Bispecific agents target endogenous murine T cells against human tumor xenografts

A variety of immunological approaches to cancer treatment are currently bei ng explored. These include strategies designed to enhance or redirect the a ctivity of T cells against tumors. Bispecific antibodies comprise a class o f agents capable of redirecting T cells by binding to a tumor antigen and t he T-cell receptor (TCR). In vivo pre-clinical testing of bispecific antibo dies against human tumors has to date been limited to the use of immunodefi cient mice that receive the bispecific agent, activated human effector T ce lls, and human tumor cells. In this report, we show that TCR transgenic/RAG -1 knockout mice (TCR/RAG) serve as a unique model allowing endogenous T ce lls to be redirected against transplanted human tumors, The findings show t hat TCR/RAG mice (i) accepted transplants of human tumors, including the fo late-receptor-positive tumor line KB; (ii) contained endogenous cytotoxic T lymphocytes that could be activated in vivo with an antigenic peptide reco gnized by the transgenic TCR; (iii) rejected human tumors after treatment w ith the activating peptide and bispecific agents that contained folic acid co-valently linked to an anti-TCR antibody, Successful rejection was achiev ed with folate conjugates of Fab or scFv fragments. Treatment with activati ng agents and bispecific conjugates resulted in the complete eradication of freshly transplanted tumors as well as significantly prolonging the surviv al of mice bearing established solid tumors. Our results highlight the impo rtance of including T-cell-activating modalities in combination with bispec ific antibodies. Additionally, we introduce a system that allows endogenous T cells to be redirected against human tumor xenografts and in which the T cells may be followed in vivo by use of a clonotypic marker. (C) 1999 Wile y-Liss, Inc.