{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T16:47:07Z","timestamp":1790095627019,"version":"4.0.1"},"reference-count":44,"publisher":"MDPI AG","issue":"24","license":[{"start":{"date-parts":[[2024,12,19]],"date-time":"2024-12-19T00:00:00Z","timestamp":1734566400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Delta-like 1 homolog (DLK1), a non-canonical Notch ligand, is highly expressed in various malignant tumors, especially in hepatocellular carcinoma (HCC). CBA-1205 is an afucosylated humanized antibody against DLK1 with enhanced antibody-dependent cellular cytotoxicity (ADCC). The binding characteristics of CBA-1205 were analyzed by enzyme-linked immunosorbent assay and fluorescence-activated cell sorting assay. The ADCC activity of CBA-1205 was assessed. The anti-tumor efficacy of CBA-1205 was evaluated in xenograft mouse models, and toxicity and toxicokinetic profiles of CBA-1205 were evaluated in cynomolgus monkeys. CBA-1205 selectively bound to DLK1 among the Notch ligands and only to monkey and human DLK1. The binding epitope was between epidermal growth factor-like domains 1 and 2 of DLK1, which are not involved in any known physiological functions. The ADCC activity of CBA-1205 was confirmed using human peripheral blood mononuclear cells as effector cells. CBA-1205 as a single agent and in combination with lenvatinib demonstrated long-lasting anti-tumor efficacy, including tumor regression, in two liver cancer xenograft models. The toxicity and toxicokinetic profiles of CBA-1205 in cynomolgus monkeys were favorable. These findings suggest that CBA-1205 has the potential to be a useful therapeutic option for drug treatment in HCC. A phase 1 study is ongoing in patients with advanced cancers (jRCT2080225288, NCT06636435).<\/jats:p>","DOI":"10.3390\/ijms252413627","type":"journal-article","created":{"date-parts":[[2024,12,20]],"date-time":"2024-12-20T04:07:40Z","timestamp":1734667660000},"page":"13627","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":3,"title":["A Novel Glycoengineered Humanized Antibody Targeting DLK1 Exhibits Potent Anti-Tumor Activity in DLK1-Expressing Liver Cancer Cell Xenograft Models"],"prefix":"10.3390","volume":"25","author":[{"ORCID":"https:\/\/orcid.org\/0009-0007-7761-3795","authenticated-orcid":false,"given":"Koji","family":"Nakamura","sequence":"first","affiliation":[{"name":"Chiome Bioscience Inc., 3-12-1 Honmachi, Shibuya-ku, Tokyo 151-0071, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kota","family":"Takahashi","sequence":"additional","affiliation":[{"name":"Chiome Bioscience Inc., 3-12-1 Honmachi, Shibuya-ku, Tokyo 151-0071, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Izumi","family":"Sakaguchi","sequence":"additional","affiliation":[{"name":"Chiome Bioscience Inc., 3-12-1 Honmachi, Shibuya-ku, Tokyo 151-0071, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Takumi","family":"Satoh","sequence":"additional","affiliation":[{"name":"Chiome Bioscience Inc., 3-12-1 Honmachi, Shibuya-ku, Tokyo 151-0071, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lingyi","family":"Zhang","sequence":"additional","affiliation":[{"name":"Chiome Bioscience Inc., 3-12-1 Honmachi, Shibuya-ku, Tokyo 151-0071, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hiroyuki","family":"Yanai","sequence":"additional","affiliation":[{"name":"Chiome Bioscience Inc., 3-12-1 Honmachi, Shibuya-ku, Tokyo 151-0071, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yukihito","family":"Tsukumo","sequence":"additional","affiliation":[{"name":"Chiome Bioscience Inc., 3-12-1 Honmachi, Shibuya-ku, Tokyo 151-0071, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2024,12,19]]},"reference":[{"key":"ref_1","unstructured":"Cancer Today (2024, June 26). Global Cancer Observatory. International Agency for Research on Cancer. World Health Organization. Available online: https:\/\/gco.iarc.who.int\/today\/en\/dataviz\/tables?mode=cancer&group_populations=1&multiple_populations=1&types=0."},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Lazzaro, A., and Hartshorn, K.L. (2023). A comprehensive narrative review on the history, current landscape, and future directions of hepatocellular carcinoma (HCC) systemic therapy. Cancers, 15.","DOI":"10.3390\/cancers15092506"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1016\/S0140-6736(18)30207-1","article-title":"Lenvatinib versus sorafenib in first-line treatment of patients with unresectable hepatocellular carcinoma: A randomised phase 3 non-inferiority trial","volume":"391","author":"Kudo","year":"2018","journal-title":"Lancet"},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"2641","DOI":"10.1002\/cam4.1517","article-title":"Lenvatinib inhibits angiogenesis and tumor fibroblast growth factor signaling pathways in human hepatocellular carcinoma models","volume":"7","author":"Matsuki","year":"2018","journal-title":"Cancer Med."},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"1918","DOI":"10.1002\/mc.23625","article-title":"The action and resistance mechanisms of Lenvatinib in liver cancer","volume":"62","author":"Buttell","year":"2023","journal-title":"Mol. Carcinog."},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"3720","DOI":"10.3748\/wjg.v26.i26.3720","article-title":"Intratumoral heterogeneity of hepatocellular carcinoma: From single-cell to population-based studies","volume":"26","author":"Zhang","year":"2020","journal-title":"World J. Gastroenterol."},{"key":"ref_7","doi-asserted-by":"crossref","unstructured":"Fang, X., Yan, Q., Liu, S., and Guan, X.Y. (2022). Cancer stem cells in hepatocellular carcinoma: Intrinsic and extrinsic molecular mechanisms in stemness regulation. Int. J. Mol. Sci., 23.","DOI":"10.3390\/ijms232012327"},{"key":"ref_8","doi-asserted-by":"crossref","first-page":"988","DOI":"10.1016\/j.bbadis.2012.02.003","article-title":"Possible roles of DLK1 in the Notch pathway during development and disease","volume":"1822","author":"Falix","year":"2012","journal-title":"Biochim. Biophys. Acta"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"17","DOI":"10.1016\/j.cytogfr.2019.03.006","article-title":"The imprinted gene Delta like non-canonical Notch ligand 1 (Dlk1) is conserved in mammals, and serves a growth modulatory role during tissue development and regeneration through Notch dependent and independent mechanisms","volume":"46","author":"Lagoni","year":"2019","journal-title":"Cytokine Growth Factor. Rev."},{"key":"ref_10","doi-asserted-by":"crossref","first-page":"1775","DOI":"10.1242\/jcs.00388","article-title":"Isolation of hepatoblasts based on the expression of Dlk\/Pref-1","volume":"116","author":"Tanimizu","year":"2003","journal-title":"J. Cell Sci."},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"209","DOI":"10.1016\/j.modgep.2004.08.003","article-title":"Expression of Dlk\/Pref-1 defines a subpopulation in the oval cell compartment of rat liver","volume":"5","author":"Tanimizu","year":"2004","journal-title":"Gene Expr. Patterns"},{"key":"ref_12","doi-asserted-by":"crossref","first-page":"1344","DOI":"10.1016\/j.eururo.2008.03.006","article-title":"Delta-like 1 (Dlk-1), a novel marker of prostate basal and candidate epithelial stem cells, is downregulated by notch signalling in intermediate\/transit amplifying cells of the human prostate","volume":"54","author":"Ceder","year":"2008","journal-title":"Eur. Urol."},{"key":"ref_13","doi-asserted-by":"crossref","first-page":"353","DOI":"10.1007\/s12015-009-9099-4","article-title":"Isolation and differentiation of chondrocytic cells derived from human embryonic stem cells using dlk1\/FA1 as a novel surface marker","volume":"5","author":"Harkness","year":"2009","journal-title":"Stem Cell Rev. Rep."},{"key":"ref_14","doi-asserted-by":"crossref","first-page":"85","DOI":"10.1093\/jb\/mvq034","article-title":"Dlk-1, a cell surface antigen on foetal hepatic stem\/progenitor cells, is expressed in hepatocellular, colon, pancreas and breast carcinomas at a high frequency","volume":"148","author":"Yanai","year":"2010","journal-title":"J. Biochem."},{"key":"ref_15","doi-asserted-by":"crossref","first-page":"21844","DOI":"10.18632\/oncotarget.25074","article-title":"Clinical outcome of hepatocellular carcinoma can be predicted by the expression of hepatic progenitor cell markers and serum tumour markers","volume":"9","author":"Seino","year":"2018","journal-title":"Oncotarget"},{"key":"ref_16","doi-asserted-by":"crossref","first-page":"71466","DOI":"10.18632\/oncotarget.12214","article-title":"Targeting endogenous DLK1 exerts antitumor effect on hepatocellular carcinoma through initiating cell differentiation","volume":"7","author":"Cai","year":"2016","journal-title":"Oncotarget"},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"1163","DOI":"10.1002\/hep.28602","article-title":"Genetic lineage tracing analysis of the cell of origin of hepatotoxin-induced liver tumors in mice","volume":"64","author":"Shin","year":"2016","journal-title":"Hepatology"},{"key":"ref_18","doi-asserted-by":"crossref","first-page":"629","DOI":"10.1158\/1535-7163.MCT-11-0531","article-title":"DLK1 as a potential target against cancer stem\/progenitor cells of hepatocellular carcinoma","volume":"11","author":"Xu","year":"2012","journal-title":"Mol. Cancer Ther."},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1607","DOI":"10.1093\/glycob\/cwq109","article-title":"Production of non-fucosylated antibodies by co-expression of heterologous GDP-6-deoxy-D-lyxo-4-hexulose reductase","volume":"20","author":"Ogorek","year":"2010","journal-title":"Glycobiology"},{"key":"ref_20","doi-asserted-by":"crossref","unstructured":"Nakamura, K., Takahashi, K., Sakaguchi, I., Lingyi, Z., Yanai, H., and Kanke, T. (April, January 29). CBA-1205, a novel glycoengineered humanized antibody targeting DLK-1 exhibits potent anti-tumor activity in DLK-1 expressing tumor xenograft models. Proceedings of the AACR Annual Meeting 2019, Atlanta, GA, USA. Abstract 1535.","DOI":"10.1158\/1538-7445.SABCS18-1535"},{"key":"ref_21","doi-asserted-by":"crossref","unstructured":"Nakamura, K., Sakaguchi, I., and Takahashi, K. (2023, January 14\u201319). Synergistic and long-lasing anti-tumor efficacy of CBA-1205, a novel glycoengineered humanized antibody targeting DLK-1, in combination with Lenvatinib in human HCC xenograft models. Proceedings of the AACR Annual Meeting 2023, Orland, FL, USA. Abstract 1862.","DOI":"10.1158\/1538-7445.AM2023-1862"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"49","DOI":"10.1046\/j.1432-0436.2000.066001049.x","article-title":"Does fetal antigen 1 (FA1) identify cells with regenerative, endocrine and neuroendocrine potentials? A study of FA1 in embryonic, fetal, and placental tissue and in maternal circulation","volume":"66","author":"Floridon","year":"2000","journal-title":"Differentiation"},{"key":"ref_23","doi-asserted-by":"crossref","first-page":"191","DOI":"10.1016\/S0140-6736(96)90374-8","article-title":"Fetal antigen 1 and growth hormone in pituitary somatotroph cells","volume":"347","author":"Larsen","year":"1996","journal-title":"Lancet"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"335","DOI":"10.1007\/BF00185891","article-title":"Fetal antigen 1 (FA1) in the human pancreas: Cell type expression, topological and quantitative variations during development","volume":"187","author":"Tornehave","year":"1993","journal-title":"Anat Embryol."},{"key":"ref_25","doi-asserted-by":"crossref","first-page":"246","DOI":"10.1016\/j.cellsig.2016.01.003","article-title":"Evidence of non-canonical NOTCH signaling: Delta-like 1 homolog (DLK1) directly interacts with the NOTCH1 receptor in mammals","volume":"28","author":"Jensen","year":"2016","journal-title":"Cell Signal."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"343","DOI":"10.1016\/j.yexcr.2004.10.001","article-title":"dlk acts as a negative regulator of Notch1 activation through interactions with specific EGF-like repeats","volume":"303","author":"Nueda","year":"2005","journal-title":"Exp. Cell Res."},{"key":"ref_27","doi-asserted-by":"crossref","first-page":"460","DOI":"10.1016\/j.ijbiomac.2017.01.067","article-title":"The non-canonical NOTCH1 ligand Delta-like 1 homolog (DLK1) self interacts in mammals","volume":"97","author":"Jensen","year":"2017","journal-title":"Int. J. Biol. Macromol."},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"3480","DOI":"10.1128\/MCB.00057-10","article-title":"Pref-1 interacts with fibronectin to inhibit adipocyte differentiation","volume":"30","author":"Wang","year":"2010","journal-title":"Mol. Cell Biol."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"1428","DOI":"10.1038\/s41416-020-0823-9","article-title":"Cancer stemness in hepatocellular carcinoma: Mechanisms and translational potential","volume":"122","author":"Tsui","year":"2020","journal-title":"Br. J. Cancer"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"1399","DOI":"10.1016\/S1470-2045(23)00469-2","article-title":"Lenvatinib plus pembrolizumab versus lenvatinib plus placebo for advanced hepatocellular carcinoma (LEAP-002): A randomised, double-blind, phase 3 trial","volume":"24","author":"Llovet","year":"2023","journal-title":"Lancet Oncol."},{"key":"ref_31","doi-asserted-by":"crossref","first-page":"101059","DOI":"10.1016\/j.tranon.2021.101059","article-title":"IRF2 regulates cellular survival and Lenvatinib-sensitivity of hepatocellular carcinoma (HCC) through regulating \u03b2-catenin","volume":"14","author":"Guo","year":"2021","journal-title":"Transl. Oncol."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"175112","DOI":"10.1016\/j.ejphar.2022.175112","article-title":"Neogambogic acid suppresses characteristics and growth of colorectal cancer stem cells by inhibition of DLK1 and Wnt\/\u03b2-catenin pathway","volume":"929","author":"Li","year":"2022","journal-title":"Eur. J. Pharmacol."},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"312","DOI":"10.1242\/bio.201411247","article-title":"The Wnt-target gene Dlk-1 is regulated by the Prmt5-associated factor Copr5 during adipogenic conversion","volume":"4","author":"Paul","year":"2015","journal-title":"Biol. Open"},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1125","DOI":"10.1016\/j.ymthe.2024.01.036","article-title":"DLK1\/DIO3 locus upregulation by a \u03b2-catenin-dependent enhancer drives cell proliferation and liver tumorigenesis","volume":"32","author":"Sanceau","year":"2024","journal-title":"Mol. Ther."},{"key":"ref_35","doi-asserted-by":"crossref","first-page":"3074","DOI":"10.1158\/1078-0432.CCR-18-1942","article-title":"WNT\/\u03b2-catenin pathway activation correlates with immune exclusion across human cancers","volume":"25","author":"Luke","year":"2019","journal-title":"Clin. Cancer Res."},{"key":"ref_36","doi-asserted-by":"crossref","first-page":"R271","DOI":"10.1530\/ERC-21-0208","article-title":"The role of delta-like non-canonical Notch ligand 1 (DLK1) in cancer","volume":"28","author":"Pittaway","year":"2021","journal-title":"Endocr. Relat. Cancer"},{"key":"ref_37","doi-asserted-by":"crossref","first-page":"697","DOI":"10.1002\/hep4.1327","article-title":"Emergence of the dedifferentiated phenotype in hepatocyte-derived tumors in mice: Roles of oncogene-induced epigenetic alterations","volume":"3","author":"Watanabe","year":"2019","journal-title":"Hepatol. Commun."},{"key":"ref_38","doi-asserted-by":"crossref","first-page":"3111","DOI":"10.1111\/cas.14996","article-title":"Generation of combined hepatocellular-cholangiocarcinoma through transdifferentiation and dedifferentiation in p53-knockout mice","volume":"112","author":"Liu","year":"2021","journal-title":"Cancer Sci."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"2711","DOI":"10.1016\/j.ajpath.2017.07.022","article-title":"Oncogenic determination of a broad spectrum of phenotypes of hepatocyte-derived mouse liver tumors","volume":"187","author":"Yamamoto","year":"2017","journal-title":"Am. J. Pathol."},{"key":"ref_40","doi-asserted-by":"crossref","first-page":"8399","DOI":"10.1007\/s13277-015-3607-8","article-title":"Serum DLK1 is a potential prognostic biomarker in patients with hepatocellular carcinoma","volume":"36","author":"Li","year":"2015","journal-title":"Tumour Biol."},{"key":"ref_41","doi-asserted-by":"crossref","first-page":"134","DOI":"10.1016\/j.lungcan.2021.01.014","article-title":"Delta-like 1 homolog (DLK1) as a possible therapeutic target and its application to radioimmunotherapy using 125I-labelled anti-DLK1 antibody in lung cancer models (HOT1801 and FIGHT004)","volume":"153","author":"Takagi","year":"2021","journal-title":"Lung Cancer"},{"key":"ref_42","doi-asserted-by":"crossref","first-page":"3201","DOI":"10.1038\/s41388-018-0658-5","article-title":"Delta-like 1 homologue promotes tumorigenesis and epithelial-mesenchymal transition of ovarian high-grade serous carcinoma through activation of Notch signaling","volume":"38","author":"Huang","year":"2019","journal-title":"Oncogene"},{"key":"ref_43","first-page":"2700","article-title":"Prognostic values of DLK1 for surgery and imatinib mesylate adjuvant therapy in gastrointestinal stromal tumors","volume":"6","author":"Xu","year":"2016","journal-title":"Am. J. Cancer Res."},{"key":"ref_44","doi-asserted-by":"crossref","first-page":"689","DOI":"10.1016\/j.neo.2020.10.005","article-title":"Niche-derived soluble DLK1 promotes glioma growth","volume":"22","author":"Grassi","year":"2020","journal-title":"Neoplasia"}],"container-title":["International Journal of Molecular Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13627\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,10]],"date-time":"2025-10-10T16:55:56Z","timestamp":1760115356000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/1422-0067\/25\/24\/13627"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2024,12,19]]},"references-count":44,"journal-issue":{"issue":"24","published-online":{"date-parts":[[2024,12]]}},"alternative-id":["ijms252413627"],"URL":"https:\/\/doi.org\/10.3390\/ijms252413627","relation":{},"ISSN":["1422-0067"],"issn-type":[{"value":"1422-0067","type":"electronic"}],"subject":[],"published":{"date-parts":[[2024,12,19]]}}}