title: Targeting Three Distinct HER2 Domains with a Recombinant Antibody Mixture Overcomes Trastuzumab Resistance.
abstract: HER2 plays an important role in the development and maintenance of the malignant phenotype of several human cancers. As such, it is a frequently pursued therapeutic target and two antibodies targeting HER2 have been clinically approved, trastuzumab and pertuzumab. It has been suggested that optimal inhibition of HER2 is achieved when utilizing two or more antibodies targeting nonoverlapping epitopes. Superior clinical activity of the trastuzumab plus pertuzumab combination in metastatic breast cancer supports this hypothesis. Because trastuzumab and pertuzumab were not codeveloped, there may be potential for further optimizing HER2 targeting. The study herein evaluated functional activity of anti-HER2 antibody combinations identifying optimal epitope combinations that provide efficacious HER2 inhibition. High-affinity antibodies to all four extracellular domains on HER2 were identified and tested for ability to inhibit growth of different HER2-dependent tumor cell lines. An antibody mixture targeting three HER2 subdomains proved to be superior to trastuzumab, pertuzumab, or a combination in vitro and to trastuzumab in two in vivo models. Specifically, the tripartite antibody mixture induced efficient HER2 internalization and degradation demonstrating increased sensitivity in cell lines with HER2 amplification and high EGFR levels. When compared with individual and clinically approved mAbs, the synergistic tripartite antibody targeting HER2 subdomains I, II, and IV demonstrates superior anticancer activity.
authors.affiliation: Symphogen A/S, Ballerup, Denmark. mwp@symphogen.com.
authors.forename: Mikkel W
authors.initials: MW
authors.lastname: Pedersen
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Helle J
authors.initials: HJ
authors.lastname: Jacobsen
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Klaus
authors.initials: K
authors.lastname: Koefoed
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Anna
authors.initials: A
authors.lastname: Dahlman
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Ida
authors.initials: I
authors.lastname: Kjær
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Thomas T
authors.initials: TT
authors.lastname: Poulsen
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Per-Johan
authors.initials: PJ
authors.lastname: Meijer
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Lars S
authors.initials: LS
authors.lastname: Nielsen
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Ivan D
authors.initials: ID
authors.lastname: Horak
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Johan
authors.initials: J
authors.lastname: Lantto
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Kragh
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000494:pharmacology; D001943:Breast Neoplasms / Q000188:drug therapy / Q000378:metabolism; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D019008:Drug Resistance, Neoplasm / Q000187:drug effects*; D004357:Drug Synergism; D066246:ErbB Receptors / Q000378:metabolism; D005260:Female; D006801:Humans; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D008819:Mice, Nude; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction / Q000187:drug effects; D000068878:Trastuzumab / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays / Q000379:methods
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; D018719:Erb-b2 Receptor Tyrosine Kinases; D000068878:Trastuzumab; C508053:ERBB2 protein, human; C485206:pertuzumab