Translating immunosuppressive risks of T-cell bispecifics using human in vitro models and systems immunology 9247

Abstract Description T cell-engaging bispecific antibodies (TCBs) depleting B cell subsets are promising therapeutics for cancer and autoimmune diseases, with several approved or in development. However, an unavoidable consequence is immunosuppression in already vulnerable patients. Depleting B cells compromises the ability to fight infections and vaccine efficacy. These risks vary with underlying disease, effects on off-target cell populations and the TCB target. Differentiating drug candidates’ secondary TCB effects is key in drug development, but preclinical models may not fully capture complex B cell biology. We employed a multimodal systems immunology approach of two human in-vitro systems: immune organoids capturing productive germinal center responses, and an immunocompetent bone marrow model with B precursor- and differentiated plasma cells. We integrated data from high-dimensional flow cytometry, single cell RNA- and CITE-sequencing, to assess the consequences of TCB-mediated immune responses across different tissues. This allowed us to capture a differential off-tumor B cell subset toxicity of TCBs directed against two therapeutically validated TCB targets, in line with the reported clinical infection risk and B cell depletion that diverge between both. Overall, this translational work shows the value of human in-vitro approaches as a preclinical evaluation for immunosuppression, by accurately capturing complex human immune biology and therapeutic activity of candidate molecules. Topic Categories Translational and Interventional Immunology (TI)