Antibody‐drug conjugates (ADCs) have exciting possibilities in targeted tumor therapy. However, in the existing ADC preparation processes, the random attachment of the payloads to the antigen‐binding fragments (Fab) greatly increases the risk of disrupting its antigen recognition ability, while the DAR is low, leading to a cumbersome preparation process and low drug delivery efficiency. Herein, we used poly(glutamic acid) to expand the number of drug binding sites, based on the “click chemistry” of azide and DBCO, and the high affinity of Fc‐III‐4C peptide to the crystalline fragment (Fc) of the monoclonal antibodies. We obtained various antibody‐polymer‐drug conjugates (APDCs) with ultra‐high DAR using this organic‐solvent‐free “Lego‐like” modular construction. Among them, aHER2‐P‐MMAE with DAR of 41.6 achieved tumor growth inhibition (TGI) of 99.7% for both medium‐sized and large SKOV‐3 ovarian tumors, and aPDL1‐P‐MMAE (DAR = 40.7) achieved TGI of 98.5% for MC38 colon tumors. In summary, we created a universal platform to prepare Fab‐nondestructive ADCs with ultra‐high DAR, which can be used to develop precision medicine for personalized anti‐cancer therapy.This article is protected by copyright. All rights reserved
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