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Title: Targeting Multiple EGFR Expressing Tumors with a Highly Potent Tumor-Selective Antibody Drug Conjugate.
Austin Authors: Anderson, Mark G;Falls, Hugh D;Mitten, Michael J;Oleksijew, Anatol;Vaidya, Kedar S;Boghaert, Erwin R;Gao, Wenqing;Palma, Joann P;Cao, Diana;Chia, Puey Ling ;John, Thomas ;Gan, Hui K ;Scott, Andrew M ;Reilly, Edward B
Affiliation: Oncology Discovery, AbbVie (United States)
AbbVie, Inc
Oncology Discovery, Abbvie Inc
Early Development, Jazz Pharmaceuticals
In Vivo Pharmacology, AbbVie, Inc
Drug Metabolism and Pharmacokinetics, AbbVie Inc
R460, AbbVie (United States)
Olivia Newton-John Cancer Research Institute
Medical Oncology, Peter MacCallum Cancer Centre
Medical Oncology
Issue Date: Oct-2020 2020-08-26
Publication information: Molecular Cancer Therapeutics 2020; 19(10):2117-2125
Abstract: ABBV-321 (serclutamab talirine), a next-generation epidermal growth factor receptor (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. 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 anti-tumor activity in cellular and in vivo studies including xenograft cell line and patient-derived xenograft (PDX) glioblastoma (GBM), colorectal, lung, head & neck and malignant mesothelioma tumor models which are less sensitive to depatux-m 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 1 clinical trials in patients with advanced EGFR-expressing malignancies.
DOI: 10.1158/1535-7163.MCT-20-0149
ORCID: 0000-0003-3399-5342
PubMed URL: 32847977
Type: Journal Article
Appears in Collections:Journal articles

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