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To enhance drug safety and efficacy, an antibody\u2010drug conjugate, TE\u20101146, comprising six lenalidomide drug molecules site\u2010specifically conjugated to a reconfigured daratumumab to deliver cytotoxic lenalidomide to tumor cells is developed. TE\u20101146 is prepared using the HighDAR platform, which employs i) a maleimide\u2010containing \u201cmulti\u2010arm linker\u201d to conjugate multiple drug molecules creating a drug bundle, and ii) a designed peptide with a Zn\n                    <jats:sup>2+<\/jats:sup>\n                    \u2010binding cysteine at the C\u2010termini of a reconfigured daratumumab for site\u2010specific drug bundle conjugation. It is shown that TE\u20101146 remains intact and effectively enters CD38\u2010expressing tumor cells, releasing lenalidomide, leading to enhanced cell\u2010killing effects compared to lenalidomide\/daratumumab alone or their combination. This reveals the remarkable potency of lenalidomide once internalized by myeloma cells. TE\u20101146 precisely delivers lenalidomide to target CD38\u2010overexpressing tumor cells. In contrast, lenalidomide without daratumumab cannot easily enter cells, whereas daratumumab without lenalidomide relies on Fc\u2010dependent effector functions to kill tumor cells.\n                  <\/jats:p>","DOI":"10.1002\/advs.202307852","type":"journal-article","created":{"date-parts":[[2024,3,13]],"date-time":"2024-03-13T08:48:59Z","timestamp":1710319739000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":7,"title":["An Antibody\u2010Drug Conjugate for Multiple Myeloma Prepared by Multi\u2010Arm Linkers"],"prefix":"10.1002","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-1365-5378","authenticated-orcid":false,"given":"Yueh\u2010Hsiang","family":"Yu","sequence":"first","affiliation":[{"name":"Immunwork, Inc.  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