EpCAM-Binding DARPins for Targeted Photodynamic Therapy of Ovarian Cancer
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...
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| Veröffentlicht in: | Cancers 2020-07, Vol.12 (7), p.1762 |
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| creator | van den Brand, Dirk van Lith, Sanne A. M. de Jong, Jelske M. Gorris, Mark A. J. Palacio-Castañeda, Valentina Couwenbergh, Stijn T. Goldman, Mark R. G. Ebisch, Inge Massuger, Leon F. Leenders, William P. J. Brock, Roland Verdurmen, Wouter P. R. |
| description | 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; 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. |
| doi_str_mv | 10.3390/cancers12071762 |
| format | Article |
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M. ; de Jong, Jelske M. ; Gorris, Mark A. J. ; Palacio-Castañeda, Valentina ; Couwenbergh, Stijn T. ; Goldman, Mark R. G. ; Ebisch, Inge ; Massuger, Leon F. ; Leenders, William P. J. ; Brock, Roland ; Verdurmen, Wouter P. R.</creator><creatorcontrib>van den Brand, Dirk ; van Lith, Sanne A. M. ; de Jong, Jelske M. ; Gorris, Mark A. J. ; Palacio-Castañeda, Valentina ; Couwenbergh, Stijn T. ; Goldman, Mark R. G. ; Ebisch, Inge ; Massuger, Leon F. ; Leenders, William P. J. ; Brock, Roland ; Verdurmen, Wouter P. R.</creatorcontrib><description>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; 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.</description><identifier>ISSN: 2072-6694</identifier><identifier>EISSN: 2072-6694</identifier><identifier>DOI: 10.3390/cancers12071762</identifier><identifier>PMID: 32630661</identifier><language>eng</language><publisher>Basel: MDPI AG</publisher><subject>Ankyrins ; Apoptosis ; Cancer therapies ; Cell adhesion & migration ; Cell adhesion molecules ; Cell culture ; Chemotherapy ; Epithelial cells ; Explants ; Flow cytometry ; Fluorophores ; Light ; Malignancy ; Metastases ; Microscopy ; Ovarian cancer ; Photodynamic therapy ; Spheroids ; Tumor cell lines ; Tumors ; Xenografts</subject><ispartof>Cancers, 2020-07, Vol.12 (7), p.1762</ispartof><rights>2020. This work is licensed under http://creativecommons.org/licenses/by/3.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.</rights><rights>2020 by the authors. 2020</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c398t-db2022416648cd1803e9de4fdf0a0b1b0af20a54e51d23294436d72e3880d7f83</citedby><cites>FETCH-LOGICAL-c398t-db2022416648cd1803e9de4fdf0a0b1b0af20a54e51d23294436d72e3880d7f83</cites><orcidid>0000-0001-8584-2546 ; 0000-0002-2463-277X ; 0000-0003-3621-226X ; 0000-0003-0066-220X ; 0000-0001-9314-4000 ; 0000-0003-0678-1023</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktopdf>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409335/pdf/$$EPDF$$P50$$Gpubmedcentral$$Hfree_for_read</linktopdf><linktohtml>$$Uhttps://www.ncbi.nlm.nih.gov/pmc/articles/PMC7409335/$$EHTML$$P50$$Gpubmedcentral$$Hfree_for_read</linktohtml><link.rule.ids>230,314,727,780,784,885,27924,27925,53791,53793</link.rule.ids></links><search><creatorcontrib>van den Brand, Dirk</creatorcontrib><creatorcontrib>van Lith, Sanne A. M.</creatorcontrib><creatorcontrib>de Jong, Jelske M.</creatorcontrib><creatorcontrib>Gorris, Mark A. J.</creatorcontrib><creatorcontrib>Palacio-Castañeda, Valentina</creatorcontrib><creatorcontrib>Couwenbergh, Stijn T.</creatorcontrib><creatorcontrib>Goldman, Mark R. G.</creatorcontrib><creatorcontrib>Ebisch, Inge</creatorcontrib><creatorcontrib>Massuger, Leon F.</creatorcontrib><creatorcontrib>Leenders, William P. J.</creatorcontrib><creatorcontrib>Brock, Roland</creatorcontrib><creatorcontrib>Verdurmen, Wouter P. R.</creatorcontrib><title>EpCAM-Binding DARPins for Targeted Photodynamic Therapy of Ovarian Cancer</title><title>Cancers</title><description>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; 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.</description><subject>Ankyrins</subject><subject>Apoptosis</subject><subject>Cancer therapies</subject><subject>Cell adhesion & migration</subject><subject>Cell adhesion molecules</subject><subject>Cell culture</subject><subject>Chemotherapy</subject><subject>Epithelial cells</subject><subject>Explants</subject><subject>Flow cytometry</subject><subject>Fluorophores</subject><subject>Light</subject><subject>Malignancy</subject><subject>Metastases</subject><subject>Microscopy</subject><subject>Ovarian cancer</subject><subject>Photodynamic therapy</subject><subject>Spheroids</subject><subject>Tumor cell lines</subject><subject>Tumors</subject><subject>Xenografts</subject><issn>2072-6694</issn><issn>2072-6694</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2020</creationdate><recordtype>article</recordtype><sourceid>8G5</sourceid><sourceid>ABUWG</sourceid><sourceid>AFKRA</sourceid><sourceid>AZQEC</sourceid><sourceid>BENPR</sourceid><sourceid>CCPQU</sourceid><sourceid>DWQXO</sourceid><sourceid>GNUQQ</sourceid><sourceid>GUQSH</sourceid><sourceid>M2O</sourceid><recordid>eNpdkc1PAjEQxRujEYKcvW7ixctKv-juXkxwRSXBQAyem9J2oQTatV1I-O8tQowyl5lkfnl5Mw-AWwQfCClgTwortQ8IwwxlDF-AdpxwylhBL__MLdANYQVjERK57Bq0CGYEMobaYDSsy8F7-mSsMnaRPA8-psaGpHI-mQm_0I1WyXTpGqf2VmyMTGZL7UW9T1yVTHbCG2GT8sfHDbiqxDro7ql3wOfLcFa-pePJ66gcjFNJirxJ1RxDjClijOZSoRwSXShNK1VBAedoDkWFoehT3UcKE1xQSpjKsCZ5DlVW5aQDHo-69Xa-0Upq23ix5rU3G-H33AnD_2-sWfKF2_GMwoKQfhS4Pwl497XVoeEbE6Rer4XVbhs4phghlMW3RvTuDF25rbfxvAMF8yyCRaR6R0p6F4LX1a8ZBPkhKX6WFPkG446EvQ</recordid><startdate>20200702</startdate><enddate>20200702</enddate><creator>van den Brand, Dirk</creator><creator>van Lith, Sanne A. 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M.</au><au>de Jong, Jelske M.</au><au>Gorris, Mark A. J.</au><au>Palacio-Castañeda, Valentina</au><au>Couwenbergh, Stijn T.</au><au>Goldman, Mark R. G.</au><au>Ebisch, Inge</au><au>Massuger, Leon F.</au><au>Leenders, William P. J.</au><au>Brock, Roland</au><au>Verdurmen, Wouter P. R.</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>EpCAM-Binding DARPins for Targeted Photodynamic Therapy of Ovarian Cancer</atitle><jtitle>Cancers</jtitle><date>2020-07-02</date><risdate>2020</risdate><volume>12</volume><issue>7</issue><spage>1762</spage><pages>1762-</pages><issn>2072-6694</issn><eissn>2072-6694</eissn><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; 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. 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| source | PubMed Central Open Access; MDPI - Multidisciplinary Digital Publishing Institute; EZB-FREE-00999 freely available EZB journals; PubMed Central |
| subjects | Ankyrins Apoptosis Cancer therapies Cell adhesion & migration Cell adhesion molecules Cell culture Chemotherapy Epithelial cells Explants Flow cytometry Fluorophores Light Malignancy Metastases Microscopy Ovarian cancer Photodynamic therapy Spheroids Tumor cell lines Tumors Xenografts |
| title | EpCAM-Binding DARPins for Targeted Photodynamic Therapy of Ovarian Cancer |
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