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A Carbohydrate Epitope Associated with Human Squamous Lung Cancer¹

Department of Clinical Chemistry, University Hospital, S-221 85 Lund, Sweden [S. M., A. L.]; Cancer Biology Laboratory, State University Hospital (Rigshospitalet) Copenhagen, Denmark [C. D., H. E., L. O.]; BioCarb AB, S-223 70 Lund, Sweden [P. P., B. N.]; and Laboratory of Pathology, National Cancer Institute, National Institutes of Health, Bethesda, Maryland 20892 [D. Z.]

A monoclonal antibody, 43-9F, specifically recognizes a tumor-associated antigen expressed both on surface membrane glycoproteins and on secreted soluble mucins of human squamous lung carcinoma (SLC) cells, and the corresponding antigen can be detected as a circulating tumor marker in plasma of SLC patients. Thin-layer chromatography immunostaining of neutral glycolipids extracted from SLC cells reveals a 43-9F-reactive glycolipid whose carbohydrate structure, as determined by fast atom bombardment-mass spectrometry, is identical with that of an Le^a-active pentaglycosylceramide described previously: Galß1-3[Fuc1-4]-GlcNAcß1-3Galß1-4Glc-Cer. However, the Le^a-active oligosaccharide hapten, lacto-N-fucopentaose II, with the same carbohydrate structure, fails to inhibit binding of 43-9F, and a well-characterized anti-Le^a monoclonal antibody blocks only 40% of 43-9F binding sites on SLC cells, suggesting that the major epitope recognized by 43-9F is more complex than the Le^a epitope. To search for a higher affinity 43-9F epitope among more complex oligosaccharides, a mixture of tritiated neutral oligosaccharide alditols from pooled human milk was passed through a 43-9F affinity column. A major retarded oligosaccharide was purified by high-performance liquid chromatography and shown by fast atom bombardment-mass spectrometry to have the following structure: Galß1-3[Fuc1-4]GlcNAcß1-3Galß1-4[Fuc1-3]GlcNAcß1-3Galß1-4Glc. Oligosaccharides containing this sugar sequence are at least 100-fold more active than lacto-N-fucopentaose II as competitive inhibitors of 43-9F. Thus, antibody 43-9F binds to the above difucosyl Le^a-X determinant with high affinity and weakly cross-reacts with the Le^a antigen under some conditions such as occurs in thin-layer chromatography and enzyme-linked immunosorbent assay where multiple weak interactions of the decavalent IgM antibody may occur.

¹ This work was supported by USPHS Grant CA-35277, The Danish Cancer Society, The Danish Medical Research Council, Gangsted Rasmussen's Foundation, The Swedish Medical Research Council (13x-2), Swedish Cancer Society 2537-B88-01XA, and The Novo Foundation.

² To whom requests for reprints should be addressed, at Department of Clinical Chemistry, University Hospital, University of Lund, S-221 85 Lund, Sweden.

Received 9/24/87. Revised 1/ 7/88. Accepted 1/20/88.

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