title: Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA specific for the ErbB2/HER2 receptor in patients with advanced solid malignomas.
abstract: BACKGROUND
  ScFv(FRP5)-ETA is a recombinant antibody toxin with binding specificity for ErbB2 (HER2). It consists of an N-terminal single-chain antibody fragment (scFv), genetically linked to truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against ErbB2-overexpressing tumor cells was previously demonstrated in vitro and in animal models. Here we report the first systemic application of scFv(FRP5)-ETA in human cancer patients.
  
  
  METHODS
  We have performed a phase I dose-finding study, with the objective to assess the maximum tolerated dose and the dose-limiting toxicity of intravenously injected scFv(FRP5)-ETA. Eighteen patients suffering from ErbB2-expressing metastatic breast cancers, prostate cancers, head and neck cancer, non small cell lung cancer, or transitional cell carcinoma were treated. Dose levels of 2, 4, 10, 12.5, and 20 microg/kg scFv(FRP5)-ETA were administered as five daily infusions each for two consecutive weeks.
  
  
  RESULTS
  No hematologic, renal, and/or cardiovascular toxicities were noted in any of the patients treated. However, transient elevation of liver enzymes was observed, and considered dose limiting, in one of six patients at the maximum tolerated dose of 12.5 microg/kg, and in two of three patients at 20 microg/kg. Fifteen minutes after injection, peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA were obtained at a dose of 10 microg/kg, indicating that predicted therapeutic levels of the recombinant protein can be applied without inducing toxic side effects. Induction of antibodies against scFv(FRP5)-ETA was observed 8 days after initiation of therapy in 13 patients investigated, but only in five of these patients could neutralizing activity be detected. Two patients showed stable disease and in three patients clinical signs of activity in terms of signs and symptoms were observed (all treated at doses > or = 10 microg/kg). Disease progression occurred in 11 of the patients.
  
  
  CONCLUSIONS
  Our results demonstrate that systemic therapy with scFv(FRP5)-ETA can be safely administered up to a maximum tolerated dose of 12.5 microg/kg in patients with ErbB2-expressing tumors, justifying further clinical development.
authors.affiliation: Department of Gynecology and Obstetrics, University Hospital Frankfurt, Germany.
authors.forename: Gunter
authors.initials: G
authors.lastname: von Minckwitz
authors.forename: Sebastian
authors.initials: S
authors.lastname: Harder
authors.forename: Sascha
authors.initials: S
authors.lastname: Hövelmann
authors.forename: Elke
authors.initials: E
authors.lastname: Jäger
authors.forename: Salah-Eddin
authors.initials: SE
authors.lastname: Al-Batran
authors.forename: Sibylle
authors.initials: S
authors.lastname: Loibl
authors.forename: Akin
authors.initials: A
authors.lastname: Atmaca
authors.forename: Christian
authors.initials: C
authors.lastname: Cimpoiasu
authors.forename: Antje
authors.initials: A
authors.lastname: Neumann
authors.forename: Aklil
authors.initials: A
authors.lastname: Abera
authors.forename: Alexander
authors.initials: A
authors.lastname: Knuth
authors.forename: Manfred
authors.initials: M
authors.lastname: Kaufmann
authors.forename: Dirk
authors.initials: D
authors.lastname: Jäger
authors.forename: Alexander B
authors.initials: AB
authors.lastname: Maurer
authors.forename: Winfried S
authors.initials: WS
authors.lastname: Wels
mesh_terms: D000328:Adult; D000906:Antibodies / Q000633:toxicity; D019540:Area Under Curve; D019496:Cancer Vaccines / Q000633:toxicity*; D004305:Dose-Response Relationship, Drug; D005098:Exotoxins / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D006801:Humans; D009369:Neoplasms / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000097:blood / Q000493:pharmacokinetics* / Q000633:toxicity*; D011994:Recombinant Proteins / Q000097:blood / Q000493:pharmacokinetics / Q000633:toxicity*; D057127:Single-Chain Antibodies
chemical_list: D000906:Antibodies; D019496:Cancer Vaccines; D005098:Exotoxins; D018719:Erb-b2 Receptor Tyrosine Kinases; D011993:Recombinant Fusion Proteins; D011994:Recombinant Proteins; D057127:Single-Chain Antibodies; C508054:scFv(FRP5)-ETA antibody toxin