title: ABT-414, an Antibody-Drug Conjugate Targeting a Tumor-Selective EGFR Epitope.
abstract: Targeting tumor-overexpressed EGFR with an antibody-drug conjugate (ADC) is an attractive therapeutic strategy; however, normal tissue expression represents a significant toxicity risk. The anti-EGFR antibody ABT-806 targets a unique tumor-specific epitope and exhibits minimal reactivity to EGFR in normal tissue, suggesting its suitability for the development of an ADC. We describe the binding properties and preclinical activity of ABT-414, an ABT-806 monomethyl auristatin F conjugate. In vitro, ABT-414 selectively kills tumor cells overexpressing wild-type or mutant forms of EGFR. ABT-414 inhibits the growth of xenograft tumors with high EGFR expression and causes complete regressions and cures in the most sensitive models. Tumor growth inhibition is also observed in tumor models with EGFR mutations, including activating mutations and those with the exon 2-7 deletion [EGFR variant III (EGFRvIII)], commonly found in glioblastoma multiforme. ABT-414 exhibits potent cytotoxicity against glioblastoma multiforme patient-derived xenograft models expressing either wild-type EGFR or EGFRvIII, with sustained regressions and cures observed at clinically relevant doses. ABT-414 also combines with standard-of-care treatment of radiation and temozolomide, providing significant therapeutic benefit in a glioblastoma multiforme xenograft model. On the basis of these results, ABT-414 has advanced to phase I/II clinical trials, and objective responses have been observed in patients with both amplified wild-type and EGFRvIII-expressing tumors. Mol Cancer Ther; 15(4); 661-9. ©2016 AACR.
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Andrew C
authors: AC
authors: Phillips
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Erwin R
authors: ER
authors: Boghaert
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Kedar S
authors: KS
authors: Vaidya
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Michael J
authors: MJ
authors: Mitten
authors: TKIS, LLC., Long Grove, Illinois.
authors: Suzanne
authors: S
authors: Norvell
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Hugh D
authors: HD
authors: Falls
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Peter J
authors: PJ
authors: DeVries
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Dong
authors: D
authors: Cheng
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Jonathan A
authors: JA
authors: Meulbroek
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Fritz G
authors: FG
authors: Buchanan
authors: AbbVie, Oncology Discovery, North Chicago, Illinois.
authors: Laura M
authors: LM
authors: McKay
authors: The Jackson Laboratory, Sacramento, California.
authors: Neal C
authors: NC
authors: Goodwin
authors: AbbVie, Oncology Discovery, North Chicago, Illinois. ed.reilly@abbvie.com.
authors: Edward B
authors: EB
authors: Reilly
mesh_terms: D000818:Animals; D000915:Antibody Affinity; D000970:Antineoplastic Agents / Q000494:pharmacology*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D003131:Combined Modality Therapy; D004195:Disease Models, Animal; D000939:Epitopes / Q000276:immunology; D066246:ErbB Receptors / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D005260:Female; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000401:mortality / Q000473:pathology; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D058990:Molecular Targeted Therapy; D009154:Mutation; D011485:Protein Binding; D047428:Protein Kinase Inhibitors / Q000494:pharmacology*; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D000939:Epitopes; D018796:Immunoconjugates; D047428:Protein Kinase Inhibitors; D066246:ErbB Receptors