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Thakker DR, Weatherspoon MR, Harrison J, Keene TE, Lane DS, Kaemmerer WF, Stewart GR, Shafer LL. Intracerebroventricular amyloid-beta antibodies reduce cerebral amyloid angiopathy and associated micro-hemorrhages in aged Tg2576 mice. Proc Natl Acad Sci U S A. 2009 Mar 17;106(11):4501-6. PubMed.
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Michigan State University
This is a very important paper that was performed very professionally and addresses a critically important question regarding immunotherapy for Alzheimer disease. The observation that centrally administered antibodies have different characteristics than peripherally administered antibodies is a critical point, first identified by Vasilevko et al. (2007). This manuscript very clearly and convincingly demonstrates that the ICV route effectively clears Aβ deposits, yet does not produce increased CAA or hemorrhage, while the same antibody administered systemically produces comparable clearance, yet does increase CAA and hemorrhage. This would imply that central administration may be a safer method for testing anti-amyloid immunotherapy as a treatment for Alzheimer disease.
An overwhelming number of studies have published results that do not increase CAA or hemorrhage, but rarely include the positive contrast to show the mice used are of appropriate age and genotype to exhibit such an effect if one were present with the treatment. The authors are to be commended for going to the effort and doing this study correctly (i.e., in aged mice). For what it’s worth, we have analyzed our own past studies using intracranial administrations and never observed buildup of vascular Aβ or hemorrhage (never published). The data here indicate that only very high exposures to centrally administered antibody results in vascular accumulation. Importantly, this vascular accumulation and microhemorrhage were found in the human brain with vaccines (Boche et al., 2008).
There is an intriguing mismatch between the systemic and central doses used for Aβ clearance. The argument made by almost everyone is that 0.1 percent of plasma antibody enters brain. If true, the effective central dose of 6E10 when administered systemically was 0.002 mg. Yet the systemic administration provided dosing slightly more effective than 0.04 mg injected centrally. One potential explanation for therapeutic equivalence at different dosages could be clearance rates. Conceivably, the centrally administered antibody is cleared more rapidly due to microglial phagocytosis, effectively reducing the concentration of antibody.
The authors claim that the antibody-Aβ complex does not interfere with their ELISA, but since no dissociation steps are undertaken, this is unlikely to be the case. They claim to have 60 nM Aβ and the antibody concentration is roughly 200 nM. Thus, about 30 percent of antibody is occupied by Aβ. Our work finds that at these ratios there is increased Aβ and increased antibody concentration found when a simple acid dissociation step is employed prior to assay (Li et al., 2007). Ultimately, this is irrelevant to the arguments being made by the authors, but I think they need to prove that there is no interference if they are going to make the statement. In fact, I suspect the Aβ ELISA uses 6E10 as the capture antibody. If 6E10-Aβ plasma complexes enter the assay, they will not be detected due to masking.
In summary, a great paper with very convincing data. It would seem to support the use of central administration of antibodies as a test of the amyloid hypothesis of Alzheimer disease.
References:
Boche D, Zotova E, Weller RO, Love S, Neal JW, Pickering RM, Wilkinson D, Holmes C, Nicoll JA. Consequence of Abeta immunization on the vasculature of human Alzheimer's disease brain. Brain. 2008 Dec;131(Pt 12):3299-310. PubMed.
Vasilevko V, Xu F, Previti ML, Van Nostrand WE, Cribbs DH. Experimental investigation of antibody-mediated clearance mechanisms of amyloid-beta in CNS of Tg-SwDI transgenic mice. J Neurosci. 2007 Dec 5;27(49):13376-83. PubMed.
Li Q, Gordon M, Cao C, Ugen KE, Morgan D. Improvement of a low pH antigen-antibody dissociation procedure for ELISA measurement of circulating anti-Abeta antibodies. BMC Neurosci. 2007;8:22. PubMed.
View all comments by Dave MorganThe Institute for Molecular Medicine
It is well known that at first anti-Aβ vaccination (active and passive) in mouse models of AD did not show clear side effects and subsequently several companies initiated active and passive vaccination trials in AD patients. There was only one unconfirmed report about lymphocyte infiltration detected in the brains of wild-type mice immunized with Aβ42 formulated in CFA/IFA followed by injection with pertussis toxin. Later, microhemorrhages in the cerebral vasculature have been observed in different strains of very old (21-26-month-old) APP/Tg mice injected weekly with high doses of anti-Aβ monoclonal antibodies, and the sites of microhemorrhage have been colocalized with cerebral vascular Aβ deposits. Collectively, these adverse events emphasized the need for further refinement of vaccines for AD in order to eliminate, or at least attenuate, the potential adverse events initiated by infiltration of autoreactive T cells and peripheral macrophages, as well as inflammation-induced cerebral vascular microhemorrhages. Accordingly, Thakker et al. initiated studies funded by Medtronic, Inc., and demonstrated in AD mouse model that delivery of anti-Aβ antibodies into the brain by direct intracerebroventricular (icv) infusions is more effective than systemic delivery of the same 6E10 monoclonal antibody. In general, these data supported previous published studies in which some groups demonstrated that both intracranial and peripheral administration of anti-Aβ antibodies could clear AD-like pathology in APP/Tg mice. What is new in this paper is that authors suggested that icv-administration of anti-Aβ antibodies is safer because it is reducing CAA and associated microhemorrhages.
While these results are interesting, we should be cautious because data from active or passive Aβ immunotherapy conducted with AD patients indicated that despite evidence of amyloid plaque removal, there is no indication of significant improvement of dementia in these patients. On top of that, from both clinical trials and animal studies we know that antibody could clear/decrease Aβ deposition without significant changes of tau pathology, neuropil threads, synaptic dysfunction, and cerebral amyloid angiopathy (CAA) even in areas where amyloid plaques had been removed. In sum, results from both clinical trials and animal studies indicate that Aβ-immunotherapy should be initiated before pathological forms of amyloid accumulated into the brain, and in this scenario icv-infusion is not feasible. Except for the difficulty associated with the delivery of anti-Aβ antibody to the brains of AD patients by icv infusions, one should expect that the high concentration of this antibody (40-200 μg) may bind a complement system in the brain and induce activation of these molecules (for example, C1q and C3). Although complement is one of the most critical defense systems of organism, its activation could induce profound brain tissue damage in AD patients. Thus, another precaution should be applied for the strategy based on icv-infusions of antibodies into the brains.
University of Oslo
This is certainly a very well performed and interesting study. The authors argue that the engagement of central mechanisms and long-term intracerebroventricular infusion of 6E10 at a low dosage leads to the favorable outcome with reduced parenchymal plaques, cerebral amyloid angiopathy (CAA) and few microhemorrhages. It would be interesting to also investigate the effects of prolonged peripheral infusion of the same antibody in dose-response experiments. This would help determine if both factors are essential for the outcome.
Intraventricular infusion is seemingly both a risky and a complicated strategy, but it is clearly feasible as shown with rituximab for the treatment of lymphoma (Pekls et al., 2003).
Careful design of an antibody with respect to pharmacokinetics, CAA-binding and a well- adjusted dosage (Schroeter et al., 2008) might be alternative ways to reach the goal of a safe and efficacious immunotherapy for Alzheimer disease.
References:
Pels H, Schulz H, Schlegel U, Engert A. Treatment of CNS lymphoma with the anti-CD20 antibody rituximab: experience with two cases and review of the literature. Onkologie. 2003 Aug;26(4):351-4. PubMed.
Schroeter S, Khan K, Barbour R, Doan M, Chen M, Guido T, Gill D, Basi G, Schenk D, Seubert P, Games D. Immunotherapy reduces vascular amyloid-beta in PDAPP mice. J Neurosci. 2008 Jul 2;28(27):6787-93. PubMed.
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