Cue Biopharma (NASDAQ:CUE) used a virtual R&D Day event on April 7, 2026, to highlight its lead autoimmune and inflammation program, CUE-401, and to outline upcoming development milestones. Interim President and CEO Lucinda Warren said the company’s “primary business focus is CUE-401,” which she described as a potential first-in-class bifunctional molecule intended to leverage both TGF-beta and IL-2 pathways to treat autoimmune and inflammatory diseases.
Pipeline updates and near-term milestones
Warren said Cue has completed manufacturing and IND-related activities for CUE-401 and plans to file an IND in the second quarter, followed by initiation of a Phase 1 trial. Chief Development Officer Dr. Daniel Baker later added that IND-enabling work is complete, including a four-week GLP toxicology study, with the IND submission “in preparation for submission in June.” He said the first-in-human Phase 1 program in healthy volunteers is expected to start shortly after, with single ascending dose (SAD) results anticipated by the end of 2026 and multiple ascending dose (MAD) results expected in the first half of 2027.
Separately, Warren said Cue’s CUE-100 series was licensed to ImmunoScape at the end of 2025. She said the agreement included $15 million upfront, high single-digit royalties on future sales, and a 40% equity stake in ImmunoScape. Warren noted that ImmunoScape continues work toward potential IND submissions for additional trials in 2027 and said Cue’s prior Phase 1 datasets for CUE-100 series candidates showed clinical activity in multiple metastatic cancers “without the significant toxicities” often seen with traditional IL-2 delivery.
CUE-401 design and intended mechanism
Dr. Baker framed CUE-401 as a therapeutic aimed at restoring immune tolerance by “directly inhibiting inflammatory pathways and enhancing T cell regulation.” He said CUE-401 combines a TGF-beta component with a modified IL-2 and is designed to leverage research indicating that concurrent signaling through IL-2 and TGF-beta receptors can induce and stabilize FoxP3, converting autoreactive effector cells into regulatory T cells (Tregs).
Baker said the company sought to address historical limitations of TGF-beta therapeutics—poor pharmacokinetics, off-target toxicity, and manufacturability—through protein engineering. He described CUE-401 as built on a “knob-in-hole Fc backbone” with attenuated cytokine components and said the design is intended to promote concomitant binding to both receptors, creating avidity and biasing activity toward immune cells expressing both IL-2 and TGF-beta receptors. Baker said the attenuation of cytokine affinities is “up to 10,000-fold.”
On manufacturing, Baker said Cue has completed production of 2,000-liter batches from a master cell bank with a production titer of about 8 grams per liter and said the half-life in non-human primates is about three days, while the pharmacodynamic effect on Tregs lasts longer, supporting intermittent dosing.
Preclinical data presented: models and immune effects
Baker and invited researchers discussed a range of in vitro and in vivo findings. In a graft-versus-host disease model, Baker said three early doses of CUE-401 resulted in 50% survival to day 95, compared with all control animals dying by day 62, along with increased Tregs in spleen and targeted tissues. He also described results in a multiple sclerosis model showing extended disease-free survival and in a delayed-type hypersensitivity model where a single dose of CUE-401 was described as “as effective as cyclosporine” dosed daily in suppressing immune activity.
Dr. Richard DiPaolo, Professor and Chair of Molecular Microbiology & Immunology at Saint Louis University, presented collaboration data and described CUE-401 as an Fc-based fusion linking an attenuated IL-2 to a “receptor-masked TGF-beta 3 variant.” He reported three main in vitro outcomes: efficient induction of FoxP3-positive induced Tregs (iTregs) from naïve CD4 T cells, expansion of endogenous Tregs that maintain FoxP3 expression, and reprogramming of effector memory T cells toward a less inflammatory state with reduced cytokine production.
In vivo, DiPaolo said a single dose expanded Tregs markedly six days after administration, from about 20% to over 60% of the CD4 compartment, while conventional CD4 T cells showed minimal activation. He said sorted Tregs from treated mice showed demethylation of the FoxP3 TSDR comparable to natural Tregs and maintained FoxP3 expression after reactivation, indicating stability. DiPaolo also described gene-expression and flow cytometry findings consistent with an activated Treg program and said comparisons to an IL-2-only variant suggested TGF-beta3 was “essential” for a regulatory gene signature while helping avoid effector activation.
In an autoimmune gastritis model, DiPaolo said mice received two doses (days 1 and 14). Sixty days later, he reported that autoreactive T cells in the stomach were reduced from 44% to 10% and that disease scores were cut in half, with some mice showing complete protection—evidence he said supports durable tolerance after early treatment.
Broader anti-inflammatory effects discussed by clinical KOL
Dr. Jonathan Kay, a rheumatologist and immunologist at UMass Chan Medical School, discussed data on CUE-401’s direct effects on other immune cell types. He described in vitro findings showing that CUE-401 inhibited production of multiple TH1, TH2, and TH17 cytokines from human CD4 memory T cells, including interferon-gamma, IL-4, IL-13, IL-17, IL-22, GM-CSF, and IL-6, while an IL-2 mutein Fc fusion protein without TGF-beta did not show the same suppressive effect in those assays.
Kay also reviewed data indicating CUE-401 inhibited IL-2-driven NK cell proliferation and granzyme B production and reduced the proportion of NK cells producing interferon-gamma and TNF in a dose-dependent manner. In B-cell experiments, he said CUE-401 had little effect on mature B cells but reduced plasmablast differentiation and suppressed antibody production.
Q&A: safety considerations, durability, and Phase 1 design
During the Q&A, Director of Translational Pharmacology Dr. Natasha Girgis addressed questions about the TGF-beta “mask,” confirming it is not conditionally activated by proteases or specific tissues. She said the mask reduces affinity up to 10,000-fold, leading to “very attenuated” signaling, and noted the molecule’s roughly three-day half-life. Girgis added that IL-2 increases avidity and may bias binding toward IL-2 receptor-positive cells and argued that intermittent dosing could limit prolonged TGF-beta agonism. She said repeat-dose non-human primate studies with more intensive dosing than anticipated clinically did not show evidence of organ fibrosis.
Asked about clinical differentiation, Kay said CUE-401’s ability to increase Tregs and convert T effector cells into Tregs “increases the efficacy” and suggested potential for steroid-sparing treatment, citing conditions including atopic dermatitis, systemic lupus erythematosus, inflammatory bowel disease, and inflammatory arthritis.
Baker, responding to a question on durability, said peak Treg generation is about seven days and that Tregs “stay around for at least 28 days” in peripheral blood and potentially longer in tissues. He said the company believes the response “will last up to months” and could support intermittent dosing.
About Cue Biopharma (NASDAQ:CUE)
Cue Biopharma is a clinical‐stage biotechnology company focused on the development of next‐generation immunotherapies for cancer and infectious diseases. The company’s proprietary platform, known as Cytokine Release & Targeting (CRT), is designed to deliver cytokine payloads directly to antigen‐specific T cells in order to enhance immune responses within targeted tissues. This approach aims to improve the therapeutic index of cytokine treatments by limiting systemic exposure and potentiating localized immune activation.
Founded in 2015 and headquartered in Cambridge, Massachusetts, Cue Biopharma has advanced multiple lead programs into early‐stage clinical studies.
