Maximum Tolerated Dose and Large Tumor Radioimmunotherapy Studies of 64Cu-labeled Monoclonal Antibody 1A3 in a Colon Cancer Model 1

The purpose of this study was 2-fold: to determine the maximum tolerated dose (MTD) of 64Cu-bromoacetamidobenzyl-l,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 <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-64BAT-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. 1 Presented at the "Seventh Conference on Radioimmunodetection and Radioimmunotherapy of Cancer," October 15-17, 1998, Princeton, NJ. Supported by the Alvin and Roxanne Frank Fund, a grant from the Jewish Foundation, and Department of Energy Grant DE-FG0287ER60512. 2 To whom requests for reprints should be addressed, at Department of Surgery, Box 8109, Washington University School of Medicine, St, Louis, MO63110. Phone: (314) 454-8039; Fax: (314) 454-5049. Email: Connettj @ msnotes.wustl.edu. Introduction RIT 3 combines the tumor targeting properties of anticancer MAbs with the cytotoxic properties of therapeutic radionuclides to cause cancer remission or regression in patients. RIT is a rapidly growing area of basic research and clinical practice, and to date, most success with this form of cancer therapy has been with hematological malignancies (i.e., leukemias and lymphomas; Refs. 1-6), which are more radiosensitive and more accessible to systemically administered radiopharmaceuticals than most solid tumors. Success with solid tumors has been limited because low tumor uptake of radiopharmaceuticals has necessitated using high doses, which in turn cause bone marrow toxicity (7-10). There is mounting evidence, however, that RIT may be useful as an adjuvant therapy to control micrometastatic disease (11-13). An important aspect in selecting a radionuclide for RIT is the energy of the [3 decay, which determines the range of the particle in tissue. The most abundant [3decay of 131I (0.606 MeV; 82%) has a maximum range in tissue of about 2-3 mm, whereas 9Oy (2.27 MeV; 100%) has a much larger 13 decay energy and consequently a maximum range in tissue of --11 mm. Thus, for tumors with diameters less than 1 cm, much of the radiation of a 9Oy decay may not be deposited in the tumor, but in surrounding tissue. There are a number of other 13emitting radionuclides that are currently being evaluated in humans, including ('7Cu, la6Re, 188Re, and t77Lu (6, 13-15). Our research in the field of RIT has focused on the use of ('4Cu as a radionuclide for RIT and targeted radiotherapy. 64Cu decays by [3 + (0.655 MeV; 19%), [3 (0.573 MeV; 40%), and electron capture (1.68 MeV; 43%), which enables diagnostic imaging by positron emission tomography and radiotherapy with the same isotope. In RIT studies, we have shown that both 64Cuand 67Cu-labeled MAb 1A3 (('7Cu: q/2 = 62 h; 100% [3-) exhibited complete tumor growth inhibition in a well-established animal model (16). An interesting aspect of our studies is that 64Cu and 67Cu demonstrated very similar lethal efficiency despite different decay schemes (16, 17). We also showed that considerably lower absorbed doses were required for 64Cuand 67Cu-labeled MAbs to effect complete tumor remission compared to doses reported for both J3 li_ and 9~ MAbs in similar animal models (16). In this study, we determined the MTD of ('4Cu-BAT-2IT1A3 in hamsters. Additionally, the efficacy of 64Cu-BAT-2IT3 The abbreviations used are: RIT, radioimmunotherapy; BAT, bromoacetamidobenzyl1,4,8,11-tetraazacyclotetradecane-N,N',N",N"tetraacetic acid; MAb, monoclonal antibody; MTD, maximum tolerated dose; 2IT, 2-iminothiolane. Research. on October 16, 2017. © 1999 American Association for Cancer clincancerres.aacrjournals.org Downloaded from 3208s MTD and Large Tumor RIT Studies of MAb 1A3