Transgenic mice expressing the tumor marker germ cell alkaline phosphatase: an in vivo tumor model for human cancer antigens

Abstract

We have generated a series of transgenic mouse lines harboring the entire human germ cell alkaline phosphatase (GCAP) gene linked to progressively longer sequences of flanking DNA. A 450-bp promoter sequence directs the expression of GCAP to the intestine and endothelial cells, while a 5' sequence of 1.7 kb directs GCAP expression to the spermatogenic lineage and to the eight-cell through the blastocyst stage of preimplantation development. The expression of GCAP in these FVB/N transgenic mice induces a cellular immune tolerance to GCAP. When mouse fibrosarcoma MO4 cells (C3H derived), stably transfected with the cloned GCAP gene, were injected s.c. in nontransgenic control (C3H x FVB/N) hybrid mice, GCAP-positive tumor cells were rejected. However, when GCAP-expressing transgenic (C3H x FVB/N) hybrid mice were challenged with these cells, GCAP-positive tumors developed. Tumors also developed in the transgenic hybrid mice upon injection of MO4 cells transfected with the highly homologous placental alkaline phosphatase (PLAP) cDNA in spite of the presence in PLAP of 10 amino acids that are different from the corresponding residues in GCAP. These GCAP transgenic mice will allow the study of the immune response associated with the repeated administration of conjugated or derivatized anti-GCAP and anti-PLAP monoclonal antibodies. They will also enable evaluation of the therapeutic potential of bifunctional antibodies for T-cell recruitment and destruction of GCAP/PLAP-producing tumor cells.