Abstract 2830: Antibody and linker selection for the anti-CD37 antibody-maytansinoid conjugate IMGN529 for the treatment of B-cell malignancies

Abstract

Abstract CD37 represents an attractive target for an antibody-maytansinoid conjugate (AMC) due to its prevalence in B-cell malignancies, such as non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL), and its restricted expression on normal tissue, where it is mainly found on B-cells in blood and lymphoid tissues. Additionally, since antibodies to CD37 have been described to have anti-tumor activity, this target has potential for the development of an AMC containing a functional antibody. To select the antibody for this AMC, a large panel of anti-CD37 antibodies was generated by immunizing mice with CD37+ cells. Anti-CD37 antibodies were selected based on their superior ability to induce apoptosis in Ramos and Raji cells in comparison to the anti-CD20 antibody, rituximab, and the anti-CD37 SMIP, TRU-016. Surprisingly, unlike TRU-016, these antibodies had potent apoptotic activity in the absence of cross-linking agent. After humanization by variable domain re-surfacing, the selected antibodies retained high affinity binding to CD37+ B-cells with an EC50 of < 1 nM. They had much stronger pro-apoptotic activity than rituximab against Ramos cells, with the K7153A antibody among those with the best EC50. They all had antibody-dependent cell-mediated cytotoxicity (ADCC) activity, with K7153A having the most potent activity against Daudi cells. When SMCC-DM1 conjugates of humanized antibodies were compared, the K7153A-SMCC-DM1 conjugate had the most potent specific cytotoxicity against Daudi and Granta-519 cells in vitro. Therefore, the K7153A anti-CD37 antibody provided the best overall anti-tumor activity in terms of its direct pro-apoptotic activity, effector function and potency when used in an AMC. To determine the most effective linker design, maytansinoid conjugates of K7153A were prepared with either hindered disulfide (SPP-DM1) or thioether (SMCC-DM1) linker chemistries. Both conjugates were highly active against lymphoma cells in vitro, with the SMCC-DM1 conjugate being somewhat more potent. In vivo, a single dose of either 10 mg/kg of K7153A-SMCC-DM1 or 5 mg/kg of K7153A-SPP-DM1 was highly active against established SU-DHL-4 sc xenograft tumors. Both treatments resulted in >50% tumor-free survivors at study end. Similarly, the same treatment dose and schedule resulted in good efficacy with both conjugates in a BJAB sc xenograft model. Thus, the K7153A-SMCC-DM1 conjugate was highly active against lymphoma xenograft tumors and, based on preclinical experience, is expected to have comparable, if not better, therapeutic index to that of the SPP-linked conjugate. Taken together, these data support the selection of the K7153A antibody and the SMCC-DM1 design as the optimal anti-CD37 antibody-maytansinoid conjugate for clinical development (designated IMGN529). 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 2830. doi:10.1158/1538-7445.AM2011-2830