{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,14]],"date-time":"2026-09-14T22:30:04Z","timestamp":1789425004413,"version":"build-2803163510"},"reference-count":53,"publisher":"MDPI AG","issue":"4","license":[{"start":{"date-parts":[[2020,4,22]],"date-time":"2020-04-22T00:00:00Z","timestamp":1587513600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100000272","name":"National Institute for Health Research","doi-asserted-by":"publisher","award":["IS-BRC-1215-20006"],"award-info":[{"award-number":["IS-BRC-1215-20006"]}],"id":[{"id":"10.13039\/501100000272","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100000265","name":"Medical Research Council","doi-asserted-by":"publisher","award":["MR\/L023091\/1"],"award-info":[{"award-number":["MR\/L023091\/1"]}],"id":[{"id":"10.13039\/501100000265","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100009794","name":"Breast Cancer Now","doi-asserted-by":"publisher","award":["147"],"award-info":[{"award-number":["147"]}],"id":[{"id":"10.13039\/100009794","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Walk the Walk","award":["C30122\/A11527"],"award-info":[{"award-number":["C30122\/A11527"]}]},{"DOI":"10.13039\/501100000289","name":"Cancer Research UK","doi-asserted-by":"publisher","award":["C30122\/A15774"],"award-info":[{"award-number":["C30122\/A15774"]}],"id":[{"id":"10.13039\/501100000289","id-type":"DOI","asserted-by":"publisher"}]},{"name":"Wales and Northern Ireland Experimental Cancer Medicine Centre","award":["C10355\/A15587"],"award-info":[{"award-number":["C10355\/A15587"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Cancers"],"abstract":"<jats:p>Despite emerging targeted and immunotherapy treatments, no monoclonal antibodies or antibody-drug conjugates (ADCs) directly targeting tumor cells are currently approved for melanoma therapy. The tumor-associated antigen chondroitin sulphate proteoglycan 4 (CSPG4), a neural crest glycoprotein over-expressed on 70% of melanomas, contributes to proliferative signaling pathways, but despite highly tumor-selective expression it has not yet been targeted using ADCs. We developed a novel ADC comprising an anti-CSPG4 antibody linked to a DNA minor groove-binding agent belonging to the novel pyrridinobenzodiazepine (PDD) class. Unlike conventional DNA-interactive pyrrolobenzodiazepine (PBD) dimer payloads that cross-link DNA, PDD-based payloads are mono-alkylating agents but have similar efficacy and substantially enhanced tolerability profiles compared to PBD-based cross-linkers. We investigated the anti-tumor activity and safety of the anti-CSPG4-(PDD) ADC in vitro and in human melanoma xenografts. Anti-CSPG4-(PDD) inhibited CSPG4-expressing melanoma cell growth and colony formation and triggered apoptosis in vitro at low nanomolar to picomolar concentrations without off-target Fab-mediated or Fc-mediated toxicity. Anti-CSPG4-(PDD) restricted xenograft growth in vivo at 2 mg\/kg doses. One 5 mg\/kg injection triggered tumor regression in the absence of overt toxic effects or of acquired residual tumor cell resistance. This anti-CSPG4-(PDD) can deliver a highly cytotoxic DNA mono-alkylating payload to CSPG4-expressing tumors at doses tolerated in vivo.<\/jats:p>","DOI":"10.3390\/cancers12041029","type":"journal-article","created":{"date-parts":[[2020,4,23]],"date-time":"2020-04-23T10:46:22Z","timestamp":1587638782000},"page":"1029","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":31,"title":["A Novel Antibody-Drug Conjugate (ADC) Delivering a DNA Mono-Alkylating Payload to Chondroitin Sulfate Proteoglycan (CSPG4)-Expressing Melanoma"],"prefix":"10.3390","volume":"12","author":[{"given":"Ricarda M.","family":"Hoffmann","sequence":"first","affiliation":[{"name":"St. John\u2019s Institute of Dermatology, School of Basic &amp; Medical Biosciences, King\u2019s College London, Tower Wing, 9th Floor, Guy\u2019s Hospital, London SE1 9RT, UK"},{"name":"NIHR Biomedical Research Centre at Guy\u2019s and St. Thomas\u2019s Hospitals and King\u2019s College London, King\u2019s College London, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1909-5957","authenticated-orcid":false,"given":"Silvia","family":"Crescioli","sequence":"additional","affiliation":[{"name":"St. John\u2019s Institute of Dermatology, School of Basic &amp; Medical Biosciences, King\u2019s College London, Tower Wing, 9th Floor, Guy\u2019s Hospital, London SE1 9RT, UK"},{"name":"NIHR Biomedical Research Centre at Guy\u2019s and St. Thomas\u2019s Hospitals and King\u2019s College London, King\u2019s College London, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Silvia","family":"Mele","sequence":"additional","affiliation":[{"name":"St. John\u2019s Institute of Dermatology, School of Basic &amp; Medical Biosciences, King\u2019s College London, Tower Wing, 9th Floor, Guy\u2019s Hospital, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eirini","family":"Sachouli","sequence":"additional","affiliation":[{"name":"St. John\u2019s Institute of Dermatology, School of Basic &amp; Medical Biosciences, King\u2019s College London, Tower Wing, 9th Floor, Guy\u2019s Hospital, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2988-2786","authenticated-orcid":false,"given":"Anthony","family":"Cheung","sequence":"additional","affiliation":[{"name":"St. John\u2019s Institute of Dermatology, School of Basic &amp; Medical Biosciences, King\u2019s College London, Tower Wing, 9th Floor, Guy\u2019s Hospital, London SE1 9RT, UK"},{"name":"Breast Cancer Now Research Unit, School of Cancer &amp; Pharmaceutical Sciences, King\u2019s College London, Guy\u2019s Cancer Centre, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Connie K.","family":"Chui","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, King\u2019s College London, London SE1 9NH, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paolo","family":"Andriollo","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, King\u2019s College London, London SE1 9NH, UK"},{"name":"Femtogenix Ltd, Lawes Open Innovation Hub, Rothamsted Research, West Common, Harpenden, Hertfordshire AL5 2JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul J. M.","family":"Jackson","sequence":"additional","affiliation":[{"name":"Femtogenix Ltd, Lawes Open Innovation Hub, Rothamsted Research, West Common, Harpenden, Hertfordshire AL5 2JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Katie E.","family":"Lacy","sequence":"additional","affiliation":[{"name":"St. John\u2019s Institute of Dermatology, School of Basic &amp; Medical Biosciences, King\u2019s College London, Tower Wing, 9th Floor, Guy\u2019s Hospital, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"James F.","family":"Spicer","sequence":"additional","affiliation":[{"name":"School of Cancer &amp; Pharmaceutical Sciences, King\u2019s College London, 3rd Floor, Guy\u2019s Hospital, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8032-7203","authenticated-orcid":false,"given":"David E.","family":"Thurston","sequence":"additional","affiliation":[{"name":"Institute of Pharmaceutical Science, School of Cancer and Pharmaceutical Sciences, King\u2019s College London, London SE1 9NH, UK"},{"name":"Femtogenix Ltd, Lawes Open Innovation Hub, Rothamsted Research, West Common, Harpenden, Hertfordshire AL5 2JQ, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4100-7810","authenticated-orcid":false,"given":"Sophia N.","family":"Karagiannis","sequence":"additional","affiliation":[{"name":"St. John\u2019s Institute of Dermatology, School of Basic &amp; Medical Biosciences, King\u2019s College London, Tower Wing, 9th Floor, Guy\u2019s Hospital, London SE1 9RT, UK"},{"name":"NIHR Biomedical Research Centre at Guy\u2019s and St. Thomas\u2019s Hospitals and King\u2019s College London, King\u2019s College London, London SE1 9RT, UK"},{"name":"Breast Cancer Now Research Unit, School of Cancer &amp; Pharmaceutical Sciences, King\u2019s College London, Guy\u2019s Cancer Centre, London SE1 9RT, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2020,4,22]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"523","DOI":"10.1038\/s41587-019-0073-7","article-title":"Engineering a HER2-specific antibody-drug conjugate to increase lysosomal delivery and therapeutic efficacy","volume":"37","author":"Kang","year":"2019","journal-title":"Nat. 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