Target Analysis - Toll-like receptors
Drugs stimulating Toll-like receptors
Development of novel therapeutics in the area of TLRs is at
quite an early stage at present. There are currently 24 drugs
in preclinical development, with a further 18 in clinical trials
(Graph 1). Aptly-named Innate Pharma is developing IPH-
32XX, a series of TLR7 modulators for the treatment of
cancer, autoimmune and infectious diseases. Also in Innate's
pipeline is IPH-31XX, a double-stranded RNA which is the
natural ligand of TLR3, usually detected during viral infection.
Activation of the TLR3 pathway leads to the activation of NFkB
and the production of type I interferons, and it is hoped
that this will be an effective method of destroying cancerous
cells present in melanoma and breast cancer. Both of Innate's
TLR candidates are in the very early stages of development,
so it will be interesting to see how they perform in the clinic.
Pfizer's agatolimod is a CpG oligonucleotide which mimics the natural ligand of TLR9 - unmethylated bacterial CpG DNA - and activates the TLR9 immunostimulatory cascade. This product is more advanced than Innate's TLR-targeted drugs and is in Phase II trials in breast and renal cancers, asthma, allergies and hepatitis-B virus infection. However, this drug has not been without setbacks, and development for advanced nsclc was discontinued after an independent DSMC found that trial data did not show increased efficacy over standard chemotherapy alone. This is not the only CpG oligonucleotide targeting TLR9 that has failed to live up to expectations for Pfizer; CpG-10101 was suspended at Phase II, when it failed to show efficacy in treating hepatitis-C.
To date, Pfizer has had more success using oligonucleotide TLR9 agonists as vaccine adjuvants; its vaccine adjuvant CpGTLR9 is currently in Phase III trials with GlaxoSmithKline's MAGE-A3 cancer vaccine. It has been argued by some that use as adjuvants is the most promising avenue for TLR agonists, as lower doses would be required which could avoid certain side-effects that may be associated with immunotherapeutics. This suggestion is borne out of the discontinuation of the TLR7 agonist ANA-975, which was under development by Anadys Pharmaceuticals as an antiviral but had unacceptable toxicity in animals. It produced intense immune stimulation, so chronic administration of this drug would have been inadvisable.
Other than use as vaccine adjuvants, another way around the problem of toxicity could be via a non-systemic route of administration. Array BioPharma's TLR7/8 agonist VTX-463, under development for the treatment of allergy, has shown efficacy in animal models of ragweed allergy. In sensitized beagles, intranasal administration of VTX-463 increased the size of the nasal cavity, and caused a selective decrease in eosinophils and nasal congestion.
Initially it may seem counterintuitive to stimulate an immune response for the treatment of allergy. However, there are differences between the types of immune response elicited by allergens and invading microorganisms. An important component of the immune system is the T-helper cell. These cells are differentiated into either Th1 helper cells, or Th2 helper cells and both subdivisions produce different cytokines. The Th1 response relies on the production of interferon-gamma, which is a pro-inflammatory cytokine that eliminates pathogens. The Th2 response involves the production of interleukins 4, 5 and 13 that promote IgE production and eosinophilic responses, which form part of the pathology of allergic diseases. It is thought that restoring the balance between these responses in favour of the Th1 response, possibly via activation of TLRs, is likely to alleviate the symptoms of allergic hypersensitivity, and this is the approach being taken by Array BioPharma with VTX-463.
