TRANSGENIC MICE EXPRESSING THE TUMOR-MARKER GERM-CELL ALKALINE-PHOSPHATASE - AN INVIVO TUMOR-MODEL FOR HUMAN CANCER ANTIGENS

We have generated a series of transgenic mouse lines harboring the ent ire human germ cell alkaline phosphatase (GCAP) gene linked to progres sively longer sequences of flanking DNA. A 450-bp promoter sequence di rects the expression of GCAP to the intestine and endothelial cells, w hile a 5' sequence of 1.7 kb directs GCAP expression to the spermatoge nic lineage and to the eight-cell through the blastocyst stage of prei mplantation development. The expression of GCAP in these FVB/N transge nic mice induces a cellular immune tolerance to GCAP. When mouse fibro sarcoma MO4 cells (C3H derived), stably transfected with the cloned GC AP gene, were injected s.c. in nontransgenic control (C3Hx FVB/N) hybr id mice, GCAP-positive tumor cells were rejected. However, when GCAP-e xpressing transgenic (C3HxFVB/N) hybrid mice were challenged with thes e cells, GCAP-positive tumors developed. Tumors also developed in the transgenic hybrid mice upon injection of MO4 cells transfected with th e highly homologous placental alkaline phosphatase (PLAP) cDNA in spit e of the presence in PLAP of 10 amino acids that are different from th e corresponding residues in GCAP. These GCAP transgenic mice will allo w the study of the immune response associated with the repeated admini stration of conjugated or derivatized anti-GCAP and anti-PLAP monoclon al antibodies. They will also enable evaluation of the therapeutic pot ential of bifunctional antibodies for T-cell recruitment and destructi on of GCAP/PLAP-producing tumor cells.