Prof. Thomas Helleday, Professor of Chemical Biology, K7 Onkologi-Patologi, Karolinska Institute, Stockholm
Q1: Having spent much of your career in cancer research, what drew you to rheumatoid arthritis?
Prof. Thomas Helleday: My laboratory has spent more than two decades studying how cells respond to DNA damage and how cancer cells rewire their metabolism to survive. Over the years, it became increasingly clear that many of the same pathways are also activated in the immune system during chronic inflammation. Rheumatoid arthritis (RA) is a particularly attractive disease model because pathogenic T cells are central drivers of the disease and display profound metabolic adaptations.
The transition to RA originated from Dr Theodora Manolakou, that wanted to join my lab to study this. It is really her energy and drive that showing that mechanisms we originally uncovered in cancer could be repurposed to selectively target disease-causing immune cells. Rather than broadly suppressing the immune system, her idea was to identify metabolic dependencies that are unique to activated inflammatory T cells. Now, this is becoming an important line of work in our laboratory.
Q2: What made you think that the metabolic vulnerabilities you were targeting in cancer might also matter in inflammatory T cells?
Prof. Thomas Helleday: The obvious idea also stem from the use of methotrexate as first-line therapy in RA for decades, hitting the same metabolic vulnerability that we are working on, but less specific. Methotrexate is also used in cancer therapy and it is well established that activated T cells and cancer cells share several important features. Both need to proliferate rapidly, synthesize large amounts of DNA, and sustain demanding biosynthetic programs. That requires high activity of one-carbon metabolism, which supplies nucleotides and supports cellular growth.
Our previous work showed that MTHFD2 and related one-carbon metabolic enzymes are important vulnerabilities in cancer. At the same time, emerging immunology studies suggested that MTHFD2 controls the balance between inflammatory and regulatory T cells. That convergence immediately caught our attention. We began asking whether inflammatory T cells might rely on the same metabolic machinery that we had already spent years studying in cancer. The answer turned out to be yes.
Q3: When you compared treatment-naïve patients with patients who did and did not respond adequately to methotrexate, what surprised you most?
Prof. Thomas Helleday: What surprised us was how strongly the metabolic state was associated with treatment response. We found that treatment-naïve patients and patients who responded inadequately to methotrexate maintained elevated MTHFD2-dependent one-carbon metabolism, whereas patients who responded well looked much more similar to healthy controls.
This suggests that persistent metabolic activation is not simply a consequence of inflammation, but may actually help sustain disease in patients who fail standard therapy. That finding was important because it suggests that metabolic reprogramming could become both a biomarker and a therapeutic target.
Q4: MTHFD1 mRNA did not differ significantly between the groups, yet MTHFD1 protein was elevated in treatment-naïve and methotrexate-inadequate responders. What did the protein data reveal that RNA alone could not?
Prof. Thomas Helleday: This is a very good example of why protein-level measurements remain essential. The RNA data suggested that MTHFD1 expression was relatively stable across groups. If we had stopped there, we might have concluded that MTHFD1 was not contributing to disease biology.
However, the protein analysis revealed a different picture. MTHFD1 protein levels were clearly elevated in treatment-naïve patients and methotrexate-inadequate responders. That tells us that important regulation occurs after transcription, at the level of protein stability, translation, or protein turnover. Since proteins are the molecules that actually perform the biological work in cells, the protein data gave us a much more accurate picture of pathway activity than RNA alone.
Q5: TH9619 inhibits both MTHFD1 and MTHFD2, while the rheumatoid arthritis study centres on MTHFD2-dependent metabolism. Why are both proteins important to the mechanism?
Prof. Thomas Helleday: MTHFD2 is the disease-associated component of the pathway. It is strongly induced in activated inflammatory T cells and is part of the metabolic program that sustains their pathogenic behaviour.
However, our earlier mechanistic studies showed that TH9619 works through coordinated inhibition of both MTHFD1 and MTHFD2. The compound creates what we described as a disease-specific folate trap, disrupting one-carbon flux in a way that selectively affects cells that are highly dependent on this pathway. In other words, MTHFD2 identifies the vulnerable cell state, while MTHFD1 inhibition helps drive the metabolic collapse that gives the compound its activity.
Q6: One-Carbon Therapeutics grew out of this broader research programme. At what point did you see enough evidence to move from an academic discovery towards a drug and a company?
Prof. Thomas Helleday: The critical step was when we had a putative clinical candidate drug that show amazing activity in killing cancer cells. Importantly, we also saw a therapeutic window. The inhibitors targeted cells with unusually high dependence on one-carbon metabolism while sparing normal tissues to a much greater extent than conventional antifolates. At that stage, it became clear that this was no longer just an interesting biological observation. It had genuine translational potential. That ultimately became the foundation for One-Carbon Therapeutics, which has now raised substantial financing and advanced TH9619 into clinical development.
Q7: TH9619 is now in the ODIN Phase 1/2 trial in cancer. What can that trial teach you that could be relevant if this approach were eventually taken into clinical development in rheumatoid arthritis?
Prof. Thomas Helleday: The first thing is safety. Any new mechanism needs to demonstrate that it can be administered safely in humans. The cancer trial provides invaluable information about tolerability, pharmacokinetics, pharmacodynamics and target engagement.
We are working very closely together with Associate Professor Katerina Chatzidionysiou, who is focusing on management of auto-immune related adverse events in cancer patients. We are working on programs to see how we could combine the clinical work in cancer together with her RA work to rapidly get proof-of-concept in humans,
Q8: You mentioned that HPA000704 was also used when you validated MTHFD1 in the cancer research. What exactly did the antibody help you establish there, and what is the value of using the same antibody again in the rheumatoid arthritis work?
Prof. Thomas Helleday: When we validated MTHFD1 as a therapeutic target in cancer, HPA000704 was one of the tools we used to establish protein expression and confirm the biological relevance of the target at the protein level. It helped us move beyond transcriptional observations and directly assess where and how much MTHFD1 protein was present.
Using the same antibody in the rheumatoid arthritis work creates continuity across projects and disease areas. It means we are comparing results generated with a well-characterized reagent that has already performed robustly in our previous studies. That consistency increases confidence that observed differences reflect genuine biology rather than technical variation.
Q9: More broadly, what role have resources such as the Human Protein Atlas and well-validated antibodies from Atlas Antibodies played in building confidence in the biology as you move towards drug development?
Prof. Thomas Helleday: Drug development is fundamentally a process of reducing uncertainty. One of the biggest risks in translational research is whether the target is actually relevant in human disease.
Resources such as the Human Protein Atlas provide an independent and highly valuable framework for understanding where proteins are expressed and how they behave across tissues and diseases. Likewise, access to well-validated antibodies is crucial because protein-level validation is often what transforms an interesting hypothesis into convincing biology.
In our case, these resources have repeatedly helped us confirm observations made using other methods and increased confidence that we are pursuing targets that truly matter in patients.
Q10: If selective MTHFD1/2 inhibition ultimately works in rheumatoid arthritis, what could it offer patients who respond inadequately to methotrexate?
Prof. Thomas Helleday: The hope is that it would provide a more precise alternative for patients whose disease remains driven by activated inflammatory T cells despite standard treatment.
Methotrexate has transformed rheumatology, but it acts broadly on folate metabolism and not all patients respond adequately. Our data suggest that MTHFD1/2 inhibition targets a specific metabolic dependency that persists in many inadequate responders. In experimental systems, TH9619 suppresses inflammatory cytokine production, promotes features associated with regulatory T cells and protects against joint damage.
If these findings translate to patients, the approach could potentially provide disease control through selective reprogramming of pathogenic immune cells rather than broad immunosuppression. That would be a meaningful advance for patients who still have active disease despite current therapies.
Referenced publications:
Manolakou T, Shen J, Boddul S, et al. Targeting NFATc1-regulated MTHFD2 one-carbon metabolism to suppress sustained T-cell-mediated inflammation in rheumatoid arthritis. Signal Transduction and Targeted Therapy. 2026;11:226. doi:10.1038/s41392-026-02752-y. (Nature)
Green AC, Marttila P, Kiweler N, et al. Formate overflow drives toxic folate trapping in MTHFD1 inhibited cancer cells. Nature Metabolism. 2023;5:642–659. doi:10.1038/s42255-023-00771-5. (Nature)
Featured Target Product
Anti-MTHFD1 Antibody HPA000704
Triple A Polyclonals™ developed through the Human Protein Atlas project.
Target protein: methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1, methenyltetrahydrofolate cyclohydrolase, formyltetrahydrofolate synthetase
Target gene: MTHFD1
Verified species reactivity: Human, Mouse, Rat
