(733) CUE-401 is a Novel TGF-beta/IL-2 Fusion Protein that Induces Selective Expansion of Functional, Stable FOXP3+ Tregs for Treatment of Autoimmunity

Introduction/Rationale: Regulatory T cells (Tregs) are critical for maintaining peripheral tolerance and immune homeostasis, making them attractive therapeutic targets for treating autoimmune and inflammatory diseases. Efforts to expand Tregs in patients have focused on delivering IL-2 to promote expansion of existing FOXP3+ Tregs. In contrast, CUE-401 was designed to combine novel attenuated variants of TGFb and IL-2 into a single fusion protein, thus delivering the two key signals that are required for conversion of effector T cells into induced Tregs (iTregs) while also promoting expansion of existing Tregs. In the context of autoimmunity or GVHD, where TCR stimulation is provided by autoantigens or alloantigens, respectively, the ability of CUE-401 to convert autoreactive CD4+ T cells into iTregs as they become activated may provide significant advantages for the treatment of patients with these diseases.

Methods: CUE-401 activity was tested in vitro in human healthy donor PBMCs and in vivo in models of xenogeneic GVHD and EAE. Treg frequency and phenotypes were assessed by flow cytometry.

Results: CUE-401 induces and expands highly functional and stable Tregs. In vivo, CUE-401 induces highly selective Treg expansion across mice, rats, and non-human primates at dose levels that are safe and that provide significant therapeutic benefit in multiple disease models, including xenogeneic GVHD and EAE. CUE-401 treatment significantly delays disease onset in EAE and GVHD while reducing effector T cell responses and expanding Tregs that are able to migrate to inflamed tissues and limit diverse types of inflammatory responses, including TH17 and TH1 responses.

Conclusion: Together, these results demonstrate that CUE-401 induces functional, stable Tregs and promotes control of diverse inflammatory responses, supporting the therapeutic potential of CUE-401 to restore immune balance for the treatment of autoimmune and inflammatory diseases.