{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T06:53:43Z","timestamp":1781506423428,"version":"3.54.1"},"reference-count":19,"publisher":"Oxford University Press (OUP)","issue":"2","license":[{"start":{"date-parts":[[2026,4,8]],"date-time":"2026-04-08T00:00:00Z","timestamp":1775606400000},"content-version":"vor","delay-in-days":7,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"CAMS Innovation Fund for Medical Sciences","award":["2021-I2M-1-026"],"award-info":[{"award-number":["2021-I2M-1-026"]}]},{"name":"CAMS Innovation Fund for Medical Sciences","award":["2025-I2M-X-108"],"award-info":[{"award-number":["2025-I2M-X-108"]}]},{"name":"Fundamental Research Funds for the Central Universities, Peking Union Medical College","award":["3332025195"],"award-info":[{"award-number":["3332025195"]}]},{"DOI":"10.13039\/501100005089","name":"Beijing Natural Science Foundation","doi-asserted-by":"publisher","award":["7242201"],"award-info":[{"award-number":["7242201"]}],"id":[{"id":"10.13039\/501100005089","id-type":"DOI","asserted-by":"publisher"}]},{"name":"SunHo (China) BioPharmaceutical Co., Ltd"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,4,1]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec>\n                    <jats:title>Background<\/jats:title>\n                    <jats:p>The immunosuppressive nature of tumor microenvironment (TME) limits the efficacy of current immunotherapies. Bispecific antibodies (bsAbs) offer a promising strategy to overcome this challenge by enabling localized immune activation. Specifically, simultaneously targeting the \u201cdon\u2019t eat me\u201d signal CD24 on tumor cells and the co-stimulatory receptor 4-1BB on immune cells may provide potent anti-tumor effects while mitigating the systemic toxicity typically associated with conventional 4-1BB agonists. Here, we present the preclinical evaluation of IBD0333, a novel bsAb targeting CD24 and 4-1BB.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p>The binding affinity of IBD0333 to CD24 and 4-1BB was evaluated, and its pharmacodynamic effects were assessed through multiple in vitro assays. Anti-tumor efficacy of IBD0333 was evaluated using C57BL\/6J-h4-1BB humanized mouse models in vivo, while pharmacokinetic and safety profiles were further investigated in cynomolgus monkeys.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Results<\/jats:title>\n                    <jats:p>IBD0333 exhibited high-binding affinity to both human and cynomolgus monkey CD24 and 4-1BB proteins. Its agonistic activity toward 4-1BB was strictly dependent on CD24, as evidenced by potent NF-\u03baB activation and cytokine induction only in the presence of CD24-positive tumor cells. IBD0333 also demonstrated appropriate Fc\u03b3R binding and no-detectable antibody-dependent cellular cytotoxicity\/complement-dependent cytotoxicity activity. In a syngeneic tumor model, complete tumor regression was achieved at doses of 1 and 3\u00a0mg\/kg. Furthermore, IBD0333 was well tolerated in cynomolgus monkeys with no observed immunotoxicity or hepatotoxicity, and the no-observed-adverse-effect level following repeated administration was established as 120\u00a0mg\/kg.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Conclusion<\/jats:title>\n                    <jats:p>IBD0333 is a tumor-conditionally activated anti-CD24\u00d74-1BB bsAb that demonstrates potent antitumor efficacy along with a favorable safety and pharmacokinetic profile. These findings support its further clinical development.<\/jats:p>\n                  <\/jats:sec>","DOI":"10.1093\/abt\/tbag014","type":"journal-article","created":{"date-parts":[[2026,4,7]],"date-time":"2026-04-07T11:34:59Z","timestamp":1775561699000},"page":"168-178","source":"Crossref","is-referenced-by-count":0,"title":["Preclinical characterization of IBD0333, a novel CD24\u00d74-1BB bispecific antibody with tumor-dependent agonistic activity for cancer immunotherapy"],"prefix":"10.1093","volume":"9","author":[{"given":"Dong-Cheng","family":"Jiang","sequence":"first","affiliation":[{"name":"Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University , Nanjing 211166, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dan-Dan","family":"Zhou","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Rui","family":"Xu","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiao-Ling","family":"Jiang","sequence":"additional","affiliation":[{"name":"SunHo (China) BioPharmaceutical Co., Ltd. , Nanjing, Jiangsu 210008 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Liu-Song","family":"Yin","sequence":"additional","affiliation":[{"name":"SunHo (China) BioPharmaceutical Co., Ltd. , Nanjing, Jiangsu 210008 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cai-Yun","family":"Zhong","sequence":"additional","affiliation":[{"name":"Department of Nutrition and Food Safety, School of Public Health, Nanjing Medical University , Nanjing 211166, Jiangsu ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6359-741X","authenticated-orcid":false,"given":"Qing-Fang","family":"Miao","sequence":"additional","affiliation":[{"name":"NHC Key Laboratory of Biotechnology for Microbial Drugs, Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences & Peking Union Medical College , Beijing 100050 ,","place":["China"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2026,4,8]]},"reference":[{"key":"2026061502262600900_ref1","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1212476","article-title":"Cancer immunotherapies: advances and bottlenecks","volume":"14","author":"Rui","year":"2023","journal-title":"Front Immunol"},{"key":"2026061502262600900_ref2","doi-asserted-by":"publisher","DOI":"10.1080\/15384047.2024.2315655","article-title":"Immunotherapy resistance in solid tumors: mechanisms and potential solutions","volume":"25","author":"Lefler","year":"2024","journal-title":"Cancer Biol Ther"},{"key":"2026061502262600900_ref3","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1186\/s12943-021-01489-2","article-title":"Combination strategies with PD-1\/PD-L1 blockade: current advances and future directions","volume":"21","author":"Yi","year":"2022","journal-title":"Mol Cancer"},{"key":"2026061502262600900_ref4","doi-asserted-by":"publisher","first-page":"539","DOI":"10.1038\/s41571-024-00905-y","article-title":"Bispecific and multispecific antibodies in oncology: opportunities and challenges","volume":"21","author":"Goebeler","year":"2024","journal-title":"Nature Rev Clin Oncol"},{"key":"2026061502262600900_ref5","doi-asserted-by":"publisher","first-page":"893","DOI":"10.1016\/j.trecan.2024.07.002","article-title":"Bispecific antibodies: advancing precision oncology","volume":"10","author":"Herrera","year":"2024","journal-title":"Trends Cancer"},{"key":"2026061502262600900_ref6","doi-asserted-by":"publisher","DOI":"10.3390\/jpm12081235","article-title":"CD24: a novel target for cancer immunotherapy","volume":"12","author":"Panagiotou","year":"2022","journal-title":"J Pers Med"},{"key":"2026061502262600900_ref7","doi-asserted-by":"publisher","first-page":"392","DOI":"10.1038\/s41586-019-1456-0","article-title":"CD24 signalling through macrophage Siglec-10 is a target for cancer immunotherapy","volume":"572","author":"Barkal","year":"2019","journal-title":"Nature"},{"key":"2026061502262600900_ref8","doi-asserted-by":"publisher","DOI":"10.3390\/biomedicines11123159","article-title":"Targeting CD24 in cancer immunotherapy","volume":"11","author":"Chen","year":"2023","journal-title":"Biomedicines"},{"key":"2026061502262600900_ref9","doi-asserted-by":"publisher","DOI":"10.1016\/j.intimp.2023.110557","article-title":"CD24 blockade as a novel strategy for cancer treatment","volume":"121","author":"Wang","year":"2023","journal-title":"Int Immunopharmacol"},{"key":"2026061502262600900_ref10","doi-asserted-by":"publisher","first-page":"1400","DOI":"10.2967\/jnumed.125.270167","article-title":"CD24 as a novel radiopharmaceutical target for hepatocellular carcinoma","volume":"66","author":"Makala","year":"2025","journal-title":"J Nucl Med"},{"key":"2026061502262600900_ref11","doi-asserted-by":"publisher","first-page":"e006704","DOI":"10.1136\/jitc-2023-006704","article-title":"CLDN18.2 and 4-1BB bispecific antibody givastomig exerts antitumor activity through CLDN18.2-expressing tumor-directed T-cell activation","volume":"11","author":"Gao","year":"2023","journal-title":"J Immunother Cancer"},{"key":"2026061502262600900_ref12","doi-asserted-by":"publisher","DOI":"10.3390\/cancers13102288","article-title":"CD137 as an attractive T cell co-stimulatory target in the TNFRSF for immuno-oncology drug development","volume":"13","author":"Hashimoto","year":"2021","journal-title":"Cancers"},{"key":"2026061502262600900_ref13","doi-asserted-by":"crossref","first-page":"1929","DOI":"10.1158\/1078-0432.CCR-16-1272","article-title":"Results from an integrated safety analysis of urelumab, an agonist anti-CD137 monoclonal antibody","volume":"23","author":"Segal","year":"2017","journal-title":"Clin Cancer Res"},{"key":"2026061502262600900_ref14","doi-asserted-by":"crossref","first-page":"1816","DOI":"10.1158\/1078-0432.CCR-17-1922","article-title":"Phase I study of single-agent utomilumab (PF-05082566), a 4-1BB\/CD137 agonist, in patients with advanced cancer","volume":"24","author":"Segal","year":"2018","journal-title":"Clin Cancer Res"},{"key":"2026061502262600900_ref15","doi-asserted-by":"publisher","first-page":"561","DOI":"10.21873\/anticanres.11349","article-title":"CD24 modulates chemosensitivity of MCF-7 breast cancer cells","volume":"37","author":"Onishi","year":"2017","journal-title":"Anticancer Res"},{"key":"2026061502262600900_ref16","doi-asserted-by":"publisher","DOI":"10.3390\/ijms20030660","article-title":"Characterization of a novel third-generation anti-CD24-CAR against ovarian cancer","volume":"20","author":"Klapdor","year":"2019","journal-title":"Int J Mol Sci"},{"key":"2026061502262600900_ref17","first-page":"2031","article-title":"Divergent effects of 4-1BB antibodies on antitumor immunity and on tumor-reactive T-cell generation","volume":"61","author":"Kim","year":"2001","journal-title":"Cancer Res"},{"key":"2026061502262600900_ref18","doi-asserted-by":"publisher","first-page":"357","DOI":"10.2174\/1568009054629681","article-title":"The therapeutic potential of 4-1BB (CD137) in cancer","volume":"5","author":"Nam","year":"2005","journal-title":"Curr Cancer Drug Targets"},{"key":"2026061502262600900_ref23","doi-asserted-by":"publisher","first-page":"e000661","DOI":"10.1136\/jitc-2020-000661","article-title":"An immune evasion mechanism with IgG4 playing an essential role in cancer and implication for immunotherapy","volume":"8","author":"Wang","year":"2020","journal-title":"J Immunother Cancer"}],"container-title":["Antibody Therapeutics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/academic.oup.com\/abt\/advance-article-pdf\/doi\/10.1093\/abt\/tbag014\/67989932\/tbag014.pdf","content-type":"application\/pdf","content-version":"am","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/abt\/article-pdf\/9\/2\/168\/67989932\/tbag014.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/academic.oup.com\/abt\/article-pdf\/9\/2\/168\/67989932\/tbag014.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,6,15]],"date-time":"2026-06-15T06:26:35Z","timestamp":1781504795000},"score":1,"resource":{"primary":{"URL":"https:\/\/academic.oup.com\/abt\/article\/9\/2\/168\/8644001"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,4,1]]},"references-count":19,"journal-issue":{"issue":"2","published-print":{"date-parts":[[2026,4,1]]}},"URL":"https:\/\/doi.org\/10.1093\/abt\/tbag014","relation":{},"ISSN":["2516-4236"],"issn-type":[{"value":"2516-4236","type":"electronic"}],"subject":[],"published-other":{"date-parts":[[2026,4]]},"published":{"date-parts":[[2026,4,1]]}}}