Enhancing CDC and ADCC of CD19 Antibodies by Combining Fc Protein-Engineering with Fc Glyco-Engineering

Antibodies
Sophia RoßkopfChristian Kellner

Abstract

Native cluster of differentiation (CD) 19 targeting antibodies are poorly effective in triggering antibody-dependent cell-mediated cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which are crucial effector functions of therapeutic antibodies in cancer immunotherapy. Both functions can be enhanced by engineering the antibody's Fc region by altering the amino acid sequence (Fc protein-engineering) or the Fc-linked glycan (Fc glyco-engineering). We hypothesized that combining Fc glyco-engineering with Fc protein-engineering will rescue ADCC and CDC in CD19 antibodies. Four versions of a CD19 antibody based on tafasitamab's V-regions were generated: a native IgG1, an Fc protein-engineered version with amino acid exchanges S267E/H268F/S324T/G236A/I332E (EFTAE modification) to enhance CDC, and afucosylated, Fc glyco-engineered versions of both to promote ADCC. Irrespective of fucosylation, antibodies carrying the EFTAE modification had enhanced C1q binding and were superior in inducing CDC. In contrast, afucosylated versions exerted an enhanced affinity to Fcγ receptor IIIA and had increased ADCC activity. Of note, the double-engineered antibody harboring the EFTAE modification and lacking fucose triggered both CDC a...Continue Reading

References

Sep 1, 1986·Archives of Biochemistry and Biophysics·J RipkaP Stanley
Mar 31, 2000·Nature Medicine·R A ClynesJ V Ravetch
Feb 13, 2001·The Journal of Immunology : Official Journal of the American Association of Immunologists·E E IdusogieM G Mulkerrin
Apr 12, 2001·The Journal of Biological Chemistry·S RadaevP D Sun
Apr 17, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Rajat BannerjiJohn C Byrd
Jul 23, 2003·The Journal of Immunology : Official Journal of the American Association of Immunologists·Nicola Di GaetanoJosée Golay
Sep 17, 2003·Journal of Clinical Oncology : Official Journal of the American Society of Clinical Oncology·Wen-Kai Weng, Ronald Levy
Feb 24, 2004·The Journal of Immunology : Official Journal of the American Association of Immunologists·Adam D KennedyRonald P Taylor
Jan 7, 2005·The Journal of Immunology : Official Journal of the American Association of Immunologists·Qian GongAndrew C Chan
Oct 12, 2005·Proceedings of the National Academy of Sciences of the United States of America·Norihito YazawaThomas F Tedder
Jul 5, 2006·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Tom van MeertenSaskia B Ebeling
Nov 23, 2006·Methods in Enzymology·Santosh Kumar Patnaik, Pamela Stanley
Feb 13, 2007·Current Opinion in Immunology·Falk Nimmerjahn, Jeffrey V Ravetch
Apr 10, 2009·International Journal of Cancer. Journal International Du Cancer·Atsushi InagakiRyuzo Ueda
Mar 20, 2012·Molecular Immunology·Sebastian Schneider, Martin Zacharias
Mar 15, 2014·Science·Christoph A DiebolderPaul W H I Parren
Oct 27, 2015·Immunological Reviews·Lekh N DahalMark S Cragg
Dec 20, 2015·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Guillaume CartronHolbrook E Kohrt
Mar 2, 2017·The New England Journal of Medicine·Hagop KantarjianMax S Topp
Apr 14, 2017·The Journal of Immunology : Official Journal of the American Association of Immunologists·Kirstie L S ClearyMark S Cragg
Oct 27, 2017·Transfusion Medicine and Hemotherapy : Offizielles Organ Der Deutschen Gesellschaft Fur̈ Transfusionsmedizin Und Immunham̈atologie·Tim WirtChristian Kellner
Oct 27, 2017·Transfusion Medicine and Hemotherapy : Offizielles Organ Der Deutschen Gesellschaft Fur̈ Transfusionsmedizin Und Immunham̈atologie·Christian KellnerMatthias Peipp
Dec 2, 2017·Nature Reviews. Drug Discovery·Paul J Carter, Greg A Lazar
Feb 23, 2019·Haematologica·Simone C OostindieRonald P Taylor

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Methods Mentioned

BETA
xenograft
glycosylation
FCS
Electrophoresis
Size Exclusion Chromatography
flow cytometry
Assay
density gradient centrifugation
transgenic

Software Mentioned

GraphPad Prism
GraphPad

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