An Antibody–Drug Conjugate Targeting MUC1-Associated Carbohydrate CA6 Shows Promising Antitumor Activities
- 1 August 2020
- journal article
- research article
- Published by American Association for Cancer Research (AACR) in Molecular Cancer Therapeutics
- Vol. 19 (8), 1660-1669
- https://doi.org/10.1158/1535-7163.mct-19-0826
Abstract
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.Keywords
Other Versions
Funding Information
- Immunogen and East Carolina University for their contribution
- Thomas Jefferson University, Philadelphia, PA
This publication has 20 references indexed in Scilit:
- A new tubulin-binding site and pharmacophore for microtubule-destabilizing anticancer drugsProceedings of the National Academy of Sciences of the United States of America, 2014
- Protocols for Lysine ConjugationPublished by Springer Science and Business Media LLC ,2013
- The role of tumour-associated MUC1 in epithelial ovarian cancer metastasis and progressionCancer and Metastasis Reviews, 2013
- Associations between the Expression of Mucins (MUC1, MUC2, MUC5AC, and MUC6) and Clinicopathologic Parameters of Human Breast Ductal CarcinomasJournal of Breast Cancer, 2013
- SAR3419: An Anti-CD19-Maytansinoid Immunoconjugate for the Treatment of B-Cell MalignanciesClinical Cancer Research, 2011
- Maytansine and Cellular Metabolites of Antibody-Maytansinoid Conjugates Strongly Suppress Microtubule Dynamics by Binding to MicrotubulesMolecular Cancer Therapeutics, 2010
- Biological and therapeutic significance of MUC1 with sialoglycans in clear cell adenocarcinoma of the ovaryCancer Science, 2007
- Semisynthetic Maytansine Analogues for the Targeted Treatment of CancerJournal of Medicinal Chemistry, 2006
- CD44 on LS174T Colon Carcinoma Cells Possesses E-Selectin Ligand ActivityCancer Research, 2005
- Humanization of murine monoclonal antibodies through variable domain resurfacing.Proceedings of the National Academy of Sciences of the United States of America, 1994