A novel anti‐amyloid‐beta oligomer antibody reduces plaque burden and slows cognitive decline in 5xFAD mice

Abstract

AbstractBackgroundThe soluble amyloid‐beta (Aβ) oligomers are the more toxic form of Aβ as compared with monomers and insoluble fibrils. Lecanemab, a humanized monoclonal antibody (mAb) with high affinity for Aβ oligomers, reduced cognitive decline in patients with early Alzheimer’s disease in a phase 3 clinical trial. Here we report a novel fully‐human anti‐Aβ oligomer mAb with profiles similar to Lecanemab.MethodAlivaMab human F(ab’)2 transgenic mice were immunized with Aβ oligomers to generate Aβ oligomer selective mAbs. The antibodies were screened for, and ranked, based on their selectivity for Aβ oligomer over monomer and ability in mediating the uptake of Aβ oligomers by microglia. Pharmacokinetics (PK) and brain penetration of lead mAb candidates was determined in mice. In vivo efficacy was evaluated in 7‐month old 5xFAD mice with weekly intraperitoneal injection of antibody lead at 1, 3, or 10 mg/kg dose levels for 4 months. After completion of dosing, open field and novel object recognition tests were performed on the treated mice and amyloid plaque burden in the brain was measured by Campbell‐Switzer stain and ELISA.ResultLead antibody 17P04 exhibited higher oligomer selectivity than that of mAb158 (mouse parental antibody of Lecanemab which served as reference antibody control) and induced antibody‐dependent cell‐mediated phagocytosis of Aβ oligomers in mouse microglia cells. PK study in mice showed that 17P04 had longer half‐life in the plasma and the brain, and demonstrated higher brain penetrance in comparison with mAb158. Subchronic treatment of 5xFAD mice with 17P04 reduced Aβ plaque burden in the brain in a dose dependent manner, reversed the abnormal activity of 5xFAD mice in open field test, and reduced cognitive decline as evaluated by novel object recognition.ConclusionWe identified a novel fully‐human anti‐Aβ oligomer antibody with superior Aβ oligomer selectivity, half‐life and brain exposure. Lead antibody 17P04 demonstrated high efficacy in plaque clearance and cognitive protection in 5xFAD mice.