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. Previous studies in rodent models of AD have shown that mice with increased TREM2 expression have reduced amyloid pathology. UTHealth inventors created and engineered an effective TREM2 agonist monoclonal antibody for the development of AD treatment.
Background
Alzheimer's disease (AD) is a neurodegenerative disorder that 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. Pathological hallmarks of AD include the deposition of oligomeric amyloid-β (Aβ) and insoluble Aβ plaques. TREM2 has been discovered as a key regulator of controlling amyloid pathology. Recent reports described multiple TREM2 agonistic antibodies (Abs) with biological benefits in AD-based in vitro and in vivo models. Though activating the TREM2 pathway via agonist Abs is a promising therapeutic option for AD treatment, more Ab engineering and mechanistic studies are needed to bring this class of therapies to the clinic.
Significance and Impact
UTHealth pioneering scientists identified TREM2 agonist monoclonal Abs by panning a phage-displayed single-chain variable fragment library. They then engineered a tetra-variable domain immunoglobulin (TVD-Ig), which increased the TREM2 activation by 100-fold. UTHealth researchers further engineered a bispecific Ab targeting TREM2 and transferrin receptor (TfR), which improved Ab brain entry by more than 10-fold with a broad brain parenchyma distribution. The Ab engineering approach enables the development of effective TREM-2 targeting therapies for AD.
Technology Highlights
•TREM2 Ab can effectively trigger TREM2 clustering without altering cellular TREM2 levels.
•The engineered TVD-Ig showed 100-fold increase in activating TREM2 signaling over the original IgG form.
•The long-term treatment using the bispecific Ab targeting TREM2 and TfR showed reduced plaque burden in 5XFAD mice (a model of AD).
Potential Applications
TREM2-regulated proteins can be associated with neurodegenerative diseases and disorders, such as AD, Parkinson’s Disease (PD), dementia, dementia with Lewy bodies (DLB), etc. The engineered TVD-Ig showed TREM2 activation increased by 100-fold, which could potentially overcome the poor Ab penetration through the blood-brain barrier (BBB). Besides therapeutic use, the engineered TREM2 Ab can be applied to TREM2 detection in diagnostic assays.
Related Publication: Zhao et al., Sci. Transl. Med. 14, eabq0095 (2022)
Intellectual Property Status
Patent Filed
PCT Publication No: PCT/US2022/076382
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.