Nicolazzi C, et al. Mol Cancer Ther 2020.
Glycosylation is a complex multi-enzyme related process which is frequently deregulated in cancer. Aberrant glycosylation can lead to the generation of novel tumor surface specific glycotopes that can be targeted by antibodies. Murine DS6 monoclonal antibody (muDS6) was generated from serous ovary adenocarcinoma immunization. It recognizes CA6, a Mucin-1 (MUC1) associated sialoglycotope that is highly detected in breast, ovarian, lung and bladder carcinomas. SAR566658 antibody drug conjugate
(ADC) is a humanized DS6 (huDS6) antibody conjugated through a cleavable linker to the cytotoxic maytansinoid derivative drug, DM4. SAR566658 binds to tumor cells with sub-nanomolar affinity, allowing good ADC internalization and intracellular delivery of DM4, resulting in tumor cell death (IC50 from 1 to 7.3 nM). SAR566658 showed in vivo anti-tumor efficacy against CA6 positive human pancreas, cervix, bladder and ovary tumor xenografts and against 3 breast patient-derived xenografts (PDX). Tumor regression was observed in all tumor models with minimal effective dose correlating with CA6 expression. SAR566658 displayed better efficacy than standard of care non-targeted tubulin binders. This data supports the development of SAR566658 in patients with CA6 expressing tumors.