Читать книгу Biomolecules from Natural Sources - Группа авторов - Страница 53

Many early attempts at introducing protein therapeutic molecules failed because the protein drug molecules were recognized as non-human and led to an immune response against the drug itself. As a result, most proteins used in clinical trials now are primarily human or are humanized, even if the original “proof of concept” work was done with non-human proteins. For example, Pulmozyme (Genentech) is a drug based on human DNAse which was developed for use in managing cystic fibrosis, following successful “proof of principle” studies with bovine pancreatic DNAse I [113]. The immunogenicity of mouse antibodies in humans was one of the major reasons why early monoclonal antibodies did not deliver the anticipated therapeutic benefits. This led to the development of chimaeric antibodies, created by fusing mouse variable domains to human constant domains to retain binding specificity while reducing the proportion of mouse sequence. TNFα-neutralizing chimaeric monoclonal antibody, was approved for use in treating Crohn’s disease and rheumatoid arthritis [114]. The reduction in monoclonal antibody immunogenicity was taken a stage further by complementarity-determining region (CDR) grafting, where the 34 CDRs of mouse antibodies were grafted onto human frameworks to reduce the proportion of mouse sequences in the drug still further while retaining binding specificity [115].