Rapid Generation and Screening of Novel Bi-Specific Single-Chain FV molecules Capable of Inhibiting the Growth of Breast Cancer

摘要

Antibodies that perturb signal transduction of cancer cells have demonstrated significant utility in the treatment of breast cancer and lymphoma. As signal transduction in the Epidermal Growth Factor Receptor (EGFR) family (EGFR, HER2, HER3, HER4) involves ligand binding and subsequent heterodimerization of two members, the most potent monoclonal antibody (MAb)- based agent would likely be one that also mediates a similar crosslinking event. The fundamental hypothesis underlying this Concept Award Project was that signal transduction through components of the EGFR family could he manipulated through the construction of novel bispecific antibodies that engage multiple epitopes of this family. The goals of this proposal were to develop a novel, rapid methodology to create bispecific single-chain Fv (bs-scFv) molecules using molecular shuffling of two large groups of scFv (libraries) specific for EER2 and HER3 and to perform preliminary evaluations of the in vitro specificity and anti-tumor effects against cells that over express both target antigens.