A biparatopic anti‐EGFR nanobody efficiently inhibits solid tumour growth
Open Access
- 25 April 2011
- journal article
- research article
- Published by Wiley in International Journal of Cancer
- Vol. 129 (8), 2013-2024
- https://doi.org/10.1002/ijc.26145
Abstract
The epidermal growth factor receptor (EGFR) has been shown to be a valid cancer target for antibody‐based therapy. At present, several anti‐EGFR monoclonal antibodies have been successfully used, such as cetuximab and matuzumab. X‐ray crystallography data show that these antibodies bind to different epitopes on the ecto‐domain of EGFR, providing a rationale for the combined use of these two antibody specificities. We have previously reported on the successful isolation of antagonistic anti‐EGFR nanobodies. In our study, we aimed to improve the efficacy of these molecules by combining nanobodies with specificities similar to both cetuximab and matuzumab into a single biparatopic molecule. Carefully designed phage nanobody selections resulted in two sets of nanobodies that specifically blocked the binding of either matuzumab or cetuximab to EGFR and that did not compete for each others' binding. A combination of nanobodies from both epitope groups into the biparatopic nanobody CONAN‐1 was shown to block EGFR activation more efficiently than monovalent or bivalent (monospecific) nanobodies. In addition, this biparatopic nanobody potently inhibited EGF‐dependent cell proliferation. Importantly, in an in vivo model of athymic mice bearing A431 xenografts, CONAN‐1 inhibited tumour outgrowth with an almost similar potency as the whole mAb cetuximab, despite the fact that CONAN‐1 is devoid of an Fc portion that could mediate immune effector functions. Compared to therapy using bivalent, monospecific nanobodies, CONAN‐1 was clearly more potent in tumour growth inhibition. These results show that the rational design of biparatopic nanobody‐based anticancer therapeutics may yield potent lead molecules for further development.Keywords
This publication has 49 references indexed in Scilit:
- Ligand-induced EGF Receptor Oligomerization Is Kinase-dependent and Enhances InternalizationOnline Journal of Public Health Informatics, 2010
- Antibodies specifically targeting a locally misfolded region of tumor associated EGFRProceedings of the National Academy of Sciences of the United States of America, 2009
- Interaction of antibodies with ErbB receptor extracellular regionsExperimental Cell Research, 2009
- Matuzumab Binding to EGFR Prevents the Conformational Rearrangement Required for DimerizationCancer Cell, 2008
- Formatted anti–tumor necrosis factor α VHH proteins derived from camelids show superior potency and targeting to inflamed joints in a murine model of collagen‐induced arthritisArthritis & Rheumatism, 2006
- Structural basis for inhibition of the epidermal growth factor receptor by cetuximabCancer Cell, 2005
- Crystal Structure of the Complex of Human Epidermal Growth Factor and Receptor Extracellular DomainsCell, 2002
- Crystal Structure of a Truncated Epidermal Growth Factor Receptor Extracellular Domain Bound to Transforming Growth Factor αCell, 2002
- Efficient tumor targeting by single‐domain antibody fragments of camelsInternational Journal of Cancer, 2002
- Extracellular domains drive homo- but not hetero-dimerization of erbB receptorsThe EMBO Journal, 2000