Mice carrying the full-length human immunoglobulin loci produce antigen-specific human antibodies with the lambda light chain

Kazuto Shimoya; Takashi Moriwaki; Kanako Kazuki; Akane Okada; Shigenori Baba; Yuana Masuda; Satoshi Abe; Yasuhiro Kazuki

doi:10.1016/j.isci.2024.111258

Mice carrying the full-length human immunoglobulin loci produce antigen-specific human antibodies with the lambda light chain

iScience. 2024 Oct 28;27(12):111258. doi: 10.1016/j.isci.2024.111258. eCollection 2024 Dec 20.

Authors

Kazuto Shimoya¹, Takashi Moriwaki^{2

3}, Kanako Kazuki², Akane Okada², Shigenori Baba³, Yuana Masuda³, Satoshi Abe², Yasuhiro Kazuki^{1

2

3

4}

Affiliations

¹ Department of Chromosome Biomedical Engineering, Integrated Medical Sciences, Graduate School of Medical Sciences, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
² Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
³ Department of Chromosome Biomedical Engineering, School of Life Science, Faculty of Medicine, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
⁴ Chromosome Engineering Research Group, The Exploratory Research Center on Life and Living Systems (ExCELLS), National Institutes of Natural Sciences, 5-1 Higashiyama, Myodaiji, Okazaki, Aichi 444-8787, Japan.

Abstract

The development of antibody drugs through animal immunization typically requires the humanization of host antibodies to address concerns about immunogenicity in humans. However, employing an animal model capable of producing human antibodies presents the opportunity to develop antibody drugs without the need for humanization. Despite the ratio of human immunoglobulin (Ig) κ to Igλ usage being approximately 60%:40%, the majority of approved antibody therapeutics are kappa antibodies, and the development of lambda antibodies as therapeutic agents has lagged behind. Therefore, in this study, we developed mice carrying the IGH and IGL loci (IGHL), which can produce human lambda antibodies, using mouse artificial chromosome (MAC) vectors. We demonstrated that IGHL mice consistently retain the human lambda antibody locus integrated on the MAC across generations and can be induced to produce specific antibodies upon antigen stimulation. These findings provide a promising platform for advancing lambda antibody drugs, which have historically been neglected.

Keywords: Biological sciences research methodologies; Genetic engineering; Immune response.