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P3‐295: Pharmacokinetic and pharmacodynamic analysis of the gamma‐secretase modulator (GSM) EVP‐0015962
Author(s) -
Felsenstein Kevin M.,
Spaulding Darcie,
Yang Zhiyong,
Hodgdon Hilliary,
Costa Don,
Nolan Scott,
Wen Melody,
Lee Winnie,
Hrdlicka Lori,
Catana Florentina,
Albayya Faris,
Tu Zhiming,
Patzke Holger,
Chesworth Richard,
Shapiro Gideon,
Zaninovic Irena,
Ahlijanian Michael,
Koenig Gerhard,
Rogers Kathryn
Publication year - 2010
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1016/j.jalz.2010.05.1795
Subject(s) - gamma secretase , in vivo , amyloid precursor protein secretase , in vitro , pharmacokinetics , pharmacology , chemistry , concomitant , biology , medicine , alzheimer's disease , biochemistry , disease , amyloid precursor protein , microbiology and biotechnology
Background: CAD106 is an active immunotherapy developed for Alzheimer’s disease. It comprises amino acids 1-6 of Ab coupled to a virus-like particle derived from E. coli bacteriophage Qb. In APP overexpressing mice, administration of CAD106 induced Ab antibodies as well as a reduction of amyloid accumulation in the brain. Infusion of antibodies or active immunization against Ab have been shown to increase the level of total Ab in plasma indicating target engagement by the antibodies. In the present study we have investigated the active Ab immunotherapy CAD106 for its effect on plasma Ab. Methods: Cynomolgus monkeys aged 3 to 6 years were administered 600 mg CAD106 per subcutaneous or intramuscular injection at days 1, 14, 28 and every 4 weeks thereafter for a total of 24 weeks. Each dose contained either Alum or MF58 as adjuvant. Controls received adjuvant only. Total plasma Ab was determined at baseline and 12 to 14 days after the injections at week 8 and 24 using two different ELISAs and Western blotting. To minimize an interference of the CAD106-induced antibodies samples were SDSdenatured prior to quantification with an ELISA using a N-terminal capturing antibody. Alternatively, an assay combining C-terminal capture and mid-region detection antibodies was used. In addition, results were verified by direct SDS-PAGE separation of plasma followed by Western blotting. Results: Following active immunotherapy with CAD106, total plasma Ab levels increased compared to baseline and further between the intermediate and final time points of the study. Individual animals showed increases of up to about 50-fold over baseline. Median group increases reached up to 25-fold. Very similar results were obtained with the different assays. Overall the Ab levels in plasma correlated well with the Ab antibody titers. Conclusions: The increase in plasma Ab indicates an interaction of CAD106 induced antibodies with Ab in vivo. Its extent is in line with observations made with Nterminal monoclonal antibodies.