Next-generation antibody-drug conjugates (ADCs) are advancing cancer therapy by delivering cytotoxic drugs directly to tumor cells, improving efficacy and reducing toxicity. These ADCs combine monoclonal antibodies with potent payloads via stable linkers, targeting tumor-associated antigens like 5T4. The 5T4-targeted ADC developed by Tubulis (currently in Phase 1 clinical trial) uses an IgG1 antibody linked to exatecan, a topoisomerase I inhibitor, through a cleavable linker, ensuring precise payload delivery. Advanced conjugation technologies enhance linker stability, preventing payload shedding and enabling higher dosing with minimal off-target effects, a significant improvement over earlier ADCs.

The 5T4 antigen, an oncofoetal glycoprotein, is a promising target for prostate cancer immunotherapy. It is expressed in prostate cancer, particularly in advanced stages, and is associated with tumor progression and metastasis. Studies demonstrate that 5T4 is present in prostate cancer cell lines and patient-derived tissues, with higher expression in metastatic castration-resistant prostate cancer (mCRPC). Vaccination strategies targeting 5T4, such as those using viral vectors, have induced CD8+ T-cell responses in preclinical models, protecting against tumor growth in prostate cancer models. These findings suggest 5T4-targeted ADCs could be effective in prostate cancer, particularly for mCRPC, where antigen expression is elevated.
Combining ADC approaches with immune-modulating payloads could further enhance efficacy by activating anti-tumor immunity, particularly in prostate cancer’s immunosuppressive microenvironment, where checkpoint inhibitors have shown limited success.

Source.

Clinical trial.