Antibody immunotherapy targeting the self-tumor antigen nucleolin (VAC5P.1129)

Abstract

Abstract Nucleolin is a multifunctional protein found in the nucleus of all cells, and it’s a self-tumor antigen. It is overexpressed on the plasma membrane and cytoplasm of the two most common forms of leukemia acute myeloid leukemia (AML) and chronic lymphocytic leukemia (CLL). The cell surface expression of nucleolin on CLL and AML cells, compared with its nuclear profile in normal cells, makes nucleolin an attractive self-antigenic target for antibody immunotherapy. Accordingly, we have utilized our patented platform technology (US Patent 8,715,743) to generate a panel of fully human monoclonal antibodies (HuMAbs) that target nucleolin (NCL) and potently induce AML cell death, while having no effect on normal blood cells (PCT/US2010/057046). Preliminary data indicated that AML cells were killed independently of complement or antibody dependent cellular cytotoxic mechanisms, possibly by interfering with nucleolin’s cellular function. This might have significant therapeutic implications, since the HuMAbs may retain activity in immunocompromised leukemia patients. We hypothesize that the anti-NCL HuMAbs have both immune mediated and immune independent antitumor activity, eliciting nucleolin specific killing through both complement and cell mediated cytotoxic mechanisms, and through interfering with the integral cellular function of nucleolin. Thus, autoreactive antibodies targeting this self-tumor antigen might be important in the treatment of leukemia.