{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,10]],"date-time":"2026-06-10T16:01:11Z","timestamp":1781107271521,"version":"3.54.1"},"reference-count":56,"publisher":"National Academy of Sciences","issue":"24","license":[{"start":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T00:00:00Z","timestamp":1654646400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"name":"Janine Goebel Fund","award":["80033760"],"award-info":[{"award-number":["80033760"]}]},{"name":"The Fetting Fund for Breast Cancer Prevention","award":["80035393"],"award-info":[{"award-number":["80035393"]}]}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2022,6,14]]},"abstract":"<jats:p>\n                    The human transferrin receptor (TFR) is overexpressed in most breast cancers, including preneoplastic ductal carcinoma in situ (DCIS). HB21(Fv)-PE40 is a single-chain immunotoxin (IT) engineered by fusing the variable region of a monoclonal antibody (HB21) against a TFR with a 40 kDa fragment of\n                    <jats:italic>Pseudomonas<\/jats:italic>\n                    exotoxin (PE). In humans, the administration of other TFR-targeted immunotoxins intrathecally led to inflammation and vascular leakage. We proposed that for treatment of DCIS, intraductal (i.duc) injection of HB21(Fv)-PE40 could avoid systemic toxicity while retaining its potent antitumor effects on visible and occult tumors in the entire ductal tree. Pharmacokinetic studies in mice showed that, in contrast to intravenous injection, IT was undetectable by enzyme-linked immunosorbent assay in blood following i.duc injection of up to 3.0 \u03bcg HB21(Fv)-PE40. We demonstrated the antitumor efficacy of HB21(Fv)-PE40 in two mammary-in-duct (MIND) models, MCF7 and SUM225, grown in NOD\/SCID\/gamma mice. Tumors were undetectable by In Vivo Imaging System (IVIS) imaging in intraductally treated mice within 1 wk of initiation of the regimen (IT once weekly\/3 wk, 1.5 \u03bcg\/teat). MCF7 tumor\u2013bearing mice remained tumor free for up to 60 d of observation with i.duc IT, whereas the HB21 antibody alone or intraperitoneal IT treatment had minimal\/no antitumor effects. These and similar findings in the SUM225 MIND model were substantiated by analysis of mammary gland whole mounts, histology, and immunohistochemistry for the proteins Ki67, CD31, CD71 (TFR), and Ku80. This study provides a strong preclinical foundation for conducting feasibility and safety trials in patients with stage 0 breast cancer.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2200200119","type":"journal-article","created":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T13:48:49Z","timestamp":1654696129000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":17,"title":["Intraductal administration of transferrin receptor-targeted immunotoxin clears ductal carcinoma in situ in mouse models of breast cancer\u2014a preclinical study"],"prefix":"10.1073","volume":"119","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-6973-2427","authenticated-orcid":false,"given":"Guannan","family":"Wang","sequence":"first","affiliation":[{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287"},{"name":"Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC 20007"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alok","family":"Kumar","sequence":"additional","affiliation":[{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7875-713X","authenticated-orcid":false,"given":"Wanjun","family":"Ding","sequence":"additional","affiliation":[{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287"},{"name":"Department of Oncology, Renmin Hospital of Wuhan University, Wuhan, 430060, China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6623-493X","authenticated-orcid":false,"given":"Preethi","family":"Korangath","sequence":"additional","affiliation":[{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tapan","family":"Bera","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Junxia","family":"Wei","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Priya","family":"Pai","sequence":"additional","affiliation":[{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen","family":"Gabrielson","sequence":"additional","affiliation":[{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287"},{"name":"Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, MD 21205"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9223-0270","authenticated-orcid":false,"given":"Ira","family":"Pastan","sequence":"additional","affiliation":[{"name":"Center for Cancer Research, National Cancer Institute, Bethesda, MD 20892"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5656-6703","authenticated-orcid":false,"given":"Saraswati","family":"Sukumar","sequence":"additional","affiliation":[{"name":"Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2022,6,8]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc2394"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1038\/ni.3601"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ijmm.2008.08.003"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom10081140"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2019.02340"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc1891"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.3389\/fmicb.2015.00963"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41375-018-0210-1"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.3390\/jcm10132800"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1080\/10428194.2021.1929959"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00710908"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1097\/PAI.0b013e318209716e"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-11-1870"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms18020410"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1097\/00006123-199711000-00005"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1215\/15228517-2008-012"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1096-9896(199902)187:3<272::AID-PATH265>3.0.CO;2-2"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.1136\/bmjopen-2018-026797"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-18-0976"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-020-00665-x"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-05-4329"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3002368"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.3007048"},{"key":"e_1_3_4_24_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8949"},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1186\/s13058-019-1217-x"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.1093\/carcin\/bgz084"},{"key":"e_1_3_4_27_2","first-page":"441","article-title":"Intraductal drug delivery to the breast: Effect of particle size and formulation on breast duct and lymph node retention","volume":"17","author":"Joseph M. K.","year":"2020","unstructured":"M. K. Joseph , Intraductal drug delivery to the breast: Effect of particle size and formulation on breast duct and lymph node retention. Mol. Pharm. 17, 441\u2013452 (2020).","journal-title":"Mol. Pharm."},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.1007\/s13346-021-00903-y"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.ccell.2016.02.002"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pone.0198143"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.21769\/BioProtoc.1744"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1634\/theoncologist.2014-0358"},{"key":"e_1_3_4_33_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom10070979"},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.86.21.8545"},{"key":"e_1_3_4_35_2","first-page":"643","article-title":"Site-specific expression of transferrin receptor by human colon cancer cells directly correlates with eradication by antitransferrin recombinant immunotoxin","volume":"17","author":"Shinohara H.","year":"2000","unstructured":"H. Shinohara , Site-specific expression of transferrin receptor by human colon cancer cells directly correlates with eradication by antitransferrin recombinant immunotoxin. Int. J. Oncol. 17, 643\u2013651 (2000).","journal-title":"Int. J. Oncol."},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.3390\/biom10091331"},{"key":"e_1_3_4_37_2","first-page":"646","article-title":"Intraductal therapy for the prevention of breast cancer","volume":"11","author":"Jacobs L.","year":"2010","unstructured":"L. Jacobs, S. Sukumar, V. Stearns, Intraductal therapy for the prevention of breast cancer. Curr. Opin. Investig. Drugs 11, 646\u2013652 (2010).","journal-title":"Curr. Opin. Investig. Drugs"},{"key":"e_1_3_4_38_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.clbc.2013.02.002"},{"key":"e_1_3_4_39_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10911-020-09453-4"},{"key":"e_1_3_4_40_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1721780115"},{"key":"e_1_3_4_41_2","first-page":"340","article-title":"Immunotoxins made with a recombinant form of Pseudomonas exotoxin A that do not require proteolysis for activity","volume":"53","author":"Theuer C. P.","year":"1993","unstructured":"C. P. Theuer, R. J. Kreitman, D. J. FitzGerald, I. Pastan, Immunotoxins made with a recombinant form of Pseudomonas exotoxin A that do not require proteolysis for activity. Cancer Res. 53, 340\u2013347 (1993).","journal-title":"Cancer Res."},{"key":"e_1_3_4_42_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41379-021-00745-6"},{"key":"e_1_3_4_43_2","doi-asserted-by":"publisher","DOI":"10.1387\/ijdb.150025dr"},{"key":"e_1_3_4_44_2","doi-asserted-by":"publisher","DOI":"10.1038\/nmeth.2019"},{"key":"e_1_3_4_45_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41523-020-0167-x"},{"key":"e_1_3_4_46_2","first-page":"6667","article-title":"Active signaling by HER-2\/neu in a subpopulation of HER-2\/neu-overexpressing ductal carcinoma in situ: Clinicopathological correlates","volume":"62","author":"DiGiovanna M. P.","year":"2002","unstructured":"M. P. DiGiovanna , Active signaling by HER-2\/neu in a subpopulation of HER-2\/neu-overexpressing ductal carcinoma in situ: Clinicopathological correlates. Cancer Res. 62, 6667\u20136673 (2002).","journal-title":"Cancer Res."},{"key":"e_1_3_4_47_2","doi-asserted-by":"publisher","DOI":"10.1158\/1055-9965.EPI-18-1262"},{"key":"e_1_3_4_48_2","doi-asserted-by":"publisher","DOI":"10.1146\/annurev-med-050715-104920"},{"key":"e_1_3_4_49_2","doi-asserted-by":"publisher","DOI":"10.1111\/his.13098"},{"key":"e_1_3_4_50_2","first-page":"916","article-title":"Transferrin receptor 1 in cancer: A new sight for cancer therapy","volume":"8","author":"Shen Y.","year":"2018","unstructured":"Y. Shen , Transferrin receptor 1 in cancer: A new sight for cancer therapy. Am. J. Cancer Res. 8, 916\u2013931 (2018).","journal-title":"Am. J. Cancer Res."},{"key":"e_1_3_4_51_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-13-1224"},{"key":"e_1_3_4_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/path.1556"},{"key":"e_1_3_4_53_2","doi-asserted-by":"publisher","DOI":"10.1007\/s12609-010-0015-3"},{"key":"e_1_3_4_54_2","doi-asserted-by":"publisher","DOI":"10.1158\/1940-6207.CAPR-12-0228"},{"key":"e_1_3_4_55_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10549-021-06488-x"},{"key":"e_1_3_4_56_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10147-021-02036-1"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2200200119","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,6,8]],"date-time":"2022-06-08T13:50:13Z","timestamp":1654696213000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.2200200119"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2022,6,8]]},"references-count":56,"journal-issue":{"issue":"24","published-print":{"date-parts":[[2022,6,14]]}},"alternative-id":["10.1073\/pnas.2200200119"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2200200119","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2022,6,8]]},"assertion":[{"value":"2022-01-05","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-04-29","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2022-06-08","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2200200119"}}