Antibody-Drug Conjugates in Urothelial Cancer: From Scientific Rationale to Clinical Development

Abstract

Antibody-drug conjugates (ADCs) have been a significant advancement in cancer therapy, particularly for urothelial cancer (UC). These innovative treatments, originally developed for hematological malignancies, use target-specific monoclonal antibodies linked to potent cytotoxic agents. This rational drug design efficiently delivers cancer cell-killing agents to cells expressing specific surface proteins, which are abundant in UC owing to their high antigen expression. UC is an ideal candidate for ADC therapy, as it enhances on-target efficacy while mitigating systemic toxicity. In recent years, considerable progress has been made in understanding the biology and mechanisms of tumor progression in UC. However, despite the introduction of immune checkpoint inhibitors, advanced UC is characterized by rapid progression and poor survival rates. Targeted therapies that have been developed include the anti-nectin 4 ADC enfortumab vedotin and the fibroblast growth factor receptor inhibitor erdafitinib. Enfortumab vedotin has shown efficacy in prospective studies in patients with advanced UC, alone and in combination with pembrolizumab. The anti-Trop-2 ADC sacituzumab govitecan has also demonstrated effectiveness in single-armed studies. This review highlights the mechanism of action of ADCs, their application in mono- and combination therapies, primary mechanisms of resistance, and future perspectives for their clinical use in UC treatment. ADCs have proven to be an increasingly vital component of the therapeutic landscape for urothelial carcinoma, filling a gap in the treatment of this progressive disease.

Keywords: ADC; ADC resistance mechanism; antibody-drug conjugates; enfortumab vedotin; urothelial carcinoma.

Figure 1

Structure of conventional ADCs. The composition of antitumor ADCs integrates three essential components: a monoclonal antibody that targets an antigen uniquely present on the surface of tumor cells, ensuring targeted delivery; a covalent linker that controls the release of the therapeutic substance within the tumor cells rather than in circulation; and a cytotoxic payload that prompts apoptosis in tumor cells by attacking critical cellular structures like DNA, microtubules, and topoisomerase 1. Created with BioRender.com.

Figure 2

Various strategies by which ADCs target and eliminate cancer cells. (a) Overview of mechanism of action of ADCs. (b) ADCs interact with immune effector cells to provoke a response against tumors, including CDC, ADCC, and ADCP effects. (c) The antibody component of the ADC maintains its functional profile, allowing it to interfere with the targeted cell’s function, suppress further signaling pathways, and thereby inhibit the proliferation of the tumor. Created with BioRender.com.

Figure 2

Various strategies by which ADCs target and eliminate cancer cells. (a) Overview of mechanism of action of ADCs. (b) ADCs interact with immune effector cells to provoke a response against tumors, including CDC, ADCC, and ADCP effects. (c) The antibody component of the ADC maintains its functional profile, allowing it to interfere with the targeted cell’s function, suppress further signaling pathways, and thereby inhibit the proliferation of the tumor. Created with BioRender.com.

Figure 3

Mechanism of action of conventional ADCs for killing cancer cells via different approaches. The process of ADC-induced cytotoxicity requires sequential key steps: (1) binding to specific antigen, (2) internalization of the ADC–antigen complex, (3) lysosomal degradation of the antibody, (4) release of payload within the cytoplasm, (5) interaction of the cytotoxic drug with intracellular target. A fraction of the payload may be released in the extra-cellular environment (6) where it can be taken up by adjacent cells, (7) causing the bystander effect. Created with BioRender.com.

Figure 4

Mechanisms of resistance and strategies to overcome resistance to ADC. Created with BioRender.com.