Mesothelin-targeted immunotoxin RG7787 has synergistic anti-tumor activity when combined with taxanes

Abstract

Recombinant immunotoxins (RITs) are antibody-based therapeutics that carry a toxin payload. The RG7787 RIT targets the cancer antigen mesothelin to deliver a recombinantly-engineered, reduced immunogenicity variant of Pseudomonas exotoxin A (PE) to the cytosol where it inhibits protein synthesis. Here we demonstrate that maximal doses of RG7787 temporarily halt growth of pancreatic cancer tumor xenografts, similar to the approved drugs gemcitabine and nab-paclitaxel, however, combination of the RIT with nab-paclitaxel produces durable complete regressions in most mice. Synergy between taxane and anti-MSLN RITs has been previously demonstrated in mouse models, but direct interaction of the combination in cell culture was not observed. Here, we show that this favorable interaction occurs in cell culture, is dependent on the dose and duration of RG7787 exposure, requires the catalytically active PE, and still occurs with RIT targeting a non-MSLN surface antigen. Unexpectedly, the combination does not increase RG7787-mediated protein synthesis inhibition nor perturb downstream apoptotic markers of RIT-mediated killing, but does augment levels of acetylated tubulin, a marker of taxane activity. Taken together, these data suggest that PE increases cell sensitivity to taxane-mediated killing by increasing taxane-mediated microtubule stability and priming cells for apoptosis by decreasing levels of the pro-survival factor Mcl-1.

Protein Synthesis Inhibition Activity of Mesothelin Targeting Immunotoxin LMB-100 Decreases Concentrations of Oncogenic Signaling Molecules and Secreted Growth Factors

“…Previously, it has been shown that LMB-100 causes a dose-dependent decrease in KLM1 new protein synthesis at 12 h with the maximal effect seen by 18 h post-initiation of treatment when using a 100 ng/mL dose. Even 24 h after washing away LMB-100, restoration of new protein synthesis is not observed [ 12 ]. We hypothesized that this prolonged protein synthesis inhibition (PSI) would lower total protein levels in cells.…”

“…Since EF-2 is a non-redundant enzyme critical for protein translation, PE activity halts new protein synthesis in target cells [ 11 ]. This is a lethal insult in many cell types, including some PDACs [ 6 , 12 ].…”

Paclitaxel synergizes with exposure time adjusted CD22-targeting immunotoxins against B-cell malignancies

“…Mesothelin-targeting rITs are enhanced by various small molecules [ 25 – 27 ] or the chemotherapeutic drug paclitaxel [ 28 – 30 ]. Paclitaxel enhances the efficacy of bolus doses of mesothelin-targeted rIT in vivo [ 28 , 29 , 31 ], which was translated in a new clinical trial testing the combination (NCT02810418).…”

Amatuximab and novel agents targeting mesothelin for solid tumors

“…Recent data confirm the hypothesis that new immunotoxins actually investigated in clinical trials, such as LMB-100 (previously named RG7787), might have synergistic anticancer effects when used in combination with taxanes or other standard chemotherapy. 39 …”