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Published on: April 25, 2025
Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA specific for the ErbB2/HER2 receptor in
Gunter von Minckwitz1, Sebastian Harder, Sascha Hövelmann
1Department of Gynecology and Obstetrics, University Hospital Frankfurt, Germany.
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 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.
Conclusion:
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.
Insights
The recombinant antibody toxin scFv(FRP5)-ETA shows safe systemic administration up to 12.5 microg/kg in patients with ErbB2-expressing tumors. Further clinical development is warranted based on these findings.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- ScFv(FRP5)-ETA is a novel recombinant antibody toxin targeting ErbB2 (HER2)-overexpressing cancer cells.
- Previous in vitro and animal studies demonstrated potent antitumoral activity.
- This study reports the first systemic administration in human cancer patients.
Purpose of the Study:
- To conduct a phase I dose-finding study of scFv(FRP5)-ETA.
- To determine the maximum tolerated dose (MTD) and dose-limiting toxicities.
- To evaluate the safety and tolerability of systemic scFv(FRP5)-ETA therapy.
Main Methods:
- A phase I dose-finding study was performed in 18 patients with ErbB2-expressing metastatic cancers.
- Patients received intravenous scFv(FRP5)-ETA at doses ranging from 2 to 20 microg/kg over two consecutive weeks.
- Maximum tolerated dose and dose-limiting toxicities were assessed.
Main Results:
- No hematologic, renal, or cardiovascular toxicities were observed.
- Transient liver enzyme elevation was the dose-limiting toxicity, occurring at 12.5 microg/kg and 20 microg/kg.
- Peak concentrations above 100 ng/ml were achieved at 10 microg/kg without significant toxic side effects.
- Antibody induction against scFv(FRP5)-ETA was detected in 13 patients, with neutralizing activity in five.
- Two patients had stable disease, and three showed clinical signs of activity at doses >= 10 microg/kg.
Conclusions:
- Systemic therapy with scFv(FRP5)-ETA is safe up to a maximum tolerated dose of 12.5 microg/kg.
- The recombinant protein can be administered at predicted therapeutic levels without significant toxicities.
- These findings support further clinical development of scFv(FRP5)-ETA for ErbB2-expressing tumors.