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 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 pmol/L. RG7787 was also effective against gastric cancer cell lines MKN28, MKN45, and MKN74 in vitro, with subnanomolar IC50s. In a nude mouse model, RG7787 treatment (2.5 mg/kg i.v. qod ×3-4) 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.

• Authors: Christine Alewine, Laiman Xiang, Takao Yamori, Gerhard Niederfellner, Klaus Bosslet, Ira Pastan
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 13 Issue 11 Pg. 2653-61 (Nov 2014) ISSN: 1538-8514 [Electronic] United States
• PMID: 25239937 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• GPI-Linked Proteins
• Immunoconjugates
• Immunotoxins
• MSLN protein, human
• Msln protein, mouse
• LMB-100
• Mesothelin

Topics

• Animals
• Cell Line, Tumor
• Female
• GPI-Linked Proteins (metabolism)
• Humans
• Immunoconjugates (pharmacology)
• Immunotoxins (therapeutic use)
• Mesothelin
• Mice
• Mice, Nude
• Stomach Neoplasms (drug therapy, metabolism)
• Triple Negative Breast Neoplasms (drug therapy, metabolism)
• Xenograft Model Antitumor Assays