Abstract

Inhibition of NAMPT to reprogram NAD + metabolism and achieve antitumor activity has become an area of intense interest in cancer metabolism. However, systemic NAMPT inhibition has been hampered by several toxicities due to the ubiquitous requirement of NAD + in normal tissues. To overcome this limitation, we engineered A9 , a GD2-directed antibody-drug conjugate that delivers a NAMPT inhibitor selectively to a neuroblastoma model. A9 demonstrated potent, GD2-dependent cytotoxicity in GD2-high cells, while showing minimal cytotoxicity in GD2-low and normal cells. Mechanistically, A9 depletes intracellular NAD + and ATP, triggering cell cycle arrest and apoptosis. Co-administration of NMN, the direct product of NAMPT, fully restored ATP levels, prevented apoptosis, and rescued cell viability, thereby confirming the on-target NAMPT inhibitory activity of the ADC. In vivo , A9 showed significant antitumor efficacy in SH-SY5Y xenograft model. Collectively, these findings establish A9 as a promising therapeutic approach for neuroblastoma, combing the metabolic vulnerability of NAMPT inhibition with the tumor selectivity of GD2-directed delivery to achieve potent and targeted antitumor activity.