Bioengineering of a New Antibody Drug Delivery Technology

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DESCRIPTION (provided by applicant): Monoclonal antibodies (MAb) are potential new therapeutics for many brain diseases, including Alzheimer's disease (AD), Parkinson's disease, mad cow disease, West Nile encephalitis, neuro-AIDS, brain injury, brain cancer, or multiple sclerosis. In almost all cases, it is necessary that the MAb therapeutic that is administered into the blood be able to access target sites within the brain. However, MAb's are large molecule drugs that do not cross the blood-brain barrier (BBB). The BBB problem prevents the brain drug development of antibody drugs. The proposed research will develop a new technology for antibody drug delivery to brain, which could also be used for other organs. This work is based on the genetic engineering of a fusion protein comprised of 2 antibodies. One antibody is the therapeutic antibody, and the other antibody is a drug delivery system. The prototype of this new technology is novel fusion protein, which is created by fusion of a single chain Fv (ScFv) antibody to the carboxyl terminus of both heavy chains of a genetically engineered MAb against the human insulin receptor (HIR). The MAb against the HIR does penetrate brain via transport across the BBB on the endogenous insulin receptor. Feasibility studies show the fusion protein retains its bi-functional properties following genetic engineering and transient expression in COS cells: the fusion antibody both binds the HIR, to enable transport across the BBB in vivo, and binds Abeta plaque, to cause amyloid disaggregation in AD transgenic mouse brain. The purpose of these Phase I studies is (1) genetically engineer a tandem vector expressing the hetero-tetrameric fusion protein, (2) to engineer a permanently transfected host cell line that expresses high levels of the fusion antibody in serum free medium, (3) to biochemically and functionally characterize the fusion antibody, and (4) determine the plasma pharmacokinetics and brain uptake of the fusion protein in the adult Rhesus monkey. If successful, this research will develop a new technology for the drug delivery of antibody therapeutics. Public Health Relevance: Monoclonal antibodies are powerful new therapeutic products of biotechnology. Antibody drugs could be applied to many serious brain disorders, such as Alzheimer's disease, Parkinson's disease, mad cow disease, West Nile encephalitis, neuro-AIDS, brain injury, brain cancer, or multiple sclerosis. However, antibody drugs cannot be developed for these disorders, because the antibody drugs do not cross the blood-brain barrier (BBB). The present research will develop a new technology for the drug delivery of antibody drugs for the brain, which could be applied to other organs.