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Horie K, Salvadó G, Barthélemy NR, Janelidze S, Li Y, He Y, Saef B, Chen CD, Jiang H, Strandberg O, Pichet Binette A, Palmqvist S, Sato C, Sachdev P, Koyama A, Gordon BA, Benzinger TL, Holtzman DM, Morris JC, Mattsson-Carlgren N, Stomrud E, Ossenkoppele R, Schindler SE, Hansson O, Bateman RJ. CSF MTBR-tau243 is a specific biomarker of tau tangle pathology in Alzheimer's disease. Nat Med. 2023 Aug;29(8):1954-1963. Epub 2023 Jul 13 PubMed.
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The MBTR of tau represents a hot area of biomarker and drug development. Fluid biomarkers that target N-terminal epitopes (e.g., p-tau181, p-tau217, p-tau231) seem to be better markers for amyloidosis than tau pathology, while tau immunotherapy with N-terminal antibodies has led to disappointing results thus far in clinical trials. These findings have shifted the focus to the tau MTBR region, which may play a more important role in tau seeding and aggregation.
The paper by Horie et al. convincingly shows, across two independent cohorts, that CSF MTBR-tau243 is more strongly correlated with tau PET and clinical measures, and is a more dynamic longitudinal biomarker across the AD continuum than CSF N-terminal p-tau biomarkers. A fluid biomarker equivalent to tau PET could would have prognostic utility, aid with disease staging (as proposed in the recent update to the NIA-AA research framework), and (based on TRAILBLAZER-ALZ2 results) may predict response to anti-amyloid monoclonal antibody treatment.
While the correlations between CSF MTBR-243 and tau PET are convincing at the group level, there still seems to me to be significant variability between the CSF measure and tau PET at the single-subject level, so I think the utility of this biomarker for disease staging at the individual patient level is still to be determined. Ultimately, this may be better accomplished with a panel of fluid biomarkers than a single measure. Furthermore, the impact of this analyte would be greatly enhanced if it can be measured reliably in plasma in addition to CSF.
With these caveats, MTBR-tau243 seems to be an interesting new biomarker, and it is especially exciting to see it utilized to measure target engagement in early phase clinical trials of MTBR-targeting tau antibodies.
View all comments by Gil RabinoviciWashington University in St. Louis
The current paper, as well as work from 2021 by Dr. Kanta Horie exploring MTBR-tau243, demonstrates that it is the best fluid biomarker proxy of insoluble tau to date. He has also done fantastic work looking at other forms of MTBR in autosomal-dominant AD (Horie et al., 2023), as well as non-AD tauopathies (Horie et al., 2022).
This work opens up promising new markers for prognostics as well as an important readout in clinical trials. Alongside the work into different ptau phosphorylation sites led by Nicolas Barthelemy, we now have a richer characterization of changes occurring in tau from the very early signs of amyloidosis up the the formation of neurofibrillary tangles.
References:
Horie K, Barthélemy NR, Sato C, Bateman RJ. CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer's disease. Brain. 2021 Mar 3;144(2):515-527. PubMed. Correction.
Horie K, Li Y, Barthélemy NR, Gordon B, Hassenstab J, Benzinger TL, Fagan AM, Morris JC, Karch CM, Xiong C, Allegri R, Mendez PC, Ikeuchi T, Kasuga K, Noble J, Farlow M, Chhatwal J, Day G, Schofield PR, Masters CL, Levin J, Jucker M, Lee JH, Roh JH, Sato C, Sachdev P, Koyama A, Reyderman L, Bateman RJ, McDade E, and the Dominantly Inherited Alzheimer Network. Change in Cerebrospinal Fluid Tau Microtubule Binding Region Detects Symptom Onset, Cognitive Decline, Tangles, and Atrophy in Dominantly Inherited Alzheimer's Disease. Ann Neurol. 2023 Jun;93(6):1158-1172. Epub 2023 Mar 16 PubMed.
Horie K, Barthélemy NR, Spina S, VandeVrede L, He Y, Paterson RW, Wright BA, Day GS, Davis AA, Karch CM, Seeley WW, Perrin RJ, Koppisetti RK, Shaikh F, Lago AL, Heuer HW, Ghoshal N, Gabelle A, Miller BL, Boxer AL, Bateman RJ, Sato C. CSF tau microtubule-binding region identifies pathological changes in primary tauopathies. Nat Med. 2022 Dec;28(12):2547-2554. Epub 2022 Nov 24 PubMed.
View all comments by Brian GordonNew York University School of Medicine
This Nature Medicine article nicely supports incorporating measurements of CSF levels of MTBR-tau as a potential biomarker for tau tangle pathology in AD. It is notable, though, that MTBR-tau in CSF was recently shown to be decreased in primary tauopathies by these same authors (Horie et al., 2022). This may complicate matters in mixed pathologies, and indicates that this epitope would have to be targeted intracellularly by therapeutic antibodies like E2814 in those non-AD tauopathies.
Regarding Jin Zhou's AAIC presentation, the safety profile and target engagement of E2814 look promising for ongoing clinical trials. Its therapeutic potential is also well supported by its reduction of MTBR-tau243 in CSF in the treated AD patients. This is not an artifact, because E2814 binds to aa 299-303 and to aa 362-366, whereas MTBR-tau243 consists of aa 243-254.
In Horie et al., 2021, tau fragments 299-317 and 354-369 showed a similar increase in AD patients as did fragment 243-254. This raises the question if these three fragments may be a part of a larger fragment in vivo that E2814 is then clearing. If this is not the case, then E2814-mediated clearance of MTBR-tau299 and MTBR-tau354 is somehow influencing clearance of MTBR-tau243. This might indicate an intracellular interaction where tau is less fragmented, whereas the clearance of the larger fragment could be intra- and/or extracellular.
With this in mind, it would be very interesting for the company to examine whether E2814 is taken up into neurons. This would greatly increase the pool of targetable tau, since most pathological tau is found inside neurons. Based on prior reports by some of these same investigators, most of extracellular tau consists of approximately amino acids 150-250, with MTBR-tau being only a minor fraction. Since extracellular tau is a tiny fraction of intracellular tau, therapeutic efficacy of tau antibodies is likely to be greatly enhanced if they can get into neurons.
We and other groups have shown that antibodies against tau and other targets can be taken up into neurons, and the degree of uptake depends at least in part on the charge of individual antibodies (Congdon et al., 2019; Congdon et al., 2022).
An AAIC poster by Sonia Talma et al. also spoke to this issue. These investigators had previously reported that the mouse version of E2814 reduced insoluble tau on the contralateral but not the ipsilateral side following brain injection of P301S tau seeds in P301S transgenic mice (Roberts et al., 2020). The effect was modest (around 30 percent reduction) although the antibody dose was high (40 mg/kg). However, treatment was acute (once a week for three weeks), which is more likely to reduce soluble tau though those levels were not reported.
On their poster presented at AAIC 2023, the authors report seeing greater efficacy of this antibody following a longer treatment period using AD tau seeds in htau transgenic mice, which better supports its clinical development. The dose required for efficacy remains rather high, though, with clearance of insoluble tau only seen at a 40 mg/kg dose but not at 3 or 10 mg/kg dose. The effective dose appears to be lower in the human study than in the mouse studies, although the measured parameters are different (CSF tau fragment vs. insoluble brain tau) so those studies cannot be directly compared.
Lastly, we have shown that an antibody’s ability to prevent tau seeding vs tau toxicity may not always go hand-in-hand (Congdon et al., 2019). It will be important to determine if this antibody and related ones against the MTBR region can reduce tau neurotoxicity in vivo and functional impairments. This has presumably already been examined, considering its advanced clinical development but it has yet to be published. We eagerly await that report and cognitive outcome of the ongoing AD trials.
References:
Horie K, Barthélemy NR, Spina S, VandeVrede L, He Y, Paterson RW, Wright BA, Day GS, Davis AA, Karch CM, Seeley WW, Perrin RJ, Koppisetti RK, Shaikh F, Lago AL, Heuer HW, Ghoshal N, Gabelle A, Miller BL, Boxer AL, Bateman RJ, Sato C. CSF tau microtubule-binding region identifies pathological changes in primary tauopathies. Nat Med. 2022 Dec;28(12):2547-2554. Epub 2022 Nov 24 PubMed.
Horie K, Barthélemy NR, Sato C, Bateman RJ. CSF tau microtubule binding region identifies tau tangle and clinical stages of Alzheimer's disease. Brain. 2021 Mar 3;144(2):515-527. PubMed. Correction.
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.
Congdon EE, Jiang Y, Sigurdsson EM. Targeting tau only extracellularly is likely to be less efficacious than targeting it both intra- and extracellularly. Semin Cell Dev Biol. 2022 Jun;126:125-137. Epub 2021 Dec 9 PubMed.
Roberts M, Sevastou I, Imaizumi Y, Mistry K, Talma S, Dey M, Gartlon J, Ochiai H, Zhou Z, Akasofu S, Tokuhara N, Ogo M, Aoyama M, Aoyagi H, Strand K, Sajedi E, Agarwala KL, Spidel J, Albone E, Horie K, Staddon JM, de Silva R. Pre-clinical characterisation of E2814, a high-affinity antibody targeting the microtubule-binding repeat domain of tau for passive immunotherapy in Alzheimer's disease. Acta Neuropathol Commun. 2020 Feb 4;8(1):13. 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.
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