Back to Search Start Over

EpCAM-Binding DARPins for Targeted Photodynamic Therapy of Ovarian Cancer

Authors :
William P.J. Leenders
Inge Ebisch
Valentina Palacio-CastaƱeda
Jelske M de Jong
Wouter P. R. Verdurmen
Dirk van den Brand
Mark A.J. Gorris
Mark R G Goldman
Leon F.A.G. Massuger
Sanne A. M. van Lith
Roland Brock
Stijn T Couwenbergh
Source :
Cancers, Vol 12, Iss 1762, p 1762 (2020), Cancers, Volume 12, Issue 7, Cancers, 12, Cancers, 12, 7
Publication Year :
2020
Publisher :
MDPI AG, 2020.

Abstract

Ovarian cancer is the most lethal gynecological malignancy due to late detection associated with dissemination throughout the abdominal cavity. Targeted photodynamic therapy (tPDT) aimed at epithelial cell adhesion molecule (EpCAM), overexpressed in over 90% of ovarian cancer metastatic lesions, is a promising novel therapeutic modality. Here, we tested the specificity and activity of conjugates of EpCAM-directed designed ankyrin repeat proteins (DARPins) with the photosensitizer IRDye 700DX in in vitro and in vivo ovarian cancer models. EpCAM-binding DARPins (Ec1: Kd = 68 pM<br />Ac2: Kd = 130 nM) and a control DARPin were site-specifically functionalized with fluorophores or IRDye 700DX. Conjugation of anti-EpCAM DARPins with fluorophores maintained EpCAM-specific binding in cell lines and patient-derived ovarian cancer explants. Penetration of DARPin Ec1 into tumor spheroids was slower than that of Ac2, indicative of a binding site barrier effect for Ec1. DARPin-IRDye 700DX conjugates killed EpCAM-expressing cells in a highly specific and illumination-dependent fashion in 2D and 3D cultures. Furthermore, they effectively homed to EpCAM-expressing subcutaneous OV90 xenografts in mice. In conclusion, the high activity and specificity observed in preclinical ovarian cancer models, combined with a high specificity in patient material, warrant a further investigation of EpCAM-targeted PDT for ovarian cancer.

Details

Language :
English
ISSN :
20726694
Volume :
12
Issue :
1762
Database :
OpenAIRE
Journal :
Cancers
Accession number :
edsair.doi.dedup.....7ec4c5b6c6632202eaaf2741a5d2916f