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

Christopher S Neumann,Michelle L Ulrich,Paul G Pittman,Robert P Lyon,Jay C Nix,Jason Neale,Peter D Senter,Martha E Anderson,Kathleen C Olivas,Jessica K Simmons,Abbie Wong,Fu Li,Margo C Zaval,Weiping Zeng,Steven Jin,Luke V Loftus,Andrew B Waight,Julia H Cochran,David W Meyer

doi:10.1158/1535-7163.mct-18-0643

Abstract

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.

Highlights

Antibody–drug conjugates (ADCs) have attracted a great deal of recent interest, with FDA approval of four drugs and promising data from several others in various stages of clinical development [1]
The analogues were evaluated for binding to nicotinamide phosphoribosyltransferase (NAMPT) using a competitive fluorescence polarization (FP) assay where they displayed varying reductions in EC50 as compared with FK-866
While NAMPT inhibitors are potent cytotoxic molecules, their utility as chemotherapeutic agents in the treatment of cancer has been hampered by toxicity

Summary

Introduction

Antibody–drug conjugates (ADCs) have attracted a great deal of recent interest, with FDA approval of four drugs and promising data from several others in various stages of clinical development [1]. Most of the advanced ADCs contain antitubulin drugs such as auristatins and maytansines, or DNAtargeted drugs such as calicheamicins and camptothecins [2,3,4,5] While these payloads have been applied to a broad spectrum of tumor types, an important objective within the field has been to extend the technology beyond these drug classes and to identify novel agents that have complementary mechanisms of activity [1]. This endeavor has proven to be quite challenging, because most drugs do not have the right profiles of potency, availability, chemical functionalities, and stability required for successful application as ADC warheads. We became interested in exploring inhibitors of nicotinamide phosphoribosyltransferase (NAMPT) as ADC payloads due to their chemical simplicity, high potencies on both their biochem-

Methods

Results

Conclusion