Three major effects of APOEε4 on Aβ immunotherapy induced ARIA

Foley, Kate E.; Wilcock, Donna M.

doi:10.3389/fnagi.2024.1412006

Cited by 6 publications

(1 citation statement)

References 58 publications

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“…Enhancing the brain delivery of therapeutic antibodies to treat NDs could increase efficacy and lower the risk of side effects like ARIA for future immunotherapies [ 56 ]. However, there has been variation in the ability of the monoclonal anti-Aβ antibodies studied in large-scale AD trials to lower insoluble brain Aβ levels (PET-detectable).…”

Section: Current Statusmentioning

confidence: 99%

Engineered Antibodies to Improve Efficacy against Neurodegenerative Disorders

Niazi,

Mariam,

Magoola

2024

IJMS

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Antibodies that can selectively remove rogue proteins in the brain are an obvious choice to treat neurodegenerative disorders (NDs), but after decades of efforts, only two antibodies to treat Alzheimer’s disease are approved, dozens are in the testing phase, and one was withdrawn, and the other halted, likely due to efficacy issues. However, these outcomes should have been evident since these antibodies cannot enter the brain sufficiently due to the blood–brain barrier (BBB) protectant. However, all products can be rejuvenated by binding them with transferrin, preferably as smaller fragments. This model can be tested quickly and at a low cost and should be applied to bapineuzumab, solanezumab, crenezumab, gantenerumab, aducanumab, lecanemab, donanemab, cinpanemab, and gantenerumab, and their fragments. This paper demonstrates that conjugating with transferrin does not alter the binding to brain proteins such as amyloid-β (Aβ) and α-synuclein. We also present a selection of conjugate designs that will allow cleavage upon entering the brain to prevent their exocytosis while keeping the fragments connected to enable optimal binding to proteins. The identified products can be readily tested and returned to patients with the lowest regulatory cost and delays. These engineered antibodies can be manufactured by recombinant engineering, preferably by mRNA technology, as a more affordable solution to meet the dire need to treat neurodegenerative disorders effectively.

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Section: Current Statusmentioning

confidence: 99%

Engineered Antibodies to Improve Efficacy against Neurodegenerative Disorders

Niazi,

Mariam,

Magoola

2024

IJMS

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Amyloid-Related Imaging Abnormalities (ARIA) in Clinical Trials of Gantenerumab in Early Alzheimer Disease

Salloway,

Wojtowicz,

Voyle

et al. 2024

JAMA Neurol

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ImportanceData from 2 phase 3 studies of gantenerumab, GRADUATE I/II, and their open-label extensions represent a resource to further characterize amyloid-related imaging abnormalities (ARIA), including long-term sequelae.ObjectivesTo describe the characteristics of ARIA and risk factors and clinical consequences of ARIA-edema (ARIA-E).Design, Setting, and ParticipantsSecondary data collection from the GRADUATE I/II phase 3 randomized, double-blind, placebo-controlled, 116-week parallel-group studies and their open-label extensions, including PostGraduate, with up to 210 (mean, 125) weeks of total gantenerumab treatment were conducted between 2018 and 2023. The study included multicenter trials at 288 sites across 30 countries. GRADUATE I/II enrolled 985 and 980 participants, respectively, with early symptomatic Alzheimer disease (AD) and amyloid-beta (Aβ) pathology who were aged 50 to 90 years. PostGraduate enrolled 1382 participants (671 previously randomized to gantenerumab). Data were analyzed from November 2, 2022, to October 10, 2023.InterventionsGRADUATE I/II participants were randomized 1:1 to gantenerumab or placebo. Nine-month uptitration was used to mitigate ARIA risk.Main outcomes and measuresPostbaseline safety monitoring, including brain magnetic resonance imaging (MRI) findings, and adverse events and cognitive assessments.ResultsThe safety-evaluable MRI population of GRADUATE I/II comprised 1939 participants (mean age, 71.7 years; 1105 female [57.0%]). Severity of AD–related Aβ neuropathology (lower cerebrospinal fluid [CSF] Aβ42, hazard ratio [HR] for CSF Aβ42: 0.4; 95% CI, 0.2-0.7) and comorbid cerebrovascular pathology (Fazekas score: HR, 1.6; 95% CI, 1.3-2.0; total superficial siderosis count: HR, 1.9; 95% CI, 1.3-2.6; total microhemorrhage count: HR, 1.3; 95% CI, 1.0-1.5) may be important baseline risk factors for ARIA-E, in addition to apolipoprotein E (APOE) ε4 status (APOE ε4 heterozygous carrier: HR, 2.0; 95% CI, 1.4-2.8 and APOE ε4 homozygous carrier: HR, 4.7; 95% CI, 3.2-6.7). At the group level, ARIA-E did not impact long-term cognitive and functional performance (relative difference in adjusted means for Clinical Dementia Rating–Sum of Boxes was −9% in pooled GRADUATE analysis at week 116 and when censored at first ARIA-E). While taking gantenerumab, ARIA-E and ARIA-hemosiderin occurred in 24.9% (247 of 993) and 22.9% (227 of 993) participants, respectively; first ARIA-E occurred by week 64 in 86.2% (213 of 247) of participants with ARIA-E. Narratives are provided for all serious symptomatic ARIA-E cases.Conclusions and RelevanceThese results show that in addition to APOE ε4 allele count, severity of Aβ neuropathology and comorbid cerebrovascular pathology may be relevant for clinicians prescribing anti-Aβ monoclonal antibodies for early AD and developing individualized safety monitoring plans. Evaluation of these risk factors in other anti-Aβ monoclonal antibodies is recommended.Trial registrationsClinicalTrials.gov Identifiers: NCT03444870, NCT03443973, NCT04374253.

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