A Novel Anti-PTH1R Receptor Antagonist Monoclonal Antibody Reverses Hypercalcemia Induced By PTH or PTHrP: A Potential Treatment of Primary Hyperparathyroidism and Humoral Hypercalcemia of Malignancy

Presentation Number: SAT 339
Date of Presentation: April 1st, 2017

Agnes Choppin, Daniel Bedinger, Rachel Hunt, Catarina Tran, Sujeewa Wijesuriya, Robyn Cotter, Elizabeth Pongo, Robert Shimizu, Jessica Chen, Khanh Pham, Amer Mirza, Kirk W. Johnson*, Toshihiko Takeuchi and Raphael Levy
XOMA Corporation, Berkeley, CA

Abstract

The PTH1R receptor is one of the family B GPCRs and the primary receptor of two ligands, parathyroid hormone (PTH) and parathyroid related protein (PTHrP). Hypercalcemia can occur when elevated levels of PTH, as seen in primary hyperparathyroidism (PHPT), or elevated levels of PTHrP, as seen in humoral hypercalcemia of malignancy (HHM), leading to excessive activation of the PTH1R receptor. A potent and long acting receptor antagonist could reverse hypercalcemia in these conditions. We therefore have developed a highly potent PTH1R antagonist monoclonal antibody for the treatment of disorders related to elevated PTH or PTHrP. This antibody was discovered using fully human phage display libraries and selected for potent binding to and antagonism of the human and murine PTH1R. PTH1R antagonism by our antibody against both the PTH and PTHrP peptides was determined by cAMP accumulation in osteosarcoma cell lines Saos-2 (human) and UMR106 (rat). The antibody showed roughly equivalent inhibition of both the human and murine receptors. We also demonstrated in vitro that this antibody inhibited both PTH- and PTHrP-induced osteoclast differentiation by greater than 10-fold in a Saos-2 and human monocyte co-culture system: the PTH1R receptor is expressed on osteoblasts and osteocytes, and stimulation by PTH or PTHrP leads these cells to increase the expression of RANKL and other factors. These drive the differentiation and activation of bone resorbing osteoclast cells, which release calcium and decrease bone density. In vivo proof-of-concept was obtained in rodent models where hypercalcemia was established in rats by SC infusion of PTH or PTHrP via osmotic pumps. IV administration of 2 and 10 mg/kg antibody dose-dependently reduced serum calcium levels by a minimum of 2 mg/dL within 48 hours of dosing. Additionally, the antibody was tested in a model of HHM wherein mice developed hypercalcemia following implantation of mouse colon tumor cells C26. In this tumor model, the antibody given at 10 mg/kg IV was capable of completely reversing hypercalcemia within 24 hours. The pharmacokinetic parameters of the antibody were also defined in rats.

This highly potent PTH1R receptor antagonist antibody has the potential to become a valuable therapeutic agent in a variety of indications including hyperparathyroidism, humoral hypercalcemia of malignancy, and, potentially, the PTHrP-mediated cachexia seen in some cancers.

 

Disclosure: AC: Employee, XOMA Corporation. DB: Employee, XOMA Corporation. RH: Employee, XOMA Corporation. CT: Employee, XOMA Corporation. SW: Employee, XOMA Corporation. RC: Employee, XOMA Corporation. EP: Employee, XOMA Corporation. RS: Employee, XOMA Corporation. JC: Employee, XOMA Corporation. KP: Employee, XOMA Corporation. AM: Employee, XOMA Corporation. KWJ: Vice President, XOMA Corporation. TT: Employee, XOMA Corporation. RL: Employee, XOMA Corporation.