Efficacy of RG7787, a Next-Generation Mesothelin-Targeted Immunotoxin, against Triple-Negative Breast and Gastric Cancers

Abstract

The RG7787 mesothelin-targeted recombinant immunotoxin (RIT) consists of an antibody fragment targeting mesothelin (MSLN) fused to a 24-kD fragment of Pseudomonas exotoxin A for cell killing. Compared with prior RITs, RG7787 has improved properties for clinical development including decreased nonspecific toxicity and immunogenicity and resistance to degradation by lysosomal proteases. MSLN is a cell surface glycoprotein highly expressed by many solid tumor malignancies. New reports have demonstrated that MSLN is expressed by a significant percentage of triple-negative breast and gastric cancer clinical specimens. Here, panels of triplenegative breast and gastric cancer cell lines were tested for surface MSLN expression, and for sensitivity to RG7787 in vitro and in animal models. RG7787 produced >95% cell killing of the HCC70 and SUM149 breast cancer cell lines in vitro with IC 50 < 100 pmol/L. RG7787 was also effective against gastric cancer cell lines MKN28, MKN45, and MKN74 in vitro, with subnanomolar IC 50s . In a nude mouse model, RG7787 treatment (2.5 mg/kg i.v. qod Â3-4) resulted in a statistically significant 41% decrease in volumes of HCC70 xenograft tumors (P < 0.0001) and an 18% decrease in MKN28 tumors (P < 0.0001). Pretreatment with paclitaxel (50 mg/kg i.p.) enhanced efficacy, producing 88% and 70% reduction in tumor volumes for HCC70 and MKN28, respectively, a statistically significant improvement over paclitaxel alone (P < 0.0001 for both). RG7787 merits clinical testing for triple-negative breast and gastric cancers. Mol Cancer Ther; 13(11); 2653-61. Ó2014 AACR.

Advances in Anticancer Immunotoxin Therapy

“…This modification also improved the therapeutic window of the molecule because PE fragments bearing this modification do not cause vascular leak syndrome in animal models and thus can be given at much higher doses than previous-generation PE molecules, like SS1P. As a single agent, RG7787 shrinkstumors in xenograft models of MSLN-expressing lung [63], gastric, and triple-negative breast cancers [64]. In addition, combination with paclitaxel resulted in marked in vivo synergy and induced complete responses in a xenograft model of pancreatic cancer [65].…”

Anticancer Effects of Mesothelin-Targeted Immunotoxin Therapy Are Regulated by Tyrosine Kinase DDR1

“…MSLN is a cell-surface glycoprotein whose expression is restricted to mesothelial cells. It is an excellent tumor target because it is highly expressed in mesothelioma, lung, gastric, pancreatic, ovarian, and triple-negative breast cancers (TNBC) (2–8). …”

Immunotoxins, Resistance and Cancer Stem Cells: Future Perspective

“…However, it was hypothesized that ABT-737 induces ER stress and facilitates its transport to the cytosol [26]. Recently, IT named RG7787, a PE-based toxin targeting mesothelin was reported to be efficient due to resistance to lysosomal degradation in breast and gastric cancers [66].…”