Abstract 770: Lorvotuzumab mertansine (IMGN901) immune effector activity and its effect on human NK cells

Abstract

Abstract Lorvotuzumab mertansine, or IMGN901, is a conjugate consisting of the cytotoxic maytansinoid, DM1, covalently linked to the monoclonal antibody, lorvotuzumab, which selectively targets CD56 (also called neural cell adhesion molecule or NCAM). This conjugate is currently being evaluated in clinical trials for the treatment of CD56+ solid tumors and multiple myeloma. It is able to inhibit tumor cell growth by disruption of microtubule dynamics through delivery of its cytotoxic DM1 payload; however, other potential cell killing mechanisms, such as the immune effector activity of its antibody component, have not been fully investigated. Herein, we report on the immune effector activity of the lorvotuzumab antibody and the lorvotuzumab mertansine conjugate and their effect on the function of CD56+ human primary NK cells in vitro. To investigate the effector activity of the antibody, lorvotuzumab was incubated with CD56+ tumor target cells in the presence of rabbit complement or purified human primary NK cells. The results show that this antibody fails to mediate complement dependent cytotoxicity (CDC) but induces antibody-dependent NK cell-mediated cytotoxity (ADCC) in dose-dependent manner. The complete conjugate showed ADCC activity comparable to lorvotuzumab alone, suggesting that DM1 conjugation did not alter the interaction between the Fc domain of the antibody and NK cell's Fc receptor. Since human primary NK cells express CD56, albeit at a low level, we tested whether lorvotuzumab mertansine or its antibody component could negatively impact the function of NK cells. The results demonstrate that incubation with this antibody or with this conjugate has no effect on rituximab-mediated ADCC activity of the NK cells. Furthermore, overnight exposure of human primary NK cells with lorvotuzumab mertansine did not change rituximab-mediated ADCC activity. In conclusion, the lorvotuzumab antibody has ADCC activity that is retained after DM1 conjugation. Furthermore, neither lorvotuzumab nor its DM1 conjugate, appear to affect the ability of NK cells (which are CD56+) to mediate ADCC through another antibody. 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 770. doi:10.1158/1538-7445.AM2011-770