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Mechanism of Amyloid Removal in Patients With Alzheimer Disease Treated With Gantenerumab
Abstract
BACKGROUND: Gantenerumab is a fully human anti-Aβ monoclonal antibody in clinical development for the treatment of Alzheimer disease (AD). OBJECTIVES: To investigate whether treatment with gantenerumab leads to a measurable reduction in the level of Aβ amyloid in the brain and to elucidate the mechanism of amyloid reduction. DESIGN: A multicenter, randomized, double-blind, placebo-controlled, ascending-dose positron emission tomographic study. Additionally, ex vivo studies of human brain slices from an independent sample of patients who had AD were performed. SETTING: Three university medical centers. PATIENTS: Patients with mild-to-moderate AD. INTERVENTION: Two consecutive cohorts of patients received 2 to 7 infusions of intravenous gantenerumab (60 or 200 mg) or placebo every 4 weeks. Brain slices from patients who had AD were coincubated with gantenerumab at increasing concentrations and with human microglial cells. MAIN OUTCOME MEASURES: Percent change in the ratio of regional carbon 11-labeled Pittsburgh Compound B retention in vivo and semiquantitative assessment of gantenerumab-induced phagocytosis ex vivo. RESULTS: Sixteen patients with end-of-treatment positron emission tomographic scans were included in the analysis. The mean (95% CI) percent change from baseline difference relative to placebo (n = 4) in cortical brain amyloid level was -15.6% (95% CI, -42.7 to 11.6) for the 60-mg group (n = 6) and -35.7% (95% CI, -63.5 to -7.9) for the 200-mg group (n = 6). Two patients in the 200-mg group showed transient and focal areas of inflammation or vasogenic edema on magnetic resonance imaging scans at sites with the highest level of amyloid reduction. Gantenerumab induced phagocytosis of human amyloid in a dose-dependent manner ex vivo. CONCLUSION: Gantenerumab treatment resulted in a dose-dependent reduction in brain amyloid level, possibly through an effector cell-mediated mechanism of action.
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“This antibody can disassemble and degrade amyloid plaques by recruiting microglia and activating phagocytosis [71,72].”
From Treatment of Alzheimer’s Disease: Beyond Symptomatic Therapies (2023) · cites this paper as [72]
In the citing paper
“Several anti-Aβ monoclonal antibodies (mAbs) have been tested in clinical trials in AD patients and were found to significantly reduce load of fibrillar Aβ as demonstrated using PET Aβ imaging [5–8].”
From APOE Genotype Differentially Modulates Effects of Anti-Aβ, Passive Immunization in APP Transgenic Mice (2017) · cites this paper as [6]
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“Approximately 25% to 35% of elderly subjects with adequate performance in cognitive tests demonstrate high cortical radiotracer amyloid imaging retention in the prefrontal, posterior cingulate and precuneus regions.(46,54,56,64,65) These findings are concordant with postmortem reports, which show that approximately 25…”
The Amyloid Cascade Hypothesis in Alzheimer’s Disease: It’s Time to Change Our Mind
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“In a first double-blind, randomized, placebo controlled PET trial, gantenerumab was shown to reduce cerebral amyloid levels in a dose-dependent fashion in mild to moderate AD patients (36% difference from placebo at the highest dose tested) [86].”
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Cummings, J. L., Osse, A. M. L., Cammann, D., Powell, J., & Chen, J. (2023) · BioDrugs · doi:10.1007/s40259-023-00633-2 · Cited by 420
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Preventing Alzheimer’s Disease
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“ARIA-E has also been reported with other Aβ immunotherapeutic agents, albeit less frequently (128) and a gamma-secretase inhibitor (129), whereas by contrast, “spontaneous ARIA-E” is uncommon.”
ResultDeveloping Therapeutic Antibodies for Neurodegenerative Disease
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“Gantenerumab-mediated disaggregation of existing plaques is consistent with the observations of vasogenic edema and microhemorrhage in human patients with AD treated with gantenerumab in clinical trials [216].”
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Ferrero, J., Williams, L., Stella, H., Leitermann, K., Mikulskis, A., O'Gorman, J., & Sevigny, J. (2016) · Alzheimer's & Dementia: Translational Research & Clinical Interventions · doi:10.1016/j.trci.2016.06.002 · Cited by 189
“It is well recognized that treatment with some amyloidtargeting drug candidates, including the monoclonal antibodies bapineuzumab and gantenerumab, are associated with incident cases of ARIA [19,20].”
BackgroundTargeting microglia for the treatment of Alzheimer’s Disease
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“ARIA is predominantly observed with clinical candidates of the human IgG1 isotype, which has a high affinity for activating FcgR as compared with other isotypes (Chiao et al., 2015; Ostrowitzki et al., 2012b; Salloway et al., 2009b) (Table 5).”
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“Early studies of aducanumab and gantenerumab also withdrew treatment on detection of ARIA-E (9, 44), while subsequent studies opted for reassignment to a lower dose upon resolution (11, 23).”
BackgroundDetection and treatment of Alzheimer’s disease in its preclinical stage
Rafii, M. S., & Aisen, P. S. S. (2023) · Nature Aging · doi:10.1038/s43587-023-00410-4 · Cited by 179
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Anti-Amyloid Immunotherapies for Alzheimer's Disease: A 2023 Clinical Update
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“In a phase 1 study, subcutaneous gantenerumab induced ARIA in two apolipoprotein (APO)E e4 carriers, with partial Aβ reduction in the same brain regions where ARIA developed [60].”
BackgroundAmyloid-β 11 C-PiB-PET imaging results from 2 randomized bapineuzumab phase 3 AD trials
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Spontaneous ARIA-like Events in Cerebral Amyloid Angiopathy–Related Inflammation
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“The immune-mediated mechanisms of spontaneous ARIAlike and therapy-induced ARIA reported in clinical trials are likely to be generated by a complex combination of genetic, vascular, and immunologic risk factors, closely related to the balance of Aβ intramural periarterial drainage/vascular deposition and to the dose-…”
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Amyloid β oligomers (AβOs) in Alzheimer’s disease
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Quaternary Structure Defines a Large Class of Amyloid-β Oligomers Neutralized by Sequestration
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“Passive immunization with two monoclonal antibodies that recognize Aβ fibrils, Bapineuzumab and Gantenerumab, reduced amyloid burdens but failed to provide cognitive or functional benefits (Alzforum, 2015a, b; Ostrowitzki et al., 2012; Rinne et al., 2010).”
Therapeutic Strategies Targeting Amyloid-β in Alzheimer’s Disease
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Antibody therapies in CNS diseases
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Preclinical trials in autosomal dominant AD: Implementation of the DIAN-TU trial
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“The AD pathological processes can be tracked with biomarkers (Blennow et al., 2012; May et al., 2011; Ostrowitzki et al., 2012; Salloway et al., 2009) to assess drugs developed to target these pathological processes (e.g., increased Aβ production, Aβ deposition, etc.).”
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Dong, Y., Li, X., Cheng, J., & Hou, L. (2019) · International Journal of Molecular Sciences · doi:10.3390/ijms20030558 · Cited by 136
Immunotherapy for neurodegenerative diseases: Focus on α-synucleinopathies
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Valera, E., Spencer, B. J., & Masliah, E. (2015) · Neurotherapeutics · doi:10.1007/s13311-015-0397-z · Cited by 135
Martins, R. N., Villemagne, V., Sohrabi, H. R., Chatterjee, P., Shah, T. M., Verdile, G., Fraser, P., Taddei, K., Gupta, V. B., Rainey-Smith, S. R., et al. (2018) · Journal of Alzheimer’s Disease · doi:10.3233/jad-171145 · Cited by 129
“A imaging with PET is therefore contributing to the development of more effective therapies by allowing better selection of patients for anti-A therapy trials and providing a means to measure their effectiveness in removing A from the brain [101, 102].”
MethodUddin, M. S., Kabir, M. T., Rahman, M. S., Behl, T., Jeandet, P., Ashraf, G. M., Najda, A., Bin-Jumah, M. N., El-Seedi, H. R., & Abdel‐Daim, M. M. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21165858 · Cited by 131
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Teter, B., Morihara, T., Lim, G. P., Chu, T., Jones, M. R., Zuo, X., Paul, R. M., Frautschy, S. A., & Cole, G. M. (2019) · Neurobiology of Disease · doi:10.1016/j.nbd.2019.02.015 · Cited by 127
Mild to moderate Alzheimer dementia with insufficient neuropathological changes
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“We found that: (1) both groups have similar gender, education level, and age of death and symptom onset; (2) APOEe4 carriers were half as likely to be Ab(2) as noncarriers; (3) although meeting criteria for mild-to-moderate dementia, the Ab(2) subjects were slightly less impaired than Ab(1) subjects; (4) more than hal…”
BackgroundMethodMR Imaging Features of Amyloid-Related Imaging Abnormalities
Barakos, J. A., Sperling, R. A., Salloway, S., Jack, C. R., Gass, A., Fiebach, J. B., Tampieri, D. I., Melançon, D., Miaux, Y., Rippon, G. A., et al. (2013) · American Journal of Neuroradiology · doi:10.3174/ajnr.a3500 · Cited by 121
“eral agents specifically designed to lower cerebral A burden have been associated with MR imaging abnormalities of the brain.(1-4) Reported MR imaging findings appear similar among”
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ARIA in patients treated with lecanemab (BAN2401) in a phase 2 study in early Alzheimer's disease
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Aβ-amyloid and Tau Imaging in Dementia
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Central nervous system myeloid cells as drug targets: current status and translational challenges
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“One phase 1 randomized, double-blind, placebocontrolled MAD study evaluated the safety, tolerability, and pharmacokinetic (PK) and pharmacodynamic (PD) characteristics of gantenerumab in patients with mild to moderate AD dementia [11].”
BackgroundInfluentialAnti-Amyloid Therapies for Alzheimer’s Disease and the Amyloid Cascade Hypothesis
Fedele, E. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241914499 · Cited by 102
“The antibody recognises both N-terminal and central regions of the peptide and induces its removal by Fc receptor-mediated microglial phagocytosis [59,60].”
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Passive anti-amyloid immunotherapy in Alzheimer's disease: What are the most promising targets?
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Immunotherapy for Alzheimer's disease
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Amyloid PET in clinical practice: Its place in the multidimensional space of Alzheimer's disease
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“Both in Rinne et al. (2010) and Ostrowitzki et al. (2012), competition assays did not reveal any alteration of the tracer affinity of amyloid plaques due to the passive immunization.”
BackgroundInfluentialPanza, F., Solfrizzi, V., Imbimbo, B. P., Tortelli, R., Santamato, A., & Logroscino, G. (2014) · Expert Review of Clinical Immunology · doi:10.1586/1744666x.2014.883921 · Cited by 103
“Gantenerumab-treated patients showed a decrease of cerebral amyloid burden imaged by (11)C PiB PET of up to 30% in a dose-dependent manner [114].”
BackgroundLacorte, E., Ancidoni, A., Zaccaria, V., Remoli, G., Tariciotti, L., Bellomo, G., Sciancalepore, F., Corbo, M., Lombardo, F. L., Bacigalupo, I., et al. (2022) · Journal of Alzheimer s Disease · doi:10.3233/jad-220046 · Cited by 104
“…PL: 4 FU: 28 weeks no data on CDR-SB mean changes (SD) at week 4 PL: 0.24 (0.15) 60 mg: 0.03 (0.24) 200 mg: –0.27 (0.45) 200 mg: 2/14 PL: 0 no data on ARIA-H Ostrowitzki 2012 [35] NCT 01224106 completed FP: 2010 Phase III RCT 797 prodromal AD (IWG criteria) MRI consistent with AD positive CSF 105…”
BackgroundInfluentialUsing Pittsburgh Compound B for In Vivo PET Imaging of Fibrillar Amyloid-Beta
Cohen, A. D., Rabinovici, G. D., Mathis, C. A., Jagust, W. J., Klunk, W. E., & Ikonomović, M. D. (2012) · Advances in pharmacology · doi:10.1016/b978-0-12-394816-8.00002-7 · Cited by 103
“Similar results were reported in a trial of gantenerumab, another human anti-Aβ monoclonal antibody, where patients receiving the drug at 60 mg (N = 6), 200 mg (N = 6), or placebo (N = 4) underwent PiB-PET at baseline and posttreatment (up to 7 monthly infusions) (Ostrowitzki et al., 2012).”
Is there still any hope for amyloid-based immunotherapy for Alzheimer's disease?
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“Thus, for a fully human IgG1 like gantenerumab, phagocytosis by murine microglia is likely not optimally supported and predictive for therapeutic use in AD (Ostrowitzki et al., 2012).”
BackgroundTaylor, X., Clark, I., Fitzgerald, G. J., Oluoch, H., Hole, J. T., Demattos, R. B., Wang, Y., & Pan, F. (2023) · Molecular Neurodegeneration · doi:10.1186/s13024-023-00649-w · Cited by 105
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“Alzheimer’s disease (AD) clinical research has entered aneweraoftherapeuticsthataimtomodifyunderlyingdisease pathology rather than ameliorate symptoms [1–3].”
Novel Disease-Modifying Therapies for Alzheimer's Disease
Jiang, T., Yu, J., & Tan, L. (2012) · Journal of Alzheimer s Disease · doi:10.3233/jad-2012-120640 · Cited by 94
Primary and Secondary Prevention Trials in Alzheimer Disease: Looking Back, Moving Forward
Hsu, D. C., & Marshall, G. A. (2016) · Current Alzheimer Research · doi:10.2174/1567205013666160930112125 · Cited by 95
“The safety and mechanism of solanezumab and gantenerumab have already been validated in several reports prior to the onset of this trial [75].”
BackgroundTreatment of Alzheimer’s Disease: Beyond Symptomatic Therapies
Buccellato, F. R., D’Anca, M., Tartaglia, G. M., Del Fabbro, M., Scarpini, E., & Galimberti, D. (2023) · International Journal of Molecular Sciences · doi:10.3390/ijms241813900 · Cited by 94
“This antibody can disassemble and degrade amyloid plaques by recruiting microglia and activating phagocytosis [71,72].”
BackgroundMo, J., Li, J., Yang, Z., Liu, Z., & Feng, J. (2017) · Annals of Clinical and Translational Neurology · doi:10.1002/acn3.469 · Cited by 96
Echeverría, V., Iarkov, A., & Aliev, G. (2016) · Progress in Neurobiology · doi:10.1016/j.pneurobio.2016.01.002 · Cited by 95
Metadata
- Authors
- Ostrowitzki, S.
- Affiliations
- F. Hoffmann-La Roche AG (CH)
- Corresponding author
- Ostrowitzki, Susanne
- Venue
- Archives of Neurology
- Publisher
- American Medical Association (AMA)
- Published
- 2012-02-01
- Volume
- 69
- Issue
- 2
- Pages
- 198
- ISSN
- 0003-9942 (ISSN-L)
- OpenAlex
- W2118753807
- Cited by
- 431
- References
- 19
- Citations by year
- 2026: 18 · 2025: 17 · 2024: 34 · 2023: 22 · 2022: 22 · 2021: 24 · 2020: 18 · 2019: 23 · 2018: 30 · 2017: 34 · 2016: 39 · 2015: 31 · 2014: 44 · 2013: 45 · 2012: 24
- FWCI
- 25.95
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Archives of Neurology (publishedVersion)
- PubMed (publishedVersion)
- Pure Amsterdam UMC (publishedVersion)
- Amsterdam UMC (VU Amsterdam) - Institutional Repository (publishedVersion)
- UCL Discovery (University College London) (submittedVersion)
- Data Archiving and Networked Services (DANS) (submittedVersion)
- Topics
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Alzheimer's disease research and treatments
- Health Sciences › Medicine › Psychiatry and Mental health › Dementia and Cognitive Impairment Research
- Life Sciences › Neuroscience › Neurology › Neuroinflammation and Neurodegeneration Mechanisms
- Keywords
- gantenerumab, Alzheimer's disease, amyloid-beta, anti-amyloid monoclonal antibodies, phagocytosis, microglia, Pittsburgh compound B, dose-dependent effects, vasogenic edema
- MeSH terms
- Aged, Alzheimer Disease, Aniline Compounds, Antibodies, Monoclonal, Brain Chemistry, Cell Count, Double-Blind Method, Female, Follow-Up Studies, Humans, Immunoglobulin G, Injections, Intravenous, Male, Middle Aged, Phagocytosis, Thiazoles, Cohort Studies, Amyloid beta-Peptides, Microglia, Sample Size, Radiopharmaceuticals, Alzheimer Vaccines, Positron-Emission Tomography, Antibodies, Monoclonal, Humanized
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