ABT-414, an Antibody-Drug Conjugate Targeting a Tumor-Selective EGFR Epitope.

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Phillips AC, Boghaert ER, Vaidya KS, Mitten MJ, Norvell S, Falls HD, DeVries PJ, Cheng D, Meulbroek JA, Buchanan FG, McKay LM, Goodwin NC, Reilly EB

ABT-414, an Antibody-Drug Conjugate Targeting a Tumor-Selective EGFR Epitope.

Mol Cancer Ther. 2016 Apr;15(4):661-9. doi: 10.1158/1535-7163.MCT-15-0901. Epub 2016 Feb 4.

PubMed ID

26846818 [ View in PubMed

]

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. (c)2016 AACR.

DrugBank Data that Cites this Article

Drugs

Depatuxizumab mafodotin

Drug Targets

Drug	Target	Kind	Organism	Pharmacological Action	Actions
Depatuxizumab mafodotin	Epidermal growth factor receptor	Protein	Humans	No	Antibody	Details