Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate
Targeting Multiple EGFR-expressing Tumors with a Highly Potent Tumor-selective Antibody-Drug Conjugate
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DOI：
10.1158/1535-7163.mct-20-0149
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发表时间：
2020-10-01
影响因子：
5.7
通讯作者：
Reilly, Edward B.
中科院分区：
文献类型：
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作者：
Anderson, Mark G.;Falls, Hugh D.;Reilly, Edward B.
ABBV-321 （serclutamab talirine）是一种新一代egfr靶向抗体-药物偶联物（ADC），它将一种强效的吡咯苯二氮卓（PBD）二聚体毒素偶联到靶向egfr的ABT-806亲和成熟的AM1抗体上。ABBV-321是继相关egfr靶向adc的发展之后，包括depatuzumab maodotin (depatux-m, ABT-414)， ABT-806偶联单甲基auristatin F (MMAF), ABBV-221 (losatuzumab vedotin)， AM1抗体偶联单甲基auristatin E （MMAE）。ABBV-321独特的肿瘤选择性使其区别于以往许多缺乏治疗窗口的高活性抗体PBD偶联物。PBD二聚体的效力，加上AM1与EGFR阳性肿瘤细胞结合的增加，使得靶向EGFR高水平过表达或扩增的肿瘤（包括那些对基于耳聋的adc不敏感的肿瘤）成为可能。ABBV-321在细胞和体内研究中显示出强大的抗肿瘤活性，包括对depuxm或ABBV-221不太敏感的异种移植物细胞系和患者来源的异种移植物胶质母细胞瘤、结直肠、肺、头颈部和恶性间皮瘤肿瘤模型。ABBV-321和depatux-m的联合研究表明，这是一种有希望的治疗选择，允许两种adc的次优剂量，但可能具有更好的耐受性，同时提供更好的效力。总的来说，这些数据表明，相对于其他EGFR adc， ABBV-321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。尽管ABBV-321具有高效的PBD二聚体有效载荷，但其肿瘤选择性，加上其药理学、毒理学和药代动力学特征，支持在晚期表达egfr的恶性肿瘤患者中继续进行I期临床试验。
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 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.