Organic‐Solvent‐Free “Lego‐Like” Modular Preparation of Fab‐Nondestructive Antibody‐Drug Conjugates with Ultrahigh Drug‐to‐Antibody Ratio

Abstract

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

Click Conjugation of Zwitterionic Peptide with DNA Strand: An Efficient Antifouling Strategy for Versatile Photoelectrochemical Aptasensor

“…The click reaction, known for its simplicity and high efficiency, has emerged as an ideal strategy for synthesizing various conjugates. , In the case of the BZP–cDNA conjugate, the click reaction successfully took place between the exposed azide group on BZP and the 3′-DBCO-functionalized hydroxyl end of cDNA. Specifically, a mixture of 500 μL of 40 μM BZP and 500 μL of 40 μM cDNA was stirred for 5 min at 37 °C on a shaker.…”

“…Click reaction has gained widespread acclaim for its remarkable capability to expediently form carbon-hetero bonds, , enabling the covalent connection of diverse molecular constituents with impressive yield and efficacy. We hereby present an ingenious antifouling strategy for a versatile PEC aptasensor, wherein the click reaction is employed to conjugate a zwitterionic peptide to a DNA strand.…”

Synthesis of Poly-γ-Glutamic Acid and Its Application in Biomedical Materials

“…Notably, the DAR of MMAE reached 41.6, effectively overcoming the challenge of the low tolerance dose of MMAE in the human body. Nevertheless, the biochemical effects induced by PGA in this process will need further confirmation through subsequent experiments ( Figure 8 B) [ 67 ].…”

Immunoswitch Nanomodulators Enable Active Targeting and Selective Proliferation of Regulatory T Cells for Multiple Sclerosis Therapy

“…This suggests that the Fc-III-4C peptide in Pep-PLG-GEE bound relatively steadily to the Fc segment in IgG and possessed a potential drug delivery ability (Figure S7). 41 Thus, the IgG NPs were conveniently assembled and maintained stable due to the high affinity of the Fc-III-4C peptide in Pep-PLG-GEE for the Fc of IgG.…”