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 t(1/2) of Ab2 was faster (<2.5 days) compared to that of the control antibody (~13 days). 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 t(1/2) similar to that observed for other humanized antibodies.
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 t(1/2) of Ab2 was faster (<2.5 days) compared to that of the control antibody (~13 days). 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 ADhumans is expected to be slow, with t(1/2) similar to that observed for other humanized antibodies.
Authors: F Bard; C Cannon; R Barbour; R L Burke; D Games; H Grajeda; T Guido; K Hu; J Huang; K Johnson-Wood; K Khan; D Kholodenko; M Lee; I Lieberburg; R Motter; M Nguyen; F Soriano; N Vasquez; K Weiss; B Welch; P Seubert; D Schenk; T Yednock Journal: Nat Med Date: 2000-08 Impact factor: 53.440
Authors: J Steven Jacobsen; Chi-Cheng Wu; Jeffrey M Redwine; Thomas A Comery; Robert Arias; Mark Bowlby; Robert Martone; John H Morrison; Menelas N Pangalos; Peter H Reinhart; Floyd E Bloom Journal: Proc Natl Acad Sci U S A Date: 2006-03-20 Impact factor: 11.205
Authors: L Holcomb; M N Gordon; E McGowan; X Yu; S Benkovic; P Jantzen; K Wright; I Saad; R Mueller; D Morgan; S Sanders; C Zehr; K O'Campo; J Hardy; C M Prada; C Eckman; S Younkin; K Hsiao; K Duff Journal: Nat Med Date: 1998-01 Impact factor: 53.440
Authors: Amita Datta-Mannan; Johnny E Croy; Linda Schirtzinger; Stacy Torgerson; Matthew Breyer; Victor J Wroblewski Journal: MAbs Date: 2016-07 Impact factor: 5.857
Authors: Daniela Bumbaca Yadav; Vikas K Sharma; Charles Andrew Boswell; Isidro Hotzel; Devin Tesar; Yonglei Shang; Yong Ying; Saloumeh K Fischer; Jane L Grogan; Eugene Y Chiang; Konnie Urban; Sheila Ulufatu; Leslie A Khawli; Saileta Prabhu; Sean Joseph; Robert F Kelley Journal: J Biol Chem Date: 2015-10-21 Impact factor: 5.157