Targeting multiple Her-2 epitopes with monoclonal antibodies results in improved antigrowth activity of a human breast cancer cell line in vitro and in vivo.
Her-2 (p185(erbB-2)) is a transmembrane tyrosine kinase receptor, which is encoded by the Her-2/neu proto-oncogene. Her-2 is overexpressed on 30% of highly malignant breast cancers. Monoclonal antibodies (MAbs) against Her-2 inhibit the growth of Her-2-overexpressing tumor cells and this occurs by a variety of mechanisms. One such MAb, Herceptin (Trastuzumab), has been approved for human use. We have generated a panel of murine anti-Her-2 MAbs against nine different epitopes on the extracellular domain of Her-2 and have evaluated the antitumor activity of three of these MAbs alone and in combination, both in vitro and in vivo. We found that MAbs (against different epitopes) make a highly effective mixture, which was more effective than the individual MAbs in treating s.c. tumor nodules of BT474 cells in SCID mice. In vitro, the MAb mixture was also more effective than the single MAbs in inducing antibody-dependent cellular cytotoxicity and complement-dependent cytotoxicity, inhibiting cell growth and inducing apoptosis, and inhibiting the secretion of vascular endothelial growth factor. Taken together, these activities might explain the superior performance of the MAb mixture in vivo.
Spiridon
Camelia I
CI
Cancer Immunobiology Center, University of Texas Southwestern Medical School, 6000 Harry Hines Boulevard, Dallas, TX 75390-8576, USA.
Ghetie
Maria-Ana
MA
Uhr
Jonathan
J
Marches
Radu
R
Li
Jia-Ling
JL
Shen
Guo-Liang
GL
Vitetta
Ellen S
ES
D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000920:Antibody-Dependent Cell Cytotoxicity; D000954:Antigens, Surface / Q000276:immunology; D017209:Apoptosis / Q000502:physiology; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002455:Cell Division / Q000502:physiology; D003167:Complement Activation; D016228:Endothelial Growth Factors / Q000378:metabolism; D000939:Epitopes / Q000276:immunology; D005260:Female; D006801:Humans; D066298:In Vitro Techniques; D036341:Intercellular Signaling Peptides and Proteins / Q000378:metabolism; D008222:Lymphokines / Q000378:metabolism; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D016513:Mice, SCID; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000037:antagonists & inhibitors / Q000276:immunology*; D015996:Survival Rate; D000068878:Trastuzumab; D014407:Tumor Cells, Cultured / Q000187:drug effects; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000954:Antigens, Surface; D016228:Endothelial Growth Factors; D000939:Epitopes; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D000090063:Proto-Oncogene Mas; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; C000715470:MAS1 protein, human