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In vitro characterization of five humanized OKT3 effector function variant antibodies.
- Source :
-
Cellular immunology [Cell Immunol] 2000 Feb 25; Vol. 200 (1), pp. 16-26. - Publication Year :
- 2000
-
Abstract
- Orthoclone OKT 3 (mOKT3) is a highly effective agent for the reversal of steroid-resistant renal allograft rejection. However, its wider use has been limited by the development of a human anti-mouse antibody response (HAMA) and by the "cytokine release syndrome" (CRS). CRS has been associated with T cell/monocyte activation and, secondarily, with activation of the complement cascade. These processes are mediated through Abs' Fc regions by their abilities to cross-link T cells and mononuclear cells and to activate complements. To alleviate these problems, a group of five huIgG1- and huIgG4-based OKT3 wild-type antibodies and their corresponding Fc mutants with altered residues at amino acids 234, 235, and 318, reported to be required for FcgammaRI and FcgammaRII binding and complement fixation, were constructed. Characterization of these humanized OKT3 Abs, denoted huOKT3gamma1, huOKT3gamma4, huOKT3gamma1(A(234), A(235)), huOKT3gamma4(A(234), A(235)), and huOKT3gamma1(A(318)), has demonstrated that huOKT3gamma1(A(234), A(235)) and huOKT3gamma4(A(234), A(235)), and have at least a 100-fold reduced binding to FcgammaRI and FcgammaRII. As expected, they are much less potent in the induction of T cell activation and cytokine release, yet retain in vitro immunosuppressive effects as potent as those of mOKT3. Unexpectedly, while huOKT3gamma1(A(318)) did not show any reduction in its ability to bind C1q and to fix a complement, huOKT3gamma1(A(234), A(235)) was completely inactive. The in vitro characteristics of huOKT3gamma1(A(234), A(235)) are consistent with recent in vivo studies, in which this Ab showed greatly reduced HAMA and CRS with the retention of its ability to reverse ongoing graft rejection in man.<br /> (Copyright 2000 Academic Press.)
- Subjects :
- Animals
Antibody Affinity
Complement Activation
Complement C1q metabolism
Dose-Response Relationship, Drug
Genetic Variation
Graft Rejection drug therapy
Humans
Immunoglobulin Constant Regions genetics
Immunoglobulin Heavy Chains genetics
Immunoglobulin Variable Region genetics
Immunosuppressive Agents isolation & purification
Immunosuppressive Agents pharmacology
Kidney Transplantation immunology
Lymphocyte Activation
Mice
Muromonab-CD3 genetics
Muromonab-CD3 isolation & purification
Muromonab-CD3 pharmacology
Mutagenesis
Protein Binding
Protein Engineering methods
Receptors, IgG metabolism
Recombinant Proteins isolation & purification
T-Lymphocytes immunology
CD3 Complex immunology
Immunosuppressive Agents immunology
Muromonab-CD3 immunology
Subjects
Details
- Language :
- English
- ISSN :
- 0008-8749
- Volume :
- 200
- Issue :
- 1
- Database :
- MEDLINE
- Journal :
- Cellular immunology
- Publication Type :
- Academic Journal
- Accession number :
- 10716879
- Full Text :
- https://doi.org/10.1006/cimm.2000.1617