Monoclonal Antibody 16D10 to the C-Terminal Domain of the Feto-Acinar Pancreatic Protein Binds to Membrane of Human Pancreatic Tumoral SOJ-6 Cells and Inhibits the Growth of Tumor Xenografts

Abstract

Feto-acinar pancreatic protein (FAPP) characterized by mAbJ28 reactivity is a specific component associated with ontogenesis and behaves as an oncodevelopment-associated antigen. We attempted to determine whether pancreatic tumoral SOJ-6 cells are expressed at their surface FAPP antigens and to examine if specific antibodies directed against these FAPP epitopes could decrease the growth of pancreatic tumors in a mice model. For this purpose, we used specific antibodies against either the whole FAPP, the O-glycosylated C-terminal domain, or the N-terminal domain of the protein. Our results indicate that SOJ-6 cells expressed at their surface a 32-kDa peptide corresponding to the C-terminal domain of the FAPP. Furthermore, we show, by using endoproteinase Lys-C or geldanamycin, a drug able to impair the FAPP secretion, that this 32-kDa peptide expressed on the SOJ-6 cell surface comes from the degradation of the FAPP. Finally, an in vivo prospective study using a preventative tumor model in nude mice indicates that targeting this peptide by the use of mAb16D10 inhibits the growth of SOJ-6 xenografts. The specificity of mAb16D10 for pancreatic tumors and the possibility to obtain recombinant structures of mucin-like peptides recognized by mAb16D10 and mAbJ28 are promising tools in immunologic approaches to cure pancreatic cancers.

Monoclonal antibody 16D10 to the COOH-terminal domain of the feto-acinar pancreatic protein targets pancreatic neoplastic tissues

“…I.p. injections of mAb16D10 in mice xenotransplanted with SOJ-6 cells decreased the growth rate of the established tumor (23). Opposite to mAb16D10, the mAbJ28 recognizes pancreatic tumor, but it has no effect on tumor growth.…”

“…These studies included immunocytologic localization of FAPP within human pancreatic tumoral tissue compared with normal tissue (19) and the targeting of nitrosamine-induced pancreatic tumor in hamster (which expressed the J28 epitope) with the radiolabeled mAbJ28 (47). A recent study showed that the mucin-like COOH-terminal domain of FAPP is actually presented at the surface of human pancreatic tumoral SOJ-6 cells (23). This glycopeptide is recognized by mAbJ28 and mAb16D10.…”

“…The formation of the J28 glycotope requires the core 2 h1,6-N-acetylglucosaminyltransferase and the a1,3/4-fucosyltransferase (24,25), two glycosyltransferases whose expression is up-regulated in pancreatic cancer (26). Furthermore, we have shown that the growth of xenografted SOJ-6 cells in nude mice was significantly decreased by preventative injections of mAb16D10 (23). To validate the potential use of this mAb16D10 in immune therapy, it was important to determine the expression of 16D10 antigen on human pancreatic adenocarcinomas.…”

“…mAb16D10 also recognized peptides presenting higher migration; in part, it reacted with 40-to 60-and 25-to 35-kDa peptides. This material could be representative of different proteolysis products of the COOH-terminal domain of FAPP, which has been recently detected at the level of the plasma membrane of pancreatic tumoral cells (23). Furthermore, mAb16D10 also binds to material with a very low migration; this material could be aggregated molecules of FAPP or FAPP associated with membrane lipid in cell lysate (5).…”

A Novel Tumor-Associated Pancreatic Glycoprotein Is Internalized by Human Dendritic Cells and Induces Their Maturation

“…FAPP is a glycoform of bile saltdependent lipase (BSDL) (31,32), a lipolytic enzyme present in normal human pancreatic juices (33). FAPP (now referred to as human pathological BSDL carrying the fucosylated J28 glycotope [pBSDL-J28]) was first characterized in human tumoral pancreas (34) and later on in human pancreatic tumor cell lines (35)(36)(37) using the murine J28 mAb (mAbJ28). mAbJ28 recognizes a carbohydrate-dependent antigenic structure (31), termed J28 glycotope, located within the O-glycosylated mucin-like C-terminal domain of pBSDL-J28 (38,39).…”