B7-H3, also referred to as CD276, is a member of the B7 family of immune regulatory proteins. B7-H3 is overexpressed on many solid cancers, including prostate cancer, renal cell carcinoma, melanoma, squamous cell carcinoma of the head and neck, non–small cell lung cancer, and breast cancer. Overexpression of B7-H3 is associated with disease severity, risk of recurrence and reduced survival. In this article, we report the preclinical development of MGC018, an antibody–drug conjugate targeted against B7-H3. MGC018 is comprised of the cleavable linker-duocarmycin payload, valine-citrulline-seco duocarmycin hydroxybenzamide azaindole (vc-seco-DUBA), conjugated to an anti-B7-H3 humanized IgG1/kappa mAb through reduced interchain disulfides, with an average drug-to-antibody ratio of approximately 2.7. MGC018 exhibited cytotoxicity toward B7-H3–positive human tumor cell lines, and exhibited bystander killing of target-negative tumor cells when cocultured with B7-H3–positive tumor cells. MGC018 displayed potent antitumor activity in preclinical tumor models of breast, ovarian, and lung cancer, as well as melanoma. In addition, antitumor activity was observed toward patient-derived xenograft models of breast, prostate, and head and neck cancer displaying heterogeneous expression of B7-H3. Importantly, MGC018 exhibited a favorable pharmacokinetic and safety profile in cynomolgus monkeys following repeat-dose administration. The antitumor activity observed preclinically with MGC018, together with the positive safety profile, provides evidence of a potentially favorable therapeutic index and supports the continued development of MGC018 for the treatment of solid cancers. Graphical Abstract: http://mct.aacrjournals.org/content/molcanther/19/11/2235/F1.large.jpg. Graphical Abstract

中文翻译：

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MGC018 的临床前开发，一种基于多卡霉素的抗体-药物偶联物，靶向 B7-H3 治疗实体癌

B7-H3，也称为 CD276，是免疫调节蛋白 B7 家族的成员。B7-H3 在许多实体癌中过表达，包括前列腺癌、肾细胞癌、黑色素瘤、头颈部鳞状细胞癌、非小细胞肺癌和乳腺癌。B7-H3 的过表达与疾病严重程度、复发风险和存活率降低有关。在本文中，我们报告了 MGC018 的临床前开发，MGC018 是一种针对 B7-H3 的抗体-药物偶联物。MGC018 由可切割的接头-多卡霉素有效负载、缬氨酸-瓜氨酸-seco 多卡霉素羟基苯甲酰胺氮杂吲哚 (vc-seco-DUBA) 组成，通过减少的链间二硫键与抗 B7-H3 人源化 IgG1/kappa mAb 缀合，平均药物-抗体比约为 2.7。MGC018 对 B7-H3 阳性人类肿瘤细胞系表现出细胞毒性，并在与 B7-H3 阳性肿瘤细胞共培养时表现出对靶阴性肿瘤细胞的旁观者杀伤。MGC018 在乳腺癌、卵巢癌和肺癌以及黑色素瘤的临床前肿瘤模型中显示出强大的抗肿瘤活性。此外，在患者来源的乳腺癌、前列腺癌和头颈癌异种移植模型中观察到抗肿瘤活性，显示出 B7-H3 的异质表达。重要的是，MGC018 在食蟹猴重复给药后表现出良好的药代动力学和安全性。用 MGC018 临床前观察到的抗肿瘤活性，以及​​积极的安全性，提供了潜在有利治疗指数的证据，并支持 MGC018 用于治疗实体癌的持续开发。图形摘要：http://mct.aacrjournals.org/content/molcanther/19/11/2235/F1.large.jpg。图形概要