Mouse analog of micvotabart pelidotin, an antibody-drug conjugate targeting extradomain-B of fibronectin, demonstrates anti-tumor efficacy in an immunotherapy-refractory syngeneic head and neck squamous cell carcinoma model

Head and neck squamous cell carcinoma (HNSCC) is a difficult-to-treat indication, with current standard of care providing limited long-term survival, underscoring the need for more effective treatment options. Micvotabart pelidotin (MICVO) is a first-in-concept antibody-drug conjugate targeting extradomain-B of fibronectin (EDB+FN), a non-cellular component of the tumor extracellular matrix that is abundantly expressed in the stroma of many malignancies, including HNSCC, but minimally in normal adult tissues, making it an attractive drug-delivery target. In preclinical studies, a murine analog of MICVO (maMICVO) demonstrated pronounced anti-tumor activity, enhanced T cell tumor infiltration, and synergy with anti-PD1, resulting in greater efficacy in syngeneic triple-negative breast cancer models, including one refractory to immunotherapy. MICVO also showed broad anti-tumor activity across multiple patient-derived xenograft models, with particularly strong responses in HNSCC. Consistent with these findings, preliminary results from a Phase 1 Part 1 trial (NCT05720117) showed favorable anti-tumor activity with MICVO monotherapy across several solid tumor types, including HNSCC. This clinical observation is further supported by the present study, in which strong maMICVO activity was observed in the poorly immunogenic, immunotherapy-refractory mouse oral carcinoma 2 (MOC2) syngeneic HNSCC model. In vitro , MOC2 cells exhibited minimal EDB+FN expression at baseline. However, tumors established in immunocompetent mice with these cells displayed markedly elevated EDB+FN expression within the extracellular space, suggesting that signals arising during tumor growth drive EDB+FN induction. To evaluate efficacy, mice bearing subcutaneous MOC2 tumors were treated with up to 6 mg/kg maMICVO, with tumor growth and body weight monitored. Treatment was well tolerated at all doses, and a dose-dependent anti-tumor effect was observed, with 6 mg/kg producing the greatest tumor growth inhibition. Notably, image analysis of MOC2 tumors after maMICVO treatment revealed trends of increased CD8 T cell infiltration, reduced regulatory T cell frequencies, and elevated PD-L1 expression, suggesting modulation of the tumor-immune landscape that may enhance susceptibility to anti-PD1 therapy in this model. Ongoing studies aim to determine whether maMICVO synergizes with anti-PD1 to enhance efficacy in this immunotherapy-refractory MOC2 model and to further define the immune changes driving this response at the cellular, molecular, and spatial levels. Collectively, these findings support the continued clinical evaluation of MICVO both as a monotherapy (NCT05720117) and in combination with pembrolizumab (NCT06795412) in difficult-to-treat HNSCC.