New antibody shows therapeutic effects in mice with Alzheimer's disease

Research led by senior author Zhiqiang An, PhD, professor and Robert A. Welch Distinguished University Chair in Chemistry at McGovern Medical School at UTHealth Houston, found that a tetra-variable domain antibody targeting thetriggering receptor expressed on myeloid 2 (TREM2) -- dubbed TREM2 TVD-lg -- reduced amyloid burden, eased neuron damage, and alleviated cognitive decline in mice with Alzheimer's disease. The study was published today in Science Translational Medicine.

"Antibody-based therapy is a viable drug modality for the treatment of Alzheimer's disease," said An, director of the Texas Therapeutics Institute with The Brown Foundation Institute of Molecular Medicine for the Prevention of Human Diseases (IMM). "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."

TREM2 is a single-pass receptor expressed by microglia -- supportive cells that function as scavengers in the central nervous system. Microglia play a crucial role in the removal of amyloids that cluster around amyloid-beta plaques, a hallmark of Alzheimer's disease.

While previous research has shown that TREM2 plays an important role in the pathophysiology of Alzheimer's disease, the recent findings suggest that increasing TREM2 activation could have therapeutic effects such as improved cognition.

"By leveraging the unique antibody drug discovery capabilities at UTHealth Houston and collaborating with scientists with complementary expertise, we 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 co-senior author Ningyan Zhang, PhD, professor at the Texas Therapeutics Institute at IMM at McGovern Medical School. "This antibody engineering approach enables the development of effective TREM2-targeting therapies for AD."

Additional authors from UTHealth Houston's IMM include Peng Zhao, PhD, postdoctoral research fellow; Yuanzhong Xu, PhD, assistant professor; Xuejun Fan, MD, PhD, research scientist; Leike Li, PhD, postdoctoral research fellow; Xin Li, research associate; and Qingchun Tong, PhD, professor and Cullen Chair in Molecular Medicine. Wei Cao, PhD, the Roy M. and Phyllis Gough Huffington Distinguished Professor of anesthesiology with McGovern Medical School, also contributed to the study. An, Tong, and Cao are also faculty members at The University of Texas MD Anderson Cancer Center UTHealth Houston Graduate School of Biomedical Sciences.

Other co-authors include LuLin Jiang, PhD, with Sanford Burnham Prebys Medical Discovery Institute in California; Hisashi Arase, MD, with Osaka University in Japan; Hui Zheng, PhD, with Baylor College of Medicine in Houston; Yingjun Zhao, PhD, with Xiamen University in China; and Huaxi Xu, PhD, with Xiamen University and Chongqing Medical University in China.

The work was in part supported by grants from the Cancer Prevention and Research Institute of Texas (RP150551 and RP190561) and Welch Foundation.