한빛사논문
- 조회53
Genentech, Inc.
Stephen P Schauer 1, Chang Hoon Cho 2, Gloriia Novikova 3, Gillie A Roth 4, Julie Lee 1, Anup D Sharma 2, Alejandro R Foley 5, Carl Ng 5, Philip Shen 6, Meena Choi 7, Taylur P Ma 7, Lilian Phu 7, Hanna G Budayeva 7, Tommy K Cheung 7, Guita Lalehzadeh 8, Jose Imperio 8, Hai Ngu 9, Ainhoa Etxeberria 8, Yuxin Liang 7, Mitchell G Rezzonico 3, Michelle Dourado 8, Kevin Huang 1, Zijuan Lai 10, Martha Hokom 5, Nikhil J Pandya 2, Dwight Newton 11, Alyaa M Abdel-Haleem 11, Pamela Chan 12, Donna Lee 13, Nardos G Tassew 13, Dewakar Sangaraju 10, Deborah O'Connor 14, Isidro Hötzel 15, Kimberly L Stark 8, Carolina Chou 16, Oded Foreman 9, Amy Easton 8, Kristin R Wildsmith 1, Gizette Sperinde 5, Christopher M Rose 7, Brad A Friedman 3, Reina N Fuji 6, Robby M Weimer 17, William J Meilandt 8, Shraddha Sadekar 4, Alicia A Nugent 2, Anne Biever 1
1Department of Translational Medicine, Genentech, Inc., South San Francisco, California, USA.
2Department of Human Pathobiology and OMNI Reverse Translation, Genentech, Inc., South San Francisco, California, USA.
3Department of Bioinformatics, Genentech, Inc., South San Francisco, California, USA.
4Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics, Genentech, Inc., South San Francisco, California, USA.
5Department of BioAnalytical Sciences, Genentech, Inc., South San Francisco, California, USA.
6Department of Safety Assessment Pathology, Genentech, Inc., South San Francisco, California, USA.
7Department of Microchemistry, Proteomics, Lipidomics, and Next Generation Sequencing, Genentech, Inc., South San Francisco, California, USA.
8Department of Neuroscience, Genentech, Inc., South San Francisco, California, USA.
9Department of Research Pathology, Genentech, Inc., South San Francisco, California, USA.
10Department of Drug Metabolism and Pharmacokinetics, Genentech, Inc., South San Francisco, California, USA.
11Roche Informatics, Hoffmann-La Roche, Ltd., Mississauga, Ontario, Canada.
12Department of Biochemical and Cellular Pharmacology, Genentech, Inc., South San Francisco, California, USA.
13Department of Safety Assessment Toxicology, Genentech, Inc., South San Francisco, California, USA.
14Department of Chemistry, Manufacturing, and Controls, Genentech, Inc., South San Francisco, California, USA.
15Department of Antibody Engineering, Genentech, Inc., South San Francisco, California, USA.
16Department of Safety Assessment Nonclinical Operations, Genentech, Inc., South San Francisco, California, USA.
17Department of Translational Imaging, Genentech, Inc., South San Francisco, California, USA.
Stephen P. Schauer, Chang Hoon Cho, Alicia A. Nugent, and Anne Biever contributed equally to this work.
Corresponding Authors: Alicia A. Nugent, Anne Biever
Abstract
Introduction: Triggering receptor expressed on myeloid cells 2 (TREM2) agonists are being clinically evaluated as disease-modifying therapeutics for Alzheimer's disease. Clinically translatable pharmacodynamic (PD) biomarkers are needed to confirm drug activity and select the appropriate therapeutic dose in clinical trials.
Methods: We conducted multi-omic analyses on paired non-human primate brain and cerebrospinal fluid (CSF), and stimulation of human induced pluripotent stem cell-derived microglia cultures after TREM2 agonist treatment, followed by validation of candidate fluid PD biomarkers using immunoassays. We immunostained microglia to characterize proliferation and clustering.
Results: We report CSF soluble TREM2 (sTREM2) and CSF chitinase-3-like protein 1 (CHI3L1/YKL-40) as PD biomarkers for the TREM2 agonist hPara.09. The respective reduction of sTREM2 and elevation of CHI3L1 in brain and CSF after TREM2 agonist treatment correlated with transient microglia proliferation and clustering.
Discussion: CSF CHI3L1 and sTREM2 reflect microglial TREM2 agonism and can be used as clinical PD biomarkers to monitor TREM2 activity in the brain.
Highlights: CSF soluble triggering receptor expressed on myeloid cells 2 (sTREM2) reflects brain target engagement for a novel TREM2 agonist, hPara.09. CSF chitinase-3-like protein 1 reflects microglial TREM2 agonism. Both can be used as clinical fluid biomarkers to monitor TREM2 activity in brain.
논문정보
- Research article
- 2024년 08월 (BRIC 등록일 2024-08-09)
- 국외 연구진
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