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Two-Step Targeting and Dosimetry for Small Cell Lung Cancer Xenograft with Anti-NCAM/Antihistamine Bispecific Antibody and Radioiodinated Bivalent Hapten

Saitama Medical Center, Saitama Medical School, Saitama
Osaka City University, Osaka, Japan
INSERM Research Unit 463, Nantes
Immunotech SA, Marseille, France

Correspondence: For correspondence or reprints contact: Makoto Hosono, MD, PhD, Department of Radiology, Saitama Medical Center, Kamoda, Kawagoe, Saitama 350-8550, Japan.

ABSTRACT

The "affinity enhancement system," a two-step targeting technique using bispecific antibody and radiolabeled bivalent hapten, has been reported to be useful for carcinoembryonic antigen-expressing tumors. The purpose of this study was to evaluate the efficacy of this method for targeting human small cell lung cancer using an antineural cell adhesion molecule antibody. Methods: Antineural cell adhesion molecule/antihistamine bispecific anti body NK1NBL1-679 was prepared by coupling an equimolecular quantity of a Fab' fragment of NK1NBL1 to a Fab fragment of antihistamine 679. Athymic mice inoculated with NCI-H69 small cell lung cancer cells expressing neural cell adhesion molecule were administered bispecific antibody and then 48 h later ¹²⁵I-labeled bivalent histamine hapten. ¹²⁵I-labeled intact NK1NBL1 was injected into other groups of mice. Biodistributions were examined as a function of time. Results: In mice of the two-step targeting, tumor uptake was 2.5 ± 0.2, 3.2 ± 0.4, 6.4 ± 2.0, 7.2 ± 2.7, 6.1 ± 2.1 and 2.2 ± 0.4 %ID/g at 5, 30 min, 5, 24, 48 and 96 h, and tumor-to-blood, tumor-to-liver and tumor-to-kidney ratios were 1.4 ± 1.1, 10.8 ± 13.2 and 4.6 ± 4.7, respectively, at 5 h, whereas ¹²⁵I-labeled NK1NBL1 showed a tumor uptake of 5.7 ± 0.4 %ID/g and tumor-to-blood, tumor-to-liver and tumor-to-kidney ratios of 0.3 ± 0.1, 1.1 ± 0.2 and 0.9 ± 0.1, respectively, at 5 h. These results were confirmed by autoradiographic studies, which demonstrated clear tumor-to-normal tissue contrast. Dosimetry showed that the affinity enhancement system could enhance the therapeutic potential of the antineural cell adhesion molecule antibody NK1NBL1. Conclusion: This two-step targeting method seems promising for the diagnosis and therapy of small cell lung cancer.

Key Words: small cell lung carcinoma • antineural cell adhesion molecule/antihistamine bispecific antibody • pretargeting • affinity enhancement system

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