Abstract 2437: Engineered human monoclonal antibodies targeting the Müllerian inhibiting substance type II receptor for ovarian cancer therapy
Authors: Karakasheva Tatiana A. , Simmons Heidi H. , Rudnick Stephen I. , Robinson Matthew K. , Adams Gregory P. 
Published: February 2011

Currently available approaches for ovarian cancer therapy have limited success in the setting of advanced disease. Antibody-based therapeutics offer new and potentially effective strategies. Müllerian inhibiting substance (MIS, or anti-Müllerian hormone, AMH) is known for its role in embryonic development, triggering regression of the Müllerian ducts in mammalian males (in females Müllerian ducts are the source for uteri, Fallopian tubes and upper vagina). MIS signals via a heterodimeric receptor, consisting of type I (MISIR) and type II (MISIIR) receptors, where MISIIR mediates the ligand specificity and MISIR triggers the downstream signaling cascade. Approximately 64% of epithelial ovarian cancers express MISIIR with the most common expression in serous and mucinous tumors (Bakkum-Gamez et. al., Gynecol. Oncol. 2008;108(1):141). MIS has been reported to inhibit the growth of tumor xenografts in vivo (Stephen et al., Clin. Cancer Res. 2002;8(8):2640) and to trigger apoptosis of primary human ovarian cancer cells in vitro (Masaikos et al., Clin. Cancer Res. 1999;5(11):3488). This, along with the highly restricted expression pattern of MISIIR in normal tissues, suggests that MISIIR is a promising target for ovarian cancer therapy. A number of single-chain Fv molecules (scFv) and their bivalent derivatives (scFv: Fc constructs) targeting MISIIR were developed in our lab by means of screening of two large naïve human scFv phage display libraries. However, to date, the potential clinical utility of these anti-MISIIR scFv molecules has been limited due to their low binding affinity.

Here, we describe the screening of a third human scFv phage display library against a fusion protein representing the extracellular domain of MISIIR with the Fc domain of human IgG1 fused to its C-terminus. This screening led to selection of six unique scFv clones that specifically target MISIIR on the surface of cells with varying efficiency. One of these scFv clones, GS45, has demonstrated excellent targeting of MISIIR by flow cytometry, ELISA and surface plasmon resonance analysis. We are currently cloning GS45 into a full-length IgG molecule in order to improve its potential clinical utility.

Antibodies (or antibody-based constructs, such as scFv or scFv: Fc) targeting MISIIR could be used as the basis of a variety of therapeutic strategies. They can be used on their own to induce agonistic signaling or direct antibody-dependent cell-mediated cytotoxicity (ADCC). Alternatively, MISIIR-targeting antibodies can be conjugated to cytotoxic drugs, radiolabels or imaging agents. The anti-MISIIR scFv GS45, described here, is currently being developed for ADCC and immunodrug conjugate applications. We believe it can be the basis of novel therapeutic strategies for ovarian cancer treatment.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2437.