Preclinical safety and pharmacology of an anti-human interleukin-13 monoclonal antibody in normal macaques and in macaques with allergic asthma.
Interleukin-13 (IL-13) plays a central role in chronic airway diseases, including asthma. These studies were conducted to evaluate the safety of administration of a human anti-IL-13 monoclonal antibody (mAb) to normal macaques and in macaques with allergic asthma. In addition, serum and bronchioalveolar lavage fluid were collected from allergic cynomolgus macaques in order to identify potential surrogate markers of IL-13 pharmacology that could be useful for subsequent clinical trials. In vitro studies demonstrated that the anti-IL-13 mAb inhibited the pharmacological actions of both human and cynomolgus macaque IL-13. Allergic macaques were treated systemically with 10 mg/kg anti-IL-13 mAb 1 day prior to inhaled Ascaris suum antigen challenge. Normal macaques were dosed intravenously with anti-IL-13 once per week for 3 weeks at doses of 10 or 50 mg/kg. Treatment of macaques with the anti-IL-13 mAb was not associated with any toxicologically significant findings. A slight treatment-related but nonadverse decrease in platelet counts was observed in both the normal and allergic macaques. In allergic macaques, the anti-IL-13 mAb treatment did not affect lung function, lung eosinophilia, or serum or BAL immunoglobulin E (IgE) concentrations but did produce a reduction in BAL and serum eotaxin concentrations (p < .05) at 6 h post antigen challenge. This study shows that administration of an anti-IL-13 mAb was well tolerated in both normal and allergic asthmatic macaques and that serum eotaxin concentrations may be a useful early in vivo marker for evaluating IL-13 inhibition in patients with asthma.
Martin
Pauline L
PL
Centocor Research and Development Inc., Radnor, Pennsylvania 19087, USA. pmarti27@cntus.jnj.com
Fisher
Dusti
D
Glass
William
W
O'Neil
Karyn
K
Das
Anuk
A
Martin
Elise C
EC
Li
Li
L
D000818:Animals; D018927:Anti-Asthmatic Agents / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D000911:Antibodies, Monoclonal / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D001249:Asthma / Q000097:blood / Q000188:drug therapy* / Q000276:immunology; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D019742:Chemokines, CC / Q000097:blood / Q000276:immunology; D004195:Disease Models, Animal; D004353:Drug Evaluation, Preclinical; D004804:Eosinophils / Q000166:cytology; D006801:Humans; D007275:Injections, Intravenous; D018793:Interleukin-13 / Q000097:blood / Q000276:immunology*; D053661:Interleukin-13 Receptor alpha1 Subunit / Q000276:immunology; D053663:Interleukin-13 Receptor alpha2 Subunit / Q000276:immunology; D008251:Macaca; D010766:Phosphorylation; D011485:Protein Binding; D011994:Recombinant Proteins / Q000009:adverse effects / Q000494:pharmacology / Q000627:therapeutic use; D050800:STAT6 Transcription Factor / Q000378:metabolism
D018927:Anti-Asthmatic Agents; D000911:Antibodies, Monoclonal; D019742:Chemokines, CC; D018793:Interleukin-13; D053661:Interleukin-13 Receptor alpha1 Subunit; D053663:Interleukin-13 Receptor alpha2 Subunit; D011994:Recombinant Proteins; D050800:STAT6 Transcription Factor; C494101:STAT6 protein, human