Characterization of ABT-806, a Humanized Tumor-Specific Anti-EGFR Monoclonal Antibody

Abstract

Despite clinical efficacy, current approved agents targeting EGFR are associated with on-target toxicities as a consequence of disrupting normal EGFR function. MAb 806 is a novel EGFR antibody that selectively targets a tumor-selective epitope suggesting that a mAb 806-based therapeutic would retain antitumor activity without the on-target toxicities associated with EGFR inhibition. To enable clinical development, a humanized variant of mAb 806 designated ABT-806 was generated and is currently in phase 1 trials. We describe the characterization of binding and functional properties of ABT-806 compared with the clinically validated anti-EGFR antibody cetuximab. ABT-806 binds the mutant EGFRvIII with high affinity and, relative to cetuximab, exhibits increased potency against glioblastoma multiforme cell line and patient-derived xenografts expressing this form of the receptor. ABT-806 also inhibits the growth of squamous cell carcinoma xenograft models expressing high levels of wild-type EGFR, associated with inhibition of EGFR signaling, although higher doses of ABT-806 than cetuximab are required for similar activity. ABT-806 enhances in vivo potency of standard-of-care therapies used to treat glioblastoma multiforme and head and neck squamous cell carcinoma. An indiumlabeled version of ABT-806, [ 111 In]-ABT-806, used to investigate the relationship between dose and receptor occupancy, revealed greater receptor occupancy at lowers doses in an EGFRvIII-expressing model and significant uptake in an orthotopic model. Collectively, these results suggest that ABT-806 may have antitumor activity superior to cetuximab in EGFRvIIIexpressing tumors, and similar activity to cetuximab in tumors highly overexpressing wild-type EGFR with reduced toxicity.

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

“…It is important that the antibody exhibit specific and efficient binding to the antigen on tumor cells with little to no binding on normal cells. Both the monoclonal antibody targeting EGFR (depatux) and the ADC in which it is used (depatux‐m) demonstrated minimal binding in normal tissues and did not lead to the other toxicities5, 6, 14 usually associated with EGFR‐targeted therapies 7, 15. The linker is less likely to drive toxicity, although its stability can influence the toxicity derived from the payloads,11 which are highly active because of their effects on cellular processes necessary for survival.…”

“…Depatuxizumab (depatux) (formerly ABT‐806) is a veneered, humanized, recombinant immunoglobulin G1κ (IgG1κ) monoclonal antibody targeting a unique conformation of human EGFR that is exposed due to EGFR overexpression (increased receptor density), high levels of gene amplification, or a mutant form of EGFR with deletion of exons 2 through 7 ( EGFR variant III [ EGFRvIII ]) 5. This EGFR epitope is largely inaccessible when EGFR is expressed normally, contributing to limited binding of depatux in normal tissues 5.…”

“…This EGFR epitope is largely inaccessible when EGFR is expressed normally, contributing to limited binding of depatux in normal tissues 5. An initial phase 1 study demonstrated that depatux had high tumor specificity,6 with no dose‐limiting acneiform skin rashes or diarrhea that commonly occur with EGFR‐directed therapies 7…”

“…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).…”

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

“…ABT-806 is a humanized form of the monoclonal antibody mAb 806, which binds a cryptic epitope in the CR1 domain of EGFR that is accessible in tumors expressing amplified and overexpressed wild-type EGFR or the deletion mutant EGFR variant III (EGFRvIII; refs. 10,11). The low normal tissue binding of ABT-806 has been demonstrated in a phase I trial, where ABT-806 was well tolerated at the highest dose tested (24 mg/kg) with the absence of the characteristic EGFR inhibitor dermatologic adverse events (12).…”