Targeted vaccination against the bevacizumab binding site on VEGF using 3D-structured peptides elicits efficient antitumor activity

Madelon Q. Wentink, Tilman M. Hackeng, Sebastien P. Tabruyn, Wouter C. Puijk, Klaus Schwamborn, Daniele Altschuh, Rob H. Meloen, Teun Schuurman, Arjan W. Griffioen, Peter Timmerman*

*Corresponding author for this work

    Research output: Contribution to journalArticleAcademicpeer-review

    18 Citations (Scopus)

    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.

    Original languageEnglish
    Pages (from-to)12532-12537
    JournalProceedings of the National Academy of Sciences of the United States of America
    Volume113
    Issue number44
    DOIs
    Publication statusPublished - 2016

    Keywords

    • Angiogenesis
    • Immunization
    • Peptide vaccines
    • Protein mimicry
    • VEGF

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