title: Characterization of a re-engineered, mesothelin-targeted Pseudomonas exotoxin fusion protein for lung cancer therapy.
abstract: 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 mm(3)) 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.
authors: Roche Pharma Research & Early Development (pRED), Discovery Oncology, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Frieder
authors: F
authors: Bauss
authors: Roche Pharma Research & Early Development (pRED), Pharmaceutical Sciences, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Martin
authors: M
authors: Lechmann
authors: Roche pRED Innovation Center Basel, Pharmaceutical Sciences, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors: Ben-Fillippo
authors: BF
authors: Krippendorff
authors: Roche Pharma Research & Early Development (pRED), Pharmaceutical Sciences, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Roland
authors: R
authors: Staack
authors: Roche Pharma Research & Early Development (pRED), Discovery Oncology, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Frank
authors: F
authors: Herting
authors: Roche pRED Innovation Center Basel, Pharmaceutical Sciences, F. Hoffmann-La Roche AG, Grenzacherstrasse 124, CH-4070 Basel, Switzerland.
authors: Matthias
authors: M
authors: Festag
authors: Roche Pharma Research & Early Development (pRED), Large Molecule Research, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Sabine
authors: S
authors: Imhof-Jung
authors: Roche Pharma Research & Early Development (pRED), Large Molecule Research, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Friederike
authors: F
authors: Hesse
authors: Roche Pharma Research & Early Development (pRED), Large Molecule Research, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Marc
authors: M
authors: Pompiati
authors: Roche Pharma Research & Early Development (pRED), Discovery Oncology, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Gwendlyn
authors: G
authors: Kollmorgen
authors: Roche Pharma Research & Early Development (pRED), Discovery Oncology, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Rita
authors: R
authors: da Silva Mateus Seidl
authors: Roche Pharma Research & Early Development (pRED), Discovery Oncology, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Birgit
authors: B
authors: Bossenmaier
authors: Roche Pharma Research & Early Development (pRED), Large Molecule Research, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Wilma
authors: W
authors: Lau
authors: Roche Pharma Research & Early Development (pRED), Large Molecule Research, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Christian
authors: C
authors: Schantz
authors: Roche Pharma Research & Early Development (pRED), Large Molecule Research, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany; Pharmaceutical Development & Supplies, Pharma Technical Development Biologics Europe, F. Hoffmann-La Roche Ltd., Basel, Switzerland.
authors: Jan O
authors: JO
authors: Stracke
authors: Roche Pharma Research & Early Development (pRED), Large Molecule Research, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Ulrich
authors: U
authors: Brinkmann
authors: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors: Masanori
authors: M
authors: Onda
authors: Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
authors: Ira
authors: I
authors: Pastan
authors: Roche Pharma Research & Early Development (pRED), Discovery Oncology, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany.
authors: Klaus
authors: K
authors: Bosslet
authors: Roche Pharma Research & Early Development (pRED), Discovery Oncology, Innovation Center Munich, Roche Diagnostics GmbH Penzberg, Nonnenwald 2, D-82377 Penzberg, Germany. Electronic address: gerhard.niederfellner@roche.com.
authors: Gerhard
authors: G
authors: Niederfellner
mesh_terms: D036002:ADP Ribose Transferases / Q000627:therapeutic use*; D000818:Animals; D001427:Bacterial Toxins / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D005098:Exotoxins / Q000627:therapeutic use*; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism*; D006801:Humans; D008099:Liver / Q000187:drug effects / Q000473:pathology; D008175:Lung Neoplasms / Q000188:drug therapy* / Q000473:pathology; D000090204:Mesothelin; D016513:Mice, SCID; D008954:Models, Biological; D015202:Protein Engineering; D011549:Pseudomonas / Q000378:metabolism*; D051381:Rats; D011993:Recombinant Fusion Proteins / Q000493:pharmacokinetics / Q000494:pharmacology / Q000627:therapeutic use*; D037521:Virulence Factors / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays; D000097668:Pseudomonas aeruginosa Exotoxin A
chemical_list: D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D005098:Exotoxins; D058851:GPI-Linked Proteins; D000090204:Mesothelin; D011993:Recombinant Fusion Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C000715528:Msln protein, mouse
keywords: De-immunization; Immunotoxin; Lung cancer; Patient-derived xenografts; Pharmacokinetics; Targeted therapy