A Humanized Monoclonal Antibody Targeting Extracellular Nicotinamide Phosphoribosyltransferase Prevents Aggressive Prostate Cancer Progression

Abstract

Prostate cancer (PCa) is the major cause of cancer-related death in males; however, effective treatments to prevent aggressive progression remain an unmet need. We have previously demonstrated that secreted extracellular nicotinamide phosphoribosyltransferase (eNAMPT) is a multifunctional innate immunity regulator that promotes PCa invasion. In the current study, we further investigate the therapeutic effects of an eNAMPT-neutralizing humanized monoclonal antibody (ALT-100 mAb) in preclinical PCa orthotopic xenograft models. We utilized human aggressive PCa cells (DU145 or PC3) for prostate implantation in SCID mice receiving weekly intraperitoneal injections of either ALT-100 mAb or IgG/PBS (control) for 12 weeks. Prostatic tumors and solid organs were examined for tumor growth, invasion, and metastasis and for biochemical and immunohistochemistry evidence of NFκB activation. ALT-100 mAb treatment significantly improved overall survival of SCID mice implanted with human PCa orthotopic prostate xenografts while inducing tumor necrosis, decreasing PCa proliferation and reducing local invasion and distal metastases. The ALT-100 mAb inhibits NFκB phosphorylation and signaling in PCa cells both in vitro and in vivo. This study demonstrates that eNAMPT neutralization effectively prevents human PCa aggressive progression in preclinical models, indicating its high potential to directly address the unmet need for an effective targeted therapy for patients with aggressive PCa.

Biochemical and genomic identification of novel biomarkers in progressive sarcoidosis: HBEGF, eNAMPT, and ANG-2

“…The identification of eNAMPT as a sarcoidosis biomarker and candidate gene is highly novel. Secreted eNAMPT, a DAMP and ligand for TLR4 ( 14 ), is a therapeutic target ( 54 – 56 ). eNAMPT-triggered inflammation dysregulates signaling pathway that disrupts fibrosis/remodeling resolution.…”

eNAMPT Neutralization Preserves Lung Fluid Balance and Reduces Acute Renal Injury in Porcine Sepsis/VILI-Induced Inflammatory Lung Injury

“…Reagents unless specifically stated were obtained from Sigma-Aldrich (St. Louis, MO). Details of the eNAMPT mAb (ALT-100) have been previously reported ( Sun et al, 2021 ; Garcia et al, 2022a ; Bermudez et al, 2022 ) and was provided by Aqualung Therapeutics (Tucson, AZ). Western blot analyses details on antibodies utilized provided in Supplemental Methods.…”

Implantable Devices for the Treatment of Breast Cancer

“…It is an immunodeficient mouse model that often reconstitutes human immune cells [83]. There are many different human-ized mouse models that provide very specific answers with respect to how implantable devices may work in the human body [84][85][86]. They may also show how sustainable these devices will be inside the human body in the future based on the immune reaction to these devices in these mouse models, and often it also depends on the graft versus host disease (GVHD) reaction of that model [84].…”