Clinical effects of Aβ immunization (AN1792) in patients with AD in an interrupted trial

Gilman, Sid; Koller, Martin; Black, Robert A.; Jenkins, Lisa; Griffith, Sue G.; Fox, Nick C.; Eisner, Larry S.; Kirby, L.; Rovira, M.; Forette, Françoise; Orgogozo, Jean‐Marc

doi:10.1212/01.wnl.0000159740.16984.3c

Cited by 1,237 publications

(977 citation statements)

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“…A single injection also induces immunological memory that can be rapidly mobilized by a single booster injection, leading to very high serum concentration of anti-beta-amyloid antibodies. Two injections of Alternative beta-amyloid immunogens F Mantile et al E2 (1)(2)(3)(4)(5)(6)(7)(8)(9)(10)(11) are sufficient to obtain a persistent, high titer anti-betaamyloid response, which is dominated by the presence of the IgG1 isotype relative to the IgG2a isotype, implying that a Th2-type response has been induced. Cells from mice immunized with (1-11)E2 produce IL-4 in response to (1-11)E2 and E2 particles, but not in response to the synthetic peptide 1-11, indicating that the Th2-like response to the (1-11)E2 vaccine is directed to a T-cell epitope internal to E2.…”

Section: Discussionmentioning

confidence: 99%

“…7,8 However, the trial was interrupted when 6% of patients developed an adverse inflammatory reaction involving infiltration of T cells into the brain; moreover, only 59 of 300 individuals who received the vaccine mounted a humoral anti-beta-amyloid response with a titer higher than 1:2200. 9 Individuals with the highest titers of anti-beta-amyloid antibodies demonstrated the most pronounced depletion of plaques. 10 The development of a Th1-type response was found to correlate with an adverse inflammatory reaction.…”

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confidence: 98%

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A multimeric immunogen for the induction of immune memory to beta‐amyloid

et al. 2010

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The development of active immunotherapy for Alzheimer's disease (AD) requires the identification of immunogens that can ensure a high titer antibody response toward beta-amyloid, whereas minimizing the risks of a cell-mediated adverse reaction. We describe here two novel anti-beta-amyloid vaccines that consist of 'virus like particles' formed by a domain of the bacterial protein E2 that is able to self-assemble into a 60-mer peptide. Peptides 1-11 and 2-6 of beta-amyloid were displayed as N terminal fusions on the surface of the E2 particles. E2-based vaccines induced a fast-rising, robust and persistent antibody response to beta-amyloid in all vaccinated mice. The immune memory induced by a single administration of vaccine (1-11) E2 can be rapidly mobilized by a single booster injection, leading to a very high serum concentration of anti-beta-amyloid antibodies (above 1 mg ml À1 ). E2 vaccination polarizes the immune response toward the production of the anti-inflammatory cytokine interleukin-4 and does not induce a T cell response to beta-amyloid. Thus, E2-based vaccines are promising candidates for the development of immunotherapy protocols for AD. Alzheimer's disease (AD) is characterized by deposition of insoluble protein aggregates in the brain, known as amyloid plaques, which are mainly composed of beta-amyloid peptide. Active and passive immunization studies performed in transgenic mouse models of beta-amyloid deposition have demonstrated that antibodies against beta-amyloid are able to reduce plaques and improve cognition (reviewed in 1-3 ). In mouse models of AD, induction of a high titer of anti-beta-amyloid antibodies correlated with the therapeutic efficacy of vaccination [4][5][6] A clinical trial of immunization of AD patients with whole preaggregated beta-amyloid peptide has shown that immunization has the potential to reduce amyloid plaques in the brains of AD patients and delay disease progression. 7,8 However, the trial was interrupted when 6% of patients developed an adverse inflammatory reaction involving infiltration of T cells into the brain; moreover, only 59 of 300 individuals who received the vaccine mounted a humoral anti-beta-amyloid response with a titer higher than 1:2200. 9 Individuals with the highest titers of anti-beta-amyloid antibodies demonstrated the most pronounced depletion of plaques. 10 The development of a Th1-type response was found to correlate with an adverse inflammatory reaction. 11 The development of an effective and safe immunotherapy protocol faces two challenges, namely, overcoming the low immunogenicity of the beta-amyloid peptide and avoiding detrimental inflammatory reactions in the brain.The N-terminus of beta-amyloid is considered the most promising antibody target for inclusion in recombinant vaccines. 1 We have previously observed reduced deposition of beta-amyloid plaques in mice that received monthly injections of phage-based vaccine fdAD (2-6), a bacteriophage that displays the epitope AEFRH of betaamyloid as an N terminal fusion to the major capsid p...

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Section: Discussionmentioning

confidence: 99%

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confidence: 98%

A multimeric immunogen for the induction of immune memory to beta‐amyloid

et al. 2010

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“…The results may be interpreted in relation to prior observations on longitudinal T-tau measurements in other brain diseases. In the AN1792 trial reduced levels of T-tau were seen in AD patients immunized against Ab and interpreted as a possible reduction of cellular degeneration (Gilman et al 2005). Patients with stroke initially have increased T-tau levels, which normalize after a few months (Hesse et al 2001).…”

Section: Amyloid Markersmentioning

confidence: 99%

Miglustat Treatment May Reduce Cerebrospinal Fluid Levels of the Axonal Degeneration Marker Tau in Niemann–Pick Type C

et al. 2011

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Introduction: Niemann-Pick disease type C (NPC) is a lysosomal storage disorder that leads to progressive neurodegeneration. The glucosylceramide synthase blocker miglustat is being used to treat NPC, but monitoring of disease progression and treatment response is difficult. NPC patients have elevated cerebrospinal fluid (CSF) levels of total-tau (T-tau) indicating axonal degeneration, and increased CSF amyloid b (Ab) indicating abnormal brain amyloid metabolism, but it is unknown if start of miglustat treatment affects these biomarker levels.Methods: Biomarkers were measured in serial CSF samples from NPC patients who started miglustat between samplings (N ¼ 5), were untreated at both samplings (N ¼ 5) or received treatment during the whole study (N ¼ 6) (median time between samplings 309 days [range 175-644]). CSF was analyzed for Ab 38 , Ab 40 , Ab 42 , a-cleaved soluble APP, b-cleaved soluble APP, T-tau and phospho-tau.Results: T-tau levels decreased in patients who started miglustat treatment (median 955 [range 338-1,271] ng/L at baseline vs. 382 ng/L at follow-up, p ¼ 0.043). Untreated patients and continuously treated patients had stable levels (p > 0.05). No changes were seen in the other biomarkers.Conclusion: Reduced CSF T-tau suggests that miglustat treatment might affect axonal degeneration in NPC. However, the results must be interpreted with caution and verified in future studies, since this pilot study was small, treatment was not randomized, and patients starting treatment had higher baseline CSF T-tau than untreated patients.

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“…The first human AD vaccine consisted of fibrillar Aβ 42 formulated in QS21 adjuvant (AN-1792 trial) that induced strong Th1-type anti-Aβ immune responses [19], even in Th2-prone BALB/c mice [20]. This AN-1792 clinical trial was halted due to the development of meningoencephalitis in a small proportion of the subjects [21][22][23][24][25][26], but follow up studies have demonstrated that strong anti-Aβ antibody responses specific to the linear Aβ [1][2][3][4][5][6][7][8] peptide [27] in some patients reduced AD pathology and diminished the cognitive decline associated with the disease [24,[27][28][29][30][31][32][33]. These data along with preclinical studies demonstrated that anti-Aβ antibodies directed to N-terminal region of Aβ 42 are effective in clearance of amyloid plaques [16,34,35].…”

Section: Introductionmentioning

confidence: 99%