Therapeutic effect of a TM4SF5-specific monoclonal antibody against colon cancer in a mouse model

Abstract

Transmembrane 4 superfamily member 5 protein (TM4SF5) is presumed to serve as a molecular target to prevent or treat hepatocellular carcinoma (HCC) and colon cancer in a mouse model. Previously, we reported the efficacy of anti-cancer peptide vaccine targeting TM4SF5. In addition, we reported an anti-proliferative effect of anti-TM4SF5 monoclonal antibody in HCC. Here, we investigated expression of TM4SF5 in 45 primary colon cancer tissues. Almost all of the colon cancer tissues expressed TM4SF5 based on immunohistochemistry using anti-TM4SF5 monoclonal antibody. The treatment of human colon cancer cells with anti-TM4SF5 antibody reduced growth of TM4SF5 expressing cells and enhanced expression of E-cadherin and β-catenin. Using mouse colon cancer models, we then evaluated the in vivo anti-cancer effect of anti-TM4SF5 antibody. Injection of the antibody significantly reduced growth of tumors priorly established by subcutaneous injection of human colon cancer cells HT-29 in a xenograft setting. We obtained similar results with mouse colon cancer cell line CT-26 in an allograft setting. Therefore, we suggest that the TM4SF5-specific monoclonal antibody has a therapeutic effect against colon cancer.

Anti-metastatic effect of the TM4SF5-specific peptide vaccine and humanized monoclonal antibody on colon cancer in a mouse lung metastasis model

“…We previously confirmed that treatment with the anti-TM4SF5 monoclonal antibody reduced the growth of human and mouse colon cancer cells [15]. Here, we found that the treatment of colon cancer cells with the humanized anti-TM4SF5 antibody significantly reduces their migration capability, based on the results from migration and wound healing assays.…”

Production of an anti-TM4SF5 monoclonal antibody and its application in the detection of TM4SF5 as a possible marker of a poor prognosis in colorectal cancer

“…Previously, we screened an efficacious B-cell peptide epitope (hTM4SF5R2-3) by immunizing BALB/c mice with various TM4SF5 peptides and characterized the prophylactic and the therapeutic effects of the peptide vaccine on hepatocellular carcinoma and colon cancer cell lines and tumor mouse models (8,9,25). We also produced TM4SF5-specific monoclonal antibodies and evaluated their therapeutic effects (18,19,26). Based on these data, we hypothesized that the hTM4SF5 protein is a reasonable target for anticancer therapy and that anti-hTM4SF5 antibodies warrant further development as therapeutic agents for the inhibition of hTM4SF5 function in cancer.…”

“…However, given the specificity of its targeting and its internalization into cells, the development of antibody-drug conjugates of mEC2-CF may be an alternative strategy for its application in anticancer therapeutics. Previously, we demonstrated a higher expression of hTM4SF5 in colon cancer tissues compared to normal tissues by analyzing commercially-available tissue microarrays using immunohistochemistry (18). The vendor provided information regarding sex, age, tumor grade, along with the tumor, node and metastasis (TNM) stage of the tissues included in the microarray.…”

“…In this study, to determine whether mEC2-CF could be internalized into cells, HT-29, HCT-116 and LoVo cells were treated with mEC2-CF and then incubated with Alexa 488-conjugated goat anti-mouse IgG. Immunofluorescence analysis using confocal microscopy revealed that mEC2-CF was successfully internalized into the HT-29 and LoVo cells, which express hTM4SF5 (18,19) (Fig. 4A and B).…”

“…We previously developed a prophylactic and therapeutic vaccine for colon and hepatocellular carcinoma (HCC) using an EC2 domain TM4SF5 peptide epitope (hTM4SF5R2-3, 138 NRTLWDRCEAPPRV 151 ) in combination with our own adjuvant formulation complex [Lipoplex(O)] (7)(8)(9). We then generated a mouse monoclonal antibody against the hTM4SF5R2-3 epitope, which displayed therapeutic effects in colon and HCC mouse tumor models (17,18). Moreover, using a novel type of cyclic peptide epitope targeting the EC2 domain (hTM4SF5EC2-C,…”