Major allergen content consistency of SQ house dust mite sublingual immunotherapy tablets and relevance across geographic regions

doi:10.1016/j.anai.2016.07.004

Annals of Allergy, Asthma & Immunology

Volume 117, Issue 3, September 2016, Pages 298-303

https://doi.org/10.1016/j.anai.2016.07.004 Get rights and content

Abstract

Background

Consistency in composition and potency, particularly regarding major allergens, is crucial for the quality of extracts for allergen immunotherapy.

Objective

To characterize the major allergen composition of house dust mite (HDM) extracts commercially available in the United States and the SQ HDM sublingual immunotherapy (SLIT) tablet, and to relate the composition to patient sensitization patterns.

Methods

Der 1/Der 2 ratios were determined in 10,000- and 30,000-AU/mL HDM extracts from 5 US companies and the SQ HDM SLIT-tablet. Allergen content was analyzed by enzyme-linked immunosorbent assay and compared with an in-house reference. Sensitivity toward Der p 1, Der p 2, and Der p 10 was determined in serum from randomly selected subgroups of 220 individuals from North American and European SQ HDM SLIT-tablet trials.

Results

Mean Der 1/Der 2 ratios in US HDM extracts ranged from 0.4 to 20.5. For the SQ HDM SLIT-tablet (20 batches), variability did not exceed 12% regarding content of Der f 1 (SD, 11.9%; 95% confidence interval [CI], 0.94–1.06), Der p 1 (SD, 6.1%; 95% CI, 0.97–1.03), and combined Der 2 allergen (SD, 6.4%; 95% CI, 0.97–1.03), indicating a consistent Der 1/Der 2 ratio. High allergen sensitivity frequencies toward Der p 1 and Der p 2 were observed regardless of geographic region. Efficacy of the SQ HDM SLIT-tablet has been demonstrated in 5 clinical trials.

Conclusion

The SQ HDM SLIT-tablet has efficacy potential for a broad range of patients because it includes a consistent 1:1 ratio of the 2 major HDM allergens to which individuals were most frequently sensitized across geographic regions. Efficacy has been demonstrated.

Introduction

Sensitization to house dust mite (HDM) is common in many countries worldwide at a prevalence of approximately one-quarter to one-third of the general population[1], [2], [3], [4], [5] and half of the population with allergic rhinitis.⁶ HDM allergy immunotherapy (AIT) modulates basic immunologic mechanisms of allergic disease and is recognized as the only treatment with the potential to alter the natural course of the disease. With the recent accumulation of statistically robust efficacy and safety data from large, double-blinded, placebo-controlled (DBPC) clinical trials, HDM AIT has re-emerged as an attractive treatment option for HDM rhinoconjunctivitis and asthma. Dermatophagoides pteronyssinus and Dermatophagoides farinae are the most common HDM species found in bedding and mattresses throughout the world⁷ and are generally considered the most relevant for HDM AIT. The major allergens for D pteronyssinus and D farinae belong to groups 1 and 2.⁸ The group 1 and 2 allergens are considered major allergens based on studies that found that 63% to 100% of patients allergic to HDM in Europe, North America, and Japan and up to 81% of children with asthma are strongly sensitized to Der p 1 and/or Der p 2.[9], [10], [11], [12] A number of other allergens are known, but sensitivity is less frequent. For example, approximately 15% of patients allergic to HDM are sensitized to Der p 10.[9], [13] Sensitization to Der 10 (tropomyosin) causes cross-reactivity and is a potential cross-sensitizing allergen to shellfish, cockroach, and other insects.

The extracts for HDM AIT are made by growing D pteronyssinus and D farinae in pure cultures, which typically contain proteins from mite bodies and mite fecal particles, and culture medium. HDM fecal particles contain high amounts of group 1 allergen, whereas mite bodies are the primary source for group 2.¹⁴ The manufacturing process among HDM AIT formulations varies, with differences in culture media and extraction processes and with limited possibility of adjusting the composition. Studies have found that the composition and content among HDM extracts from various manufacturers in Europe and the United States highly differ.[15], [16], [17], [18]

As part of the standardization program of allergen extracts, the US Food and Drug Administration (FDA) assigns the strengths of HDM extracts by comparison with the FDA reference standard in an IgE antigen-binding competition enzyme-linked immunosorbent assay (ELISA) using a human IgE serum pool provided by the FDA.¹⁹ The results of a manufacturer's product are then expressed in allergy units (AU) per milliliter relative to the FDA reference standard,²⁰ although this does not indicate the composition or allergen content of the extract.²¹ Because extract production processes differ among manufacturers, FDA-standardized HDM extracts (as defined by AU per milliliter) may contain various amounts of any allergen and, most importantly, differing amounts and ratios of major allergens. Consistency in total allergenic potency and composition of the AIT extracts, particularly regarding major allergens, will affect the clinical efficacy of the product and is crucial for safety. Recognition of the need for consistency of the extracts, which was previously largely missing from available AIT products, prompted the development of sublingual immunotherapy (SLIT) tablets that are manufactured in a consistent, characterized process. SQ HDM SLIT-tablets (MK-8237; Merck & Co Inc, Kenilworth, New Jersey, and ALK, Hørsholm, Denmark) contain extracts that are produced by a controlled process that allows for the use of body and fecal fractions of D farinae and D pteronyssinus to achieve a 1:1:1:1 ratio between Der f 1/2 and Der p 1/2 allergens.²² In addition to an equal and controlled ratio of the 4 major allergens, the controlled use of body and fecal particles ensures a content with the broadest possible range of HDM allergens in each tablet. The objectives of this report are to describe the results of studies assessing the major allergen composition of HDM extracts commercially available in the United States and the SQ HDM SLIT-tablet, and to relate the composition to patient sensitization patterns.

Section snippets

HDM Extracts

Standardized HDM extracts commercially available for diagnostic purposes and subcutaneous immunotherapy from 5 US manufacturers (ALK-Abelló Inc, Greer, Allergy Labs, Antigen Labs, and Hollister-Stier) were assessed. All the extracts had labeled specific activities of 10,000 or 30,000 AU/mL as determined by the FDA.

Potency and Allergen Content

IgE-binding potency of 20 batches of the SQ HDM SLIT-tablet was determined using an automated ADVIA Centaur assay (Siemens, Ballerup, Denmark).²³ Measured potency was determined

Der 1 and Der 2 Content of Available HDM Products in the United States

Differences in the content of Der 1 and Der 2 in the commercially available HDM extracts were observed despite equivalent concentration labeling (Table 1). The mean Der 1/Der 2 ratio ranged from 0.4 to 20.5.

Potency and Allergen Content of SQ HDM SLIT-Tablet

Analysis of 20 batches of SQ HDM SLIT-tablet yielded a normalized mean (SD) of IgE-binding potency of 1.000 (0.045; 95% confidence interval [CI], 0.98–1.02) (Table 2). Variability (as determined by SD) did not exceed 12% with regard to content of Der f 1, Der p 1, and combined Der 2 allergen

Discussion

Substantial differences in major allergen content were observed in HDM extracts labeled with identical AU/mL as determined by the FDA reference standards. By comparison, the SQ HDM SLIT-tablet contained equal and consistent amounts of Der 1 and Der 2 from D pteronyssinus and D farinae, the HDM species to which humans are most commonly exposed. Furthermore, the 1:1:1:1 ratio of Der p 1, Der f 1, Der p 2, and Der f 2 content in the SQ HDM SLIT-tablet was consistent, with SDs of less than 12%

Acknowledgments

We acknowledge Henrik Ipsen of ALK, Horsholm, Denmark, for his help with the serum comparison data. Medical writing and editorial assistance was provided by Erin P. Scott, PhD, and Benjamin Scott, PhD, of Scott Medical Communications LLC. This assistance was funded by Merck & Co Inc, Kenilworth, New Jersey.

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: Disclosures: Drs Nolte and Bollen are employees of Merck Sharp & Dohme Corp, a subsidiary of Merck & Co Inc, Kenilworth, New Jersey. Drs Plunkett, Grosch, Larsen, and Lund are employees of ALK.

: Funding Source: Funding for this research was provided by Merck & Co Inc, Kenilworth, New Jersey, and ALK, Hørsholm, Denmark.

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Original articleInterventionsMajor allergen content consistency of SQ house dust mite sublingual immunotherapy tablets and relevance across geographic regions

Abstract

Background

Objective

Methods

Results

Conclusion

Introduction

Section snippets

HDM Extracts

Potency and Allergen Content

Der 1 and Der 2 Content of Available HDM Products in the United States

Potency and Allergen Content of SQ HDM SLIT-Tablet

Discussion

Acknowledgments

J Allergy Clin Immunol

Trends Mol Med

J Allergy Clin Immunol

J Allergy Clin Immunol

Ann Allergy Asthma Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Clin Biochem

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

J Allergy Clin Immunol

Asthma, allergy and atopy in southern Chinese school students

Clin Exp Allergy

Prevalence of allergic sensitization versus allergic rhinitis symptoms in an unselected population

Int Arch Allergy Immunol

Geographical variations in the prevalence of atopic sensitization in six study sites across Canada

Allergy

Geographical variation in the prevalence of positive skin tests to environmental aeroallergens in the European Community Respiratory Health Survey I

Allergy

Prevalence and rate of diagnosis of allergic rhinitis in Europe

Eur Respir J

Original article
Interventions
Major allergen content consistency of SQ house dust mite sublingual immunotherapy tablets and relevance across geographic regions