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.