transgenic animals for antibody discovery
Thioredoxin-displayed multipeptide immunogens. These animals have an enhanced humoral response and an expanded IgM repertoire (36). The most widely used adjuvants include the water-in-oil emulsions and the aluminum salts (46). Ponziani S, Di Vittorio G, Pitari G, Cimini AM, Ardini M, Gentile R, Iacobelli S, Sala G, Capone E, Flavell DJ, Ippoliti R, Giansanti F. Int J Mol Sci. Coupled with the ability to determine the corresponding antibody sequences using NGS, deep interrogation of antibody repertoires is within reach. Curr Drug Discov Technol (2014) 11(1):74–84. Fitzgerald V, Leonard P. Single cell screening approaches for antibody discovery. These include (1) preparation and presentation of the immunogen, (2) choice of adjuvant, (3) immunization method, and (4) the impact of T-cell tolerance. Mol Aspects Med (2018) 59:47–61. We have had limited success extracting ECLs and immunizing them as peptides or when grafting them onto heterologous carrier proteins, despite the existence of successful reports (79, 80). Lonberg N. Human monoclonal antibodies from transgenic mice. 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. Immunol Rev (2015) 268(1):269–87. A repertoire of monoclonal antibodies with human heavy chains from transgenic mice. MAbs. Because of this, we favor genetic and cell-based immunogens for this target class, both of which can be readily produced using the same expression plasmid (44, 45). Immunol Rev (2004) 197:102–15. doi:10.1371/journal.pone.0090383, 27. Silva M, Nguyen TH, Philbrook P, Chu M, Sears O, Hatfield S, et al. The remarkable ability of these animals to assimilate mouse biology and human antibody sequence information has revolutionized biotechnology by providing access to a diverse source of fully human antibodies. Indeed, we routinely observe biases among the strains with regard to their response to specific antigens. Combining these modifications with a human antibody discovery platform may yield animals capable of producing nonstandard repertoires. Transgenic mouse strains as platforms for the successful discovery and development of human therapeutic monoclonal antibodies. Epub 2013 Oct 30. If the initial candidate fails biophysical characterization, a unique backup molecule has already been identified. For membrane targets that contain ECDs that are difficult to purify or that cannot easily be overexpressed, an alternative strategy is to artificially tether them to the surface of a cellular expression host (40). 2001;49(3):203-8. USA.gov. Shakya AK, Gill HS. Epub 2020 May 27. | Genetic immunization is a simple method for eliciting an immune response. While the engineering details differ, these platforms share the ability to raise an immune response that is comprised of antibodies with fully human idiotypes. Fully human antibodies from transgenic animals account for an increasing number of new therapeutics. J Biomol Screen (2015) 20(4):492–7. Ideal antibody candidates are often required to bind with high affinity to a specific epitope, cross-react to a non-human ortholog, lack binding to paralogs, and survive the rigors of the stringent drug development process (6). Evidence of the native conformation can be obtained using functional bioassays or by assessing relevant biophysical interactions. Impact Factor 5.085 | CiteScore 5.4More on impact ›, In Vivo and In Vitro Strategies for Generating Diverse Human Antibody Repertoires
doi:10.1038/emm.2015.105, 8. Abdiche YN, Harriman R, Deng X, Yeung YA, Miles A, Morishige W, et al. Temchura V, Kalinin S, Nabi G, Tippler B, Niezold T, Uberla K. Divergence of primary cognate B- and T-cell proliferative responses to subcutaneous and intravenous immunization with virus-like particles. Seah YFS, Hu H, Merten CA. 2020 Aug;85:106639. doi: 10.1016/j.intimp.2020.106639. Petrovsky N. Comparative safety of vaccine adjuvants: a summary of current evidence and future needs. Methods Mol Biol. doi:10.1038/nprot.2014.104, 87. PLoS One (2014) 9(9):e106699. © 2016 John Wiley & Sons A/S. Methods Mol Biol (2014) 1060:245–76. It is now possible to use next-generation sequencing (NGS) to determine all of the individual sequences that make up the complete antibody repertoire of an animal (96, 97). Irving MB, Craig L, Menendez A, Gangadhar BP, Montero M, van Houten NE, et al. The editor and reviewers' affiliations are the latest provided on their Loop research profiles and may not reflect their situation at the time of review. doi:10.1016/j.molimm.2009.10.015, 44. The first approved therapy derived from a transgenic platform--the epidermal growth factor receptor antagonist panitumumab to treat advanced colorectal cancer--was developed using XenoMouse(®) technology. Sercarz EE, Maverakis E. Mhc-guided processing: binding of large antigen fragments. Regardless of how the antigen is engineered, it is important to validate it prior to use. J Exp Med. eCollection 2018. Apostolico Jde S, Lunardelli VA, Coirada FC, Boscardin SB, Rosa DS. Thus, antibodies satisfying all the design goals may be extremely rare, if they are elicited at all. The success of this strategy depends on the degree to which the design goals are tied to a specific functional epitope or if targeting multiple epitopes within a structural region is permitted. Vaccine (2009) 27(32):4370–80. Crescendo’s TKO. The first approved therapy derived from a transgenic platform--the epidermal growth factor receptor antagonist panitumumab to treat advanced colorectal cancer--was developed using XenoMouse(®) technology. Eur J Immunol. Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. The biomedical sciences rely heavily on animal models as tools for the discovery and development of therapeutic interventions. -, Bruggemann M. Human antibody expression in transgenic mice. Coimmunization with an optimized IL15 plasmid adjuvant enhances humoral immunity via stimulating B cells induced by genetically engineered DNA vaccines expressing consensus JEV and WNV E DIII. Diversity of the antibody response to tetanus toxoid: comparison of hybridoma library to phage display library. Although the predominant transgenic host species has been mouse, the genomes of rats, rabbits, chickens, and cows have also been modified to express human antibodies. Lin Z, Chiang NY, Chai N, Seshasayee D, Lee WP, Balazs M, et al. In this perspective, we describe some of the strategies and considerations we use for manipulating the immune systems of transgenic animal platforms (such as XenoMouse®) with a focus on maximizing the diversity of the primary response and steering the ensuing antibody repertoire toward a desired outcome. Thus, finding the ideal location within the antigen of interest is a critical factor that must be determined empirically. Human antibody expression in transgenic rats: comparison of chimeric IgH loci with human VH, D and JH but bearing different rat C-gene regions. doi:10.1002/eji.200526134, 93. High-affinity IgG antibodies develop naturally in Ig-knockout rats carrying germline human IgH/Igkappa/Iglambda loci bearing the rat CH region. WC and CM are full-time employees of, and hold stock in, Amgen, Inc. Nat Immunol (2017) 18(4):456–63. Schneider Z, Cervenak J, Baranyi M, Papp K, Prechl J, Laszlo G, et al. doi:10.1016/j.sbi.2016.10.019, 30. Cameron B, Dabdoubi T, Berthou-Soulié L, Gagnaire M, Arnould I, Severac A, Soubrier F, Morales J, Leighton PA, Harriman W, Ching K, Abdiche Y, Radošević K, Bouquin T. PLoS One. 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. Human antibody production in transgenic animals. eCollection 2015. Unfortunately, these methods are generally low throughput, labor intensive, and restricted to simple assays, which limits their usefulness to mine significant fractions of the elicited repertoire. Preparing the target antigen such that it is an effective immunogen is a critical first step. Dubois AR, Buerckert JP, Sinner R, Faison WJ, Molitor AM, Muller CP. Exploring peptide mimics for the production of antibodies against discontinuous protein epitopes. To ensure our lead candidates can meet this stringent design goal, we frequently incorporate the orthologous antigen from the toxicology species into our immunization protocols. As such, they are potentially rich sources of antibody repertoires that may help address challenging targets or design goals. doi:10.1073/pnas.0909775106, 39. Immunity (2000) 12(4):391–8. Meijer PJ, Andersen PS, Haahr Hansen M, Steinaa L, Jensen A, Lantto J, et al. Human antibodies from V-gene libraries displayed on phage. Ann N Y Acad Sci (1995) 764:525–35. The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. Although the precise details depend on the nature of the target antigen, our general approach is to use validated forms of immunogens and present them to the immune system in variety of ways. Lonberg N, Taylor LD, Harding FA, Trounstine M, Higgins KM, Schramm SR, et al. Starkie DO, Compson JE, Rapecki S, Lightwood DJ. These challenges have been met with a number of novel approaches focused on the generation of large, high-quality, and diverse antibody repertoires. This serves two purposes: (1) it increases the likelihood of finding antibodies that meet the functional design goals and (2) it increases the probability of identifying lead candidates that are sequence diverse (6). Spiller OB, Harris CL, Morgan BP. doi:10.1038/nbt.2825, 18. 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. The authors would like to thank Chadwick King, Karyn McFadden, and the anonymous internal Amgen, Inc. reviewers for critical reading of the manuscript. BMC Biotechnol (2016) 16(1):83. doi:10.1186/s12896-016-0314-5, 43. The observation that the immune systems of these animals are able to recognize and respond to a wide range of therapeutically relevant human targets has led to a surge in antibody-derived drugs in current development. Achieving these new heights in antibody drug discovery will ultimately bring better medicines to patients. (65–68). Nat Biotechnol (2007) 25(10):1134–43. Epub 2017 Dec 14. PLoS One (2016) 11(3):e0152282. Capture and display of antibodies secreted by hybridoma cells enables fluorescent on-cell screening. doi:10.1073/pnas.1323896111, 19. 2015 Jun 24;10(6):e0130699. Production of human monoclonal and polyclonal antibodies in TransChromo animals.
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