Abstract A115: Mouse analog of micvotabart pelidotin sensitizes a refractory syngeneic breast cancer model to anti-PD1 therapy

Abstract Background: Micvotabart pelidotin (micvo/PYX-201) is an antibody-drug conjugate that targets the non-cellular extradomain B of fibronectin (EDB+FN), an extracellular matrix protein abundantly expressed in tumors compared to normal adult tissues—making it an ideal drug delivery target. Preliminary results from a Phase 1, Part 1 clinical trial (NCT05720117) showed that micvo exhibited favorable anti-tumor activity across multiple solid tumor types. In preclinical models, a mouse analog of micvo converted immune-excluded EMT6 tumors into T cell–infiltrated, inflamed tumors, thereby enhancing their responsiveness to anti–PD1 therapy. Here, a similar effect was observed in the poorly immunogenic 4T1 breast tumor model, where the mouse analog of micvo promoted immune engagement and sensitized tumors to anti–PD1 therapy—further supporting its role in driving immunogenic cell death and enhancing anti-PD1 response in a mouse model refractory to immunotherapy. Methods: Immunocompetent mice bearing subcutaneous 4T1 tumors were treated with a mouse analog of micvo (Q4Dx3), anti–mouse PD1 (Q3Dx4), or the combination. Body weight and tumor volumes were measure bi-weekly. Tumor expression of EDB+FN was evaluated by immunohistochemistry. Immune and stromal cell populations in resected tissues were profiled by flow cytometry, while their spatial distribution within tumors was assessed by multiplex immunofluorescence. Results: Treatment of 4T1 tumor-bearing mice with the mouse analog of micvo resulted in robust tumor growth inhibition, highlighting its strong single-agent anti-tumor activity. As expected, anti–PD1 therapy alone had no measurable effect on 4T1 tumor outgrowth. However, combining anti–PD1 with the mouse analog of micvo produced significantly greater tumor growth inhibition than either treatment alone. This combination effect was sustained through the end of the study, indicating prolonged anti-tumor activity that continued to surpass either monotherapy. Consistent with previous findings, the mouse analog of micvo increased immune cell infiltration into 4T1 tumors, including myeloid populations with elevated expression of antigen-presenting molecules and T cells capable of responding to anti–PD1 therapy. All treatments were well tolerated, with no significant weight loss observed. These results suggest that micvo promotes immunogenic remodeling of the tumor microenvironment, enabling anti–PD1 responsiveness in an otherwise refractory model. Conclusions: These results demonstrate that the mouse analog of micvo induced anti-tumor activity, drove tumor-immune remodeling and enabled responsiveness to anti-PD1 therapy. Ongoing studies aim to further define the activation and spatial distribution of immune and stromal cells driving this response. Nonetheless, these findings support the ongoing clinical evaluation of micvo as a monotherapy (NCT05720117) and in combination with pembrolizumab for difficult-to-treat cancers (NCT06795412). Citation Format: Anthony B. Rodriguez, Amanda Facklam, Justin Trickett, Sara Lewandowski, Matthew Iovino, Chuan Shen, Frank Wang, Nicolas Severe, Marsha Crochiere. Mouse analog of micvotabart pelidotin sensitizes a refractory syngeneic breast cancer model to anti-PD1 therapy [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2025 Oct 22-26; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2025;24(10 Suppl):Abstract nr A115.