Mesenchymal stem cells display coordinated rolling and adhesion behavior on endothelial cells

Retargeting of natural killer–cell cytolytic activity to ErbB2-expressing cancer cells results in efficient and selective tumor cell destruction

Delayed Engraftment of Nonobese Diabetic/Severe Combined Immunodeficient Mice Transplanted With Ex Vivo–Expanded Human CD34+ Cord Blood Cells

Introduction ScFv(FRP5)-ETA is a recombinant antibody toxin with binding specificity for ErbB2 (HER2). It consists of an Nterminal single-chain antibody fragment (scFv), genetically linked to truncated Pseudomonas exotoxin A (ETA). Potent antitumoral activity of scFv(FRP5)-ETA against ErbB2overexpressing 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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Phase I clinical study of the recombinant antibody toxin scFv(FRP5)-ETA specific for the ErbB2/HER2 receptor in patients with advanced solid malignomas.

ScFv(FRP5)-ETA is a recombinant single-chain antibody-toxin with binding specificity for ErbB2/HER2. Previously potent antitumoral activity of the molecule against ErbB2 overexpressing tumor cells was demonstrated in vitro and in animal models. Here we report on the first application of scFv(FRP5)-ETA in human cancer patients summarizing case reports collected in four different clinical centers. Eleven patients suffering from metastatic breast and colorectal cancers and from malignant melanoma were treated on a compassionate-use basis by intratumoral injection of scFv(FRP5)-ETA into cutaneous lesions once daily for 7-10 days. Total daily doses ranged from 60 to 900 microg, and total doses per treatment cycle ranged from 0.6 to 6.0 mg. Treatment caused injected tumors to shrink in six of the 10 cases evaluated (60%). Complete regression of injected tumor nodules was accomplished in four patients (40%) and partial reduction in tumor size in another two patients (20%). Adverse reactions were restricted to local symptoms such as pain and inflammation at injection sites which were fully reversible. Only in one patient treated at the highest daily doses systemic liver toxicity of grade 2 was observed and treatment was discontinued on day 7. No hematologic, renal, and/or cardiovascular toxicities were noted. Our results demonstrate that local therapy with scFv(FRP5)-ETA can be effective against ErbB2 expressing tumors justifying further clinical development of this reagent.

Regression of cutaneous tumor lesions in patients intratumorally injected with a recombinant single-chain antibody-toxin targeted to ErbB2/HER2.

Purging of mammary carcinoma cells during ex vivo culture of CD34+ hematopoietic progenitor cells with recombinant immunotoxins.

Minimal residual disease in autologous hematopoietic harvests from breast cancer patients

Proliferation and survival of mammary carcinoma cells are influenced by culture conditions used for ex vivo expansion of CD34(+) blood progenitor cells.

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Purging of mammary carcinoma cells during ex vivo culture of CD34+ hematopoietic progenitor cells with recombinant immunotoxins.

Minimal residual disease in autologous hematopoietic harvests from breast cancer patients

Proliferation and survival of mammary carcinoma cells are influenced by culture conditions used for ex vivo expansion of CD34(+) blood progenitor cells.