A Mutant Chaperone Converts a Wild-Type Protein into a Tumor-Specific Antigen
Andrea Schietinger,1,3*
Mary Philip,2*
Barbara A. Yoshida,1
Parastoo Azadi,4
Hui Liu,4
Stephen C. Meredith,1
Hans Schreiber1
Monoclonal antibodies have become important therapeutic agents against certain cancers. Many tumor-specific antigens are mutant proteins that are predominantly intracellular and thus not readily accessible to monoclonal antibodies. We found that a wild-type transmembrane protein could be transformed into a tumor-specific antigen. A somatic mutation in the chaperone gene Cosmc abolished function of a glycosyltransferase, disrupting O-glycan Core 1 synthesis and creating a tumor-specific glycopeptidic neo-epitope consisting of a monosaccharide and a specific wild-type protein sequence. This epitope induced a high-affinity, highly specific, syngeneic monoclonal antibody with antitumor activity. Such tumor-specific glycopeptidic neo-epitopes represent potential targets for monoclonal antibody therapy.
1 Department of Pathology, Committee on Immunology, Committee on Cancer Biology, University of Chicago, Chicago, IL 60637, USA.
2 Department of Medicine, University of Chicago, Chicago, IL 60637, USA.
3 Institute of Immunology, Ludwig-Maximilians-University Munich, Munich 80336, Germany.
4 Complex Carbohydrate Research Center, University of Georgia, Athens, GA 30602, USA.
* These authors contributed equally to this work.
To whom correspondence should be addressed. E-mail: aschieti{at}uchicago.edu
