. PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019 Jan 28;10(1):465. PubMed.

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  1. We read with great interest the very extensive publication from Dr. Schwartz’ group, which significantly expands on their previous work on checkpoint blockade for treating neurodegenerative diseases. Using both anti-PD-1 and now anti-PD-L1 antibodies, they demonstrate in a large series of animal studies prevention and reversion of cognitive deficits in the well-characterized 5xFAD amyloid transgenic model, and significant protection against cerebral pathology, together with the new finding of increased anti-inflammatory IL10 cytokine. Very interestingly, they extend these findings to tau transgenic animals and further analyze the possible underlying mechanisms.

    We have previously tried to generalize the checkpoint blockade concept to other amyloid transgenic mouse models, with different genetic backgrounds, and in three different animal facilities in pharmaceutical companies. While the checkpoint blockade was confirmed in the periphery in one case, collectively we could not observe a significant impact on brain amyloid pathology in any model (Latta-Mahieu et al., 2018). Experimental conditions cannot be identical (discussed in detail in Latta-Mahieu et al.), and according to Rosenzweig et al. it is indeed of outmost importance to “optimize treatments with the tested antibody in each animal model at each facility.”

    We note that in the two publications from Dr. Schwartz, xenogenic rat anti-PD1 or anti PD-L1 and human anti-PD-L1 antibodies are used and most recently at significant doses, 0.5 and 1.5 mg per mouse. Those, together with the concomitant checkpoint blockade, could participate in enhancing peripheral immune responses and the mobilization of innate immunity in brain. It would be important that such potential “sensitizing/potentiating” factors be elucidated in the future.

    We welcome and congratulate Dr. Schwartz’s group on this new publication and are looking forward to more teams in the world generalizing the checkpoint blockade concept for treating neurodegenerative diseases.

    References:

    . Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models. Glia. 2018 Mar;66(3):492-504. Epub 2017 Nov 14 PubMed.

    View all comments by Andreas Ebneth
  2. With regard to Latta-Mahieu et al., 2018, I am confident that the three groups that published this paper would have been able to repeat the positive effect of anti-PD-1 antibody on plaque burden, if they had calibrated the antibody and the treatment protocol in the mouse model that they used, and taken into account the different stages of the disease. The manuscript describes three single experiments, employing animal models that are different from those used in either of our papers. Below, I elaborate on the factors that could explain the failure to detect a decrease in plaque burden, the only read-out that was used to monitor the treatment effect.

    The target of the treatment with anti-PD-1 or anti-PD-L1 is not directed against β-amyloid plaques, but rather, this therapy evokes an immunological pathway that starts in the immune system and facilitates, in synergy with inflammatory cues coming from the brain, the recruitment of immune cells to the brain, together leading to multiple effects that ultimately result in cognitive improvement and neuroprotection. Accordingly, the beneficial effect of the treatment on disease modification is an outcome of the modulation of many processes that contribute to disease escalation; these include, but are not limited to, the clearance of amyloid plaques. In contrast to a treatment that is specifically directed against amyloid pathology, with the primary goal of reducing plaques, and which may or may not affect cognitive performance, in the case of immune checkpoint blockade, the beneficial effect is an outcome of several events that are affected by the therapy, the primary one being immune modulation.  

    Our first paper (Baruch et al., 2016) introduced the concept of adopting immune checkpoint blockade for treating AD, by reporting results of a single dose of anti-PD-1 antibody in 5xFAD mice. In order to generalize the phenomenon, further experiments were needed, including those addressing the mechanism, optimization of the dose/regimen, and testing in additional mouse models, which are all presented in our most recent publication (Rosenzweig et al., 2019). 

    We found that the effect of the antibody is dependent on the dose, and its affinity. Moreover, we found that elevation of IFN-γ, indicating peripheral engagement, is an essential response to the treatment, but is not sufficient. Thus, dosages that were sufficient to induce a peripheral response were insufficient to evoke a central one. In line with that observation, we found that the peripheral immune response can be evoked in wild-type animals as well, though there is no effect on monocyte infiltration and immune activity in their brains, suggesting that IFN-γ is important, but is not a valid marker of efficacy on disease progression of this treatment. In addition, in animal models of dementia, which show no plaque burden, treatment using the correct dose and timing resulted in improved cognition and reduced Tau pathology.

    In Latta-Mathieu et al., 2018, results from three different facilities were presented, which summarize three single experiments. Two of the three experiments reported used Fc chimeras (mIgG1) derived from the RPM1-14 anti-PD-1 antibody; importantly, it was shown that the chimeric Fc region significantly affects the pharmacokinetic profile of such antibodies (Ober et al., 2001), and obviously requires adjustment of the therapeutic dose/regimen. The only experiment which used the same antibody that our team used (Baruch et al., 2016) was carried out by Janssen using the commercially available rat IgG2a anti-PD-1 from BioXcell (clone RMP1-14; Catalog number, BE0146), but was tested on the ThyAPP/PS1 mouse model.

    In light of the above, we suspect that the lack of amyloid-β plaque clearance in all the experiments described in Latta-Mahieu et al., 2018, indicates that the authors, using a single dose, were working under sub-optimal experimental conditions. Based on our understanding of the mechanism, we are currently establishing the nature of the immunological marker of the response induced by the antibody that most closely correlates with treatment efficacy in Alzheimer’s disease modification; such a marker could be used to predict a response leading to disease modification. Until these markers are disseminated, and since the antibodies are not directed at amyloid plaque, the primary dose calibration in any mouse model or facility should be based on disease modification as measured by cognitive performance.

    References:

    . Systemic immune-checkpoint blockade with anti-PD1 antibodies does not alter cerebral amyloid-β burden in several amyloid transgenic mouse models. Glia. 2018 Mar;66(3):492-504. Epub 2017 Nov 14 PubMed.

    . PD-1 immune checkpoint blockade reduces pathology and improves memory in mouse models of Alzheimer's disease. Nat Med. 2016 Feb;22(2):135-7. Epub 2016 Jan 18 PubMed.

    . PD-1/PD-L1 checkpoint blockade harnesses monocyte-derived macrophages to combat cognitive impairment in a tauopathy mouse model. Nat Commun. 2019 Jan 28;10(1):465. PubMed.

    . Differences in promiscuity for antibody-FcRn interactions across species: implications for therapeutic antibodies. Int Immunol. 2001 Dec;13(12):1551-9. PubMed.

    View all comments by Michal Schwartz
  3. This paper is interesting and extends the group's previous findings. The authors show PD-1 or PD-L1 blockade improved murine AD and tauopathy models. Interestingly, they found that macrophages expressing scavenger receptors are involved in this process. However, the relationship between the PD-1/PD-L1 system, which works in T cells, and macrophage/microglial scavenger receptors has not been well-elucidated. To extend this effect observed in mice to the clinic, it is necessary to clarify the detailed mechanism of how PD-1/PD-L1 blockade reduces plaque burden. It must be cautioned that this treatment may promote neuroinflammation, like multiple sclerosis.

    View all comments by Akihiko Yoshimura

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