Systematic review of recent advancements in antibody-drug and bicycle toxin conjugates for the treatment of urothelial cancer

Abstract

Antibody-drug conjugates and bicycle toxin conjugates represent a tremendous advance in drug delivery technology and have shown great promise in the treatment of urothelial cancer. Previously approved systemic therapies, including chemotherapy and immunotherapy, are often impractical due to comorbidities, and outcomes for patients with advanced disease remain poor, even when receiving systemic therapy. In this setting, antibody-drug and bicycle toxin conjugates have emerged as novel treatments, dramatically altering the therapeutic landscape. These drugs harness unique designs consisting of antibody or bicycle peptide, linker, and cytotoxic payload with more targeted delivery than conventional chemotherapy, thus eliminating malignant cells while reducing systemic toxicities. Potential targets investigated in urothelial cancer include Nectin-4, TROP2, HER2, and EphA2. Initial clinical trials demonstrated efficacy in treatment of refractory advanced urothelial cancer, as well as improvement in quality of life. These initial studies led to FDA approval of two antibody-drug conjugates, enfortumab vedotin and sacituzumab govitecan. Moreover, antibody-drug and bicycle toxin conjugates are being studied in ongoing clinical trials in frontline treatment of advanced disease as well as for localized cancer. These studies highlight the potential for additional future therapies with novel targets, novel antibodies, cytotoxic and immunomodulatory payloads, and unique structural designs enhancing efficacy and safety. There is increasing evidence that combinations with other cancer therapies, especially immunotherapy, improve treatment outcomes. The combination of enfortumab vedotin and pembrolizumab was recently approved for first-line treatment of advanced urothelial carcinoma. Despite the great promise of these novel drugs, robust predictive biomarkers are needed to determine the patients who would maximally benefit. This review surveys the rationale and current state of the evidence for these new drugs and describes future directions actively being explored.

Keywords: ASG-15ME; antibody-drug conjugates; bicycle toxin conjugates; bladder cancer; disitamab vedotin; enfortumab vedotin; sacituzumab govitecan; trastuzumab deruxtecan; trastuzumab emtansine; urothelial cancer.

Figure 1.

Structures of antibody-drug conjugates and bicycle toxin conjugates. (a) ADCs are composed of an antibody engineered to target an antigen preferentially expressed on tumor cells. This is connected via a cleavable or non-cleavable linker to a cytotoxic payload with antitumor effect. Additional tumor death may be instituted by a bystander effect. The typical ratio of payload to antibody 3:1 or 4:1. (b) BTCs are composed of a peptide constrained by three cysteine residues that target a tumor antigen, thereby forming a bicycle structure. This is connected to cytotoxic payload via a molecular spacer to reduce steric hindrance by the bicycle and a cleavable linker, which is cleaved extracellularly. The peptide to payload ratio is 1:1. ADC, antibody-drug conjugate; BTC, bicycle toxin conjugate.

Figure 2.

Consort diagram consisting of inclusion and exclusion of studies reviewed. 601 sources were identified via EMBASE that potentially discussed ADCs and BTCs in urothelial carcinoma. Exclusion criteria included preclinical studies, review articles, and case reports in order to select completed and ongoing clinical trials. A second search of ClinialTrials.gov was necessary to ensure all relevant studies were included. ADC, antibody-drug conjugate; BTC, bicycle toxin conjugate.