title: Maximum tolerated dose and large tumor radioimmunotherapy studies of 64Cu-labeled monoclonal antibody 1A3 in a colon cancer model.
abstract: The purpose of this study was 2-fold: to determine the maximum tolerated dose (MTD) of 64Cu-bromoacetamidobenzyl- 1,4,8,11-tetraazacyclotetradecane-N,N',N'',N'''-tetraacetic acid (BAT)-2-iminothiolane (2IT)-monoclonal antibody (MAb) 1A3 in hamsters, and second, to determine the therapeutic efficacy of 64Cu-BAT-2IT-MAb 1A3 at various dose levels in hamsters with large (600 mg), 7-day-old GW39 human colorectal carcinoma tumors. In the MTD studies, non-tumor-bearing hamsters were injected with varying amounts of Cu-64-BAT-2IT MAb 1A3 (>10 mCi) normalized to mCi injected/kg of hamster body weight. Results indicated that the MTD was 150 mCi of Cu-64/kg of body weight. Hamsters receiving higher doses (170-190 mCi/kg) lost greater than 20% of their body weight, and all died between 8 and 13 days (n = 3). All hamsters receiving doses < or = 150 mCi/kg (120-150 mCi; n = 13) survived to the experimental end point (6 weeks) with an overall gain in weight. WBC and platelet counts were depressed in all animals 7 days after treatment but returned to normal values in the survivors by 2 weeks. For larger tumor therapy studies, 40% (8 of 20) of hamsters receiving a single dose of 7.0 mCi and 62.5% (5 of 8) of hamsters receiving 15 mCi of Cu-64-BAT-2IT-MAb 1A3 remained tumor free 4 months after treatment. In dose fractionation studies, hamsters received two 3.5 mCi doses separated by 24 or 48 h with 44% (4 of 9) and 25% (2 of 8) survival, respectively. In every large tumor experimental group, 100% of animals experienced tumor growth inhibition compared to saline control animals. Together, the MTD and the large tumor therapy studies confirm that 64Cu-labeled agents are excellent candidates for radioimmunotherapy trials.
authors.affiliation: Department of Surgery, Washington University School of Medicine, St. Louis, Missouri 63110, USA. Connettj@msnotes.wustl.edu
authors.forename: J M
authors.initials: JM
authors.lastname: Connett
authors.forename: T L
authors.initials: TL
authors.lastname: Buettner
authors.forename: C J
authors.initials: CJ
authors.lastname: Anderson
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D003110:Colonic Neoplasms / Q000532:radiotherapy*; D003301:Copper Radioisotopes / Q000627:therapeutic use*; D006224:Cricetinae; D006801:Humans; D008297:Male; D008647:Mesocricetus; D051379:Mice; D009368:Neoplasm Transplantation; D016499:Radioimmunotherapy; D011879:Radiotherapy Dosage; D014183:Transplantation, Heterologous
chemical_list: D000911:Antibodies, Monoclonal; D003301:Copper Radioisotopes