bapineuzumab (AAB-001) / Pfizer, J&J, Perrigo Company - LARVOL DELTA

The structural foundations of anti-amyloid-β immunotherapies: Unravelling antibody-antigen interactions in Alzheimer's disease treatment. (PubMed, J Alzheimers Dis) - "BackgroundAnti-amyloid-β (Aβ) immunotherapies are emerging as treatments for Alzheimer's disease (AD).ObjectiveThis review examines the structure-activity relationships of anti-Aβ therapeutics tested in phase 3 trials.MethodsWe analyzed crystallographic data and molecular models to elucidate the Aβ binding mechanisms of donanemab, lecanemab, aducanumab, bapineuzumab, gantenerumab, solanezumab, and crenezumab.ResultsLecanemab recognizes minimally degraded Aβ missing 1-2 residues, avoiding common Aβ in circulation and further degraded material sequestered in plaques. This focal point may account for the significant cognitive effects of lecanemab. The structure of aducanumab suggests a broadly neutralizing role has evolved for natural immunity to AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Vascular Neurology • APOE

High-affinity transferrin receptor binding improves brain delivery of bispecific antibodies at tracer dose. (PubMed, Fluids Barriers CNS) - "This study supports the hypothesis that stronger TfR affinity enhances brain uptake at a tracer dose. With the more effective detection of Aβ pathology, stronger TfR affinity is a crucial design feature for future bispecific immunoPET radioligands for intrabrain targets via TfR-mediated transcytosis."

Journal • Alzheimer's Disease • CNS Disorders

Fluorine-18 ImmunoPET Imaging of Antibody Brain Kinetics and Amyloid-Beta Pathology. (PubMed, ACS Pharmacol Transl Sci) - "Here, we have studied the Aβ antibody Bapineuzumab (Bapi) and its bispecific variant Bapi-Fab8D3, which contains a fragment of the TfR-binding antibody 8D3, enabling receptor-mediated transcytosis into the brain...PET data quantification demonstrated that while the brain concentration of [18F]-F-BapiFcRn- declined, that of [18F]-F-Bapi-Fab8D3FcRn- increased throughout the 9 h time period, indicative of its active transport into the brain. PET imaging discriminated App NL‑G‑F from WT mice at 12 h after [18F]-F-Bapi-Fab8D3FcRn- administration, suggesting that this novel antibody-based tracer may be used for the same-day PET imaging of Aβ."

Journal • Alzheimer's Disease • CNS Disorders

A non-parametric U-statistic testing approach for multi-arm clinical trials with multivariate longitudinal data. (PubMed, J Multivar Anal) - "Extensive simulations demonstrate that this method maintains excellent Type I error control while providing greater power compared to the two-arm LRST with multiplicity adjustments. Application to the Bapineuzumab (Bapi) 301 trial further validates the multi-arm LRST's practical utility and robustness, confirming its efficacy in complex clinical trial analyses."

Clinical • Journal

Characterizing Treatment Non-responders and Responders in Completed Alzheimer's Disease Clinical Trials. (PubMed, AMIA Annu Symp Proc) - "Our study aims to identify heterogeneous treatment effects and pre-treatment features that moderate the treatment effect of Galantamine, Bapineuzumab, and Semagacestat from completed trial data. For example, in Galantamine trials, whole brain volume (1092.54 vs. 1060.67 ml, P < .001) and right hippocampal volume (2.43e-3 vs. 2.79e-3, P < .001) are significantly different between responsive and non-responsive subgroups. Overall, our implementation of causal forests in AD clinical trials reveals the heterogeneous treatment effects and different moderators for AD drug responses, highlighting promising personalized treatment based on patient-specific characteristics in AD research and drug development."

Journal • Alzheimer's Disease • CNS Disorders

The Efficacy of Anti-amyloid Monoclonal Antibodies in Early Alzheimer's Dementia: A Systematic Review. (PubMed, Ann Indian Acad Neurol) - "Our findings highlight the need to consider the complex pathophysiology of AD in treatment development. Focusing solely on the amyloid-beta hypothesis may be inadequate; further research is necessary to understand the underlying mechanisms and develop treatments for the multifactorial nature of the disease."

Journal • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

TRANSCRIPTIONAL RESPONSES OF MICROGLIA AND ENDOTHELIAL CELLS TO ANTI -ABETA TREATMENT IN MICE WITH ARIA (ADPD 2025) - "This study aimed to compare 3D6 -L mAb, a murine version of bapineuzumab, with IgG2a, an isotype c ontrol, to explore cell -specific transcriptional changes in the brain following passive immunization... In summary, 3D6 -L reduced plaque burden and increased C1q levels but caused more microhemorrhages. Microglia showed increased complement and immune -related gene expression, while endothelial cells exhibited increased inflammation and lipid metabolism genes, indicating potential therapeutic targets to mitigate ARIA."

Preclinical • Hematological Disorders • Inflammation • Metabolic Disorders • ABCA1 • CD31 • CXCL12 • IL1R1 • PECAM1

DECIPHERING THE ROLE OF COMPLEMENT C3 IN ANTI-AMYLOID ANTIBODY-INDUCED ARIA (ADPD 2025) - "Eighteen-month-old mice were injected intraperitoneally (i.p.) with either tamoxifen (TAM) or corn oil (CO, control) for 5 consecutive days. After 3 weeks, all mice received weekly i.p. injections of 25 mg/kg 3D6-L anti-Aβ mAb, a murine analog of bapineuzumab known to cause microhemorrhages, for 7 weeks...Conclusions Our Results suggest that C3 lowering might protect against anti-amyloid-induced microhemorrhages. Additional analyses are underway to identify mechanisms underlying this process and the potential of C3 as a therapeutical target for AD."

Alzheimer's Disease • CNS Disorders • Hematological Disorders • Inflammation

PRE-RECORDED: COMPLEMENT, CAA AND ANTI-AMYLOID INDUCED ARIA (ADPD 2025) - "These studies compared 3D6-L mAb, a murine version of bapineuzumab with an IgG2a isotype control to explore mechanisms underlying ARIA...These findings highlight potential therapeutic targets to mitigate ARIA. Funding: NIH RF1 AG05865 and R01 NS136122 (CAL); Cure Alzheimer's Fund Keywords: anti-amyloid antibodies, vascular amyloid, complement, ARIA"

Alzheimer's Disease • CNS Disorders • Hematological Disorders • Inflammation • APOE • C1QA • C1QB • FCGR2A • FCGR3A • GFAP • LGALS3

New Discoveries in Amyloid-Related Imaging Abnormalities with Hemorrhage (ARIA-H) and Anti-Amyloid Beta Monoclonal Antibodies (ISC 2025) - "For monoclonal antibodies targeting Aβ clearance, we selected seven: Aducanumab, Bapineuzumab, Crenezumab, Donanemab, Gantenerumab, Lecanemab, and Solanezumab. Besides, ARIA-H is associated with the characteristics of mAb. (1)More mature Aβ clearance is associated with a higher risk of ARIA-H.(2)Lower clearance of Aβ oligomers is associated with a higher risk of ARIA-H.(3)Aβ clearance closer to the N-terminus is associated with a higher risk of ARIA-H.(4)mAb with an IgG4 structure are more likely to cause ARIA-H than those with an IgG1 structure.(5)Faster achievement of Aβ clearance thresholds is associated with a higher risk of ARIA-H.CONCLUSION This research enhances our understanding of ARIA-H and may guide future monoclonal antibody drug development, which may improve the cognition and overall prognosis of Alzheimer's disease patients."

Alzheimer's Disease • CNS Disorders • Hematological Disorders

Second-generation anti-amyloid monoclonal antibodies for Alzheimer's disease: current landscape and future perspectives. (PubMed, Transl Neurodegener) - "First-generation MABs targeting the non-toxic monomeric Aβ, such as solanezumab, bapineuzumab, and crenezumab, failed to demonstrate clinical benefit for AD in clinical trials. In contrast, second-generation MABs, including aducanumab, lecanemab, donanemab, and gantenerumab directed against pathogenic Aβ species and aggregates have shown that reducing Aβ deposition can be an effective strategy to slow cognitive impairment in AD. In this review, we provide a comprehensive overview of the current status, mechanisms, outcomes, and limitations of second-generation MABs for the clinical treatment of AD. Moreover, we discuss the perspectives and future directions of anti-amyloid MABs in the treatment of AD."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia • Inflammation

Developing Topics. (PubMed, Alzheimers Dement) - "The cumulative mean changes for CDR-SB were -0.08; for ADAS-Cog it was -0.53, with both 95%CI including zero. The score range for CDR-SB is 0 to 18; the range for ADAS-Cog is 0 to 70/90. These mean differences across the many trials conducted cannot be considered to be either clinically or statistically significant."

Journal • Review

Public Health. (PubMed, Alzheimers Dement) - "Clinical trials using anti-amyloid drugs have failed to represent the majority of individuals living with AD-related cognitive impairment on a global scale. It ultimately increases the disparities presented in the diagnosis and treatment of individuals with dementia. Ideally, anti-amyloid trials should incorporate the epidemiology of individuals with dementia worldwide. These observations underscore the urgent need for coordinated efforts involving scientists, societies, local governments, and industry to prioritize equity as a central goal in science."

Journal • Review • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

A systematic review of the efficacy and safety of anti-amyloid beta monoclonal antibodies in treatment of Alzheimer's disease. (PubMed, Expert Opin Biol Ther) - "According to CDR-SB measurements, lecanemab showed effectiveness in reducing brain amyloid and cognitive decline, with a change from baseline of 1.21. Aducanumab resulted in a decrease of -0.39 (-22%). Bapineuzumab showed no significant benefit, with scores of 2.4 (2.8). Gantenerumab, scoring 1.69 (1.37, 2.01), reduces amyloid, particularly in early Alzheimer's stages. Crenezumab was ineffective, with a score of 3.61...Further research is needed, highlighting the necessity of AD therapeutic research to alter AD's trajectory and provide reliable treatment. www.crd.york.ac.uk/prospero identifier is CRD42024504358."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia

Amyloid-β (Aβ) immunotherapy induced microhemorrhages are linked to vascular inflammation and cerebrovascular damage in a mouse model of Alzheimer's disease. (PubMed, Mol Neurodegener) - "In summary, our study has established a significant link between CAA-Aβ antibody immune complex formation, immune activation and vascular damage leading to smooth muscle cell loss. However, the full implications of this cascade on the development of microhemorrhages requires further exploration. Additional investigations are warranted to unravel the precise molecular mechanisms leading to microhemorrhage, the interplay of diverse immune populations and the functional roles played by various Trem2+ macrophage populations in response to Aβ immunotherapy."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Fibrosis • Hematological Disorders • Immunology • Inflammation

Deciphering the role of complement C3 in anti-amyloid antibody-induced ARIA (Neuroscience 2024) - "After 3 weeks, all mice received weekly i.p. injections of 25 mg/kg 3D6-L anti-Aβ mAb, a murine analog of bapineuzumab known to cause microhemorrhages, for 7 weeks...Our results suggest that C3 lowering might protect against anti-amyloid-induced microhemorrhages. Additional analyses are underway to identify mechanisms underlying this process and the potential of C3 as a therapeutical target for AD."

Alzheimer's Disease • CNS Disorders

Engineered Antibodies to Improve Efficacy against Neurodegenerative Disorders. (PubMed, Int J Mol Sci) - "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. 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."

Journal • Review • Alzheimer's Disease • CNS Disorders

Anti-Amyloid Immunotherapy for AD: A Potential Link between ARIA and Complement (AAIC 2024) - "Here, we compared recombinant 3D6-L, a murine version of bapineuzumab, and an isotype control IgG2a monoclonal antibody (mAb) to investigate potential mechanisms, including complement activation, involved in these side effects (ARIA-H or microhemorrhages) following passive immunization... Passive immunization against Aβ using 3D6-L amplified CAA-associated complement activation and altered expression of genes related to extracellular matrix degradation and vascular inflammation. The observed microhemorrhages appear to result from complement-mediated vascular inflammation induced by the binding of 3D6-L to vascular amyloid. These findings suggest potential biomarkers or targets for therapeutic interventions in the context of anti-Aβ immunization."

IO biomarker • Alzheimer's Disease • Hematological Disorders • Inflammation • Metabolic Disorders • ABCA1 • APOE • C1QA • C1QB • CD31 • CXCL12 • FCGR2A • FCGR3A • GFAP • IL1R1 • LGALS3 • MMP9 • PECAM1

(In)Equity in Alzheimer's Clinical Trials: A Long Road Ahead? (AAIC 2024) - " A total of 16055 individuals over 12 trials were evaluated in this work (ENGAGE, EMERGE, GRADUATE I and II, CLARITY-AD, A4, EXPEDITION3, ELN115727, CREAD and CREAD 2, TRAILBLAZER-ALZ 1 and 2)... Clinical trials using anti-amyloid drugs have failed to represent the majority of individuals living with AD-related cognitive impairment on a global scale. It ultimately increases the disparities presented in the diagnosis and treatment of individuals with dementia. Ideally, anti-amyloid trials should incorporate the epidemiology of individuals with dementia worldwide."

Clinical • Alzheimer's Disease • CNS Disorders • Cognitive Disorders • Dementia

A Review of Recent Advances in the Management of Alzheimer's Disease. (PubMed, Cureus) - "The conventional pharmacological agents revised comprise cholinesterase inhibitors, monoclonal antibodies, and other therapies, such as memantine, valproic acid, and rosiglitazone. The innovative reviewed pharmacological agents comprise the monoclonal antibodies: donanemab, gantenerumab, solanezumab, bapineuzumab, crenezumab, and semorinemab...Tau and amyloid-targeting treatments include methylthioninium moiety (MT), leuco-methylthioninium bis (LMTM), an oxidized form of MT, and tramiprosate, which inhibits the beta-amyloid (Aβ) monomer aggregation into toxic oligomers...The antidiabetic drugs include NE3107, an anti-inflammatory and insulin sensitizer, and the diabetes mainstream drug metformin. The anti-neuroinflammatory AD therapies include the use of sodium oligomannate (GV-971), infusions with intravenous immunoglobulin aiming to decrease plasma levels of the constituents of Aβ plaques, and masitinib, a tyrosine kinase inhibitor that impacts mast and microglia..."

Journal • Review • Alzheimer's Disease • CNS Disorders • Dementia • Diabetes • Inflammation • Insomnia • Metabolic Disorders • Sleep Disorder

Amyloid-beta antibody binding to cerebral amyloid angiopathy fibrils and risk for amyloid-related imaging abnormalities. (PubMed, Sci Rep) - "Solanezumab and crenezumab showed negligible CAA fibril binding and these antibodies have no reported ARIA-E cases. Lecanemab showed a low binding to CAA fibrils, consistent with its relatively low ARIA-E frequency of 12.6%, while aducanumab, bapineuzumab, and gantenerumab all showed higher binding to CAA fibrils and substantially higher ARIA-E frequencies (25-35%). An ARIA-E frequency of 24% was reported for donanemab, and its binding to CAA fibrils correlated with the amount of pyroglutamate-modified Aβ present. The findings of this study support the proposal that Aβ antibody-CAA interactions may relate to the ARIA-E frequency observed in patients treated with Aβ-based immunotherapies."

Journal • Alzheimer's Disease • CNS Disorders

Passive immunotherapy for Alzheimer's disease: challenges & future directions. (PubMed, J Transl Med) - "(N Engl J Med 10.1056/NEJMoa2305032, 2023) reported that solanezumab, a monoclonal antibody targeting Aβ peptide, failed to slow cognitive decline in AD patients. Previously, three other anti-Aβ antibodies, bapineuzumab, crenezumab, and gantenerumab, have also failed to show similar beneficial effects...However, other anti-Aβ antibodies, such as lecanemab (a humanized mAb binds to soluble Aβ protofibrils), donanemab (a humanized mAb binds to insoluble, N-terminal truncated form of Aβ peptides) and aducanumab (a human mAb binds to the aggregated form of Aβ), have been shown to slow the decline of cognitive functions in early stage AD patients...There are several challenges and limitations of passive immunotherapy using anti-Aβ antibodies and long term longitudinal studies are needed to assess their efficacy, side effects and cost effectiveness in a wider spectrum of subjects, from pre-dementia to more advanced dementia. A combination therapeutic approach using both..."

Journal • Alzheimer's Disease • CNS Disorders • Dementia

Lessons learned from the failure of solanezumab as a prospective treatment strategy for Alzheimer's disease. (PubMed, Expert Opin Drug Discov) - "Given that a systemic failure of Aβ clearance was supposed to primarily contribute to AD development and progression, disease-modifying therapies with anti-Aβ monoclonal antibodies (e.g. solanezumab, bapineuzumab, gantenerumab, aducanumab, lecanemab and donanemab) are ongoing in randomized clinical trials (RCTs) with contrasting results. Solanezumab was one of the first anti-Aβ monoclonal antibodies to be tested in preclinical and clinical AD showing to reduce brain Aβ level by acting on soluble monomeric form of Aβ peptide without significant results on deposits. Unfortunately, this compound showed to accelerate cognitive decline in both asymptomatic and symptomatic trial participants, and this failure of solanezumab further questioned the Aβ cascade hypothesis of AD."

Clinical • Journal • Alzheimer's Disease • CNS Disorders • Inflammation

Abeta-Responsive Cells as a Therapy in Alzheimer's Disease (ASGCT 2024) - " As measured by luciferase expression, Aβ receptors constructed from bapineuzumab, gantenerumab, and donanemab recognize synthetic Aβ42 and Aβ40. Aβ synNotch receptors represent a promising new therapeutic approach to treating AD. Capitalizing on their native surveillance functions in the brain, astrocytes expressing these receptors can specifically recognize Aβ as a marker of disease and respond via direct upregulation of a programmed therapeutic transgene. Due to the versatility of the synNotch platform, it is possible to produce many different transgenes under control of Aβ receptors (Fig."

Alzheimer's Disease • CNS Disorders • Gene Therapies • Inflammation • Aβ42 • IL6 • TNFA

Reducing neonatal Fc receptor binding enhances clearance and brain-to-blood ratio of TfR-delivered bispecific amyloid-β antibody. (PubMed, MAbs) - "Here, two antibodies were designed based on the Aβ antibody bapineuzumab (Bapi) - one monospecific IgG (Bapi) and one bispecific antibody with an antigen binding fragment (Fab) of the transferrin receptor (TfR) antibody 8D3 fused to one of the heavy chains (Bapi-Fab8D3) for active, TfR-mediated transport into the brain...Ex vivo autoradiography showed specific antibody retention in areas with abundant Aβ pathology. Taken together, these results suggest that reducing FcRn binding of a full-sized bispecific antibody increases the systemic elimination and could thereby drastically reduce the time from injection to in vivo imaging."

IO biomarker • Journal • Alzheimer's Disease • CNS Disorders