Inhaled vs subcutaneous effects of a dual IL-4/IL-13 antagonist in a monkey model of asthma.
BACKGROUND
Pitrakinra is a recombinant protein derived from human interleukin-4 (IL-4) that binds to IL-4Ralpha and acts as a competitive antagonist of IL-4 and IL-13. The studies reported here compare the dose-ranging effects of pitrakinra on allergen-induced airway hyperresponsiveness (AHR) and airway eosinophilia when administered subcutaneously (s.c.) or by inhalation to the Ascaris suum-sensitive cynomolgus monkey for the purpose of elucidating the primary site of pitrakinra's anti-asthmatic action.


METHODS
Airway responsiveness to inhaled methacholine and bronchoalveolar lavage cell composition was determined before and after three allergen exposures with a 1-week course of twice-daily (b.i.d.) s.c. or inhaled pitrakinra or placebo treatment.


RESULTS
Treatment with s.c. pitrakinra significantly reduced allergen-induced AHR, with a maximum effect of a 2.8- to 3.8-fold increase in methacholine PC(100) relative to control (P < 0.05) observed at b.i.d. s.c. doses of 0.05-0.5 mg/kg. Inhaled pitrakinra also significantly reduced AHR with a similar maximum effect of a 2.8- to 3.2-fold increase in methacholine PC(100) relative to control (P < 0.05) at nominal b.i.d. doses of 3-100 mg. The maximal effect on AHR following inhalation was observed at a plasma concentration which exhibited no efficacy via the subcutaneous route. The effect of pitrakinra on lung eosinophilia was not statistically significant following either route of administration, although lung eosinophil count was reduced in all studies relative to control.


CONCLUSIONS
Local administration of pitrakinra to the lung is sufficient to inhibit AHR, one of the cardinal features of asthma, indicating the therapeutic potential of inhaled pitrakinra in the treatment of atopic asthma.
Tomkinson
A
A
Aerovance Inc., Berkeley, CA 94710, USA.
Tepper
J
J
Morton
M
M
Bowden
A
A
Stevens
L
L
Harris
P
P
Lindell
D
D
Fitch
N
N
Gundel
R
R
Getz
E B
EB
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000008:administration & dosage* / Q000493:pharmacokinetics; D019540:Area Under Curve; D001249:Asthma / Q000188:drug therapy* / Q000276:immunology; D016535:Bronchial Hyperreactivity / Q000188:drug therapy / Q000276:immunology; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D004802:Eosinophilia / Q000188:drug therapy / Q000209:etiology; D006801:Humans; D006969:Hypersensitivity, Immediate / Q000188:drug therapy* / Q000276:immunology; D019570:Inhalation Exposure; D007279:Injections, Subcutaneous; D018793:Interleukin-13 / Q000037:antagonists & inhibitors*; D015847:Interleukin-4 / Q000008:administration & dosage* / Q000037:antagonists & inhibitors* / Q000493:pharmacokinetics; D008214:Lymphocytes / Q000187:drug effects; D008252:Macaca fascicularis; D008297:Male
D018927:Anti-Asthmatic Agents; D018793:Interleukin-13; D015847:Interleukin-4