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 (ADPD 2026) - " 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

EFFECTS OF COMBINED SEMAGLUTIDE TREATMENT AND ANTI-AMYLOID IMMUNOTHERAPY IN APP KNOCKIN MICE: NEUROPATHOLOGICAL OUTCOMES (ADPD 2026) - " 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 anti-amyloid immunotherapy. Funding: NIH/NIA-R01AG084531 (CAL)."

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... 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 anti-Abeta antibody treatment to improve the safety profile of Alzheimer's disease immunotherapy. Funding: 5R01AG063839-05 (CAL/PL)."

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. 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

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) are being injected subcutaneously (s.c.) daily for 2 weeks with increasing doses of semaglutide (to 120µg/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 (20mg/kg), the murine precursor of bapineuzumab known to cause ARIA in the presence of cerebral amyloid angiopathy (CAA)... The results of our experiment (Q1/2026) will show if co-administration of semaglutide with 3D6 will mitigate ARIA as well as improve 3D6 efficacy. If so, combination therapy may improve the safety and efficacy of anti-amyloid immunotherapy in humans."

IO biomarker • Preclinical • Hematological Disorders • Inflammation

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."

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

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