29S), (C24, 31S), S281I, I486F, I568T, A623I, or V656F, or a combination thereof.