Our goal is to engineer and express, in mammalian cells, a whole antibody/ricin immunotoxin with therapeutic qualities that exceed bacterially-produced recombinant immunotoxins. Ricin is a plant toxin comprised of a non-toxic B-chain that attaches the toxin to cell surfaces and facilitates penetration of cell membranes by the toxic A- chain, an N-glycosidase that catalytically inactivates mammalian ribosomes. The two-chain subunit structure of ricin presents the unique opportunity to express the non-toxic B-chain as a fusion protein with a full length heavy chain of an antibody in a mammalian cell such as a non- secreting myeloma. Once the Ig/B-chain fusion hybrid is purified, it can be re-associated with ricin A-chain to form a recombinant immunotoxin that can be used to treat diseases of clonogenic origin. Currently, recombinant immunotoxins are made by fusion of bacterial toxins to antibody fragments, which can only be produced in bacteria. These single-chain toxins have very brief half-lives in vivo and pre-existing antibodies to toxins like Pseudomonas exotoxin and diphtheria toxin preclude their use in some patients. A recombinant ricin immunotoxin expressed in myeloma employs whole Ig, which has a long serum half-life (weeks) that could produce increased therapeutic efficacy in patients. A recombinant ricin immunotoxin that incorporates whole antibody has therapeutic potential in the treatment of cancer, graft vs host disease, transplant rejection, auto-immune disease and allergies.Awardee's statement of the potential commercial applications of the research: It is estimated that 60 000 new cases of lethal forms of blood cell cancers, such as leukemias and Lymphomas, for which there is no effective long term therapy, occur in the United States annually. That figure may jump to 100,000 cases per year as the incidence of AIDS-lymphoma increases. Immunotoxins have application in treating diseases of clonogenic origin. These include treatment of cancer, graft versus host disease, transplantation rejection, auto-immune disease and allergies. Recombinant ricin immunotoxins are designed to treat these diseases.National Cancer Institute (NCI)
