4.6 Article

Cellular-Resolution Imaging of Bystander Payload Tissue Penetration from Antibody-Drug Conjugates

期刊

MOLECULAR CANCER THERAPEUTICS
卷 21, 期 2, 页码 310-321

出版社

AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1535-7163.MCT-21-0580

关键词

-

类别

资金

  1. NIH [R35 GM128819, P30 CA046592]

向作者/读者索取更多资源

After several clinical failures, anti-body-drug conjugates (ADC) have recently achieved significant progress, with seven new FDA approvals in the last 3 years. The shift towards mechanistically informed ADC design has played a key role in these successes. However, there are still fundamental aspects of ADC design that are not fully understood, such as payload distribution. This study used tumor spheroids and pharmacodynamic marker staining to evaluate tissue penetration of different classes of ADC agents. The results show that the physicochemical properties and potency of the payload can significantly affect tissue penetration and bystander potential.
After several notable clinical failures in early generations, anti-body-drug conjugates (ADC) have made significant gains with seven new FDA approvals within the last 3 years. These successes have been driven by a shift towards mechanistically informed ADC design, where the payload, linker, drug-to-antibody ratio, and conjugation are increasingly tailored to a specific target and clinical indication. However, fundamental aspects needed for design, such as payload distribution, remain incompletely understood. Payloads are often classified as bystander or nonbystander depending on their ability to diffuse out of targeted cells into adjacent cells that may be antigen-negative or more distant from tumor vessels, helping to overcome heterogeneous distribution. Seven of the 11 FDA-approved ADCs employ these bystander payloads, but the depth of penetration and cytotoxic effects as a function of physicochemical properties and mechanism of action have not been fully characterized. Here, we utilized tumor spheroids and pharmacodynamic marker staining to quantify tissue penetration of the three major classes of agents: microtu-bule inhibitors, DNA-damaging agents, and topoisomerase inhi-bitors. PAMPA data and coculture assays were performed to compare with the 3D tissue culture data. The results demonstrate a spectrum in bystander potential and tissue penetration depend-ing on the physicochemical properties and potency of the pay-load. Generally, directly targeted cells show a greater response even with bystander payloads, consistent with the benefit of deeper ADC tissue penetration. These results are compared with computational simulations to help scale the data from in vitro and preclinical animal models to the clinic.

作者

我是这篇论文的作者
点击您的名字以认领此论文并将其添加到您的个人资料中。

评论

主要评分

4.6
评分不足

次要评分

新颖性
-
重要性
-
科学严谨性
-
评价这篇论文

推荐

暂无数据
暂无数据