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

Author

Listed:
  • Hiroyuki Satofuka

    (Tottori University)

  • Satoshi Abe

    (Tottori University
    Trans Chromosomics Inc.)

  • Takashi Moriwaki

    (Tottori University
    Tottori University)

  • Akane Okada

    (Tottori University)

  • Kanako Kazuki

    (Tottori University)

  • Hiroshi Tanaka

    (Trans Chromosomics Inc.)

  • Kyotaro Yamazaki

    (Tottori University)

  • Genki Hichiwa

    (Tottori University
    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
    Tottori University
    Tottori University)

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.

Suggested Citation

  • Hiroyuki Satofuka & Satoshi Abe & Takashi Moriwaki & Akane Okada & Kanako Kazuki & Hiroshi Tanaka & Kyotaro Yamazaki & Genki Hichiwa & Kayoko Morimoto & Haruka Takayama & Yuji Nakayama & Shinya Hatano, 2022. "Efficient human-like antibody repertoire and hybridoma production in trans-chromosomic mice carrying megabase-sized human immunoglobulin loci," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    • Handle: RePEc:nat:natcom:v:13:y:2022:i:1:d:10.1038_s41467-022-29421-2
    DOI: 10.1038/s41467-022-29421-2
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    References listed on IDEAS

    as
    1. Zahra Sabouri & Samuel Perotti & Emily Spierings & Peter Humburg & Mehmet Yabas & Hannes Bergmann & Keisuke Horikawa & Carla Roots & Samantha Lambe & Clara Young & T. Dan Andrews & Matthew Field & Ans, 2016. "IgD attenuates the IgM-induced anergy response in transitional and mature B cells," Nature Communications, Nature, vol. 7(1), pages 1-11, December.
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