Abstract 4324: Maytansinoid conjugates of a novel type III anti-CD20 antibody with potent antitumor activity.

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Abstract Previously identified anti-CD20 antibodies have been classified as either Type I antibodies with lipid raft and complement-dependent cytotoxicity (CDC) activity or Type II antibodies with strong pro-apoptotic activity, but not both. We describe here a novel anti-CD20 antibody with a unique combination of functional properties that defines a new Type III anti-CD20 antibody classification. In addition, when conjugated to the potent, microtubule-acting maytansinoids DM1 or DM4, it demonstrated enhanced cell-killing activity. Novel anti-CD20 antibodies were generated by immunizing mice with CD20-positive cells. One of these murine monoclonal anti-CD20 antibodies demonstrated very strong pro-apoptotic activity against Ramos and Raji lymphoma cells in the absence of cross-linking agents, similar to the activity of Type II antibodies. The humanized version of the antibody, termed D1302A, had a stronger pro-apoptotic effect against Ramos cells than other CD20 antibodies tested including rituximab, tositumumab (B1) and GA101-NG (non-glycoengineered GA101/afutuzumab). Strikingly, D1302A also induced CD20-redistribution to lipid rafts and showed CDC activity similar to the Type I antibody rituximab, while the Type II antibodies tositumumab and GA101-NG lacked these activities. D1302A, rituximab, and ofatumumab demonstrated comparable antibody-dependent cell mediated cytotoxicity (ADCC) activity on Ramos cells with human natural killer effector cells. In vivo, D1302A showed strong efficacy in an SU-DHL-4 xenograft model (at 1 or 10 mg/kg x3) and was more active than rituximab. D1302A was conjugated to DM1 via the non-cleavable SMCC thioether linker and to DM4 via the sulfo-SPDB disulfide linker. The resulting antibody-drug conjugates retained all the functional activities of the unconjugated antibody including binding affinity, pro-apoptotic, CDC and ADCC activities, and showed enhanced and specific in vitro cytotoxicity against Granta-519 and Farage lymphoma cells. In vivo, single-dose treatment with maytansinoid conjugates of D1302A elicited enhanced activity in Daudi and SU-DHL-4 xenograft models as compared to the antibody alone and showed comparable efficacy as standard of care treatment regimens such as rituximab or rituximab + chemotherapy (R-CHOP). D1302A is a novel Type III anti-CD20 antibody that has the functional properties of both Type I (potent CDC activity) and Type II (strong pro-apoptotic activity) antibodies, together with ADCC activity. Conjugation of D1302A with maytansinoids further increases anticancer activity in vitro and in vivo, combining the potent antibody-produced activities with a fourth cytotoxic mechanism distinct from that of other CD20 targeted agents. Therefore, D1302A-maytansinoid conjugates provide a unique combination of anti-tumor activities and are promising therapeutic candidates for the treatment of CD20+ lymphomas and leukemias. Citation Format: Jutta Deckert, Peter U. Park, Yong Yi, Sharon Chicklas, Min Li, Erin K. Maloney, Rui Wu, Leanne Lanieri, Jennifer A. Coccia, Joe Ponte, Lingyun Rui, Daniel J. Tavares, Jan Pinkas, Thomas Chittenden. Maytansinoid conjugates of a novel type III anti-CD20 antibody with potent antitumor activity. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4324. doi:10.1158/1538-7445.AM2013-4324