2013) and OmniMouse (http://www.omtinc.net), Kymouse (Lee et al. After immunization, diverse human monoclonal antibodies of high affinity can be obtained from transgenic rodents, while large animals, such as transchromosomic cattle, have produced respectable amounts of specific human immunoglobulin (Ig) in serum. Exp. A challenge to the transgenic antibody technology was the large size of the human Ig loci (Cook and Tomlinson 1995; Frippiat et al. rats and mice) is that their transgene usage varies. This allowed the insertion of three linear and overlapping BAC regions with homologous end sequences 5′ and 3′, which provided about half of all human V genes, all D and all J segments (Osborn et al. Science 325:433, Green LL, Hardy MC, Maynard-Currie CE et al (1994) Antigen-specific human monoclonal antibodies from mice engineered with human Ig heavy and light chain YACs. Nat Genet 3:88–94, Matsushita H, Sano A, Wu H et al (2014) Triple immunoglobulin gene knockout transchromosomic cattle: bovine lambda cluster deletion and its effect on fully human polyclonal antibody production. World-leading biopharmaceutical companies are now using these animals to generate future human therapeutic antibodies for a wide range of conditions. 2014; Murphy 2009). The success of these mouse lines accelerated the shift from using murine and chimeric antibodies to fully human antibodies (reviewed in Bruggemann et al. Nature 368:856–859, Ma B, Osborn MJ, Avis S et al (2013) Human antibody expression in transgenic rats: comparison of chimeric IgH loci with human VH, D and JH but bearing different rat C-gene regions.

0000094172 00000 n 2014). Strategies to link human IgH V genes, D and J segments with mouse or rat CH genes made use of BAC and YAC technology for (1) sub-cloning and joining large regions to secure overlapping integration by DNA microinjection into oocytes (Ma et al. In contrast, randomly integrated fully human Igκ or Igλ transloci could be cleanly expressed—without residual rodent Ig in KO lines—and extensive levels and diversity similar to WT have been obtained (Osborn et al. doi: 10.1084/jem.170.6.2153. The immunogenicity of chimeric antibodies. PubMed  0000009877 00000 n a The complete V H , D and J H…, NLM 1997), TransChromo Mouse (Ishida et al. 2014). startxref 1994; Taylor et al. 0000085428 00000 n 1a, the human IgH locus with all VHs, Ds and JH genes/segments is illustrated. 0000011120 00000 n In animals with knocked-out endogenous Ig loci and integrated large IgH loci, containing many human Vs, all D and all J segments linked to endogenous C genes, highly diverse human antibody production similar to normal animals was obtained. 0000071864 00000 n 63, 101–108 (2015). Significant improvements were obtained when the human V-region genes were linked to the endogenous CH-region, either on large constructs or, separately, by site-specific integration, which could also silence the endogenous Ig locus by gene replacement or inversion. Several larger fully human IgL loci were highly expressed even in a WT background, which showed successful competition with the endogenous L-chain loci.  |  This meant that V genes had to be gathered in close proximity, D and J segments were tightly linked and C genes had to be carefully chosen. b Transgenic constructs and features. In many cases, the size of the fully human Ig constructs assembled, for example, in plasmids, cosmids or phages, limited the number of genes that could be included as these vectors could only accommodate regions below ~100 kb. FDA approved and marketed fully human mAbs produced from the early mouse strains are listed in Table 1. PLoS One 8:e78119, Taylor LD, Carmack CE, Huszar D et al (1994) Human immunoglobulin transgenes undergo rearrangement, somatic mutation and class switching in mice that lack endogenous IgM. 344 58 This article is published under an open access license. 2013).

2014). Google Scholar, Bruggemann M, Smith JA, Osborn MJ et al (2007) Part I: Selecting and shaping the antibody molecule, selection strategies III: transgenic mice. CAS  0000009419 00000 n Endogenous CH genes will also allow optimal physiological interactions necessary in the regulation of immune responses by the various host Fc receptors (Nimmerjahn and Ravetch 2007; Rowland et al. 2015 Jun 24;10(6):e0130699. In many epithelial tumors, epidermal growth factor receptor is expressed at high levels and the tumor cell load of many patients could be reduced with Vectibix (see: http://www.vectibix.com). 1996; Lonberg et al. 2014; Zhang et al.

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