Bispecific antibody and bivalent hapten radioimmunotherapy in CEA-producing medullary thyroid cancer xenograft.

摘要

The purpose of this study was to compare the toxicity and efficacy of two-step radioimmunotherapy using a bispecific anticarcinoembryonic antigen (CEA)/anti-diethylenetriamine pentaacetic acid (DTPA) antibody (F6-734 bispecific monoclonal antibodies (BsMAbs) and an 131I-di-DTPA-TL bivalent hapten with F(ab')2 fragments of the same directly labeled anti-CEA 131-F6. METHODS: Eight groups of nude mice subcutaneously grafted with the human TT medullary thyroid cancer cell line were injected once tumor volume reached about 200 mm3. Two groups received 37 or 92.5 MBq (1 or 2 nmol) 131I-di-DTPA-TL 48 h after injection of 2 or 4 nmol F6-734 BsMAb and two groups received 37 or 92.5 MBq (250 microg) 131I-F6. Four control groups were treated respectively with (a) 92.5 MBq nonspecific 131I-734 fragments, (b) 92.5 MBq 131I-di-DTPA-TL 48 h after injection of a mixture of irrelevant F6-679 (anti-CEA/anti-histamine) and G7A5-734 (anti-melanoma/anti-DTPA) BsMAb, (c) 250 microg nonradiolabeled F6, and 250 microg F6-734 BsMAb and then 48 h later 1.25 nmol of nonradiolabeled hapten. A control group received no injections. Toxicity was evaluated by determining animal weight and the number of leukocytes and platelets, and efficacy by variation in tumor volume and thyrocalcitonin during a 90-d period. Histological analysis of tumors and statistical studies were performed. RESULTS: The time required for the tumor to double in size was respectively 57 and 86 d with 37 and 92.5 MBq F6-734/131I-di-DTPA-TL and 44 and 65 d with 37 and 92.5 MBq 131I-F6. Changes in thyrocalcitonin levels were parallel to those in tumor volume. Weight loss was 5%, leukocyte nadirs respectively 1640+/-838 and 1560+/-1160/mm3 and platelet nadirs 1.46+/-0.52 10(6)/mm3 and 0.73+/-0.38 10(6)/mm3 after injections of 37 and 92.5 MBq F6-734/1311-di-DTPA-TL. Weight loss was respectively 8% and 16%, leukocyte nadirs 50+/-100/mm3 and 175+/-50/mm3 and platelet nadirs 0.71+/-0.18 10(6)/mm3 and 0.48+/-0.11 10(6)/mm3 after injections of 37 and 92.5 MBq 131I-F6. CONCLUSION: Two-step radioimmunotherapy was as efficient as the one-step system and markedly less toxic.