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

  • Nat Neurosci. 2023 Mar;26(3):416-429. doi: 10.1038/s41593-022-01240-0.
Bettina van Lengerich  #  1 ,  Lihong Zhan  #  1 ,  Dan Xia  #  1 ,  Darren Chan  1 ,  David Joy  1 ,  Joshua I Park  1 ,  David Tatarakis  1 ,  Meredith Calvert  1 ,  Selina Hummel  2  3 ,  Steve Lianoglou  1 ,  Michelle E Pizzo  1 ,  Rachel Prorok  1 ,  Elliot Thomsen  1 ,  Laura M Bartos  3 ,  Philipp Beumers  3 ,  Anja Capell  4 ,  Sonnet S Davis  1 ,  Lis de Weerd  2 ,  Jason C Dugas  1 ,  Joseph Duque  1 ,  Timothy Earr  1 ,  Kapil Gadkar  1 ,  Tina Giese  1 ,  Audrey Gill  1 ,  Johannes Gnörich  3 ,  Connie Ha  1 ,  Malavika Kannuswamy  1 ,  Do Jin Kim  1 ,  Sebastian T Kunte  3 ,  Lea H Kunze  2  3 ,  Diana Lac  1 ,  Kendra Lechtenberg  1 ,  Amy Wing-Sze Leung  1 ,  Chun-Chi Liang  1 ,  Isabel Lopez  1 ,  Paul McQuade  5 ,  Anuja Modi  1 ,  Vanessa O Torres  1 ,  Hoang N Nguyen  1 ,  Ida Pesämaa  2  6 ,  Nicholas Propson  1 ,  Marvin Reich  2  6 ,  Yaneth Robles-Colmenares  1 ,  Kai Schlepckow  2 ,  Luna Slemann  3 ,  Hilda Solanoy  1 ,  Jung H Suh  1 ,  Robert G Thorne  1 ,  Chandler Vieira  1 ,  Karin Wind-Mark  2  3 ,  Ken Xiong  1 ,  Y Joy Yu Zuchero  1 ,  Dolo Diaz  1 ,  Mark S Dennis  1 ,  Fen Huang  1 ,  Kimberly Scearce-Levie  1 ,  Ryan J Watts  1 ,  Christian Haass  2  4  7 ,  Joseph W Lewcock  1 ,  Gilbert Di Paolo  1 ,  Matthias Brendel  2  3  7 ,  Pascal E Sanchez  8 ,  Kathryn M Monroe  9
Affiliations
  • 1. Denali Therapeutics, Inc., South San Francisco, CA, USA.
  • 2. German Center for Neurodegenerative Diseases (DZNE), Munich, Germany.
  • 3. Department of Nuclear Medicine, University Hospital of Munich, Ludwig Maximilians University, Munich, Germany.
  • 4. Biomedical Center (BMC), Division of Metabolic Biochemistry, Faculty of Medicine, Ludwig Maximilians University, Munich, Germany.
  • 5. Takeda Pharmaceutical Company, Cambridge, MA, USA.
  • 6. Graduate School of Systemic Neurosciences, Ludwig Maximilians University Munich, Planegg-Martinsried, Germany.
  • 7. Munich Cluster for Systems Neurology (SyNergy), Munich, Germany.
  • 8. Denali Therapeutics, Inc., South San Francisco, CA, USA. [email protected].
  • 9. Denali Therapeutics, Inc., South San Francisco, CA, USA. [email protected].
  • # Contributed equally.
PMID: 36635496 DOI: 10.1038/s41593-022-01240-0
Abstract

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.

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