Off-target platelet activation in macaques unique to a therapeutic monoclonal antibody

Toxicologic Pathology
Michael J SantostefanoNancy Everds

Abstract

AMG X, a human neutralizing monoclonal antibody (mAb) against a soluble human protein, caused thrombocytopenia, platelet activation, reduced mean arterial pressure, and transient loss of consciousness in cynomolgus monkeys after first intravenous administration. In vitro, AMG X induced activation in platelets from macaque species but not from humans or baboons. Other similar mAbs against the same pharmacological target failed to induce these in vivo and in vitro effects. In addition, the target protein was known to not be expressed on platelets, suggesting that platelet activation occurred through an off-target mechanism. AMG X bound directly to cynomolgus platelets and required both the Fab and Fc portion of the mAb for platelet activation. Binding to platelets was inhibited by preincubation of AMG X with its pharmacological target or with anti-human Fc antibodies or by preincubation of platelets with AMG X F(ab')(2) or human immunoglobulin (IVIG). AMG X F(ab')(2) did not activate platelets. Thus, platelet activation required both recognition/binding of a platelet ligand with the Fab domain and interaction of platelet Fc receptors (i.e., FcγRIIa) with the Fc domain. These findings reflect the complexity of the mechanism of act...Continue Reading

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Citations

Sep 17, 2015·Journal of Pharmacokinetics and Pharmacodynamics·Dhaval K Shah
Dec 18, 2014·MAbs·Leon A G J M van AertsChristian K Schneider
Aug 15, 2013·Drug Discovery Today·Sven KronenbergThomas Singer
Feb 27, 2016·Toxicological Sciences : an Official Journal of the Society of Toxicology·Rama PaiDonna M Dambach
Oct 23, 2012·Toxicologic Pathology·Daniel G Rudmann
Mar 9, 2013·Toxicologic Pathology·Nancy E Everds, Jacqueline M Tarrant
May 31, 2018·Toxicological Sciences : an Official Journal of the Society of Toxicology·Padmakumar NarayananScott P Henry
Jan 24, 2019·Current Protocols in Toxicology·Padma Kumar Narayanan, Nianyu Li
Dec 21, 2016·The Journal of Biological Chemistry·Ling LiuJeanine L Bussiere

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Methods Mentioned

BETA
flow cytometry
PMA
enzyme-linked immunosorbent assay
Assay

Software Mentioned

Pharsight Knowledgebase Server ( PKS
FlowJo
PONEMAH
WinNonlin

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