Abstract A114: Micvotabart pelidotin, an ADC targeting non-cellular EDB+FN, induces an immune response 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, and mobilize an anti-tumor immune response. Support for the latter was shown in preclinical studies where a mouse analogue of micvo induced CD3+ T-cell infiltration into tumors from syngeneic mice. The present study aimed to confirm micvo’s ability to mobilize an anti-tumor immune response in tumor samples from clinical trial participants with advanced solid tumors in the dose escalation part of a phase 1 study (NCT05720117) and characterize this pharmacodynamic response. Baseline and matched on-treatment biopsies from participants were collected prior to study enrollment 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 using AI-powered digital pathology to characterize the tumor-immune interaction. Multiplex-immunofluorescence (mIF) staining, coupled with digital pathology analysis, was deployed using a panel designed to characterize changes in the tumor immune microenvironment. Gene expression analysis with RNA isolated from tumor biopsies was evaluated using the Nanostring IO360 panel. Micvo induced an increase in the proportion of lymphocytes within the cancer epithelium of clinical tumors after treatment as determined by digital pathology. Using an orthogonal technique, micvo increased the density of CD3 staining in tumor nests as determined by mIF assessment. This increased density of CD3 staining within tumor nests was not accompanied by an increase in FoxP3 staining. Notably, the magnitude of T-cell infiltration was greater in participants with a stable disease response compared to those with progressive disease, per RECIST v1.1. Greater T-cell infiltration after treatment correlated with a longer total time on study. Lastly, gene expression profiling revealed an increase in the expression of immune-related signatures (e.g. antigen presentation and leukocyte migration) after treatment supporting the histology-based observations of lymphocyte infiltration and suggesting concurrent myeloid changes. Collectively, these results support micvo’s ability to mobilize an anti-tumor immune response across participants’ solid tumors and the resulting T-cell infiltration provides further rationale for the ongoing clinical trial in combination with a PD-1 inhibitor across cancer types. Micvo’s ability to remodel tumor stroma is also under investigation in these biopsies. These pharmacodynamic responses will be further characterized in tumor-specific expansion cohorts from the ongoing clinical evaluation of micvo as monotherapy (NCT05720117) and in combination with pembrolizumab (NCT06795412). Citation Format: Eugene Lurie, Sara Lewandowski, Justin Trickett, Krystal Watkins, Anthony W. Tolcher, Katherine Clifton, Benedito A. Carneiro, Jason T. Henry, Shiraj Shen, Nuria Kotecki, Sylvie Rottey, Rachel Galot, Hongwei Wang, Marsha Crochiere. Micvotabart pelidotin, an ADC targeting non-cellular EDB+FN, induces an immune response 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 A114.