Abstract A113: Micvotabart pelidotin, a non-cellular targeting ADC, remodels the tumor microenvironment in tumors from participants in a phase 1 dose escalation study

Abstract Micvotabart pelidotin (micvo) is an antibody-drug conjugate (ADC) that targets extradomain-B of fibronectin (EDB+FN), a non-cellular structural component within the tumor extracellular matrix that is highly expressed in tumors compared to normal adult tissues. Micvo is designed to kill cancer cells, remodel the tumor microenvironment (TME), and mobilize an anti-tumor immune response. Part 1 of the phase 1 dose escalation study (NCT05720117) assessed the safety, tolerability, pharmacokinetics, pharmacodynamics, and preliminary efficacy of micvo monotherapy in participants with advanced solid tumors. Histologic approaches to characterize the tumor and stromal compartments were recently evaluated on nonclinical human tumor samples and in animal models and here were deployed on the clinical tumor biopsies from the dose escalation study to characterize the pharmacodynamic response to micvo in the TME. Baseline and matched on-treatment biopsies from participants in the dose escalation study were collected prior to study treatment and during Cycle 2 of micvo treatment, respectively. Biopsies were evaluated for pharmacodynamic biomarkers and correlation to drug response. H&E-stained tumor sections were evaluated by a board-certified pathologist for percent stroma and using AI-powered digital pathology to characterize the stromal composition and architecture. EDB+FN immunohistochemistry, scored by a board-certified pathologist, was used to assess EDB+FN target expression. Multiplex-immunofluorescence (mIF) staining, coupled with digital pathology analysis, was deployed to assess changes in the TME. Histological changes reflective of drug activity and clinical outcome were evident in the tumor epithelium after two cycles of micvo treatment, including decreased density of cancer cells in the tumor epithelium and clinical response-specific changes in tumor cell proliferation and apoptosis. Stromal remodeling was also apparent in response to micvo treatment, including decreased cellularity in regions of the TME where EDB+FN was present, regardless of clinical response. Notably, total percent stroma and EDB+FN target expression in the stroma, quantified by stromal H-score, were unchanged in on-treatment biopsies compared to baseline samples. Additional stromal remodeling, including changes in ECM fiber organization, stromal cell composition, and proportional changes in histological stromal subtypes within the tumor stroma correlated with clinical outcome. Collectively, these data demonstrate a pharmacodynamic effect of micvo on both tumor cells and stromal remodeling, reflective of the mechanism of action of this novel non-cellular targeting ADC. Micvo’s ability to mobilize an anti-tumor immune response is also under investigation in these biopsies. These pharmacodynamic changes will be further characterized in indication-specific expansion cohorts from the ongoing clinical evaluation of micvo as monotherapy (NCT05720117) and in combination with pembrolizumab (NCT06795412). Citation Format: Sara Lewandowski, Justin Trickett, Eugene Lurie, Krystal Watkins, Anthony W. Tolcher, Katherine Clifton, Benedito A. Carneiro, Jason T. Henry, Judy Wang, Shiraj Sen, Nuria Kotecki, Sylvie Rottey, Jean-Pascal Machiels, Hongwei Wang, Marsha Crochiere. Micvotabart pelidotin, a non-cellular targeting ADC, remodels the tumor microenvironment in tumors from participants in a phase 1 dose escalation study [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 A113.