Many systemic cancer chemotherapies comprise a combination of drugs, yet all clinically used antibody–drug conjugates (ADCs) contain a single-drug payload. These combination regimens improve treatment outcomes by producing synergistic anticancer effects and slowing the development of drug-resistant cell populations. In an attempt to replicate these regimens and improve the efficacy of targeted therapy, the field of ADCs has moved towards developing techniques that allow for multiple unique payloads to be attached to a single antibody molecule with high homogeneity. However, the methods for generating such constructs—homogeneous multi-payload ADCs—are both numerous and complex owing to the plethora of reactive functional groups that make up the surface of an antibody. Here, by summarizing and comparing the methods of both single- and multi-payload ADC generation and their key preclinical and clinical results, we provide a timely overview of this relatively new area of research. The methods discussed range from branched linker installation to the incorporation of unnatural amino acids, with a generalized comparison tool of the most promising modification strategies also provided. Finally, the successes and challenges of this rapidly growing field are critically evaluated, and from this, future areas of research and development are proposed.

许多全身性癌症化疗包含药物组合，但所有临床使用的抗体药物偶联物 (ADC) 都包含单一药物有效负载。这些组合疗法通过产生协同抗癌作用并减缓耐药细胞群的发展来改善治疗结果。为了复制这些方案并提高靶向治疗的功效，ADC 领域已转向开发技术，允许将多个独特的有效负载以高同质性附着到单个抗体分子上。然而，由于构成抗体表面的反应性官能团过多，生成此类构建体（同质多有效负载 ADC）的方法既众多又复杂。在这里，通过总结和比较单有效负载和多有效负载 ADC 的生成方法及其关键的临床前和临床结果，我们及时概述了这个相对较新的研究领域。讨论的方法范围从分支接头安装到非天然氨基酸的掺入，还提供了最有希望的修饰策略的通用比较工具。最后，对这个快速发展的领域的成功和挑战进行了批判性评估，并据此提出了未来的研究和开发领域。