Abstract 4581: IMGN529 is an anti-CD37-maytansinoid conjugate with potent in vitro and in vivo activity against NHL and CLL cell lines

Abstract

Abstract IMGN529 is an antibody-drug conjugate consisting of the functional anti-CD37 antibody K7153A conjugated by a non-cleavable SMCC linker to the highly cytotoxic maytansinoid, DM1. Expression of CD37 in normal tissues is mainly limited to B-cells in blood and lymphoid tissues such as spleen, tonsil and lymph nodes. To evaluate the potential for targeting CD37 in B-cell malignancies by IMGN529, CD37 expression was compared to that of CD20, a well-validated target for antibody-directed therapy in lymphoma. CD37 exhibited a similar prevalence as CD20 in subtypes of NHL such as follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), Burkitt's lymphoma (BL) and mantle cell lymphoma (MCL) as assessed by immunohistochemistry using tumor microarrays. In addition, CD37 and CD20 antigen levels were measured by quantitative flow cytometry in NHL and B-CLL cell lines. All of the CD20+ B-cell lines examined also expressed CD37 at antigen levels ranging from 17,000 to 360,000 ABC (antibodies bound per cell). The activity of IMGN529 and its antibody component (K7153A) were evaluated against NHL and CLL cell lines in vitro. K7153A was active against an array of NHL-derived lymphoma cell lines including the DLBCL cell line SU-DHL-4, the FL cell line DOHH-2, the MCL cell line Granta-519, as well as B-CLL cell lines such as JVM-2 and JVM-3. The antibody showed only minimal activity against the BL cell lines Daudi and BJAB. Importantly, IMGN529 demonstrated enhanced and specific cytotoxicity against these cell lines when compared to either unconjugated K7153A antibody or a non-targeted control conjugate (EC50 10 – 400 pM). In contrast, the anti-CD37 compound, TRU-016, had no direct effect on any of these cell lines. The anti-CD20 antibody rituximab showed less direct activity than K7153A in most of these cell lines despite the often higher CD20 expression levels. In vivo, while the K7153A antibody showed anti-tumor efficacy in established tumor xenograft models of DLBCL (SU-DHL-4), FL (DOHH-2) and B-CLL (JVM-3), IMGN529 was significantly more active in these models. In addition, IMGN529 was active against established BL-derived BJAB tumors at doses (5 or 10 mg/kg single dose) where the unconjugated antibody was not active. In the FL-derived DOHH-2 tumor model, a single treatment of IMGN529 at 10 mg/kg resulted in tumor growth delay that was similar to rituximab given at 5 mg/kg twice weekly for 3 weeks and was better than treatment with CVP (cyclophosphamide/vincristine/prednisone). A single 5 mg/kg dose of IMGN529 demonstrated better activity than the anti-CD20 antibody ofatumumab (5 mg/kg twice weekly × 3) or bendamustine (50 mg/kg x1) in the B-CLL-derived JVM-3 xenograft model. In conclusion, IMGN529 is highly active in vitro and in vivo against representative B-cell lines from NHL and CLL suggesting the utility of this functional antibody-maytansinoid conjugate as a therapeutic in these disease indications. 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 4581. doi:10.1158/1538-7445.AM2011-4581