Paul Laidler

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

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.

Fel d 1–derived peptide antigen desensitization shows a persistent treatment effect 1 year after the start of dosing: A randomized, placebo-controlled study

BACKGROUND Allergic rhinoconjunctivitis is an increasingly common source of morbidity, with sensitivity to cats accounting for 10% to 15% of disease burden. Allergy to cats is also a major risk factor for the development of asthma. OBJECTIVES We sought to probe the persistence of the treatment effect of a novel F el d 1-derived peptide antigen desensitization (Cat-PAD) 1 year after the start of treatment in subjects with cat allergy-induced rhinoconjunctivitis after standardized allergen challenge. METHODS In a randomized, double-blind, placebo-controlled, parallel-group clinical trial, subjects attended an environmental exposure chamber in which they were exposed to cat allergen before and after treatment with 2 different regimens of Cat-PAD over a 3-month period. Clinical efficacy was assessed as a change in total rhinoconjunctivitis symptom scores 18 to 22 weeks and 50 to 54 weeks after the start of treatment. RESULTS Treatment with Cat-PAD showed greater efficacy with 4 administrations of a 6-nmol dose 4 weeks apart than with 8 administrations of a 3-nmol dose 2 weeks apart. The treatment effect of 6 nmol persisted 1 year after the start of treatment and was significantly different from that of 3 nmol (P = .0342) and placebo (P = .0104). The treatment effect was apparent on both nasal and ocular symptoms at 1 year. CONCLUSIONS A short course of Cat-PAD improves the ocular and nasal components of rhinoconjunctivitis symptoms in subjects with cat allergy, with the treatment effect persisting 1 year after the start of treatment.

Immunotherapy – 2067. FEL d 1 peptide antigen desensitization safety and efficacy in a double-blind, placebo-controlled environmental exposure chamber study

Background Allergic rhinoconjunctivitis is an increasing problem worldwide with significant impact on quality of life and productivity. Sensitivity to cats accounts for 10-15% of the disease burden. Previous immunotherapy studies with two 27aa peptides were unsuccessful as a result of early and late phase responses. Cat Peptide Antigen Desensitisation (Cat-PAD) is a mixture of seven T-cell epitopes (13-17aa) derived from Fel d1. This study evaluated safety and relationship between dose, dosing regimen and symptom scores in cat allergic subjects with rhinoconjunctivitis 1721weeks(wk) after starting treatment using a standardized allergen challenge in an Environmental Exposure Chamber (EEC).

Immunotherapy – 2080. Fel d 1 derived peptide antigen desensitization results in a persistent treatment effect on symptoms of cat allergy 1 year after 4 doses

Background Previously, we identified a series of T-cell epitopes from the major cat allergen Fel d1 and showed these were safe and well-tolerated when administered to cat allergic subjects. In the current study, we evaluated persistence of the treatment effect (tolerance) one year after start of dosing for two treatment regimens with the same cumulative dose. Methods Subjects underwent Baseline Challenge in an Environmental Exposure Chamber (EEC) on 4 consecutive days, consisting of 3-hour allergen exposures (Fel d1 50.19±3.70 ng/m3). Subjects scored four nasal and four ocular symptoms every 30 minutes each on a scale of 0-3. 202 subjects were randomised to placebo, 8x3nmol Cat Peptide Antigen Desensitisation (Cat-PAD) 2weeks(wk) apart or 4x6nmol Cat-PAD 4wk apart. Subjects re-attended the EEC for 4 consecutive days, of 3-hours, 18-22wk after the start of treatment. 50-54wk after commencement of treatment subjects were invited to participate in a blinded follow-on study without further dosing. 89 subjects were enrolled and had a further 4 consecutive days, of 3-hours in the EEC.

Mechanisims of asthma and allergic disease – 1085. Safety and tolerability of escalating doses of house dust mite peptide antigen desensitisation

Methods Potential T-cell epitopes were identified by algorithm, screened for ability to stimulate T-cell responses in exvivo blood samples from HDM allergic subjects and tested to confirm they did not cause basophil histamine release. A second group of HDM allergic subjects attended a challenge where Conjunctival Provocation Test (CPT) response and Early (EPSR) and Late Phase Skin Response (LPSR) were measured. Subjects were randomised to one of 5 cohorts of 10 subjects. In each cohort 8 subjects received HDM peptide antigen desensitisation (PAD) using the identified T-cell epitope mixture and 2 subjects received placebo. The first cohort received 4x0.03nmol 4weeks(wk) apart; successive cohorts received 4 administrations 4wk apart of 0.3, 1, 3 and 12nmol, respectively. EPSR, LPSR and CPT were re-measured 18-22wk after starting treatment.