Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism

Stephen P Schauer; Chang Hoon Cho; Gloriia Novikova; Gillie A Roth; Julie Lee; Anup D Sharma; Alejandro R Foley; Carl Ng; Philip Shen; Meena Choi; Taylur P Ma; Lilian Phu; Hanna G Budayeva; Tommy K Cheung; Guita Lalehzadeh; Jose Imperio; Hai Ngu; Ainhoa Etxeberria; Yuxin Liang; Mitchell G Rezzonico; Michelle Dourado; Kevin Huang; Zijuan Lai; Martha Hokom; Nikhil J Pandya; Dwight Newton; Alyaa M Abdel-Haleem; Pamela Chan; Donna Lee; Nardos G Tassew; Dewakar Sangaraju; Deborah O'Connor; Isidro Hötzel; Kimberly L Stark; Carolina Chou; Oded Foreman; Amy Easton; Kristin R Wildsmith; Gizette Sperinde; Christopher M Rose; Brad A Friedman; Reina N Fuji; Robby M Weimer; William J Meilandt; Shraddha Sadekar; Alicia A Nugent; Anne Biever

doi:10.1002/alz.13921

Primate cerebrospinal fluid CHI3L1 reflects brain TREM2 agonism

Alzheimers Dement. 2024 Sep;20(9):5861-5888. doi: 10.1002/alz.13921. Epub 2024 Aug 1.

Authors

Stephen P Schauer¹, Chang Hoon Cho², Gloriia Novikova³, Gillie A Roth⁴, Julie Lee¹, Anup D Sharma², Alejandro R Foley⁵, Carl Ng⁵, Philip Shen⁶, Meena Choi⁷, Taylur P Ma⁷, Lilian Phu⁷, Hanna G Budayeva⁷, Tommy K Cheung⁷, Guita Lalehzadeh⁸, Jose Imperio⁸, Hai Ngu⁹, Ainhoa Etxeberria⁸, Yuxin Liang⁷, Mitchell G Rezzonico³, Michelle Dourado⁸, Kevin Huang¹, Zijuan Lai¹⁰, Martha Hokom⁵, Nikhil J Pandya², Dwight Newton¹¹, Alyaa M Abdel-Haleem¹¹, Pamela Chan¹², Donna Lee¹³, Nardos G Tassew¹³, Dewakar Sangaraju¹⁰, Deborah O'Connor¹⁴, Isidro Hötzel¹⁵, Kimberly L Stark⁸, Carolina Chou¹⁶, Oded Foreman⁹, Amy Easton⁸, Kristin R Wildsmith¹, Gizette Sperinde⁵, Christopher M Rose⁷, Brad A Friedman³, Reina N Fuji⁶, Robby M Weimer¹⁷, William J Meilandt⁸, Shraddha Sadekar⁴, Alicia A Nugent², Anne Biever¹

Affiliations

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

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.

Keywords: Alzheimer's disease; cerebrospinal fluid; chitinase‐3‐like protein 1; microglia; pharmacodynamic biomarker; triggering receptor expressed on myeloid cells 2.

MeSH terms

Alzheimer Disease / cerebrospinal fluid
Alzheimer Disease / drug therapy
Animals
Biomarkers* / cerebrospinal fluid
Brain* / metabolism
Chitinase-3-Like Protein 1* / cerebrospinal fluid
Humans
Induced Pluripotent Stem Cells
Male
Membrane Glycoproteins* / agonists
Microglia* / drug effects
Microglia* / metabolism
Receptors, Immunologic* / agonists

Substances

Biomarkers
CHI3L1 protein, human
Chitinase-3-Like Protein 1
Membrane Glycoproteins
Receptors, Immunologic
TREM2 protein, human

Grants and funding

Genentech, Inc