Inhibition of Spontaneous Breast Cancer Metastasis by Anti—Thomsen-Friedenreich Antigen Monoclonal Antibody JAA-F11

Abstract

Thomsen-Friedenreich antigen (TF-Ag) is expressed in many carcinomas, including those of the breast, colon, bladder, and prostate. TF-Ag is important in adhesion and metastasis and as a potential immunotherapy target. We hypothesized that passive transfer of JAA-F11, an anti-TF-Ag monoclonal antibody, may create a survival advantage for patients with TF-Ag-expressing tumors by cytotoxicity, blocking of tumor cell adhesion, and inhibition of metastasis. This was tested using in vitro models of tumor cell growth; cytotoxicity assays; in vitro, ex vivo, and in vivo models of cancer metastasis; and, finally, in vivo effects in mice with metastatic breast cancer. Unlike some anti-TF-Ag antibodies, JAA-F11 did not enhance breast carcinoma cell growth. JAA-F11 did not induce the killing of 4T1 tumor cells through complement-dependent cytotoxicity or apoptotic mechanisms. However, JAA-F11 blocked the stages of metastasis that involve the adhesion of human breast carcinoma cells to human endothelial cells (human umbilical vein endothelial cells and human bone marrow endothelial cells 60) in in vitro static adhesion models, in a perfused ex vivo model, and in murine lung vasculature in an in vivo metastatic deposit formation assay. JAA-F11 significantly extended the median survival time of animals bearing metastatic 4T1 breast tumors and caused a > 50% inhibition of lung metastasis.

Purification and refolding of anti-T-antigen single chain antibodies (scFvs) expressed in Escherichia coli as inclusion bodies

“…Since protein-carbohydrate interactions are generally weak, these human scFv proteins with rather high affinities for oncofetal T-antigen have high potential for future development of cancer therapeutics. For example, an anti-T-antigen monoclonal antibody JAA-F11 has been shown to block the adhesion of human and mouse tumor cells in metastatic models in in vitro and in vivo studies (27). Further characterization of 1E8 and 1E6 scFv proteins, their affinity improvement, and their effects on tumor growth and metastasis will be needed for future clinical application of these scFv proteins.…”

Glycodendrimers: versatile tools for nanotechnology

“…Our group showed that a highly specific immunoglobulin IgG 3 monoclonal antibody (MAb) developed against the TF-Ag (JAA-F11) (Rittenhouse-Diakun et al, 1998) impeded TF-Ag binding to vascular endothelium, blocking a primary metastatic step and providing a survival advantage (Heimburg et al, 2006). In addition, in patients, even low levels of antibodies to TF-Ag seem to improve prognosis; thus, it is expected that vaccines generating antibodies toward TF-Ag would be clinically valuable.…”

CD176 antiserum treatment leads to a therapeutic response in a murine model of leukemia

“…CD176 is also expressed in leukemia and lymphoma cells (4,6), and may be a promising prognostic marker in T-cell acute lymphoblastic leukemia (7,8). In addition, CD176 is expressed in some cancer stem cells (9), and it is functionally involved in the liver metastasis process of tumors (1,10), the adhesion of human breast cancer cells to the endothelium (11,12) and the apoptosis of leukemic cells (13). Therefore, CD176 may be a promising target for cancer immunotherapy.…”

“…Liver colonization of CD176 (TF)-positive syngeneic tumor cells was suppressed by pretreatment with a CD176 (TF) antibody (18). CD176 (TF) antibody markedly inhibited the adhesion of human breast cancer cells to the endothelium and caused an extension of survival time in mice carrying a 4T1 metastatic breast CD176 antiserum treatment leads to a therapeutic response in a murine model of leukemia (12). Based on these observations, we hypothesized that CD176 antibody might have a therapeutic effect on patients with CD176 + cancer.…”