Abstract B40: Anti-EMP2 IgG Mono Methyl Auristatin E (MMAE) antibody-drug conjugate (ADC) as a potential cancer therapeutic

Abstract

Despite significant advances in biology and medicine, the incidence and mortality due to cancer world-wide is still unacceptably high. With the goal of detection and eradication of disease, our overall strategy had been to identify a novel molecular indicator, Epithelial Membrane Protein 2 (EMP2), which is ‘targetable' and ‘permeable'. EMP2 is a tetraspan protein that is expressed in a distinct subset of several cancers including breast, endometrial, ovarian, and brain. For instance, EMP2 expression is increased in 65% of breast cancer patients, independent of hormone receptor status and human epidermal growth factor receptor-2 (HER2) expression. EMP2 levels are elevated in early cancer lesions as well as during tumor progression and in metastasis. These factors allowed us to propose utilizing EMP2 as a target for cancer therapy of EMP2 positive tumors. We have previously shown that an anti-EMP2 IgG1 is successful at reducing breast and endometrial cancer tumor load. As the antibody-antigen complex rapidly internalizes, we have created an anti-EMP2 drug conjugate to improve on the efficacy of the naked antibody. Our second generation antibody includes the toxin monomethyl auristatin (MMAE), a potent microtubule-disrupting toxin, conjugated to the fully human anti-EMP2 IgG1 through both the protease cleavable linker and chemical non-cleavable linker. In this conjugation strategy, MMAE was conjugated using Click Chemistry reaction to the hinge region of the anti-EMP2 IgG1 antibody through rebridging disulfide bond technology to improve ADC stability, homogeneity, and especially pharmacological properties in vivo. The resulting anti-EMP2 IgG-MMAE ADC efficacy was evaluated and compared to the naked antibody in the aspect of antigen binding and specificity as well as in vitro cytotoxic effects. In vivo, the anti-EMP2 ADCs were evaluated for serum stability and anti-tumor efficacy. Anti-EMP2 IgG1 drug conjugate exhibits potent in vitro binding, internalization and cytotoxicity on a number of EMP2 positive and negative cancer cell lines. As a successful proof of principle, both the cleavable and non-cleavable anti-EMP2 IgG1-MMAE antibodies showed potent cytotoxic effects using a panel of cell lines including breast, ovarian, and endometrial cancer cells with an EC50 at least 10 times less than that required for the naked antibody. Currently, we are evaluating the anti-tumor efficacy of the antibody in vivo with the ultimate goal of showing that the anti-EMP2 drug conjugate improves survival as a single agent with minimal to no toxicity. Acknowledgement: Funded by the UCLA Tumor Cell Biology Training Program (USHHS Ruth L. Kirschstein Institutional National Research Service Award # T32 CA009056) and Citation Format: Shabnam Mohandessi, Teevit Dunnsiri, Chinmayi Aryasomayajula, Madhuri Wadehra. Anti-EMP2 IgG Mono Methyl Auristatin E (MMAE) antibody-drug conjugate (ADC) as a potential cancer therapeutic. [abstract]. In: Proceedings of the AACR Precision Medicine Series: Targeting the Vulnerabilities of Cancer; May 16-19, 2016; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2017;23(1_Suppl):Abstract nr B40.