title: Inhibition of pancreatic carcinoma by homo- and heterocombinations of antibodies against EGF-receptor and its kin HER2/ErbB-2.
abstract: Due to intrinsic aggressiveness and lack of effective therapies, prognosis of pancreatic cancer remains dismal. Because the only molecular targeted drug approved for pancreatic ductal adenocarcinoma is a kinase inhibitor specific to the epidermal growth factor receptor (EGFR), and this receptor collaborates with another kinase, called HER2 (human EGF-receptor 2), we assumed that agents targeting EGFR and/or HER2 would effectively retard pancreatic ductal adenocarcinoma. Accordingly, two immunological strategies were tested in animal models: (i) two antibodies able to engage distinct epitopes of either EGFR or HER2 were separately combined, and (ii) pairs of one antibody to EGFR and another to HER2. Unlike the respective single monoclonal antibodies, which induced weak effects, both types of antibody combinations synergized in animals in terms of tumor inhibition. Immunological cooperation may not depend on receptor density, antigenic sites, or the presence of a mutant RAS protein. Nevertheless, both types of antibody combinations enhanced receptor degradation. Future efforts will examine the feasibility of each strategy and the potential of combining them to achieve sustained tumor inhibition.
authors.affiliation: Departments of Immunology and Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors.forename: Ruth
authors.initials: R
authors.lastname: Maron
authors.forename: Bilha
authors.initials: B
authors.lastname: Schechter
authors.forename: Maicol
authors.initials: M
authors.lastname: Mancini
authors.forename: Georg
authors.initials: G
authors.lastname: Mahlknecht
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
authors.forename: Michael
authors.initials: M
authors.lastname: Sela
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology / Q000627:therapeutic use*; D021441:Carcinoma, Pancreatic Ductal / Q000188:drug therapy* / Q000276:immunology; D004357:Drug Synergism; D066246:ErbB Receptors / Q000276:immunology*; D005260:Female; D005455:Fluorescent Antibody Technique; D051379:Mice; D008819:Mice, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D015398:Signal Transduction / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases
keywords: combination therapy; signal transduction