Cancer cell sensitization to TRAIL therapy using PEGylated long-acting TRAIL combined with a tumor-homing nanoparticle TRAIL sensitizer

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UNMET NEED: Recombinant human tumor necrosis factor (TNF)-related apoptosis inducing ligand (hrTRAIL) and its agonistic antibodies have been under intense focus as crucial molecularly-targeted antitumor biologics due to their ability to selectively induce death receptor (DR)-mediated apoptosis in cancer cells while sparing healthy tissue. Yet, natural TRAIL resistance and the extremely short half-life of rhTRAIL have impeded clinical translation. Disclosed herein is a series of long-acting PEGylated TRAIL (TRAILPEG) with enhanced stability and half-life, and their use in combination with a tumor-homing nanoparticle TRAIL sensitizer to effectively induce apoptosis in cancer tissue. Advantages include:
  • TRAILPEG peptides with enhanced stability and half-life
  • Combination of TRAILPEG and a tumor-homing nanoparticle TRAIL sensitizer to effectively induce apoptosis in cancer cells in vivo with minimal systemic toxicity
TECHNICAL DETAILS: TRAIL has attracted great interest as a cancer therapy because it selectively induces death receptor (DR)-mediated apoptosis in cancer cells while sparing normal tissue. However, recombinant human TRAIL demonstrates limited therapeutic efficacy in clinical trials, possibly due to TRAIL-resistance of primary cancers and its inherent short half-life. Here inventors introduced drug delivery approaches to maximize in vivo potency of TRAIL in TRAIL-resistant tumor xenografts by (1) extending the half-life of the ligand with TRAILPEG and (2) concentrating a TRAIL sensitizer in tumors via tumor-homing nanoparticles. Antitumor efficacy of TRAILPEG with tumor-homing sensitizer was evaluated in HCT116 and HT-29 colon xenografts. Western blot, real-time PCR, immunohistochemistry and cell viability assays were employed to investigate mechanisms of action and antitumor efficacy of the combination. Doxorubicin (DOX) was shown to sensitize TRAIL-resistant HT-29 colon cancer cells to TRAIL by upregulating mRNA expression of DR5 by 60% in vitro. DOX encapsulated in hyaluronic acid-based nanoparticles (HAC/DOX) and intravenously administered with TRAILPEG potentiated DR-mediated apoptosis in HT-29 tumors by upregulating DR5 protein expression by 70% and initiated both extrinsic and intrinsic apoptotic pathways with reduced systemic toxicity. This study demonstrates a unique approach to overcome TRAIL-based therapy drawbacks using sequential administration of a tumor-homing TRAIL sensitizer and long-acting TRAILPEG.
PATENT STATUS: Pending PCT Application WO 2016/149264
INVENTORS: Seulki Lee, Martin Pomper, Yumin Oh, Magdalena Swierczewska
ASSOCIATED PUBLICATIONS and TECHNOLOGIES: JHU Ref C13688J Control Release. 2015 Dec 28;220(Pt B):671-81.
Patent Information:
Title App Type Country Serial No. Patent No. File Date Issued Date Expire Date Patent Status
COMPOSITIONS AND METHODS FOR SENSITIZING CELLS TO TRAIL-INDUCED APOPTOSIS PCT: Patent Cooperation Treaty United States 15/559,108 9/18/2017     Pending
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