4.7 Article

Antibody variable sequences have a pronounced effect on cellular transport and plasma half-life

期刊

ISCIENCE
卷 25, 期 2, 页码 -

出版社

CELL PRESS
DOI: 10.1016/j.isci.2022.103746

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资金

  1. Research Council of Norway through its Center of Excellence funding scheme [179573]
  2. Research Council of Norway [230526, 274993, 287927]
  3. South-Eastern Norway Regional Health Authority [2018052]
  4. Roche postdoctoral fellowship program

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The variable region sequences of IgG antibodies significantly impact their cellular uptake, recycling, and degradation, as well as their binding to FcRn. Differences in charge patch also modulate binding and transport properties. Fc-engineering may improve FcRn binding and overcome unfavorable charge patches for longer plasma half-life.
Monoclonal IgG antibodies are the fastest growing class of biologics, but large differences exist in their plasma half-life in humans. Thus, to design IgG antibodies with favorable pharmacokinetics, it is crucial to identify the determinants of such differences. Here, we demonstrate that the variable region sequences of IgG antibodies greatly affect cellular uptake and subsequent recycling and rescue from intracellular degradation by endothelial cells. When the variable sequences are masked by the cognate antigen, it influences both their transport behavior and binding to the neonatal Fc receptor (FcRn), a key regulator of IgG plasma halflife. Furthermore, we show how charge patch differences in the variable domains modulate both binding and transport properties and that a short plasma half-life, due to unfavorable charge patches, may partly be overcome by Fc-engineering for improved FcRn binding.

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