title: The combination of trastuzumab and pertuzumab administered at approved doses may delay development of trastuzumab resistance by additively enhancing antibody-dependent cell-mediated cytotoxicity.
abstract: Although the recently concluded CLEOPATRA trial showed clinical benefits of combining trastuzumab and pertuzumab for treating HER2-positive metastatic breast cancer, trastuzumab monotherapy is still the mainstay in adjuvant settings. Since trastuzumab resistance occurs in over half of these cancers, we examined the mechanisms by which treatment of intrinsically trastuzumab-resistant and -sensitive tumors can benefit from the combination of these antibodies. F(ab')2of both trastuzumab and pertuzumab were generated and validated in order to separately analyze antibody-dependent cell-mediated cytotoxicity (ADCC)-based and direct biological effects of the antibodies. Compared to monotherapy, combination of the two antibodies at clinically permitted doses enhanced the recruitment of natural killer cells responsible for ADCC, and significantly delayed the outgrowth of xenografts from intrinsically trastuzumab-resistant JIMT-1 cells. Antibody dose-response curves of in vitro ADCC showed that antibody-mediated killing can be saturated, and the two antibodies exert an additive effect at sub-saturation doses. Thus, the additive effect in vivo indicates that therapeutic tissue levels likely do not saturate ADCC. Additionally, isobole studies with the in vitro trastuzumab-sensitive BT-474 cells showed that the direct biological effect of combined treatment is additive, and surpasses the maximum effect of either monotherapy. Our results suggest the combined therapy is expected to give results that are superior to monotherapy, whatever the type of HER2-positive tumor may be. The combination of both antibodies at maximum clinically approved doses should thus be administered to patients to recruit maximum ADCC and cause maximum direct biological growth inhibition.
authors.affiliation: a Department of Biophysics and Cell Biology , Faculty of Medicine, University of Debrecen , Debrecen , Hungary.
authors.forename: Gábor
authors.initials: G
authors.lastname: Tóth
authors.affiliation: a Department of Biophysics and Cell Biology , Faculty of Medicine, University of Debrecen , Debrecen , Hungary.
authors.forename: Árpád
authors.initials: Á
authors.lastname: Szöőr
authors.affiliation: a Department of Biophysics and Cell Biology , Faculty of Medicine, University of Debrecen , Debrecen , Hungary.
authors.forename: László
authors.initials: L
authors.lastname: Simon
authors.affiliation: b Department of Biological Regulation , The Weizmann Institute of Science , Rehovot , Israel.
authors.forename: Yosef
authors.initials: Y
authors.lastname: Yarden
authors.affiliation: a Department of Biophysics and Cell Biology , Faculty of Medicine, University of Debrecen , Debrecen , Hungary.|c MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine.
authors.forename: János
authors.initials: J
authors.lastname: Szöllősi
authors.affiliation: a Department of Biophysics and Cell Biology , Faculty of Medicine, University of Debrecen , Debrecen , Hungary.|c MTA-DE Cell Biology and Signaling Research Group, Faculty of Medicine.|d Faculty of Pharmacy, University of Debrecen , Debrecen , Hungary.
authors.forename: György
authors.initials: G
authors.lastname: Vereb
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage*; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects*; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology*; D001943:Breast Neoplasms / Q000276:immunology*; D045744:Cell Line, Tumor; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D005260:Female; D006801:Humans; D051379:Mice; D016513:Mice, SCID; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab / Q000008:administration & dosage*; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab
keywords: Antibody-dependent cell-mediated cytotoxicity (ADCC); HER2; Herceptin resistance; combination antibody therapy; pertuzumab; resistance; trastuzumab