气候变化领域集成服务门户(CCPortal): An in vivo method for diversifying the functions of therapeutic antibodies

CCPortal

DOI	10.1073/pnas.2025596118
	An in vivo method for diversifying the functions of therapeutic antibodies
	Tian M.; Cheng H.-L.; Kimble M.T.; McGovern K.; Waddicor P.; Chen Y.; Cantor E.; Qiu M.; Tuchel M.-E.; Dao M.; Alt F.W.
发表日期	2021
ISSN	00278424
卷号	118 期号:10
英文摘要	V(D)J recombination generates mature B cells that express huge repertoires of primary antibodies as diverse immunoglobulin (Ig) heavy chain (IgH) and light chain (IgL) of their B cell antigen receptors (BCRs). Cognate antigen binding to BCR variable region domains activates B cells into the germinal center (GC) reaction in which somatic hypermutation (SHM) modifies primary variable region-encoding sequences, with subsequent selection for mutations that improve antigen-binding affinity, ultimately leading to antibody affinity maturation. Based on these principles, we developed a humanized mouse model approach to diversify an anti-PD1 therapeutic antibody and allow isolation of variants with novel properties. In this approach, component Ig gene segments of the anti-PD1 antibody underwent de novo V(D)J recombination to diversify the anti-PD1 antibody in the primary antibody repertoire in the mouse models. Immunization of these mouse models further modified the anti-PD1 antibodies through SHM. Known anti-PD1 antibodies block interaction of PD1 with its ligands to alleviate PD1-mediated T cell suppression, thereby boosting antitumor T cell responses. By diversifying one such anti-PD1 antibody, we derived many anti-PD1 antibodies, including anti-PD1 antibodies with the opposite activity of enhancing PD1/ligand interaction. Such antibodies theoretically might suppress deleterious T cell activities in autoimmune diseases. The approach we describe should be generally applicable for diversifying other therapeutic antibodies. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Antibody optimization; Immunoglobulin; Mouse model
语种	英语
scopus关键词	nivolumab; pembrolizumab; programmed death 1 ligand 1; animal cell; animal experiment; animal model; antibody isolation; antibody specificity; Article; autoimmune disease; binding affinity; cancer immunotherapy; cell activity; cell function; controlled study; genetic recombination; genetic variability; human; immunization; in vivo study; mouse; nonhuman; priority journal; protein function; protein interaction; somatic hypermutation; T lymphocyte
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180333
作者单位	Program in Cellular and Molecular Medicine, Boston Children’s Hospital, Boston, MA 02115, United States; Department of Genetics, Harvard Medical School, Boston, MA 02115, United States; HHMI, Boston Children’s Hospital, Boston, MA 02115, United States
推荐引用方式 GB/T 7714	Tian M.,Cheng H.-L.,Kimble M.T.,et al. An in vivo method for diversifying the functions of therapeutic antibodies[J],2021,118(10).
APA	Tian M..,Cheng H.-L..,Kimble M.T..,McGovern K..,Waddicor P..,...&Alt F.W..(2021).An in vivo method for diversifying the functions of therapeutic antibodies.Proceedings of the National Academy of Sciences of the United States of America,118(10).
MLA	Tian M.,et al."An in vivo method for diversifying the functions of therapeutic antibodies".Proceedings of the National Academy of Sciences of the United States of America 118.10(2021).