A New Anticancer Glycolipid Monoclonal Antibody, SC104, which Directly Induces Tumor Cell Apoptosis

Abstract

A novel monoclonal antibody was raised by immunization of mice with colorectal tumor cell lines. The fusion was screened by immunohistochemistry for binding to primary colorectal tumors. Subsequent analysis on primary disaggregated colorectal tumors show that the antibody recognizes a cell surface antigen expressed by the majority of colorectal tumors. Antigen characterization has shown that the antibody recognizes a sialyltetraosylceramide but does not bind to GM1, GD1a, GT1b, or sialyl Lewis X antigens. Binding to a frozen panel of tumor and normal tissue sections revealed that the antigen was also strongly expressed on esophageal, gastric, and endometrial tumors. Its normal tissue distribution was largely restricted to moderate staining of large intestine. Surprisingly, SC104 antibody directly induces tumor cell death without the need for immune effector cells or complement. This may be related in part to its homophilic binding properties that allow cross-linking of antibody and receptors on the cell surface. Caspase activation can be detected following SC104 treatment of colorectal cells, and cotreatment with caspase inhibitors has been shown to inhibit cell death. This suggests that SC104 induces death by a classic apoptotic pathway. Furthermore, SC104 antibody shows additive killing with complement and 5-fluorouracil/leucovorin in vivo, suggesting a new therapeutic approach for this class of antibodies. (Cancer Res 2006; 66(11): 5901-9)

Suppression of human prostate tumor growth by a unique prostate-specific monoclonal antibody F77 targeting a glycolipid marker

“…Some have been used in trials of antibody therapy for melanoma, colon cancer, and other cancers (24)(25)(26). Studies indicate that these glycolipid antigens are effective for complement lysis because of the short distance between the site of complement activation and the cell membrane (27)(28)(29).…”

Tumor-associated CD75s- and iso-CD75s-gangliosides are potential targets for adjuvant therapy in pancreatic cancer

“…Thus, the clustered assembly in microdomains renders gangliosides excellent candidates for tumor targeting employing lectins, toxins, or monoclonal antibodies directed toward tumor-associated gangliosides. As an example, a novel anti-ganglioside monoclonal antibody has been recently produced (32), which binds to a ganglioside and directly induces apoptosis of targeted tumor cells without the need for immune effector cells or complement, suggesting a new therapeutic approach for this class of antibodies. Interestingly, the tumor-associated target ganglioside has been thus far preliminarily characterized as a sialyltetraosylceramide, thereby excluding GM1 or sialyl-Lewis x antigens as binding structures.…”

Monoclonal Antibodies Targeting LecLex-Related Glycans with Potent Antitumor Activity

“…Glycolipid extract from 2 Â 10 6 COLO205 cells (20) spotted onto Merck high-performance thin-layer chromatography (HPTLC) silica plates and developed twice in chloroform: methanol:H 2 O (60:30:5) followed by twice hexane:diethyl ether:acetic acid (80:20:1.5). The dried plates were sprayed with 0.1% (w/v) polyisobutylmethacrylate (Sigma) in acetone and blocked with PBS 2% (w/v) BSA (PBS/BSA) for 1 hour at room temperature.…”

“…The murine IgM mAb 43-9F, targeted Le a /Le x epitopes, cross-reacting with simple and extended Le a epitopes, but had no in vivo antitumor reactivity (19). The mAb 504/4 (SC104, murine IgG1), recognized sialyl (S) Le-related glycans, induced antibody-dependent cellular cytotoxicity (ADCC) and CDC, as well as direct tumor cell death and importantly, demonstrated tumor growth inhibition in vivo (20).…”