RECOMBINANT BISPECIFIC ANTITUMOR MOLECULES

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The overall goal of this project is to develop a model system using an innovative protein-based therapy for the treatment of human cancer. To achieve this goal, we will construct bispecific molecules which are comprised of a single-chain T cell receptor (scTCR) linked to a single- chain antibody molecule(scFv). These bispecific hybrid molecules will be used to form a bridge between the effector T cells and the tumor cells. Effector T cells are activated by crosslinking with the scFv portion of the hybrid molecule and binding of tumor cells is dependent on the tumor specific scTCR portion of the hybrid molecule which recognizes a processed tumor antigen in the context of HLA antigens. Activation of effector T cells during this bridging process are anticipated to cause lysis of the scTCR targeted tumor cell. The scTCR used in our bispecific hybrid molecule recognizes a naturally processed peptide derived from human wild-type p53 in the context of HLA-A2.1. To evaluate the efficacy of tumor suppression by these hybrid molecules in vitro, we will carry out T cell cytotoxic assays using human tumor cells. In addition, studies will be carried out to measure the anti- tumor activity of these hybrid molecules in a model system using SCID mice implanted with human tumors overexpressing p53 antigen. The results from these studies should provide valuable information regarding the anti-tumor activity of the bispecific hybrid molecules and will be useful in determining their potential efficacy in treatment of human cancer. PROPOSED COMMERCIAL APPLICATION The goal of this proposal is to establish whether our bispecific hybrid molecules are efficacious against human tumor cells by testing for anti- tumor activity in vitro and in a model system using SCID mice implanted with human tumors. Results from these studies will then be used to devise humanized scTCR/scFv bispecific molecules for the treatment of human malignant diseases.