OncoFAP-GlyPro-MMAE

The targeted delivery of radionuclides and cytotoxic drugs represents a viable alternative to conventional chemotherapy, aiming to improve therapeutic efficacy and reduce systemic toxicity by selective accumulation of the active payload at the tumor site. Our group has developed radioligand therapeutics (RLTs) and small molecule-drug conjugates (SMDCs) targeting fibroblast activation protein (FAP), a tumor-associated antigen abundantly and selectively expressed in the majority of solid human malignancies. Among these, ¹⁷⁷Lu-OncoFAP-23 and OncoFAP-GlyPro-MMAE showed selective accumulation in FAP-positive tumors in murine models and demonstrated potent anticancer activity. To further enhance the therapeutic efficacy, combining targeted drugs with immunotherapy may provide synergistic benefits by engaging both direct tumor cell killing and immune system activation. In this work, we explored the combination of FAP-targeting cytotoxic and radioactive therapeutics with three different immunocytokines targeting the Extra Domain B (EDB) of fibronectin: L19-hIL2, L19-mIL12, and L19-mTNF. A therapy experiment in immunocompetent mice bearing low FAP-expressing tumors showed that the combination with L19-hIL2 potentiated the antitumoral activity of ¹⁷⁷Lu-OncoFAP-23 and OncoFAP-GlyPro-MMAE. These results provided the motivation for the clinical development of these combinations for treating FAP-positive solid tumors.