Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism-Reference-Cited by-同舟云学术

Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism

Published:2024-08 Issue: Volume: Page:
ISSN:1552-5260
Container-title:Alzheimer's & Dementia
language:en
Short-container-title:Alzheimer's & Dementia

Author:

Schauer Stephen P.¹,Cho Chang Hoon²,Novikova Gloriia³,Roth Gillie A.⁴,Lee Julie¹,Sharma Anup D.²,Foley Alejandro R.⁵,Ng Carl⁵,Shen Philip⁶,Choi Meena⁷,Ma Taylur P.⁷,Phu Lilian⁷,Budayeva Hanna G.⁷,Cheung Tommy K.⁷,Lalehzadeh Guita⁸,Imperio Jose⁸,Ngu Hai⁹,Etxeberria Ainhoa⁸,Liang Yuxin⁷,Rezzonico Mitchell G.³,Dourado Michelle⁸,Huang Kevin¹,Lai Zijuan¹⁰,Hokom Martha⁵,Pandya Nikhil J.²,Newton Dwight¹¹,Abdel‐Haleem Alyaa M.¹¹,Chan Pamela¹²,Lee Donna¹³,Tassew Nardos G.¹³,Sangaraju Dewakar¹⁰,O'Connor Deborah¹⁴,Hötzel Isidro¹⁵,Stark Kimberly L.⁸,Chou Carolina¹⁶,Foreman Oded⁹,Easton Amy⁸,Wildsmith Kristin R.¹,Sperinde Gizette⁵,Rose Christopher M.⁷,Friedman Brad A.³,Fuji Reina N.⁶,Weimer Robby M.¹⁷,Meilandt William J.⁸,Sadekar Shraddha⁴,Nugent Alicia A.²,Biever Anne¹^ORCID

Affiliation:

1. Department of Translational Medicine Genentech, Inc. South San Francisco California USA

2. Department of Human Pathobiology and OMNI Reverse Translation Genentech, Inc. South San Francisco California USA

3. Department of Bioinformatics Genentech, Inc. South San Francisco California USA

4. Department of Preclinical and Translational Pharmacokinetics and Pharmacodynamics Genentech, Inc. South San Francisco California USA

5. Department of BioAnalytical Sciences Genentech, Inc. South San Francisco California USA

6. Department of Safety Assessment Pathology Genentech, Inc. South San Francisco California USA

7. Department of Microchemistry Proteomics, Lipidomics, and Next Generation Sequencing Genentech, Inc. South San Francisco California USA

8. Department of Neuroscience Genentech, Inc. South San Francisco California USA

9. Department of Research Pathology Genentech, Inc. South San Francisco California USA

10. Department of Drug Metabolism and Pharmacokinetics Genentech, Inc. South San Francisco California USA

11. Roche Informatics Hoffmann‐La Roche, Ltd. Mississauga Ontario Canada

12. Department of Biochemical and Cellular Pharmacology Genentech, Inc. South San Francisco California USA

13. Department of Safety Assessment Toxicology Genentech, Inc. South San Francisco California USA

14. Department of Chemistry Manufacturing, and Controls Genentech, Inc. South San Francisco California USA

15. Department of Antibody Engineering Genentech, Inc. South San Francisco California USA

16. Department of Safety Assessment Nonclinical Operations Genentech, Inc. South San Francisco California USA

17. Department of Translational Imaging Genentech, Inc. South San Francisco California USA

Abstract

AbstractINTRODUCTIONTriggering 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.METHODSWe 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.RESULTSWe 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.DISCUSSIONCSF 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.

Publisher

Wiley

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