T CELL RECEPTOR-BASED IMMUNOTHERAPEUTICS FOR CANCER

DESCRIPTION: (Adapted from the applicant's abstract) The overall goal of this project is to demonstrate proof-of-principle for using T-cell receptor (TCR)-based therapeutics in the treatment of cancer. To achieve this goal, they cloned a single chain TCR (scTCR) from a high avidity cytotoxic T lymphocyte (CTL) cell line derived from an HLA-A2 transgenic mouse. The TCR recognizes a naturally processed peptide fragment from human wild-type p53 in the context of HLA-A2.1. Recently, they expressed the TCR as a soluble single-chain TCR-kappa fusion protein in Chinese hamster ovary (CHO) cells. The purified protein has been characterized and its affinity constant (Kd=107 M-1) has been determined. Due to its high affinity (especially its longer dissociation half-life), they proceeded to use this scTCR-kappa fusion protein for preparation of an immunoconjugate. The process involved cross-linking doxorubicin (Dox) molecules onto the scTCR-kappa fusion protein using a proprietary coupling technology. To evaluate the efficacy of tumor suppression by this novel immunoconjugate in vitro, they will carry out cytotoxic assays using peptide-pulsed cells, and later, human breast carcinoma cell lines. In addition, studies are proposed to measure the anti-tumor activity of the TCR-Dox immunoconjugate using two different murine systems. These models are proposed to provide valuable information on the dosage and route of administration for the TCR-Dox conjugate and generate preliminary in vivo data to support proof-of-principle for using scTCR-conjugates in the treatment of human cancer. PROPOSED COMMERCIAL APPLICATION: NOT AVAILABLE