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Antisense Therapy against CCR3 and the Common Beta Chain Attenuates Allergen-induced Eosinophilic Responses

¹ Department of Medicine, McMaster University, Hamilton, Ontario, Canada; ² Institut de Cardiologie et de Pneumologie de l'Université Laval, Hôpital Laval, Quebec City, Quebec, Canada; ³ Division of Respiratory Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada; ⁴ University of Montreal, Montreal, Quebec, Canada; and ⁵ Topigen Pharmaceuticals, Montreal, Quebec, Canada

Correspondence and requests for reprints should be addressed to Gail Gauvreau, Ph.D., HSC 3U25, McMaster University, 1200 Main Street West, Hamilton, ON, Canada L8N 3Z5. E-mail: gauvreau{at}mcmaster.ca

Rationale: The drug product TPI ASM8 contains two modified phosphorothioate antisense oligonucleotides designed to inhibit allergic inflammation by down-regulating human CCR3 and the common beta chain (β_c) of IL-3, IL-5, and granulocyte-macrophage colony–stimulating factor receptors.

Objectives: This study examined the effects of inhaled TPI ASM8 on sputum cellular influx, CCR3 and β_c mRNA and protein levels, and the airway physiologic response after inhaled allergen.

Methods: Seventeen subjects with mild atopic asthma were randomized in a crossover study to inhale 1,500 µg TPI ASM8 or placebo by nebulizer, once daily for 4 days. On Day 3, subjects underwent allergen inhalation challenge. Sputum samples were collected before and after allergen. CCR3 and β_c protein levels were measured by flow cytometry, mRNA was measured using real-time quantitative polymerase chain reaction, and the FEV₁ was measured over 7 hours after challenge.

Measurements and Main Results: Compared with placebo, TPI ASM8 inhibited sputum eosinophil influx by 46% (P = 0.02) and blunted the increase in total cells (63%) after allergen challenge. TPI ASM8 significantly reduced the early asthmatic response (P = 0.04) with a trend for the late asthmatic response (P = 0.08). The allergen-induced (Day 2 to Day 3) levels of β_c mRNA and CCR3 mRNA in sputum-derived cells were inhibited by TPI ASM8 (P = 0.039 and P = 0.054, respectively), with no significant effects on the cell surface protein expression of CCR3 and β_c (P > 0.05). No serious adverse events were reported.

Conclusions: TPI ASM8 attenuates the allergen-induced increase in target gene mRNA and airway responses in subjects with mild asthma.

Clinical trial registered with www.clinicaltrials.gov (NCT 00264966).

Key Words: antisense oligonucleotides • eosinophils • allergen inhalation • airway inflammation

AT A GLANCE COMMENTARY Scientific Knowledge on the Subject Antisense oligonucleotide therapy targeting the receptors for eotaxin (CCR3) and IL-5, IL-3, and granulocyte-macrophage colony–stimulating factor (common β chain) has been successful in animal models of asthma. This has not been studied in humans. What This Study Adds to the Field This study demonstrates that antisense therapy inhibits allergen-induced asthmatic responses in humans.