P17-19 Comparative analysis of AZD0486-mediated cytokine release in healthy donors and systemic lupus erythematosus patients

AZD0486 is a fully human bispecific anti-CD3-CD19 T cell engager (TCE) being developed for the treatment of B-cell non-Hodgkin lymphoma (NHL), B-cell acute lymphoblastic leukemia (BALL), and moderate to severe systemic lupus erythematosus (SLE). SLE is a heterogeneous, potentially fatal chronic autoimmune disease affecting one or more organ systems with complex pathogenesis in which cytokines play an essential role. Cytokine release syndrome (CRS) is one of the most reported acute and dose-limiting toxicity associated with therapeutic TCEs. Compared to Oncology patients, CRS tolerance with TCE is expected to be lower in SLE patients, considering the altered interaction between innate and adaptive immunity. Currently, no in vitro or in vivo models fully recapitulate CRS preclinically, leading to a major discrepancy between preclinical safety assessment and clinical outcomes with TCEs. The objective of this study was to evaluate the effects of AZD0486 on cytokine production using whole blood (WB) from SLE patients compared to healthy donors. Cytokine levels and immunophenotyping in WB samples from 15 consented healthy donors and 9 lupus patients were measured at 24 and 72 hours. Overall, AZD0486 induced low levels of TNF-α, IL-1β, IFN-γ, and IL-6 compared to the relevant positive controls (anti-CD3 and Immunocult) and comparator molecules (GlofitamabTm and BlincytoTm) in healthy individuals and SLE patients at the comparable concentrations. The level of cytokines induced by AZD0486 at the different concentrations tested was similar to those observed with the isotype control, an antibody binding only to T cells with no CD19 binding domain. Collectively, we observed lower basal levels of cytokines in healthy donors compared to lupus patients, suggestive of a hyperregulated immune response in autoimmune patients and potentially higher CRS risk.