Toll-like receptors (TLR) belongs to Pattern Recognition Receptors (PRR) used by the immune system to recognize molecular structures from pathogens. The Company’s positioning is in TLR receptors detecting RNA. Two programs have been developed up to preclinical validation at Innate Pharma: IPH 3102 targeting TLR3; IPH 3201 targeting TLR7/8.
The Company now looks for a partner for these programs.
 

Immuno-modulation of Toll-like receptors (« TLRs »)

Notably expressed by dendritic cells, receptors belonging to the Toll-like receptor (TLR) family play an essential role in triggering immune responses, particularly in anti-infectious immunity. In this respect, “danger signals” have been referred to in describing the physiological role of this receptor family. To date, ten TLR receptors have been described. They are expressed on dendritic cells and, for some of them, by certain classes of cancer cells. 

More on TLR agonists as vaccine adjuvants

Therapeutic potential

TLR3: activation of immunity and direct apoptosis triggering of tumor cells
To date, approaches targeting TLR receptors have been aimed at triggering the mobilizations of a cellular immune response. Another mechanism of action could be involved in the anti-tumor activity of TLR3 ligands. Recent observations have shown that the TLR3 receptor could be directly expressed by some cancer cells and that the activation of TLR3 could induce apoptosis in these cells. TLR3 ligands thus appear to be able to combine two effects: a stimulation effect on the anti-tumor immune response and a direct cytotoxic effect on malignant cells. These two mechanisms of action work together synergistically; the apoptosis of cancer cells presents the immune system with a new repertoire of tumor antigens in a TLR activation context that is favorable to the development of long-term immune responses.


Potential of TLR7 activation
In June 2007, the Company announced it had licensed the intellectual property rights for new Toll-like receptor 7 agonist compounds with Cancer Research Technology Limited (“CRT”), Cancer Research UK’s research enhancement corporation.
TLR7 modulators have strong potential as therapeutic agents against cancers, autoimmune diseases and infectious diseases. Toll-like receptor 7 is found in certain immune cells and plays a role in recognizing invasive pathogens. In anti-cancer therapy, TLR modulators can be used to mobilize the effector cells of the immune system against tumors and to trigger the secretion of inflammatory mediators.

Bibliography

Publications supporting TLR3 program

1. F. Andre, C. Massard, H. Assi, B. Besse, J. Sabourin and  L. Zitvogel (2006). Toll like receptor 3 expression and efficacy of adjuvant treatment with polyadenylic-polyuridylic acid in patients with axillary node positive breast cancer: Results from two randomized trials. Journal of Clinical Oncology, 2006 ASCO Annual Meeting Proceedings Part I. Vol 24, No. 18S (June 20 Supplement),  10563
2. Conforti, R., Ma, Y., Morel, Y., Paturel, C., Terme, M., Viaud, S., Ryffel, B., Ferrantini, M., Uppaluri, R., Schreiber, R., et al.(2009) Opposing effects of toll-like receptor (TLR3) signaling in tumors can be therapeutically uncoupled to optimize the anticancer efficacy of TLR3 ligands. Cancer research 70, 490-500.

Publications supporting TLR7 program

1. Diebold, S.S., Massacrier, C., Akira, S., Paturel, C., Morel, Y., and Reis e Sousa, C. (2006). Nucleic acid agonists for Toll-like receptor 7 are defined by the presence of uridine ribonucleotides. European journal of immunology 36, 3256-3267.
2. Rajagopal, D., Paturel, C., Morel, Y., Uematsu, S., Akira, S., and Diebold, S.S (2010). Plasmacytoid dendritic cell-derived type I interferon is crucial for the adjuvant activity of Toll-like receptor 7 agonists. Blood. ahead of print 2010