Intellect Neurosciences Inc. (fka ILNS)

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6-Month Chronic Study with Ponezumab (PF-04360365) Chinese Hamster Ovary (CHO)-derived Murine Surrogate in 18-Month-Old Tg2576 Mice
P3-013
Background: Cerebral vasogenic edema and microhemorrhages have been raised as potential safety concerns for compounds intended to treat Alzheimer's disease by targeting amyloid ß. Here, we describe the safety of an anti-amyloid ß monoclonal antibody chronically administered to amyloid ß-bearing mice. Methods: 18-month-old female Tg2576 (APP K670N;M671L) mice were selected for this study because at 12 and 24 months of age they have abundant cerebral parenchymal and vascular amyloid ß and are thus a relevant animal model. Mice (N=200) were injected intraperitoneally with a murine surrogate of the humanized anti-amyloid ß monoclonal antibody ponezumab (PF-04360365) once weekly for up to 26 weeks at doses of 10, 30, or 100 mg/kg. Mortality, clinical signs, body weight, food consumption, and anatomic pathology were evaluated. Brains were examined microscopically for microhemorrhages, and other tissues were evaluated from all animals dying prior to scheduled study termination to ascertain if such deaths were compound-related. All work was approved by an Institutional Animal Care and Use Committee and, for the most part, was conducted under Good Laboratory Practice conditions. Results: There were no compound-related changes in clinical signs, body weight, or food consumption. The numbers of surviving animals were generally similar in all groups. No compound-related anatomic macroscopic or microscopic findings were present. The incidence of Perl's iron-positive brain microhemorrhages was low and similar across all groups, and there was no increase in severity in mice given the test antibody, even at the highest dose. As expected, drug exposure and plasma amyloid ß levels increased with increasing dose of test article, and higher plasma drug levels were correlated with higher plasma amyloid ß levels. Most spontaneous deaths were attributed to age-related neoplasms typical of mice this age. Similar to other deglycosylated murine antibodies, this antibody demonstrated reduced binding against a panel of recombinant murine Fc gamma receptors, indicating a low potential to increase immune effector function. Conclusions: Within the limits of this study, administration of this CHO-derived surrogate of ponezumab to 18-month-old amyloid ß-bearing Tg2576 mice for up to 26 weeks did not result in an increase in microhemorrhages or other pathologies.
Gary Bruce Freeman, Pfizer Global Research and Development
Karin Wallace, Pfizer Global Research and Development
Thomas Brown, Pfizer Global Research and Development
Kelly Bales, Pfizer Global Research and Development

poster session ICAD 2011
http://icad.sclivelearningcenter.com/index.aspx