One popular approach involves the in vitro isolation of antigen-specific antibodies using display strategies involving human antibody fragments expressed on the surface of phage, bacteria, or yeast ( 12). Thus, a variety of systems were developed to create humanized or fully human therapeutic antibodies ( 7 – 18). The use of humanized and/or fully human antibodies avoided immunogenicity problems and allowed long-term treatment of chronic diseases. Early therapeutic mAbs were derived from mouse sources, retained mouse sequences, and were thus immunogenic when used in human patients, limiting the ability to dose repeatedly. A large number of mAbs have been approved for therapeutic use or are in development ( 1 – 6). Monoclonal antibodies (mAbs) are a rapidly growing class of therapeutics that combine high binding affinities and specificities with long in vivo half-lives. The efficiency of the VelocImmune approach is confirmed by the rapid progression of 10 different fully human antibodies into human clinical trials. We show that these mice, termed VelocImmune mice because they were generated using VelociGene technology, efficiently produce human:mouse hybrid antibodies (that are rapidly convertible to fully human antibodies) and have fully functional humoral immune systems indistinguishable from those of WT mice. We reasoned the introduced human variable region gene segments would function indistinguishably in their new genetic location, whereas the retained mouse constant regions would allow for optimal interactions and selection of the resulting antibodies within the mouse environment. As we describe in the companion paper, we attempted to make mice that more efficiently use human variable region segments in their humoral responses by precisely replacing 6 Mb of mouse Ig heavy and kappa light variable region germ-line gene segments with their human counterparts while leaving the mouse constant regions intact, using a unique in situ humanization approach. Heretofore, HumAb mice have been generated by disrupting the endogenous mouse Ig genes and simultaneously introducing human Ig transgenes at a different and random location KO-plus-transgenic humanization. Unfortunately, existing HumAb mice do not have fully functional immune systems, perhaps because of the manner in which their genetic humanization was carried out. Mice genetically engineered to be humanized for their Ig genes allow for human antibody responses within a mouse background (HumAb mice), providing a valuable platform for the generation of fully human therapeutic antibodies.
0 Comments
Leave a Reply. |
AuthorWrite something about yourself. No need to be fancy, just an overview. ArchivesCategories |