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);

Epidermal Growth Factor Receptor Variant III (EGFRvIII) Positivity in EGFR-Amplified Glioblastomas: Prognostic Role and Comparison between Primary and Recurrent Tumors

“…Accumulating preclinical evidence has attributed an important function of EGFRvIII-expressing glioblastoma cells in driving tumor heterogeneity and progression by promoting glioma cell proliferation, invasion, angiogenesis, stemness, and therapy resistance in different model systems (36)(37)(38)(39)(40)(41)(42)(43). In addition, several therapeutic approaches targeting overexpressed wild type EGFR protein or specifically EGFRvIII have already entered, or are about to enter clinical evaluation, including peptide-based vaccines (44)(45)(46), chimeric antigen receptor (CAR) T cells (47,48), as well as anti-EGFR antibodybased approaches (22,49,50).…”

“…Because of the ongoing development and clinical evaluation of various targeted treatment strategies directed against wild-type EGFR and/or against EGFRvIII (10), including, for example, peptide-based vaccines such as rindopepimut (21) and monoclonal antibody (mAb)-based immunotoxins such as ABT-414 (22), a better understanding of the biological role and the prognostic significance of EGFR amplification and EGFRvIII status in glioblastoma is urgently needed. In particular, the prognostic role of EGFRvIII within the population of patients with EGFR-amplified glioblastoma has not been conclusively determined.…”

Antibody–Drug Conjugates (ADCs) for Personalized Treatment of Solid Tumors: A Review

“…Depatuxizumab mafodotin (ABT-414) is an anti-epidermal growth factor receptor (EGFR) antibody–auristatin conjugate wherein the charged auristatin MMAF is conjugated to the antibody via an uncleavable linker [81]. The ADC targets a domain on the activated form of EGFR that is only present at high levels on tumors whose growth is driven by overexpression of EGFR.…”

Efficacy and safety results of depatuxizumab mafodotin (ABT‐414) in patients with advanced solid tumors likely to overexpress epidermal growth factor receptor

“…A major advantage of ADCs is their ability to deliver a toxic payload directly to a tumor, bypassing downstream resistance mechanisms 8. Depatuxizumab mafodotin (depatux‐m) (formerly ABT‐414) is a novel ADC targeting EGFR in which cysteine (cys) residues of the depatux antibody were conjugated to a potent antimicrotubule agent, monomethyl auristatin F (MMAF), through a noncleavable maleimidocaproyl (mc) linker (mc‐MMAF [mafodotin]) 5, 9. The antibody selectively binds the depatux tumor‐selective EGFR epitope on the surface of the cell, is internalized and degraded, and releases Cys‐mcMMAF (Cys‐mafodotin).…”