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The alternatively spliced extra domains A and B (EDA and EDB) of fibronectin offer appealing targets for ADC development, because the antigen is strongly expressed in many solid human tumors and nearly undetectable in normal tissues except for the female reproductive system. In this study, we describe the properties of a set of ADCs based on an antibody targeting the alternatively spliced EDA of fibronectin coupled to one of a set of potent cytotoxic drugs (DM1 or one of two duocarmycin derivatives). The DM1 conjugate SIP(F8)-SS-DM1 mediated potent antitumor activity in mice bearing DM1-sensitive F9 tumors but not DM1-insensitive CT26 tumors. Quantitative biodistribution studies and microscopic analyses confirmed a preferential accumulation of SIP(F8)-SS-DM1 in the subendothelial extracellular matrix of tumors, similar to the pattern observed for unmodified antibody. Notably, we found that treatments were well tolerated at efficacious doses that were fully curative and compatible with pharmaceutical development. Our findings offer a preclinical proof-of-concept for curative ADC targeting the tumor microenvironment that do not rely upon antigen internalization. Cancer Res; 74(9); 2569\u201378. \u00a92014 AACR.<\/jats:p>","DOI":"10.1158\/0008-5472.can-13-2990","type":"journal-article","created":{"date-parts":[[2014,2,12]],"date-time":"2014-02-12T00:54:47Z","timestamp":1392166487000},"page":"2569-2578","update-policy":"https:\/\/doi.org\/10.1158\/crossmark_policy","source":"Crossref","is-referenced-by-count":119,"title":["Curative Properties of Noninternalizing Antibody\u2013Drug Conjugates Based on Maytansinoids"],"prefix":"10.1158","volume":"74","author":[{"given":"Elena","family":"Perrino","sequence":"first","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Z\u00fcrich; 2Philochem AG, Otelfingen, Zurich, Switzerland; 3Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; and 4Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa, Portugal"}]},{"given":"Martina","family":"Steiner","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Z\u00fcrich; 2Philochem AG, Otelfingen, Zurich, Switzerland; 3Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; and 4Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa, Portugal"}]},{"given":"Nikolaus","family":"Krall","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Z\u00fcrich; 2Philochem AG, Otelfingen, Zurich, Switzerland; 3Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; and 4Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa, Portugal"}]},{"given":"Gon\u00e7alo J.L.","family":"Bernardes","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Z\u00fcrich; 2Philochem AG, Otelfingen, Zurich, Switzerland; 3Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; and 4Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa, Portugal"},{"name":"Authors' Affiliations:\u20081Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Z\u00fcrich; 2Philochem AG, Otelfingen, Zurich, Switzerland; 3Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; and 4Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa, Portugal"},{"name":"Authors' Affiliations:\u20081Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Z\u00fcrich; 2Philochem AG, Otelfingen, Zurich, Switzerland; 3Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; and 4Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa, Portugal"}]},{"given":"Francesca","family":"Pretto","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Z\u00fcrich; 2Philochem AG, Otelfingen, Zurich, Switzerland; 3Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; and 4Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa, Portugal"}]},{"given":"Giulio","family":"Casi","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Z\u00fcrich; 2Philochem AG, Otelfingen, Zurich, Switzerland; 3Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; and 4Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. Prof. Egas Moniz, Lisboa, Portugal"}]},{"given":"Dario","family":"Neri","sequence":"additional","affiliation":[{"name":"Authors' Affiliations:\u20081Department of Chemistry and Applied Biosciences, Institute of Pharmaceutical Sciences, ETH Z\u00fcrich; 2Philochem AG, Otelfingen, Zurich, Switzerland; 3Department of Chemistry, University of Cambridge, Cambridge, United Kingdom; and 4Instituto de Medicina Molecular, Faculdade de Medicina da Universidade de Lisboa, Av. 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