Abstract C163: Understanding the mechanism for synergistic anti-tumor activity of a meosthelin-targeted immunotoxin and taxanes

Recombinant immunotoxins (RITs) are antibody-based therapies that carry a bacterial toxin payload. RG7787 is a next generation RIT that targets the cancer antigen mesothelin (MSLN) to deliver a recombinantly engineered variant of Pseudomonas exotoxin A (PE) into the cell cytosol. PE irreversibly modifies elongation factor-2 (EF-2) by catalyzing addition of an ADP-ribose moiety. This causes EF-2 inactivation, inhibition of new protein synthesis, and a drop in the short-lived pro-survival factor mcl-1, triggering apoptosis. Combination of RG7787 with paclitaxel or nab-paclitaxel results in boosted anti-tumor efficacy in several mouse models. In the KLM1 pancreatic cancer xenograft model, either drug alone halts tumor growth while the combination produces complete regressions. Here, we show that enhanced efficacy is also seen using an identically structured RIT that targets the transferrin receptor instead of mesothelin (LMB-74), but is not seen when RIT is combined with gemcitabine, suggesting that the effect is specific to both taxane and PE. Further, we have found that the interaction of RG7787 and taxane can be modeled in vitro. Under these conditions, the interaction is dependent on the dose of RG7787, and cannot be replicated by a chemical inhibitor of protein synthesis. Co-treatment with taxane does not affect the depth, rate of onset or recovery of cells from RG7787-mediated protein synthesis inhibition. Tumor cell killing occurs over a delayed time course and is not associated with an early drop in mcl-1 levels as is seen when using a cytotoxic dose of RG7787 alone. Taken together, these data suggest that PE treatment sensitizes cancer cells to taxane-mediated killing. Citation Format: Christine Campo Alewine, Emily Kolyvas, Ira Pastan. Understanding the mechanism for synergistic anti-tumor activity of a meosthelin-targeted immunotoxin and taxanes. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics; 2015 Nov 5-9; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2015;14(12 Suppl 2):Abstract nr C163.