Effects of anti-tryptase antibody in upper and lower airway of asthmatics

Abstract

Tryptase is a major mast cell product that induces airway smooth muscle contraction and hyperreactivity. MTPS9579A, a full length humanized anti-tryptase antibody, inhibits tryptase activity by irreversibly dissociating active tetramers into inactive monomers. The pharmacodynamic (PD) effects of MTPS9579A on total and active tryptase levels, in relationship to MTPS9579A pharmacokinetics (PK), were evaluated in mucosal lining fluid collected by bronchosorption (lower airway) and nasosorption (upper airway) in a Phase 1c multicenter, randomized, observer-blinded, placebo-controlled study of moderate-severe asthmatics (EudraCT No. 2018-003562-14). A single dose of 300 mg (n=8) or 1800 mg (n=8) of MTPS9579A, or matching placebo (n=8), was administered intravenously on Day 1. Serum and nasosorption for PK and PD assessments were collected pre-dose and Days 1 (serum PK only), 15, 22, 29, 57, and 78 of study conduct. Bronchosorption was collected via bronchoscopy pre-dose and 22 days post-dose. Serum and nasosorption PK were consistent with data in healthy subjects; bronchosorption PK was highly variable, with lack of dose proportionality. Significantly higher levels of total (34.5-fold) and active (114-fold) tryptase were observed in bronchosorption compared to nasosorption at baseline (paired t-test, p<0.05). In nasosorption, complete inhibition of active tryptase was observed post-dose at both dose levels; however, no consistent reduction was observed in bronchosorption at the highest dose tested. PK/PD modeling supports that lack of PD effect in bronchosorption is likely due to insufficient MTPS9579A partitioning to inhibit the high levels of active tryptase in the lower airway.