Targeted therapy of schwannoma cells in immunocompetent rats with an erbB2-specific antibody-toxin
U Altenschmidt1, M Schmidt, B Groner
1Institute for Experimental Cancer Research, Tumor Biology Center, Freiburg, Germany.
Abstract:
Over-expression of the erbB2-receptor tyrosine kinase is frequently observed in many human tumors of epithelial origin. Due to its causal involvement in malignant transformation and its presence on the tumor cell surface erbB2 is an attractive target for directed tumor therapy. We earlier described the potent anti-tumoral activity of the recombinant single-chain antibody toxin scFv(FRP5)-ETA in vitro and in nude mouse tumor models in vivo. This molecule consists of the variable domains of the heavy and light chains of an erbB2-specific antibody genetically fused to a truncated Pseudomonas exotoxin A. Here we have investigated the in vivo effects of this immunotoxin on erbB2 expressing NV2Cd schwannoma cells growing as s.c. tumors in syngeneic BDIX rats. Established tumors were treated either locally by intra-tumoral injection of scFv(FRP5)-ETA or systemically by injection into the tail vein. Both routes of application resulted in pronounced inhibition of tumor growth with local treatment being more effective. Treatment with 25 micrograms/day of scFv(FRP5)-ETA for 10 days suppressed tumor growth almost completely. Antibodies directed mainly against the toxin domain of the fusion protein developed in all animals treated.
Insights
This study shows that scFv(FRP5)-ETA, an antibody toxin, effectively inhibits erbB2-expressing schwannoma tumor growth in rats. Local administration proved more effective than systemic delivery for this targeted cancer therapy.
Area of Science:
- Oncology
- Immunotherapy
- Molecular Biology
Background:
- Over-expression of the erbB2-receptor tyrosine kinase is common in epithelial tumors.
- erbB2 is a validated target for directed tumor therapy due to its role in malignant transformation.
- Recombinant single-chain antibody toxin scFv(FRP5)-ETA demonstrated prior anti-tumoral activity.
Purpose of the Study:
- To investigate the in vivo efficacy of scFv(FRP5)-ETA against erbB2-expressing schwannoma cells.
- To compare the effectiveness of local versus systemic administration of the immunotoxin.
- To assess tumor growth inhibition in a syngeneic rat model.
Main Methods:
- Established NV2Cd schwannoma tumors in BDIX rats were treated with scFv(FRP5)-ETA.
- Treatment was administered either via intra-tumoral injection (local) or tail vein injection (systemic).
- Tumor growth was monitored following treatment with 25 micrograms/day for 10 days.
Main Results:
- Both local and systemic administration of scFv(FRP5)-ETA significantly inhibited tumor growth.
- Local intra-tumoral injection was more effective in suppressing tumor progression.
- Complete tumor growth suppression was observed with 10 days of local treatment at 25 micrograms/day.
- Antibody development against the toxin domain occurred in all treated animals.
Conclusions:
- scFv(FRP5)-ETA is a potent immunotoxin for targeting erbB2-expressing tumors in vivo.
- Local administration offers a more effective therapeutic strategy for schwannoma treatment.
- Further research into antibody responses against the immunotoxin is warranted.
