Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA specific for the ErbB2/HER2 receptor in patients with advanced solid malignomas

  • Introduction: 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 μg/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 μg/kg, and in two of three patients at 20 μg/kg. Fifteen minutes after injection, peak concentrations of more than 100 ng/ml scFv(FRP5)-ETA were obtained at a dose of 10 μg/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 ≥ 10 μg/kg). Disease progression occurred in 11 of the patients. Conclusion: Our results demonstrate that systemic therapy with scFv(FRP5)-ETA can be safely administered up to a maximum tolerated dose of 12.5 μg/kg in patients with ErbB2-expressing tumors, justifying further clinical development.

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Author:Gunter von MinckwitzORCiDGND, Sebastian HarderGND, Sascha Hövelmann, Elke Jäger, Salah-Eddin al- BatranORCiDGND, Sibylle LoiblORCiDGND, Akin Atmaca, Christian Cimpoiasu, Antje Neumann, Aklil Abera, Alexander Knuth, Manfred KaufmannGND, Dirk Jäger, Alexander B. MaurerGND, Winfried WelsORCiDGND
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Parent Title (English):Breast cancer research
Publisher:BioMed Central
Place of publication:London
Document Type:Article
Date of Publication (online):2005/06/22
Date of first Publication:2005/06/01
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2005/06/22
Page Number:10
First Page:R617
Last Page:R626
© 2005 von Minckwitz et al, licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License ( 2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is cited:

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Source:Breast Cancer Research 2005, 7:R617-R626 ,
Institutes:Medizin / Medizin
Angeschlossene und kooperierende Institutionen / Georg-Speyer-Haus
Dewey Decimal Classification:6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 2.0