Shimoya Kazuto, Moriwaki Takashi, Kazuki Kanako, Okada Akane, Baba Shigenori, Masuda Yuana, Abe Satoshi, Kazuki Yasuhiro
Department of Chromosome Biomedical Engineering, Integrated Medical Sciences, Graduate School of Medical Sciences, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
Chromosome Engineering Research Center, Tottori University, 86 Nishi-cho, Yonago, Tottori 683-8503, Japan.
iScience. 2024 Oct 28;27(12):111258. doi: 10.1016/j.isci.2024.111258. eCollection 2024 Dec 20.
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 and 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.
通过动物免疫开发抗体药物通常需要对宿主抗体进行人源化，以解决对人体免疫原性的担忧。然而，使用能够产生人抗体的动物模型为开发无需人源化的抗体药物提供了机会。尽管人类免疫球蛋白（Ig）κ与Igλ的使用比例约为60%:40%，但大多数已批准的抗体疗法都是κ抗体，而λ抗体作为治疗剂的开发滞后。因此，在本研究中，我们使用小鼠人工染色体（MAC）载体开发了携带人类λ轻链恒定区基因座（IGHL）的小鼠，其能够产生人λ抗体。我们证明，IGHL小鼠在几代中始终保留整合在MAC上的人λ抗体基因座，并且在抗原刺激下可被诱导产生特异性抗体。这些发现为推进历史上被忽视的λ抗体药物提供了一个有前景的平台。
