Science

Tridek-One is a growing Paris-based biopharmaceutical company developing molecules acting as agonists of the physiologic CD31 immunomodulatory activities as a new therapeutic strategy to treat immunoinflammatory diseases.
The initial discovery at the heart of the Tridek One therapeutic approach was made by Giuseppina Caligiuri and Antonino Nicoletti (INSERM U1148, team “Cardiovascular Immunobiology” at Bichat Hospital in Paris, France). These two experienced researchers showed that the stabilization of CD31 clustering at the cell membrane by an agonist molecule upholds the inhibitory activity of CD31 in spite of its truncation in activated immune and endothelial cells, thereby moderating the excess immune response. As compared to current immunosuppressive approaches, the side effects of our strategy are limited because the agonists only target activating cells and exert a regulatory effect, rather than fully blocking cell activation.

Scientific rationale

CD31 (also known as PECAM-1) is a transmembrane glycoprotein member of the immunoglobulin family. CD31 is constitutively expressed on all leukocytes, platelets, and endothelial cells. The ability of CD31 to regulate multiple functions of immune cells, endothelial cells and platelets, including their activation, survival and trafficking, establishes CD31’s role as a key player in the dynamic tuning of both innate and adaptive immunity, and as such represents a target of choice for therapeutic intervention. CD31 is a single-chain molecule comprising 6 Ig-like extracellular domains, a short transmembrane segment and a cytoplasmic tail containing two immunotyrosine-based inhibitory motifs (ITIM). During cell activation, trans-homophilic interactions between the 1-domains of two different cells entering in contact cause CD31 clustering at the membrane and subsequent cis-homophilic interactions between the respective 6-domains. As CD31 is not endowed with intrinsic kinase activity, phosphorylation of ITIM occurs through kinases recruited via co-clustered ITAM. Phosphorylated ITIM domains of CD31 then become docking sites for the recruitment of protein phosphatases to the cell membrane, which mediate global homeostatic functions by down-modulating the activation of leukocytes and platelets while exerting vital physiological effects of endothelial cells.

  1. Trans-homophilic interaction between Domains 1 0f CD31
  2.  
  3. Induction of CD31 clustering and homophilic interaction between CD31 domains 6, in CIS
  4.  
  5. Phosphorylation of ITIM by Protein Tyrosine Kinase (PTK) recruited by co-clustered activating receptors
  6.  
  7. Recruitment and activation of SH2-Protein Tyrosine Phosphatases (PTP
  8.  
  9. Inhibition of PTK-dependent cellular pathways signals and activation of PTP-dependent signaling

Upon activation of CD31 expressing cells, CD31 molecules undergo a proteolytic cleavage and shedding.
CD31 shedding results in an increase of circulating extracellular soluble sCD31 fragments which can explain the reported rise of plasma soluble levels of CD31 in patients with active inflammatory conditions including rheumatoid arthritis, lupus, multiple sclerosis and acute ischemia-reperfusion injury and point at the therapeutic potential of CD31 agonists in such situations.

Indeed, the loss of CD31 1-domains with its shedding invalidates its transhomophilc engagement and favors leukocyte activation because the CD31 molecular clusters are dispersed resulting in the loss of the intercellular ITIM-mediated inhibitory signaling.

The Tridek-One proprietary CD31 agonist molecules can maintain the CD31 cluster beyond its shedding, thus prolonging the modulatory effect of CD31 and maintaining a physiological threshold of activation of the immune response. Following on from the earlier demonstration of proof of mechanism of one of our CD31 agonists in several animal models of inflammatory disease, the goal of Tridek-One is to advance an optimized lead candidate to clinical proof of mechanism in an as yet unannounced indication with significant unmet medical need.

 

 

 

Cell residual, truncated CD31:

  • Ability to mediate signalling
  • Potential target for immunomodulation

CD31 Agonist Molecule

  • based on Domain 6 of CD31
  • Perpetuates CD31 signalling
  • Includes Immune cell inhibition

Scientific publications

An immunologist's guide
to CD31 function in T-cells

TridekOne

CD31 is a key coinhibitory receptor in the
development of immunogenic dentritic cells