Radioimmunotherapy of athymic mice bearing human colon carcinomas with monoclonal antibody B72.3: histological and autoradiographic study of effects on tumors and normal organs.
Monoclonal antibody (MAb) B72.3 has been linked successfully to several radionuclides forming stable complexes and analyzed in vitro and in vivo without significant loss of its immunoreactivity. Previous studies have demonstrated that radioiodinated B72.3 can selectively bind to human colorectal carcinomas grown in athymic mice. The same successful localization has been obtained more recently in clinical trials in patients with metastatic colorectal carcinomas. The high degree of selective binding of this MAb has led us to investigate its potential as a radioimmunotherapeutic agent. Athymic mice bearing human colon carcinoma xenografts were injected with either 300 or 500 microCi of 131I-B72.3 IgG to assess the effect o the radiolabeled MAb on the tumor growth as well as potential toxic side effects in vital organs. In mice treated with the 131I-B72.3 IgG, a marked inhibition of the growth of the human colon carcinoma xenografts was noticed in comparison with control mice injected with PBS or control mice that received unlabeled B72.3 IgG. The tumors from these control mice weighed 2.7 to 3.7 times more than the tumors from the treated mice at 17 days post-inoculation of the radiolabeled MAb. Autoradiographic studies demonstrated a heterogeneous distribution of radioactivity throughout the tumor mass at 11 days post-administration of MAb. With time, the periphery of the tumor contained significantly less radioactivity than the medial areas composed of predominantly nonviable tissue; these findings suggest that the more biologically active peripheral tumor zones, with higher mitotic rates, could have partially escaped the radiation effect of the single dose administered. The tumor cells could have continued dividing when the levels of circulating radiolabeled monoclonal antibody had decreased. Toxicity was readily evident in the mice injected with the high-dose regimen (500 microCi), with confirmed bone marrow aplasia that proved lethal for 2 of 10 animals. The lower dose (300 microCi) resulted in a bone marrow suppression of approx. 50% of the cells, which proved to be non-lethal. The tumors in the treated mice showed extensive necrosis caused by the lethal dose of 131I-B72.3 that irreversibly damaged the cells. Radiation-induced terminal differentiation of cells was also found as manifested by the drastically decreased mitotic count (0-2 vs. 12-14 per 10 high power fields seen in control tumors) in treated animals.
Esteban
J M
JM
Laboratory of Tumor Immunology and Biology, National Cancer Institute, Bethesda, MD 20892.
Schlom
J
J
Mornex
F
F
Colcher
D
D
D002288:Adenocarcinoma, Mucinous / Q000473:pathology / Q000532:radiotherapy*; D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D001345:Autoradiography; D001853:Bone Marrow / Q000528:radiation effects; D002460:Cell Line; D003110:Colonic Neoplasms / Q000473:pathology / Q000532:radiotherapy*; D005260:Female; D006801:Humans; D007457:Iodine Radioisotopes / Q000627:therapeutic use*; D051379:Mice; D008819:Mice, Nude; D009336:Necrosis; D011833:Radiation Injuries, Experimental / Q000473:pathology; D013154:Spleen / Q000528:radiation effects
D000911:Antibodies, Monoclonal; D007457:Iodine Radioisotopes