Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery

E-Chiang Lee, Qi Liang, Hanif Ali, Luke Bayliss, Alastair Beasley, Tara Bloomfield-Gerdes, Laura Bonoli, Richard Brown, Jamie Campbell, Adam Carpenter, Sara Chalk, Alison Davis, Nick England, Alla Fane-Dremucheva, Bettina Franz, Volker Germaschewski, Helen Holmes, Steve Holmes, Ian Kirby, Miha KosmacAnais Legent, Hui Lui, Anais Manin, Siobhan O'Leary, Jemima Paterson, Rocco Sciarrillo, Anneliese Speak, Dominik Spensberger, Laura Tuffery, Nikole Waddell, Wei Wang, Sophie Wells, Vivian Wong, Andrew Wood, Michael J Owen, Glenn A Friedrich, Allan Bradley

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

If immunized with an antigen of interest, transgenic mice with large portions of unrearranged human immunoglobulin loci can produce fully human antigen-specific antibodies; several such antibodies are in clinical use. However, technical limitations inherent to conventional transgenic technology and sequence divergence between the human and mouse immunoglobulin constant regions limit the utility of these mice. Here, using repetitive cycles of genome engineering in embryonic stem cells, we have inserted the entire human immunoglobulin variable-gene repertoire (2.7 Mb) into the mouse genome, leaving the mouse constant regions intact. These transgenic mice are viable and fertile, with an immune system resembling that of wild-type mice. Antigen immunization results in production of high-affinity antibodies with long human-like complementarity-determining region 3 (CDR3H), broad epitope coverage and strong signatures of somatic hypermutation. These mice provide a robust system for the discovery of therapeutic human monoclonal antibodies; as a surrogate readout of the human antibody response, they may also aid vaccine design efforts.

Original languageEnglish
Pages (from-to)356-63
Number of pages8
JournalNature Biotechnology
Volume32
Issue number4
DOIs
Publication statusPublished - Apr 2014

Cite this

Lee, E-C., Liang, Q., Ali, H., Bayliss, L., Beasley, A., Bloomfield-Gerdes, T., ... Bradley, A. (2014). Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery. Nature Biotechnology, 32(4), 356-63. https://doi.org/10.1038/nbt.2825