Recombinant chimeric OKT3/IgM antibodies for immune suppression: evaluation in a human CD3 transgenic mouse model

ScOKT3-γΔIgM VAEVD is a recombinant chimeric anti-CD3 antibody variant consisting of the light and heavy variable binding domains of the OKT3 monoclonal antibody and the CH3 and CH4 domains of a human IgM mutation linked by a human IgG3 hinge region. Due to the IgM Fc domains, scOKT3-γΔIgM VAEVD ant...

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Bibliographic Details
Published in:Immunology letters 2002-02, Vol.80 (2), p.125-128
Main Authors: Choi, Ingrid, Schmitt, Wolfgang E, Bähre, Alexandra, Little, Melvyn, Cochlovius, Björn
Format: Article
Language:English
Subjects:
Adjuvant-induced inflammation
Animals
CD3 antigen
CD3 Complex - immunology
Humans
Immunoglobulin M - genetics
Immunoglobulin M - immunology
Immunoglobulin M - therapeutic use
Immunosuppressive Agents - immunology
Immunosuppressive Agents - therapeutic use
Inflammation - drug therapy
Interferon-gamma - blood
Interleukin-2 - blood
Mice
Mice, Transgenic
Models, Animal
Muromonab-CD3 - genetics
Muromonab-CD3 - immunology
Muromonab-CD3 - therapeutic use
Recombinant antibody
Recombinant Fusion Proteins - immunology
Recombinant Fusion Proteins - therapeutic use
Time Factors
Transgenic mice
Tumor Necrosis Factor-alpha - metabolism
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Summary:ScOKT3-γΔIgM VAEVD is a recombinant chimeric anti-CD3 antibody variant consisting of the light and heavy variable binding domains of the OKT3 monoclonal antibody and the CH3 and CH4 domains of a human IgM mutation linked by a human IgG3 hinge region. Due to the IgM Fc domains, scOKT3-γΔIgM VAEVD antibodies are able to form polymeric structures. Independent of their polymerization state, they possess in vitro CD3 modulating and immunosuppressive properties while inducing only minimal T cell activation compared to their monoclonal counterpart. To evaluate the in vivo efficacy of the antibodies, an adjuvant-induced chronic inflammation was established in human CD3 transgenic mice. Administration of four doses of 15 μg of isolated scOKT3-γΔIgM VAEVD monomers and pentamers significantly reduced diameters of inflamed ankle joints in a manner comparable to the monoclonal antibody OKT3. Additionally, the antibody treatment lead to a significant reduction of the cytokine levels (IL-2, TNF-α and INF-γ) in the mice's sera. These results suggest that scOKT3-γΔIgM VAEVD antibodies may provide a useful alternative to the OKT3 mAb for clinical immunosuppressive treatment for auto-aggressive diseases or for organ-transplantation.
ISSN:0165-2478
1879-0542
DOI:10.1016/S0165-2478(01)00302-9