A TREM2-activating antibody with a blood–brain barrier transport vehicle enhances microglial metabolism in Alzheimer’s disease models
Bettina van Lengerich, Lihong Zhan, Dan Xia, Darren Chan, David Joy, Joshua I. Park, David Tatarakis, Meredith Calvert, Selina Hummel, Steve Lianoglou, Michelle E. Pizzo, Rachel Prorok, Elliot R. Thomsen, Laura M. Bartos, Philipp Beumers, Anja Capell, Sonnet S. Davis, Lis de Weerd, Jason C. Dugas, Joseph Duque, Timothy Earr, Kapil Gadkar, Tina Giese, Audrey Gill, Johannes Gnörich, Connie Ha, Malavika Kannuswamy, Do Jin Kim, Sebastian T. Kunte, Lea H. Kunze, Diana Lac, Kendra J. Lechtenberg, Amy Wing-Sze Leung, Chun-chi Liang, Isabel Álvarez, Paul McQuade, Anuja Modi, Vanessa O. Torres, Hoang N. Nguyen, Ida Pesämaa, Nicholas E. Propson, Marvin Reich, Yaneth Robles‐Colmenares, Kai Schlepckow, Luna Slemann, Hilda Solanoy, Jung H. Suh, Robert G. Thorne, Chandler Vieira, Karin Wind, Ken Xiong, Y. Joy Yu Zuchero, Dolo Diaz, Mark S. Dennis, Fen Huang, Kimberly Scearce‐Levie, Ryan J. Watts, Christian Haass, Joseph W. Lewcock, Gilbert Di Paolo, Matthias Brendel, Pascal E. Sanchez, Kathryn M. Monroe
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.