- Tyrosine / MPL Products
- Orally Administered Vaccines
AT's current portfolio of competitive products includes marketed products containing allergoids (modified allergens), tyrosine depot and MPL® adjuvant. These technologies offer significant benefits over older allergy vaccination technologies. AT's development programme is designed to improve product characteristics e.g. provide an improved safety profile and reduce the number of injections over the treatment period, resulting in well-accepted registered products likely to be prescribed by a higher percentage of physicians.
The aim of allergy vaccination is to reduce allergy symptoms and the need for symptomatic medication use during periods of particularly high pollen count and ultimately to 'cure' the patient by modifying the disease state.
Allergy vaccination is also known to act preventatively to protect against the advance of progressive allergic conditions that can often culminate in severe, life-threatening asthma. There are already studies supporting the use of allergy vaccination to prevent hayfever suffers (i.e. patients that are already atopic) from developing asthma(1).
Once the progressive asthmatic deterioration of the airways has commenced, allergy vaccination cannot reverse the damage: such patients will continue to require their inhaled steroids and bronchodilators. AT's development strategy recognises the treatment options are often complementary.
1 Moeller et al. Pollen immunotherapy reduces the development of asthma in children with season rhinoconjunctivitis (the PAT study). J Allergy Clin Immunol 2002; 109:251-256.
Tyrosine / MPL Products
Allergy Vaccination - Mode of Action
Allergy is thought to be caused by an imbalance between different parts of the immune system. The allergic reaction, which is characterised by inflammation and antibody production involves several cell types and many different immune mediators.
When the body is challenged by foreign material, specialised cells called Helper T cells (Th cells) are responsible for guiding the immune response in the appropriate direction. Th1 and Th2 responses regulate each other with a high Th1 response being associated with low Th2 responses and vice versa.
Allergy occurs when the body generates a Type I hypersensitive reaction against an otherwise innocuous substance (which is termed an allergen). This Th2 mediated reaction leads to the production of a large number of IgE antibodies against the allergen. These IgE antibodies coat mast cells located on the mucus membranes and in the skin. When these membrane bound IgE antibodies encounter the allergen they recognise, they activate the cell which then releases inflammatory factors such as histamine, resulting in the typical allergic symptoms of hay fever or asthma.
The goal of allergy vaccination is to move the immune response away from the Th2 response back to the Th1 response. This involves chemically modifying allergens so that the body recognises them as Th1 inducers and including adjuvants in the vaccine formulation that either up-regulate Th1 or T regulatory responses.
Early allergy vaccines were typically composed of extracts containing allergens from natural materials to which people had an allergic reaction. Various local and occasional systemic adverse events were associated with the treatment, which consisted of increasing dose regimens which specifically desensitised the patient.
Formulations have been developed over the years to increase both the efficacy and safety of such treatment. Bencard, now AT, has long been at the forefront of innovation in the specific allergy vaccination field, and first introduced the chemical modification of the allergen extract to produce allergoids. These are semi-purified allergen extracts which have been chemically treated (eg. with glutaraldehyde) which reduces the IgE reactivity whilst maintaining their IgG inducing profile, thus improving the efficacy of allergy vaccination. The objective is to enable safe and rapid administration of allergens achieving desensitisation with fewer injections.
The Company has pioneered the concept of slow-release depot formulations for allergy vaccines, increasing the safety profile and enhancing the efficacy-associated immunological changes. Whereas other manufacturers still use mainly aluminium hydroxide (alum), AT uses L-tyrosine, a natural amino acid, in its vaccine formulations. Tyrosine is a good adsorbant for protein at neutral pH, it enhances antibody production(2), has a half-life of 48 hours at the site of injection and, unlike alum, it is fully metabolised within the body. Studies in animal models also indicate that tyrosine, unlike alum, is not Th2 inducing.
(2) Wheeler AW et al. L-tyrosine as an immunological adjuvant. Int Arch Allergy appl Immunol 1982; 69: 113-119.
Much of AT's new vaccine product development programme involves the exploitation of MPL® (Monophosphoryl lipid A), an immunological adjuvant that AT has licensed from GSK. MPL® has demonstrable T helper cell activity and a suitably non-toxic profile in both animals and humans. The maximum dose and a safety profile of MPL® in allergy vaccines have been established (3) (since 1999 over 864,000 injections have been administered to over 105,000 patients world wide) in man and the current safety database includes data from over 25,000 patients.
(3) Patel P and Salatapek AMF. Pollinex Quattro: a novel and well-tolerated, ultra short-course allergy vaccine. Expert Rev. Vaccines 2006; 5 (5): 617-629
MPL® and tyrosine synergy
Studies in mice injected with formulations containing both MPL® and tyrosine have shown that the induction of antibody response is indicative of a synergistic relationship between these components(4), with respect to the specific Th1 response. By formulating modified allergens with tyrosine in combination with MPL®, AT has maximised the chances of a beneficial shift from an allergen-specific Th2-like to a more Th1-like profile, thereby enhancing the efficacy and safety profile of AT vaccines.
(4) Wheeler AW, Marshall JS, Ulrich JT. A Th-1 inducing adjuvant, MPL, enhances antibody profiles in experimental animals suggesting it has the potential to improve the efficacy of allergy vaccines. Int Arch Allergy Immunol 2001; 126: 135-139
The addition of MPL® technology has lead to a step-change in the product profile, with more efficacious formulations leading firstly to fewer injections in subcutaneous therapies and later to more effective sub-lingual formulations.The convenience of these formulations means that the patient has the option of fewer injections or no injections at all with the sub-lingual products. These two options make this form of therapy much more attractive to patients than traditional long course allergen immunotherapy. A reduction in the need to attend clinics could be important both to healthcare providers and payers and also to the employers of allergy sufferers. To learn more about MPL® click on the link below.
Orally Administered Vaccines
AT is developing a range of orally administered allergy vaccines comprising common allergens combined with MPL®. These vaccines could overcome the need for injections and signal the way forward for the widespread acceptance and administration of allergy vaccines. The possibility of self-administration and GP prescription will improve the convenience of the product and further remove dependence on clinically supervised administration.
AT has a strong patent portfolio with the main product and technology development platforms being covered by patents, some of which have broad generic definitions. AT's policy has been to consolidate the patents assigned from SmithKline Beecham and to seek patent protection for new products and technology in the US, Europe, Japan and in some cases in other territories.
As at May 2005, AT has 5 patent families affording broad coverage and underpinning AT's product development programme. Protection also exists for antigens outside the field of allergy therapy, for example use in infectious diseases and cancer, which could provide some valuable out-licensing opportunities.
MPL® an Adjuvant for Allergy Immunotherapy