Abstract 4569: Cell death-inducing ICAM-1 antibody has broad and potent anti-myeloma activity in vivo

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL We previously developed combined target and drug discovery methodology enabling isolation of tumor cell death-inducing antibodies from the human antibody library n-CoDeR®. Among several antibodies targeting different tumor cell associated receptors with documented cell death-inducing properties, antibodies specific for intercellular adhesion molecule-1 (ICAM-1) – a receptor not previously associated with tumor cell death- were obtained. We here characterize the ICAM-1 specific antibody BI-505 with respect to in vivo anti-tumor activity in different well-established tumor disease models, and explore mechanisms underlying its anti-tumor activity. We demonstrate in different tumor xenograft models that BI-505 is equally or more efficacious in preventing CD20 positive B cell tumor growth and in pro-longing tumor-bearing mouse survival compared to CD20 mAb Rituximab in vivo. Moreover, BI-505 showed significant anti-tumor activity against a panel of CD20 negative myeloma tumors in vivo, and BI-505 conferred enhanced mouse survival compared to the proteasome inhibitor bortesomib – approved for treatment of relapsed refractory multiple myeloma – in an experimental model of advanced multiple myeloma. Preliminary data indicate that the BI-505 epitope is highly expressed on myeloma cells in patients with multiple myeloma. The differential in vitro and in vivo anti-tumor activities of BI-505 Fc-variants correlated with binding to recombinant human FcγRIIIa and mouse FcγRIV receptors, respectively. These differences could not be explained by altered antigen-binding properties as all Fc-variants retained near identical EC50 values for binding to recombinant or cell surface expressed ICAM-1 protein. These observations are consistent with cell death and FcγR-dependent anti-tumor immunity being important mechanisms underlying BI-505 therapeutic activity. Collectively, our results demonstrate proof-of-principle for our human antibody based combined target and drug discovery methodology, and provide a rationale for further pre-clinical and clinical evaluation of BI-505 in the treatment of MM. An open multicenter phase I dose-escalation clinical trial with BI-505 in relapsed/refractory MM has recently started in the United States and Sweden. 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 4569. doi:10.1158/1538-7445.AM2011-4569