TY - JOUR T1 - CSF-1 Antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes JF - Journal of Pharmacology and Experimental Therapeutics JO - J Pharmacol Exp Ther DO - 10.1124/jpet.118.254128 SP - jpet.118.254128 AU - Francois Pognan AU - Philippe Couttet AU - Ivan Demin AU - Birgit Jaitner AU - Yinuo Pang AU - Ronenn Roubenoff AU - Esther Sutter AU - Yoav Timsit AU - Marie Anne Valentin AU - Beate Vogel AU - Gaetane Woerly AU - Armin Wolf AU - Ursula Schramm Y1 - 2019/01/01 UR - http://jpet.aspetjournals.org/content/early/2019/03/20/jpet.118.254128.abstract N2 - The colony-stimulating factor-1 (CSF-1) receptor pathway has been implicated in a variety of diseases, and CSF-1–dependent mechanisms are also involved in bloodborne protein clearance. Lacnotuzumab is a novel, high-affinity, humanized, anti-CSF-1 monoclonal antibody that prevents CSF-1 mediated receptor activation. This phase 1, two-part, double-blind study in healthy volunteers assessed the safety and tolerability of lacnotuzumab and its pharmacokinetics (PK) and pharmacodynamic properties. Part A (n = 36) was a single, ascending-dose assessment of eight lacnotuzumab doses (0.01-20 mg/kg); in part B (n = 16), lacnotuzumab was administered at either 5 or 10 mg/kg. In each study cohort, individuals were randomized 3:1 to lacnotuzumab or placebo. Lacnotuzumab was generally well tolerated. At higher doses (10 and 20 mg/kg), creatine kinase (CK) elevations (>5x the upper limit of normal, but asymptomatic and reversible) and mild transient periorbital swelling were reported. The majority of adverse events (AEs) were low grade, no unexpected or novel AEs were observed, and there were no discontinuations for AEs. Free/unbound lacnotuzumab serum concentration–time profiles showed nonlinear PK across doses from 0.01 to 20 mg/kg, with faster apparent elimination at lower doses or concentrations; this was consistent with apparent target-mediated drug disposition. Lacnotuzumab also showed dose-dependent, on-target effects on multiple downstream biomarkers. Preclinical investigations of the CK elevation and periorbital swelling observed after lacnotuzumab administration suggest that these are reversible, nonpathological events linked to inhibition of the CSF-1 pathway. These data support further evaluation of lacnotuzumab in clinical studies. ER -