Research and Pre-Clinical Development
Our anti-nucleolin antibodies are based on preclinical research by our scientific founder that was supported by research grants from the National Cancer Institute, the Leukemia and Lymphoma Society and the US Department of Defense. The goals of this research were to identify and validate a unique therapeutic target in oncology and to develop first-in-class fully human monoclonal antibodies that bind specifically to this target. A key concept which drove the selection process was that the tumor antigen should be present on the surface of a wide variety of cancer cells with negligible or no expression on the surface of the corresponding normal tissues. In addition, cell surface expression of the therapeutic target should be necessary for the survival of most types of cancer cells. After nearly a decade of preclinical research, we have discovered that cell surface nucleolin meets all of these criteria and represents a high value therapeutic target in oncology.
Several of our fully human anti-nucleolin monoclonal antibodies have potent activity against a wide variety of tumor cells in vitro and ex vivo. These include the most common solid tumors (breast, prostate, lung, colon, and pancreas) and hematological malignancies (patient-derived AML, CLL). In contrast, these antibodies, even at very high concentrations, induced negligible or no toxicity to normal human breast epithelium, normal human lung fibroblasts, normal human gastric mucosa cells or normal B or myeloid cells from patients. In addition to these highly desirable properties, nucleolin is known to shuttle among the cell surface, cytoplasm and nucleus of tumor cells (12), and it is thought to be the receptor for nucleolin-mediated endocytosis or pinocytosis (6). Anti-nucleolin antibodies have been shown to exploit this shuttling function of nucleolin to gain intracellular access in a temperature-dependent process (9-11). Following incubation of human tumor vascular endothelial cells with a polyclonal anti-nucleolin antibody, the antibody was internalized and induced tumor endothelial cell apoptosis (11). In addition, the anti-nucleolin antibody blocked tumor angiogenesis in mice. Since anti-nucleolin antibodies are internalized into a variety of tumor cells, this raises the possibility that these antibodies, when conjugated to an anticancer drug or toxin, can be used for selective delivery of an anticancer agent into tumor cells but not normal cells which lack cell surface nucleolin. View our complete list of referenced publications.