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Open AccessArticle

VHH-Photosensitizer Conjugates for Targeted Photodynamic Therapy of Met-Overexpressing Tumor Cells

1
QVQ Holding BV, Yalelaan 1, 3584 CL Utrecht, The Netherlands
2
Cell Biology Division, Department of Biology, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
3
Crystal & Structural Chemistry, Bijvoet Center for Biomolecular Research, Faculty of Science, Utrecht University, Padualaan 8, 3584 CH Utrecht, The Netherlands
4
Argenx BVBA, Industriepark-Zwijnaarde 7, 9052 Gent, Belgium
5
Pharmaceutics Division, Department of Pharmaceutical Sciences, Faculty of Science, Utrecht University, Universiteitsweg 99, 3584 CG Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
Antibodies 2019, 8(2), 26; https://doi.org/10.3390/antib8020026
Received: 27 February 2019 / Revised: 9 March 2019 / Accepted: 28 March 2019 / Published: 4 April 2019
(This article belongs to the Special Issue Nanobody)
Photodynamic therapy (PDT) is an approach that kills (cancer) cells by the local production of toxic reactive oxygen species upon the local illumination of a photosensitizer (PS). The specificity of PDT has been further enhanced by the development of a new water-soluble PS and by the specific delivery of PS via conjugation to tumor-targeting antibodies. To improve tissue penetration and shorten photosensitivity, we have recently introduced nanobodies, also known as VHH (variable domains from the heavy chain of llama heavy chain antibodies), for targeted PDT of cancer cells overexpressing the epidermal growth factor receptor (EGFR). Overexpression and activation of another cancer-related receptor, the hepatocyte growth factor receptor (HGFR, c-Met or Met) is also involved in the progression and metastasis of a large variety of malignancies. In this study we evaluate whether anti-Met VHHs conjugated to PS can also serve as a biopharmaceutical for targeted PDT. VHHs targeting the SEMA (semaphorin-like) subdomain of Met were provided with a C-terminal tag that allowed both straightforward purification from yeast supernatant and directional conjugation to the PS IRDye700DX using maleimide chemistry. The generated anti-Met VHH-PS showed nanomolar binding affinity and, upon illumination, specifically killed MKN45 cells with nanomolar potency. This study shows that Met can also serve as a membrane target for targeted PDT. View Full-Text
Keywords: targeted photodynamic therapy; hepatocyte growth factor receptor; HGFR; c-Met; Met; nanobodies; VHH; photosensitizer targeted photodynamic therapy; hepatocyte growth factor receptor; HGFR; c-Met; Met; nanobodies; VHH; photosensitizer
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Heukers, R.; Mashayekhi, V.; Ramirez-Escudero, M.; de Haard, H.; Verrips, T.C.; van Bergen en Henegouwen, P.M.; Oliveira, S. VHH-Photosensitizer Conjugates for Targeted Photodynamic Therapy of Met-Overexpressing Tumor Cells. Antibodies 2019, 8, 26.

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