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

Abstract

ABBV-321 (serclutamab talirine), a next-generation EGFRtargeted antibody-drug conjugate (ADC) incorporates a potent pyrrolobenzodiazepine (PBD) dimer toxin conjugated to the EGFRtargeting 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. Potency of the PBD dimer, combined with increased binding of AM1 to EGFR-positive tumor cells, opens the possibility to target a wide array of tumors beyond those with high levels of EGFR overexpression or amplification, including those insensitive to auristatin-based ADCs. ABBV-321 exhibits potent antitumor activity in cellular and in vivo studies including xenograft cell line and patient-derived xenograft glioblastoma, colorectal, lung, head and neck, and malignant mesothelioma tumor models that are less sensitive to depatuxm or ABBV-221. Combination studies with ABBV-321 and depatux-m suggest a promising treatment option permitting suboptimal, and potentially better tolerated, doses of both ADCs while providing improved potency. Collectively, these data suggest that ABBV-321 may offer an extended breadth of efficacy relative to other EGFR ADCs while extending utility to multiple EGFR-expressing tumor indications. Despite its highly potent PBD dimer payload, the tumor selectivity of ABBV-321, coupled with its pharmacology, toxicology, and pharmacokinetic profiles, support continuation of ongoing phase I clinical trials in patients with advanced EGFR-expressing malignancies.

Potentiating Therapeutic Effects of Epidermal Growth Factor Receptor Inhibition in Triple-Negative Breast Cancer

“…ABT-806 is a humanized, tumor-specific anti-EGFR IgG1 monoclonal antibody [ 527 ]. The antibody–drug conjugates (ADCs) ABT-414 (depatuxizumab mafodotin) [ 528 ] and ABBV-321 (serclutamab talirine) [ 529 ] are composed of the antibody ABT-806 conjugated to the cytotoxic monomethyl auristatin F (MMAF) and the affinity-maturated version of ABT-806 conjugated to an ultrapotent pyrrolobenzodiazepine dimer, respectively. Navitoclax (ABT-263) is a small-molecule inhibitor of BCL-xL, BCL2, and BCL2L2 with anticancer activity [ 433 ].…”

Targeting and Efficacy of Novel mAb806-Antibody-Drug Conjugates in Malignant Mesothelioma

“…The ability of ADCs to deliver highly potent payloads in the targeted cancer cell (e.g., with EGFR expression) with reduced off-target toxicity makes this approach very attractive in the management of MM. We have previously reported that mAb806-ADC has markedly superior antitumor efficacy in animal models compared to antibody alone and the drug alone at similar concentrations [21]. The ability of mAb806 ADCs to target a conformational epitope exposed in tumor-specific conditions allows effective tumor targeting without the conventional EGFR inhibitor-mediated toxicities [13].…”

“…ABBV-221 was evaluated in a phase I clinical trial in patient EGFR-expressing solid tumors [19,20]. ABBV-322 is another mAb806-ADC derivative, comprised of the nonaffinity matured version of ABT-806 engineered to include an S238C point mutation that permits site-specific conjugation to a DNA minor groove crosslinking agent, pyrrolobenzodiazepine (PBD), via a cathepsin-cleavable Val-Ala linker with a DAR of two [15,18,21,22] (Supplementary Figure S1).…”

ABBV-176, a PRLR antibody drug conjugate with a potent DNA-damaging PBD cytotoxin and enhanced activity with PARP inhibition

“…Binding kinetics of ABBV-176 and the h16f parental mAb to recombinant human and cynomolgus PRLR ECD were determined by surface plasmon resonance-based measurements made on Biacore T200 instrument (GE Healthcare) using previously described methods [ 22 ].…”