PO.TB04.08 · 肿瘤生物学
超过800种！建立跨多种肿瘤细胞系的ADC载荷疗效数据库：优化体外ADC评估与药物开发的基础
Over 800! Establishment of an ADC payload efficacy database across diverse tumor cell lines: Foundation for optimized in vitro ADC evaluation and drug development
作者与单位 Authors & Affiliations
摘要 Abstract
中文摘要
自2000年首个抗体药物偶联物（ADC）Mylotarg获批以来，ADC市场已扩展至迄今为止15个获批产品，而另有超过210个正在临床试验中。这表明ADC药物开发已步入蓬勃发展的阶段——尤其是在靶向HER2、EGFR、Trop2、CLDN18.2和Nectin-4等分子时，ADC已展现出显著的疗效和良好的安全性。因此，ADC疗法在癌症治疗领域具有极为广阔的应用前景。抗体药物偶联物（ADC）由三个核心组分构成：单克隆抗体、连接子和毒素。其中，ADC毒素——也称为ADC载荷——是ADC药物的关键要素，因为它是决定药物效力的关键因素。已获批ADC中使用的载荷具有高毒性；主要例子包括MMAE/MMAF、卡奇霉素、DM1/DM4和SN38/Dxd。与传统化疗药物相比，这些载荷的毒性高出1到2个数量级，有些甚至达到皮摩尔（pM）级别的毒性水平。对于目前正在开发中的载荷，其作用机制主要分为四类：DNA烷化剂、DNA拓扑异构酶抑制剂、微管破坏剂和RNApolII抑制剂。我们已建立了一个庞大的细胞库，其中储存有超过800种人类肿瘤细胞系和100种动物肿瘤细胞系，覆盖所有类型的癌症。凭借这一丰富的细胞资源，我们正在构建一个ADC筛选平台。通过全面检测，我们收集不同ADC载荷在各种细胞系中的疗效数据——这些数据继而指导我们选择合适的细胞系用于体外ADC评估。截至目前，我们已使用多种ADC载荷（如MMAE、SN38、Dxd和依沙替康）完成了超过700种常用细胞系的检测。作为一项大规模举措，该ADC筛选平台有望在ADC药物的筛选和评估中发挥积极的支持作用。
查看英文原文 English abstract
Ever since the first antibody-drug conjugate (ADC), Mylotarg, received approval back in 2000, the ADC market has expanded to include 15 approved products so far, while more than 210 others are currently in clinical trials. This indicates that ADC drug development has stepped into a thriving phase-especially when targeting molecules like HER2, EGFR, Trop2, CLDN18.2, and Nectin-4, ADCs have demonstrated notable efficacy and favorable safety profiles. As such, ADC therapy holds extremely broad application prospects in the field of cancer treatment.Antibody-drug conjugates (ADCs) consist of three core components: a monoclonal antibody, a linker, and a toxin. Among these, the ADC toxin-also referred to as the ADC payload-is a critical element of ADC drugs, as it serves as the key factor determining the drug's potency. The payloads used in approved ADCs are highly toxic; major examples include MMAE/MMAF, calicheamicin, DM1/DM4, and SN38/Dxd. Compared with traditional chemotherapy drugs, these payloads are 1 to 2 orders of magnitude more toxic, and some even reach toxicity levels in the picomolar (pM) range. For payloads currently under development, their mechanisms of action mainly fall into four categories: DNA alkylating agents, DNA topoisomerase inhibitors, microtubule disruptors, and RNApolII inhibitors.We have established an extensive cell bank, which houses over 800 human tumor cell lines and 100 animal tumor cell lines, covering all types of cancers. Leveraging this rich cell resource, we are constructing an ADC screening platform. Through comprehensive testing, we collect efficacy data of different ADC payloads across various cell lines-this data then guides us in selecting appropriate cell lines for in vitro ADC evaluation. Up to now, we have already finished over 700 commonly used cell lines using several ADC payloads, such as MMAE, SN38, Dxd, and exatecan. As a large-scale initiative, the ADC screening platform is expected to play a positive and supportive role in the screening and evaluation of ADC drugs.
利益披露 Disclosure
G. Wang,
Kyinno Biotechnology Co., LTD Employment.
Y. Tang,
Kyinno Biotechnology Co., LTD Employment.
J. Xu,
Kyinno Biotechnology Co., LTD Employment.
T. Lv,
Kyinno Biotechnology Co., LTD Employment.
J. ning,
Kyinno Biotechnology Co., LTD Employment.
F. Hao,
Kyinno Biotechnology Co., LTD Employment.