{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T13:00:36Z","timestamp":1790600436873,"version":"4.1.0"},"reference-count":24,"publisher":"American Chemical Society (ACS)","issue":"9","license":[{"start":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T00:00:00Z","timestamp":1786665600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2026,9,28]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:p>Antibody-drug conjugates (ADCs) represent an emerging pharmaceutical category that leverages antibodies to facilitate drug delivery to target cells. A key challenge for ADCs is increasing the drug-antibody ratio (DAR) to improve efficacy without compromising their properties, such as pharmacokinetics. Here, we present a novel polypeptide-based platform that substantially increases the DAR of antibody-payload ADCs while minimally compromising the ADCs\u2019 inherent characteristics. A polypeptide-based antibody-drug conjugate lead (polypeptide ADC 6c), capable of achieving a DAR of up to 61, was synthesized using the versatile click reaction method based on our polypeptide-based platform. 6c could efficiently recognize antigens, be subsequently endocytosed, and achieve subnanomolar activity at the cellular level. Moreover, 6c exhibited excellent pharmacokinetic parameters and potent antitumor efficacy in mice. Collectively, this study provides and characterizes a highly variable polypeptide backbone platform that can be used to efficiently develop innovative ADCs with high payloads for the treatment of various cancers<\/jats:p>","DOI":"10.1021\/jacsau.6c01025","type":"journal-article","created":{"date-parts":[[2026,8,14]],"date-time":"2026-08-14T22:01:21Z","timestamp":1786744881000},"page":"5362-5369","source":"Crossref","is-referenced-by-count":0,"title":["Development of a\nPolypeptide-Based Platform to Construct\nAntibody-Drug Conjugates with High Potency"],"prefix":"10.1021","volume":"6","author":[{"given":"Ruyao","family":"Tang","sequence":"first","affiliation":[{"name":"Peking University , , ,","place":["Beijing, People\u2019s Republic of China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fusheng","family":"Guo","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, People\u2019s Republic of China, 100871"]},{"name":"Chinese Academy of Medical Sciences & Peking Union Medical College , , ,","place":["Beijing, People\u2019s Republic of China, 100193"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jinyi","family":"Bai","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, People\u2019s Republic of China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0380-8035","authenticated-orcid":true,"given":"Xiaoguang","family":"Lei","sequence":"additional","affiliation":[{"name":"Peking University , , ,","place":["Beijing, People\u2019s Republic of China, 100871"]},{"name":"Peking University , , ,","place":["Beijing, People\u2019s Republic of China, 100871"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"316","published-online":{"date-parts":[[2026,8,14]]},"reference":[{"key":"2026092808085323500_cit1","doi-asserted-by":"publisher","first-page":"209","DOI":"10.3322\/caac.21660","article-title":"Global cancer statistics\n2020: GLOBCAN estimates of incidence and mortality worldwide for 36\ncancers in 185 countries. CA","volume":"71","author":"Sung","year":"2021","journal-title":"Cancer J. Clin."},{"key":"2026092808085323500_cit2","doi-asserted-by":"publisher","first-page":"59","DOI":"10.1046\/j.1523-5394.1999.07205.x","article-title":"Perception\nof chemotherapy side effects\ncancer versus noncancer patients","volume":"7","author":"Lindley","year":"1999","journal-title":"Cancer Pract."},{"key":"2026092808085323500_cit3","doi-asserted-by":"publisher","first-page":"116709","DOI":"10.1016\/j.ejmech.2024.116709","article-title":"Antibody-drug\nconjugates for targeted cancer therapy: Recent advances in potential\npayloads","volume":"276","author":"Xi","year":"2024","journal-title":"Eur. J. Med. Chem."},{"key":"2026092808085323500_cit4","doi-asserted-by":"publisher","first-page":"93","DOI":"10.1038\/s41392-022-00947-7","article-title":"Antibody drug\nconjugate:\nthe \u201cbiological missile\u201d for targeted cancer therapy","volume":"7","author":"Fu","year":"2022","journal-title":"Signal Transduction Targeted Ther"},{"key":"2026092808085323500_cit5","doi-asserted-by":"publisher","first-page":"7063","DOI":"10.1158\/1078-0432.CCR-04-0789","article-title":"Effects\nof Drug Loading on the Antitumor Activity of a Monoclonal Antibody\nDrug Conjugate","volume":"10","author":"Hamblet","year":"2004","journal-title":"Clin. Cancer Res."},{"key":"2026092808085323500_cit6","doi-asserted-by":"publisher","first-page":"4336","DOI":"10.1021\/jm020149g","article-title":"Monoclonal\nantibody conjugates of doxorubicin prepared with branched peptide\nlinkers: inhibition of aggregation by methoxytriethyleneglycol chains","volume":"45","author":"King","year":"2002","journal-title":"J. Med. Chem."},{"key":"2026092808085323500_cit7","first-page":"127","article-title":"Immunoconjugates\ncontaining novel maytansinoids: promising anticancer drugs","volume":"52","author":"Chari","year":"1992","journal-title":"Cancer Res."},{"key":"2026092808085323500_cit8","doi-asserted-by":"publisher","first-page":"1278","DOI":"10.3390\/cancers15041278","article-title":"Mechanisms of resistance\nto antibody-drug conjugates","volume":"15","author":"Abelman","year":"2023","journal-title":"Cancers"},{"key":"2026092808085323500_cit9","doi-asserted-by":"publisher","first-page":"713","DOI":"10.3390\/cancers15030713","article-title":"Mechanisms\nof ADC toxicity and strategies\nto increase ADC tolerability","volume":"15","author":"Nguyen","year":"2023","journal-title":"Cancers"},{"key":"2026092808085323500_cit10","doi-asserted-by":"publisher","first-page":"733","DOI":"10.1038\/nbt.3212","article-title":"Reducing\nhydrophobicity of homogeneous antibody-drug\nconjugates improves pharmacokinetics and therapeutic index","volume":"33","author":"Lyon","year":"2015","journal-title":"Nat. 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Sci."},{"key":"2026092808085323500_cit14","doi-asserted-by":"publisher","first-page":"3365","DOI":"10.1158\/0008-5472.CAN-15-0129","article-title":"A Polymer-Based\nAntibody-Vinca Drug\nConjugate Platform: Characterization and Preclinical Efficacy","volume":"75","author":"Yurkovetskiy","year":"2015","journal-title":"Cancer Res."},{"key":"2026092808085323500_cit15","doi-asserted-by":"publisher","first-page":"354","DOI":"10.1002\/open.201900066","article-title":"Dextramabs:\na Novel Format of Antibody-Drug Conjugates Featuring a Multivalent\nPolysaccharide Scaffold","volume":"8","author":"Schneider","year":"2019","journal-title":"ChemistryOpen"},{"key":"2026092808085323500_cit16","doi-asserted-by":"publisher","first-page":"1011","DOI":"10.1038\/s41587-025-02772-z","article-title":"Antibody-bottlebrush prodrug conjugates for targeted\ncancer therapy","volume":"44","author":"Liu","year":"2026","journal-title":"Nat. Biotechnol."},{"key":"2026092808085323500_cit17","doi-asserted-by":"publisher","first-page":"1863","DOI":"10.1021\/mp500666j","article-title":"Site-specific conjugation of monomethyl\nauristatin E to anti-CD30 antibodies improves their pharmacokinetics\nand therapeutic index in rodent models","volume":"12","author":"Lhospice","year":"2015","journal-title":"Mol.\nPharmaceutics"},{"key":"2026092808085323500_cit18","doi-asserted-by":"publisher","first-page":"184","DOI":"10.1016\/j.jconrel.2016.06.040","article-title":"Anti-PEG antibodies in the clinic:\ncurrent issues and beyond PEGylation","volume":"244","author":"Zhang","year":"2016","journal-title":"J. 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Chem."},{"key":"2026092808085323500_cit23","doi-asserted-by":"publisher","first-page":"698","DOI":"10.1080\/19420862.2016.1151590","article-title":"An enzymatic\ndeconjugation method for the analysis of small molecule active drugs\non antibody-drug conjugates","volume":"8","author":"Li","year":"2016","journal-title":"mAbs"},{"key":"2026092808085323500_cit24","doi-asserted-by":"publisher","first-page":"958","DOI":"10.1158\/1535-7163.MCT-15-1004","article-title":"Molecular basis of Valine- Citrulline-PABC\nlinker instability in site-specific ADCs and its mitigation by linker\ndesign","volume":"15","author":"Dorywalska","year":"2016","journal-title":"Mol. Cancer Ther."}],"container-title":["JACS Au"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pubs.acs.org\/doi\/pdf\/10.1021\/jacsau.6c01025","content-type":"application\/pdf","content-version":"vor","intended-application":"unspecified"},{"URL":"https:\/\/pubs.acs.org\/jaaucr\/article-pdf\/6\/9\/5362\/66573807\/jacsau.6c01025.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/pubs.acs.org\/jaaucr\/article-pdf\/6\/9\/5362\/66573807\/jacsau.6c01025.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,9,28]],"date-time":"2026-09-28T12:32:52Z","timestamp":1790598772000},"score":1,"resource":{"primary":{"URL":"https:\/\/pubs.acs.org\/jaaucr\/article\/6\/9\/5362\/5257206\/Development-of-a-Polypeptide-Based-Platform-to"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,14]]},"references-count":24,"journal-issue":{"issue":"9","published-online":{"date-parts":[[2026,8,14]]},"published-print":{"date-parts":[[2026,9,28]]}},"URL":"https:\/\/doi.org\/10.1021\/jacsau.6c01025","relation":{},"ISSN":["2691-3704"],"issn-type":[{"value":"2691-3704","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,8,14]]}}}