Blocking EGFR Activation with Anti-EGF Nanobodies via Two Distinct Molecular Recognition Mechanisms

Angewandte Chemie
Salvador GuardiolaErnest Giralt

Abstract

One of the hallmarks of cancer is the overproduction of growth factors such as EGF. Despite the clinical success achieved by EGFR-targeted therapies, their long-term efficacy is compromised by the onset of drug-resistant mutations. To address this issue, a family of camelid-derived single-domain antibodies (Nbs) were generated, obtaining the first direct EGF inhibitors that prevent EGFR phosphorylation and pathway activation through this new mechanism of action. The two best Nbs were subjected to a detailed investigation of their interaction mechanism that revealed important differences in their binding kinetics and equilibrium thermodynamics. These distinct behaviors at the biophysical level translate into an equally efficient inhibition of the cellular EGFR phosphorylation, thus proving the efficacy of these Nbs to turn off the initiation of this key oncogenic pathway in cancer cells.

References

Jun 3, 1993·Nature·C Hamers-CastermanR Hamers
Apr 24, 1999·FEBS Letters·J T JonesM X Sliwkowski
Mar 14, 2000·Vitamins and Hormones·E J Van ZoelenM L Van de Poll
Aug 3, 2007·The Journal of Clinical Investigation·Hongtao ZhangMark I Greene
Apr 17, 2008·Biochemistry·Peter J Tummino, Robert A Copeland
Jul 10, 2010·Proceedings of the National Academy of Sciences of the United States of America·Moshit LindzenYosef Yarden
Oct 30, 2010·Biochemical and Biophysical Research Communications·Hsiao-Wen HuangC Yu
Mar 19, 2013·Annual Review of Biochemistry·Serge Muyldermans
May 3, 2013·Frontiers in Pharmacology·Rolando PerezErnesto Moreno
Nov 10, 2013·Nature Medicine·Curtis R Chong, Pasi A Jänne
Nov 26, 2013·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Robert Roskoski
Jan 27, 2015·Annual Review of Biochemistry·Erika KovacsJohn Kuriyan
Dec 18, 2015·Chembiochem : a European Journal of Chemical Biology·Salvador GuardiolaErnest Giralt
Mar 2, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Pedro C RodriguezElia Neninger
Nov 16, 2016·ESMO Open·Teresa TroianiFortunato Ciardiello
Nov 7, 2017·Chembiochem : a European Journal of Chemical Biology·Salvador GuardiolaErnest Giralt
Dec 26, 2017·Frontiers in Immunology·Roghaye ArezumandSerge Muyldermans

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Citations

Apr 23, 2019·Journal of Peptide Science : an Official Publication of the European Peptide Society·Cristina FusterMeritxell Teixidó
Jul 4, 2019·Chembiochem : a European Journal of Chemical Biology·Cristina Díaz-PerlasErnest Giralt
Jun 8, 2019·SLAS Discovery·James Woods
Jun 4, 2019·Chembiochem : a European Journal of Chemical Biology·Monica VareseErnest Giralt
Aug 15, 2020·Frontiers in Oncology·Emily Y Yang, Khalid Shah
Nov 11, 2019·Trends in Pharmacological Sciences·Salvador GuardiolaErnest Giralt

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