Characterization of a re‐engineered, mesothelin‐targeted Pseudomonas exotoxin fusion protein for lung cancer therapy

Autor: Frieder Bauss, Martin Lechmann, Ben-Fillippo Krippendorff, Roland Staack, Frank Herting, Matthias Festag, Sabine Imhof-Jung, Friederike Hesse, Marc Pompiati, Gwendlyn Kollmorgen, Rita da Silva Mateus Seidl, Birgit Bossenmaier, Wilma Lau, Christian Schantz, Jan O. Stracke, Ulrich Brinkmann, Masanori Onda, Ira Pastan, Klaus Bosslet, Gerhard Niederfellner
Jazyk: angličtina
Rok vydání: 2016
Předmět:
Zdroj: Molecular Oncology, Vol 10, Iss 8, Pp 1317-1329 (2016)
Druh dokumentu: article
ISSN: 1878-0261
1574-7891
DOI: 10.1016/j.molonc.2016.07.003
Popis: Mesothelin overexpression in lung adenocarcinomas correlates with the presence of activating KRAS mutations and poor prognosis. Hence SS1P, a mesothelin‐targeted immunotoxin, could offer valuable treatment options for these patients, but its use in solid tumor therapy is hampered by high immunogenicity and non‐specific toxicity. To overcome both obstacles we developed RG7787, a de‐immunized cytotoxic fusion protein comprising a humanized SS1 Fab fragment and a truncated, B‐cell epitope silenced, 24 kD fragment of Pseudomonas exotoxin A (PE24). Reactivity of RG7787 with sera from immunotoxin‐treated patients was >1000 fold reduced. In vitro RG7787 inhibited cell viability of lung cancer cell lines with picomolar potency. The pharmacokinetic properties of RG7787 in rodents were comparable to SS1P, yet it was tolerated up to 10 fold better without causing severe vascular leak syndrome or hepatotoxicity. A pharmacokinetic/pharmacodynamic model developed based on NCI‐H596 xenograft studies showed that for RG7787 and SS1P, their in vitro and in vivo potencies closely correlate. At optimal doses of 2–3 mg/kg RG7787 is more efficacious than SS1P. Even large, well established tumors (600 mm3) underwent remission during three treatment cycles with RG7787. Also in two patient‐derived lung cancer xenograft models, Lu7336 and Lu7187, RG7787 showed anti‐tumor efficacy. In monotherapy two treatment cycles were moderately efficacious in the Lu7336 model but showed good anti‐tumor activity in the KRAS mutant Lu7187 model (26% and 80% tumor growth inhibition, respectively). Combination of RG7787 with standard chemotherapies further enhanced efficacy in both models achieving near complete eradication of Lu7187 tumors.
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