Recombinant chimeric OKT3/IgM antibodies for immune suppression: evaluation in a human CD3 transgenic mouse model.
ScOKT3-gammaDeltaIgM 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-gammaDeltaIgM 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 microg of isolated scOKT3-gammaDeltaIgM 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-alpha and INF-gamma) in the mice's sera. These results suggest that scOKT3-gammaDeltaIgM VAEVD antibodies may provide a useful alternative to the OKT3 mAb for clinical immunosuppressive treatment for auto-aggressive diseases or for organ-transplantation.
Choi
Ingrid
I
Recombinant Antibody Research Group, German Cancer Research Center (DKFZ), Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. i.choi@dkfz.de
Schmitt
Wolfgang E
WE
Bähre
Alexandra
A
Little
Melvyn
M
Cochlovius
Björn
B
D000818:Animals; D017252:CD3 Complex / Q000276:immunology*; D006801:Humans; D007075:Immunoglobulin M / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D007166:Immunosuppressive Agents / Q000276:immunology* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy; D007371:Interferon-gamma / Q000097:blood; D007376:Interleukin-2 / Q000097:blood; D051379:Mice; D008822:Mice, Transgenic; D023421:Models, Animal; D016853:Muromonab-CD3 / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000627:therapeutic use; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D017252:CD3 Complex; D007075:Immunoglobulin M; D007166:Immunosuppressive Agents; D007376:Interleukin-2; D016853:Muromonab-CD3; D011993:Recombinant Fusion Proteins; D014409:Tumor Necrosis Factor-alpha; D007371:Interferon-gamma