Therapeutic Efficacy of the Murine Precursor to PBD‐C06: a Novel CDC‐Mutant Anti‐pGlu3Aβ mAb

Abstract

AbstractBackgroundPyroglutamate‐3Aβ (pGlu3Aβ) is a toxic N‐terminally truncated and modified form of Aβ that leads to faster aggregation and seeding of plaques, making it an important target in Alzheimer’s disease. Anti‐amyloid antibodies, e.g., bapineuzumab, are associated with Amyloid‐Related Imaging Abnormalities (ARIA) involving vasogenic edema and microhemorrhages in AD patients, especially in ApoE4 carriers. Previously, we demonstrated reductions in plaques and cognitive deficits using an anti‐pGlu3Ab mAb, 07/2a. Here, we tested a novel CDC‐mutant version (07/2a‐k, murine precursor to PBD‐C06) to avoid C1q activation to reduce vascular‐related inflammation associated with anti‐amyloid antibodies.MethodTo estimate an effective therapeutic dose, 12 mo‐old APP/PS1dE9 mice were treated weekly (i.p.) for 5 weeks with 150, 300 or 600 µg 07/2a‐k or IgG2a (n=10‐12/group). General Ab and pGlu3Aβ levels were quantified by ELISA and immunohistochemistry. Next, 16 mo‐old APP/PS1dE9; hApoE4 mice were treated weekly (i.p.) for 15 weeks with 350 µg of 07/2a‐k, 3D6‐L (a murine analog of bapineuzumab), or IgG2a, while hApoE4 mice were treated with PBS (n=10‐13 mice/group). Subsequently, cognitive testing was performed over 3 weeks using the Spatial Novelty Y Maze (SNYM), Novel Object Recognition (NOR), and the Barnes Maze followed by euthanasia.ResultFive weekly treatments with 07/2a‐k in the dosing study did not alter general and pGlu3 Aβ biochemical levels; however, hippocampal pGlu3Aβ plaques were significantly reduced (300 µg, p<0.0005; 600 µg, p<0.005). In the therapeutic study, 3D6‐L reduced Aβx‐42 levels (p<0.009) by ELISA but not Abx‐40 levels. 07/2a‐k did not significantly alter Aβx‐42 or Abx‐40 levels. Both antibodies improved performance in the NOR test (07/2a‐k, p<0.05; 3D6‐L, p=0.05) and showed a non‐significant trend for improvement in the SNYM and Barnes maze compared to IgG2a controls. Macro‐hemorrhages were visible in 33% of 3D6‐L treated mice but not in 07/2a‐k treated mice.ConclusionTreatment with the 3D6‐L mAb, a murine analog of bapineuzumab, lowered cerebral Aβ levels and improved cognition but induced macro‐hemorrhages in aged APP/PS1dE9;hApoE4 mice, while treatment with 07/2a‐k, the precursor to PBD‐C06, did not alter general Ab levels but improved cognition in the absence of macro‐hemorrhages. Further analyses are underway to quantify cerebral pGlu3Ab levels, plaques, CAA, microhemorrhages and gliosis. (NIH 1RF1AG058657‐CAL)