Engineering of antibodies simultaneously targeting multiple cancer-associated cell surface receptors
Dysregulation of the epidermal growth factor receptor(EGFR) is a driving factor in the development of many types of cancer, making it a strong candidate for targeting in anti-cancer therapies. However, existing EGFR-based therapies, while initially successful in certain cases, become ineffective due to the emergence of secondary resistance mechanisms in the tumor. ErbB3, another receptor in the EGFR family, has been implicated in many of these resistances, and presents a new target for the development of more effective EGFR-based treatments.
We have previously designed binders against EGFR using the tenth domain of type 3 fibronectin (Fn3) as a protein scaffold, and have developed a novel antibody-like construct in which these EGFR binders have been joined to an existing EGFR-targeting antibody. This triepitopic antibody-Fn3 fusion has been shown to control the growth of tumors in preclinical studies. Our current studies aim to expand the established antibody-Fn3 platform through the engineering of novel antibodies with dual specificity for EGFR and ErbB3, which will be used with our existing EGFR Fn3 binders. Through use of both in vitro experiments assaying signaling and receptor levels, as well as in vivo experiments observing efficacy in controlling tumor growth, we will validate these therapeutics’ success as a means of subverting resistance to EGFR-based treatments.