Oncotarget

Research Papers:

Denosumab mimics the natural decoy receptor osteoprotegerin by interacting with its major binding site on RANKL

Aneta Schieferdecker, Mareike Voigt, Kristoffer Riecken, Friederike Braig, Thorsten Schinke, Sonja Loges, Carsten Bokemeyer, Boris Fehse and Mascha Binder _

PDF  |  HTML  |  Supplementary Files  |  How to cite  |  Order a Reprint

Oncotarget. 2014; 5:6647-6653. https://doi.org/10.18632/oncotarget.2160

Metrics: PDF 2521 views  |   HTML 2456 views  |   ?  


Abstract

Aneta Schieferdecker1, Mareike Voigt1, Kristoffer Riecken2, Friederike Braig1, Thorsten Schinke3, Sonja Loges1,4, Carsten Bokemeyer1, Boris Fehse2 and Mascha Binder1

1 Department of Oncology and Hematology, BMT with section Pneumology, Hubertus Wald Tumorzentrum / UCCH, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

2 Research Department Cell and Gene Therapy, Department of Stem Cell Transplantation, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

3 Department of Osteology and Biomechanics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

4 Institute for Tumor Biology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany

Correspondence:

Mascha Binder, email:

Keywords: denosumab, RANK, RANKL, OPG, epitope, monoclonal antibody

Received: June 4, 2014 Accepted: July 2, 2014 Published: July 3, 2014

Abstract

Bone homeostasis critically relies on the RANKL-RANK-OPG axis which can be targeted by the fully human monoclonal antibody denosumab in conditions with increased bone resporption such as bone metastases. The binding site and therefore the molecular mechanism by which this antibody inhibits RANKL has not been characterized so far. Here, we used random peptide phage display library screenings to identify the denosumab epitope on RANKL. Alignments of phage derived peptide sequences with RANKL suggested that this antibody recognized a linear epitope between position T233 and Y241. Mutational analysis confirmed the core residues as critical for this interaction. The spatial localization of this epitope on a 3-dimensional model of RANKL showed that it overlapped with the major binding sites of OPG and RANK on RANKL. We conclude that denosumab inhibits RANKL by both functional and molecular mimicry of the natural decoy receptor OPG.


Creative Commons License All site content, except where otherwise noted, is licensed under a Creative Commons Attribution 3.0 License.
PII: 2160