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Preclinical Analysis of Intraperitoneal Administration of ¹¹¹In-labeled Human Tumor Reactive Monoclonal IgM AC6C3-2B12¹

Departments of Experimental Radiotherapy [S. M. Q., A. B. M. X-Z. T., H. M. V.] and Gynecologic Oncology, Section of Experimental Gynecology [R. P., R. S. F.], The University of Texas M. D. Anderson Cancer Center, Houston, Texas 77030-4095

An IgM human tumor cell-reactive monoclonal antibody was developed that reacts with cells of ovarian cancer, colorectal cancer, breast cancer, and certain other malignancies. The monoclonal antibody AC6C3-2B12, which was obtained from a recent recloning, was purified from tissue culture supernatants and analyzed by high-performance liquid chromatography and sodium dodecyl sulfate-PAGE. An animal model was developed in which human tumors grew either as solid peritoneal metastases or as s.c. nodules utilizing the human colorectal carcinoma cell line SW620. The biodistribution of ¹¹¹In-labeled IgM conjugate was studied after i.v. or i.p. administration in nude mice bearing an s.c. xenograft or peritoneal tumor lumps of a human colorectal carcinoma (SW620). IgM administered i.v. cleared rapidly from blood and was deposited mainly in the liver [50% injected dose/g (ID/g)], pancreas (20% ID/g), and kidney (10% ID/g) at 24 h. Tumor deposition was low (1.0% ID/g) in the s.c. tumor xenograft. In contrast, high tumor targeting (29% ID/g) was found in peritoneal tumor lumps after i.p. administration of ¹¹¹In-labeled IgM. The biological half-life of IgM in the tumor was 100 h. Long peritoneal residence time (t = 67 h) and low liver uptake (7% ID/g) were observed after i.p. administration. Blood activity was <1% of the injected activity. Tumor:normal organ ratios were high (range, 2–290) from 2 to 144 h after i.p. administration. Whole body autoradiograms at 24 h after i.p. ¹¹¹In-labeled IgM administration confirmed the biodistribution results. In normal beagle dogs, 75% of the i.p.-administered ¹¹¹In-IgM decayed in the peritoneal cavity. The majority of the remaining radioactivity was taken up by mediastinal lymph nodes. Biological half-life in both locations was approximately 137 h. The i.p. administration of intact, specific radiolabeled IgM provides prolonged retention of radioactivity in tumor, low normal tissue uptake, a long peritoneal residence time, and very limited spillover of IgM into the circulation. This approach offers a promising new method for the diagnosis and treatment of certain patients with peritoneal carcinomatosis.