For anti-tau antibodies, researchers are still learning what strategies work best. Sometimes, however, the lessons are unclear. Case in point: Two new papers conflict about which antibody isotype ameliorates tau pathology most effectively. In the May 12 Science Translational Medicine, researchers led by Reina Fuji and Geoffrey Kerchner of Genentech in San Francisco report preclinical and Phase 1 data from the company’s anti-tau antibody, semorinemab. The data explain the rationale for using an IgG4 backbone. In cultures of mouse neurons and microglia, the IgG4 version protected neurons from tau toxicity better than did an IgG1. This may be because the IgG1 isotype binds more strongly to microglial receptors, causing these cells to release pro-inflammatory cytokines that damage neurons, the authors noted.
- An IgG4 version of semorinemab protected neurons better than did an IgG1 version.
- For AX004, an IgG1 version best cleared tau oligomers.
- The optimal isotype may depend on an antibody’s intended mechanism of action.
However, last year, another paper using a different experimental paradigm came to the opposite conclusion. In the May 29, 2020, Acta Neuropathologica Communications, researchers led by Monika Zilkova of Axon Neuroscience, Bratislava, Slovak Republic, and Jeroen Hoozemans of Vrije University, Amsterdam, suggest IgG1 antibodies as the better option for anti-tau therapy. In human microglial cultures, IgG1s promoted more tau uptake than did IgG4s. In contrast to Genentech’s study, neither isotype triggered cytokine release.
What to make of this? To Martin Citron of UCB Pharma, Brussels, the data are not directly comparable. “They are looking at different settings and readouts,” Citron wrote to Alzforum. In general, isotype choice should be driven by the mode of action of a particular antibody, he suggested. Some tau antibodies are designed to stop the protein from spreading, while others are slated to clear tangles. It remains unknown what strategy will work best in the human brain, because no anti-tau antibodies have posted positive efficacy data yet.
Semorinemab was developed by AC Immune and Genentech, the latter being part of the Roche group. The antibody binds to the N-terminus of tau and recognizes all six human isoforms, regardless of their phosphorylation state. It was designed to stop the spread of tau pathology by preventing neurons from taking up extracellular tau. In September 2020, Roche reported top-line results for the Phase 2 TAURIEL study of 457 prodromal AD patients, in which semorinemab neither slowed cognitive decline nor budged tau PET. It found its target, as seen by less tau in cerebrospinal fluid, but did not affect downstream biomarkers of degeneration and inflammation (Mar 2021 conference news). The Phase 2 LAURIET trial in moderate AD continues.
In the new paper, Fuji and colleagues describe the preclinical data underlying their approach. They added recombinant tau oligomers to primary cultures of mouse hippocampal neurons, then treated them with semorinemab that had either an IgG4 or an IgG1 backbone. Either isotype worked equally well to prevent tau uptake and protect neurons from toxicity. When the authors added mouse microglia to the mix, however, things changed. While both isotypes still suppressed tau uptake, the IgG1 version failed to protect neurons. Neuronal damage, as measured by fragmentation of the cytoskeletal protein MAP2, was as high in IgG1-treated cultures as in untreated ones. Based on previous work, the authors believe this is because IgG1 stimulated microglia to release harmful cytokines (Lee et al., 2016).
Because the goal of semorinemab treatment is to stop neuronal uptake of tau oligomers, it is not necessary for the antibody to also activate microglia, the authors noted. Supporting this, either isotype of semorinemab lowered soluble phospho-tau in P30lL tauopathy model mice. “[This] convinced us that a reduced effector function IgG4 antibody may have the best therapeutic properties on balance overall,” a Genentech spokesperson wrote to Alzforum.
However, Einar Sigurdsson of New York University School of Medicine noted that p-tau was only modestly reduced in these mice. “Based on these findings, it is not clear to me why this antibody, and its effectorless version, was selected for clinical trials,” he wrote to Alzforum. Nor does the published data provide insight into why the treatment failed in trials, he added. “Hopefully, additional analyses of these subjects, including quantitation of various tau species, and the ongoing trial, will shed light on this,” Sigurdsson wrote.
Meanwhile, Zilkova and colleagues studied a new anti-tau antibody, AX004. This is a humanized version of the mouse antibody DC8E8, which was generated using the same tau epitope deployed in Axon Neuroscience’s active tau vaccine AADvac1 (Apr 2020 conference news). AX004 recognizes truncated tau fragments missing their N-termini.
The authors tested IgG1 and IgG4 versions of AX004 in pure microglial cultures derived from postmortem human control or Alzheimer’s disease brain. The scientists added oligomers of truncated tau and, 20 minutes later, assessed how well microglia took them up. AX004-IgG4 boosted microglial tau uptake twofold; AX004-IgG1 2.5-fold. In other words, IgG1 stimulated 50 percent more phagocytosis than did IgG4. The source of the microglia made no difference, with those from AD brain responding similarly to control microglia.
What about inflammatory responses? Human microglia in culture spewed cytokines after being exposed to tau, but neither antibody isotype caused any additional increase. The authors concluded that both isotypes were equally safe, hence the more effective IgG1 would be preferable for human therapy.
Commenters noted several limitations of this study. Cynthia Lemere of Brigham and Women’s Hospital, Boston, cautioned that the Axon Neuroscience group did not directly examine the neurotoxicity of either isotype. One way to do this would be to add conditioned media from the treated microglial cultures to neurons, she suggested. Sigurdsson emphasized that microglia behave differently in a dish than in brain, leaving the significance of in-vitro findings unclear (Jul 2016 conference news; Jun 2017 news). Likewise, Citron wondered if culturing microglia with the growth factor GMCSF, as was done in these experiments, might have caused them to assume a phenotype more akin to dendritic immune cells, which primarily present antigens to B and T cells and lack some of the specialized functions of microglia.
So: Which isotype is better? For anti-Aβ amyloid therapy, where the goal is to clear plaque, IgG1 antibodies such as aducanumab and gantenerumab have had more success in clinical trials than IgG4 antibodies such as crenezumab. For anti-tau immunotherapy, however, this may be less of an issue.
Citron noted that UCB Pharma’s anti-tau antibody beprenemab, currently in Phase 1, is, like semorinemab, intended to prevent tau uptake by neurons, rather than to activate microglia. “We neither envisioned a need for high immune effector function nor a need to completely suppress it, so we chose IgG4 with relatively low immune effector function,” he wrote to Alzforum.
The two anti-tau antibodies gosuranemab and tilavonemab also have IgG4 backbones; both have posted negative Phase 2 results in progressive supranuclear palsy, but continue in AD trials (Jul 2019 news; Dec 2019 news).
Except for bepranemab, the newer crop of antibodies favors the IgG1 isotype. These include BIIB076, which binds in the N-terminal quarter of the protein, E2814, and JNJ-63733657, which bind the microtubule-binding domain region, and LuAF87908, which recognizes an epitope even further toward the C-terminus. The field may have to await more data to find out which works better in clinical practice.
Sigurdsson noted another, more fundamental, wrinkle. Because most tau is intraneuronal, antibodies may have to be taken up by neurons to dramatically affect accumulation. In that case, an antibody’s electrical charge, which appears to influence its neuronal uptake, may be more important than its isotype or effect on microglial phagocytosis, he suggested (Congdon et al., 2019).—Madolyn Bowman Rogers
- Lu AF87908
- N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore
- Active Tau Vaccine: Hints of Slowing Neurodegeneration
- When a Microglia Is No Longer a Microglia
- What Makes a Microglia? Tales from the Transcriptome
- AbbVie’s Tau Antibody Flops in Progressive Supranuclear Palsy
- Gosuranemab, Biogen’s Anti-Tau Immunotherapy, Does Not Fly for PSP
- 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.
- 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.
- Microglia in Tauopathy: Not Just Homeostatic Versus DAM
- N-Terminal Tau Antibodies Fade, Mid-Domain Ones Push to the Fore
- Aiming at the Tangle’s Heart? DIAN-TU Trial to Torpedo Tau’s Core
- Anti-Tau Antibody Looks Safe, Hits Target
- New Antibody Binds to Mid-Region, and Aggregates, of Tau
- To Block Tau’s Proteopathic Spread, Antibody Must Attack its Mid-Region
- 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.
- 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.