{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,7]],"date-time":"2026-03-07T12:49:18Z","timestamp":1772887758921,"version":"3.50.1"},"reference-count":11,"publisher":"Wiley","issue":"3","license":[{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"},{"start":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T00:00:00Z","timestamp":1770854400000},"content-version":"tdm","delay-in-days":0,"URL":"http:\/\/doi.wiley.com\/10.1002\/tdm_license_1.1"}],"content-domain":{"domain":["chemistry-europe.onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["ChemMedChem"],"published-print":{"date-parts":[[2026,2,12]]},"abstract":"<jats:p>\n                    Site\u2010specific antibody\u2010drug conjugates (ADCs) represent a promising class of biotherapeutics with enhanced pharmacological profiles. we herein report a novel one\u2010step strategy for preparing homogeneous ADCs with a drug\u2010to\u2010antibody ratio (DAR) of 4. This approach leverages a Fc ligand\u2010directed thioester\u2010based acylating reagent combined with a\n                    <jats:italic>\u03b2<\/jats:italic>\n                    \u2010glutamic acid\u2010based branching linker to enable precise conjugation of four MMAE molecules per antibody. Through systematic optimization of buffer composition and pH, we successfully mitigated the hydrophobicity\u2010driven aggregation typically associated with K248\u2010linked DAR4 ADCs, while maintaining exceptional conjugation efficiency. The method demonstrates excellent tolerance to protein concentration and is applicable to multiple IgG subtypes, including those targeting HER2, cMet, ROR1, and FR\u03b1. All resulting ADC products exhibited high homogeneity. Notably,\n                    <jats:bold>ADC\u20104<\/jats:bold>\n                    , functionalized with a VK(SO\n                    <jats:sub>3<\/jats:sub>\n                    H)\u2010modified linker, showed enhanced aggregation stability, potent tumor suppression, and a favorable safety profile, highlighting its promising therapeutic potential.\n                  <\/jats:p>","DOI":"10.1002\/cmdc.202501075","type":"journal-article","created":{"date-parts":[[2026,2,12]],"date-time":"2026-02-12T17:50:17Z","timestamp":1770918617000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["One\u2010Step Assembly of Homogeneous DAR4 ADCs via a Traceless Fc Ligand\u2010Directed Acylation Strategy"],"prefix":"10.1002","volume":"21","author":[{"given":"Yue","family":"Zeng","sequence":"first","affiliation":[{"name":"Key Laboratory of Glyco\u2010drug Research of Zhejiang Province School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences  Hangzhou China"},{"name":"State Key Laboratory of Drug Research Center for Biotherapeutics Discovery Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Yuyu","family":"Lin","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica Nanjing University of Chinese Medicine  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Qi","family":"Sun","sequence":"additional","affiliation":[{"name":"School of Chinese Materia Medica Nanjing University of Chinese Medicine  Nanjing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jiaying","family":"Hang","sequence":"additional","affiliation":[{"name":"Key Laboratory of Glyco\u2010drug Research of Zhejiang Province School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences  Hangzhou China"},{"name":"State Key Laboratory of Drug Research Center for Biotherapeutics Discovery Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"},{"name":"University of Chinese Academy of Sciences  Beijing China"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Wei","family":"Shi","sequence":"additional","affiliation":[{"name":"Key Laboratory of Glyco\u2010drug Research of Zhejiang Province School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences  Hangzhou China"},{"name":"State Key Laboratory of Drug Research Center for Biotherapeutics Discovery Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"},{"name":"University of Chinese Academy of Sciences  Beijing 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of Glyco\u2010drug Research of Zhejiang Province School of Pharmaceutical Science and Technology Hangzhou Institute for Advanced Study University of Chinese Academy of Sciences  Hangzhou China"},{"name":"State Key Laboratory of Drug Research Center for Biotherapeutics Discovery Research Shanghai Institute of Materia Medica Chinese Academy of Sciences  Shanghai China"},{"name":"University of Chinese Academy of Sciences  Beijing China"},{"name":"School of Chinese Materia Medica Nanjing University of Chinese Medicine  Nanjing 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