Novel mRNA-based Therapeutics to Modulate T and B Cell Signaling and Function

Abstract

Abstract Autoimmunity is considered a T cell driven disease and in many cases B cells contribute to the underlying pathology. Many of the current therapeutics used to treat autoimmunity and organ transplantation are broadly immunosuppressive and can result in increased susceptibility to infection and cancer. We have designed several mRNA-encoded chimeric polypeptides containing an inhibitory motif and a location motif that are expected to disrupt signaling downstream of the T and B cell receptor (T/BCR) and blunt activation. We found that lipid nanoparticle (LNP)-encapsulated mRNA encoding TCR disruptors (Immune LNP-TCRi) containing either a constitutively active CSK (CA.Csk), ITIM, or SHIP1 inhibitory motif reduced in vitro proliferation and cytokine production in primary T cells. In an in vivo xeno-GVHD model Immune LNP-TCRi significantly delayed T cell-mediated mortality. BCR disruptors were engineered by creating mRNA encoding chimeric proteins containing components of the BCR complex (CD79a, CD79b and CD19) and either the CD22 intracellular ITIM or SHIP1 inhibitory motif. Encapsulated in Immune LNP, these BCR disruptors downregulated B cell activation as measured by phosphorylation of Syk, suppressed BCR-induced IgM/G, IL6 and IL10 secretion, as well as reduced B cell in vitro proliferation. In NSG mice engrafted with healthy human PBMC, Immune LNP-BCRi also suppressed humoral immunity against tetanus toxoid and reduced serum IgM and IgG levels. Unlike corticosteroids and anti-CD20 Ab, co-engagement of chimeric T/BCR disruptors did not significant decrease the number of lymphocytes. Thus, amplification of T/BCR disruptor pathway may represent a novel therapeutic approach for autoimmune diseases.