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Tk, a New Colon Tumor-associated Antigen Resulting from Altered O-Glycosylation¹

INSERM U419, Institut de Biologie, 44093 Nantes, France [M. M., J. R., J. L. P.]; Shemyakin Institute for Bioorganic Chemistry, 117871 Moscow, Russia [O. G., N. B.]; Zelinsky Institute of Organic Chemistry, 117334 Moscow, Russia [N. N., A. S.]; Department of Pathology, University Hospital, 44093 Nantes, France [E. C., M. F. H.]; INSERM U482, Saint Antoine Hospital, 75571 Paris, France [J. B.]; and Blood Transfusion Centre, ML8 5ES Carluke, Scotland [R. H. F.]

Erythrocyte polyagglutination antigens T and Tn are truncated O-glycan chains that are also carcinoma-associated antigens. We investigated whether Tk polyagglutination antigen could similarly be a carcinoma-associated marker and a target of immunotherapy. Monoclonal antibody LM389 was raised against Tk erythrocytes and tested by immunohistochemistry. LM389 strongly reacted with 48% human colorectal carcinomas. Labeling of normal tissues was visible on epithelial cells, mainly digestive, but was confined at a supranuclear level. Expression of the antigen on cloned human carcinoma cells correlated with sialosyl-Tn expression. O-Sialoglycoprotein endopeptidase treatment revealed that on carcinomas and cell lines, the epitope was present on O-glycans. Antibody specificity was determined using synthetic carbohydrates. Direct binding and inhibition studies indicated that LM389 best ligands were terminated by two branched N-acetylglucosamine units. Screening of murine cellular cell lines with LM389 allowed development of an experimental model with Tk-positive and -negative cells in syngeneic BDIX rats. Vaccination of rats with Tk erythrocytes provided a protection against growth of rat Tk-positive, but not of Tk-negative, tumor cells in association with the development of antibodies. Taken together, the results indicate that Tk polyagglutination antigen is a new colorectal carcinoma-associated antigen, absent from the normal cell surface, resulting from alteration of O-glycans biosynthesis and with potential as a target of immunotherapy.

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