title: Complete humanization of the mouse immunoglobulin loci enables efficient therapeutic antibody discovery.
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.
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: E-Chiang
authors.initials: EC
authors.lastname: Lee
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Qi
authors.initials: Q
authors.lastname: Liang
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Hanif
authors.initials: H
authors.lastname: Ali
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Luke
authors.initials: L
authors.lastname: Bayliss
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Alastair
authors.initials: A
authors.lastname: Beasley
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Tara
authors.initials: T
authors.lastname: Bloomfield-Gerdes
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Bonoli
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Brown
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Jamie
authors.initials: J
authors.lastname: Campbell
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Adam
authors.initials: A
authors.lastname: Carpenter
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Sara
authors.initials: S
authors.lastname: Chalk
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Alison
authors.initials: A
authors.lastname: Davis
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Nick
authors.initials: N
authors.lastname: England
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Alla
authors.initials: A
authors.lastname: Fane-Dremucheva
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Bettina
authors.initials: B
authors.lastname: Franz
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Volker
authors.initials: V
authors.lastname: Germaschewski
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Helen
authors.initials: H
authors.lastname: Holmes
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Steve
authors.initials: S
authors.lastname: Holmes
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Ian
authors.initials: I
authors.lastname: Kirby
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Miha
authors.initials: M
authors.lastname: Kosmac
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Anais
authors.initials: A
authors.lastname: Legent
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Hui
authors.initials: H
authors.lastname: Lui
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Anais
authors.initials: A
authors.lastname: Manin
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Siobhan
authors.initials: S
authors.lastname: O'Leary
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Jemima
authors.initials: J
authors.lastname: Paterson
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Rocco
authors.initials: R
authors.lastname: Sciarrillo
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Anneliese
authors.initials: A
authors.lastname: Speak
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Dominik
authors.initials: D
authors.lastname: Spensberger
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Laura
authors.initials: L
authors.lastname: Tuffery
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Nikole
authors.initials: N
authors.lastname: Waddell
authors.affiliation: Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Wei
authors.initials: W
authors.lastname: Wang
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Sophie
authors.initials: S
authors.lastname: Wells
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Vivian
authors.initials: V
authors.lastname: Wong
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Andrew
authors.initials: A
authors.lastname: Wood
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Owen
authors.affiliation: Kymab Ltd., Babraham Research Campus, Cambridge, UK.
authors.forename: Glenn A
authors.initials: GA
authors.lastname: Friedrich
authors.affiliation: 1] Kymab Ltd., Babraham Research Campus, Cambridge, UK. [2] Wellcome Trust Sanger Institute, Hinxton, Cambridge, UK.
authors.forename: Allan
authors.initials: A
authors.lastname: Bradley
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics* / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000502:physiology; D022202:Chromosomes, Artificial, Bacterial / Q000235:genetics; D005260:Female; D005818:Genetic Engineering / Q000379:methods*; D006801:Humans; D007135:Immunoglobulin Variable Region / Q000235:genetics*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D019076:Transgenes / Q000235:genetics*
chemical_list: D000911:Antibodies, Monoclonal; D007135:Immunoglobulin Variable Region