Yamada K, Yabuki C, Seubert P, Schenk D, Hori Y, Ohtsuki S, Terasaki T, Hashimoto T, Iwatsubo T. Abeta immunotherapy: intracerebral sequestration of Abeta by an anti-Abeta monoclonal antibody 266 with high affinity to soluble Abeta. J Neurosci. 2009 Sep 9;29(36):11393-8. PubMed.
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Although a number of mechanisms have been proposed for how Aβ immunotherapy might work to prevent deposition, or clear, Aβ from the brain, no definitive answer has emerged. Some active and passive immunization studies show correlation between the efficacy of immunization and the ability of anti-Aβ monoclonal antibodies (mAbs) to recognize amyloid. Others show quite the opposite—certain mAbs that effectively reduce Aβ loads bind preferentially to monomeric Aβ. Such data raise the possibility that there may be multiple ways in which anti-Aβ antibodies influence amyloid deposition and other AD-like pathologies. However, important as it is, few studies were actually dedicated to the question of, How does anti-Aβ immunization work?
In our mechanism of immunization study (Levites et al., 2006) we have shown that, at least in mice, the following statements are true:
Now, a very elegant study by Takeshi Iwatsubo and colleagues proposes a novel mechanism of anti-Aβ immunotherapy, whereby an antibody that binds soluble Aβ sequesters the peptide in the CNS. The researchers used radiolabeled Aβ, which enabled them to extract clean data and to show the dynamics of Aβ depletion from the brain with high accuracy.
The questions that remain to be asked, and are crucial for predicting whether immunotherapy with this antibody will be efficient in humans, are the following:
Additionally, the fact that only the anti-soluble Aβ antibody, not anti-fibrillar one, prolonged the half-life of radioactive Aβ in the brain might suggest that this antibody has better blood-brain barrier penetration qualities and presents at a higher level in the CNS, thus being more efficient.
As we proposed in our studies, there might be great potential to an antibody that binds soluble oligomers with high affinity, and may be efficient in a therapeutic and not only prophylactic setting.
References:
Levites Y, Smithson LA, Price RW, Dakin RS, Yuan B, Sierks MR, Kim J, McGowan E, Reed DK, Rosenberry TL, Das P, Golde TE. Insights into the mechanisms of action of anti-Abeta antibodies in Alzheimer's disease mouse models. FASEB J. 2006 Dec;20(14):2576-8. Epub 2006 Oct 26 PubMed.
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