Abstract 2907: Identification and optimization of a novel NAMPT inhibitor-based ADC payload class for cancer therapy

Abstract

Abstract Inhibition of intracellular nicotinamide phosphoribosyltransferase (NAMPT) represents a differentiated mode-of-action for tumor-targeting antibody-drug conjugates (ADCs) independent from cell proliferation. This opens up the possibility to target slowly growing tumors as well as resting antigen-positive tumor cells in addition to highly proliferative tumors. We developed a novel structural class of NAMPT inhibitors as ADC payloads to complement the currently available effector chemistries. An SAR-driven approach supported by available structural information was pursued to identify a suitable attachment point for the linker to connect the NAMPT inhibitor with the antibody. Optimization of scaffold and linker led to highly potent effector chemistries which were conjugated to anti-C4.4a (LYPD3) or anti-B7H3 (CD276) antibodies and tested on antigen-positive and -negative cancer cell lines derived from solid and hematological tumor indications. Furthermore, tuning of the hydrophilicity of the linker and the conjugation method ensured low aggregation of the NAMPT inhibitor ADCs. Pharmacokinetic studies were performed in human plasma to assess the stability of the linkage of the NAMPT inhibitor payload to the antibody. Moreover, permeability studies of the payload metabolites helped to evaluate potential by-stander effects of the ADCs. This led to the development of highly potent NAMPT inhibitor ADCs with a very good selectivity profile versus the corresponding isotype control ADCs. In depth in vitro and in vivo studies on the internalization and the metabolism allowed analysis of the intracellular fate of the payload metabolites and revealed the formation of the phosphoribosylated catabolite adducts in C4.4a expressing A549-cells. Taken together, we hereby present the development of a new NAMPT inhibitor-based payload class applicable for conjugation to diverse antibodies with a good technical profile and high potency and selectivity in antigen-positive cancer models. Citation Format: Niels Böhnke, Markus Berger, Nils Griebenow, Anja Giese, Judith Günther, Anette Sommer, Stefanie Hammer, Sandra Berndt, Antje M. Wengner, Rudolf Beier, Beatrix Stelte-Ludwig, Christoph Mahlert, Simone Greven, Lisa Dietz, Hannah Joerissen, Antje Rottmann, Michael Erkelenz, Naomi Barak, Ulf Bömer, Dominik Mumber, Bertolt Kreft, Lars Linden, Carl Friedrich Nising, Hilmar Weinmann. Identification and optimization of a novel NAMPT inhibitor-based ADC payload class for cancer therapy [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 2907.