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Bispecific Antibody and Bivalent Hapten Radioimmunotherapy in CEA-Producing Medullary Thyroid Cancer Xenograft

INSERM Research Unit 463, Anatomopathology Department and Regional Cancer Center, Nantes
Immunotech SA, Marseille, France

Correspondence: For correspondence or reprints contact: Françoise Kraeber-Bodéré, MD, Research Unit, 463 INSERM, Institut de biologie, 9, quai Moncousu, Nantes 44093, Cedex 01, France.

ABSTRACT

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 ¹³¹I-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 µg) 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 (antimelanoma/anti-DTPA) BsMAb, (c) 250 µg nonradiolabeled F6, and 250 µg 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 ± 0.52 10⁶/mm³ and 0.73 ± 0.38 10⁶/mm³ after injections of 37 and 92.5 MBq F6-734/¹³¹I-di-DTPA-TL. Weight loss was respectively 8% and 16%, leukocyte nadirs 50 ± 100/mm³ and 175 ± 50/mm³ and platelet nadirs 0.71 ± 0.18 10⁶/mm³ and 0.48 ± 0.11 10⁶/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.

Key Words: radioimmunotherapy • bispecific antibody • two-step targeting • medullary thyroid cancer

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