{"title":"探索针对 T 细胞恶性肿瘤的人源化抗 CD99 ScFv 和抗体的生物活性。","authors":"Nuchjira Takheaw, Thanathat Pamonsupornwichit, Ratthakorn Chaiwut, Kamonporn Kotemul, Kanokporn Sornsuwan, On-Anong Juntit, Umpa Yasamut, Passaworn Cheyasawan, Witida Laopajon, Watchara Kasinrerk, Chatchai Tayapiwatana","doi":"10.3390/biom14111422","DOIUrl":null,"url":null,"abstract":"<p><p>CD99, a type I transmembrane protein, emerges as a promising therapeutic target due to its heightened expression in T cell acute lymphoblastic leukemia (T-ALL). This characteristic renders it a potential marker for minimal residual disease detection and an appealing target for antibody-based treatments. Previous studies have revealed that a mouse monoclonal antibody, mAb MT99/3, selectively binds to CD99, triggering apoptosis in T-ALL/T-LBL cells while preserving the integrity of healthy cells. By targeting CD99, mAb MT99/3 suppresses antigen presentation and disrupts T cell functions, offering promise for addressing hyperresponsive T cell conditions. To facilitate clinical translation, we developed a humanized ScFv variant of mAb MT99/3, termed HuScFvMT99/3 in \"ScFvkh\" design. Structural analysis confirms its resemblance to the original antibody, and the immunoreactivity of HuScFvMT99/3 against CD99 is preserved. The fully humanized version of antibody HuMT99/3 was further engineered, exhibiting similar binding affinity at the 10<sup>-10</sup> M level and specificity to the CD99 epitope without antigenic shift. HuMT99/3 demonstrates remarkable selectivity, recognizing both malignant and normal T cells but inducing apoptosis only in T-ALL/T-LBL cells, highlighting its potential for safe and targeted therapy.</p>","PeriodicalId":8943,"journal":{"name":"Biomolecules","volume":"14 11","pages":""},"PeriodicalIF":4.8000,"publicationDate":"2024-11-08","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592157/pdf/","citationCount":"0","resultStr":"{\"title\":\"Exploring the Biological Activity of a Humanized Anti-CD99 ScFv and Antibody for Targeting T Cell Malignancies.\",\"authors\":\"Nuchjira Takheaw, Thanathat Pamonsupornwichit, Ratthakorn Chaiwut, Kamonporn Kotemul, Kanokporn Sornsuwan, On-Anong Juntit, Umpa Yasamut, Passaworn Cheyasawan, Witida Laopajon, Watchara Kasinrerk, Chatchai Tayapiwatana\",\"doi\":\"10.3390/biom14111422\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><p>CD99, a type I transmembrane protein, emerges as a promising therapeutic target due to its heightened expression in T cell acute lymphoblastic leukemia (T-ALL). This characteristic renders it a potential marker for minimal residual disease detection and an appealing target for antibody-based treatments. Previous studies have revealed that a mouse monoclonal antibody, mAb MT99/3, selectively binds to CD99, triggering apoptosis in T-ALL/T-LBL cells while preserving the integrity of healthy cells. By targeting CD99, mAb MT99/3 suppresses antigen presentation and disrupts T cell functions, offering promise for addressing hyperresponsive T cell conditions. To facilitate clinical translation, we developed a humanized ScFv variant of mAb MT99/3, termed HuScFvMT99/3 in \\\"ScFvkh\\\" design. Structural analysis confirms its resemblance to the original antibody, and the immunoreactivity of HuScFvMT99/3 against CD99 is preserved. The fully humanized version of antibody HuMT99/3 was further engineered, exhibiting similar binding affinity at the 10<sup>-10</sup> M level and specificity to the CD99 epitope without antigenic shift. HuMT99/3 demonstrates remarkable selectivity, recognizing both malignant and normal T cells but inducing apoptosis only in T-ALL/T-LBL cells, highlighting its potential for safe and targeted therapy.</p>\",\"PeriodicalId\":8943,\"journal\":{\"name\":\"Biomolecules\",\"volume\":\"14 11\",\"pages\":\"\"},\"PeriodicalIF\":4.8000,\"publicationDate\":\"2024-11-08\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC11592157/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Biomolecules\",\"FirstCategoryId\":\"99\",\"ListUrlMain\":\"https://doi.org/10.3390/biom14111422\",\"RegionNum\":2,\"RegionCategory\":\"生物学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q1\",\"JCRName\":\"BIOCHEMISTRY & MOLECULAR BIOLOGY\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Biomolecules","FirstCategoryId":"99","ListUrlMain":"https://doi.org/10.3390/biom14111422","RegionNum":2,"RegionCategory":"生物学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"BIOCHEMISTRY & MOLECULAR BIOLOGY","Score":null,"Total":0}
引用次数: 0
摘要
CD99 是一种 I 型跨膜蛋白,由于其在 T 细胞急性淋巴细胞白血病(T-ALL)中的高表达,CD99 已成为一个很有前景的治疗靶点。这一特性使其成为检测极小残留病的潜在标志物,也是基于抗体的治疗方法的诱人靶点。先前的研究发现,一种小鼠单克隆抗体 mAb MT99/3 可选择性地与 CD99 结合,从而引发 T-ALL/T-LBL 细胞凋亡,同时保持健康细胞的完整性。通过靶向 CD99,mAb MT99/3 可抑制抗原递呈并破坏 T 细胞功能,有望解决 T 细胞反应过强的问题。为了促进临床转化,我们开发了一种人源化的 mAb MT99/3 ScFv 变体,以 "ScFvkh "设计命名为 HuScFvMT99/3。结构分析证实了它与原始抗体的相似性,并保留了 HuScFvMT99/3 对 CD99 的免疫活性。进一步设计的完全人源化抗体 HuMT99/3 在 10-10 M 水平上表现出相似的结合亲和力,对 CD99 表位具有特异性,不会发生抗原转移。HuMT99/3 具有显著的选择性,既能识别恶性 T 细胞,也能识别正常 T 细胞,但只能诱导 T-ALL/T-LBL 细胞凋亡,这突显了它在安全和靶向治疗方面的潜力。
Exploring the Biological Activity of a Humanized Anti-CD99 ScFv and Antibody for Targeting T Cell Malignancies.
CD99, a type I transmembrane protein, emerges as a promising therapeutic target due to its heightened expression in T cell acute lymphoblastic leukemia (T-ALL). This characteristic renders it a potential marker for minimal residual disease detection and an appealing target for antibody-based treatments. Previous studies have revealed that a mouse monoclonal antibody, mAb MT99/3, selectively binds to CD99, triggering apoptosis in T-ALL/T-LBL cells while preserving the integrity of healthy cells. By targeting CD99, mAb MT99/3 suppresses antigen presentation and disrupts T cell functions, offering promise for addressing hyperresponsive T cell conditions. To facilitate clinical translation, we developed a humanized ScFv variant of mAb MT99/3, termed HuScFvMT99/3 in "ScFvkh" design. Structural analysis confirms its resemblance to the original antibody, and the immunoreactivity of HuScFvMT99/3 against CD99 is preserved. The fully humanized version of antibody HuMT99/3 was further engineered, exhibiting similar binding affinity at the 10-10 M level and specificity to the CD99 epitope without antigenic shift. HuMT99/3 demonstrates remarkable selectivity, recognizing both malignant and normal T cells but inducing apoptosis only in T-ALL/T-LBL cells, highlighting its potential for safe and targeted therapy.
BiomoleculesBiochemistry, Genetics and Molecular Biology-Molecular Biology
CiteScore
9.40
自引率
3.60%
发文量
1640
审稿时长
18.28 days
期刊介绍:
Biomolecules (ISSN 2218-273X) is an international, peer-reviewed open access journal focusing on biogenic substances and their biological functions, structures, interactions with other molecules, and their microenvironment as well as biological systems. Biomolecules publishes reviews, regular research papers and short communications. Our aim is to encourage scientists to publish their experimental and theoretical results in as much detail as possible. There is no restriction on the length of the papers. The full experimental details must be provided so that the results can be reproduced.