Monoclonal antibodies against the extracellular domain of the erbB-2 receptor function as partial ligand agonists.
In this paper we describe the isolation and characterization of four monoclonal antibodies (FRP5, FSP16, FWP51, and FSP77) which specifically recognize the human erbB-2 protein. All of the antibodies recognize epitopes on the extracellular domain of the receptor protein. FRP5 and FSP16 compete with one another for binding while FWP51 and FSP77 each recognize a different epitope. The effects of the antibodies on the erbB-2 receptor protein have been analyzed. Two different erbB-2-expressing cell lines, SKBR3 breast tumor cells and HC11 R111 cells, were examined. The SKBR3 cells express approximately 1 x 10(6) molecules of the erbB-2 protein/cell; HC11 R111 cells, a clone of mouse mammary epithelial cells derived by transfection of a human erbB-2 expression plasmid, contain 10-fold less erbB-2 protein than the SKBR3 cells. Treatment of the two cell lines with FRP5, FSP16, and FWP51 led to a rapid increase in the phosphotyrosine content of the erbB-2 protein. Three of the antibodies, FRP5, FSP16, and FSP77, stimulated the turnover of the erbB-2 protein. Binding of the antibodies did not stimulate DNA synthesis in HC11 R111 cells. Thus, the erbB-2-specific monoclonal antibodies behave as partial ligand agonists. The antibodies were examined for their effects upon the growth of SKBR3 and HC11 R111 cells. The growth of SKBR3 cells was inhibited by 90% following long term treatment of the cells with FSP77.
Harwerth
I M
IM
Friedrich Miescher Institute, Basel, Switzerland.
Wels
W
W
Marte
B M
BM
Hynes
N E
NE
D000911:Antibodies, Monoclonal / Q000378:metabolism*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000378:metabolism; D005434:Flow Cytometry; D006801:Humans; D008024:Ligands; D010766:Phosphorylation; D011233:Precipitin Tests; D011518:Proto-Oncogene Proteins / Q000276:immunology*; D011519:Proto-Oncogenes; D018719:Erb-b2 Receptor Tyrosine Kinases; D013936:Thymidine / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014415:Tunicamycin / Q000494:pharmacology; D014443:Tyrosine / Q000378:metabolism
D000911:Antibodies, Monoclonal; D008024:Ligands; D011518:Proto-Oncogene Proteins; D018719:Erb-b2 Receptor Tyrosine Kinases; D013936:Thymidine; D014415:Tunicamycin; D014443:Tyrosine