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

Belinda L Sun,Edwin Posadas,Xiaoguang Sun,Sara M Camp,Anne E Cress,Joe G N Garcia,Lin Tang,Alexander N Garcia

doi:10.3390/ph14121322

Belinda L Sun, Edwin Posadas + Show 6 more

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https://doi.org/10.3390/ph14121322

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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.

Highlights

We previously demonstrated that extracellular nicotinamide phosphoribosyltransferase is a damage-associated molecular pattern protein (DAMP) with the capacity to uniquely bind and activate Toll-like receptor
We tested the therapeutic efficacy of the ALT-100 mAb-treated group (mAb) in human Prostate cancer (PCa) orthotopic xenograft mouse models in which human DU145 or PC3 cells were implanted into the prostate of SCID male mice as primary tumor models of PCa [19] (Figure 1A–C)
Similar to studies targeting extracellular nicotinamide phosphoribosyltransferase (eNAMPT) in preclinical models of radiation pneumonitis [21] and pulmonary hypertension [22], we evaluated the therapeutic effects of an eNAMPT-neutralizing humanized monoclonal antibody, ALT-100, in two human PCa orthotopic xenograft SCID mice models with implantation of aggressive PCa cells, DU145 or PC3, representing both PTEN-positive (DU145) and PTEN-negative (PC3) tumor subtypes

Summary

Introduction

Prostate cancer (PCa) is the most common cancer and the second leading cause of cancer-related death in men in the United States [1]. Lethal PCa evolves through disease progression [2], mostly from androgen-driven adenocarcinomas to castration-resistant prostate cancer (CRCP), with reduced responsiveness to current standard androgen deprivation therapy and chemotherapy [3,4,5]. The overall 5-year survival rate declines from 98%. To 30% in progressed metastatic PCa [6,7]. There is an urgent unmet need to develop therapeutic approaches to treat PCa aggressive progression and reduce PCa lethality

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