Staff Publications

Staff Publications

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    'Staff publications' is the digital repository of Wageningen University & Research

    'Staff publications' contains references to publications authored by Wageningen University staff from 1976 onward.

    Publications authored by the staff of the Research Institutes are available from 1995 onwards.

    Full text documents are added when available. The database is updated daily and currently holds about 240,000 items, of which 72,000 in open access.

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Record number 509503
Title Targeted vaccination against the bevacizumab binding site on VEGF using 3D-structured peptides elicits efficient antitumor activity
Author(s) Wentink, Madelon Q.; Hackeng, Tilman M.; Tabruyn, Sebastien P.; Puijk, Wouter C.; Schwamborn, Klaus; Altschuh, Daniele; Meloen, Rob H.; Schuurman, Teun; Griffioen, Arjan W.; Timmerman, Peter
Source Proceedings of the National Academy of Sciences of the United States of America 113 (2016)44. - ISSN 0027-8424 - p. 12532 - 12537.
DOI http://dx.doi.org/10.1073/pnas.1610258113
Department(s) ASG DetacheringenDetacheringen
Publication type Refereed Article in a scientific journal
Publication year 2016
Keyword(s) Angiogenesis - Immunization - Peptide vaccines - Protein mimicry - VEGF
Abstract

Therapeutic targeting of the VEGF signaling axis by the VEGFneutralizing monoclonal antibody bevacizumab has clearly demonstrated clinical benefit in cancer patients. To improve this strategy using a polyclonal approach, we developed a vaccine targeting VEGF using 3D-structured peptides that mimic the bevacizumab binding site. An in-depth study on peptide optimization showed that the antigen's 3D structure is essential to achieve neutralizing antibody responses. Peptide 1 adopts a clear secondary, native-like structure, including the typical cysteine-knot fold, as evidenced by CD spectroscopy. Binding and competition studies with bevacizumab in ELISA and surface plasmon resonance analysis revealed that peptide 1 represents the complete bevacizumab binding site, including the hairpin loop (β5-turn-β6) and the structure-supporting β2-α2-β3 loop. Vaccination with peptide 1 elicited high titers of cross-reactive antibodies to VEGF, with potent neutralizing activity. Moreover, vaccination-induced antisera displayed strong angiostatic and tumor-growth-inhibiting properties in a preclinical mouse model for colorectal carcinoma, whereas antibodies raised with peptides exclusively encompassing the β5-turn-β6 loop (peptides 15 and 20) did not. Immunization with peptide 1 or 7 (murine analog of 1) in combinationwith the potent adjuvant raffinose fatty acid sulfate ester (RFASE) showed significant inhibition of tumor growth in the B16F10 murine melanoma model. Based on these data, we conclude that this vaccination technology,which is currently being investigated in a phase I clinical trial (NCT02237638), can potentially outperform currently applied anti-VEGF therapeutics.

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