Tu153 - Treatment of a Humanized GVHD Model with PanTreg Is Clinically Superior to Adalimumab and Induces Infectious Immune Tolerization of the Systemic Immunome

Abstract Text: PanTreg design: The antigen binding domain is directed towards TNF-alpha. This enables homing to the diseased microenvironment of any autoimmune disease in which TNF-alpha is expressed and drives pathogenesis, including Rheumatoid Arthritis, Psoriasis, IBD, and also GVHD. The construct constitutively expresses FoxP3, to confer and stabilise a Treg functional phenotype. Tolerogenic cytokines IL-10 and TGF-beta are induced upon TNF binding. Thus, upon activation, PanTreg cells target a main pathogenic pathway, without depending on a purported etiologic antigen. Inducible cytokine production also reduces risks of off-target effects. PanTreg can target virtually any disease where TNF is pathogenically relevant.
We validated this approach in a humanised model of GVHD, leading to a complete control of the disease with highly significant differences in clinical outcomes when compared with state of art therapies such as anti-TNF (Adalimumab), or polyclonal Tregs.
We compared the changes induced by PanTreg on the architecture of the Immunome systemically with Adalimumab treatment, leveraging an AI-powered single cell proteomics platform. PanTreg treatment determined a significant decline in inflammatory Teff and an increase in the production of tolerogenic cytokines, all elements associated with the induction of infectious immune tolerance. Conversely, treatment with Adalimumab did not reduce inflammatory memory Teff, possibly attributing its inferior clinical efficacy with a simple inhibition of a circulating cytokine, without affecting, unlike PanTreg, the underlying cellular mechanisms of autoimmunity. Spacial transcriptomics data showed a preservation of tissue architecture and minimal inflammatory infiltration in PanTreg-treatment, as opposed to Adalimumab, where tissue destruction was accompanied by inflammatory Teff infiltration.