title: 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.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Christine
authors.initials: C
authors.lastname: Alewine
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland.
authors.forename: Laiman
authors.initials: L
authors.lastname: Xiang
authors.affiliation: Center for Product Evaluation, Pharmaceuticals and Medical Device Agency, Tokyo, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Yamori
authors.affiliation: Pharmaceutical Research and Early Development (pRED), Discovery Oncology, F. Hoffman-La Roche, Penzberg, Germany.
authors.forename: Gerhard
authors.initials: G
authors.lastname: Niederfellner
authors.affiliation: Pharmaceutical Research and Early Development (pRED), Discovery Oncology, F. Hoffman-La Roche, Penzberg, Germany.
authors.forename: Klaus
authors.initials: K
authors.lastname: Bosslet
authors.affiliation: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, NIH, Bethesda, Maryland. pastani@mail.nih.gov.
authors.forename: Ira
authors.initials: I
authors.lastname: Pastan
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D000922:Immunotoxins / Q000627:therapeutic use*; D000090204:Mesothelin; D051379:Mice; D008819:Mice, Nude; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D064726:Triple Negative Breast Neoplasms / Q000188:drug therapy* / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D058851:GPI-Linked Proteins; D018796:Immunoconjugates; D000922:Immunotoxins; C000715527:MSLN protein, human; C000715528:Msln protein, mouse; C000597116:LMB-100; D000090204:Mesothelin