Abstract 4625: IMGN529, a CD37-directed antibody-drug conjugate for the treatment of B-cell malignancies, has a favorable in vitro safety profile (2012)

Abstract The B-cell surface antigen CD37 is an attractive target for antibody-drug conjugate (ADC) mediated therapies, as it is widely expressed on malignant B cells in NHL and CLL. In normal human tissues, high CD37 expression is mainly restricted to B cells, with substantially lower expression seen in T cells, NK cells, monocytes and granulocytes. The CD37-targeting K7153A antibody was selected from a panel of antibodies for its potent pro-apoptotic, CDC and ADCC activity against B-cell lymphoma cell lines in vitro. The K7153A antibody was conjugated to the maytansinoid DM1 via the SMCC linker to yield the IMGN529 conjugate, which retained the intrinsic functions of the antibody and demonstrated enhanced in vitro and in vivo activity through targeted delivery of its payload. To complement preclinical in vivo toxicity studies with IMGN529 in animal models, we conducted extensive in vitro safety studies, with the aim of identifying any potential negative effects on normal human blood cells. Depletion of B cells, T cells and monocytes from peripheral blood cells by K7153A, IMGN529, the anti-CD20 antibody rituximab or the anti-CD52 antibody alemtuzumab was determined by flow cytometry. Proliferation of peripheral blood mononuclear cells (PBMCs) in response to K7153A or IMGN529 was evaluated by CFDA staining. Cytokine release of TNF-α, IFN-γ, IL-2, IL-4, IL-6 and IL-10 by normal human PBMCs was measured by ELISpot and cytometric bead array following exposure to compounds in both soluble and immobilized form. K7153A and IMGN529 specifically depleted B cells in a dose-dependent manner, but had no effect on T cells or monocytes, consistent with the much lower CD37 expression levels in these cells. K7153A and IMGN529 were more potent than rituximab and more specific than alemtuzumab, which depleted T cells and monocytes in addition to B cells. Incubation with IMGN529 did not increase the percentage of proliferating cells, while the anti-CD3 control antibody was able to strongly stimulate T cell proliferation. Treatment with K7153A or IMGN529 did not specifically induce cytokine release as compared to non-binding antibody controls, while treatment with the anti-CD3 control antibody resulted in significant cytokine release for all donors. Rituximab treatment caused release of low levels of IFN-γ and TNF in some donors. In contrast, treatment with alemtuzumab resulted in release of IFN-γ, TNF-α and IL-6 for most donors consistent with its potential for cytokine release in patients. In conclusion, the CD37-directed IMGN529 maytansinoid conjugate demonstrated potent in vitro and in vivo efficacy combined with a favorable in vitro safety profile with respect to cytokine release. Our analysis confirmed that the primary target cells of IMGN529 are B cells. Together, these data support the clinical development of this ADC for the treatment of B-cell malignancies. 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 4625. doi:1538-7445.AM2012-4625