A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models.

Autor: van Lengerich B; Denali Therapeutics, Inc., South San Francisco, CA, USA., Zhan L; Denali Therapeutics, Inc., South San Francisco, CA, USA., Xia D; Denali Therapeutics, Inc., South San Francisco, CA, USA., Chan D; Denali Therapeutics, Inc., South San Francisco, CA, USA., Joy D; Denali Therapeutics, Inc., South San Francisco, CA, USA., Park JI; Denali Therapeutics, Inc., South San Francisco, CA, USA., Tatarakis D; Denali Therapeutics, Inc., South San Francisco, CA, USA., Calvert M; Denali Therapeutics, Inc., South San Francisco, CA, USA., Hummel S; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilians University, Munich, Germany., Lianoglou S; Denali Therapeutics, Inc., South San Francisco, CA, USA., Pizzo ME; Denali Therapeutics, Inc., South San Francisco, CA, USA., Prorok R; Denali Therapeutics, Inc., South San Francisco, CA, USA., Thomsen E; Denali Therapeutics, Inc., South San Francisco, CA, USA., Bartos LM; Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilians University, Munich, Germany., Beumers P; Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilians University, Munich, Germany., Capell A; Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, Ludwig Maximilians University, Munich, Germany., Davis SS; Denali Therapeutics, Inc., South San Francisco, CA, USA., de Weerd L; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany., Dugas JC; Denali Therapeutics, Inc., South San Francisco, CA, USA., Duque J; Denali Therapeutics, Inc., South San Francisco, CA, USA., Earr T; Denali Therapeutics, Inc., South San Francisco, CA, USA., Gadkar K; Denali Therapeutics, Inc., South San Francisco, CA, USA., Giese T; Denali Therapeutics, Inc., South San Francisco, CA, USA., Gill A; Denali Therapeutics, Inc., South San Francisco, CA, USA., Gnörich J; Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilians University, Munich, Germany., Ha C; Denali Therapeutics, Inc., South San Francisco, CA, USA., Kannuswamy M; Denali Therapeutics, Inc., South San Francisco, CA, USA., Kim DJ; Denali Therapeutics, Inc., South San Francisco, CA, USA., Kunte ST; Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilians University, Munich, Germany., Kunze LH; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilians University, Munich, Germany., Lac D; Denali Therapeutics, Inc., South San Francisco, CA, USA., Lechtenberg K; Denali Therapeutics, Inc., South San Francisco, CA, USA., Leung AW; Denali Therapeutics, Inc., South San Francisco, CA, USA., Liang CC; Denali Therapeutics, Inc., South San Francisco, CA, USA., Lopez I; Denali Therapeutics, Inc., South San Francisco, CA, USA., McQuade P; Takeda Pharmaceutical Company, Cambridge, MA, USA., Modi A; Denali Therapeutics, Inc., South San Francisco, CA, USA., Torres VO; Denali Therapeutics, Inc., South San Francisco, CA, USA., Nguyen HN; Denali Therapeutics, Inc., South San Francisco, CA, USA., Pesämaa I; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Graduate School of Systemic Neurosciences, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany., Propson N; Denali Therapeutics, Inc., South San Francisco, CA, USA., Reich M; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Graduate School of Systemic Neurosciences, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany., Robles-Colmenares Y; Denali Therapeutics, Inc., South San Francisco, CA, USA., Schlepckow K; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany., Slemann L; Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilians University, Munich, Germany., Solanoy H; Denali Therapeutics, Inc., South San Francisco, CA, USA., Suh JH; Denali Therapeutics, Inc., South San Francisco, CA, USA., Thorne RG; Denali Therapeutics, Inc., South San Francisco, CA, USA., Vieira C; Denali Therapeutics, Inc., South San Francisco, CA, USA., Wind-Mark K; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilians University, Munich, Germany., Xiong K; Denali Therapeutics, Inc., South San Francisco, CA, USA., Zuchero YJY; Denali Therapeutics, Inc., South San Francisco, CA, USA., Diaz D; Denali Therapeutics, Inc., South San Francisco, CA, USA., Dennis MS; Denali Therapeutics, Inc., South San Francisco, CA, USA., Huang F; Denali Therapeutics, Inc., South San Francisco, CA, USA., Scearce-Levie K; Denali Therapeutics, Inc., South San Francisco, CA, USA., Watts RJ; Denali Therapeutics, Inc., South San Francisco, CA, USA., Haass C; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, Ludwig Maximilians University, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Lewcock JW; Denali Therapeutics, Inc., South San Francisco, CA, USA., Di Paolo G; Denali Therapeutics, Inc., South San Francisco, CA, USA., Brendel M; German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.; Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilians University, Munich, Germany.; Munich Cluster for Systems Neurology (SyNergy), Munich, Germany., Sanchez PE; Denali Therapeutics, Inc., South San Francisco, CA, USA. sanchez@dnli.com., Monroe KM; Denali Therapeutics, Inc., South San Francisco, CA, USA. monroe@dnli.com.
Jazyk: angličtina
Zdroj: Nature neuroscience [Nat Neurosci] 2023 Mar; Vol. 26 (3), pp. 416-429. Date of Electronic Publication: 2023 Jan 12.
DOI: 10.1038/s41593-022-01240-0
Abstrakt: Loss-of-function variants of TREM2 are associated with increased risk of Alzheimer's disease (AD), suggesting that activation of this innate immune receptor may be a useful therapeutic strategy. Here we describe a high-affinity human TREM2-activating antibody engineered with a monovalent transferrin receptor (TfR) binding site, termed antibody transport vehicle (ATV), to facilitate blood-brain barrier transcytosis. Upon peripheral delivery in mice, ATV:TREM2 showed improved brain biodistribution and enhanced signaling compared to a standard anti-TREM2 antibody. In human induced pluripotent stem cell (iPSC)-derived microglia, ATV:TREM2 induced proliferation and improved mitochondrial metabolism. Single-cell RNA sequencing and morphometry revealed that ATV:TREM2 shifted microglia to metabolically responsive states, which were distinct from those induced by amyloid pathology. In an AD mouse model, ATV:TREM2 boosted brain microglial activity and glucose metabolism. Thus, ATV:TREM2 represents a promising approach to improve microglial function and treat brain hypometabolism found in patients with AD.
(© 2023. The Author(s).)
Databáze: MEDLINE
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