title: Comparative oncology: ErbB-1 and ErbB-2 homologues in canine cancer are susceptible to cetuximab and trastuzumab targeting.
abstract: To facilitate comparative oncology trials we compared the biological and molecular homologies of canine (dog; Canis lupus familiaris) and human tumor-associated antigens ErbB-1 and -2. Further, we investigated whether they could serve as targets for anti-ErbB-1 (cetuximab) and anti-ErbB-2 antibodies (trastuzumab), which are highly relevant in human clinical oncology. Immunohistochemistry of canine mammary cancer showed ErbB-1 overexpression in 3/10 patients and ErbB-2 in 4/10. We report 91% amino acid homology for ErbB-1 and 92% for ErbB-2 between canine and human molecules. Modeling of canine on human ErbB-1 revealed that the cetuximab epitope only differs by 4 amino acids: Lys443 is replaced by Arg, Ser468 by Asn, Gly471 by Asp, and Asn473 by Lys in canines. The trastuzumab binding site is identical in human and canine ErbB-2 apart from a single amino acid change (Pro557 to Ser). Binding of cetuximab and trastuzumab to canine mammary carcinoma cells CF33, CF41, Sh1b and P114 was confirmed by flow cytometry. Both antibodies significantly inhibited canine tumor cell proliferation partly due to growth arrest in G(0)/G(1) phase. We explain the lower efficiency on the tested canine than on human SKBR3 and A431 cells, by a 2-log lower expression level of the canine ErbB-1 and -2 molecules. Our results indicate significant homology of human and canine Erb-1 and -2 tumor associated antigens. The fact that the canine homologues express the cetuximab and trastuzumab epitopes may facilitate antibody-based immunotherapy in dogs. Importantly, the striking similarities of ErbB-1 and -2 molecules open up avenues towards comparative strategies for targeted drug development.
authors.affiliation: Institute of Pathophysiology and Allergy Research, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria.
authors.forename: Josef
authors.initials: J
authors.lastname: Singer
authors.forename: Marlene
authors.initials: M
authors.lastname: Weichselbaumer
authors.forename: Thomas
authors.initials: T
authors.lastname: Stockner
authors.forename: Diana
authors.initials: D
authors.lastname: Mechtcheriakova
authors.forename: Yury
authors.initials: Y
authors.lastname: Sobanov
authors.forename: Erika
authors.initials: E
authors.lastname: Bajna
authors.forename: Friedrich
authors.initials: F
authors.lastname: Wrba
authors.forename: Reinhard
authors.initials: R
authors.lastname: Horvat
authors.forename: Johann G
authors.initials: JG
authors.lastname: Thalhammer
authors.forename: Michael
authors.initials: M
authors.lastname: Willmann
authors.forename: Erika
authors.initials: E
authors.lastname: Jensen-Jarolim
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000032:analysis; D001943:Breast Neoplasms / Q000737:chemistry / Q000235:genetics* / Q000662:veterinary*; D002453:Cell Cycle / Q000187:drug effects; D002469:Cell Separation; D002470:Cell Survival / Q000187:drug effects; D000068818:Cetuximab; D004285:Dogs; D066246:ErbB Receptors / Q000737:chemistry / Q000235:genetics*; D005260:Female; D005434:Flow Cytometry; D005455:Fluorescent Antibody Technique; D006801:Humans; D007150:Immunohistochemistry; D020836:Protein Structure, Quaternary; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics*; D017386:Sequence Homology, Amino Acid; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D000068818:Cetuximab; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab