Abstract 2513: Evaluation of CD37 expression by calibrated IHC identifies non-Hodgkin's lymphoma as a therapeutic target for IMGN529, an anti-CD37-maytansinoid conjugate

Abstract

Abstract Background: CD37 is a B-cell surface antigen reported to be widely expressed on malignant B cells in patients with non-Hodgkin's lymphoma (NHL) and chronic lymphocytic leukemia (CLL). Expression of CD37 in normal tissues is mainly restricted to B cells in blood and lymphoid tissues. This suggests that CD37 may be an attractive target for development of a therapeutic antibody drug conjugate (ADC). The antibody maytansinoid conjugate, IMGN529 consists of a CD37-binding monoclonal antibody, K7153A, with the DM1 maytansinoid cytotoxic agent attached via an SMCC linker. IMGN529 has demonstrated potent in vitro and in vivo anti-tumor activities supporting its development as a treatment for CD37-expressing lymphomas and CLL. Objective: The objectives of this study were to assess the potential utility of IMGN529 for treatment of lymphoma patients by: (1) determining the extent of CD37 expression in NHL tissue samples relative to CD20, a well-validated target for antibody-directed therapies against B-cell malignancies; (2) identifying xenograft models with similar CD37 expression as seen in NHL patient samples; and (3) evaluating IMGN529 efficacy in these xenograft models. Methods: CD37 expression in human lymphoma cell lines was determined by quantitative flow cytometry. Cell pellet controls were prepared from human lymphoma cell lines that represented a range of CD37 expression to establish a calibrated IHC method. Using this IHC method, CD37 and CD20 expression levels were evaluated on a panel of FFPE biopsy samples from patients with NHL and from NHL-derived tumor xenograft models. For all stained biopsy samples, the extent and intensity of immunostaining was evaluated and antigen expression levels were estimated by comparing to the quantified cell pellet controls. In vivo efficacy was evaluated in subcutaneous xenograft models in SCID mice. Results: Biopsy samples from patients with B-cell NHL including subtypes such as follicular lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, and mantle cell lymphoma showed similar prevalence for CD37 and CD20. Most biopsy samples from patients with NHL showed strong and uniform expression levels of the CD37 antigen. As expected, no positive CD37 staining was seen in multiple myeloma and T-cell lymphoma biopsies. IMGN529 was highly active at a single dose of 10 mg/kg in tumor xenografts with CD37 expression levels similar to NHL patient samples. Conclusion: CD37 is expressed widely in B-cell lymphomas, including all major subtypes, which confirms CD37 as target for development of a therapeutic antibody drug conjugate. The CD37-targeting ADC, IMGN529, shows strong in vivo efficacy in lymphoma xenograft models with comparable CD37 expression levels as seen in lymphoma patients. Together these data support the development of IMGN529 for treatment of NHL. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 2513. doi:1538-7445.AM2012-2513