Combined TNF-α and OX40L targeting as a new treatment option for hidradenitis suppurativa
By: Mohamad Bazzi
Many HS patients often live with painful lumps, abscesses, and tunnels that do not respond well to current treatments. A new medicine, SAR442970, could be hope for these patients!
This new drug is unique since it blocks two major sources of inflammation within the immune system at once! Think of a car (the immune system) driving very fast because it has two gas pedals (inflammatory proteins) stuck at the same time. Current treatments only work to lift one gas pedal, so the car keeps speeding. However, SAR442970 lifts both pedals at the same time, helping the immune system significantly slow down inflammation in the body.
SAR442970 was studied in the lab using mice, human immune cells, and monkeys. Scientists found that SAR442970 reduced swelling, redness, and calmed the overactive immune system better than older drugs. Now it’s moving into clinical trials, bringing hope for longer-lasting relief for people living with HS.
Hidradenitis Suppurativa (HS) is thought to occur due to over-activation of inflammation by the immune system. This inflammation eventually leads to the development of painful lumps, tunnels, and abscesses.
The Why
The main treatment for HS patients is to prevent and reduce the inflammation. Therefore, many patients start a medication called Humira (generic name: adalimumab) which is a monoclonal antibody* but unfortunately, many patients still do not get enough relief with it. That is why scientists in this paper are looking at a way to target the immune system to help provide more relief for HS patients.
- *Your body naturally makes antibodies to recognize and fight off harmful things. Monoclonal antibodies are lab-made proteins (similar to antibodies that your body makes) and is designed to be a very specific target to proteins that cause inflammation in the immune system. By specifically targeting one part of the immune system, monoclonal antibodies block one problem in the immune system, while leaving the rest of your immune system working normally!
Overview of this paper:
In the paper researchers developed a new medication called SAR442970 that targets two immune pathways, TNF-α and OX40L, at once! The goal is to see how effective this drug is as a possible treatment option for HS patients!
SAR442970 targets the following:
- TNF- α, a protein in the body that drives inflammation and is currently targeted by many biologic medications.
- OX40L. This molecule is a ligand (or in simple terms, a “key” that is inserted into and turns on the ignition of the immune system. The engine of the immune system is the T-cell, a cell with many important functions, but in HS it produces too much inflammation.
- Once the engine (aka the T-cell is turned on), this cell produces inflammation. Normally, a little inflammation is necessary to fight off bad things in the body, but sometimes, the inflammation can be much more than what is normally needed.
- In HS it is thought that this T-cell engine is over-revving and producing A LOT more inflammation than necessary.
- Therefore, by targeting this pathway, scientists hope to prevent the over-revving engine of the immune system that might be a driving force behind HS.
- Once the engine (aka the T-cell is turned on), this cell produces inflammation. Normally, a little inflammation is necessary to fight off bad things in the body, but sometimes, the inflammation can be much more than what is normally needed.
What the study showed:
The scientists used mice models, cell models, and monkey models to see if SAR442970 reduces inflammation:
Animal Model (lab mice):
- Using lab mice without immune systems, given human immune cells were introduced into the mice in order to cause a very strong inflammatory reaction.
- Because the inflammation was so severe, the mice that did NOT receive the SAR442970 lived only 29 days, versus the mice that DID receive the SAR442970, lived much longer (about 86 days).** This showed that the drug worked to control inflammation much more than mice that were not treated.
- The goal of this part of the study was to see if the new treatment, SAR442970, could calm down this immune attack…. And it did! The treated mice lived longer than the untreated mice.
- **Note, you might be questioning why the mice died during the study. Well, it is because the mice were part of a lab model called “xenograft graft-versus-host disease” model. Essentially, mice that did NOT have an immune system had human immune cells were introduced into them that causes very strong inflammatory reactions which damaged the mice’s body.
Cell Models:
Researchers used human T-cells (part of the immune system) and activated them by exposing them to the molecules (OX40L and TNF- α) that revs-up the inflammation within the immune system. By introducing more OX40L and TNF- α to the human immune cells, the scientists were able to make the immune cells more active, survive longer, and release more inflammatory molecules.
- When the human t-cells became activated, they produced higher levels of inflammatory signals and behaved similar to how they would in HS, i.e., they became more activated with more inflammatory signals.
- When SAR442970 was added, the drug was able to block TNF-α and OX40L at the SAME time, it calmed down the T-cells as there were less IL-2 produced (IL-2 is a protein that tells T-cells to grow and produce more inflammation).
Cynomolgus monkeys (type of monkeys used in research studies).
Scientist used cynomolgus monkeys (an animal who has an immune system and skin biology closer to humans than mice)
- Researchers caused a controlled immune challenge in the skin. Essentially, they caused skin inflammation in the monkeys that is similar to what would be seen in humans having HS flares. The monkeys then developed redness, swelling, and immune cells built up in their skins.
- The scientists then treated with the monkeys with either:
1. TNF-α blocker2. OX40L blocker3. SAR442970 (blocks 1 & 2 together)
What did they find?
- Blocking only TNF-α blocker only provided partial reduction in inflammation.
- Blocking only OX40L blocker only provided partial reduction in inflammation.
-Using SAR442970 significantly reduced inflammation in the skin leading to less immune cells in the skin after treatment.
–Additionally, SAR442970 helped normalize about 75% of the genes that drive inflammation (in HS patients, there are some genes that are turned on too strong and contribute to extra inflammation). Therefore, SAR442970 helped tune down genes back to the normal levels by resetting the genetic inflammatory signals inside of the skin.
Summary:
- HS is challenging to treat, but even with new medical advancements, some HS patients may still flare on these medications.
- Researchers show HS inflammation can be driven by multiple pathways, and by targeting them together with SAR442970, they were able to calm the inflammatory signs and normalize the genes promoting inflammation in HS patients.
Next steps for this study:
- SAR442970 is now in Phase 2 clinical trials using a large group of HS patients with moderate and/or severe HS. If this trial helps HS patients by demonstrating safety in HS patients, reduces flares, and offers better control than other treatment options, this study could pave the path to a new treatment option for HS patients who have not found relief with their symptoms using current biologic treatment.
Reference for paper:
- Leeuw T, Šimaitė D, Heyninck K, Levin C, Cornelis S, Hijazi Y, Rommelaere H, Kreutzberg T, Florian P, Kohlmann M, Brembach TC, Nestle F, Wolk K, Sabat R, Herrmann M. Combined TNF-α and OX40L targeting as a new treatment option for hidradenitis suppurativa. J Allergy Clin Immunol Glob. 2025 Apr 23;4(3):100483. doi: 10.1016/j.jacig.2025.100483. PMID: 40502542; PMCID: PMC12155757.