Efficacy of RG7787, a Next Generation Mesothelin-targeted Immunotoxin, Against Triple-negative Breast and Gastric Cancers
Menée sur des lignées cellulaires de cancer du sein triplement négatif et de cancer de l'estomac, puis à l'aide d'un modèle murin, cette étude évalue l'activité antitumorale d'une immunotoxine recombinante ciblée sur la mésothéline (RG7787)
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 to prior RITs, RG7787 has improved properties for clinical development including decreased non-specific 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 MSLN is expressed by a significant percentage of triple-negative breast and gastric cancer clinical specimens. Here, panels of triple-negative 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 IC50 < 100 pM. RG7787 was also effective against gastric cancer cell lines MKN28, MKN45 and MKN74 in vitro, with subnanomolar IC50's. In a nude mouse model, RG7787 treatment (2.5 mg/kg I.V. qod x3-4) 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). Pre-treatment with paclitaxel (50 mg/kg ip) 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.
http://mct.aacrjournals.org/content/early/2014/09/19/1535-7163.MCT-14-0132.abstract