SPIREs: a new horizon for allergic disease treatment?

Abstract

Allergic diseases are common and specific immunotherapy provides a therapeutic approach. Specific immunotherapy has its limits, as whole allergen extracts are used. These may contain proteins that patients might not be sensitized to. A required long-term treatment (3–5 years) might activate a potential risk of IgE-mediated severe allergic reactions. A new promising therapeutic approach is to apply short synthetic T-cell peptides. Such synthetic peptides consist of immunoregulatory epitopes (SPIREs) that are 13–17 amino acids in length. Recent clinical data, derived from chamber studies, suggest a clinical efficacy with a good tolerability of SPIREs.

Keywords:

• allergy
• IgG4
• mechanism
• specific immunotherapy
• synthetic peptides

Allergic diseases are common and affect up to 25% of the population in the Western countries [1]. Among allergic diseases, type 1 allergy is characterized by IgE-induced mast cell degranulation with the onset of immediate allergic symptoms. The IgE response is a consequence from a deviated immune response that is TH2 dominated, resulting in IgE production mainly mediated by IL-4 and IL-13 [2].

Specific immunotherapy is supposedly the only treatment of IgE-dependent diseases shown by numerous clinical placebo-controlled trials [3–11], resulting in long-term efficacy. In clinical practice, currently two forms of specific immunotherapy are established: one is the subcutaneous and the other the sublingual route. Both routes of specific immunotherapy have shown clinical efficacy and tolerability, although the clinical response among different allergens may differ. Grass pollen, for example, showed approximately 50% clinical efficacy when specific immunotherapy was given subcutaneously in comparison with placebo; here the result is approximately 35% for the sublingual route [4,5,10,11]. On the other hand, sublingual-specific immunotherapy has a better safety profile with a lower risk of systemic side effects. Until now, no fatal and only very few severe systemic reactions have been reported in the context of sublingual immunotherapy [11].

The mechanisms of specific allergen immunotherapy include not only the reduction of the immediate clinical reactivity but also the inhibition of the late phase responses. At the immunological level, it is thought that a regulatory T-cell response is favored upon specific immunotherapy as well as an increased TH1 response. Consecutively, IgE decreases over time, whereas specific IgG4 increases upon specific immunotherapy [2]. At present, the regimens for specific immunotherapy consider preseasonal and perennial schedules for at least 3 years.

Various chemical modifications of allergen extracts have been developed to enhance efficacy and improve safety of specific immunotherapy; however, a breakthrough with a new preparation leading to a high efficacy with no or low effects is still missing.

The concept to apply synthetic T-cell tolerating peptides in the context of specific immunotherapy was introduced for the first time in mid-1990 with first evidence that synthetic T-cell tolerating peptides are able to induce tolerance and can thereby provide an option for treating IgE dependent diseases [12]. These first-generation peptides that were longer in regard to the number of peptides (>30) suffered from a late-onset event profile. Moreover, the therapeutic results were not superior to conventional subcutaneous immunotherapy [12]. Therefore, further development of this approach was stopped in the late 1990s.

Today, a new promising approach into peptide epitopes was initiated at Imperial College by Larché and Kay with the second generation of synthetic peptides consisting immunoregulatory epitopes (SPIREs) [13–16]. These synthetic T-cell tolerating peptides contain 13–17 amino acids in length and are administered in the range of 75–750 µg. Their selection was based on not only T-cell stimulation activity but also non-IgE-binding capacity was considered [13]. Interestingly, the selected route of administration is intradermal as this route has been proven to be superior regarding immunological activity and tolerability [17].

The initial clinical trials performed with cat SPIRE resulted in excellent tolerability and promising clinical efficacy [18,19]. Until today, the data on clinical efficacy have been exclusively obtained in the environmental exposure chamber, which provides a controlled setting in which efficacy of allergen-specific immunotherapy can be evaluated independently from environmental exposure. First-dose ranging studies indicated again no serious adverse events and suggests clinical efficacy in comparison with placebo [20]. The most recent study failed to reach statistical significance due to low numbers of participants (n = 17 and n = 11 verum versus n = 22 placebo) regarding sustained clinical efficacy after a 2-year follow-up [20].

However, after 4 × 6 nmol CAT-PAD compared with placebo between 2 and 3 h on days 1–4 of EEC challenge at 2 years was significant. The 8 × 3 nmol dose did not show a meaningful effect, indicating the importance of an optimal time and dosing schedule for such peptide-based treatment.

Currently, the Phase III clinical field study with cat SPIRE is ongoing. In this double-blind, placebo-controlled clinical trial in adolescent and adults aged 12–65 years, the patients are randomized into three groups, receiving 4 × 6 nmol of cat SPIRE every 4 weeks followed by four injections of placebo or 4 × 6 nmol of cat SPIRE doses, eight-times every 4 weeks or placebo eight doses 4 weeks apart. The primary endpoint of this multicenter clinical trial with >1000 included patients throughout Europe is the mean total rhinoconjunctivitis symptom score during weeks 52–54 after randomization in the cat SPIRE group compared with the mean total rhinoconjunctivitis symptom score in the placebo-treated group.

Specific immunotherapy is the most important therapeutic approach in IgE-dependent allergic diseases as it follows the concept to re-programming a deviated immune response. The treatments available until today are based on allergen extracts derived from natural allergenic sources, for example, pollen. This results in a situation in which proteins may be given to patients to which they are not sensitized building the risk for the onset of new sensitizations. Furthermore, allergenic extracts contain besides proteins other molecules that may also have an impact on the immune response. Therefore, new concepts that include a more specific immunological approach and moreover improved safety are warranted. The concept of SPIRE using short immunogenic peptides for the induction of tolerance is such an innovative approach with so far an excellent safety profile and the potential of clinical efficacy as shown in exposure chambers. As the state of the art, studies in specific immunotherapy today are based on field studies. The data from the current clinical Phase III trial will prove whether in such setting the effectiveness can be confirmed.

Financial & competing interests disclosure

M Worm received consulting honoraria from Circassia Ltd. and was the principal investigator of the Phase II clinical study Cat-PAD (EudraCT Number 2007–002715-11), sponsored by Circassia Ltd. The author has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.