Journal Article

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

Satofuka, Hiroyuki, Tomizuka, Kazuma, Moriwaki, Takashi, Kazuki, Kanako, Okada, Akane, Murakami, Yasufumi, Takayama, Haruka, Tanaka, Hiroshi, Hichiwa, Genki, Morimoto, Kayoko, Nakayama, Yuji, Oshimura, Mitsuo, Hatano, Shinya, Baba, Yoshihiro, Yada, Yutaro, Abe, Satoshi, Kazuki, Yasuhiro, Yamazaki, Kyotaro

2022

Overview

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. Trans-chromosomic (Tc) mice have helped the development of therapeutic antibodies, but chromosome instability limits its application. Here the authors develop a new line of Tc mice with full human Ig heavy and kappa loci integrated into the mouse artificial chromosome for stable passage, and confirm efficient generation of B cell responses and specific antibodies.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/1 / 13/51 / 38/39 / 42/100 / 49/31 / 631/1647/664/2228 / 631/250/2152/2153/1291 / 631/250/248 / 631/61/17/1511 / 64/60 / Animals / Antibodies / Antibodies, Monoclonal / Antigens / Artificial chromosomes / Chromosomes / Chromosomes, Artificial, Yeast / DNA sequencing / Humanities and Social Sciences / Humans / Hybridomas / Immune response / Immune system / Immunoglobulin Heavy Chains - genetics / Immunoglobulin kappa-Chains - genetics / Immunoglobulins / Loci / Mice / Mice, Transgenic / Monoclonal antibodies / multidisciplinary / Plasma cells / Science / Science (multidisciplinary)