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An in vivo method for diversifying the functions of therapeutic antibodies.
- Source :
-
Proceedings of the National Academy of Sciences of the United States of America . 3/9/2021, Vol. 118 Issue 10, p1-11. 11p. - Publication Year :
- 2021
-
Abstract
- 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. [ABSTRACT FROM AUTHOR]
- Subjects :
- *B cell receptors
*IMMUNOGLOBULINS
*GERMINAL centers
*IMMUNOGLOBULIN genes
*B cells
Subjects
Details
- Language :
- English
- ISSN :
- 00278424
- Volume :
- 118
- Issue :
- 10
- Database :
- Academic Search Index
- Journal :
- Proceedings of the National Academy of Sciences of the United States of America
- Publication Type :
- Academic Journal
- Accession number :
- 149280901
- Full Text :
- https://doi.org/10.1073/pnas.2025596118