Therapeutic IgG4 antibodies engage in Fab-arm exchange with endogenous human IgG4 in vivo

被引：223

作者：

Labrijn, Aran F. ^{[1
]}

Buijsse, Antonio Ortiz ^{[1
]}

van den Bremer, Ewald T. J. ^{[1
]}

Verwilligen, Annemiek Y. W. ^{[1
]}

Bleeker, Wim K. ^{[1
]}

Thorpe, Susan J. ^{[2
]}

Killestein, Joep ^{[3
]}

Polman, Chris H. ^{[3
]}

Aalberse, Rob C. ^{[4
]}

Schuurman, Janine ^{[1
]}

van de Winkel, Jan G. J. ^{[1
,5
]}

Parren, Paul W. H. I. ^{[1
]}

机构：

[1] Genmab, Utrecht, Netherlands

[2] Natl Inst Biol Stand & Controls, Potters Bar, Herts, England

[3] VU Med Ctr, Dept Neurol, Amsterdam, Netherlands

[4] Sanquin Res AMC Landsteiner Lab, Dept Immunopathol, Amsterdam, Netherlands

[5] Univ Med Ctr, Immunotherapy Lab, Dept Immunol, Utrecht, Netherlands

来源：

NATURE BIOTECHNOLOGY | 2009年 / 27卷 / 08期

关键词：

PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY; PLACEBO-CONTROLLED TRIAL; ACUTE MYELOID-LEUKEMIA; MONOCLONAL-ANTIBODY; MULTIPLE-SCLEROSIS; CYTOKINE STORM; HUMAN CD4; T-CELLS; PHASE-I; NATALIZUMAB;

D O I：

10.1038/nbt.1553

中图分类号：

Q81 [生物工程学（生物技术）]; Q93 [微生物学];

学科分类号：

071005 ; 0836 ; 090102 ; 100705 ;

摘要：

Two humanized IgG4 antibodies, natalizumab and gemtuzumab, are approved for human use, and several others, like TGN1412, are or have been in clinical development. Although IgG4 antibodies can dynamically exchange half-molecules(1), Fab-arm exchange with therapeutic antibodies has not been demonstrated in humans. Here, we show that natalizumab exchanges Fab arms with endogenous human IgG4 in natalizumab-treated individuals. Gemtuzumab, in contrast, contains an IgG4 core-hinge mutation that blocks Fab-arm exchange to undetectable levels both in vitro and in a mouse model. The ability of IgG4 therapeutics to recombine with endogenous IgG4 may affect their pharmacokinetics and pharmacodynamics. Although pharmacokinetic modeling lessens concerns about undesired cross-linking under normal conditions, unpredictability remains and mutations that completely prevent Fab-arm exchange in vivo should be considered when designing therapeutic IgG4 antibodies.

引用

页码：767 / U122

页数：7

共 30 条

[1] A SINGLE AMINO-ACID SUBSTITUTION ABOLISHES THE HETEROGENEITY OF CHIMERIC MOUSE/HUMAN (IGG4) ANTIBODY [J].