Synergistic therapeutic benefit by combining the antibody drug conjugate, depatux-m with temozolomide in pre-clinical models of glioblastoma with overexpression of EGFR.

Purpose: Depatux-m is an antibody drug conjugate (ADC) that targets and inhibits growth of cancer cells overexpressing the epidermal growth factor receptor (EGFR) or the 2-7 deletion mutant (EGFRvIII) in tumor models in vitro and in vivo. Treatment of patients suffering from relapsed/refractory glioblastoma (GBM) with a combination of depatux-m and temozolomide (TMZ) tended to increase overall survival. As a first step to understand the nature of the interaction between the two drugs, we investigated whether the interaction was synergistic, additive or antagonistic.

Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate.

ABBV-321 (serclutamab talirine), a next-generation EGFR-targeted antibody-drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFR-targeting ABT-806 affinity-matured AM1 antibody. ABBV-321 follows the development of related EGFR-targeted ADCs including depatuxizumab mafodotin (depatux-m, ABT-414), ABT-806 conjugated to monomethyl auristatin F (MMAF), and ABBV-221 (losatuxizumab vedotin), AM1 antibody conjugated to monomethyl auristatin E (MMAE). The distinct tumor selectivity of ABBV-321 differentiates it from many previous highly active antibody PBD conjugates that lack a therapeutic window.

Characterization of ABBV-221, a Tumor-Selective EGFR-Targeting Antibody Drug Conjugate.

Depatuxizumab mafodotin (depatux-m, ABT-414) is a tumor-selective antibody drug conjugate (ADC) comprised of the anti-EGFR antibody ABT-806 and the monomethyl auristatin F (MMAF) warhead. Depatux-m has demonstrated promising clinical activity in glioblastoma multiforme (GBM) patients and is currently being evaluated in clinical trials in first-line and recurrent GBM disease settings. Depatux-m responses have been restricted to patients with amplified EGFR, highlighting the need for therapies with activity against tumors with nonamplified EGFR overexpression.

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

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.

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

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.