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

Differential Induction of ARIA-like Pathologies by Anti-Aβ Immunotherapies in 5XFAD Mice: A Comprehensive Analysis of 12-Weeks Dosing with Clinical-Stage Antibodies (Neuroscience 2026) - " We treated 8-month-old 5XFAD mice (n=5-10 group) for 12 weeks with weekly (QW) intraperitoneal injections of: 1) Isotype-mIgG2 control, 2) 3D6-mIgG2 (murine precursor of bapineuzumab), 3) Aducanumab-mIgG2 (humanized), or 4) Remternetug-mIgG2 (humanized). This head-to-head study in a robust amyloidosis model demonstrates that the risk of inducing ARIA-like pathology is highly dependent on the specific antibody's properties. These preclinical findings provide critical mechanistic insights into ARIA pathogenesis and underscore the importance of antibody screening for mitigating treatment-emergent adverse events."

Preclinical • Alzheimer's Disease • CNS Disorders

Association Of ARIA And Brain Volume Changes With Cognitive Outcomes In Bapineuzumab Therapy (AAIC 2026) - No abstract available

Early binding of anti-amyloid antibodies to CAA drives complement activation, inflammation and ARIA in mice. (PubMed, Mol Neurodegener) - "To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models...Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Hematological Disorders • Inflammation • APOE • MMP9

Aβ- and tau-detecting synthetic receptors to build a programmable Alzheimer’s disease therapy (ASGCT 2026) - "Monoclonal antibodies (mAbs) targeting Aβ or tau have been investigated in clinical trials, and several anti-Aβ mAbs (lecanemab, donanemab) have received FDA approval for their ability to clear Aβ...Bapineuzumab was used to construct the Aβ-detecting receptor Bap-Notch; Sem-Notch (semorinemab) detects tau...To this end, we’ve adapted receptor circuits to be compatible with AAV for transduction of endogenous brain cells with native surveillance functions, like astrocytes. The modularity of this platform allows for use with many therapeutic transgenes, including those that are anti-inflammatory, as demonstrated here."

Alzheimer's Disease • CNS Disorders • Gene Therapies • Inflammation • Aβ42 • CSF2 • SERPINA3 • TNFRSF1A

Amyloid-beta-targeting monoclonal antibodies for people with mild cognitive impairment or mild dementia due to Alzheimer's disease. (PubMed, Cochrane Database Syst Rev) - "The effect of amyloid-beta-targeting monoclonal antibodies on cognitive function and dementia severity at 18 months in people with mild cognitive impairment or mild dementia due to Alzheimer's disease is trivial, while on functional ability, it is small at best. Amyloid-beta-targeting monoclonal antibodies increase the risk of amyloid-related imaging abnormalities. Both desirable outcomes and adverse events were inconsistently reported in the studies included in the review. Successful removal of amyloid from the brain does not seem to be associated with clinically meaningful effects in people with mild cognitive impairment or mild dementia due to Alzheimer's disease. Future research on disease-modifying treatments for Alzheimer's disease should focus on other mechanisms of action."

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

Early Binding of Anti-Amyloid Antibodies to CAA Drives Complement Activation, Inflammation and ARIA in Mice. (PubMed, bioRxiv) - "To investigate mechanisms underlying ARIA, we examined the binding and temporal vascular effects of immunization with 3D6, the precursor to the anti-amyloid antibody bapineuzumab, in two aged Alzheimer's disease amyloid mouse models...Perivascular macrophages co-localized with complement-decorated CAA in 3D6-treated mice. These findings implicate complement activation as an early key driver of ARIA and suggest that therapeutic targeting of complement may reduce ARIA risk."

Journal • Preclinical • Alzheimer's Disease • CNS Disorders • Hematological Disorders • Inflammation • APOE • MMP9

EFFECTS OF COMBINED SEMAGLUTIDE TREATMENT AND ANTI-AMYLOID IMMUNOTHERAPY IN APP KNOCKIN MICE: NEUROPATHOLOGICAL OUTCOMES (ADPD 2026) - "We hypothesize that co-treating with semaglutide, which has anti-inflammatory and pro-vascular health effects, will mitigate vascular side effects known as Amyloid-Related Imaging Abnormalities (ARIA) associated with AA immunotherapy and reduce brain inflammation. Fifteen-month-old AppNL-G-F homozygous mice (n=12/group) are being injected subcutaneously (s.c.) daily for 2 weeks with increasing doses of semaglutide (to 60µg/kg) or vehicle followed by an additional 8 weeks of daily s.c. injections of semaglutide with weekly intraperitoneal injection of 20 mg/kg isotype control (IgG2a) or 3D6 anti-amyloid mAb, the murine precursor of bapineuzumab, for the first dose then reduced to 10 mg/kg thereafter... The results of our experiment will determine whether co-administration of semaglutide with an ARIA-inducing anti-amyloid antibody will mitigate ARIA and protect the cerebrovasculature. If so, combination therapy may help mitigate ARIA in AD patients undergoing..."

Preclinical • Alzheimer's Disease • CNS Disorders • Hematological Disorders • Inflammation • CD68 • GFAP

EVALUATING ANTIHISTAMINE TREATMENT TO REDUCE VASCULAR INFLAMMATION IN AN AMYLOID MOUSE MODEL OF ANTI-AMYLOID-BETA ANTIBODY-INDUCED ARIA (ADPD 2026) - "Lecanemab, which has the lowest ARIA incidence rates among approved anti-Abeta immunotherapies, caused infusion reactions in ~26.4% of patients, leading to clinical guidelines for pretreatment with antihistamine diphenhydramine and acetaminophen in those who develop symptoms...We hypothesize that mast cell activation contributes to the vascular inflammation associated with anti-Abeta antibody treatment and that inhibition of histamine signaling may mitigate these effects. Eight-month-old BxW.APP/PS1 mice are being treated with weekly intraperitoneal injections for eight weeks of either 3D6 (20mg/kg; n=20), the murine precursor of bapineuzumab, or IgG2a-isotype control (20mg/kg; n=20), each given with (n=10) or without (n=10) oral diphenhydramine (50mg/kg) and acetaminophen (200mg/kg) pretreatment... Diphenhydramine and acetaminophen are safe and well-tolerated over-the-counter medications. This work explores the translational potential of combining these drugs with..."

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

ASSESSMENT OF THE ABILITY OF TRANSFERRIN RECEPTOR-TARGETED ANTIBODIES TO CROSS THE BLOOD-BRAIN BARRIER IN VITRO AND IN VIVO (ADPD 2026) - "We examined BBB transport of the bispecific VNAR antibody TXB4-PD-L1 and Bapineuzumab-Fab8D3 (Babi-Fab8D3) and compared it to the high-affinity anti-TfR antibody Ri7. BBB transport was analyzed in vitro using non-contact co-cultures consisting of primary murine brain endothelial cells (mBECs) and mixed glial cells. In spite, being internalized by mBECs and neurons, TXB4-PD-L1 seems to enter the brain by a mechanism unrelated to BBB-mediated transcytosis. As expected, the Ri7 antibody did not pass the BBB in vitro nor in vivo."

Preclinical • CNS Disorders

DIFFERENTIAL INDUCTION OF ARIA-LIKE PATHOLOGIES BY ANTI-AΒ IMMUNOTHERAPIES IN 5XFAD MICE: A COMPREHENSIVE ANALYSIS OF 12-WEEKS DOSING WITH CLINICAL-STAGE ANTIBODIES (ADPD 2026) - "Aims: The pathophysiological mechanisms and the differential risk profiles among antibodies, particularly next-generation agents like Remternetug, remain incompletely understood in aspect of Amyloid-Related Imaging Abnormalities (ARIA), adverse events associated with anti-amyloid-beta (Aβ) immunotherapies for Alzheimer's disease. We treated 40-weeks-old 5XFAD mice (n=5-10 group) for 12 weeks with weekly (QW) intraperitoneal injections of: 1) Isotype-mIgG2 control, 2) 3D6-mIgG2 (murine precursor of bapineuzumab), 3) Aducanumab-mIgG2 (humanized), or 4) Remternetug-mIgG2 (humanized). This head-to-head study in a robust amyloidosis model demonstrates that the risk of inducing ARIA-like pathology is highly dependent on the specific antibody's properties. These preclinical findings provide critical mechanistic insights into ARIA pathogenesis and underscore the importance of antibody selection for mitigating treatment-emergent adverse events."

Preclinical • Alzheimer's Disease • Amyloidosis • CNS Disorders • Hematological Disorders • GFAP

DOES COMBINING SEMAGLUTIDE TREATMENT WITH ANTI-AMYLOID IMMUNOTHERAPY MITIGATE ARIA IN APP KNOCKIN MICE? (ADPD 2026) - "We hypothesize that the neurotropic and anti-inflammatory effects of semaglutide will reduce ARIA and synergistically improve the efficacy of anti-amyloid treatment on cognitive outcomes. Fifteen-month-old AppNL-G-F homozygous mice (n=12/group) were injected subcutaneously (s.c.) daily for 2 weeks with increasing doses of semaglutide (to 60µg/kg) or vehicle followed by an additional 8 weeks of daily s.c. injections of semaglutide with weekly intraperitoneal injection of isotype control (IgG2a) or 3D6 (10mg/kg), the murine precursor of bapineuzumab known to cause ARIA in the presence of cerebral amyloid angiopathy (CAA)... Co-administration of semaglutide with 3D6 lowered ARIA. Further investigation will delineate the anti-inflammatory mechanisms and thus elucidate if combination therapy may improve the safety and efficacy of anti-amyloid immunotherapy in humans. Prevention studies underway."

IO biomarker • Preclinical • Hematological Disorders • Inflammation • Mood Disorders

ADVANCING IMMUNOTHERAPY WITH BISPECIFIC ANTIBODIES THAT CROSS THE BLOOD-BRAIN BARRIER (ADPD 2026) - "1A) were engineered based on either the anti-amyloid-beta antibody Bapineuzumab or Lecanemab, combined with TfR-binding domains...Preclinical and clinical data indicated that, at therapeutic dosing, monovalent TfR-binding (as in Trontinemab) or moderate rather than high TfR affinity favoured efficient delivery. Bispecific antibodies offer a promising approach to AD therapy by improving brain penetration and treatment efficacy. Their distinct route of brain entry also reduces vascular antibody accumulation, a likely contributor to adverse effects such as amyloid-related imaging abnormalities (ARIA), that are commonly observed with conventional amyloid-beta antibodies."

Bispecific • Alzheimer's Disease • CNS Disorders

TEMPORAL CEREBROVASCULAR CHANGES WITH ANTI-AMYLOID IMMUNOTHERAPY IN MICE (ADPD 2026) - "Previously, we reported that chronic immunization with an anti-amyloid monoclonal antibody, 3D6 (murine precursor of bapineuzumab), induced microhemorrages in amyloid mouse models of Alzheimer's disease (AD) if given after the development of cerebral amyloid angiopathy (CAA)...Transcriptomics revealed upregulation of genes related to complement, inflammation, vascular dysfunction and lipid response. Complement activation plays a role in ARIA and may represent a therapeutic target for intervention."

Preclinical • Alzheimer's Disease • CNS Disorders • Hematological Disorders • Inflammation • C1Q • MMP9

The influence of bapineuzumab and semagacestat on rapid progressors: A retrospective cohort study. (PubMed, J Prev Alzheimers Dis) - "This study provides crucial insights for clinical practice and trial design. The distinct response patterns between progression groups suggest that early identification and balancing of RPs between groups could improve clinical trial efficiency. The findings support the development of personalized treatment approaches for rapid progressors, who have aggressive disease progression. These results may significantly modify clinical trial design and patient care in Alzheimer's disease."

Clinical • Journal • Retrospective data • Alzheimer's Disease • CNS Disorders • Cognitive Disorders

Developing Topics. (PubMed, Alzheimers Dement) - "Anti-amyloid antibodies initially bind vascular amyloid and trigger complement activation. Sustained treatment promotes C3 and C5b-9 accumulation, RBC leakage, and recruitment of peripheral immune cells to the BBB; driven potentially by C3a/C5a signaling. These results highlight complement and vascular immune cell changes as potential early indicators of ARIA and as therapeutic targets."

IO biomarker • Journal • Alzheimer's Disease • Cerebral Hemorrhage • CNS Disorders • Hematological Disorders • Inflammation • APOE • CD8

Developing Topics. (PubMed, Alzheimers Dement) - "The minimal differences between treatment and placebo-relative to the wide scoring scales-suggest that targeting amyloid plaques may be insufficient as a disease-modifying approach. These findings underscore the urgent need for alternative strategies. One such approach is NA-831, Biomed's novel small-molecule therapy based on neurogenesis and neuroprotection. Unlike amyloid-targeted antibodies, NA-831 aims to restore neuronal function and cognition by stimulating endogenous brain repair mechanisms. These emerging strategies may better align with the complex pathophysiology of AD and represent a promising new frontier in treatment."

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

Developing Topics. (PubMed, Alzheimers Dement) - "Characterization of Aβ peptides in isolated cerebral vessels confirmed a predominance of Aβ40 and low levels of truncated Aβp3-x. Higher levels of CAA target engagement were observed for amyloid-targeting antibodies that bind deposited full-length Aβ (gantenerumab, lecanemab, bapinezumab) as opposed to truncated and pyro-glu modified Aβ (donanemab). These results suggest factors other than ability to bind CAA are important for the manifestation of ARIA."

Journal

Basic Science and Pathogenesis. (PubMed, Alzheimers Dement) - "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."

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

Severe symptomatic amyloid-related imaging abnormalities in Alzheimer's disease: Two case reports and systematic review of reported cases. (PubMed, J Alzheimers Dis) - "Fifteen cases were associated with lecanemab, 10 with gantenerumab, 6 with donanemab, and 5 with other antibodies...Standardized diagnostic and therapeutic guidelines are needed to minimize ARIA-related morbidity and mortality.PROSPERO registration no. CRD420251055067."

Journal • Review • Alzheimer's Disease • CNS Disorders • Epilepsy • Hematological Disorders • Pain • APOE

ScFv-h3D6 Prevents Bapineuzumab-Induced Hemorrhagic Events in the APP23 Mouse Model of Alzheimer's Disease. (PubMed, Biomolecules) - "In conclusion, the scFv-h3D6 format appears safer than the full-length mAb in the APP23 model of AD and CAA. This finding is highly relevant in light of the new FDA- and EMA-approved mAbs, which exclude APOEε4 allele carriers due to the occurrence of hemorrhages."

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

NEW DISCOVERIES IN AMYLOID-RELATED IMAGING ABNORMALITIES WITH HEMORRHAGE AND ANTI-AMYLOID BETA MONOCLONAL ANTIBODIES (WCN 2025) - "(5)Amyloid Beta Clearance Rate. The risk of ARIA-H, from highest to lowest, is as follows: Donanemab, Aducanumab, Bapineuzumab, Lecanemab, Gantenerumab, Crenezumab, Solanezumab. 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

Structural and Functional Determinants of ARIA-H Risk in Anti-Amyloid Monoclonal Antibodies: A Comparative Mechanistic Framework for Alzheimer's Immunotherapy Development. (PubMed, Curr Neuropharmacol) - "These findings establish a mechanistic framework for ARIA-H risk and provide concrete molecular predictors to guide antibody engineering strategies. Prioritizing mAbs with controlled amyloid clearance, C-terminal binding domains, and IgG1 frameworks may enhance therapeutic safety, advancing precision immunotherapy for Alzheimer's disease."

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

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