The Evolving Landscape of Antibody-Drug Conjugates for Urothelial Carcinoma

Overview of Common Antibody Therapeutic Designs (A) the Prototypical Monoclonal Antibody With 2 Identical Variable Components (Fv) That Engage Target Antigens. (B) T-cell-dependent Bispecific Antibodies, With 2 Differing Variable Regions Capable of Targeting Differing Antigens, Resulting in Unique Modes of Action Such as Bringing Target Tumor Cells in Close Proximity With Leukocytes. (C) ADCs Containing Variable Ratios of Cytotoxic Small Molecule Payloads Per Antibody That Act Through an Additional Mechanism Involving the Attached Chemotherapeutic. (D) MMAE, the Small Molecule Payload of Enfortumab/Vedotin, is Depicted Linked to Its Native Antibody via a Covalent Peptide Linker Metastatic urothelial carcinoma (UC) carries a poor prognosis and a 5-year overall survival of less than 5%, despite standard of care therapy using cisplatin-based chemotherapy and immune checkpoint inhibitors. Thus, novel agents that improve survival and have an acceptable toxicity profile are urgently needed. Antibody-drug conjugates (ADCs) represent a promising new treatment option that utilizes the targeting ability of an antibody to deliver cytotoxic drugs directly to tumors. Many ADCs are currently being investigated for treatment of UC, with enfortumab vedotin being recently approved by the US Food and Drug Administration for treatment of metastatic UC with progressive disease after chemotherapy and/or immune checkpoint inhibitors. Overall, ADCs hold promise as a long-awaited treatment option for UC.