Abstract
Tagging of RNases, such as the ribotoxin α-sarcin, with the variable domains of antibodies directed to surface antigens that are selectively expressed on tumor cells endows cellular specificity to their cytotoxic action. A recombinant single-chain immunotoxin based on the ribotoxin α-sarcin (IMTXA33αS), produced in the generally regarded as safe (GRAS) yeast Pichia pastoris, has been recently described as a promising candidate for the treatment of colorectal cancer cells expressing the glycoprotein A33 (GPA33) antigen, due to its high specific and effective cytotoxic effect on in vitro assays against targeted cells. Here we report the in vivo antitumor effectiveness of this immunotoxin on nude mice bearing GPA33-positive human colon cancer xenografts. Two sets of independent assays were performed, including three experimental groups: control (PBS) and treatment with two different doses of immunotoxin (50 or 100 μg/ injection) (n = 8). Intraperitoneal administration of IMTXA33αS resulted in significant dose-dependent tumor growth inhibition. In addition, the remaining tumors excised from immunotoxin-treated mice showed absence of the GPA33 antigen and a clear inhibition of angiogenesis and proliferative capacity. No signs of immunotoxin-induced pathological changes were observed from specimens tissues. Overall these results show efficient and selective cytotoxic action on tumor xenografts, combined with the lack of severe side effects, suggesting that IMTXA33αS is a potential therapeutic agent against colorectal cancer.
Highlights
Colon cancer is among the most deadly ones with a significant worldwide incidence
We have reported the first ribotoxin-basedscFv recombinant immunotoxin directed against human colorectal cancer cells by the fusion of humanized scFvA33 and α-sarcin (IMTXA33αS) (Carreras-Sangrà et al 2012)
IMTXA33αS reduces tumor growth in vivo To study the in vivo effect of the immunotoxin, the development of solid tumors was induced in nude mice by inoculation of SW1222 cells, as glycoprotein A33 (GPA33)-positive cell model, in the rear right flank
Summary
Colon cancer is among the most deadly ones with a significant worldwide incidence. Its treatment by immunotherapy is becoming relatively successful with three monoclonal antibodies already approved for clinical use (Eng 2010; Tol and Punt 2010; Sliwkowski and Mellman 2013). Its late diagnosis and metastatic progression makes the development of more efficient drugs necessary. In this scenario, immunotoxins are highly specific therapeutic agents that hold promise as antitumoral agents. Immunotoxins are highly specific therapeutic agents that hold promise as antitumoral agents They combine the specificity of an antibody fragment with. Immunotherapeutic approaches using antibodies have been widely explored against a variety of tumors but an effective treatment of solid tumors still remains as a problem because therapeutic antibodies must diffuse into tumors through a disordered vasculature and against a hydrostatic pressure gradient (Jain 2001; Dienstmann et al 2012). Because low–molecular weight antibody fragments have been shown to have better tumor diffusion properties, single-chain variable fragments (scFv) have
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