Kopp Anna, Dong Shujun, Kwon Hyeyoung, Wang Tiexin, Desai Alec A, Linderman Jennifer J, Tessier Peter, Thurber Greg M
Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48109.
Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48109.
bioRxiv. 2024 Apr 10:2024.04.06.588433. doi: 10.1101/2024.04.06.588433.
Antibody-drug conjugates (ADCs) have experienced a surge in clinical approvals in the past five years. Despite this success, a major limitation to ADC efficacy in solid tumors is poor tumor penetration, which leaves many cancer cells untargeted. Increasing antibody doses or co-administering ADC with an unconjugated antibody can improve tumor penetration and increase efficacy when target receptor expression is high. However, it can also reduce efficacy in low-expression tumors where ADC delivery is limited by cellular uptake. This creates an intrinsic problem because many patients express different levels of target between tumors and even within the same tumor. Here, we generated High-Avidity, Low-Affinity (HALA) antibodies that can automatically tune the cellular ADC delivery to match the local expression level. Using HER2 ADCs as a model, HALA antibodies were identified with the desired HER2 expression-dependent competitive binding with ADCs . Multi-scale distribution of trastuzumab emtansine and trastuzumab deruxtecan co-administered with the HALA antibody were analyzed , revealing that the HALA antibody increased ADC tumor penetration in high-expression systems with minimal reduction in ADC uptake in low-expression tumors. This translated to greater ADC efficacy in immunodeficient mouse models across a range of HER2 expression levels. Furthermore, Fc-enhanced HALA antibodies showed improved Fc-effector function at both high and low expression levels and elicited a strong response in an immunocompetent mouse model. These results demonstrate that HALA antibodies can expand treatment ranges beyond high expression targets and leverage strong immune responses.
在过去五年中，抗体药物偶联物（ADC）的临床获批数量激增。尽管取得了这一成功，但ADC在实体瘤中的疗效存在一个主要限制，即肿瘤穿透性差，这使得许多癌细胞未被靶向。当靶受体表达水平较高时，增加抗体剂量或与未偶联抗体联合使用ADC可以提高肿瘤穿透性并增强疗效。然而，在低表达肿瘤中，由于细胞摄取限制了ADC的递送，这种方法也可能降低疗效。这就产生了一个内在问题，因为许多患者的肿瘤之间甚至同一肿瘤内部的靶标表达水平都不同。在此，我们生成了高亲和力、低亲和力（HALA）抗体，其能够自动调节细胞对ADC的递送，以匹配局部表达水平。以HER2 ADC作为模型，我们鉴定出了具有所需的HER2表达依赖性竞争性结合ADC特性的HALA抗体。分析了与HALA抗体联合使用的曲妥珠单抗恩杂鲁胺和曲妥珠单抗德卢替康的多尺度分布，结果显示HALA抗体在高表达系统中增加了ADC的肿瘤穿透性，同时在低表达肿瘤中ADC摄取量的减少最小。这在一系列HER2表达水平的免疫缺陷小鼠模型中转化为更高的ADC疗效。此外，Fc增强的HALA抗体在高表达和低表达水平均显示出改善的Fc效应器功能，并在免疫活性小鼠模型中引发了强烈反应。这些结果表明，HALA抗体可以扩大治疗范围，超越高表达靶点，并利用强大的免疫反应。
