{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,27]],"date-time":"2026-10-27T02:34:00Z","timestamp":1793068440352,"version":"4.5.0"},"reference-count":36,"publisher":"National Academy of Sciences","issue":"6","license":[{"start":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T00:00:00Z","timestamp":1769990400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,2,10]]},"abstract":"<jats:p>\n                    Delta-like ligand 3 (DLL3) is a tumor-selective cell surface protein upregulated in high-grade neuroendocrine tumors, including small-cell lung cancer (SCLC) and neuroendocrine prostate cancer (NEPC). Here, we report on the development of anti-DLL3 radioimmunoconjugates for use as either a diagnostic imaging tracer based on the positron-emitter zirconium-89 (\n                    <jats:sup>89<\/jats:sup>\n                    Zr) or a therapeutic agent utilizing the beta-emitter lutetium-177 (\n                    <jats:sup>177<\/jats:sup>\n                    Lu). To begin, we generated a panel of human monoclonal antibodies targeting human DLL3 by immunizing transgenic mice engineered with a human immunoglobulin repertoire. The panel was extensively screened to identify high-affinity internalizing monoclonal antibodies (mAbs) recognizing a diversity of DLL3 epitopes. Select mAbs were reformatted as fully human Fab-arm exchange-deficient IgG4 to reduce effector function and then produced by recombinant methods. A pilot immunoPET study was performed in athymic female nude mice bearing human NCI-H82 SCLC tumors to nominate a lead candidate. ImmunoPET identified [\n                    <jats:sup>89<\/jats:sup>\n                    Zr]Zr-DFO-TDI-Y-010 as the top-performing diagnostic tracer, with excellent in vivo biodistribution and tumor-to-background-organ ratios consistently &gt;4. Therapeutic studies with [\n                    <jats:sup>177<\/jats:sup>\n                    Lu]Lu-CHX-A\"-DTPA-TDI-Y-010 demonstrated strong antitumor effects, significantly improving (\n                    <jats:italic toggle=\"yes\">\n                      <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    <\/jats:italic>\n                    &lt;0.05) overall survival compared with the benchmark clone [\n                    <jats:sup>177<\/jats:sup>\n                    Lu]Lu-CHX-A\"-DTPA-SC16.56 in two SCLC tumor models (NCI-H82 and Lu149) and achieving comparable overall survival in a NEPC tumor model.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2505785123","type":"journal-article","created":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T20:07:36Z","timestamp":1770062856000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":10,"title":["Next-generation anti-DLL3 radiopharmaceuticals targeting high-grade neuroendocrine lung and prostate cancers"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-9058-0982","authenticated-orcid":false,"given":"Salomon","family":"Tendler","sequence":"first","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Roberto","family":"De Gregorio","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Balderes","sequence":"additional","affiliation":[{"name":"Tri-Institutional Therapeutics Discovery Institute","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alexa L.","family":"Michel","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tran T.","family":"Hoang","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3051-7997","authenticated-orcid":false,"given":"David","family":"Bauer","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathryn M.","family":"Tully","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Joshua A.","family":"Korsen","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ivo C.","family":"Lorenz","sequence":"additional","affiliation":[{"name":"Tri-Institutional Therapeutics Discovery Institute","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Abdul G.","family":"Khan","sequence":"additional","affiliation":[{"name":"Tri-Institutional Therapeutics Discovery Institute","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4848-4190","authenticated-orcid":false,"given":"Lukas","family":"Carter","sequence":"additional","affiliation":[{"name":"Department of Medical Physics, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olivia","family":"Vergnolle","sequence":"additional","affiliation":[{"name":"Tri-Institutional Therapeutics Discovery Institute","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1693-9392","authenticated-orcid":false,"given":"Irina V.","family":"Lebedeva","sequence":"additional","affiliation":[{"name":"Tri-Institutional Therapeutics Discovery Institute","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elisabeth K.","family":"Nyakatura","sequence":"additional","affiliation":[{"name":"Tri-Institutional Therapeutics Discovery Institute","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6930-7383","authenticated-orcid":false,"given":"Lisa","family":"Bodei","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9454-0096","authenticated-orcid":false,"given":"Michael J.","family":"Morris","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"name":"Department of Medicine, Weill Cornell Medicine","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John T.","family":"Poirier","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"name":"Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-5204-3465","authenticated-orcid":false,"given":"Charles M.","family":"Rudin","sequence":"additional","affiliation":[{"name":"Department of Medicine, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"name":"Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"name":"Department of Pharmacology, Weill Cornell Medicine","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7065-4534","authenticated-orcid":false,"given":"Jason S.","family":"Lewis","sequence":"additional","affiliation":[{"name":"Department of Radiology, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"name":"Molecular Pharmacology Program, Memorial Sloan Kettering Cancer Center","place":["New York"]},{"name":"Department of Pharmacology, Weill Cornell Medicine","place":["New York"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[2026,2,2]]},"reference":[{"key":"e_1_3_4_1_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aac9459"},{"key":"e_1_3_4_2_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1410419111"},{"key":"e_1_3_4_3_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.aav0891"},{"key":"e_1_3_4_4_2","doi-asserted-by":"publisher","DOI":"10.1038\/s43018-023-00539-6"},{"key":"e_1_3_4_5_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.2005.04.4859"},{"key":"e_1_3_4_6_2","doi-asserted-by":"publisher","DOI":"10.1093\/oncolo\/oyac161"},{"key":"e_1_3_4_7_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2307980"},{"key":"e_1_3_4_8_2","doi-asserted-by":"publisher","DOI":"10.1200\/JCO.23.00148"},{"key":"e_1_3_4_9_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-3-031-39005-0_1"},{"key":"e_1_3_4_10_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(24)01653-2"},{"key":"e_1_3_4_11_2","doi-asserted-by":"publisher","DOI":"10.1007\/s11912-020-01003-9"},{"key":"e_1_3_4_12_2","doi-asserted-by":"publisher","DOI":"10.1158\/0008-5472.CAN-17-0299"},{"key":"e_1_3_4_13_2","doi-asserted-by":"publisher","DOI":"10.1158\/1078-0432.CCR-21-1533"},{"key":"e_1_3_4_14_2","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.121.263221"},{"key":"e_1_3_4_15_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.2203820119"},{"key":"e_1_3_4_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(24)00249-3"},{"key":"e_1_3_4_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.jtho.2021.07.012"},{"key":"e_1_3_4_18_2","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.00292"},{"key":"e_1_3_4_19_2","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.121.262383"},{"key":"e_1_3_4_20_2","doi-asserted-by":"publisher","DOI":"10.1007\/978-1-61779-931-0_7"},{"key":"e_1_3_4_21_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41564-023-01389-9"},{"key":"e_1_3_4_22_2","doi-asserted-by":"publisher","DOI":"10.1126\/scitranslmed.abe8195"},{"key":"e_1_3_4_23_2","doi-asserted-by":"publisher","DOI":"10.3389\/fphar.2016.00131"},{"key":"e_1_3_4_24_2","first-page":"706","article-title":"Determination of immunoreactive fraction of radiolabeled monoclonal antibodies: What is an appropriate method?","volume":"19","author":"Konishi S.","year":"2004","unstructured":"S. Konishi , Determination of immunoreactive fraction of radiolabeled monoclonal antibodies: What is an appropriate method?. Cancer Biother. Radiopharm. 19, 706\u2013715 (2004).","journal-title":"Cancer Biother. Radiopharm."},{"key":"e_1_3_4_25_2","doi-asserted-by":"publisher","DOI":"10.1038\/nrc3925"},{"key":"e_1_3_4_26_2","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.121.262751"},{"key":"e_1_3_4_27_2","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.118.222844"},{"key":"e_1_3_4_28_2","doi-asserted-by":"publisher","DOI":"10.18632\/oncotarget.8390"},{"key":"e_1_3_4_29_2","doi-asserted-by":"publisher","DOI":"10.2967\/jnumed.123.266392"},{"key":"e_1_3_4_30_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41698-021-00214-y"},{"key":"e_1_3_4_31_2","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2020.1829338"},{"key":"e_1_3_4_32_2","doi-asserted-by":"publisher","DOI":"10.1038\/s41577-023-00871-z"},{"key":"e_1_3_4_33_2","first-page":"138","article-title":"Immunoglobulin G4-related kidney disease: Pathogenesis, diagnosis, and treatment","volume":"3","author":"Zheng K.","year":"2017","unstructured":"K. Zheng, F. Teng, X. M. Li, Immunoglobulin G4-related kidney disease: Pathogenesis, diagnosis, and treatment. Chronic Dis. Transl. Med. 3, 138\u2013147 (2017).","journal-title":"Chronic Dis. Transl. Med."},{"key":"e_1_3_4_34_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1470-2045(18)30198-0"},{"key":"e_1_3_4_35_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa2107322"},{"key":"e_1_3_4_36_2","doi-asserted-by":"publisher","DOI":"10.1530\/EC-20-0611"}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.2505785123","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,2,2]],"date-time":"2026-02-02T20:08:12Z","timestamp":1770062892000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/10.1073\/pnas.2505785123"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,2,2]]},"references-count":36,"journal-issue":{"issue":"6","published-print":{"date-parts":[[2026,2,10]]}},"alternative-id":["10.1073\/pnas.2505785123"],"URL":"https:\/\/doi.org\/10.1073\/pnas.2505785123","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,2,2]]},"assertion":[{"value":"2025-03-14","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2025-12-23","order":2,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2026-02-02","order":3,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}],"article-number":"e2505785123"}}