Back to Search
Start Over
Construction and characterization of a humanized anti-human CD3 monoclonal antibody 12F6 with effective immunoregulation functions.
- Source :
- Immunology; Dec2005, Vol. 116 Issue 4, p487-498, 12p, 9 Graphs
- Publication Year :
- 2005
-
Abstract
- 12F6 is a murine anti-human CD3 monoclonal antibody, which competes with OKT3 for binding to human T cells and possesses more effective T-cell suppression and activation properties compared to OKT3. It thus exhibits the potential to be developed as an immunoregulation agent for manipulating T-cell functions and preventing acute allograft rejection. In an attempt to minimize the immunogenicity of murine 12F6 (m12F6) for potential clinical application, a humanized version of 12F6, denoted as hu12F6, was successfully constructed by complementary determining region (CDR) grafting and shown to maintain both T-cell activation and suppression activities similar to m12F6. Furthermore, in order to reduce the first dose reaction syndrome caused by T-cell activation following the first administration of anti-CD3 antibodies, two amino acid mutations were introduced into the Fc region of hu12F6, resulting in the Fc-mutated 12F6 humanized antibody (hu12F6mu). This Fc-mutated version displayed a similar antigen-binding affinity and specificity compared with hu12F6 and m12F6 but with much weaker FcR binding activity. hu12F6mu was shown to be much less potent in the induction of T-cell proliferation, cytokine release (tumour necrosis factor-α, interferon-γ and interleukin-10) and early activation marker expression on the cell surface (CD69 and CD25) than parental 12F6 and OKT3 did. In contrast, hu12F6mu was effective in modulating T-cell receptor/CD3 and inhibiting mixed lymphocyte reaction with a similarity as compared to m12F6 and OKT3. In conclusion, the resultant hu12F6mu was much less mitogenic to T cells but retained potent immunosuppression, suggesting it might be an alternative to OKT3 as an immunosuppressive drug with less immunogenicity and toxicity for clinical application. [ABSTRACT FROM AUTHOR]
Details
- Language :
- English
- ISSN :
- 00192805
- Volume :
- 116
- Issue :
- 4
- Database :
- Complementary Index
- Journal :
- Immunology
- Publication Type :
- Academic Journal
- Accession number :
- 18856559
- Full Text :
- https://doi.org/10.1111/j.1365-2567.2005.02247.x