Chronic administration of an aglycosylated murine antibody of ponezumab does not worsen microhemorrhages in aged Tg2576 mice.
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 (APP(K670N;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 Aβ(1-x) and Aβ(x-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.
Pfizer Worldwide Research and Development, Groton, CT 06340, USA. Gary.B.Freeman@pfizer.com
Gary B
GB
Freeman
Thomas P
TP
Brown
Karin
K
Wallace
Kelly R
KR
Bales
D000375:Aging; D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology*; D000818:Animals; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage / Q000009:adverse effects* / Q000493:pharmacokinetics; D001929:Brain Edema / Q000473:pathology*; D002543:Cerebral Hemorrhage / Q000473:pathology*; D004195:Disease Models, Animal; D005260:Female; D051379:Mice; D008822:Mice, Transgenic
D061067:Antibodies, Monoclonal, Humanized; C572721:ponezumab