title: Pan-HER, an Antibody Mixture Simultaneously Targeting EGFR, HER2, and HER3, Effectively Overcomes Tumor Heterogeneity and Plasticity.
abstract: OBJECTIVE
  Accumulating evidence indicates a high degree of plasticity and compensatory signaling within the human epidermal growth factor receptor (HER) family, leading to resistance upon therapeutic intervention with HER family members.
  
  
  RESULTS
  We have generated Pan-HER, a mixture of six antibodies targeting each of the HER family members EGFR, HER2, and HER3 with synergistic pairs of antibodies, which simultaneously remove all three targets, thereby preventing compensatory tumor promoting mechanisms within the HER family. Pan-HER induces potent growth inhibition in a range of cancer cell lines and xenograft models, including cell lines with acquired resistance to therapeutic antibodies. Pan-HER is also highly efficacious in the presence of HER family ligands, indicating that it is capable of overcoming acquired resistance due to increased ligand production. All three target specificities contribute to the enhanced efficacy, demonstrating a distinct benefit of combined HER family targeting when compared with single-receptor targeting.
  
  
  CONCLUSIONS
  Our data show that simultaneous targeting of three receptors provides broader efficacy than targeting a single receptor or any combination of two receptors in the HER family, especially in the presence of HER family ligands. Pan-HER represents a novel strategy to deal with primary and acquired resistance due to tumor heterogeneity and plasticity in terms of HER family dependency and as such may be a viable alternative in the clinic.
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: Thomas T
authors.initials: TT
authors.lastname: Poulsen
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: Klaus
authors.initials: K
authors.lastname: Koefoed
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Jette W
authors.initials: JW
authors.lastname: Sen
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Dietmar
authors.initials: D
authors.lastname: Weilguny
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Bolette
authors.initials: B
authors.lastname: Bjerregaard
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Christina R
authors.initials: CR
authors.lastname: Andersen
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: Mikkel W
authors.initials: MW
authors.lastname: Pedersen
authors.affiliation: Symphogen A/S, Ballerup, Denmark.
authors.forename: Michael
authors.initials: M
authors.lastname: Kragh
authors.affiliation: Symphogen A/S, Ballerup, Denmark. jol@symphogen.com.
authors.forename: Johan
authors.initials: J
authors.lastname: Lantto
mesh_terms: D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000737:chemistry*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002470:Cell Survival; D019008:Drug Resistance, Neoplasm / Q000276:immunology; D066246:ErbB Receptors / Q000737:chemistry* / Q000276:immunology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D008024:Ligands; D051379:Mice; D008819:Mice, Nude; D009374:Neoplasms, Experimental / Q000188:drug therapy; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry* / Q000276:immunology; D020893:Receptor, ErbB-3 / Q000737:chemistry* / Q000276:immunology; D015398:Signal Transduction; D023041:Xenograft Model Antitumor Assays
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D066246:ErbB Receptors; D008024:Ligands; D018719:Erb-b2 Receptor Tyrosine Kinases; D020893:Receptor, ErbB-3; C512478:EGFR protein, human; C508053:ERBB2 protein, human; C581292:ERBB3 protein, human