Claims for Patent: 10,519,250

Summary for Patent: 10,519,250

Title:	Parathyroid hormone receptor 1 (PTH1R) antibodies and uses thereof
Abstract:	The present disclosure relates, in general, human antibodies against human parathyroid hormone receptor 1 (PTH1R) and methods of use of such antibodies in the treatment of cancer, Humoral Hypercalcemia of Malignancy (HHM), or Primary Hyperparathyroidism (PHPT) and Secondary Hyperparathyroidism (SHPT) and cachexia.
Inventor(s):	Levy; Raphael D. (Berkeley, CA), Issafras; Hassan (Berkeley, CA), Holmes; Agnes Choppin (Berkeley, CA), Johnson; Kirk W. (Berkeley, CA), Mirza; Amer M. (Berkeley, CA), Bedinger; Daniel H. (Berkeley, CA), Hunt; Rachel A. (Berkeley, CA), Takeuchi; Toshihiko (Berkeley, CA), Ahluwalia; Kiranjit Kaur (Berkeley, CA), Cotter; Robyn (Berkeley, CA)
Assignee:	XOMA (US) LLC (Emeryville, CA)
Application Number:	15/665,788
Patent Claims:	1. An antibody that binds parathyroid hormone receptor 1 (PTH1 R) with an affinity K.sub.d of 2.times.10.sup.-6 M or less, wherein the antibody comprises (a) a heavy chain CDR1 amino acid sequence set forth in SEQ ID NOs: 30 or 45; (b) a heavy chain CDR2 amino acid sequence set forth in SEQ ID NOs: 31 or 46; (c) a heavy chain CDR3 amino acid sequence set forth SEQ ID NOs: 32 or 47; (d) a light chain CDR1 amino acid sequence set forth in SEQ ID NOs: 134 or 149; (e) a light chain CDR2 amino acid sequence set forth SEQ ID NOs: 135 or 150; and (f) a light chain CDR3 amino acid sequence set forth in SEQ ID NOs: 136 or 151. 2. The antibody of claim 1 wherein the antibody binds the N-terminal portion of PTH1R. 3. The antibody of claim 1 wherein the antibody does not bind parathyroid hormone receptor 2 (PTH2R). 4. The antibody of claim 1, wherein the antibody binds PTH1R on the surface of a cell. 5. The antibody of claim 1, wherein the antibody binds allosterically to PTH1R. 6. The antibody of any claim 1, wherein the antibody is a negative modulator antibody, optionally wherein the antibody is capable of weakening the binding affinity between PTH or PTHrP and with PTH1R by at least about 2-fold, optionally up to 1000-fold. 7. The antibody of claim 1, wherein the antibody inhibits calcium flux in a cell in response to stimulation of the receptor with parathyroid hormone (PTH) or parathyroid hormone related protein (PTHrP). 8. The antibody of claim 1, wherein the antibody inhibits PTH- or PTHrP-mediated cyclic adenosine mono-phosphate (cAMP) accumulation. 9. The antibody of claim 1 that is a monoclonal antibody. 10. The antibody of claim 1, that comprises i) an amino acid sequence at least 90% identical to a heavy chain variable region amino acid sequence set forth in SEQ ID NOs: 2 or 7; and ii) an amino acid sequence at least 90% identical to a light chain variable region amino acid sequence set forth in SEQ ID NOs: 106 or 111. 11. The antibody of claim 1, in which one or more light chain framework amino acids have been replaced with corresponding amino acid(s) from another human antibody amino acid sequence, optionally wherein the framework comprises one or more of the changes set out in FIG. 21. 12. An isolated nucleic acid molecule comprising a nucleotide sequence that encodes the heavy chain or light chain of claim 1. 13. An expression vector comprising the nucleic acid molecule of claim 12 operably linked to an expression control sequence. 14. A host cell comprising the vector of claim 13. 15. The host cell of claim 14, comprising a nucleic acid molecule encoding a heavy chain and a light chain variable region, wherein the heavy chain and light chain nucleic acids are expressed by different nucleic acids or on the same nucleic acid. 16. A method of using the host cell of claim 14 to produce an antibody, comprising culturing the host cell of claim 14 under suitable conditions and recovering said antibody. 17. A sterile pharmaceutical composition comprising the antibody of claim 1 and a pharmaceutically acceptable carrier. 18. A method for treating hypercalcemia associated with increased parathyroid hormone or parathyroid hormone related protein expression comprising the step of administering to a subject in need thereof a therapeutically effective amount of an antibody of claim 1 or a pharmaceutical composition of claim 17. 19. A method for treating a disease, condition or disorder associated with increased parathyroid hormone expression, increased parathyroid hormone related protein expression or parathyroid hormone receptor 1 (PTH1R) expression comprising the step of administering to a subject in need thereof a therapeutically effective amount of an antibody of claim 1 or a pharmaceutical composition of claim 17. 20. The method of claim 19, wherein the disease, condition or disorder is selected from the group consisting of cancer, PTH- or PTHrP-induced hypercalcemia, Humoral Hypercalcemia of Malignancy (HHM), familial hypocalciuric hypercalcemia, tuberculosis, sarcoidosis, Primary Hyperparathyroidism (PHPT), Secondary Hyperparathyroidism (SHPT) and cachexia. 21. The method of claim 20 wherein the disease is PHPT and the subject is a non-surgical patient or a patient who has failed surgery. 22. The method of claim 20 wherein the disease is SHPT and the subject has chronic kidney disease. 23. The method of claim 18 wherein the administration reduces the incidence of cancer metastasis in the subject compared to a subject not receiving the antibody. 24. The method of claim 23 wherein the metastasis includes metastasis to the bone or skeletal tissues, liver, lung, kidney or pancreas. 25. The method of claim 18 wherein the administration ameliorates one or more symptoms of hypercalcemia. 26. The method of claim 18, wherein the administration extends HHM survival due to reduced hypercalcemia and/or wasting syndrome. 27. The method of claim 18 wherein the antibody is administered intravenously, intraarterially, intraperitoneally, intramuscularly, intradermally or subcutaneously. 28. The method of claim 18 wherein the antibody is administered in combination with a second agent. 29. The method of claim 18 wherein the antibody is administered once per week, once every 2 weeks, twice per month, once monthly, once every two months, or once every three months. 30. A composition comprising an antibody of claim 1 or a pharmaceutical composition of claim 17 for use in treating a condition or disorder associated with increased parathyroid hormone expression or increased parathyroid hormone related protein expression. 31. A composition comprising an antibody of claim 1 or a pharmaceutical composition of claim 17 for use in treating a condition or disorder associated with hypercalcemia. 32. The antibody of claim 1, further comprising a heavy chain constant region, wherein the heavy chain constant region is a modified or unmodified IgG, IgM, IgA, IgD, IgE, a fragment thereof, or combinations thereof. 33. The antibody of claim 32, further comprising a human light chain constant region. 34. The antibody of claim 33, wherein the light chain constant region is a modified or unmodified lambda light chain constant region, a kappa light chain constant region, a fragment thereof, or combinations thereof.

Details for Patent 10,519,250

Applicant	Tradename	Biologic Ingredient	Dosage Form	BLA	Approval Date	Patent No.	Expiredate
Nps Pharmaceuticals, Inc.	NATPARA	parathyroid hormone	For Injection	125511	01/23/2015		2036-08-01