A newly developed antibody that increases the activation of TREM2—a receptor on microglia—reduces amyloid burden and alleviates cognitive decline in mice exhibiting Alzheimer’s disease (AD) pathology. These findings indicate that the antibody, Ab18 TVD-Ig/aTfR, may have promise as a treatment for the disease.

The work was led by Zhiqiang An, PhD, professor at McGovern Medical School at the University of Texas Health Science Center at Houston, and Ningyan Zhang, PhD, professor at the Texas Therapeutics Institute at the Brown Foundation Institute of Molecular Medicine. Their team published their work in Science Translational Medicine in an article entitled, “A tetravalent TREM2 agonistic antibody reduced amyloid pathology in a mouse model of Alzheimer’s disease.”

Alzheimer’s disease, which is characterized by the loss of memory and thinking skills, affects more than 10% of the elderly population. Amyloid-beta oligomers and plaques in the parenchyma of the brain are pathological hallmarks of the disease.

Microglia in the brain play crucial roles in amyloid-beta pathology. TREM2, a receptor expressed by microglia, regulates the migration of microglia toward and phagocytosis of amyloid-beta oligomers and plaques.

The research team postulated that increasing TREM2 activation on the microglia would enhance these effects. They identified an antibody that could accomplish this task and then engineered it to enhance its potency and brain penetrance.

“Here, we identified a TREM2 agonist monoclonal Ab (Ab18) by panning a phage-displayed single-chain variable fragment Ab library,” they wrote.

“By engineering the bivalent immunoglobulin G1 (IgG1) to tetra-variable domain immunoglobulin (TVD-Ig), we further increased the TREM2 activation by 100-fold,” they continued. “An engineered bispecific Ab targeting TREM2 and transferrin receptor (TfR; Ab18 TVD-Ig/aTfR) improved Ab brain entry by more than 10-fold with a broad parenchyma distribution.”

An attributed their success to the resources and expertise of his collaborators. “One of the major areas of focus at the Texas Therapeutics Institute is developing technologies to deliver antibody-based therapies across the blood-brain barrier for potential treatment of the disease,” he said.

The researchers then treated a mouse model of Alzheimer’s disease with the engineered antibody. “Weekly treatment of 5XFAD mice (a model of AD) with Ab18 TVD-Ig/aTfR showed a considerable reduction of amyloid burden with increased microglia migration to and phagocytosis of amyloid plaques, improved synaptic and neuronal marker intensity, improved cognitive functions, reduced endogenous tau hyperphosphorylation, and decreased phosphorylated neurofilament H immunostaining,” they wrote.

In sum, the results indicated that antibody-mediated TREM2-targeting therapies might be effective for treating Alzheimer’s disease, but the researchers say that more work is needed before they can be brought to the clinic.

“[W]e demonstrated the feasibility of engineering multivalent TREM2 agonistic antibodies coupled with TfR-mediated brain delivery to enhance microglia functions and reduce amyloid pathology in vitro and in vivo,” said Zhang. “This antibody engineering approach enables the development of effective TREM2-targeting therapies for AD.”

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