PT  - JOURNAL ARTICLE
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
TI  - Colony-Stimulating Factor-1 Antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes
AID  - 10.1124/jpet.118.254128
DP  - 2019 Jun 01
TA  - Journal of Pharmacology and Experimental Therapeutics
PG  - 428--442
VI  - 369
IP  - 3
4099  - http://jpet.aspetjournals.org/content/369/3/428.short
4100  - http://jpet.aspetjournals.org/content/369/3/428.full
SO  - J Pharmacol Exp Ther2019 Jun 01; 369
AB  - 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 (>5× the upper limit of normal, but asymptomatic and reversible) and mild transient periorbital swelling were reported. Most 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 finding 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.