Passive immunization with anti-parathyroid hormone-related protein monoclonal antibody markedly prolongs survival time of hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors

Abstract

Malignancy-associated hypercalcemia is mainly caused by excessive production of parathyroid hormone-related protein (PTHrP) by the tumor. Using anti-PTHrP-(1-34) monoclonal murine antibody (anti-PTHrP MoAb), we studied whether repeated injection of the homologous antibody would continuously decrease the serum calcium concentration in hypercalcemic nude mice bearing transplanted human PTHrP-producing tumors, leading to prolongation of their survival time. Daily SC injections of anti-PTHrP 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 into 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 mice (n = 10) showed an increase in body weight and survived for at least 25 days. Histologic examination of the treated mice revealed a marked decrease in osteoclastic bone resorption, without toxicologic findings in the kidney and liver. These results suggest that passive immunization against PTHrP can continuously ameliorate the hypercalcemia and markedly prolong the survival time of severely hypercalcemic, tumor-bearing mice. If a human monoclonal antibody against PTHrP-(1-34) could be developed, then passive immunization would be potentially one of the most effective therapies for patients with malignancy-associated hypercalcemia due to excessive production of PTHrP.

Tumour-derived PTH-related protein triggers adipose tissue browning and cancer cachexia

“…PTHrP was previously linked to cachexia associated with hypercalcemia of malignancy 20-22 . However, its direct roles in the muscle wasting process and the browning of adipose tissues have not been reported.…”

Structural Basis for Antibody Discrimination between Two Hormones That Recognize the Parathyroid Hormone Receptor

“…Likewise, polyclonal antibodies against PTHrP-(1-34) that neutralized its effects completely in vitro in promotion of cyclic AMP production in response to PTHrP without any detectable neutralizing effect on PTH were used to prevent and to treat hypercalcemia in nude mice bearing xenografts of PTHrP-secreting human cancers (11,12). Similar results were obtained with a neutralizing mouse monoclonal antibody against PTHrP (13). Subsequently, after the finding that breast cancer metastases to bone were enriched in PTHrP production (14), Guise and Mundy (15) used an experimental model in nude mice in which human breast cancer cells grow as lytic deposits in bone after intracardiac injection and showed that PTHrP production by the cancers contributed to the process of tumor establishment and growth in bone by promoting osteoclast formation and bone resorption.…”

“…The consistent finding that antibodies can readily be prepared against PTHrP that do not recognize PTH, even in great excess, has been very helpful in the development of discriminatory plasma assays and in the study of tissue distribution of PTHrP using immunohistology (2). The same specificity has been applied to a number of polyclonal antisera that have been used in vivo (12,39) and to the monoclonal antibodies used by Sato et al (13) and Guise et al (16). Such discrimination would be essential for an antibody to be used therapeutically because as the excess PTHrP is neutralized and serum calcium returns to normal, the suppressed PTH level rises, and normal physiological controls return.…”

“…Establishment of a Mouse Anti-human PTHrP-(1-34) Antibody-The antibody was developed against synthetic PTHrP-(1-34) and shown to be effective in treating hypercalcemia in a nude mouse model of the humoral hypercalcemia of malignancy (13). The cells were re-cloned and the hybridoma, #23-57-137-1, was established as a monoclonal cell line by Mitsubishi Kagaku BCL.…”

Hypercalcemia during Pregnancy, Puerperium, and Lactation: Review and a Case Report of Hypercalcemic Crisis after Delivery Due to Excessive Production of PTH-related Protein (PTHrP) without Malignancy (Humoral Hypercalcemia of Pregnancy)

“…Although bisphosphonate is contraindicated in pregnancy, intravenous administration of pamidronate is very effective in ameliorating severe hypercalcemia, without any apparent ill effects on the newborn [30,31]. If a humanized neutralizing antibody against PTHrP is available, administration of such a monoclonal antibody would be a more efficient and safer treatment for these pregnant patients [32].…”