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Mol Cancer Ther. 2018 Sep 21. pii: molcanther.0643.2018. doi: 10.1158/1535-7163.MCT-18-0643. [Epub ahead of print]

Targeted delivery of cytotoxic NAMPT inhibitors using antibody-drug conjugates.

Author information

1
Seattle Genetics, Inc. cneumann@seagen.com.
2
Seattle Genetics, Inc.
3
DMPK, Magenta Therapeutics.
4
Advanced Light Source, Lawrence Berkeley Laboratory.

Abstract

Antibody-drug conjugates (ADCs) are a therapeutic modality that enable 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. Anti-tumor efficacy is demonstrated in five mouse xenograft models using ADCs directed to indication-specific antigens. In rat toxicology models, a non-binding control ADC was tolerated at >10-fold the typical efficacious dose used in xenografts. Moderate, reversible hematological 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.

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