PMID- 30894455 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20191214 IS - 1521-0103 (Electronic) IS - 0022-3565 (Linking) VI - 369 IP - 3 DP - 2019 Jun TI - Colony-Stimulating Factor-1 Antibody Lacnotuzumab in a Phase 1 Healthy Volunteer Study and Mechanistic Investigation of Safety Outcomes. PG - 428-442 LID - 10.1124/jpet.118.254128 [doi] 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 (>5x 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. CI - Copyright (c) 2019 by The American Society for Pharmacology and Experimental Therapeutics. FAU - Pognan, Francois AU - Pognan F AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Couttet, Philippe AU - Couttet P AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Demin, Ivan AU - Demin I AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Jaitner, Birgit AU - Jaitner B AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Pang, Yinuo AU - Pang Y AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Roubenoff, Ronenn AU - Roubenoff R AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Sutter, Esther AU - Sutter E AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Timsit, Yoav AU - Timsit Y AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Valentin, Marie Anne AU - Valentin MA AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Vogel, Beate AU - Vogel B AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Woerly, Gaetane AU - Woerly G AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Wolf, Armin AU - Wolf A AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.). FAU - Schramm, Ursula AU - Schramm U AD - Novartis Pharma AG, Basel, Switzerland (F.P., P.C., I.D., B.J., R.R., E.S., M.A.V., B.V., G.W., A.W., U.S.) and Novartis Institutes for BioMedical Research, Cambridge, Massachusetts (Y.P., Y.T.) ursula.schramm@novartis.com. LA - eng PT - Journal Article DEP - 20190320 PL - United States TA - J Pharmacol Exp Ther JT - The Journal of pharmacology and experimental therapeutics JID - 0376362 SB - IM EDAT- 2019/03/22 06:00 MHDA- 2019/03/22 06:01 CRDT- 2019/03/22 06:00 PHST- 2018/10/16 00:00 [received] PHST- 2019/03/18 00:00 [accepted] PHST- 2019/03/22 06:00 [pubmed] PHST- 2019/03/22 06:01 [medline] PHST- 2019/03/22 06:00 [entrez] AID - jpet.118.254128 [pii] AID - 10.1124/jpet.118.254128 [doi] PST - ppublish SO - J Pharmacol Exp Ther. 2019 Jun;369(3):428-442. doi: 10.1124/jpet.118.254128. Epub 2019 Mar 20.