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, and the new technology will be applied to AD. This work is based on the genetic engineering of a fusion protein comprised of 2 antibodies. One antibody is the therapeutic antibody against the Abeta amyloid peptide of AD, and the other antibody is a drug delivery system, which is directed at an endogenous transporter on the human BBB. The Phase I studies accomplished the following: (1) genetic engineering of a tandem vector expressing the hetero-tetrameric fusion protein, (2) cloning of a permanently transfected host cell line that expresses high levels of the fusion antibody in serum free medium, (3) biochemical and functional characterizion of the fusion antibody, and (4) determination of the plasma pharmacokinetics (PK) and brain uptake of the fusion protein in the adult Rhesus monkey. The phase II studies will accomplish the following: (1) growth of the host cell line in a 50L bioreactor, followed by 3-column downstream processing that can be replicated in a GMP lab;(2) biochemical analysis of the fusion protein with over 15 analytical tests;(3) dose finding PK and toxicity study in Rhesus monkeys. These studies will enable future submission of an IND for human testing of this new fusion protein for AD.
Monoclonal antibodies are powerful new therapeutic products of biotechnology. Antibody drugs could be applied to many serious brain disorders, such as Alzheimer's disease (AD), 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 diseases such as AD.