Efficient human-like antibody repertoire and hybridoma production in trans-chromosomic mice carrying megabase-sized human immunoglobulin loci

Hiroyuki Satofuka, Satoshi Abe, Takashi Moriwaki, Akane Okada, Kanako Kazuki, Hiroshi Tanaka, Kyotaro Yamazaki, Genki Hichiwa, Kayoko Morimoto, Haruka Takayama, Yuji Nakayama, Shinya Hatano, Yutaro Yada, Yasufumi Murakami, Yoshihiro Baba, Mitsuo Oshimura, Kazuma Tomizuka and Yasuhiro Kazuki ()
Additional contact information
Hiroyuki Satofuka: Tottori University
Satoshi Abe: Tottori University
Takashi Moriwaki: Tottori University
Akane Okada: Tottori University
Kanako Kazuki: Tottori University
Hiroshi Tanaka: Trans Chromosomics Inc.
Kyotaro Yamazaki: Tottori University
Genki Hichiwa: Tottori University
Kayoko Morimoto: Trans Chromosomics Inc.
Haruka Takayama: Trans Chromosomics Inc.
Yuji Nakayama: Tottori University
Shinya Hatano: Kyushu University
Yutaro Yada: Kyushu University
Yasufumi Murakami: Order-made Medical Research Inc.
Yoshihiro Baba: Kyushu University
Mitsuo Oshimura: Trans Chromosomics Inc.
Kazuma Tomizuka: Tokyo University of Pharmacy and Life Sciences
Yasuhiro Kazuki: Tottori University

Nature Communications, 2022, vol. 13, issue 1, 1-15

Abstract: Abstract Trans-chromosomic (Tc) mice carrying mini-chromosomes with megabase-sized human immunoglobulin (Ig) loci have contributed to the development of fully human therapeutic monoclonal antibodies, but mitotic instability of human mini-chromosomes in mice may limit the efficiency of hybridoma production. Here, we establish human antibody-producing Tc mice (TC-mAb mice) that stably maintain a mouse-derived, engineered chromosome containing the entire human Ig heavy and kappa chain loci in a mouse Ig-knockout background. Comprehensive, high-throughput DNA sequencing shows that the human Ig repertoire, including variable gene usage, is well recapitulated in TC-mAb mice. Despite slightly altered B cell development and a delayed immune response, TC-mAb mice have more subsets of antigen-specific plasmablast and plasma cells than wild-type mice, leading to efficient hybridoma production. Our results thus suggest that TC-mAb mice offer a valuable platform for obtaining fully human therapeutic antibodies, and a useful model for elucidating the regulation of human Ig repertoire formation.

Date: 2022
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DOI: 10.1038/s41467-022-29421-2

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