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Exploration of Pyrrolobenzodiazepine (PBD)-Dimers Containing Disulfide-Based Prodrugs as Payloads for Antibody-Drug Conjugates.

Pei, Zhonghua; Chen, Chunjiao; Chen, Jinhua; Cruz-Chuh, Josefa Dela; Delarosa, Reginald; Deng, Yuzhong; Fourie-O'Donohue, Aimee; Figueroa, Isabel; Guo, Jun; Jin, Weiwei; Khojasteh, S Cyrus; Kozak, Katherine R; Latifi, Brandon; Lee, James; Li, Guangmin; Lin, Eva; Liu, Liling; Lu, Jiawei; Martin, Scott; Ng, Carl; Nguyen, Trung; Ohri, Rachana; Lewis Phillips, Gail; Pillow, Thomas H; Rowntree, Rebecca K; Stagg, Nicola J; Stokoe, David; Ulufatu, Sheila; Verma, Vishal A; Wai, John; Wang, Jing; Xu, Keyang; Xu, Zijin; Yao, Hui; Yu, Shang-Fan; Zhang, Donglu; Dragovich, Peter S.
Mol Pharm; 15(9): 3979-3996, 2018 Sep 04.
Artigo em Inglês | MEDLINE | ID: mdl-30040421
A number of cytotoxic pyrrolobenzodiazepine (PBD) monomers containing various disulfide-based prodrugs were evaluated for their ability to undergo activation (disulfide cleavage) in vitro in the presence of either glutathione (GSH) or cysteine (Cys). A good correlation was observed between in vitro GSH stability and in vitro cytotoxicity toward tumor cell lines. The prodrug-containing compounds were typically more potent against cells with relatively high intracellular GSH levels (e.g., KPL-4 cells). Several antibody-drug conjugates (ADCs) were subsequently constructed from PBD dimers that incorporated selected disulfide-based prodrugs. Such HER2 conjugates exhibited potent antiproliferation activity against KPL-4 cells in vitro in an antigen-dependent manner. However, the disulfide prodrugs contained in the majority of such entities were surprisingly unstable toward whole blood from various species. One HER2-targeting conjugate that contained a thiophenol-derived disulfide prodrug was an exception to this stability trend. It exhibited potent activity in a KPL-4 in vivo efficacy model that was approximately three-fold weaker than that displayed by the corresponding parent ADC. The same prodrug-containing conjugate demonstrated a three-fold improvement in mouse tolerability properties in vivo relative to the parent ADC, which did not contain the prodrug.
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