A new antibody turbocharges TREM2, the most ardent supporter of microglia. In mice, that is. According to a study published March 10 in the EMBO Journal, a monoclonal antibody trained against the mouse microglial receptor prevents shedding of its ectodomain from the cell surface, and cross-links neighboring receptors. This enhances its signaling. Researchers led by Christian Haass of Ludwig Maximilians University, Munich, reported that in cultured cells, it bolstered microglial survival and uptake of Aβ peptides. In mice, the antibody helped microglia clear Aβ plaques.
- The 4D9 antibody activates TREM2 receptor signaling.
- The antibody bolsters microglial survival and Aβ uptake.
- It boosts plaque clearance in mouse model of amyloidosis.
The researchers are working with Denali Therapeutics, South San Francisco, to move a human version of the antibody toward clinical trials.
Haass had reported that the monoclonal antibody, 4D9, binds to the stalk region of TREM2, shielding the extracellular portion of the receptor from the ADAM10 and ADAM17 proteases that snip it off the cell surface. The antibody enhanced expression of the full-length receptor, and also likely cross-linked receptors on the cell surface, leading to increased signaling. This, in turn, bolstered the microglia’s survival and their phagocytosis of myelin debris. According to the paper, 4D9 also upped the cells’ appetite for Aβ42 peptides, at least in cell culture.
Does this work inside the brain? First author Kai Schlepckow and colleagues found that 24 hours after an intravenous injection of 10mg/kg 4D9, virtually all of the shed, soluble TREM2 in mouse cerebrospinal fluid was bound by the antibody. This suggests target engagement even though only a tiny fraction of the injected antibody crossed into the brain. In addition, the researchers detected more TREM2 within the brains of mice one day after 4D9 treatment, suggesting the antibody helped retain TREM2 on the surface of cells.
The researchers next tested the antibody in 6-month-old mutant APP knock-in mice. Microglia in these mice express more TREM2 than do those in wild-type mice, which researchers believe indicates their transition to a disease-associated microglia (DAM) phenotype (Jun 2017 news). Injecting mice with 50 mg/kg of 4D9 four times over a 10-day period upped microglial TREM2 expression further. In contrast, this regimen lowered expression of P2RY12, a marker of homeostatic microglia. Microglia expressing high TREM2 and low P2RY12 congregated around Aβ plaques.
Dual Action? Arms of 4D9 antibody latch onto the stalk region of neighboring TREM2 receptors. This blocks their cleavage by ADAM10/17 proteases, and enhances signaling by cross-linking the receptors. [Courtesy of Schlepckow et al., EMBO, 2020.]
The four treatments reduced cortical plaque load in the APP knock-in mice by about a third. Specifically, 4D9 treatment erased the fuzzy halo around plaques, and reduced levels of soluble, but not insoluble, Aβ42 in the brain. These findings suggest that revving up TREM2 signaling helps microglia ingest non-fibrillar forms of Aβ, Haass said. That APP knock-in mice tend to have fluffier, more diffuse plaques than do other models such as APP/PS1 likely helped the researchers rapidly detect an effect of the antibody, he added.
The findings complement previous studies in TREM2-deficient APP/PS1 mice, in which plaques became more diffuse in the absence of the microglial receptor, Haass said (Jan 2019 news). Haass said he plans to use RNA sequencing to investigate how 4D9 binding changes the transcriptomes of the microglia.
Rousting Microglial Clean-Up. Plaque load shrank in APP knock-in mice treated with 4D9 (bottom), compared with mice treated with an isotype control. [Courtesy of Schlepckow et al., EMBO, 2020.]
Haass’ group has developed an antibody against human TREM2 that appears to function similarly to 4D9. He is collaborating with Denali Therapeutics to develop a version hitched to an “antibody transport vehicle,” which smuggles the antibody across the blood-brain barrier by attaching to transferrin receptors. The goal is to boost exposure in the brain.
A different TREM2 antibody, AL002, also reportedly activates the receptor (May 2019 conference news). Developed by Alector and AbbVie, AL002 entered a Phase 1 trial in people with mild to moderate AD last year; the trial is slated to finish this month (see clinicaltrials.gov).—Jessica Shugart
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- Schlepckow K, Monroe KM, Kleinberger G, Cantuti-Castelvetri L, Parhizkar S, Xia D, Willem M, Werner G, Pettkus N, Brunner B, Sülzen A, Nuscher B, Hampel H, Xiang X, Feederle R, Tahirovic S, Park JI, Prorok R, Mahon C, Liang CC, Shi J, Kim DJ, Sabelström H, Huang F, Di Paolo G, Simons M, Lewcock JW, Haass C. Enhancing protective microglial activities with a dual function TREM2 antibody to the stalk region. EMBO Mol Med. 2020 Mar 10;:e11227. PubMed.