# Targeted Therapy in Metastatic Bladder Cancer: Present Status and Future Directions
## 7 Promising Targeted Treatment Approach: Antibody-Drug Conjugates  
Antibody-drug conjugates (ADCs) are drugs comprised of a monoclonal antibody tethered to a cytotoxic drug using a linker. ADCs rely on monoclonal antibodies to guide (highly) cytotoxic drugs to the proximity of target cells, whereupon the drug is released. Ideally, the monoclonal antibody component targets antigens that are exclusively and homogeneously expressed on cell membranes of cancer cells [60]. For maximal on-target effects, ADC-targeted antigens are not to be secreted and are ideally internalized upon ADC binding [61; 62]. Drugs tethered using non-cleavable linkers are only released following a complete proteasomal breakdown of the antibody component and will remain linked to an amino acid residue derived from the degraded antibody [63]. Cleavable linkers are designed to release drugs in response to particular extracellular and intracellular environments (pH, redox potential) or following enzymatic cleavage [63].  
The first ADC that received FDA approval for the treatment of mUC patients was entortumab vedotin. Enfortumab targets nectin-4 and is tethered to the cytotoxic agent vedotin using a protease-cleavable linker. FDA approval was based on results of a phase I clinical trial showing a promising ORR of 42% and a CR of 9% in mUC [64]. Side-effects most often associated with enfortumab vedotin or other vedotin-based ADCs are fatigue, peripheral neuropathy, rash, and hyperglycemia [65].  
Enfortumab vedotin paves the way for other ADCs to be used against MIBC, and ADCs targeting ErbB family members are currently being evaluated. HER2 overexpression in BC has been targeted by ADCs, even though the anticancer effect of HER2 inhibition was found to be minimal. Disitamab vedotin (RC48-ADC) combines the HER2-specific desitamab with vedotin using a protease-cleavable linker and has shown a promising ORR of 60% in HER2-positive mUC patients that have progressed on prior platinum-based therapy [66; 67]. ADCs based on trastuzumab are also being investigated. Trastuzumab deruxteen (DS-8201a) is trastuzumab tethered to the chemotherapeutic agent deruxteen via a cleavable peptide linker and is currently being investigated in combination with nivolumab as a second-line therapy in a phase I trial for patients with HER2-positive metastatic breast cancer or mUC (NCT03523572). Common grade 3 adverse events associated with trastuzumab denxtecan are interstitial lung disease, neutropenia, anemia, or thrombocytopenia. Trastuzumab emtansine (T-DM1) combines trastuzumab with cytotoxic entamsine and has a non-cleavable linker. Common side effects are conjunctivitis, dry eyes, and neutropenia. Trastuzumab entamsine was evaluated in a phase I clinical trial that enrolled patients with multiple tumor types carrying HER2 amplifications but did not yield any response in the three mUC patients available for analysis [68].  
In conclusion, HER2-targeted ADCs, like enfortumab vedotin, are a promising new class of drugs that exploit HER2 overexpression, irrespective of the anticancer effect of HER2 inhibition.  
Patients with EGFR or HER2 overexpression are an interesting population to further investigate the effect of ADCs. Phase II and phase III clinical trials evaluating EGFR or FGFR-targeted ADCs in mUC are awaited.