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

• 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
• ISSN: 0165-2478; 1879-0542
• DOI: 10.1016/S0165-2478(01)00302-9

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.