**3. Antibody-Drug Conjugates**

Antibody-drug conjugates (ADCs) are the most mature offshoot of unmodified mAb therapeutics [54]. ADCs are mAbs conjugated to a small molecule chemotherapeutic via a chemical crosslinker. Although ADCs are considered biological therapeutic agents, the concept can also be viewed as 'targeted chemotherapy'. ADC therapeutic efficacy is reliant on the ability to efficiently internalize and accumulate the delivered cytotoxic drug inside diseased cells. Cells constantly internalize extracellular ligands via receptor-mediated endocytosis. Often, these internalized ligand-receptor complexes are encapsulated inside endosomes and trafficked to lysosomes for enzymatic degradation. Mechanistically, ADCs exert their cytotoxic activity by binding to target antigen receptors on the surface of tumor cells where they are internalized by a process known as receptor-mediated internalization and are entrapped inside endosomes in the intracellular space. Motor proteins then naturally traffic endosomes to lysosomes for membrane fusion and transfer of the encapsulated contents. Lysosomal proteases digest the antibody backbone or cleave the chemical crosslinker and liberate functional chemotherapeutic metabolites. The metabolites are able to permeate the lysosomal membrane and diffuse and bind their target and inhibit their function [54]. We highlight two recent clinically successful ADCs for bladder cancer.
