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Passive immunization with anti‐parathyroid hormone‐related protein monoclonal antibody markedly prolongs survival time of hypercalcemic nude mice bearing transplanted human PTHrP‐producing tumors
Author(s) -
Sato Kanji,
Yamakawa Yukiko,
Shizume Kazuo,
Satoh Tomoko,
Nohtomi Kyoko,
Demura Hiroshi,
Akatsu Takuhiko,
Nagata Naokazu,
Kasahara Tadashi,
Ohkawa Hiroyuki,
Ohsumi Kazuoki
Publication year - 1993
Publication title -
journal of bone and mineral research
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.882
H-Index - 241
eISSN - 1523-4681
pISSN - 0884-0431
DOI - 10.1002/jbmr.5650080711
Subject(s) - parathyroid hormone related protein , medicine , endocrinology , in vivo , monoclonal antibody , antibody , parathyroid hormone , calcium , immunology , biology , microbiology and biotechnology
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 (˜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.