GD2-directed NAMPT inhibition using antibody-drug conjugates in neuroblastoma
Jing Liu1, Qi Cheng2, Shangwei Huangfu2
1Shanghai Institute for Advanced Immunochemical Studies, ShanghaiTech University, Shanghai, 201210, China; School of Life Science and Technology, ShanghaiTech University, Shanghai, 201210, China; Shanghai Clinical Research and Trial Center, Shanghai, 201210, China.
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.
Insights
Targeting NAMPT (nicotinamide phosphoribosyltransferase) with antibody-drug conjugates like A9 offers a novel strategy for neuroblastoma treatment. This approach selectively delivers the inhibitor, reducing toxicity and enhancing antitumor effects.
Area of Science:
- Biochemistry
- Oncology
- Pharmacology
Background:
- Targeting NAMPT (nicotinamide phosphoribosyltransferase) is a promising strategy in cancer metabolism for reprogramming NAD+ levels and achieving antitumor activity.
- Systemic NAMPT inhibition faces challenges due to toxicities in normal tissues requiring NAD+.
Purpose of the Study:
- To develop a targeted therapy for neuroblastoma by selectively inhibiting NAMPT.
- To evaluate the efficacy and mechanism of action of a GD2-directed antibody-drug conjugate (A9) delivering a NAMPT inhibitor.
Main Methods:
- Engineered A9, a GD2-directed antibody-drug conjugate carrying a NAMPT inhibitor.
- Assessed A9's cytotoxicity in GD2-high, GD2-low, and normal cells.
- Investigated the mechanism of action, including NAD+ and ATP depletion, cell cycle arrest, and apoptosis.
- Conducted in vivo studies using a SH-SY5Y xenograft model.
Main Results:
- A9 exhibited potent, GD2-dependent cytotoxicity in GD2-high neuroblastoma cells with minimal toxicity in normal cells.
- A9 induced cell cycle arrest and apoptosis by depleting intracellular NAD+ and ATP.
- Co-administration of NMN (nicotinamide mononucleotide) rescued cell viability, confirming on-target NAMPT inhibition.
- A9 demonstrated significant antitumor efficacy in vivo.
Conclusions:
- A9 is a promising therapeutic candidate for neuroblastoma, leveraging targeted delivery to exploit NAMPT's metabolic vulnerability.
- This approach combines the benefits of NAMPT inhibition with the specificity of GD2-directed delivery for potent antitumor activity.
