Cue Biopharma has received positive Pre-Investigational New Drug (Pre-IND) feedback from the U.S. Food and Drug Administration for CUE-401, its lead autoimmune therapy candidate. The FDA reviewed the company's first-in-human trial design, including dose escalation plans, proposed patient populations, and safety monitoring protocols. Based on this feedback, the clinical-stage biopharmaceutical company intends to file an IND application pending completion of final IND-enabling studies.
CUE-401 represents a first-in-class bispecific fusion protein designed to induce and expand regulatory T cells (Tregs) in vivo through the combined activity of transforming growth factor beta (TGF-β) and a modified variant of interleukin 2 (IL-2). The therapy targets T-cell mediated autoimmune and inflammatory diseases by selectively engaging and modulating disease-specific T cells.
Novel Mechanism of Action
The therapeutic approach leverages what researchers describe as the "master switch" for T cell conversion. According to Dr. Dan Baker, chief development officer of Cue Biopharma, "CUE-401's mechanistic design extends beyond nTreg proliferation by transforming effector/autoreactive responses to an anti-inflammatory and/or suppressive response, with the prospects of establishing tolerance. The combination of interleukin 2 (IL-2) and transforming growth factor beta (TGF-β) is considered the 'master switch' for conversion of activated T effector cells into T cells with a regulatory phenotype."
The drug has been engineered to harness the Treg induction capacity of TGF-β combined with IL-2 signaling to provide what the company believes to be superior quality and stability of regulatory T cells. The design specifications have been guided by scientific publications demonstrating that both IL-2 and TGF-β are required for stable and efficient production of active and durable Tregs.
Preclinical Evidence and Differentiated Design
CUE-401 is designed to overcome multiple therapeutic hurdles through a first-in-class bispecific molecule that integrates a masked TGF-β with a clinically validated, attenuated IL-2 and an antibody Fc fragment. This novel design provides "conditional binding" and avoids off-target activity while simplifying manufacturing processes.
In preclinical models, CUE-401 functions as a master switch to convert autoreactive effector T cells into stable, induced T-regulatory cells (iTregs). The findings suggest that CUE-401 establishes a "tolerance positive feedback loop" that not only increases nonspecific Treg populations but critically reduces and converts specific autoreactive T cells into transdifferentiated iTregs that are specific for disease-causing autoantigens.
Clinical Development Strategy
Daniel Passeri, chief executive officer of Cue Biopharma, expressed confidence in the regulatory pathway forward: "We are highly encouraged by the FDA's positive feedback on our proposed development plan for this important program. We believe CUE-401, with its first-in-class mechanism exploiting the combined activities of TGF-β and IL-2 is a potentially disruptive approach differentiated from other Treg-directed therapies, and has the potential to provide durable, long-lasting immune rebalance and tolerance addressing multiple, significant disease indications."
The company's proprietary Immuno-STAT (Selective Targeting and Alteration of T cells) platform is designed to harness the curative potential of the body's intrinsic immune system without the adverse effects of broad systemic immune modulation. This approach represents a departure from conventional immunosuppressive therapies by specifically targeting disease-relevant T cells while preserving overall immune function.
Regulatory Pathway and Next Steps
The positive FDA feedback positions Cue Biopharma to advance CUE-401 toward clinical testing following completion of final IND-enabling studies. The regulatory milestone represents a significant step forward for the Boston-based company's autoimmune disease program and validates the scientific rationale underlying the Treg-directed therapeutic approach.
The development of CUE-401 addresses a significant unmet medical need in autoimmune disease treatment, where current therapies often provide broad immunosuppression rather than targeted immune modulation. The therapy's potential to establish immune tolerance while maintaining overall immune competence could represent a paradigm shift in autoimmune disease management.
