T cell dependent bispecific antibodies (TDBs) promote T cell redistribution through organ-specific alteration of vascular endothelial cell (scRNAseq)

TDBs (T cell dependent bispecific antibodies) have an agonistic anti-CD3 arm paired with a tumor-targeting arm that recognizes tumor-restricted/enriched cell-surface proteins. Preclinical and clinical studies demonstrated that TDBs can induce systemic changes in addition to their expected action in tumors, including transient loss of circulating leukocytes (margination), systemic cytokine release, and accumulation of lymphocytes in normal tissues. These reactions can lead to undesirable symptoms including cytokine release syndrome and liver enzyme elevation. Here, we report for the first-time an in-depth characterization of acute responses in tumor and liver upon TDB treatment. We observed rapid and substantial accumulation of lymphocytes around large blood vessels in normal organs such as the liver, accompanied by elevated vascular endothelial cell (EC) activation markers. We hypothesized that organ-specific EC phenotypes may account for the differential T cell accumulation in normal tissues versus tumors. Despite ongoing efforts to better characterize specific properties of ECs, the underlying transcriptional changes of specific endothelial cell subtypes influencing the T cell trafficking and accumulation in non-target-expressing organs (like here liver) upon TDB treatment are unknown. The purpose of the study is to investigate the effect of anti-HER2/CD3 TDB treatment on the endothelial cells in the liver and characterize possible transcriptional changes occurring. Overall design: scRNA sequenced from dissociated liver tissue of three control-treated and three anti-HER2/CD3 TDB-treated mice