The promise and challenges of combination therapies with antibody-drug conjugates in solid tumors

Abstract

Antibody-drug conjugates (ADCs) represent an important class of cancer therapies that have revolutionized the treatment paradigm of solid tumors. To date, many ongoing studies of ADC combinations with a variety of anticancer drugs, encompassing chemotherapy, molecularly targeted agents, and immunotherapy, are being rigorously conducted in both preclinical studies and clinical trial settings. Nevertheless, combination therapy does not always guarantee a synergistic or additive effect and may entail overlapping toxicity risks. Therefore, understanding the current status and underlying mechanisms of ADC combination therapy is urgently required. This comprehensive review analyzes existing evidence concerning the additive or synergistic effect of ADCs with other classes of oncology medicines. Here, we discuss the biological mechanisms of different ADC combination therapy strategies, provide prominent examples, and assess their benefits and challenges. Finally, we discuss future opportunities for ADC combination therapy in clinical practice.

Keywords: Antibody-drug conjugate; Combination therapy; Immunotherapy; Solid tumor; Targeted therapy.

Fig. 1

Structure and mechanism of action of conventional ADCs. ADCs consist of three essential components: a monoclonal antibody that binds to an antigen primarily expressed on the surface of tumor cells, providing specificity in targeting tumor cells; a linker that prevents premature release of the payload in the bloodstream but instead releases it in the tumor cells; and a cytotoxic payload that triggers tumor cell death by targeting critical components such as DNA, microtubules, and topoisomerase. ADC cytotoxicity involves a series of sequential stages: ① binding of the antibody to the antigen, ② internalization of the ADC-antigen complex, ③ degradation of the ADC in the lysosomes, ④ release of the payload in the cytoplasm, ⑤ its interaction with the target; ⑥ possible discharge of a fraction of the payload into the extracellular milieu, ⑦ subsequent occurrence of the bystander effect where it is internalized by neighboring cells in the tumor microenvironment. Abbreviation: TME, tumor microenvironment