CHALLENGE

The co-stimulatory CD40-CD40L dyad is crucial in the development and progression of immune re- sponses and chronic inflammatory diseases, such as atherosclerosis, obesity and multiple sclerosis. However, long-term antibody-mediated inhibition of CD40L or CD40 is not clinically feasible as it re- sults in thromboembolic events and severe immune suppression. More downstream inhibition of the CD40L-CD40 pathway is therefore preferable, especially tumor necrosis factor receptor-associated fac- tors (TRAFs) recruited by CD40.

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INNOVATION

Several TRAF knock-out mouse models indicated that CD40-TRAF6 interactions play an essential role in inflammatory diseases. Here a set of inhibitors that selectively block CD40-TRAF6 interactions is presented. The rest of the CD40 cascade is left unaffected preventing unwanted immune-suppressive sideeffects.

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COMMERCIAL OPPORTUNITIES

The new inhibitors offer promising candidates as therapeutic agents for the treatment of chronic in- flammatory diseases, such as atherosclerosis, obesity and multiple sclerosis. The selective blockage of the CD40-TRAF6 interactions therefore strongly reduces inflammation, whereas unwanted immu- ne-suppressive side effects are limited.

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Figure A: Inhibitor treatment reduces atherosclerotic burden in Apoe-/- mice by limiting plaque inflammation; representative longitudinal images of the aortic arch and brachiocephalic trunk (H+E staining); Apoe-/- mice were treated with inhibitor at 10 µmol/kg/day for 6 weeks, starting at the age of 12 weeks. Figure B: Inhibitor treatment improves adipose tissue inflammation; representative H&E-stained sections from livers of control- or inhibitor-trea- ted mice; WT mice were fed a high fat diet for 12wk receiving vehicle/inhibitor starting at week 6 of feeding.

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DEVELOPMENT STATUS

• Selective small molecule inhibition of the CD40-TRAF6 pathway
• No side effects in mouse model observed
• Reduction of pro-inflammatory leukocytes
• Efficacyshown in mouse models for metabolicdiseases (obesity,diabetes), atherosclerosis, sep- sis, EAE

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REFERENCES

1. Aarts et al., J Neuroinflammation. 2017;14(1):105
2. ZarzyckaetalJChemInfModel.2015;55(2):294-307
3. Chatzigeorgiou et al, PNAS. 2014;111(7):2686-91
4. VandenBergetal.IntJObes.2015;39(5):782-90