CD20 and CD37 antibodies synergize to activate complement by Fc-mediated clustering

Haematologica
Simone OostindieRonald P Taylor

Abstract

CD20 monoclonal antibody therapies have significantly improved the outlook for patients with B-cell malignancies. However many patients acquire resistance, demonstrating the need for new and improved drugs. We previously demonstrated that the natural process of antibody hexamer formation on targeted cells allows for optimal induction of complement-dependent cytotoxicity. Complement-dependent cytotoxicity can be potentiated by introducing a single point mutation such as E430G in the IgG Fc domain that enhances intermolecular Fc-Fc interactions between cell-bound IgG molecules, thereby facilitating IgG hexamer formation. Antibodies specific for CD37, a target that is abundantly expressed on healthy and malignant B cells, are generally poor inducers of complement-dependent cytotoxicity. Here we demonstrate that introduction of the hexamerization-enhancing mutation E430G in CD37-specific antibodies facilitates highly potent complement-dependent cytotoxicity in chronic lymphocytic leukemia cells ex vivo. Strikingly, we observed that combinations of hexamerization-enhanced CD20 and CD37 antibodies cooperated in C1q binding and induced superior and synergistic complement-dependent cytotoxicity in patient-derived cancer cells compared ...Continue Reading

Citations

Nov 2, 2019·Nature Reviews. Cancer·Lubka T RoumeninaWolf Herman Fridman
Jul 30, 2020·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Eriberto Noel NataliMaria Scarselli
Mar 7, 2020·Immunology and Cell Biology·Benjamin S Goldberg, Margaret E Ackerman
Sep 10, 2020·Antibodies·Ronald P Taylor, Margaret A Lindorfer
Jan 7, 2021·Trends in Immunology·Liriye Kurtovic, James G Beeson
Nov 1, 2020·Antibodies·Josée Golay, Ronald P Taylor
Dec 17, 2020·HemaSphere·Hilma J van der HorstTuna Mutis
Dec 19, 2020·International Journal of Molecular Sciences·Malgorzata BobrowiczMagdalena Winiarska
Oct 30, 2020·Antibodies·Margot RevelLubka T Roumenina
Dec 17, 2019·Current Opinion in Biotechnology·Christoph Rader
Apr 5, 2020·Journal of Nuclear Medicine : Official Publication, Society of Nuclear Medicine·Marion M MalengeAda H V Repetto-Llamazares
Jun 15, 2021·Frontiers in Public Health·David A SpencerAnn J Hessell
Oct 27, 2021·Seminars in Immunopathology·Richard B Pouw, Daniel Ricklin

❮ Previous
Next ❯

Methods Mentioned

BETA
flow cytometry
FACS
FRET
Confocal microscopy
fluorescence microscopy
fluorescence resonance
confocal
xenograft

Software Mentioned

GraphPad Prism
CompuSyn
Zen
GeneArt

Related Concepts

Related Feeds

B-Cell Leukemia (Keystone)

B-cell leukemia includes various types of lymphoid leukemia that affect B cells. Here is the latest research on B-cell leukemia.