 Juan Carlos Lopez |
 Andy Marshall |
This year’s Nobel Prize for Physiology or Medicine was awarded to Mary Brunkow, Fred Ramsdell and Shimon Sakaguchi for the discovery of regulatory T cells (Tregs)— white blood cells whose role it is to suppress overactivation of our immune system. The prize was unusual in that Brunkow made her discoveries while leading an industry R&D team at Darwin Molecular (now defunct). Ramsdell and Sakaguchi are also co-founders of two prominent biotech companies developing Treg therapies: Ramsdell’s Sonoma Biotherapeutics is developing autologous Treg therapies against arthritis and hidradenitis suppurativa, together with a LFA3-IgG1 fusion molecule for depleting CD2+ effector T cells; and Sakaguchi’s Coya Therapeutics is developing a low-dose interleukin 2 (IL-2)/CTLA-IgG1 fusion combination for amyotrophic lateral sclerosis and other neurodegenerative disorders; the Nobel prize likely helped boost Coya’s announcement in October to raise $20 million in follow-on funding on the public markets.
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Tregs have long attracted the attention of drug developers interested in autoimmune conditions, diseases where the immune system is overactive. But progress in this field has been slow, and the first clinical results for T-reg cell therapies are only now beginning to emerge in liver transplantation and kidney transplantation. (Low-dose IL-2 treatments that promote Tregs have also begun to show promise in lupus and systemic sclerosis patients.)
The overarching idea behind Treg cell therapy has been to isolate these cells from a patient, introduce/upregulate expression of the FOXP3 transcription factor that marks them from other T cells, and expand them before giving them back to the patient.
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Early attempts to develop this autologous therapy failed in part because Tregs are less numerous in the peripheral blood than effector CD4/CD8 T cells, difficult to isolate and problematic to expand. Moreover, the isolated Tregs are polyclonal, targeting multiple antigens. Approaches that expanded this unmodified polyclonal population of cells and put them back into patients resulted in a ‘diluted’, clinically insignificant, therapeutic effect.
To address this problem, companies are now turning to leverage advances in the chimeric antigen receptor (CAR)-T cell therapy field. A whole slew of Treg cell therapies is being engineered with CARs or T-cell receptors (TCRs), allowing targeting to specific antigens in specific organs.
As we mentioned above, the most advanced of these are in the organ-transplantation field, where chronic immunosuppression renders patients susceptible to infections that can be lethal. Sangamo Therapeutics’ TX200 and Quell Therapeutics’ QEL-001 are CAR-Treg therapies for renal- and liver-transplant rejection, respectively. These assets, which are in phase 1/2, both bind to human leukocyte antigen HLA-A2, which is exclusively expressed on the transplanted donor organ, ensuring that the Tregs travel exclusively to the place where they are needed. Elsewhere, Sonoma is also developing an autologous CAR-Treg therapy, SBT-77-7101, that targets citrullinated proteins abundant in rheumatoid arthritis (for which Sonoma recently announced positive interim phase 1 data) and the skin condition hidradenitis suppurativa.
A second focus for companies has been on TCR-engineered Tregs. The great theoretical advantages of TCRs over CARs are that 1) they have high sensitivity at low antigen density, 2) they focus exclusively on antigen-presenting cells which then reeducate/suppress effector T cells; 3) they don’t bind soluble antigen and 4) most autoimmune diseases are driven by intracellular proteins presented as processed peptides in the context of HLA. As yet, however, only a few companies are pursuing the approach. One example is GentiBio, which is developing GNTI-122 for type 1 diabetes. This Treg product expresses a TCR targeting a fragment (IGRP 305–324) of the pancreatic islet-specific antigen glucose-6-phosphatase catalytic subunit-related protein (IGRP). Another pioneer in this area, Abata Therapeutics, had also been developing a TCR-engineered Treg therapy (targeting myelin peptide/HLA-DRB1*15:01 for multiple sclerosis); however, the frosty financing environment in the first half of 2025 meant it ran out of cash and Abata closed its doors in August.
One challenge that all Treg cell therapies face is the plasticity of these cells and their tendency to shape shift into effector T cells, a phenotypic change that, in the therapeutic setting, could lower efficacy or even exacerbate pathology. One approach to address this problem has been to modify the cells by overexpressing the transcription factor FOXP3, the master regulator of Treg development. For example, as methylation of the FOXP3 promoter under inflammatory conditions can turn Tregs Into effector T cells, Quell’s Tregs are engineered with a methylation-resistant FOXP3 that compels the cells to remain in their suppressor phenotype. And to bring us back to where we started, Nobel laureate Sakaguchi turns out to be a serial entrepreneur, founding another company, Regcell, that recently relocated from Japan to the US on the back of a $45.8 million financing back in March. The company is using small-molecule CDK8/19 inhibitors that act as epigenetic modulators to lock in FOXP3+ Tregs that show a stable suppressive phenotype in vivo.
But Treg cell therapies still face stiff competition. Ironically, perhaps, from their antithesis: the effector CAR-T cell. Pioneering work by Georg Schett’s group at Friedrich Alexander University Erlangen-Nuremberg has galvanized numerous efforts to develop CAR-T depleters of pathogenic B-cell or plasma-cell subsets in autoimmune conditions. Evidence is growing for the clinical efficacy of this approach in diseases such as lupus or myasthenia gravis.
But the holy grail would be to dispense with cell therapy altogether and promote Treg activity in situ, without the need for purification and modification/expansion outside the body. By focusing on injectable biologics, many companies can bring products to market that are easily accommodated into current clinical practice, dispensing with the need for leukopheresis (an approach alien to most rheumatologists) and the complex logistics of ex vivo cell therapy.
Nektar Therapeutics’ rezpegaldesleukin is a pegylated IL-2 given at low doses that acts on CD25, the high-affinity IL-2 receptor enriched in Tregs. The company recently reported positive phase 2 data in atopic dermatitis. Elsewhere, Egle Therapeutics and Mozart Therapeutics have discovery programs developing bispecific antibody Treg engagers for multiple autoimmune diseases. TrexBio has developed a peptide agonist of tumor necrosis factor receptor 2 (TNFR2), announcing in June the dosing of its first participant in a phase 1 trial for atopic dermatitis and other inflammatory diseases. Zag Bio is another T-cell engager play that recently came out of stealth,
The Treg field can rightly celebrate its Nobel recognition and the progress made towards bringing this cell type to patients. Although it will likely be several years before we gain a full picture of how Treg biology can be leveraged to fight autoimmune disease, the field eagerly awaits the readout from early efficacy trials of cell therapies and potentially an FDA-approved product for the biologics in later development.
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