In 2009, a study conducted by National Cancer Institute Translational Research Working Group ranked MUC1 as the second best potential target out of 75 tumor-associated antigens. Indeed, aberrant expression of truncated immature O-glycans in MUC1 extracellular tandem repeats is a common feature of most adenocarcinomas and strongly associated with poor prognosis and low overall survival. Advent of antibodies recognizing precisely MUC1 fragments bearing immature truncated glycoforms both with glycan and peptide sequence specificities has been strongly required because such antibodies can greatly contribute to insights into the biological significance of glycosylation in MUC1 and development of novel anticancer therapeutic and diagnostic antibodies. The present study provides the first X-ray crystal structure of anti-MUC1 monoclonal antibody recognizing a designated “glycopeptidic neoepitope” (IgG1: SN-101). We established a novel strategy allowing for the generation of antibodies interacting specifically with dynamic glycopeptide epitopes by using homogeneous synthetic MUC1 glycopeptides designed for the streamlined process of immunization, antibody screening, three-dimensional (3D) structure analysis, epitope mapping and biochemical analysis. We revealed for the first time the molecular mechanism in the antibody recognition of the dynamic glycopeptidic neoepitope generated by cancer-specific immature O-glycosylation of MUC1 extracellular tandem repeating domain. Versatility and advantage of the present approach is evident because the 3D structure of liganded SN-101 provides a provocative template for engineering new antibodies exhibiting higher affinity and needed specificity to improve clinical performance of the anti-MUC1 mAbs. The present approach will facilitate greatly the development of new class of epitope-defined antibodies targeting of “dynamic neoepitopes” elaborated widely by disease-relevant posttranslational glycosylation not only at mucin glycoproteins but also at the intrinsically disordered regions of various cell surface glycoproteins.

Antibodies recognizing dynamic neoepitopes generated by cancer-specific truncated immature O-glycosylation

Macromolecular Chemistry: The Second Century

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ACS Spring 2020 National Meeting & Expo

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.