. A TREM2-activating antibody with a blood-brain barrier transport vehicle enhances microglial metabolism in Alzheimer's disease models. Nat Neurosci. 2023 Jan 12; PubMed.

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  1. It is very intriguing that the ATV:TREM2-activating antibody enhances brain exposure and pharmacodynamic microglial responses compared to an anti-TREM2 antibody. Moving forward, it will be interesting to see how this increased brain exposure affects Aβ and tau pathology in various mouse models. Additional experiments will lead to a better understanding of the interplay between TREM2 activation, timing of treatment, and effective doses on in vivo changes in AD pathology.

    View all comments by Nimansha Jain
  2. I find this a very stimulating paper that shows the vast potential of collaborations between academics and industry. I think this is the way forward and we should foster these types of interactions.

    The authors describe a robust strategy to induce TREM2 activation in vivo, in mice. It is clear that the strategy works and that the biologicals developed by Denali do increase the biodistribution in the brain and therefore the activity of the TREM2-activating antibodies.

    It is also nice to see multiple indicators of target engagement in the form of transcriptomics and metabolic changes, some of which could be translated to humans using imaging techniques. However, there are a number of questions:

    Why is the activation of TREM2 via antibodies not able to elicit a DAM response? It is certain that TREM2 is necessary for microglia to develop a DAM response, but is it the only receptor engaged by plaques, or are there other receptors that need to be co-activated to trigger a DAM response? Or could this be explained by the specific effect of this antibody, whereas others would have potential to induce a full response?

    Clearly, there is target engagement, because the treatment with the antibody induces several changes in the microglia. Is this enough to modify disease in any way? This paper still misses a key element, which is whether exogenous activation of TREM2 can modify microglial function in such a way that they at least react more robustly—and hopefully clear Aβ.

    Lastly, given recent data that attenuation of the microglial response might be beneficial in tauopathies, it will be essential to determine the effect of this antibody beyond amyloid models of AD.

    View all comments by Renzo Mancuso
  3. Human genetics data strongly argue that microglial dysfunction contributes to Alzheimer’s disease. One striking example is the identification of loss-of-function TREM2 mutations that confer greatly increased risk for AD. Meanwhile, a body of murine studies argues that deficient TREM2 function limits protective microglial responses to amyloid pathology such as engulfment and plaque compaction, potentially by impairing appropriate metabolic adaptation.

    Accordingly, multiple groups have tested TREM2 agonist antibodies in animal models and humans as a strategy to treat AD. Studies support the conclusion that enhancing TREM2 agonism reduces pathology and improves behavioral deficits in amyloid models, correlated with microglial proliferation, plaque containment, metabolic fitness, and phagocytosis. Studies vary, however, in which specific disease phenotypes respond to TREM2 agonism. For example, some studies note reduced plaque burden, while others do not. Further, a recent study found that one TREM2 agonist antibody exacerbated tau pathology, while genetic manipulation of TREM2 leads to sometimes conflicting, opposite results between labs and models. In sum, the role of TREM2 agonism in AD treatment is very promising, but our still unclear understanding of when and how it influences AD pathogenesis limits therapy development. A related uncertainty is the degree to which differences between studies are explained by specific TREM2 antibodies used, and their properties.

    This work of van Lengerich and colleagues is exciting for several reasons. First, it introduces a new candidate therapeutic for study in humans with an engineered transferrin receptor binding site, and a defined binding epitope in the stalk region near the ADAM17 cleavage site, similar to a well-characterized murine equivalent. Second, the study builds upon prior understanding of how antibody-based TREM2 agonism affects microglia and the brain, showing that agonism elicits transient microglial states distinct from the well-described DAM phenotype, correlated with many effects that include enhanced proliferation, phagocytosis, glucose metabolism, and mitochondrial metabolism. Third, the authors present evidence that the transferrin receptor binding not only increases delivery to the brain as intended, but also increases TREM2 clustering and signaling via additional interactions with the transferrin receptor, though the degree to which this occurs in vivo remains to be studied.

    These findings enhance our framework for how to measure and describe the effects of TREM2 agonism, and suggest that we are only scratching the surface of how agonist antibodies may be customized for CNS applications. With careful engineering, it may be possible to further tune TREM2 signaling, both quantitatively and qualitatively, to gain even more precise control over microglial responses. It would be interesting to benchmark various TREM2 agonist antibodies across the assays presented in this study, along with murine amyloid models, to better understand which design features are most critical for which downstream effects. 

    By demonstrating new ways to enhance TREM2 signaling, this study raises another question: How much agonism is too much? It seems possible that with too much agonism, microglia may be at risk of adopting detrimental states, and perhaps there are qualitative and quantitative “sweet spots” for optimal therapeutic effects. This interesting study sustains excitement over targeting microglia to treat AD.

    View all comments by Chris Bennett
  4. In this exciting study, Lengerich and Zhan et al. have grafted the transferrin receptor (TfR) binding site onto two anti-TREM2-stalk-region antibodies to boost the antibody delivery into the CNS in an amyloid mouse model. In line with the previous work with anti-TREM2 treatments, this paper further demonstrates the efficacy of TREM2 agonist antibodies to enhance microglial response against Alzheimer’s pathology through TREM2-dependent signaling. The paper contains several novel and interesting points:

    1. It provides evidence that the “shuttle” approach can be effective in inducing microglia activation using low doses of antibody. This is relevant for therapy, as it may reduce the therapeutic costs and may potentially lead to administration routes different from intravenous infusion, such as subcutaneous administration.
    2. It provides detailed information on a new anti-human TREM2 antibody.

    We are happy to see that the comprehensive characterizations of a single injection of anti-TREM2 antibody in this study recapitulates the induction of microglia proliferation and state shifts induced by a single acute treatment that we reported in previous studies with different antibodies (Ellwanger et al., 2021; Wang et al., 2020). It is interesting that the authors further examine the duration of anti-TREM2-stimulated responses. The new data demonstrates waning of microglia activation 14 days after treatment. It is possible that different antibodies with different pharmacokinetics may have distinct duration. It will be important to follow up these studies with long-term treatments to check the duration of TREM2 activation after multiple injections.

    It is nice to see that the gain-of-function experiments with the anti-TREM2-TfR antibody presented in this study corroborate our previous work on TREM2 loss-of-function with regard to the impact of susceptibility to CSF1 deprivation and mTOR activation (Ulland et al.., 2017; Wang et al., 2015). With two different anti-TREM2 antibodies (all binding to stalk region of TREM2), Lengerich and Zhan et al. showed a promising enhancement of the same pathways. We recently showed that TREM2 signals through DAP12 but also DAP10, at least in an animal model (Wang et al., 2022). Thus, it would be interesting to know whether anti-TREM2 treatment affects both downstream pathways. Another interesting question is whether this enhancement can be applied to some clinically relevant variants such as TREM2 R47H and TREM2 R62H.

    It has been hypothesized that the beneficial effect of anti-TREM2 may depend on timing. Even though many groups have shown the protective role of TREM2 signaling in different amyloid models, recent studies on tau models have raised some concern that TREM2 activation may be detrimental at late-stage disease (Jain et al., 2023; Sayed et al., 2018). It will be important to investigate what the outcome of the TfR-shuttle delivery method is in these models.

    Another question for future studies concerns the potential side effects of global changes in the biodistribution due to TfR-anti-TREM2 fusion. The authors showed no changes in immune cells in different organs. However, the study was limited to single dose in a 12-week period; moreover, no disease models have been investigated. For example, TREM2 blockade has a beneficial impact on tumorigenesis (Molgora et al., 2020). Will enhanced biodistribution of TfR-fused anti-TREM2 antibody to peripheral organs modify the risk for other diseases?

    Finally, a short-term treatment with TfR-fused anti-TREM2 antibody had no impact on Aβ plaques, which is consistent with our previous studies. However, an anti-mouse TREM2 mAb from the same group was shown to reduce plaques after short treatment. It will be important to clarify whether acute and chronic treatment with anti-TREM2 affect Aβ load.

    View all comments by Marco Colonna
  5. This is an interesting paper. Delivery of large-molecule drugs across the blood-brain barrier (BBB) is increasingly being seen as an achievable goal. Several technologies have been described where following peripheral administration, the molecules can be detected in the brain. The authors have clearly demonstrated this in 2- to 3-month-old mice expressing human TfR, After intravenous injection, ATV-4D9 shows sixfold more permeability than 4D9 across the brain and no immune-cell changes were detected up to 12 weeks after treatment. Binding of 4D9 antibody to transferrin receptor activates microglia and promotes glucose metabolism, it would be interesting to investigate the effectiveness of this antibody conjugated with transferrin on various conformational structures of Aβ, tau, and secretases involved in APP pathways.

    Previously, Genentec has used various bispecific antibodies with optimized binding to the transferrin receptor (TfR) that target β-secretase (BACE1), can cross the BBB, and reduce brain Aβ in human TfR knock-in mice in a TfR affinity-dependent fashion. Intravenous dosing of monkeys with anti-TfR/BACE1 antibodies also reduced Aβ both in cerebral spinal fluid and in brain tissue, and the degree of reduction correlated with the brain concentration of anti-TfR/BACE1 antibody.

    View all comments by Suhail Rasool

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