Because cognition in Alzheimer’s disease declines as tangles spread, and tau research tools are finally in hand, researchers are increasingly homing in on tau immunotherapy. At the second biannual Advances in Alzheimer’s and Parkinson’s Therapies Focus Meeting (AAT-AD/PD), held virtually from April 2 to 5, speakers gave updates on two active tau vaccines currently in clinical trials and on passive tau immunotherapies still in preclinical research. For the active vaccines, researchers are evaluating safety and immunogenicity. One of them, AADvac1, reportedly slowed neurodegeneration biomarkers in Phase 2. The other, ACI-35, elicited a weak immune response in people, and needed to be redesigned to boost immunogenicity.

  • Did an active tau vaccine put the brakes on neurodegeneration in AD?
  • Another clinical tau vaccine went back to drawing board.
  • Studies targeting other forms of toxic tau remain preclinical.

Each tau immunotherapy covered in this story targets a different form of pathologic tau: N-truncated, phosphorylated, oligomeric, or acetylated. Researchers are unsure which of these, if any, is the main culprit. “What is the best tau therapy? Only clinical trials will tell us, and all approaches have to be evaluated,” Luc Buée of the University of Lille, France, wrote to Alzforum.

So far, the passive tau immunotherapies ABBV-8E12 and gosuranemab have failed to budge progression in the primary tauopathy progressive supranuclear palsy, but are still in trials for Alzheimer’s disease (Jul 2019 news; Dec 2019 news). Other anti-tau antibodies, like semorinemabzagotenemab, and JNJ-63733657, are in early stage trials and did not post results at AAT-AD/PD.

Did Neurodegeneration Slow Down?
Only two active tau vaccines are currently in trials. The furthest along is ADDvac1, developed by the biotech company Axon Neuroscience in Vienna. It is based on work from Michal Novak, then at the Slovak Academy of Sciences in Bratislava. Novak reported that truncated forms of tau could damage synapses and seed neurofibrillary tangles, and founded Axon Neuroscience to develop tau therapies (Feb 2013 news). The ADDvac1 peptide elicits generation of antibodies that recognize truncated monomeric tau, as well as truncated oligomeric or aggregated tau, more strongly than full-length monomeric tau, according to company CEO Michal Fresser. “The antibodies are selective toward pathological tau species,” Fresser told Alzforum.

At AAT-AD/PD, Fresser presented results from the two-year Phase 2 ADAMANT trial. It enrolled 196 people who had mild AD by NIA-AA criteria, along with medial temporal lobe atrophy by MRI or, in a few cases, cerebrospinal fluid Aβ and tau levels consistent with AD. Fresser did not give a breakdown of how many participants had MRI and/or lumbar punctures at baseline. Participants were from eight European countries, with an average age of 71 and MMSE of 23. They received subcutaneous injections of 40 μg AADvac1 or placebo once a month for six months, followed by quarterly booster doses thereafter. Altogether, participants received 11 doses of vaccine and were followed for two years.

Initially, there were 117 participants in the active and 79 in the placebo group. About 17 percent dropped out, leaving 100 active and 63 placebo by the end. Fresser noted that he had planned for 25 percent dropouts, so the study remained well-powered. The primary outcome was safety, which was met. The vaccine was well-tolerated, with no difference in adverse events between the vaccine and placebo groups except for more injection-site reactions in the former. A secondary outcome, immunogenicity, was also positive, Fresser claimed. Throughout the trial, participants maintained about 1.5 μg/ml antibodies, which Fresser called a robust immune response to the vaccine. Most participants produced antibodies with an affinity for tau of 1 nM or better, similar to the affinity of tau monoclonal antibodies. These were the only two parameters Fresser showed to characterize the immune response. However, in an email to Alzforum, Fresser said that, based on analysis of a prior Phase 1 trial, these antibodies are mainly of the IgG1 isotype and bind to aggregated tau in tissue slices from AD, PSP, CBD, and FTD brains. They also inhibit neuronal uptake of pathologic tau in cellular assays, Fresser wrote.

For exploratory biomarkers, Axon researchers report a marked effect on plasma NfL, which is thought to flag neurodegeneration. In normal aging, plasma NfL has been shown to rise about 14 percent over two years, while in mild AD, it goes up by 24 percent (Mattsson et al., 2019). 

The placebo group in this trial resembled these observational data. Their plasma NfL rose 28 percent, or 4.9 pg/ml, over the course of the study. In the treatment group, plasma NfL rose 13 percent, or 2.1 pg/ml, similar to the rise seen in aging. The difference between the groups appeared mostly during the second year of treatment, when NfL levels stabilized in the vaccinated participants. The difference between the groups was statistically significant, with a p value of 0.004, and fairly large, with a Cohen’s d of 0.48.

The treatment group posted no overall cognitive benefit over placebo. Because tau imaging data associate tangle burden with cognitive decline more tightly in younger than in older people (Apr 2018 conference news), the researchers ran a preplanned subgroup analysis of participants 67 or younger. In this comparison of 32 vaccinated people versus 11 on placebo, cognitive decline slowed by 42 percent on the CDR-SB, 31 percent on the MMSE, and 26 percent on Activities of Daily Living in the treatment group, Fresser said. The finding was not statistically significant.

This younger subgroup also posted larger biomarker changes than the full cohort. Their reduction in plasma NfL was twice that of the full group, and cortical atrophy on MRI scans slowed by 47 percent, a statistically significant result with a Cohen’s d effect size of 0.91.

The study collected CSF from few participants. Fresser presented CSF data on 20 people on treatment and seven on placebo, who were not stratified by age. Both p-tau181 and p-tau217 dropped in the treatment group, the former by about 5 pg/ml, the latter by 50 pg/ml; these markers stayed stable in the seven on placebo controls. Total tau held steady in the treatment group; it rose in controls by about 60 pg/ml. Fresser did not specify the initial concentrations of CSF p-tau and total tau. The CSF changes were not statistically significant. In another small substudy of 20 people, diffusion tensor MR imaging suggested better white-matter integrity in 13 vaccinated participants compared with seven controls.

“AADvac1 showed a highly significant impact on neurodegeneration, as measured by plasma NfL and supported by an effect on CSF tau, p-tau, and DTI,” Fresser concluded. He believes the data indicate a disease-modifying effect, particularly in younger AD patients. Axon Neuroscience is planning a Phase 3 trial that will run for 24 to 30 months.

Optimizing Immune Response
Researchers at AC Immune in Lausanne, Switzerland, approach tau immunization differently. Marija Vukicevic described the company’s liposomal supra-antigen vaccine approach, which binds a synthetic peptide eight to 60 amino acids long to a liposome. The peptide can be conjugated to the bilayer in such a way as to stabilize a particular shape, producing a conformation-specific immune response. The liposome also holds adjuvants to boost the immune response.

To induce tau antibodies, the researchers used a synthetic peptide based on human p-tau396/404, although Vukicevic did not say what region or conformation (Jun 2012 conference news). The resulting vaccine, ACI-35, preserved motor abilities and extended survival of mice carrying a P301L mutation (Aug 2014 news). 

At AAT-AD/PD, Vukicevic reported results from the Phase 1b trial. The vaccine was well-tolerated but elicited a weak immune response, and booster shots had little effect. So the researchers redesigned the vaccine, adding a second adjuvant plus an epitope that activated the HLA-DR receptor on T-cells.

In rhesus monkeys, this second-generation vaccine, ACI-35.030, produced a stronger immune response. Over six months, vaccination with ACI-35.030 generated 50 times as many antibodies as did ACI-35, and booster shots added a more robust effect. As with ACI-35, antibodies generated by the new vaccine were specific for p-tau over tau, showing about 100-fold selectivity in rhesus monkeys, and they recognized paired helical filaments extracted from AD brain.

In collaboration with Janssen, AC Immune is testing this vaccine in a multicenter Phase 1b/2a safety and immunogenicity study in AD patients.

Pinning Down Toxic Tau
One roadblock for tau immunotherapies is that scientists do not yet know which form of tau is most toxic. Different groups are chasing distinct forms, and many approaches are wending their ways through preclinical studies. At AAT-AD/PD, Alice Bittar of the University of Texas Medical Branch presented data on monoclonal antibodies specific to tau oligomers. These so-called TOMAs lower oligomeric tau, but not monomeric p-tau or neurofibrillary tangles, in mouse models of tauopathy. In middle-aged tau mice, TOMA treatment improved cognition (Castillo-Carranza et al., 2014; Castillo-Carranza et al., 2014; Castillo-Carranza et al., 2015). 

How about in old mice? Working with Rakez Kayed at UTMB, Bittar characterized two clones, TOMA1 and TOMA3, in 1-year-old JNPL3 mice and 2-year-old hTau mice. She injected 120 micrograms TOMA or control IgG into their tail veins, then tested cognition three or four days later.

Results varied according to the specific antibody clone, Bittar reported. TOMA1 improved JNPL3 mouse performance in the Y-maze and novel-object-recognition tasks, while TOMA3 helped hTau mice. Immunohistochemistry of the mouse brains offered a rationale, as TOMA1 lowered tau oligomers in JNPL3 mice, but not hTau animals, while the opposite was true for TOMA3, Bittar said.

These clones have different staining patterns in postmortem human brain samples. TOMA1 reacts most strongly to Parkinson’s brain, less to AD, and least to PSP. TOMA3, on the other hand, binds to AD brain but not to the others, suggesting it may be specific for the paired helical filaments of 3R/4R tau that accumulate in that disease. The data indicate that tau antibodies are specific to particular tau proteopathies, Bittar said. She proposed that certain diseases might require a combination of therapeutic tau antibodies. Kayed’s group is now testing combinations in mouse models. They are also humanizing two TOMA clones for human trials, but Bittar did not say which ones.

Also at AAT-AD/PD, Buée discussed a different form of pathologic tau. His group analyzed Alzheimer’s brain homogenate by mass spectrometry and found it was enriched for an N-truncated version of tau that starts at Met11. This amino acid is also acetylated. Further research determined that acetylated Met11-tau is only present in AD brain, not other tauopathies. It occurs in insoluble tau fractions along with paired helical filaments, and is found in tau transgenic mouse brain.

Buée injected a viral vector carrying either Met11 or full-length tau into young Thy-Tau 30 mice. Met11-tau potentiated tau pathology more potently than did full-length tau, boosting the number of hippocampal neurons containing tau-positive inclusions by about 50 percent. This confirmed its toxicity. The researchers then generated an antibody to Met11 tau, and injected 10 mg/kg into Thy-Tau22 mice seven times over the course of five months. This treatment squelched accumulation of insoluble tau.

Met11-tau may represent a new target for immunotherapy, Buée suggested. He is looking for a company to partner with to bring the approach to clinical trials.—Madolyn Bowman Rogers

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References

Therapeutics Citations

  1. C2N 8E12
  2. Gosuranemab
  3. Semorinemab
  4. Zagotenemab
  5. JNJ-63733657
  6. AADvac1
  7. ACI-35

News Citations

  1. AbbVie’s Tau Antibody Flops in Progressive Supranuclear Palsy
  2. Gosuranemab, Biogen’s Anti-Tau Immunotherapy, Does Not Fly for PSP
  3. Truncated Tau Triggers Tangles, Transmits Pathology
  4. News From the PET Front: Early Amyloid Networks and Tau Mystery
  5. Stockholm: New Strategies for Immunotherapy
  6. Therapies Take Aim at Tau

Research Models Citations

  1. JNPL3(P301L)
  2. hTau.P301S

Paper Citations

  1. . Association Between Longitudinal Plasma Neurofilament Light and Neurodegeneration in Patients With Alzheimer Disease. JAMA Neurol. 2019 Jul 1;76(7):791-799. PubMed.
  2. . Specific targeting of tau oligomers in Htau mice prevents cognitive impairment and tau toxicity following injection with brain-derived tau oligomeric seeds. J Alzheimers Dis. 2014;40 Suppl 1:S97-S111. PubMed.
  3. . Passive immunization with Tau oligomer monoclonal antibody reverses tauopathy phenotypes without affecting hyperphosphorylated neurofibrillary tangles. J Neurosci. 2014 Mar 19;34(12):4260-72. PubMed.
  4. . Tau immunotherapy modulates both pathological tau and upstream amyloid pathology in an Alzheimer's disease mouse model. J Neurosci. 2015 Mar 25;35(12):4857-68. PubMed.

External Citations

  1. ADAMANT

Further Reading