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Physicochemical and Metabolic Optimization of NAMPT Inhibitors Enables Effective Antibody-Drug Conjugates for Liquid
Pablo Ruedas1, Hendrik Gruss1, Alexander Hempelmann1
1Heidelberg Pharma Research GmbH, Gregor-Mendel-Strasse 22, 68526, Ladenburg, Germany.
Abstract:
Antibody drug conjugates (ADCs) enable selective delivery of highly potent small molecules, yet most clinically validated payloads target solely cell-division pathways with several drawbacks such as high off-target toxicity and a lack of efficacy on nondividing tumor cells (e.g., tumor stem cells). Metabolic targets such as nicotinamide phosphoribosyltransferase (NAMPT) offer a complementary mode of action and are predestined as ADC payloads since systemic toxicities have prevented clinical use of NAMPT inhibitors (NAMPTi) as free drugs. Here we show that highly hydrophobic NAMPTi, especially cyanoguanidine-containing inhibitors, are chemically and metabolically suboptimal for ADC deployment due to limited efficacy likely due to lysosomal conversion to inactive guanylureas. Guided by structure-based design, and molecular dynamics simulations, we developed two next-generation NAMPT inhibitors featuring (i) a tertiary alcohol to balance hydrophilicity and (ii) an isoindoline-urea group to improve lysosomal stability in comparison to the cyanoguanidine. The optimized inhibitors retained high affinity to the NAMPT enzyme and showed strong cellular activity upon targeted delivery through ADCs. When conjugated to anti-CD30, anti-HER2, or anti-TROP2 antibodies, the resulting ADCs showed durable responses in hematologic and solid tumor models, including complete regressions in the metabolically stringent NCI-N87 gastric carcinoma xenograft after a single 2 mg/kg dose. These findings highlight physicochemical tuning and lysosomal stability as key design principles for NAMPT-based payloads and support NAMPT inhibition as a very promising mode of action (MoA) for next-generation ADC therapeutics.
Insights
Next-generation antibody-drug conjugates (ADCs) utilize novel metabolic targeting via nicotinamide phosphoribosyltransferase inhibitors (NAMPTi) to overcome limitations of traditional chemotherapy, showing potent anti-tumor activity.
Area of Science:
- Oncology
- Pharmacology
- Bioconjugation Chemistry
Background:
- Antibody-drug conjugates (ADCs) offer targeted delivery of potent drugs, but current payloads primarily target cell division, leading to toxicity and limited efficacy in non-dividing cells.
- Metabolic targets like nicotinamide phosphoribosyltransferase (NAMPT) present a complementary approach, but NAMPT inhibitors (NAMPTi) have systemic toxicity issues as free drugs.
Purpose of the Study:
- To develop novel NAMPT inhibitors optimized for ADC payloads, addressing limitations of existing hydrophobic inhibitors and improving lysosomal stability.
- To evaluate the efficacy of these next-generation NAMPTi-based ADCs in preclinical cancer models.
Main Methods:
- Structure-based design and molecular dynamics simulations were used to engineer new NAMPT inhibitors with improved physicochemical properties (tertiary alcohol for hydrophilicity, isoindoline-urea for stability).
- Developed ADCs by conjugating optimized NAMPTi to anti-CD30, anti-HER2, and anti-TROP2 antibodies.
- Assessed ADC efficacy in hematologic and solid tumor xenograft models, including the NCI-N87 gastric carcinoma model.
Main Results:
- Engineered NAMPT inhibitors demonstrated retained high enzyme affinity and potent cellular activity when delivered via ADCs.
- ADCs exhibited durable responses in various hematologic and solid tumor models.
- A single low dose of ADC achieved complete regressions in a metabolically demanding gastric cancer xenograft model.
Conclusions:
- Physicochemical tuning and enhanced lysosomal stability are critical for developing effective NAMPT-based ADC payloads.
- NAMPT inhibition represents a promising mode of action for next-generation ADC therapeutics, overcoming limitations of current treatments.
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