MOLECULAR ENGINEERING OF MONOCLONAL ANTIBODIES FOR THE MANAGEMENT OF CANCER

点击翻译按钮获取中文摘要

Several problems limiting the use of monoclonal antibodies (MAbs) for the diagnosis and therapy of diseases are addressed using the techniques of molecular biology. The approaches of humanization will be undertaken in an attempt to reduce the immunogenicities elicited by multiple injections of rodent antibodies. The MAbs used for this research include PAM4 (anti-pancreatic cancer), MN-14 (anti-colorectal cancer) and Mu-9 (anti-colorectal cancer), which have been demonstrated to have significant clinical utilities. Favorable pharmacokinetic and biodistribution characteristics, such as faster blood clearance, lower liver and kidney uptake, etc., will be engineered in MAbs. This can be achieved by the deletion of the CH2 domain from the whole IgG molecule. Humanized MN-14 antibody will be used as the prototype for the initial construction and evaluation of this new form of MAb. Moreover, to facilitate and increase the loading capacity for radiolabeling, whole IgG or F(ab')2 fragments containing an IgG3 hinge region, instead of that of IgG1, will be constructed. The improvement in the ease of labeling and radioisotope loading capacity of the IgG3 hinge-containing molecules will be compared to those carrying the IgG1 hinge regions. Hopefully, a humanized, CH2-deleted antibody with a long IgG3 hinge region will serve as a non-immunogenic, highly radioactive biopharmaceutical that can be used repeatedly for the treatment for diseases, without undesirable accumulations in normal tissues and organs. Large quantities of these recombinant MAbs are required for their clinical efficacy assessment; however, the current system for production of MAbs is inadequate. New DNA vectors and transfection protocols will be developed to allow for high level of expression of the recombinant MAbs in a bioreactor.