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Targeting of Interleukin 2 to Human Ovarian Carcinoma by Fusion with a Single-Chain Fv of Antifolate Receptor Antibody¹

Division of Experimental Oncology "D" [C. M., D. N., V. R., G. P., M. P. C.] and "E" [M. F., E. L., S. C.], Istituto Nazionale Tumori, 20133 Milan, Italy; Immunochemistry Unit, DIBIT, H. S. Raffaele, 20132 Milan, Italy [G. C.]; and Department of Immunology, The Weizmann Institute of Science, 76100 Rehovot, Israel [Z. E.]

To provide a new tool for the immunotherapy of human ovarian carcinoma, we constructed a fusion protein between interleukin-2 (IL-2) and the single-chain Fv (scFv) of MOV19, a monoclonal antibody directed against -folate receptor (-FR), known to be overexpressed on human nonmucinous ovarian carcinoma. This was accomplished by fusing the coding sequences in a single open reading frame and expressing the IL-2/MOV19 scFv chimera under the control of the murine immunoglobulin promoter in J558L plasmacytoma cells. The design allowed the construction of a small molecule combining the specificity of MOV19 with the immunostimulatory activity of IL-2. This might improve the tissue penetration and distribution of the fusion protein within the tumor, reduce its immunogenicity, and avoid the toxicity related to the systemic administration of IL-2. The IL-2/MOV19 fusion protein was stable on purification from the cell supernatant and was biologically active. Importantly, this construct was able to target IL-2 onto the surface of -FR-overexpressing tumor cells and stimulated the proliferation of the IL-2-dependent CTLL-2 cell line as well as that of human resting peripheral blood lymphocytes. In a syngeneic mouse model, IL-2/MOV19 scFv specifically targeted -FR gene-transduced metastatic tumor cells without accumulating in normal tissues, due to its fast clearance from the body. Prolonged release of IL-2/MOV19 scFv by in vivo transplanted J558-EF6.1 producer cells protected 60% of mice from the development of lung metastases caused by an i.v. injection of -FR gene-transduced tumor cells. Moreover, treatment with IL-2/MOV19 scFv, but not with recombinant IL-2, significantly reduced the volume of s.c. tumors. The pharmacokinetics and biological characteristics of IL-2/MOV19 scFv might allow us to combine the systemic administration of this molecule with the adoptive transfer of in vitro retargeted T lymphocytes for the treatment of ovarian cancer, thereby providing local delivery of IL-2 without toxicity.

¹ Supported by the Associazione Italiana Ricerca sul Cancro and the Italian Ministry of Health.

² To whom request for reprints should be addressed, at Division of Experimental Oncology "D," Istituto Nazionale Tumori, via Venezian 1, 20133 Milan, Italy. E-mail: melani@istitutotumori.mi.it.

³ Present address: Argonex Pharmaceuticals, Inc., 706 Forrest Street, Charlottesville, VA 22903.

Received 5/ 1/98. Accepted 7/17/98.

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