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In this study, we present a novel pre\u2010targeting approach that integrates host\u2010guest chemistry with an antibody\u2010recruiting concept to create mAbs with superior effector functions. Using rituximab (RTX), a clinically approved anti\u2010CD20 mAb, as our model, we modified RTX by conjugating it with adamantane (Ada) derivatives and various polyethylene glycol (PEG) linkers to produce RTX\u2010Ada conjugates. These conjugates effectively formed RTX\u2010rhamnose (Rha) complexes in\u2005situ through self\u2010assembly, driven by host\u2010guest interactions with Rha\u2010modified \u03b2\u2010cyclodextrin. This mechanism successfully redirected endogenous anti\u2010Rha antibodies to target cells, enhancing the availability of Fc domains for improved effector functions, including complement\u2010dependent cytotoxicity (CDC). A structure\u2010activity relationship study indicated that the potency of these in\u2005situ complexes was significantly influenced by the length of the PEG linker used; shorter PEG linkers correlated with higher CDC activity. Given the variability in endogenous antibody levels among individuals, this strategy presents a flexible and promising platform for enhancing the efficacy of mAb\u2010based cancer immunotherapy.<\/jats:p>","DOI":"10.1002\/chem.202403539","type":"journal-article","created":{"date-parts":[[2024,10,27]],"date-time":"2024-10-27T05:29:56Z","timestamp":1730006996000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":4,"title":["In Situ Self\u2010Assembly of Antibody\u2010Rhamnose Complex as a Pre\u2010Targeting Strategy for Enhanced Cancer Immunotherapy"],"prefix":"10.1002","volume":"31","author":[{"given":"Haofei","family":"Hong","sequence":"first","affiliation":[{"name":"The Key Laboratory of Carbohydrate Chemistry &amp; Biotechnology Ministry of Education School of Biotechnology Jiangnan University  Wuxi 214122 China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kun","family":"Zhou","sequence":"additional","affiliation":[{"name":"The Key Laboratory of Carbohydrate Chemistry &amp; 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