Solid tumor antibody-drug conjugates (ADCs) have experienced more clinical success in the last five years than the previous 18-year span since the first ADC approval in 2000. While recent advances in protein engineering, linker design, and payload variations have played a role in this success, high expression and readily internalized targets have also been crucial to solid tumor therapy. However, these factors are also paradoxically connected to poor tissue penetration and lower efficacy. Previous work shows that potent ADCs can benefit from slower internalization under subsaturating doses to improve tissue penetration and increase tumor response. In contrast, faster internalization is predicted to increase efficacy under higher, tumor saturating doses. In this work, the intracellular delivery of SN-38 conjugated to an anti-carcinoembryonic antigen (anti-CEA) antibody (Ab) is increased by co-administering a non-competing (crosslinking) anti-CEA antibody to improve efficacy in a colorectal carcinoma animal model. The SN-38 payload enables broad tumor saturation with clinically-tolerable doses, and under these saturating conditions, utilizing a second CEA receptor cross-linking Ab yields faster internalization, which increases tumor killing efficacy. Our spheroid results show indirect bystander killing can also occur, but the more efficient direct cell killing from targeted intracellular payload release drives a greater tumor response. These results provide a strategy to increase therapeutic effectiveness with improved intracellular delivery under tumor saturating doses with the potential to expand the ADC target repertoire.

中文翻译：

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改善针对癌胚抗原的抗体药物缀合物的细胞内递送可提高临床相关剂量的体内疗效

自 2000 年首次批准 ADC 以来，实体瘤抗体药物偶联物 (ADC) 在过去 5 年中取得了比之前 18 年更多的临床成功。虽然蛋白质工程、接头设计和有效负载变化方面的最新进展发挥了重要作用在这一成功中，高表达和易于内化的靶点对于实体瘤治疗也至关重要。然而，这些因素也与不良的组织渗透性和较低的功效相关。先前的研究表明，有效的 ADC 可以受益于亚饱和剂量下较慢的内化，从而改善组织渗透并增强肿瘤反应。相反，预计更快的内化会在更高的肿瘤饱和剂量下提高疗效。在这项工作中，通过共同施用非竞争性（交联）抗 CEA 抗体，增加了与抗癌胚抗原（抗 CEA）抗体 (Ab) 缀合的 SN-38 的细胞内递送，以提高结直肠癌的疗效癌症动物模型。SN-38 有效负载能够以临床可耐受的剂量实现广泛的肿瘤饱和，并且在这些饱和条件下，利用第二种 CEA 受体交联抗体可产生更快的内化，从而提高肿瘤杀伤功效。我们的球体结果显示，间接旁观者杀伤也可能发生，但靶向细胞内有效负载释放的更有效的直接细胞杀伤可驱动更大的肿瘤反应。这些结果提供了一种策略，通过在肿瘤饱和剂量下改善细胞内递送来提高治疗效果，并有可能扩大 ADC 靶点库。