Stockholm: New Strategies for Immunotherapy

Series - International Stockholm / Springfield Symposium on Advances in Alzheimer Therapy, 2012:

Immunotherapy continues to be a major therapeutic strategy for Alzheimer’s disease, and more recently for other neurodegenerative diseases as well. At the 12th International Stockholm/Springfield Symposium on Advanced in Alzheimer Therapy, researchers discussed some new immune-based approaches for therapy, including those capitalizing on the body’s own antibodies for passive immunotherapy and novel antigens for active vaccination.

Andreas Muhs from the company AC Immune, Lausanne, Switzerland, have adopted the latter strategy. Muhs and colleagues develop a lipospome-based antigens. The researchers are interested in targeting toxic forms of tau. As Muhs noted in his talk, there is now evidence that tau, a normally cytosolic protein, finds its way into the extracellular space from where toxic forms of the protein may spread to healthy cells (see related ARF news). This makes targeting extracellular tau a potential valuable strategy, said Muhs.

Their vaccines use synthetic peptides are coupled to a linker that is attached to a lipid bilayer (see Hickman et al., 2011). The linkers can be designed to make the liposome aggregate, boosting immunogenicity, while the use of synthetic peptides rather than whole proteins increases the specificity of the vaccine. Muhs and colleagues used this strategy to vaccinate six to nine month old mice with liposomes carrying a fragment of human tau containing a phosphorylated serine 396, which is found in paired helical fragments of tau. The antigen generated robust immune responses in wild-type and tau P301L transgenic animals. The antibodies recognized PS396 forms of tau but not un-phosphorylated forms of the protein. In the P301L animals, the vaccination reduced both soluble and insoluble tau in the brain and delayed the emergence of motor problems (poor grip strength) seen in this animal model.

A company called AFFiRiS AG, in Vienna, Austria, is also pursuing novel antigens. Markus Mandler explained that the company’s "affitopes" are short antigens that mimic other epitopes without sharing any primary amino acid structure. An Aβ affitope would mimic the Aβ secondary structure, for example, without having Aβ sequences. Such an epitope could then elicit an immune response against itself and Aβ. Mandler explained that the advantages are specificity (affitopes would not elicit an antibody response to native proteins or homologs) and side-stepping auto-reactive T-cell responses, which can lead to dangerous neuroinflammatory responses, as happened with the first Aβ vaccine tested in clinical trials (see related ARF news).

Mandler and colleagues have developed affitope vaccines for both Alzheimer’s and Parkinson’s diseases. Achim Schneeberger, also from AFFiRiS, reported on premilinary clinical data using two AD01 and AD02 affitopes that mimic the N-terminus of Aβ. In these Phase 1 studies, patients with mild to moderate AD (MMSE 16-26) received four monthly injections of the vaccine. Patients on AD02 got another booster shot at week 20. The patients developed antibodies peaking around week 10, and increasing further after the booster, said Schneeberger. He showed fluorescent-activated cell sorting data to demonstrate that the antibodies did not react with APP.

Though this was a small trial, the results look encouraging, said Schneeberger. Patients whose MMSE was above 20 at the start of the trial remained stable on the MMSE and performed better than controls in activities of daily living, functional scales, and in the neuropsychiatric inventory. The responses seemed to correlate with the titer of the antibody against Aβ aggregates, suggesting some cause and effect.

Mandler also reviewed preclinical data on PD01, an affitope that mimics an α-synuclein sequence. This antigen induces antibodies that recognize α- but not β-synuclein, said Mandler. The company tested PDO1 in mice overexpressing human synuclein under control of the PDGF promoter. These animals are more model of Lewy body dementia than Parkinson’s disease. PD01 reduced soluble and insoluble α-synuclein in whole brain extracts from these mice and also in the cerebral cortex and hippocampus as viewed by immunohistochemistry. Vaccinated mice retained twice as many dendrites as controls and about fifty percent more neurons. They outperformed controls in the Morris water maze test of spatial learning. The antibodies induced by PDO1 somehow get across the blood brain barrier into the brain, said Mandler, because they turn up in neuronal lysosomes and in the perivascular space. AFFiRiS is testing PD01 in a Phase 1 clinical trial.

Another new approach, taken by Roger Nitsch, Christoph Hock, and colleagues at Neurimmune, Schlieren, Switzerland, capitalizes on the body’s own immune defenses against amyloidogenic proteins. Hock and colleagues isolated antibodies from circulating B cells of healthy centenarians and screened for those with high-affinity binding to Abeta aggregates (see ARF related news). In Stockholm, Nitsch reported that a similar strategy, termed reverse translational medicine, yielded an antibody, NI-204A, against superoxide dismutase 1 (SOD1). SOD aggregates in both familial and sporadic forms of amyotrophic lateral sclerosis (ALS). NI-204A binds to the spinal cord of transgenic mice expressing a mutant (G93A) form of SOD1 that causes familial ALS, reported Nitsch. The antibody also binds to epitopes in the spinal cord of 80 percent of ALS patients. The frequency most likely reflects the heterogeneity of the disease, said Nitsch.

Can this antibody work as a therapeutic? By pumping the antibody into the brain ventricles of transgenic SOD mice over their entire lifespan, Nitsch and colleagues stemmed the loss of spinal cord motorneurons. The treated animals had twice as many neurons as transgenic controls, though this was not quite enough to bring them back to normal function, said Nitsch. For that, another doubling of motoneurons would be required. Nevertheless, the treated animals did reap some benefits. As they aged they gained more body weight than untreated SOD mice, and they developed stronger grip. They also survived longer than controls, though only by about 20 days. Nitsch said that Neurimmune plans to test NI-204A in the clinic and that it is turning the reverse translational medicine strategy to other neurodegenerative diseases, as well. Hock reviewed preclinical data on the BIIB037 Abeta antibody that the company previously presented (see related ARF news).

Last but not least, Daniel Michaelson from the University of Tel Aviv, Israel, outlined a monoclonal antibody (mAb) approach for reining in potential toxic functions of ApoE4. To make these antibodies, Michaelson used immune cells from ApoE-deficient mice that had been vaccinated with a peptide containing the ApoE4 allele (an arginine at position 112). He obtained several cell lines producing mAbs that, by a variety of tests (ELIAS, Western blot, immuniprecipitation and immunohistochemistry), react with ApoE4 but not with ApoE3. In mice that have their endogenous ApoE replaced with the human ApoE4, these mAbs reduce the apolipoprotein in the CA3 layer of the hippocampus and also toned down the amount of phosphorylated tau as judged using the AT8 antibody. Interestingly, the mAbs did not prevent accumulation of Aβ42 in the hippocampus or deficits in the presynaptic glutamate transporter VGlut1. Michaelson did not know why the mAbs reduced tau but not Aβ. It may be due to bioavailability, he suggested, but acknowledged that there is debate in the field as to whether loss or gain of function underlies ApoE effects in AD and that Abeta effects may be due to the former. He told Alzforum that he believes boosting ApoE may help in people who have no E4 allele, but that targeting ApoE4 for removal would help those who carry the risk allele.—Tom Fagan.

Comments

  1. This is very good news, and I hope this new form of therapeutic immunization is successful in treating those with degenerative neurological conditions. If these treatments are successful, the symptoms of many diseases could potentially be prevented and controlled, instead of simply being masked.

    View all comments by Justin Hall

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References

News Citations

  1. Brain Microdialysis Reveals Tau, Synuclein Outside of Cells
  2. Human Aβ Vaccine Snagged by CNS Inflammation
  3. Barcelona: Antibody to Sweep Up Aβ Protofibrils in Human Brain

Paper Citations

  1. Hickman DT, López-Deber MP, Ndao DM, Silva AB, Nand D, Pihlgren M, Giriens V, Madani R, St-Pierre A, Karastaneva H, Nagel-Steger L, Willbold D, Riesner D, Nicolau C, Baldus M, Pfeifer A, Muhs A. Sequence-independent control of peptide conformation in liposomal vaccines for targeting protein misfolding diseases. J Biol Chem. 2011 Apr 22;286(16):13966-76. PubMed.

External Citations

  1. AD01
  2. AD02
  3. Phase 1 clinical trial

Further Reading

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