Description:
Triggering Receptor Expressed on Myeloid cells 2 (TREM2) plays a key regulatory role in Alzheimer’s disease (AD) by controlling microglia activation and metabolic activities in brain tissues. TREM2 signaling inhibition is mediated by leukocyte immunoglobulin-like receptor subfamily B member 2 (LILRB2). UTHealth inventors created and engineered an effective monoclonal antibody that blocks LILRB2/ligand interactions and rescues the inhibition of TREM2 signaling by LILRB2, suggesting a novel therapeutic strategy for improving microglial functions.
Background
AD is a neurodegenerative disorder with limited treatment options. AD affects more than 10% of the elderly population and is one of the leading causes of death in the United States. AD is characterized by memory loss and cognitive decline. TREM2 affects AD by its regulation of microglia functions. LILRB2, an inhibitory receptor bearing three immunoreceptor tyrosine-based inhibitory motifs (ITIM), has been shown to plat important roles in neurological functions. LILRB2 is expressed selectively in monocytes, macrophages, and dendritic cells.
Significance and Impact
UTHealth pioneering scientists observed the ligands shared between LILRB2 and TREM2 were found to induce TREM2 and LILRB2 co-ligation and induced signal inhibition mediated by LILRB2, negatively affecting microglia functions. They then created and engineered a monoclonal antibody (Ab29) blocks LILRB2/ligand interactions. Ab29 was then studied in human induced pluripotent stem cell (iPSC)-derived microglia (hMGLs) and in stereotaxic grafted microglia in 5XFAD mice. The study showed Ab29 completely prevented LILRB2-mediated TREM2 signaling inhibition by blocking ligand-LILRB2 interactions and promoting microglia functions in vitro and in vivo.
Technology Highlights
- The monoclonal antibody (Ab29) blocks LILRB2/ligand interactions and prevents TREM2 signaling inhibition mediated by LILRB2.
- Ab29 enhanced microglia phagocytosis, TREM2 signaling, migration, and cytokine responses to the oAβ-lipoprotein complex in hMGL and microglia cell line HMC3.
- Ab29 significantly enhanced clustering of microglia around plaques with a prominent increase in microglial amyloid plaque phagocytosis in vivo.
Potential Applications
LILRB2-mediated inhibition of TREM2 signaling in microglia demonstrated a novel approach of enhancing TREM2-mediated microglia functions by blocking LILRB2-ligand interactions. The LILBR2 blocking monoclonal antibody (Ab29) is a promising novel therapeutic strategy for AD.
Related Publication: Zhao et al., Mol Neurodegener 17(1): 44 (2022)
Intellectual Property Status
Patent applications filed in US, EP, CN, TW, CA, PCT Publication No: PCT/US2022/076383
Available for licensing.
About the Inventors
Zhiqiang An, Ph.D.
Vice President of Drug Discovery at UTHealth Houston
Ningyan Zhang, Ph.D.
Professor at UTHealth Houston and Co-Director of the CPRIT Therapeutic Antibody Core.