Géraud Arthur, Gougis Paul, de Nonneville Alexandre, Beaufils Mathilde, Bertucci François, Billon Emilien, Brisou Gabriel, Gravis Gwenaelle, Greillier Laurent, Guerin Mathilde, Mezni Essia, Mitry Emmanuel, Noel Robin, Pignon Joséphine, Sabatier Renaud, Seguin Lorène, Spano Jean-Philippe, Vicier Cécile, Viret Frederic, Goncalves Anthony, Ciccolini Joseph
Aix-Marseille Univ, CNRS, INSERM, Institut Paoli-Calmettes, Department of Medical Oncology, CRCM, Marseille, France; COMPO Team, Centre de Recherche en Cancérologie de Marseille (CRCM), Inserm U1068, Aix Marseille University, 13009 Marseille, France.
Department of Medical Oncology, Pitié-Salpêtrière, Assistance Publique - Hôpitaux de Paris (AP-HP), 75013 Paris, France; Sorbonne Université, Institut National de la Santé et de la Recherche Médicale (INSERM), Assistance Publique - Hôpitaux de Paris (AP-HP), Clinical Investigation Center (CIC-1901), Department of Pharmacology, Pitié-Salpêtrière Hospital, Paris, France; Residual Tumor & Response to Treatment Laboratory, RT2Lab, INSERM, U932 Immunity and Cancer, Institut Curie, France.
Cancer Treat Rev. 2025 Apr;135:102922. doi: 10.1016/j.ctrv.2025.102922. Epub 2025 Mar 25.
Antibody-drug conjugates (ADCs) are a rising therapeutic class in oncology and hematology, with eleven drugs approved by the US Food and Drug Administration as of January 2025. These "magic bullets" have a complex structure, including a monoclonal antibody, a linker, attachment sites, and a payload usually disrupting microtubules, targeting DNA, or inhibiting topoisomerase 1. By targeting specific tumor antigens, they are expected to be exquisitely effective in releasing "supertoxic" payloads inside tumor cells after intracellular trafficking. Additionally, they may exert a bystander effect, wherein the released payloads act on neighboring cells, amplifying their therapeutic impact regardless of target expression. ADCs have been game-changing drugs to treat tumors with once dismal prognoses or with previously considered unactionable targets, such as HER2-low or triple-negative breast cancer. To what extent there is room for personalized medicine to improve the toxicity/efficacy ratio remains unknown. However, there are inherent issues related to the complexity of the pharmacokinetics of ADCs and their assessments: efficacy or toxicity may be influenced by the clearance of the intact ADC, the circulating payload, or the payload-linker complex. Deciphering these multifaceted exposure-outcomes relationships for both efficacy and safety endpoints, is critical for advancing precision medicine and enabling personalized dosing strategies. To improve future developments and broaden their therapeutic scope, several strategies can be developed, including developing adequate combinations with other treatment classes (cytotoxic agents, immune-checkpoint inhibitors, oral molecular-targeted therapies). In this review, we will discuss the PK/PD aspects of ADCs and their dosing to improve their use in current and future indications.
抗体药物偶联物（ADCs）是肿瘤学和血液学领域中新兴的一类治疗药物，截至2025年1月，已有11种药物获得美国食品药品监督管理局批准。这些“神奇子弹”结构复杂，包括单克隆抗体、连接子、连接位点以及通常用于破坏微管、靶向DNA或抑制拓扑异构酶1的有效载荷。通过靶向特定肿瘤抗原，预计它们在细胞内转运后能在肿瘤细胞内精准释放“超毒性”有效载荷，从而发挥高效作用。此外，它们可能产生旁观者效应，即释放的有效载荷作用于邻近细胞，无论靶标表达情况如何，都能增强治疗效果。ADCs已成为治疗预后一度不佳或此前认为无法治疗的靶点（如HER2低表达或三阴性乳腺癌）的变革性药物。个性化医疗在多大程度上能够改善毒性/疗效比仍不明确。然而，ADCs的药代动力学及其评估的复杂性存在一些固有问题：疗效或毒性可能受完整ADCs、循环有效载荷或有效载荷-连接子复合物清除率的影响。解读这些针对疗效和安全性终点的多方面暴露-结果关系，对于推进精准医疗和制定个性化给药策略至关重要。为了促进未来发展并拓宽其治疗范围，可以制定多种策略，包括与其他治疗类别（细胞毒性药物、免疫检查点抑制剂、口服分子靶向疗法）进行适当联合。在本综述中，我们将讨论ADCs的药代动力学/药效学方面及其给药方式，以改善其在当前和未来适应症中的应用。
