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

Targeting tumor overexpressed epidermal growth factor receptor with an antibody drug conjugate 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) commonly found in glioblastoma multifome. ABT-414 exhibits potent cytotoxicity against GBM patient-derived xenograft models expressing either wild-type EGFR or EGFR variant III 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 multifome xenograft model. Based on these results ABT-414 has advanced to Phase 1/2 clinical trials and objective responses have been observed in patients with both amplified wild-type and EGFR variant III-expressing tumors.

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