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Plaque Clearance, Antibody Isotype Are Key for Passive Aβ Immunization
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6 February 2003. Plaque clearance is a better correlate of neural protection via passive amyloid immunization than soluble amyloid-beta (Aβ) clearance, and this protection is based on Fc receptor-mediated Aβ phagocytosis. These are the conclusions reported in the February 3 online PNAS, by Frederique Bard and colleagues at Elan Pharmaceuticals in South San Francisco, California, after a comparison of various Aβ antibody isotypes and their affinities for different epitopes of Aβ.
In the aftermath of Elan’s halted vaccination trial, these and other researchers have taken a step back to try to understand how Aβ pathology interacts with the immune system, and also to determine if passive immunization with antibodies to Aβ could become a safe and effective alternative to active immunization with Aβ peptide (see related ARF discussion and ARF related news story).
In the present study, the researchers first compared antibodies directed against various epitopes of the Aβ1-42 peptide. They found that only antibodies that bind the N-terminal region were effective in binding plaques in unfixed brain tissue from PDAPP transgenic mouse brain or in triggering plaque clearance by phagocytosis in an ex-vivo assay (see ARF related news story and ARF related news story. Similar results were found in vivo. The authors report that plaque-binding correlated with clearance and neural protection, whereas the affinity of antibodies for soluble Aβ correlated less well with these measures of efficacy.
They also report that the isotype of the antibodies determined its efficacy in plaque clearance and neuronal protection; IgG2a antibodies were more effective than IgG1 or IgG2b. IgG2a has a much higher affinity for the phagocytic Fc receptors, and the authors conclude that antibody efficacy is primarily mediated by Fc receptors and not by complement system receptors.-Hakon Heimer.
Reference:
Bard F, Barbour R, Cannon C, Carretto R, Games D, Guido T, Hoenow K, Hu K, Johnson-Wood K, Khan K, Kholodenko D, Lee C, Lee M, Motter R, Nguyen M, Reed A, Schenk D, Tang P, Vasquez N, Seubert P, Yednock T. Epitope and isotype specificities of antibodies to beta-amyloid peptide for protection against Alzheimer's disease-like neuropathology. Proc Natl Acad Sci U S A. 2003 Feb 18;100(4):2023-8. Abstract
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Comments on News and Primary Papers |
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Comment by: Beka Solomon
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Submitted 13 February 2003
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Posted 13 February 2003
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The immunological concept in the treatment of conformational diseases, such as Alzheimer’s, is based on antibody-antigen interactions involving conformational changes in both antibody and antigen. Appropriate mAbs interact at strategic sites where protein aggregation is initiated, stabilize the protein and prevent further aggregation. For such an active role, the mAbs require a high binding constant to the "strategic" positions on the antigen molecule (Solomon, 2002). The existence of strategic positions where conformational changes are initiated has been shown in model systems (Silen et al., 1989; Solomon et al., 1995), recently in Alzheimer’s Aβ peptide (Frenkel et al., 1998; Frenkel et al., 1999) and prion-related diseases (Peretz et...
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 View all comments by Beka Solomon
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Primary Papers: Epitope and isotype specificities of antibodies to beta -amyloid peptide for protection against Alzheimer's disease-like neuropathology.
Comment by: Todd Golde, ARF Advisor
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Submitted 19 February 2003
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Posted 19 February 2003
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 I recommend this paper
This is a study on a quite impressive scale that compares different isotypes of anti-Abeta antibodies with respect to efficacy in attenuating amyloid loads in PDAPP mice. The conclusion is anti-Abeta IgG with high affinity for Fc receptors are more effective then those with lower affinity for FcR. This supports this group's hypothesis that microglial uptake of anti-Abeta:Abeta complexes is important in Abeta immunotherapy.
Our group is currently preparing a manuscript that is not easily reconcilable with these findings. Our data has also been presented at recent meetings. We find that Abeta immunotherapy is equally effective in Tg2576 mice crossed into an FcR gamma knockout background mice as it is in wt Tg2576 mice. Our studies would seem to preclude FcR mediated uptake of anti-Abeta:Abeta complexes as a factor in determing efficacy of immunization.
Although there was no good correlation between efficacy in the bard study and binding affinites of the antibodies to soluble or aggregated Abeta, perhaps there is some other property of the anibodies that is more closely...
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View all comments by Todd Golde
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Comment by: jeff ik
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Submitted 21 May 2004
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Posted 21 May 2004
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I recommend the Primary Papers
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Comments on Related News |
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Related News: Following Footsteps of AD Vaccination: Passive Shots Against Prions Protect Mice
Comment by: Dave Morgan (Disclosure)
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Submitted 7 March 2003
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Posted 7 March 2003
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This is a very exciting development for a rapidly fatal disease, for which there is no known therapy. Particularly important is that the passive immunotherapy can be started relatively late in the replication phase of the disease. While not identical, both Alzheimer's and prion disorders result in accumulations of fibrils of conformationally abnormal proteins that cause neurodegeneration. If immunotherapy shows any benefit in human prion disorders, it should encourage further development of immunotherapy for Alzheimer's patients. To my knowledge, this is the only therapy which appears to "cure" scrapie in mice.
View all comments by Dave Morgan
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Related News: Following Footsteps of AD Vaccination: Passive Shots Against Prions Protect Mice
Comment by: Blas Frangione
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Submitted 10 March 2003
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Posted 10 March 2003
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We are pleased that White and colleagues confirm our recent findings that anti-prion antibodies have the potential to be used as prophylaxes following scrapie exposure (Sigurdsson et al., 2002; Sigurdsson et al., 2003). We were surprised that they did not quote our 2003 study that was published before their paper was accepted. In addition, the editors of Nature were well aware of our work, as we submitted it to their journal in June 2002. Together, these in-vivo studies support previous in-vitro findings and results from transgenic mice expressing anti-prion antibodies, as referenced in our articles.
By administering 2 mg of anti-prion antibodies twice a week, White et al. achieved a substantially better therapeutic effect than we did by injecting 50 μg once a week. Although extrapolation of an effective dose in a mouse to a human dose is not an exact science, 2 mg/20 g mouse corresponds to a 6 g/60 kg individual. Hopefully, a...
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View all comments by Blas Frangione
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Related News: Following Footsteps of AD Vaccination: Passive Shots Against Prions Protect Mice
Comment by: Simon Hawke
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Submitted 10 March 2003
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Posted 10 March 2003
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Having proof that established prion replication in the living situation can be controlled, there is no reason why these mouse monoclonal antibodies should not be humanized and infused into the brains of patients with human prion diseases.
View all comments by Simon Hawke
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Related News: Alzheimer’s Vaccine: In Some Patients, at Least, It Might Just Work
Comment by: John Hardy, ARF Advisor
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Submitted 21 May 2003
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Posted 21 May 2003
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This an extremely interesting preliminary report. The editorial by Winblad and Blum is very careful in conveying both the excitement this data causes,
and also the caution that needs to be exercised in its interpretation. Hock and his colleagues are to be congratulated for their astuteness in taking
part in the Elan trial, but negotiating themselves some freedom in using their own data from their trial subjects. Let's hope that when Elan releases the data on the whole trial, the overall results confirm these
preliminary data. Even if immunization turns out not to be the way forward for safety reasons, such an outcome would imply that other Aβ-reducing
strategies have every chance of clinical success.
View all comments by John Hardy
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Related News: Alzheimer’s Vaccine: In Some Patients, at Least, It Might Just Work
Comment by: David Holtzman
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Submitted 21 May 2003
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Posted 21 May 2003
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It is encouraging that in a subset (n=30) of the more than 300 subjects enrolled in the Elan study who were analyzed, there is preliminary evidence that there may be a positive response. This preliminary analysis suggests that further, more conclusive studies of the immunization approach (active and passive) should continue. Though the analysis argues for more studies, the title and some of the conclusions of this study are
not yet justified. As pointed out in the accompanying commentary by Winblad and Blum, the control group, which is really N=6 who received placebo or N=10 total who did not generate "antibodies," is very small. More importantly, not only is the control group small, that group deteriorated at a much faster rate than subjects with mild to moderate Alzheimer's disease normally worsen. The amount of MMSE decline in the group treated with immunization is actually what is described in patients with Alzheimer's who are on cholinesterase inhibitors, (which many of these patients were on), namely about one to three points in the first year
of follow-up. It would have...
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View all comments by David Holtzman
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Related News: Alzheimer’s Vaccine: In Some Patients, at Least, It Might Just Work
Comment by: Vincent Marchesi, ARF Advisor
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Submitted 21 May 2003
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Posted 21 May 2003
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Since this is a clinical study involving human subjects, one cannot expect it to be without unavoidable limitations. The numbers of patients are small, the follow-up is of relatively short duration, and these are both problems, as Winblad and Blum point out. The mental state of AD patients can fluctuate widely, so I think more specific functional tests will have to be done to strengthen the case for a positive effect.
Let's assume that some of the patients show improvement and this is correlated with antibody levels. Can we rule out some nonspecific immunological reactions that cause improvement independent of the ability of the antibodies to bind to Aβ? If these were experimental animals, one would be able to test the effects of immunizing with different forms of synthetic peptides. This is clearly not possible with human subjects. I am also concerned about the different results that are reported for the ELISA tests and the authors' tissue amyloid plaque assay. It is possible that they are looking at different conformational epitopes, as the authors suggest, but one...
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View all comments by Vincent Marchesi
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Related News: Alzheimer’s Vaccine: In Some Patients, at Least, It Might Just Work
Comment by: Dave Morgan (Disclosure)
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Submitted 21 May 2003
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Posted 21 May 2003
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This paper continues the rollercoaster of emotion regarding the use of amyloid vaccines to treat Alzheimer's disease. The identification that Aβ vaccination could dramatically reduce amyloid deposition in the PDAPP mouse (Schenk et al., 1999), followed by demonstration that the vaccine also protected mice from learning and memory deficits (Janus et al., 2000; Morgan et al., 2000), led to early trials of the vaccine in humans. Although Phase I trials found no adverse consequences, six percent of the Phase II trial patients developed aseptic meningoencephalitis (Schenk, 2002), which in some cases was severe (Nicoll et al., 2003). This led to premature termination of the trial, with cessation of any further inoculations with the Aβ...
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View all comments by Dave Morgan
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Related News: Alzheimer’s Vaccine: In Some Patients, at Least, It Might Just Work
Comment by: Claudio Soto (Disclosure)
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Submitted 22 May 2003
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Posted 22 May 2003
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During the last 10 years, much evidence has been reported in support of the amyloid hypothesis for the progression of AD. However, the key finding of whether inhibitors of Aβ amyloidogenesis would lead to a cognitive improvement was missing. In this very interesting article, Hock et al. report for the first time preliminary results indicating that this may be the case. In addition to the practical implications for treatment, in my opinion the great importance of this study, as well as the previous publication by Nicoll et al., is that it provides crucial data to understand the molecular mechanism of AD pathogenesis in humans. It should also boost the race to develop safer immunization strategies and other anti-Aβ production, misfolding, and aggregation approaches for AD treatment. I concur with Winblad and Blum's caution on the interpretation of results with very small number of patients, but Hock, Nitsch, and colleagues should be congratulated for making these results public and imitated by the rest of the...
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View all comments by Claudio Soto
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Related News: Alzheimer’s Vaccine: In Some Patients, at Least, It Might Just Work
Comment by: Karen Hsiao Ashe
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Submitted 23 May 2003
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Posted 23 May 2003
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This paper shows that immunization with Aβ may slow the progression of Alzheimer’s disease, but does not restore cognitive function. These results contrast with studies of immunoneutralization of Aβ in AβPP-transgenic mice, which demonstrate reversal of memory loss and restoration of cognitive function (Kotilinek et al., 2002; Dodart et al., 2002). The most likely explanation for this discrepancy is that important differences in pathology exist between AβPP-transgenic mice and Alzheimer’s disease.
During the first year following the appearance of memory deficits in Tg(APPNL)2576 mice, neurons and synapses are largely intact (Irizarry et al., 1997). During the second year, postsynaptic markers decline, while presynaptic markers and neurons remain unchanged (G. Cole and B. Hyman, personal communication). We have proposed that soluble Aβ assemblies...
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View all comments by Karen Hsiao Ashe
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Related News: Alzheimer’s Vaccine: In Some Patients, at Least, It Might Just Work
Comment by: Beka Solomon
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Submitted 27 May 2003
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Posted 27 May 2003
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One of the critical questions in β-amyloid immunotherapy is whether depletion of the amyloid plaques is accompanied by improvement in behavioral/neurophysiological impairments and in a reduction in the nerve cell death of Alzheimer’s disease. In other words, does immunization with Aβ simply clear a neuropathological byproduct, or can it cure the disease?
Anti-β-amyloid immunization of the AD mouse model showed remarkable efficacy in reducing amyloid and restoring cognitive function. The present data is the first attempt to compare cognitive test results in human AD patients—a small number so far—before and one year after vaccination. Indeed, patients with serum antibodies against β-amyloid plaques showed diminished cognitive decline and slowed disease progression, and the "dose-response" relationship between antibody levels and clinical effects constitutes evidence that amyloid proteins are indeed a primary cause of Alzheimer’s symptoms. The treated patients, suffering mild or moderate dementia, received only two injections and throughout the year...
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View all comments by Beka Solomon
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Related News: New Orleans: Immunotherapy—The Game Is Still in Town
Comment by: Ryszard Pluta
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Submitted 21 November 2003
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Posted 21 November 2003
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I am really happy that science is going to immunotherapy of Alzheimer's disease. I presented some of my data at the 6th International Conference on Alzheimer's Disease and Related Disorders, July 1998 in Amsterdam, The Netherlands, and this data is published. When I presented disappearing diffuse amyloid plaques in brain in my experimental model and proposed as a mechanism that they probably were disappearing because of "possible immunization," the leading scientists in the Alzheimer's disease arena did not believe me. Next I published a full paper in NeuroReport. In the discussion I write, "Probably antibodies against amyloid might act as an artificial chaperone for extra- and intracellular amyloid. Our data raise the possibility of vaccination with amyloid against AD (Alzheimer's disease)." In conclusion: "Collectively, the results raise the possibility that frequent injection with amyloid may be sufficient in preventing and treating the...
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View all comments by Ryszard Pluta
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Related News: Window to the Brain Shows Dystrophic Neurites Shrinking
Comment by: Samuel Gandy
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Submitted 31 January 2005
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Posted 31 January 2005
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"Until the Last Dog(ma) Dies": Some Neuritic Dystrophy Is Reversible by Passive Immunization of PDAPP Mice
A multidisciplinary group has demonstrated that at least some neuritic dystrophy in PDAPP mice is reversible. Holtzman from Wash U, Paul from Lilly, Mathis and Klunk from Pitt, and Bacskai and Hyman from MGH contributed their considerable talent to a new paper in the current issue of The Journal of Clinical Investigation. Using the open skull method and Congo red derivative methoxy-X04 devised by the MGH and Pittsburgh groups, respectively, the team followed with serial imaging the morphology of swollen (dystrophic) neurites surrounding cortical amyloid deposits in the PDAPP mouse. Conventional wisdom would have predicted that these swellings might be permanent, but the new paper describes how passive immunization with anti-Aβ antibodies had a significant effect on partially normalizing the shapes of the processes.
The new paper builds on earlier work by the MGH group (Lombardo et al., 2003): The advance of...
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View all comments by Samuel Gandy
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Related News: Window to the Brain Shows Dystrophic Neurites Shrinking
Comment by: J. Lucy Boyd
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Submitted 1 February 2005
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Posted 1 February 2005
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I recommend the Primary Papers
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Related News: Window to the Brain Shows Dystrophic Neurites Shrinking
Comment by: Elizabeth Petersen
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Submitted 2 February 2005
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Posted 4 February 2005
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I recommend the Primary Papers
Thank you for offering such a variety of papers by people who are spending their lives looking for answers.
PS: Footnotes for lay persons would help.
View all comments by Elizabeth Petersen
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