Presented at:
24th Symposium of Collegium Internationale Allergoligicum, Bermuda. November 1, 2002.
Immunotherapy (IT) with immunostimulatory oligonucleotides linked to purified ragweed (RW) Amb a 1 allergen: Effects on nasal allergen provocation, antibody (Ab) production, and seasonal rhinitis endpoints
PS Creticos, JJ Eiden, D Broide, SL Balcer-Whaley, JT Schroeder, A Khattignavong, H Li, PS Norman, LM Lichtenstein, and RG Hamilton
Johns Hopkins University, Dynavax Technologies Corporafion, and UCSD
Various chemical modifications of allergens have been attempted to enhance efficacy, improve safety, and foster compliance with IT. These approaches have been unsuccessful in that the allergenicity and immunogenicity have either decreased, or increased in tandem, with no resultant efficacy/safety benefit ratio. However, linkage of a highly active immunostimulatory phosphorothioate oligodeoxyribonucleotide (Dynavax 1018-ISS) to RW (Amb a 1) [AIC] greatly enhances the Amb a 1-specific Th1 immune response in animals [Tighe] and in humans (Marshall), and is capabe of diminishing RW-induced pulmonary hyperreactivity in mice (Wills-Carp). Moreover, AIC is demonstrably less allergenic than unconjugated Amb a a or RW extract.
Our initial safety study of AIC demonstrated markedly reduced allergenicity in both BHR [~50 fold (mn) reduction and quantitative intradermal endpoint titration [~185 fold (mn) less reactive than licensed RW extract. Our 1st clinical (cx) trial with sq injection (inj) of AIC demonstrated that the vaccine induced an IgG anti-Amb a 1 ab response similar to conventional IT and did not boost IgE. This combination of decreased allergenicity and enhanced Amb a 1-specific immune response with AIC may offer the 1st allergen modification capable of simultaneously providing improved cx efficacy, an enhanced safety profile, and a more convenient dosing regimen.
We now report an exploratory, placebo (PL)-controlled, randomized, investigator-blinded, cx study in RW allergic adults that employed a 6 inj IT regimen to a target dose of l2ug of AIC. Our study included 25 patients (pts) [10 M, 15 F] mean age: 39 years; puncture skin test sensitivity to RW: 47-98 mm (mn: 71 mm). Subjects were evaluated for safety, tolerability, and response to RW nasal challenge before and after treatment (tx). Pts were also followed for immune response and cx symptoms during the RW season. Clinical endpoints demonstrated cx relevant improvement with AIC in total symptom (sx) scores (p=.06), rhinitis sx scores (p=.03), visual analog scores (p=.006). and QOL (p=.05). The AIC treated group also used less supplemental "relief meds". These cx findings were paralleled by a 3-fold rise in IgG anti-Amb a 1 (p=.002), a modest increase in IgE-Amb a 1 (~1.5 fold), and no rise in total IgE [pretreatment vs post-treatment. We will present these outcomes, a detailed analysis of Ab measurements, T cell studies, nasal challenge parameters (cytokines/mediators), nasal scrapings (cellular response), and cx endpoints from the seasonal symptom/medication and adverse event diaries.
This research was performed as a project of the Immune Tolerance Network, supported by the National Institute of Allergy and Infectious Diseases, the National Institute of Diabetes and Digestive and Kidney Diseases, and the Juvenile Diabetes Research Foundation.