The journey of targeted drug conjugates in solid tumors: moving beyond antibody drug conjugates

Antibody drug conjugates (ADCs) selectively deliver cytotoxins to tumor cells using highly specific monoclonal antibodies. While ADCs are a standard treatment paradigm in oncology, safety- and efficacy-related challenges remain. Additional platforms are needed to deliver more effective targeted therapy with differentiated safety profiles. This narrative review discusses the preclinical and clinical journey of ADCs, their shortcomings, and avenues for refinement. Development of novel antibody fragment-drug conjugates, small molecule-drug conjugates (SMDCs), peptide drug conjugates (PDCs), and Bicycle drug conjugate (BDC) molecules are discussed based on targeted literature searches for each technology described; searches were not bound by specific terms or dates in PubMed or ClinicalTrials.gov. Targeted delivery of cytotoxins will continue to be a powerful tool against cancer; however, we believe novel SMDCs, PDCs, and BDC molecules will help circumvent current challenges surrounding cytotoxin-containing ADCs and provide differentiated treatment options in solid tumors, including those particularly difficult to treat. We expect promising preclinical and clinical data emerging for SMDCs, PDCs, and BDC molecules will translate into approvals, such as BDC molecules that are under pivotal randomized phase II clinical investigation. These novel treatments will increase survival and quality of life for patients with solid tumors.