Abstract 4562: Superior targeting of the human epidermal growth factor receptor 2 (HER-2) with recombinant monoclonal antibody mixtures

Abstract

Abstract Human epidermal growth factor receptor 2 (HER2) is involved in development and maintenance of malignant phenotypes of several human cancers and therefore represent an attractive therapeutic target. Trastuzumab is currently the only anti-HER2 antibody approved for treatment of human cancers and although succesful more efficacious treatments are warranted. Mixtures of recombinant monoclonal antibodies are promising candidates as the next generation of antibody therapeutics due to their multipotent activities. The aim of the present study was to identify mixtures of anti-HER2 antibodies with superior activity to existing monoclonal antibodies. Anti-HER2 antibodies were raised in mice by immunizations with HER-2 in different antigen presenting formats. A large antibody repertoire consisting of approximately 150 unique anti-HER-2 antibodies was cloned from the mice using the mSymplex™ technology. Based on a thorough sequence and binding analysis, 40 antibodies were selected for functional evaluation. The 40 antibodies were tested as individual antibodies and in mixtures of two and three for the ability to inhibit the growth of four human cancer cell lines using a standard viability assay. In total, more than 1300 mixtures were evaluated for ability to inhibit growth of the four cell lines. The 20 mixtures with the highest levels of growth inhibition were further characterized with regard to potency (IC50) and ability to engage in ADCC and CDC. The results demonstrated that HER2 mixtures were superior to trastuzumab, pertuzumab and the mixture of the two at inhibiting the growth of seven of the 10 cell lines investigated. Interestingly, the mixtures also inhibited the growth of the trastuzumab resistant breast cancer cell line HCC202, reflecting the differentiated mechanisms of anti-HER2 antibody mixtures. In vivo, anti-HER2 mixtures had superior activity compared to the monoclonal anti-HER2 antibody trastuzumab in two models of human gastric cancer. Based on these results, a candidate mixture was selected and referred to as Sym005. In conclusion, these data demonstrate that the novel antibody mixture Sym005 has a unique set of HER2 inhibitory mechanisms, which translates into superior anti-cancer activity in HER2-positive tumor xenografts. Furthermore, the results provide a clear rationale for evaluation of Sym005 in clinical trials on patients with HER2 positive tumors. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 4562. doi:10.1158/1538-7445.AM2011-4562