Akram Fatima, Ali Amna Murrawat, Akhtar Muhammad Tayyab, Fatima Taseer, Shabbir Ifrah, Ul Haq Ikram
Dr. Ikram-ul-Haq Institute of Industrial Biotechnology, Government College University, Lahore 54000, Pakistan; Department of Biology, Saint Louis University, St. Louis, MO, USA.
Dr. Ikram-ul-Haq Institute of Industrial Biotechnology, Government College University, Lahore 54000, Pakistan.
Bioorg Med Chem. 2025 Jan 1;117:118010. doi: 10.1016/j.bmc.2024.118010. Epub 2024 Nov 24.
Antibody-drug conjugates (ADCs) represent a powerful class of targeted cancer therapies that harness the specificity of monoclonal antibodies to deliver cytotoxic payloads directly to tumor cells, minimizing off-target effects. This review explores the advancements in ADC technologies, focusing on advancing next-generation ADCs with novel payloads, conjugation strategies, and enhanced pharmacokinetic profiles. In particular, we highlight innovative payloads, including microtubule inhibitors, spliceosome modulators, and RNA polymerase inhibitors, that offer new mechanisms of cytotoxicity beyond traditional apoptosis induction. Additionally, the introduction of sophisticated conjugation techniques, such as site-specific conjugation using engineered cysteines, enzymatic methods, and integration of non-natural amino acids, has greatly improved the homogeneity, efficacy, and safety of ADCs. Furthermore, the review delves into the mechanistic insights into ADC action, detailing the intracellular pathways that facilitate drug release and cell death, and discussing the significance of bioconjugation methods in optimizing drug-antibody ratios (DARs). The establishment of comprehensive databases like ADCdb, which catalog vital pharmacological and biological data for ADCs, is also explored as a critical resource for advancing ADC research and clinical application. Finally, the clinical landscape of ADCs is examined, with a focus on the evolution of FDA-approved ADCs, such as Gemtuzumab Ozogamicin and Trastuzumab Emtansine, as well as emerging candidates in ongoing trials. As ADCs continue to evolve, their potential to revolutionize cancer therapy remains immense, offering new hope for more effective and personalized treatment options. ADCs also offer a significant advancement in targeted cancer therapy by merging the specificity of monoclonal antibodies with cytotoxic potency of chemotherapeutic agents. Hence, this dual mechanism intensifies tumor selectivity while minimizing systemic toxicity, paving the way for more effective and safer cancer treatments.
抗体药物偶联物（ADCs）是一类强大的靶向癌症治疗药物，它利用单克隆抗体的特异性将细胞毒性药物直接递送至肿瘤细胞，从而将脱靶效应降至最低。本综述探讨了ADC技术的进展，重点关注开发具有新型药物、偶联策略和改善药代动力学特征的下一代ADCs。特别地，我们强调了创新型药物，包括微管抑制剂、剪接体调节剂和RNA聚合酶抑制剂，它们提供了超越传统凋亡诱导的细胞毒性新机制。此外，引入复杂的偶联技术，如使用工程化半胱氨酸的位点特异性偶联、酶法以及非天然氨基酸的整合，极大地提高了ADCs的均一性、疗效和安全性。此外，本综述深入探讨了ADC作用的机制，详细阐述了促进药物释放和细胞死亡的细胞内途径，并讨论了生物偶联方法在优化药物-抗体比率（DARs）中的重要性。还探讨了建立像ADCdb这样的综合数据库，该数据库收录了ADCs重要的药理学和生物学数据，是推进ADC研究和临床应用的关键资源。最后，研究了ADCs的临床现状，重点关注FDA批准的ADCs的演变，如吉妥珠单抗奥唑米星和曲妥珠单抗 emtansine，以及正在进行的试验中的新兴候选药物。随着ADCs不断发展，它们彻底改变癌症治疗的潜力仍然巨大，为更有效和个性化的治疗选择带来了新希望。ADCs还通过将单克隆抗体的特异性与化疗药物的细胞毒性相结合，在靶向癌症治疗方面取得了重大进展。因此，这种双重机制增强了肿瘤选择性，同时将全身毒性降至最低，为更有效、更安全的癌症治疗铺平了道路。
