Tu114 - CUE-401: A Novel il-2/tgf-beta Fusion Protein for the Induction of CD4+ FOXP3+ Regulatory T Cells

Nicholas Jackson – PhD Student, Molecular Microbiology & Immunology, Saint Louis University; Natasha Girgis – Associate Director, Cue Biopharma; Stella Hoft – PhD Student, Molecular Microbiology & Immunology, Saint Louis University; Natalie Yakobian – MD Student, Molecular Microbiology & Immunology, Saint Louis University; Eric Ford – Scientist, Molecular Microbiology & Immunology, Saint Louis University; Jamie Tweedle – Scientist, Cue Biopharma; Emily Christie – Scientist, Cue Biopharma; Kristin Yeung – Scientist, Cue Biopharma; Simon Low – Director, Cue Biopharma; Steven Quayle – Vice President, Cue Biopharma; Ray Moniz – Associate Director, Cue Biopharma; Anish Suri – President and CSO, Cue Biopharma; Rich DiPaolo – Professor and Chair, Molecular Microbiology & Immunology, Saint Louis University

Abstract Text: Strategies that increase the number and/or function of regulatory T cells, including IL-2 therapies and Treg cell-based therapies, are being developed to treat autoimmunity and chronic inflammatory diseases. We have developed a first-in-class biologic, CUE-401, that is comprised of attenuated IL-2 and TGFβ variants linked to an Fc molecule. Co-delivering signals through both IL-2 and TGFβ receptors represents a novel approach to not only expand existing Tregs but to induce new subsets of iTregs specific for disease related antigens.

In vitro data demonstrate that CUE-401 effectively induces de novo FOXP3-expressing iTregs from both mouse and human CD4+ T cells, while also expanding existing Tregs. These iTregs are functionally suppressive and phenotypically indistinguishable from iTregs induced with recombinant TGFβ and IL-2. In vivo, CUE-401 expanded FOXP3+ Tregs in mice with ongoing autoimmunity without inducing proliferation of autoreactive T cells. Single cell RNA-Seq analysis revealed that CUE-401 induced a subset of Tregs that express signatures similar to those described for TGFβ-induced iTregs. Finally, administration of CUE-401 led to long-term suppression of organ specific autoimmune inflammation in a well-established T cell transfer model of autoimmunity. The ability of CUE-401 to potently induce iTregs and suppress autoimmune inflammation represents a novel therapeutic approach. Bias toward iTreg induction rather than manipulation of the limited number and repertoire of existing nTregs may provide significant opportunities for the treatment of patients with various autoimmune diseases as well as treatment of GVHD.