Targeted Delivery of Cytotoxic NAMPT Inhibitors Using Antibody-Drug Conjugates.

Autor:	Neumann CS; Seattle Genetics, Inc., Bothell, Washington. cneumann@seagen.com., Olivas KC; Seattle Genetics, Inc., Bothell, Washington., Anderson ME; Seattle Genetics, Inc., Bothell, Washington., Cochran JH; Seattle Genetics, Inc., Bothell, Washington., Jin S; Seattle Genetics, Inc., Bothell, Washington., Li F; Seattle Genetics, Inc., Bothell, Washington., Loftus LV; Seattle Genetics, Inc., Bothell, Washington., Meyer DW; Seattle Genetics, Inc., Bothell, Washington., Neale J; Seattle Genetics, Inc., Bothell, Washington., Nix JC; Advanced Light Source, Lawrence Berkeley Laboratory, Berkeley, California., Pittman PG; Seattle Genetics, Inc., Bothell, Washington., Simmons JK; Seattle Genetics, Inc., Bothell, Washington., Ulrich ML; Seattle Genetics, Inc., Bothell, Washington., Waight AB; Seattle Genetics, Inc., Bothell, Washington., Wong A; Seattle Genetics, Inc., Bothell, Washington., Zaval MC; Seattle Genetics, Inc., Bothell, Washington., Zeng W; Seattle Genetics, Inc., Bothell, Washington., Lyon RP; Seattle Genetics, Inc., Bothell, Washington., Senter PD; Seattle Genetics, Inc., Bothell, Washington.
Jazyk:	angličtina
Zdroj:	Molecular cancer therapeutics [Mol Cancer Ther] 2018 Dec; Vol. 17 (12), pp. 2633-2642. Date of Electronic Publication: 2018 Sep 21.
DOI:	10.1158/1535-7163.MCT-18-0643
Abstrakt:	Antibody-drug conjugates (ADCs) are a therapeutic modality that enables the targeted delivery of cytotoxic drugs to cancer cells. Identification of active payloads with unique mechanisms of action is a key aim of research efforts in the field. Herein, we report the development of inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) as a novel payload for ADC technology. NAMPT is a component of a salvage biosynthetic pathway for NAD, and inhibition of this enzyme results in disruption of primary cellular metabolism leading to cell death. Through derivatization of the prototypical NAMPT inhibitor FK-866, we identified potent analogues with chemical functionality that enables the synthesis of hydrophilic enzyme-cleavable drug linkers. The resulting ADCs displayed NAD depletion in both cell-based assays and tumor xenografts. Antitumor efficacy is demonstrated in five mouse xenograft models using ADCs directed to indication-specific antigens. In rat toxicology models, a nonbinding control ADC was tolerated at >10-fold the typical efficacious dose used in xenografts. Moderate, reversible hematologic effects were observed with ADCs in rats, but there was no evidence for the retinal and cardiac toxicities reported for small-molecule inhibitors. These findings introduce NAMPT inhibitors as active and well-tolerated payloads for ADCs with promise to improve the therapeutic window of NAMPT inhibition and enable application in clinical settings. (©2018 American Association for Cancer Research.)
Databáze:	MEDLINE
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