Commemorating 100 years of immunotherapy
Development and preliminary clinical evaluation of a peptide immunotherapy vaccine for cat allergy

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Background

Allergic sensitization to cat allergens is common and represents a major risk factor for asthma. Specific immunotherapy (SIT) is effective but cumbersome and associated with IgE-dependent adverse events. Immunotherapy targeting allergen-specific T cells, with synthetic peptides representing T-cell epitopes, might improve safety and reduce the duration of treatment.

Objective

We sought to define major T-cell epitopes of Fel d 1 for peptide immunotherapy, generate a peptide vaccine, and evaluate its safety and tolerability in subjects with cat allergy.

Methods

We determined the binding affinities of Fel d 1 peptides for 10 commonly expressed HLA-DR molecules. Functionally immunodominant peptides were identified by means of proliferation and cytokine secretion. Histamine-releasing activity was assessed, and a peptide vaccine was formulated. Safety and tolerability were evaluated in a dose-ranging phase IIa clinical trial.

Results

MHC-binding sequences were identified throughout Fel d 1. Some regions contained multiple overlapping T-cell epitopes that bound multiple MHC molecules. Immunodominant sequences were identified on the basis of proliferative and cytokine (IFN-γ, IL-10, and IL-13) responses. Cat allergen extract, but not peptides, induced histamine release in blood basophils. A single administration of peptide vaccine was safe and well tolerated. The dose of vaccine resulting in the greatest inhibition of the late-phase skin response to intradermal whole allergen challenge was 3 nmol.

Conclusions

Fel d 1 contains multiple overlapping MHC-binding motifs. A peptide vaccine comprising the immunodominant regions of the allergen was safe and well tolerated when given to subjects with cat allergy as a single dose. The dose of vaccine resulting in the greatest reduction in late-phase skin response was defined for future clinical development.

Section snippets

Peptides

For in vitro studies, Fel d 1 peptides were synthesized by using standard Fmoc chemistry, purified (>90%) by means of HPLC, and presented as a lyophilized solid (Advanced Biotechnology Centre, Imperial College London, United Kingdom, or Bachem, Wirral, United Kingdom; see Table E1 in this article’s Online Repository at www.jacionline.org). The peptide vaccine for the clinical study (ToleroMune Cat; also known as Cat-PAD) was an equimolar mixture of 7 peptides from Fel d 1 supplied as a frozen

Multiple, overlapping MHC-binding sequences within Fel d 1

The binding affinity of 16 Fel d 1 peptides for 10 commonly expressed HLA-DR molecules was determined and transformed into ratios of affinity between the test peptide and positive control peptide to account for the differences in sensitivity of the binding assays (Table I). Arbitrary thresholds were established to define high- and moderate-affinity binding. All of the MHC class II molecules except HLA-DRB3 bound at least 1 Fel d 1 sequence. Several peptides contained multiple overlapping

Discussion

The purpose of this study was (1) to identify the immunodominant T-cell epitopes best suited for peptide immunotherapy from the major cat allergen Fel d 1, (2) to develop a peptide-based therapeutic vaccine for the treatment of cat allergy, (3) to evaluate the safety and tolerability of the vaccine in subjects with allergic rhinoconjunctivitis (with or without mild asthma) triggered by cats, and (4) to identify a vaccine dose for future efficacy studies. Vaccines composed of short synthetic

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    Supported by Circassia Ltd.

    Disclosure of potential conflict of interest: R. P. Hafner and P. Laidler are employees of Circassia Ltd. A. B. Kay is a founder, stockholder, and consultant for Circassia Ltd. M. Larché is founder, stockholder, and consultant of Circassia Ltd and a founding scientist of Adiga Life Sciences and has received research support from both companies. The rest of the authors have declared that they have no conflict of interest.

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