caa a22 4500 445312432 CHVBK 20180317142634.0 cr unu---uuuuu 170323e20110701xx s 000 0 eng 10.1007/s11095-011-0405-x doi (NATIONALLICENCE)springer-10.1007/s11095-011-0405-x Complex Pharmacokinetics of a Humanized Antibody Against Human Amyloid Beta Peptide, Anti-Abeta Ab2, in Nonclinical Species [Elektronische Daten] [Yulia Vugmeyster, Pam Szklut, David Wensel, John Ross, Xin Xu, Michel Awwad, Davinder Gill, Lioudmila Tchistiakov, Garvin Warner] ABSTRACT: Purpose: Anti-Aβ Ab2 (Ab2) is a humanized monoclonal antibody against amino acids 3-6 of primate (but not rodent) amyloid β (Aβ) and is being evaluated for the treatment of Alzheimer's disease (AD). This study was conducted to predict the human pharmacokinetics of Ab2. Methods: In vivo PK profile of Ab2 in preclinical species and in vitro mechanistic studies in preclinical and human systems were used for pharmacokinetic predictions. Results: In Tg2576 and PSAPP mice that have ~100-fold higher circulating levels of human Aβ compared to humans, elimination of Ab2 was target-mediated, such that exposure was 5-10 fold lower compared to wild-type rodents or to PDAPP mice that have human Aβ concentrations in plasma similar to humans. In cynomolgus monkeys, the t1/2 of Ab2 was faster (<2.5days) compared to that of the control antibody (~13days). The fast elimination of Ab2 in cynomolgus monkeys was linked to off-target binding to cynomolgus monkey fibrinogen that was also causing incomplete recovery of Ab2 in cynomolgus monkey serum in blood partitioning experiments. Ab2 had significantly weaker to undetectable binding to human (and mouse) fibrinogen and had good recovery in human serum in blood partitioning experiments. Conclusions: These data predict that elimination of Ab2 in healthy or AD humans is expected to be slow, with t1/2 similar to that observed for other humanized antibodies. Springer Science+Business Media, LLC, 2011 Alzheimer's disease nationallicence anti-Abeta antibody nationallicence fibrinogen nationallicence human PK prediction nationallicence pharmacokinetics nationallicence Vugmeyster Yulia Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., 01810, Andover, Massachusetts, USA aut Szklut Pam Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., 01810, Andover, Massachusetts, USA aut Wensel David Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., 01810, Andover, Massachusetts, USA aut Ross John Department of Global Biotherapeutics Technologies, Pfizer Inc., Cambridge, Massachusetts, USA aut Xu Xin Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., 01810, Andover, Massachusetts, USA aut Awwad Michel Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., 01810, Andover, Massachusetts, USA aut Gill Davinder Department of Global Biotherapeutics Technologies, Pfizer Inc., Cambridge, Massachusetts, USA aut Tchistiakov Lioudmila Department of Global Biotherapeutics Technologies, Pfizer Inc., Cambridge, Massachusetts, USA aut Warner Garvin Department of Drug Safety Research and Development, Pfizer Inc., 01810, Andover, Massachusetts, USA aut Pharmaceutical Research Springer US; http://www.springer-ny.com 28/7(2011-07-01), 1696-1706 0724-8741 28:7<1696 2011 28 11095 https://doi.org/10.1007/s11095-011-0405-x text/html Onlinezugriff via DOI 1 research-article jats NATIONALLICENCE 856 40 https://doi.org/10.1007/s11095-011-0405-x text/html Onlinezugriff via DOI NATIONALLICENCE 700 1- Vugmeyster Yulia Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., 01810, Andover, Massachusetts, USA aut NATIONALLICENCE 700 1- Szklut Pam Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., 01810, Andover, Massachusetts, USA aut NATIONALLICENCE 700 1- Wensel David Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., 01810, Andover, Massachusetts, USA aut NATIONALLICENCE 700 1- Ross John Department of Global Biotherapeutics Technologies, Pfizer Inc., Cambridge, Massachusetts, USA aut NATIONALLICENCE 700 1- Xu Xin Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., 01810, Andover, Massachusetts, USA aut NATIONALLICENCE 700 1- Awwad Michel Department of Pharmacokinetics, Dynamics, and Metabolism, Pfizer Inc., 01810, Andover, Massachusetts, USA aut NATIONALLICENCE 700 1- Gill Davinder Department of Global Biotherapeutics Technologies, Pfizer Inc., Cambridge, Massachusetts, USA aut NATIONALLICENCE 700 1- Tchistiakov Lioudmila Department of Global Biotherapeutics Technologies, Pfizer Inc., Cambridge, Massachusetts, USA aut NATIONALLICENCE 700 1- Warner Garvin Department of Drug Safety Research and Development, Pfizer Inc., 01810, Andover, Massachusetts, USA aut NATIONALLICENCE 773 0- Pharmaceutical Research Springer US; http://www.springer-ny.com 28/7(2011-07-01), 1696-1706 0724-8741 28:7<1696 2011 28 11095 Metadata rights reserved Springer special CC-BY-NC licence nationallicence BK010053 XK010053 XK010000 NATIONALLICENCE NATIONALLICENCE NL-springer