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Licensing opportunity DI 04/107

Prostaglandin E2 induces indoleamine 2.3 deoxygenase expression and works in synergy with TNF-SF and TLR ligands to trigger its activity

Inventors: M. ALBERT et al.

Description of invention: 

The present invention relates to controlling and / or manipulating dendritic cells by modulating the expression and activity of indoleamine 2,3 deoxygenase (IDO). Specifically, it discloses a two-step mechanism for activating the IDO enzyme.

Specific advandages

This discovery permits overcoming dendritic cell-mediated or tumor-mediated tolerance in cancer patients. The ability to control and / or modulate the maturation of dendritic cells offers several advantages :
Assessing substances for their potential to provide immuno-therapy and / or anti-tumor effect.
Providing a method to predict the ability of a tumor in a patient to mediate immune evasion by measuring IDO expression and / or enzymatic activity in patient dendritic cells. 

 Potential applications:
 Use of COX-2 overexpression in tumors as a biomarker for IDO activity, a predictor for the tumors’ ability to mediate immune evasion.
 Use of systemic IDO inhibitors (or inhibitors of the tryptophan catabolism pathway) in COX-2 expressing tumors.
 Use of IDO inhibitors (or inhibitors of the tryptophan catabolism pathway) during DC maturation for use in adaptive immune therapy protocols. This strategy will block the negative effects of PGE-2 (IDO upregulation), while preserving its beneficial activity in stimulating DC migration. 
Patent Status:
  PCT application (PCT/EP 2005/011796) filed on October 18th, 2005 

 US 11/251,877 filed on October 18th, 2005
 Both under the priority of US 60/629,896 filed on November 23rd, 2004. 

 A two step induction of indoleamine 2,3 deoxygenase (IDO) activity during dendritic cell maturation.
Deborah Braun, Randy S. Longman and Matthew L. Albert.
Blood. 106: 2375-81 (2005).
 Indoleamine 2,3-deoxygenase-expressing dendritic cells form suppurative granulomas following Listeria
monocytogenes infection.
Popov, Z. Abdullah, C. Wickenhauser, T. Saric, J. Driesen, F.-G. Hanisch, E. Domann, E. L. Raven, O. Dehus, C. Hermann, D. Eggle, S. Debey, T. Chakraborty, M. Kronke, O. Utermohlen, and J. L. Schultze. J. Clin. Invest., December 1, 2006; 116(12): 3160 - 3170.
 CD25 and indoleamine 2,3 deoxygenase are up-regulated by prostaglandin E2 and expressed by tumor
associated dendritic cells in vivo: additional mechanisms of T-cell inhibition.
Michael S. von Bergwelt-Baildon, Alexey Popov, Tomo Saric, Jens Chemnitz, Sabine Classen, Marc S. Stoffel, Francesca Fiore, Udo Roth, Marc Beyer, Svenja Debey, Claudia Wickenhauser, Franz-Georg Hanisch, and Joachim L. Schultze
Blood, 1 July 2006, Vol. 108, No. 1, pp. 228-237.

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