Ayalon G, Lee SH, Adolfsson O, Foo-Atkins C, Atwal JK, Blendstrup M, Booler H, Bravo J, Brendza R, Brunstein F, Chan R, Chandra P, Couch JA, Datwani A, Demeule B, DiCara D, Erickson R, Ernst JA, Foreman O, He D, Hötzel I, Keeley M, Kwok MC, Lafrance-Vanasse J, Lin H, Lu Y, Luk W, Manser P, Muhs A, Ngu H, Pfeifer A, Pihlgren M, Rao GK, Scearce-Levie K, Schauer SP, Smith WB, Solanoy H, Teng E, Wildsmith KR, Bumbaca Yadav D, Ying Y, Fuji RN, Kerchner GA. Antibody semorinemab reduces tau pathology in a transgenic mouse model and engages tau in patients with Alzheimer's disease. Sci Transl Med. 2021 May 12;13(593) PubMed.

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  1. These reports by Ayalon and Zilkova are helpful to the field of tau immunotherapy. It is interesting that they do not reach the same conclusion regarding the importance of antibody effector function for microglial phagocytosis. Similar differences between studies have been reported previously for Aβ antibodies and likely relate to the models used and/or experimental design. The argument for considering this issue is also much stronger for Aβ antibodies because most of Aβ pathology is extracellular, whereas most of tau pathology is intracellular. Culture studies are necessary for mechanistic insight, but it is well established that microglia in a dish behave differently than in animals, which makes it difficult to extrapolate such data to any in vivo situation.

    There is not a tremendous difference in the effects of the isotypes in the study by Zilkova and colleagues, and they acknowledge that the strong effect of tau alone on microglial cytokine production makes it difficult to say much about effects of isotype on cytokine release. It would be helpful if the authors could comment on how the tau concentration in the culture assay relates to its extracellular levels in vivo. The authors mention in their article that the justification for Genentech/AC Immune’s claim for enhanced safety of tau antibodies that have no effector function appears to rest on them not causing MAP2 fragmentation in culture. This ideally should be supported by additional assays. It is doubtful that Genentech/AC Immune would have made such an important decision without additional data on other toxicity markers to support it, but it is not included in their current article.

    Given the inherent difficulties in relying on and comparing culture data using different models and/or study design, Ayalon et al. rightly compared the two versions of their mouse antibody in a tauopathy mouse model. The version with effector function was effective at a lower dose than the effector-less antibody, but their clearance of pathological tau was not robust. On brain sections, it reduced one phospho-tau epitope but had no effect on a different soluble phospho-tau epitope on western blots. Possible effects on the insoluble tau fraction seen on western blots do not appear to have been analyzed. Further, comparison of the two antibody versions on astro- and microgliosis did not reveal any effect of either antibody compared to controls, which is in line with prior in vivo studies on other tau antibodies.

    In summary, the murine version of semorinemab was modestly effective in the mice, a version with effector function worked at a lower dose than its effector-less counterpart, and neither one was toxic in these animals. Based on these findings, it is not clear to me why this antibody, and its effector-less version, was selected for clinical trials. Functional studies are not included in the article but I would assume that some behavioral or neuronal activity benefit in animal studies would have been needed to green-light clinical trials, and presumably will be published in due course. The data from the nonhuman primates and the clinical plasma data is informative, but does not provide insight into why the trial failed. Hopefully, additional analyses of these subjects, including quantitation of various tau species, and the ongoing trial with tau PET imaging will shed light on this.

    Comparing the efficacy of different isotypes of tau antibodies is certainly warranted, and is being done in my lab, but it is important to remember that most of pathological tau is inside neurons, where several tau antibodies can target it (for recent reviews see Sandusky-Beltran and Sigurdsson, 2020; Sigurdsson 2019). The electrical charge of the antibody, which appears to influence its neuronal uptake, may be a more important consideration than its effector function for microglial phagocytosis (Congdon et al., 2019). It makes sense to target pathological tau where most of it is located, namely inside neurons.

    References:

    Sandusky-Beltran LA, Sigurdsson EM. Tau immunotherapies: Lessons learned, current status and future considerations. Neuropharmacology. 2020 Sep 15;175:108104. Epub 2020 Apr 28 PubMed.

    Sigurdsson EM. Alzheimer's therapy development: A few points to consider. Prog Mol Biol Transl Sci. 2019;168:205-217. Epub 2019 Jun 26 PubMed.

    Congdon EE, Chukwu JE, Shamir DB, Deng J, Ujla D, Sait HB, Neubert TA, Kong XP, Sigurdsson EM. Tau antibody chimerization alters its charge and binding, thereby reducing its cellular uptake and efficacy. EBioMedicine. 2019 Apr;42:157-173. Epub 2019 Mar 22 PubMed.

    View all comments by Einar Sigurdsson

  2. Understanding the role of the isotype in developing antibody therapies for Alzheimer’s disease is indeed critical. The work from our group also supports the use of tau antibodies in an IgG4 (low effector function) isotype in clinical trials. In a direct comparison of our 2N tau-specific antibody, RN2N, in a murine IgG2a (high effector function) and murine IgG1 (low effector function) format, we demonstrated that IgG2a, but not IgG1, increased the secretion of pro-inflammatory cytokines in vitro (Bajracharaya et al., 2021). Furthermore, only the IgG1 isotype was able to reduce microgliosis in vivo and demonstrated enhanced efficacy compared to IgG2a following treatment of P301L tau transgenic mice. Together, our work and that of Ayalon et al. demonstrate that high microglial activation is not required for tau antibody efficacy and suggests that enhanced pro-inflammatory cytokine secretion may hinder antibody efficacy in vivo.

    References:

    Bajracharya R, Brici D, Bodea LG, Janowicz PW, Götz J, Nisbet RM. Tau antibody isotype induces differential effects following passive immunisation of tau transgenic mice. Acta Neuropathol Commun. 2021 Mar 12;9(1):42. PubMed.

    View all comments by Jürgen Götz

  3. This is an interesting report by Ayalon et al. on humanized, anti-tau, N-terminus-specific IgG4 monoclonal antibody (mAb), semorinemab. This mAb did not slow the rate of clinical decline in early AD (prodromal to mild) compared to placebo, but it was safe even at very high doses (~34g/month).

    Data presented by the authors (Fig S5) demonstrated that both IgG1 and IgG4 semorinemab inhibited oligomeric tau uptake by mouse hippocampal neurons. However, in the presence of microglia, only the latter mAb was protective against exogenous tau-mediated toxicity in cultured neurons.

    These data support their previous report demonstrating that effector function of the mAb is not required for the reduction of tau pathology (Lee et al., 2016). However, recent results with another humanized mAb, AX004, demonstrated that both IgG1 and IgG4 variants stimulated abnormal tau protein uptake by human adult primary microglial cells (Zilkova et al., 2020). Importantly, although Zilkova and colleagues found that IgG1 more effectively promoted tau uptake than the IgG4 isotype, neither mAb-tau complex increased production of pro-inflammatory (IL1β, IL6, IFNγ, and TNFα) or anti-inflammatory (IL4 and IL10) cytokines by human primary microglia compared with a tau control. Interestingly, the  authors also showed that Fab fragments of IgG1 and IgG4 AX004 alone do not promote tau uptake by human microglia. 

    It is difficult to compare these studies. Ayalon and coauthors used mouse neurons for tau uptake studies and microglia-neuron co-culture along with humanized IgG1 and IgG4 mAb with human Fc fragments. Of note, it was reported that human IgGs recognize mouse and human FcγR with similar binding affinity. Zilkova et al. generated primary human microglia stimulated in vitro for eight to 14 days with GM-CSF and used them with humanized AX004 IgG1 and IgG4 mAbs.  Importantly, they did not use human neurons co-cultured with these microglia.

    While further studies may help us to understand the significance of full-effector or effector-less mAbs for reduction/clearance of pathological molecules involved in neurodegenerative diseases, I need to mention, regrettably, that all AD immunotherapy trials have been uniformly unsuccessful. Although some clinical trials are still in progress, overall, the field is moving to earlier interventions (i.e., preventive treatment of people at preclinical phase).  

    Unfortunately, due to the complexity, the cost, and the need for monthly intravenous injections of asymptomatic people with high concentrations of mAb, passive vaccination is impractical for preventive treatment. By contrast, active vaccines generating sufficient levels of immune responses may protect the host from overt diseases and have been used as preventive measures for over 100 years. Therefore, it is likely that safe and immunogenic preventive Aβ and tau vaccines, or even dual vaccine targeting both pathological molecules initiated in non-demented subjects based on disease-related blood, brain, and CSF biomarkers, may inhibit/reduce oligomerization of Aβ and tau aggregation and delay downstream pathological processes.

    References:

    Lee SH, Le Pichon CE, Adolfsson O, Gafner V, Pihlgren M, Lin H, Solanoy H, Brendza R, Ngu H, Foreman O, Chan R, Ernst JA, DiCara D, Hotzel I, Srinivasan K, Hansen DV, Atwal J, Lu Y, Bumbaca D, Pfeifer A, Watts RJ, Muhs A, Scearce-Levie K, Ayalon G. Antibody-Mediated Targeting of Tau In Vivo Does Not Require Effector Function and Microglial Engagement. Cell Rep. 2016 Aug 9;16(6):1690-700. Epub 2016 Jul 28 PubMed.

    Zilkova M, Nolle A, Kovacech B, Kontsekova E, Weisova P, Filipcik P, Skrabana R, Prcina M, Hromadka T, Cehlar O, Rolkova GP, Maderova D, Novak M, Zilka N, Hoozemans JJ. Humanized tau antibodies promote tau uptake by human microglia without any increase of inflammation. Acta Neuropathol Commun. 2020 May 29;8(1):74. PubMed.

    View all comments by Michael G. Agadjanyan

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