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. 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 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 I clinical trials in patients with advanced EGFR-expressing malignancies.

中文翻译：

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使用高效的肿瘤选择性抗体药物偶联物靶向多种 EGFR 表达肿瘤

ABBV-321（serclutamab talirine），一种下一代EGFR靶向抗体-药物偶联物（ADC），结合了一种与EGFR靶向ABT-806亲和力成熟的AM1抗体偶联的强效吡咯并苯二氮卓（PBD）二聚体毒素。ABBV-321 跟随相关 EGFR 靶向 ADC 的开发，包括 depatuxizumab mafodotin（depatux-m，ABT-414）、ABT-806 与单甲基 auristatin F（MMAF）和 ABBV-221（losatuxizumab vedotin）、AM1 抗体与单甲基auristatin E (MMAE)。ABBV-321 独特的肿瘤选择性使其与许多以前缺乏治疗窗口的高活性抗体 PBD 偶联物区分开来。PBD 二聚体的效力，加上 AM1 与 EGFR 阳性肿瘤细胞的结合增加，除了那些具有高水平 EGFR 过度表达或扩增的肿瘤之外，包括那些对基于 auristatin 的 ADC 不敏感的肿瘤，开辟了靶向多种肿瘤的可能性。ABBV-321 在细胞和体内研究中表现出强大的抗肿瘤活性，包括异种移植细胞系和患者来源的异种移植胶质母细胞瘤、结肠直肠、肺、头颈部和对 depatux-m 或 ABBV-221 不太敏感的恶性间皮瘤肿瘤模型。ABBV-321 和 depatux-m 的联合研究表明一种有前景的治疗选择，允许次优且可能更好耐受的两种 ADC 剂量，同时提供更好的效力。总的来说，这些数据表明 ABBV-321 相对于其他 EGFR ADC 可能提供更广泛的疗效，同时将效用扩展到多种表达 EGFR 的肿瘤适应症。