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Tumor Cell Targeting with Antibody-Avidin Complexes and Biotinylated Tumor Necrosis Factor ¹

Dipartimento di Ricerca Biologica e Tecnologica, San Raffaele Hospital Scientific Institute, via Olgettina 58, 20132 Milan [M. M., M. P., G. F., P. D., G. C., A. C.]; European Institute of Oncology, 20141 Milan [G. P.]; and Department of Biology and Genetics for Medical Sciences, University of Milan, 20132 Milan [A. G. S.], Italy

Tumor pretargeting with biotinylated antibodies and avidin, followed by a delayed delivery of radioactive-labeled biotin, is currently used for in vivo diagnosis and therapy in cancer patients. Herein, we describe the use of a three-step antibody/avidin targeting approach to increase the local concentration and the persistence of biotinylated human tumor necrosis factor (bio-TNF) on a mouse tumor. Mouse RMA lymphoma cells were transfected with the Thy 1.1 allele (RMA-Thy 1.1) to generate a unique tumor-associated antigen. In vitro pretargeting of RMA-Thy 1.1 cells with the biotinylated anti-Thy 1.1 monoclonal antibody 19E12 (bio-19E12) and NeutrAvidin increased the amount of bio-TNF that bound to the cell (10–20 times in comparison with non-pretargeted cells), as well as its half-life on the surface (> 30 times). Furthermore, cell pretargeting reduced by more than 2 orders of magnitude the LD₅₀ of bio-TNF in a cytolytic assay with actinomycin D. Finally, RMA-Thy 1.1 cells, pretreated in vitro with bio-TNF according to the three-step procedure and injected into syngeneic C57/BL6 mice, were less tumorigenic than controls.

These results indicate that the three-step targeting approach markedly increases the amount and the persistence of bio-TNF on the cell surface and that cell-bound bio-TNF can trigger cytolytic effects in vitro and antitumor effects in vivo. Tumor pretargeting with biotinylated antibodies and avidin could be a novel strategy for increasing the therapeutic index of TNF.

¹ This work was supported by Associazione Italiana Ricerca sul Cancro (AIRC). M. M. was recipient of a fellowship from AIRC.

² To whom requests for reprints should be addressed.

Received 11/ 7/96. Accepted 3/24/97.

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