Abstract 2907: Everolimus enhances the cytotoxic action of the immunotoxin, HA22, directed to CD22 on B-cell malignancies

Abstract

Abstract Recombinant immunotoxins, antibody-toxin fusion proteins, are therapeutic proteins designed as targeted anti-cancer agents. Clinical trials of immunotoxins directed to surface CD22 or mesothelin are ongoing with a 50% complete response rate in patients with refractory Hairy Cell Leukemia as well as dramatic responses in some patients with advanced mesothelioma. To identify agents that could improve clinical efficacy further, a screen of 500 approved or near-approved compounds (MIPE-4) was conducted, revealing everolimus as a potential enhancer of Pseudomonas exotoxin-based recombinant immunotoxins. When the immunotoxin HA22 (moxetumomab pasudotox), which targets CD22, was added to various B-cell lines, everolimus enhanced cytotoxicity by 2-10-fold. Kinetic analyses indicated that combinations of HA22 and everolimus (0.25 uM) accelerated the cessation of protein synthesis in Nalm-6 and CA46 cells compared to either agent alone. Likewise, in CellTiterGlo assays of cell viability, combinations of HA22 and everolimus resulted in a greater loss of ATP from cells. Western blot analysis of key survival proteins indicated an early loss of Mcl-1 in combination treatments. Additional experiments are ongoing to extend these observations with the goal of uncovering insights in the mechanism of synergy seen with these two compounds. Citation Format: Antonella Antignani, Matteo Pasetto, Chris Choo, Evan Angelus, Lesley Mathews, Rajarshi Guha, Paul Shinn, Marc Ferrer, Craig J. Thomas, Ira Pastan, David J. Fitzgerald. Everolimus enhances the cytotoxic action of the immunotoxin, HA22, directed to CD22 on B-cell malignancies. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2907. doi:10.1158/1538-7445.AM2014-2907