Radioimmunolocalization of human carcinoma xenografts with B72.3 second generation monoclonal antibodies (original) (raw)
Related papers
PubMed, 1990
212Bi is a radioisotope that emits highly cytotoxic alpha-particles. alpha-particles have a high linear energy transfer over a short path length. These properties and the 1-h half-life make this isotope suitable for radioimmunotherapy of peritoneal tumors. Therefore, we wanted to test whether monoclonal antibodies labeled with 212Bi would be effective in treating such tumors. We conjugated the antibody B72.3, which is reactive with many human adenocarcinomas, to the chelator linker glycyltyrosyl-lysyl-N-epsilon-diethylenetriaminepentaacetic acid, by reductive amination to the carbohydrate residues of the antibody (J. Rodwell, et al. Proc. Natl. Acad. Sci. USA, 83: 2632-2636, 1986). Athymic nude mice were injected i.p. with LS174T cells, a human colon cancer cell line. Seven to 13 days later the mice were treated with the 212Bi-labeled antibody. We treated the mice using single doses of 180-450 microCi or multiple doses of 80-180 microCi on consecutive days. Dissections were performed 9-16 days after the end of treatment. Both the single and multiple doses resulted in a decrease in tumor burden when compared to tumor from mice receiving unlabeled antibody. Mice in the optimum group showed tumor reductions of greater than 90%. Treatment with a 212Bi-labeled irrelevant antibody was significantly less effective than that with labeled B72.3 antibody. Survival studies showed that mice receiving the labeled antibody had a prolonged survival when compared to control mice.
European Journal of Cancer and Clinical Oncology, 1987
antibody (MAb) B72.3 has been linked successfully to several radio-n&ides forming stable complexes and analyzed in vitro and in vivo without significant loss of its immunoreactivi&. 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 me&static colorectal carcinomas. The high degree of selective binding of this MAb has led us to investigate its potential as a radioimmutwtherapeutic agent. Athymic mice bearing human colon car&toma xenografts were injected with either 300 or 500 @i of '3'I-B72.3 IgG to assess the effect of the radiolabeled MAb on the tumor growth as well as potential toxic side effects in vital organs. In mice treated with the '3'I-B72.3 IgG, a marked inhibition of the growth of the human colon carcinoma xenograft was noticed in comparison with control mice injected with PBS or control mice that received unlabeled B72.3 IgG. Th 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 significantb less radioactivity than the medial areas composed of predominantly nonviable tissue; these&dings 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.
Labeled Monoclonal Antibody A33 in a Human Colon Cancer Xenograft
2000
A33, a monoclonal antibody that targets colon carcinomas, was labeled with 125 I or 131 I and the relative therapeutic efficacy of the 2 radiolabeled species was compared in a human colon cancer xenograft system. Methods: Nude mice bearing human SW1222 colon carcinoma xenografts were administered escalating activities of 125 I-A33 (9.25-148 MBq) or 131 I-A33 (0.925-18.5 MBq), 125 I-and 131 I-labeled control antibodies, unlabeled antibody, or no antibody. The effects of treatment were assessed using the endpoints of tumor growth delay and cure. Results: Tumor growth delay increased with administered activity for all radiolabeled antibodies. Approximately 4.5 times more activity was required for 125 I-A33 to produce therapeutic effects that were equivalent to those of 131 I-A33. This ratio was approximately 7 for a nonspecific, noninternalizing isotypematched, radiolabeled control antibody. Unlabeled A33 antibody had no effect on tumor growth. Approximately 10 times more activity of 125 I-A33 produced toxicity similar to that of 131 I-A33, and this ratio fell to approximately 6 for radiolabeled control antibody. Conclusion: Treatment with 125 I-A33 resulted in a relative therapeutic gain of approximately 2 compared with 131 I-A33 in this experimental system.
Journal of nuclear medicine : official publication, Society of Nuclear Medicine, 1986
F(ab')2 fragments of monoclonal antibodies (MAbs) GA 73-3 and CO 29.11, with specific binding reactivity in vitro to human tumors of the gastrointestinal tract, were radioiodinated and injected into nude mice bearing human colon carcinoma xenografts. Fragments of both MAbs preferentially localized in tumor tissue compared with normal mouse tissue, as determined by differential tissue counting of radioactivity. The fragments localized specifically only in those tumors to which they bind in vitro and not in unrelated tumors. Radiolabeled fragments of an anti-hepatitis virus MAb did not localize in the tumors. Whole-body scintigraphy demonstrated tumor localization with 131I-labeled fragments without background subtraction. Best tumor contrast, as quantitated by analyzing digital computer scans, was obtained between Days 2 and 5 after injection. Tumor contrast was significantly enhanced when a mixture of both MAb F(ab')2 fragments was used. The biologic half-life of the MAb mix...
Radioimmunotherapy of Human Colon Cancer Xenografts with 131I-Labeled Anti-CEA Monoclonal Antibody
Bioconjugate Chemistry, 2010
Purpose: Therapeutic efficacy, suitable dose, and administration times of 131 I-CAb 1 F(ab=) 2 , a new monoclonal antibody therapeutics specifically directed against a cell surface-associated glycoprotein of colon cancer, were investigated in this article. Methods and Materials: In human colon cancer xenografts, 131 I-CAb 1 F(ab=) 2 at the dose of 125 Ci, 375 Ci, and 1125 Ci were administrated intraperitoneally on Days 6 and 18 after implantation of HR8348 cells with CAb 1 high reactivity. Survival time and tumor growth inhibition rate were used to evaluate the efficacy and safety of 131 I-CAb 1 F(ab=) 2 in treatment of colon cancer xenografts. Results: Treatment of 125, 375, and 1125 Ci 131 I-CAb1 F(ab=) 2 did not significantly decrease the mean survival time of nude mice when compared with nontreated groups (p ؍ 0.276, 0.865, 0.582, respectively). Moreover, the mean survival times of nude mice receiving 375 Ci and 1125 Ci 131 I-CAb1 F(ab=) 2 were significantly longer than that of 5-FU-treated groups (p ؍ 0.018 and 0.042). Tumor growth inhibition rates of the first therapy were 35.67% and 41.37%, with corresponding 131 I-labeled antibody dosage of 375 Ci and 1125 Ci. After single attack dosage, second reinforcement therapy may rise efficacy significantly. Tumor growth inhibition rates of 125 Ci, 375 Ci, and 1125 Ci 131 I-labeled antibody on Day 20 posttherapy were 42.65%, 56.56%, and 84.41%, respectively. Histopathology examination revealed that tissue necrosis of various degrees was found in 131 I-CAb1 F(ab=) 2-treated groups. Conclusion: 131 I-CAb 1 F(ab=) 2 is safe and effective for colon cancer. It may be a novel and potentially adjuvant therapeutics for colon cancer.
Cancer research, 1990
Monoclonal antibody (MAb) B72.3 was generated using a membrane-enriched fraction of a human mammary carcinoma biopsy. It has demonstrated reactivity to the majority of human adenocarcinomas including colorectal, gastric, pancreatic, ovarian, endometrial, mammary, and nonsmall cell lung cancer as well as weak or nondetectable reactivity to the majority of normal adult tissues, with the exception of secretory endometrium. Radiolabeled B72.3 has demonstrated MAb localization of carcinoma in approximately 70% of several hundred colorectal and ovarian carcinoma patients. The B72.3-reactive antigen, tumor-associated glycoprotein 72, has been purified from a human colon cancer xenograft and used as an immunogen to generate second generation MAbs. Twenty-eight of these MAbs, designated CC (colon cancer), were shown to be reactive with tumor-associated glycoprotein 72; direct-binding radioimmunoassays, Western blotting, live cell surface binding assays, liquid competition radioimmunoassays, ...
Nuclear Medicine and Biology, 1993
The therapeutic effects of '251-labelled (18-97 MBq) monoclonal antibodies (MAb) C-242, C-2 15 and S-S. 1 were studied in nude mice with human colorectal adenocarcinoma tumours. The antibodies were administered 2 or lo-16 days after implantation of the tumour cells. The monoclonal antibody C-242 was internalized into the tumour cells, C-21 5 was internalized to a lower degree while S-S. 1 (unspecific MAb) was not internalized at all. No enhanced therapeutic effect of '2s1-C-242 was observed, as a result of Auger electrons, compared with '25I-C-215 and "'1-S-S. 1
Cure of metastatic human colonic cancer in mice with radiolabeled monoclonal antibody fragments
Clinical cancer research : an official journal of the American Association for Cancer Research, 2000
There is currently no method to cure patients with disseminated colorectal cancer, which is the third leading cancer killer in the Western World. This report shows that the GW-39 intrapulmonary micrometastatic human colonic cancer model in nude mice can be cured with radiolabeled antibodies against carcinoembryonic antigen, and that this approach of radioimmunotherapy is superior to conventional chemotherapy with 5-fluorouracil and leucovorin (5-FU/LV). Monovalent Fab fragments labeled with 131I are superior to intact IgG when survival was evaluated 3, 7, and 14 days after implantation, leading to cures in up to 90% of the mice. Histological results provide support for the differences in therapeutic efficacy observed. Microautoradiography was used to evaluate the intratumoral distribution of each form of antibody. The enhanced tumor control by Fab compared with IgG could be explained in part by the homogeneity of radioantibody distribution of Fab. Biodistribution analysis and initia...
International Journal of Radiation Oncology*Biology*Physics, 1993
The choice of radionuclide remains an important question in clinical radioimmunotherapy. Therefore, a study was initiated, using an in viva model system, to assess the relative merits of "'I-and "Y-labeled 17-IA monoclonal antibody as therapeutic agents in the treatment of colon cancer. 13'Iodine-and !"%-labeled 17-IA were assessed in animal therapy trials using athymic nude mice bearing LS174T human colon cancer xenografts. '3'Iodine-labeled 17-IA decreased tumor growth in a dose-dependent fashion without lethality. In contrast, the doses of WY-labeIed 17-IA which were required to produce a significant increase in tumor doubling time also caused marked toxicity.