Cerebral vasogenic edema and microhemorrhages are potential safety concerns for compounds intended to treat
subjects with Alzheimer’s disease (AD) by targeting amyloid β (Aβ). Ponezumab (PF-04360365) is an investigational
anti-Aβ monoclonal antibody. Two hundred female mice (APPK670N;M671L; Tg2576) 16–19 months old received an aglycosylated
CHO-derived murine surrogate of ponezumab by intraperitoneal administration once weekly for up to 26 weeks
at doses of 0, 10, 30, or 100 mg/kg. Drug exposure and plasma Aβ levels increased with increasing dose. After 26 weeks,
the 100 mg/kg group had significantly greater plasma levels of Aβ1-x and Aβx-40 than the vehicle group (p < 0.001). Brain
microhemorrhages were identified histologically using hematoxylin and eosin and/or Perls’ Prussian blue iron staining.
The incidence in the vehicle group was equal to or higher than those of the treated groups. There was no evidence of
vasogenic edema. In summary, intraperitoneal administration of a murine surrogate of ponezumab to aged Tg2576 mice
for up to 6 months did not produce any compound-related brain microhemorrhage or other pathologies.
Keywords: Microhemorrhage, murine surrogate, ponezumab (PF-04360365), safety, Tg2576 mice, Aβ, CAA, Cerebral vasogenic edema, amyloid plaques, brain magnetic resonance imaging, cell-mediated cytotoxicity.
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