The antibody, linker, and payload moieties all play a significant role in giving the ADC its unique therapeutic potential. The antibody subclass employed in ADCs is determined based on relative individual receptor affinities and pharmacokinetics. Meanwhile, the linker used in an ADC can either be cleavable or non-cleavable. ADC therapy comprises antibody-dependent mechanisms in addition to the direct cytotoxic effects of the payload. These include antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, and antibody-dependent cellular phagocytosis, as well as the “bystander effect”, which refers to the diffusion of a portion of the cytotoxic molecules out of the target cell, exerting its cytotoxic effect on the adjacent cells. Target antigens of ADCs are expected to be expressed on the membranes of the cancer cells facing the external matrix, although new approaches utilize antigens regarding tumor-associated cells, the tumor microenvironment, or the tumor vasculature. These target antigens of ADCs not only determine the efficacy of these agents but also impact the off-targets and related adverse effects. The majority of ADC-related toxicities are associated with off-targets. The proposed mechanisms of ADC resistance include disrupted intracellular drug trafficking, dysfunctional lysosomal processing, and the efflux of the cytotoxic molecule via ATP-binding cassette (ABC) transporters. The latter mechanism is especially prominent for multi-drug-resistant tumors. An important limitation of ADCs is the penetration of the conjugate into the tumor microenvironment and their delivery to target cancer cells. Cancerous tissues’ vascular profile and the steric “binding site barrier” formed around the peripheral vessels of tumors stand as potential challenges of ADC therapy for solid tumors. As research efforts focus on reducing toxicities, overcoming resistance, and improving pharmacokinetics, ADC options for cancer therapy are expected to continue to diversify, including standalone approaches and combination therapies.
抗体、连接子及有效载荷部分均对赋予抗体药物偶联物（ADC）独特治疗潜力起着至关重要的作用。ADC中采用的抗体亚类需根据相对受体亲和力及药代动力学特性进行选择。同时，ADC使用的连接子可分为可裂解型与不可裂解型。除有效载荷的直接细胞毒作用外，ADC疗法还包含抗体依赖性作用机制，包括抗体依赖性细胞介导的细胞毒作用、补体依赖性细胞毒作用、抗体依赖性细胞吞噬作用，以及"旁观者效应"——即部分细胞毒性分子从靶细胞扩散至邻近细胞发挥细胞毒作用。ADC的靶抗原通常表达于面向细胞外基质的癌细胞膜表面，而新兴策略则利用肿瘤相关细胞、肿瘤微环境或肿瘤血管系统的抗原。这些靶抗原不仅决定ADC的疗效，还影响其脱靶效应及相关不良反应。多数ADC相关毒性均与脱靶效应相关。已提出的ADC耐药机制包括细胞内药物转运紊乱、溶酶体处理功能异常，以及通过ATP结合盒转运蛋白外排细胞毒性分子。后者在多药耐药肿瘤中尤为显著。ADC的重要局限性在于偶联物对肿瘤微环境的渗透及其向靶癌细胞的递送效率。肿瘤组织的血管特征及肿瘤外周血管形成的空间"结合位点屏障"，构成了ADC治疗实体瘤的潜在挑战。随着研究重点转向降低毒性、克服耐药性及改善药代动力学，预计癌症治疗中的ADC方案将持续多元化发展，包括单药疗法与联合治疗策略。
肿瘤(癌症)患者之家