Human Antibody Production in Transgenic Animals

Archivum Immunologiae et Therapiae Experimentalis - Tập 63 - Trang 101-108 - 2014
Marianne Brüggemann1,2, Michael J. Osborn1, Biao Ma1, Jasvinder Hayre1, Suzanne Avis1, Brian Lundstrom2, Roland Buelow2
1Recombinant Antibody Technology Ltd., Babraham, UK
2Open Monoclonal Technology, Inc., Palo Alto, USA

Tóm tắt

Fully human antibodies from transgenic animals account for an increasing number of new therapeutics. 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. Several strategies to derive animals expressing human antibody repertoires have been successful. In rodents, gene loci on bacterial artificial chromosomes or yeast artificial chromosomes were integrated by oocyte microinjection or transfection of embryonic stem (ES) cells, while ruminants were derived from manipulated fibroblasts with integrated human chromosome fragments or human artificial chromosomes. In all strains, the endogenous Ig loci have been silenced by gene targeting, either in ES or fibroblast cells, or by zinc finger technology via DNA microinjection; this was essential for optimal production. However, comparisons showed that fully human antibodies were not as efficiently produced as wild-type Ig. This suboptimal performance, with respect to immune response and antibody yield, was attributed to imperfect interaction of the human constant region with endogenous signaling components such as the Igα/β in mouse, rat or cattle. 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. 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.

Tài liệu tham khảo

Bruggemann M, Caskey HM, Teale C et al (1989a) A repertoire of monoclonal antibodies with human heavy chains from transgenic mice. Proc Natl Acad Sci USA 86:6709–6713 Bruggemann M, Winter G, Waldmann H et al (1989b) The immunogenicity of chimeric antibodies. J Exp Med 170:2153–2157 Bruggemann M, Spicer C, Buluwela L et al (1991) Human antibody production in transgenic mice: expression from 100 kb of the human IgH locus. Eur J Immunol 21:1323–1326 Bruggemann M, Neuberger MS (1996) Strategies for expressing human antibody repertoires in transgenic mice. Immunol Today 17:391–397 Bruggemann M (2001) Human antibody expression in transgenic mice. Arch Immunol Ther Exp 49:203–208 Bruggemann M, Smith JA, Osborn MJ et al (2007) Part I: Selecting and shaping the antibody molecule, selection strategies III: transgenic mice. In: Dübel S (ed) Handbook of therapeutic antibodies. Wiley-VCH Verlag, Weinheim, pp 69–93 Bruggemann M, Osborn MJ, Ma B et al (2014) Transgenic animals derived by DNA microinjection. In: Dübel S, Reichert JM (eds) Handbook of therapeutic antibodies, 2nd edn. Wiley-VCH Verlag, Weinheim Chen J, Trounstine M, Alt FW et al (1993a) Immunoglobulin gene rearrangement in B cell deficient mice generated by targeted deletion of the JH locus. Int Immunol 5:647–656 Chen J, Trounstine M, Kurahara C et al (1993b) B cell development in mice that lack one or both immunoglobulin kappa light chain genes. EMBO J 12:821–830 Choi TK, Hollenbach PW, Pearson BE et al (1993) Transgenic mice containing a human heavy chain immunoglobulin gene fragment cloned in a yeast artificial chromosome. Nat Genet 4:117–123 Cook GP, Tomlinson IM (1995) The human immunoglobulin VH repertoire. Immunol Today 16:237–242 Cui X, Ji D, Fisher DA et al (2011) Targeted integration in rat and mouse embryos with zinc-finger nucleases. Nat Biotechnol 29:64–67 Davies NP, Rosewell IR, Bruggemann M (1992) Targeted alterations in yeast artificial chromosomes for inter-species gene transfer. Nucleic Acids Res 20:2693–2698 Davies NP, Bruggemann M (1993) Extension of yeast artificial chromosomes by cosmid multimers. Nucleic Acids Res 21:767–768 Davies NP, Rosewell IR, Richardson JC et al (1993) Creation of mice expressing human antibody light chains by introduction of a yeast artificial chromosome containing the core region of the human immunoglobulin kappa locus. Biotechnology 11:911–914 Fishwild DM, O’Donnell SL, Bengoechea T et al (1996) High-avidity human IgG kappa monoclonal antibodies from a novel strain of minilocus transgenic mice. Nat Biotechnol 14:845–851 Flisikowska T, Thorey IS, Offner S et al (2011) Efficient immunoglobulin gene disruption and targeted replacement in rabbit using zinc finger nucleases. PLoS One 6:e21045 Frippiat JP, Williams SC, Tomlinson IM et al (1995) Organization of the human immunoglobulin lambda light-chain locus on chromosome 22q11.2. Hum Mol Genet 4:983–991 Geurts AM, Cost GJ, Freyvert Y et al (2009) Knockout rats via embryo microinjection of zinc-finger nucleases. 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 7:13–21 Green LL, Jakobovits A (1998) Regulation of B cell development by variable gene complexity in mice reconstituted with human immunoglobulin yeast artificial chromosomes. J Exp Med 188:483–495 Green LL (2014) Transgenic mouse strains as platforms for the successful discovery and development of human therapeutic monoclonal antibodies. Curr Drug Discov Technol 11:74–84 Hjelm F, Carlsson F, Getahun A et al (2006) Antibody-mediated regulation of the immune response. Scand J Immunol 64:177–184 Ishida I, Tomizuka K, Yoshida H et al (2002) Production of human monoclonal and polyclonal antibodies in TransChromo animals. Cloning Stem Cells 4:91–102 Kakeda M, Hiratsuka M, Nagata K et al (2005) Human artificial chromosome (HAC) vector provides long-term therapeutic transgene expression in normal human primary fibroblasts. Gene Ther 12:852–856 Kim JM, Ashkenazi A (2013) Fcgamma receptors enable anticancer action of proapoptotic and immune-modulatory antibodies. J Exp Med 210:1647–1651 Kitamura D, Roes J, Kuhn R et al (1991) A B cell-deficient mouse by targeted disruption of the membrane exon of the immunoglobulin mu chain gene. Nature 350:423–426 Kohler G, Milstein C (1975) Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495–497 Kuroiwa Y, Yoshida H, Ohshima T et al (2002) The use of chromosome-based vectors for animal transgenesis. Gene Ther 9:708–712 Lachmann PJ, Oldroyd RG, Milstein C et al (1980) Three rat monoclonal antibodies to human C3. Immunology 41:503–515 Lee EC, Liang Q, Ali H et al (2014) Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery. Nat Biotechnol 32:356–363 Lefranc MP, Lefranc G (2001) The immunoglobulin factsbook. Academic Press, London, pp 45–68 Liu J, Lange MD, Hong SY et al (2013) Regulation of VH replacement by B cell receptor-mediated signaling in human immature B cells. J Immunol 190:5559–5566 Lonberg N, Taylor LD, Harding FA et al (1994) Antigen-specific human antibodies from mice comprising four distinct genetic modifications. 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. J Immunol Methods 400–401:78–86 Matsuda F, Shin EK, Nagaoka H et al (1993) Structure and physical map of 64 variable segments in the 3′0.8-megabase region of the human immunoglobulin heavy-chain locus. 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. PLoS One 9:e90383 McCafferty J, Griffiths AD, Winter G et al (1990) Phage antibodies: filamentous phage displaying antibody variable domains. Nature 348:552–554 Mellor JD, Brown MP, Irving HR et al (2013) A critical review of the role of Fc gamma receptor polymorphisms in the response to monoclonal antibodies in cancer. J Hematol Oncol 6:1 Mendez MJ, Green LL, Corvalan JR et al (1997) Functional transplant of megabase human immunoglobulin loci recapitulates human antibody response in mice. Nat Genet 15:146–156 Menoret S, Iscache AL, Tesson L et al (2010) Characterization of immunoglobulin heavy chain knockout rats. Eur J Immunol 40:2932–2941 Murphy A (2009) Recombinant antibodies for immunotherapy. Cambridge University Press, Cambridge, pp 100–108 Murphy AJ, Macdonald LE, Stevens S et al (2014) Mice with megabase humanization of their immunoglobulin genes generate antibodies as efficiently as normal mice. Proc Natl Acad Sci USA 111:5153–5158 Nemazee D, Weigert M (2000) Revising B cell receptors. J Exp Med 191:1813–1817 Neuberger M, Bruggemann M (1997) Monoclonal antibodies. Mice perform a human repertoire. Nature 386:25–26 Nicholson IC, Zou X, Popov AV et al (1999) Antibody repertoires of four- and five-feature translocus mice carrying human immunoglobulin heavy chain and kappa and lambda light chain yeast artificial chromosomes. J Immunol 163:6898–6906 Nimmerjahn F, Ravetch JV (2007) Fc-receptors as regulators of immunity. Adv Immunol 96:179–204 Osborn MJ, Ma B, Avis S et al (2013) High-affinity IgG antibodies develop naturally in Ig-knockout rats carrying germline human IgH/Igkappa/Iglambda loci bearing the rat CH region. J Immunol 190:1481–1490 Ouled-Haddou H, Ghamlouch H, Regnier A et al (2014) Characterization of a new V gene replacement in the absence of activation-induced cytidine deaminase and its contribution to human B-cell receptor diversity. Immunology 141:268–275 Pallares N, Lefebvre S, Contet V et al (1999) The human immunoglobulin heavy variable genes. Exp Clin Immunogenet 16:36–60 Popov AV, Butzler C, Frippiat JP et al (1996) Assembly and extension of yeast artificial chromosomes to build up a large locus. Gene 177:195–201 Popov AV, Zou X, Xian J et al (1999) A human immunoglobulin lambda locus is similarly well expressed in mice and humans. J Exp Med 189:1611–1620 Presta LG (2006) Engineering of therapeutic antibodies to minimize immunogenicity and optimize function. Adv Drug Deliv Rev 58:640–656 Pruzina S, Williams GT, Kaneva G et al (2011) Human monoclonal antibodies to HIV-1 gp140 from mice bearing YAC-based human immunoglobulin transloci. Protein Eng Des Sel 24:791–799 Ren L, Zou X, Smith JA, Bruggemann M (2004) Silencing of the immunoglobulin heavy chain locus by removal of all eight constant-region genes in a 200-kb region. Genomics 84:686–695 Rowland SL, Tuttle K, Torres RM et al (2013) Antigen and cytokine receptor signals guide the development of the naive mature B cell repertoire. Immunol Res 55:231–240 Sanchez P, Drapier AM, Cohen-Tannoudji M et al (1994) Compartmentalization of lambda subtype expression in the B cell repertoire of mice with a disrupted or normal C kappa gene segment. Int Immunol 6:711–719 Sano A, Matsushita H, Wu H et al (2013) Physiological level production of antigen-specific human immunoglobulin in cloned transchromosomic cattle. 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. Int Immunol 6:579–591 Tomizuka K, Shinohara T, Yoshida H et al (2000) Double trans-chromosomic mice: maintenance of two individual human chromosome fragments containing Ig heavy and kappa loci and expression of fully human antibodies. Proc Natl Acad Sci USA 97:722–727 Wagner SD, Popov AV, Davies SL et al (1994) The diversity of antigen-specific monoclonal antibodies from transgenic mice bearing human immunoglobulin gene miniloci. Eur J Immunol 24:2672–2681 Wagner SD, Gross G, Cook GP et al (1996) Antibody expression from the core region of the human IgH locus reconstructed in transgenic mice using bacteriophage P1 clones. Genomics 35:405–414 Weichhold GM, Ohnheiser R, Zachau HG (1993) The human immunoglobulin kappa locus consists of two copies that are organized in opposite polarity. Genomics 16:503–511 Xian J, Zou X, Popov AV et al (1998) Comparison of the performance of a plasmid-based human Igk minilocus and YAC-based human Igk transloci for the production of human antibody repertoires in transgenic mice. Transgenics 2:333–343 Zhang Z, Zemlin M, Wang YH et al (2003) Contribution of Vh gene replacement to the primary B cell repertoire. Immunity 19:21–31 Zhang B (2009) Ofatumumab. MAbs 1:326–331 Zou X, Piper TA, Smith JA et al (2003) Block in development at the pre-B-II to immature B cell stage in mice without Ig kappa and Ig lambda light chain. J Immunol 170:1354–1361