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Immunotoxins Containing Recombinant Anti-CTLA-4 Single-Chain Fragment Variable Antibodies and Saporin: In Vitro Results and In Vivo Effects in an Acute Rejection Model¹

Pier-Luigi Tazzari^*, Letizia Polito, Andrea Bolognesi^2,, Maria-Pia Pistillo, Paolo Capanni, Giulio Lelio Palmisano, Roberto M. Lemoli, Antonio Curti, Luigi Biancone^¶, Giovanni Camussi^¶, Roberto Conte^*, Giovanni B. Ferrara and Fiorenzo Stirpe

^* Service of Transfusion Medicine, S. Orsola-Malpighi Hospital, Bologna, Italy; Department of Experimental Pathology and Institute of Haematology and Medical Oncology "Seràgnoli," University of Bologna, Bologna, Italy; Immunogenetics Laboratory, National Cancer Research Institute and Department of Oncology, Biology, and Genetics c/o Advanced Biotechnology Center, Genoa, Italy; and ^¶ Department of Internal Medicine, University of Turin, Turin, Italy

Immunotoxins containing recombinant human-derived single-chain fragment variable (scFv) reagents (83 and 40) against CTLA-4 (CD152) linked to saporin, a ribosome-inactivating protein, were prepared and tested on CD3/CD28-activated T lymphocytes, MLRs, CTLA-4-positive cell lines, and hemopoietic precursors. Immunotoxins induced apoptosis in activated T lymphocytes and were able to specifically inhibit MLR between T lymphocytes and dendritic cells. The 83-saporin immunotoxin also inhibited the T cell activation in an MLR between T lymphocytes and an EBV-positive lymphoblastoid B cell line. Toxicity tests on hemopoietic precursors showed little or no effects in inhibiting colonies’ growth. As the 83 scFv Ab was reactive also with activated mouse T lymphocytes, 83-saporin was tested in a model of tumor rejection consisting of C57BL/6 mice bearing a murine H.end endothelioma cell line, derived from DBA/2 mice. The lymphoid infiltration due to the presence of the tumor was reduced to a high extent, demonstrating that the immunotoxin was actually available and active in vivo. Thus, taking the results altogether, this study might represent a new breakthrough for immunotherapy, showing the possibility of targeting CTLA-4 to kill activated T cells, using conjugates containing scFv Abs and type 1 ribosome-inactivating protein.

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