Abstract
Abstract Members of the human epidermal growth factor receptor (HER)-family, i.e. EGFR, HER2, and HER3, are key oncogenic drivers in numerous cancer forms. Monoclonal antibody therapeutics targeting EGFR and HER2 have been clinically approved and HER3-targeting antibodies are in clinical development. However, resistance to single HER treatment occurs due to mechanisms such as incomplete target elimination and a switch of receptor dependency in the resistant cancer cell population. Another potential escape mechanism for the cancer cells to become resistant and maintain oncogenic signaling is receptor heterodimerization. It is therefore relevant to investigate how heterodimers can be downregulated when targeted with antibodies against a single or multiple HER targets. It is well established that mixtures of two or more antibodies against a single HER family receptor induce superior and rapid receptor downregulation and elimination compared with monoclonal antibodies. However, the effect of antibody mixtures on HER heterodimer distribution has not been investigated. At Symphogen, we have generated Pan-HER, a combination of two EGFR-, two HER2-, and two HER3-targeting monoclonal antibodies with non-overlapping epitopes in a single drug compound. Detection and quantification of the HER family member distribution in selected cancer cell lines, as well as proliferation assays with combinations of the antibody components comprising Pan-HER have been performed to investigate the effects of 2-, 4- and 6-mixtures of antibodies. Results from studies focusing on characterization of receptor levels, surface expression and heterodimer formation in Pan-HER responsive cancer cell lines will be presented, as well as the effect of Pan-HER on receptor heterodimer distribution, investigated by Co-IP and Duolink Proximity Ligation Assay technology. Our results show that mixtures of antibodies against more than one HER family member potently downregulate the HER family receptor levels and significantly alter the HER family heterodimerization pattern upon short- and long-term exposure to HER-targeting antibodies. Citation Format: Sofie Ellebæk, Thomas Bouquin, Michael V. Grandal, Michael Kragh, Thomas T. Poulsen. Effect of antibody mixtures on HER-family heterodimerization. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 655. doi:10.1158/1538-7445.AM2014-655
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