Slide 1: Enhanced Brain Delivery of Sabirnetug in a Mouse Model of Alzheimer's Disease
Enhanced Brain Delivery of Sabirnetug in a Mouse Model of Alzheimer’s Disease after Fusion with an anti-Transferrin Receptor Antibody Fragment Paul Shughrue, PhD VP Research and Strategy, Acumen Pharmaceuticals ADPD Copenhagen, Denmark March 17-21, 2026 1
Slide 2: Disclosures
Disclosures Dr. Shughrue is an employee of Acumen Pharmaceuticals and is a minor shareholder. 2
Slide 3: Forward-Looking Statements
Forward-Looking Statements This presentation contains forward-looking statements within the meaning of The Private Securities Litigation Reform Act of 1995. Any statement describing Acumen’s goals, expectations, financial or other projections, intentions or beliefs is a forward-looking statement and
Slide 4: TfR-Mediated Uptake: A Strategy for Enhanced Brain Delivery (EBD) of Immunotherapeutic Agents
TfR-Mediated Uptake: A Strategy for Enhanced Brain Delivery (EBD) of Immunotherapeutic Agents • Receptor-mediated transcytosis has been used to enhance brain delivery of molecules including therapeutic antibodies • JCR has developed a library of J-Brain Cargo fragments (scFv and VHH) that target the
Slide 5: The Development of Mouse Conjugate Antibodies to Explore Aβ Target Engagement
The Development of Mouse Conjugate Antibodies to Explore A Target Engagement in a Mouse Model of AD • ACU193, ACU234, and the bispecific constructs bind Aβ oligomers and monomers with similar affinity *K s in table from same run (n = 1); Aggregate AβO K for all other runs, ACU193 = 0.5 ± 0.2 nM (n
Slide 6: Initial Work in Wild Type Mice Showed Enhanced Brain Levels vs ACU193
Initial Work in Wild Type Mice Demonstrated that the Mouse Conjugate Antibodies had Enhanced Brain Levels when Compared with ACU193 1.2 Drug Concentration in Brain 1.0 (µg/g wet tissue) 0.8 0.6 ~ 35X @ 3 hrs 0.4 ~ 17X @ 24 hrs 0.2 0.0 0 10 20 30 40 50 Hours After Administration ACU193 193-1 193-2 23
Slide 7: Use of the ARTE10 AD Mouse Model to Investigate Target Engagement
Use of the ARTE10 AD Mouse Model to Investigate Target Engagement of Bispecific Antibodies Aβ species in the ARTE10 Mouse Brain Study Design: • Inject 10-month-old male ARTE10 mice (n=9) IV with 2 mg/kg of o 193-1 o 193-2 o 234-2 o ACU193 o ACU234 • 24 hours post injection collect brains and process
Slide 8: Bispecific Antibodies Show Enhanced Delivery to the ARTE10 Mouse Brain
Bispecific Antibodies Show Enhanced Delivery to the ARTE10 Mouse Brain when Compared with ACU193 or ACU234 Concentration of antibody 0.5 (μg antibody/g wet weight) 63X 65X 0.4 68X 0.3 0.2 0.1 0.0 -0.1 3 1 2 4 2 3- 3- 4- 19 23 19 19 23 U U C C A A • Results from the ARTE10 mice suggest that antibodie
Slide 9: Immunohistochemical Localization of Bispecific Constructs in the ARTE10 Mouse Brain
Immunohistochemical Localization of Bispecific Constructs in the ARTE10 Mouse Brain 24 hours after IV dosing Immunodetection of human IgG2 (193.2) Total A (6E10/4G8) G C F B A D E H • Note the dramatically reduced dense core plaque staining (white boxes, D vs. H) with fusion antibodies 9
Slide 10: Differential Staining of Aβ Structures in the ARTE10 Mouse Thalamus
Differential Staining of A Structures in the ARTE10 Mouse Thalamus 24 hours after IV Dosing of Bispecific Antibodies WT Mouse 10
Slide 11: Localization of Bispecific Antibodies in the ARTE10 Mouse Cerebral Cortex
Localization of Bispecific Antibodies in the ARTE10 Mouse Cerebral Cortex 11
Slide 12: Staining for 193-1 Suggests Antibody Localized to the Capillary Wall
Staining for 193-1 in the Cortex Suggests that Antibody is Localized to the Capillary Wall and Not in the Parenchyma 12
Slide 13: A Comparison of Capillary Staining Among the Three Bispecific Antibodies
A Comparison of Capillary Staining Among the Three Bispecific Antibodies * capillary lumen capillary wall 13
Slide 14: Summary
Summary • Bispecific constructs of ACU193 or ACU234 with a mouse anti-TfR scFv retain their ability to bind the TfR and to selectively bind A oligomers • Studies in wild type mice demonstrated that all mouse bispecific antibody constructs had enhanced brain delivery (17-35X), as compared to ACU193
Slide 15: Thank you!
Thank you! Coauthors: Collaborators: ARTE10 Mouse Studies Acumen Pharmaceuticals Department of Epidemiology, University of Maryland School Elizabeth Johnson of Medicine, Baltimore, Maryland Alex Davis Istvan Merchenthaler Malcolm Lane Jasna Jerecic Tom Lavoie Human Brain Samples Liean Schenck Iowa N