PASSIVE-IMMUNIZATION WITH ANTI-PARATHYROID HORMONE-RELATED PROTEIN MONOCLONAL-ANTIBODY MARKEDLY PROLONGS SURVIVAL-TIME OF HYPERCALCEMIC NUDE-MICE BEARING TRANSPLANTED HUMAN PTHRP-PRODUCING TUMORS

Malignancy-associated hypercalcemis is mainly caused by excessive prod uction of parathyroid hormone-related protein (PTHrP) by the tumor. Us ing anti-PTHrP-(1-34) monoclonal murine antibody (anti-PTHrP MoAb), we studied whether repeated injection of the homologous antibody would c ontinuously decrease the serum calcium concentration in hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors, leading t o prolongation of their survival time. Daily SC injections of anti-PTH rP MoAb decreased the serum calcium concentration almost to within the normal range in nude mice bearing transplanted human PTHrP-producing tumors (T3M-1, EC-GI, PC-3, and FA-6) but not in a nude mouse bearing a transplanted parathyroid carcinoma. The antibody did not affect FA-6 tumor growth either in vitro or in vivo. Pancreatic carcinoma cells ( FA-6), which caused the most severe hypercalcemia, were inoculated int o 6-week-old nude mice. When severe hypercalcemia (approximately 19 mg /dl) had developed, daily SC injection of anti-PTHrP MoAb was started. Within 18 days of this time point, all untreated tumor-bearing mice ( n = 10) died of hypercalcemia and cachexia, whereas all the treated mi ce (n = 10) showed an increase in body weight and survived for at leas t 25 days. Histologic examination of the treated mice revealed a marke d decrease in osteoclastic bone resorption, without toxicologic findin gs in the kidney and liver. These results suggest that passive immuniz ation against PTHrP can continuously ameliorate the hypercalcemia and markedly prolong the survival time of severely hypercalcemic, tumor-be aring mice. If a human monoclonal antibody against PTHrP-(1-34) could be developed, then passive immunization would be potentially one of th e most effective therapies for patients with malignancy-associated hyp ercalcemia due to excessive production of PTHrP.