{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,7]],"date-time":"2026-09-07T10:21:30Z","timestamp":1788776490590,"version":"build-2803163510"},"reference-count":30,"publisher":"Springer Science and Business Media LLC","issue":"8","license":[{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"},{"start":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T00:00:00Z","timestamp":1747872000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Leukemia"],"published-print":{"date-parts":[[2025,8]]},"DOI":"10.1038\/s41375-025-02642-2","type":"journal-article","created":{"date-parts":[[2025,5,22]],"date-time":"2025-05-22T03:54:29Z","timestamp":1747886069000},"page":"1848-1856","update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["KK2845, a PBD dimer-containing antibody-drug conjugate targeting TIM-3-expressing AML"],"prefix":"10.1038","volume":"39","author":[{"ORCID":"https:\/\/orcid.org\/0009-0005-9119-7383","authenticated-orcid":false,"given":"Jian","family":"Zou","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Haruka","family":"Kinosada","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5158-1920","authenticated-orcid":false,"given":"Shin-ichiro","family":"Takayanagi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toshihiko","family":"Ishii","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Toru","family":"Amano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kaito","family":"Nihira","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shohei","family":"Kanie","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Maiko","family":"Adachi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Harunobu","family":"Tahara","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Teppei","family":"Sakoda","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-7721-1696","authenticated-orcid":false,"given":"Yoshikane","family":"Kikushige","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7763-5723","authenticated-orcid":false,"given":"Koichi","family":"Akashi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hidetaka","family":"Satou","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2025,5,22]]},"reference":[{"key":"2642_CR1","doi-asserted-by":"publisher","first-page":"730","DOI":"10.1038\/nm0797-730","volume":"3","author":"D Bonnet","year":"1997","unstructured":"Bonnet D, Dick JE. Human acute myeloid leukemia is organized as a hierarchy that originates from a primitive hematopoietic cell. Nat Med. 1997;3:730.","journal-title":"Nat Med"},{"key":"2642_CR2","doi-asserted-by":"publisher","first-page":"738","DOI":"10.1038\/ni1080","volume":"5","author":"KJ Hope","year":"2004","unstructured":"Hope KJ, Jin L, Dick JE. Acute myeloid leukemia originates from a hierarchy of leukemic stem cell classes that differ in self-renewal capacity. Nat Immunol. 2004;5:738\u201343.","journal-title":"Nat Immunol"},{"key":"2642_CR3","doi-asserted-by":"publisher","first-page":"645","DOI":"10.1038\/367645a0","volume":"367","author":"T Lapidot","year":"1994","unstructured":"Lapidot T, Sirard C, Vormoor J, Murdoch B, Hoang T, Caceres-Cortes J, et al. A cell initiating human acute myeloid leukaemia after transplantation into SCID mice. Nature. 1994;367:645\u20138.","journal-title":"Nature"},{"key":"2642_CR4","doi-asserted-by":"publisher","first-page":"502","DOI":"10.1002\/ajh.26822","volume":"98","author":"S Shimony","year":"2023","unstructured":"Shimony S, Stahl M, Stone RM. Acute myeloid leukemia: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023;98:502\u201326.","journal-title":"Am J Hematol"},{"key":"2642_CR5","first-page":"7","volume":"71","author":"RL Siegel","year":"2021","unstructured":"Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer Statistics, 2021. CA Cancer J Clin. 2021;71:7\u201333.","journal-title":"CA Cancer J Clin"},{"key":"2642_CR6","doi-asserted-by":"publisher","first-page":"1315","DOI":"10.1038\/nbt1350","volume":"25","author":"F Ishikawa","year":"2007","unstructured":"Ishikawa F, Yoshida S, Saito Y, Hijikata A, Kitamura H, Tanaka S, et al. Chemotherapy-resistant human AML stem cells home to and engraft within the bone-marrow endosteal region. Nat Biotechnol. 2007;25:1315\u201321.","journal-title":"Nat Biotechnol"},{"key":"2642_CR7","doi-asserted-by":"publisher","first-page":"104","DOI":"10.1038\/nature22993","volume":"547","author":"LI Shlush","year":"2017","unstructured":"Shlush LI, Mitchell A, Heisler L, Abelson S, Ng SWK, Trotman-Grant A, et al. Tracing the origins of relapse in acute myeloid leukaemia to stem cells. Nature. 2017;547:104\u20138.","journal-title":"Nature"},{"key":"2642_CR8","doi-asserted-by":"publisher","DOI":"10.1080\/19420862.2021.1951427","volume":"13","author":"AQ Dean","year":"2021","unstructured":"Dean AQ, Luo S, Twomey JD, Zhang B. Targeting cancer with antibody-drug conjugates: Promises and challenges. MAbs. 2021;13:1951427.","journal-title":"MAbs"},{"key":"2642_CR9","first-page":"68","volume":"10","author":"C Selby","year":"2019","unstructured":"Selby C, Yacko LR, Glode AE. Gemtuzumab Ozogamicin: Back Again. J Adv Pr Oncol. 2019;10:68\u201382.","journal-title":"J Adv Pr Oncol"},{"key":"2642_CR10","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1182\/blood-2017-06-789800","volume":"131","author":"EM Stein","year":"2018","unstructured":"Stein EM, Walter RB, Erba HP, Fathi AT, Advani AS, Lancet JE, et al. A phase 1 trial of vadastuximab talirine as monotherapy in patients with CD33-positive acute myeloid leukemia. Blood. 2018;131:387\u201396.","journal-title":"Blood"},{"key":"2642_CR11","doi-asserted-by":"publisher","first-page":"1094","DOI":"10.1182\/blood-2017-10-813493","volume":"131","author":"F Zammarchi","year":"2018","unstructured":"Zammarchi F, Corbett S, Adams L, Tyrer PC, Kiakos K, Janghra N, et al. ADCT-402, a PBD dimer-containing antibody drug conjugate targeting CD19-expressing malignancies. Blood. 2018;131:1094\u2013105.","journal-title":"Blood"},{"key":"2642_CR12","doi-asserted-by":"publisher","first-page":"64","DOI":"10.1038\/s41375-018-0180-3","volume":"33","author":"S Haubner","year":"2019","unstructured":"Haubner S, Perna F, Kohnke T, Schmidt C, Berman S, Augsberger C, et al. Coexpression profile of leukemic stem cell markers for combinatorial targeted therapy in AML. Leukemia. 2019;33:64\u201374.","journal-title":"Leukemia"},{"key":"2642_CR13","doi-asserted-by":"publisher","first-page":"708","DOI":"10.1016\/j.stem.2010.11.014","volume":"7","author":"Y Kikushige","year":"2010","unstructured":"Kikushige Y, Shima T, Takayanagi S, Urata S, Miyamoto T, Iwasaki H, et al. TIM-3 is a promising target to selectively kill acute myeloid leukemia stem cells. Cell Stem Cell. 2010;7:708\u201317.","journal-title":"Cell Stem Cell"},{"key":"2642_CR14","doi-asserted-by":"publisher","first-page":"2053","DOI":"10.1182\/bloodadvances.2022008405","volume":"7","author":"T Sakoda","year":"2023","unstructured":"Sakoda T, Kikushige Y, Miyamoto T, Irifune H, Harada T, Hatakeyama K, et al. TIM-3 signaling hijacks the canonical Wnt\/\u03b2-catenin pathway to maintain cancer stemness in acute myeloid leukemia. Blood Adv. 2023;7:2053\u201365.","journal-title":"Blood Adv"},{"key":"2642_CR15","doi-asserted-by":"publisher","first-page":"5009","DOI":"10.1073\/pnas.1100551108","volume":"108","author":"M Jan","year":"2011","unstructured":"Jan M, Chao MP, Cha AC, Alizadeh AA, Gentles AJ, Weissman IL, et al. Prospective separation of normal and leukemic stem cells based on differential expression of TIM3, a human acute myeloid leukemia stem cell marker. Proc Natl Acad Sci USA. 2011;108:5009\u201314.","journal-title":"Proc Natl Acad Sci USA"},{"key":"2642_CR16","doi-asserted-by":"publisher","first-page":"269","DOI":"10.1111\/j.1349-7006.1996.tb00216.x","volume":"87","author":"H Asou","year":"1996","unstructured":"Asou H, Suzukawa K, Kita K, Nakase K, Ueda H, Morishita K, et al. Establishment of an undifferentiated leukemia cell line (Kasumi-3) with t(3;7)(q27;q22) and activation of the EVI1 gene. Jpn J Cancer Res. 1996;87:269\u201374.","journal-title":"Jpn J Cancer Res"},{"key":"2642_CR17","doi-asserted-by":"publisher","first-page":"1233","DOI":"10.1182\/blood.V66.6.1233.1233","volume":"66","author":"H Saito","year":"1985","unstructured":"Saito H, Bourinbaiar A, Ginsburg M, Minato K, Ceresi E, Yamada K, et al. Establishment and characterization of a new human eosinophilic leukemia cell line. Blood. 1985;66:1233\u201340.","journal-title":"Blood"},{"key":"2642_CR18","first-page":"67","volume":"56","author":"T Nagano","year":"1992","unstructured":"Nagano T, Ohga S, Kishimoto Y, Kimura T, Yasunaga K, Adachi M, et al. Ultrastructural analysis of platelet-like particles from a human megakaryocytic leukemia cell line (CMK11-5). Int J Hematol. 1992;56:67\u201378.","journal-title":"Int J Hematol"},{"key":"2642_CR19","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-28533-4","volume":"8","author":"JA Hartley","year":"2018","unstructured":"Hartley JA, Flynn MJ, Bingham JP, Corbett S, Reinert H, Tiberghien A, et al. Pre-clinical pharmacology and mechanism of action of SG3199, the pyrrolobenzodiazepine (PBD) dimer warhead component of antibody-drug conjugate (ADC) payload tesirine. Sci Rep. 2018;8:10479.","journal-title":"Sci Rep"},{"key":"2642_CR20","doi-asserted-by":"publisher","first-page":"105","DOI":"10.21037\/atm.2019.01.42","volume":"7","author":"C Lo Nigro","year":"2019","unstructured":"Lo Nigro C, Macagno M, Sangiolo D, Bertolaccini L, Aglietta M, Merlano MC. NK-mediated antibody-dependent cell-mediated cytotoxicity in solid tumors: biological evidence and clinical perspectives. Ann Transl Med. 2019;7:105.","journal-title":"Ann Transl Med"},{"key":"2642_CR21","doi-asserted-by":"publisher","first-page":"54","DOI":"10.1002\/1878-0261.12600","volume":"14","author":"M Gymnopoulos","year":"2020","unstructured":"Gymnopoulos M, Betancourt O, Blot V, Fujita R, Galvan D, Lieuw V, et al. TR1801-ADC: a highly potent cMet antibody-drug conjugate with high activity in patient-derived xenograft models of solid tumors. Mol Oncol. 2020;14:54\u201368.","journal-title":"Mol Oncol"},{"key":"2642_CR22","doi-asserted-by":"publisher","first-page":"983","DOI":"10.1021\/acsmedchemlett.6b00062","volume":"7","author":"AC Tiberghien","year":"2016","unstructured":"Tiberghien AC, Levy JN, Masterson LA, Patel NV, Adams LR, Corbett S, et al. Design and Synthesis of Tesirine, a Clinical Antibody-Drug Conjugate Pyrrolobenzodiazepine Dimer Payload. ACS Med Chem Lett. 2016;7:983\u20137.","journal-title":"ACS Med Chem Lett"},{"key":"2642_CR23","doi-asserted-by":"crossref","unstructured":"Lucas AT, Price LSL, Schorzman AN, Storrie M, Piscitelli JA, Razo J, et al. Factors Affecting the Pharmacology of Antibody-Drug Conjugates. Antibodies (Basel). 2018;7.","DOI":"10.3390\/antib7010010"},{"key":"2642_CR24","doi-asserted-by":"crossref","unstructured":"Acharya N, Sabatos-Peyton C, Anderson AC Tim-3 finds its place in the cancer immunotherapy landscape. J Immunother Cancer 2020 Jun; 8.","DOI":"10.1136\/jitc-2020-000911"},{"key":"2642_CR25","unstructured":"Zeidan AM, Xiao ZJ, Sanz G, Giagounidis A, Sekeres MA, Lao ZT, et al. Primary results of the Phase III STIMULUS-MDS2 study of sabatolimab + azacitidine vs placebo + azacitidine as frontline therapy for patients with higher-risk MDS or CMML-2. EHA, Madrid: Abs S180, Jun 2024.Retrieved from: https:\/\/library.ehaweb.org\/eha\/2024\/eha2024congress\/document?c_id=422284&cm_id=437116&type=document437116."},{"key":"2642_CR26","doi-asserted-by":"publisher","DOI":"10.1093\/immadv\/ltac019","volume":"2","author":"S Schwartz","year":"2022","unstructured":"Schwartz S, Patel N, Longmire T, Jayaraman P, Jiang X, Lu H, et al. Characterization of sabatolimab, a novel immunotherapy with immuno-myeloid activity directed against TIM-3 receptor. Immunother Adv. 2022;2:ltac019.","journal-title":"Immunother Adv"},{"key":"2642_CR27","doi-asserted-by":"publisher","first-page":"3909","DOI":"10.1182\/blood-2009-02-206946","volume":"114","author":"R Le Dieu","year":"2009","unstructured":"Le Dieu R, Taussig DC, Ramsay AG, Mitter R, Miraki-Moud F, Fatah R, et al. Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts. Blood. 2009;114:3909\u201316.","journal-title":"Blood"},{"key":"2642_CR28","doi-asserted-by":"publisher","first-page":"1702","DOI":"10.1158\/1535-7163.MCT-20-0155","volume":"20","author":"WHS Lee","year":"2021","unstructured":"Lee WHS, Ye Z, Cheung AM, Goh YS, Oh HLJ, Rajarethinam R, et al. Effective Killing of Acute Myeloid Leukemia by TIM-3 Targeted Chimeric Antigen Receptor T Cells. Mol Cancer Ther. 2021;20:1702\u201312.","journal-title":"Mol Cancer Ther"},{"key":"2642_CR29","doi-asserted-by":"publisher","first-page":"455","DOI":"10.1007\/s12185-024-03809-w","volume":"120","author":"S Saito","year":"2024","unstructured":"Saito S, Nakazawa Y. CAR-T cell therapy in AML: recent progress and future perspectives. Int J Hematol. 2024;120:455\u201366.","journal-title":"Int J Hematol"},{"key":"2642_CR30","doi-asserted-by":"publisher","first-page":"173","DOI":"10.1038\/s41577-019-0224-6","volume":"20","author":"Y Wolf","year":"2020","unstructured":"Wolf Y, Anderson AC, Kuchroo VK. TIM3 comes of age as an inhibitory receptor. Nat Rev Immunol. 2020;20:173\u201385.","journal-title":"Nat Rev Immunol"}],"container-title":["Leukemia"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02642-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02642-2","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02642-2.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,9,6]],"date-time":"2025-09-06T15:16:42Z","timestamp":1757171802000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/s41375-025-02642-2"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,5,22]]},"references-count":30,"journal-issue":{"issue":"8","published-print":{"date-parts":[[2025,8]]}},"alternative-id":["2642"],"URL":"https:\/\/doi.org\/10.1038\/s41375-025-02642-2","relation":{},"ISSN":["0887-6924","1476-5551"],"issn-type":[{"value":"0887-6924","type":"print"},{"value":"1476-5551","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,5,22]]},"assertion":[{"value":"30 January 2025","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"26 April 2025","order":2,"name":"revised","label":"Revised","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"6 May 2025","order":3,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"22 May 2025","order":4,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"J.Z., H.K., S.T., T.I., T.A., K.N., S.K., M.A., H.T., and H.S. are employees of Kyowa Kirin. T.S., Y.K., and K.A. are collaborators who received financial support from Kyowa Kirin.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}},{"value":"The use of human-derived materials was approved by the Research Ethics Review Committee of Kyowa Kirin Co., Ltd., Kyushu University, or the vendor\u2019s ethical regulations. Informed consent was obtained from all human subjects. All experiments involving animals were approved by the Institutional Animal Care and Use Committee and performed in accordance with the animal welfare guidelines of Kyowa Kirin Co., Ltd., and Shin Nippon Biomedical Laboratories, Ltd., both of which are accredited by AAALAC International.","order":2,"name":"Ethics","group":{"name":"EthicsHeading","label":"Ethics statement"}}]}}