Presentation Abstract

Abstract Number: 1560
Presentation Title: VE-PTP inhibitor AKB-9778 mitigates IL-2-induced VLS and interacts positively with IL-2 against melanoma and renal cancer tumors in mice
Presentation Time: Monday, Apr 19, 2010, 9:00 AM -12:00 PM
Location: Exhibit Hall A-C, Poster Section 23
Poster Section: 23
Poster Board Number: 13
Author Block: Mingli Cao1, Dan Lindner1, Ernest Borden1, Robert Shalwitz2, Taolin Yi1. 1The Cleveland Clinic, Cleveland, OH; 2Akebia Therapeutics, Inc, Mason, OH
Abstract Body: IL-2 induces complete responses (CR) durable more than 10 years in a subpopulation of patients with advanced melanoma or renal cell carcinoma, establishing the clinical effectiveness of immunotherapy for human malignancies. However, the application and clinical efficacy of IL-2 have been limited by its major dose-limiting toxicity vascular leak syndrome (VLS), which occurs in the majority (~65%) of the patients and often necessitates cessation of the cytokine treatment. Being a life-threatening toxicity, VLS is managed by supportive care with no specific treatment. Therapeutics for IL-2-induced VLS might improve the efficacy and tolerance of the cytokine.
Recent studies implicated heightened Ang2 as a potential mediator of VLS via antagonizing Ang1 and thus blocking Tie2/AKT signaling in endothelial cells. Being a regulator of Tie2 phosphorylation, vascular endothelial protein tyrosine phosphatase (VE-PTP) might be targeted to modulate Tie2/AKT signaling although tthe effects and tolerance of targeting VE-PTP were not well-defined.
Our work herein identified compound AKB-9778 as a VE-PTP inhibitor capable of inducing pTie2 and down stream pAKT in endothelial cells, interacting positively with Ang1 and/or Ang2 to increase cellular pTie2 levels, reducing IL-2-induced circulating Ang2 in mice and protecting mice from IL-2-induced VLS. AKB-9778 also interacted positively with IL-2 against B16 melanoma and Renca renal cancer tumors in mice in a tolerated manner. These data provide pre-clinical proof of concept evidence of targeting VE-PTP to mitigate IL-2-induced VLS. AKB-9778 may provide beneficial adjunctive therapy in combination with IL-2 in cancer treatment by reducing VLS and enhancing efficacy.