A Novel NAMPT Inhibitor-Based Antibody-Drug Conjugate Payload Class for Cancer Therapy.

Area of Science:

• Oncology
• Medicinal Chemistry
• Pharmacology

Background:

• Intracellular nicotinamide phosphoribosyltransferase (NAMPT) inhibition is a novel mechanism for cancer-targeting antibody-drug conjugates (ADCs).
• Existing ADC effector chemistries can be expanded with new classes of inhibitors.

Purpose of the Study:

• To develop a novel structural class of NAMPT inhibitors as ADC payloads.
• To optimize these inhibitors for conjugation to antibodies targeting C4.4a, HER2, or B7H3.
• To evaluate the efficacy and characteristics of these novel NAMPT inhibitor ADCs.

Main Methods:

• Structure-activity relationship studies and protein structural information guided the design of NAMPT inhibitors.
• Inhibitors were conjugated to antibodies targeting C4.4a, HER2, or B7H3.
• In vitro and in vivo studies assessed ADC potency, selectivity, pharmacokinetics, metabolite profiling, and antitumor efficacy in xenograft models.

Main Results:

• Highly potent NAMPT inhibitor (NAMPTi) effector chemistries were developed.
• Optimized NAMPTi-ADCs showed potent in vivo antitumor efficacy in relevant xenograft models.
• These ADCs demonstrated good selectivity and the generation of NAMPTi payload metabolites was observed in vitro and in vivo.

Conclusions:

• NAMPT inhibitor ADCs represent an attractive new payload class for cancer treatment.
• These ADCs exhibit potent efficacy and selectivity, with potential for treating solid and hematological cancers.
• The study demonstrates, for the first time, the generation of NAMPTi payload metabolites from NAMPTi-ADCs.