Abstract 2445: Involvement of neutrophils and natural killer cells in the anti-tumor activity of alemtuzumab in xenograft tumor models

Abstract

Abstract Alemtuzumab (Campath) is a recombinant humanized IgG1 monoclonal antibody directed against CD52, an antigen expressed at high levels on the surface of normal and malignant B and T lymphocytes. Alemtuzumab is approved for the treatment of B-cell chronic lymphocytic leukemia (B-CLL), but the exact mechanism by which the antibody depletes malignant lymphocytes in vivo is not clearly defined. To address this issue, the anti-tumor activity of alemtuzumab was studied in disseminated and subcutaneous xenograft tumor models. The density of CD52 target antigen on the surface of tumor cells appeared to be an important factor as an overall correlation was observed between the anti-tumor activity of alemtuzumab and levels of CD52 expression. Deglycosylation of alemtuzumab resulted in a loss of complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro and was found to abolish anti-tumor activity in vivo. Individual inactivation of these effector mechanisms in tumor-bearing mice indicated that the protective activity of alemtuzumab in vivo was primarily dependent on ADCC mediated by neutrophils and to a lesser extent NK cells, as evidenced by the loss of tumor growth inhibition caused by removal of these populations with antibodies to Gr-1 or asialo-GM-1, respectively. In contrast, inactivation of complement by treatment with cobra venom factor or depletion of macrophages using clodronate liposomes had no significant impact on the anti-tumor activity of alemtuzumab in vivo. Increasing the number of circulating neutrophils by treatment with G-CSF enhanced the anti-tumor activity of the antibody thus providing further evidence for the involvement of neutrophils as effector cells in the activity of alemtuzumab. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2445.