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Published on: October 30, 2013
Novel EGFR‑bispecific recombinant immunotoxin based on cucurmosin shows potent anti‑tumor efficiency in vitro
Caiyun Zhang1, Yumei Cai1, Xiaoxue Dai1
1Department of Pharmacology, School of Pharmacy, Fujian Provincial Key Laboratory of Natural Medicine Pharmacology, Fujian Medical University, Fuzhou, Fujian 350122, P.R. China.
Abstract:
Epidermal growth factor receptor (EGFR) is overexpressed in various tumors and is associated with cancer initiation, progression, and poor prognosis. Despite the achievements made by tyrosine kinase inhibitors and monoclonal antibodies in certain cases, many patients have not benefited from such treatment due to resistance. Immunotoxins (ITs) are antibody‑cytotoxin chimeric molecules with specific cell killing ability, which have achieved different degrees of success in the treatment of a wide range of cancers in clinical trials. The aim of the current study was to examine a novel targeting EGFR recombinant immunotoxin Bs/cucurmosin (CUS) generated by fusing CUS to the EGFR‑specific nanobody 7D12‑9G8. Bs/CUS was successfully expressed in Escherichia coli strain BL21 (DE3) in a soluble form. Furthermore, it retained binding capacity and specificity with EGFR and was superior to rE/CUS, a monospecific IT we reported previously. In vitro results showed that Bs/CUS could be internalized into the cytoplasm and selectively kill cells in the picomolar range. Flow cytometry showed that Bs/CUS killed the cells mediated by the apoptosis pathway. Taken together, results of the current study indicated that Bs/CUS is a promising candidate that should be further evaluated as a cancer therapeutic for the treatment of EGFR‑positive tumors.
Insights
A novel EGFR-targeting immunotoxin, Bs/CUS, shows potent and selective cancer cell killing via apoptosis. This promising therapeutic candidate warrants further evaluation for EGFR-positive tumors.
Area of Science:
- Oncology
- Molecular Biology
- Immunotherapy
Background:
- Epidermal growth factor receptor (EGFR) overexpression is linked to various cancers, driving initiation, progression, and poor prognosis.
- Current treatments like tyrosine kinase inhibitors face resistance, limiting patient benefit.
- Immunotoxins (ITs) offer targeted cancer cell killing but require further development.
Purpose of the Study:
- To develop and evaluate a novel EGFR-targeting recombinant immunotoxin, Bs/cucurmosin (Bs/CUS).
- To assess the efficacy and mechanism of action of Bs/CUS against EGFR-positive cancer cells.
Main Methods:
- Bs/CUS was generated by fusing cucurmosin (CUS) to an EGFR-specific nanobody (7D12-9G8).
- Expression and purification were performed in Escherichia coli BL21 (DE3).
- In vitro assays assessed binding, internalization, cytotoxicity, and apoptosis induction.
Main Results:
- Bs/CUS was successfully expressed in a soluble form and demonstrated specific binding to EGFR.
- It showed superior performance compared to a previously reported monospecific IT (rE/CUS).
- Bs/CUS was internalized into cancer cells and exhibited potent cytotoxicity in the picomolar range, inducing apoptosis.
Conclusions:
- Bs/CUS is a highly effective and specific immunotoxin targeting EGFR-positive cancer cells.
- The apoptosis-mediated cell death mechanism highlights its therapeutic potential.
- Bs/CUS represents a promising candidate for further preclinical and clinical evaluation in cancer therapy.
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