Human IgG2 variants of chimeric anti-CD3 are nonmitogenic to T cells.
The mouse anti-human CD3 mAb OKT3 is a potent immunosuppressive agent used for the treatment of acute transplant rejection. OKT3 therapy is associated with acute toxicity resulting from in vivo T cell activation and systemic cytokine release, and a human anti-mouse Ab response. T cell activation is thought to be triggered by CD3 cross-linking mediated by the Abs bridging T cells and Fc receptor-bearing cells. Recent studies in a mouse model indicate that anti-mouse CD3 Abs with low affinity for Fc receptors can achieve immunosuppression without T cell activation, toxicity, or an anti-Ab response. To obtain an analogous Ab to improve the current anti-human CD3 therapy, a humanized Ab with low affinity for Fc receptors is needed. In this study, we introduced mutations into the upper CH2 region of IgG2 and expressed the altered Fc as chimeric OKT3 Abs. Compared with chimeric OKT3 IgG1, IgG2, IgG3, and IgG4, the IgG2 mutants were less mitogenic to T cells, and they did not induce the release of TNF-alpha, IFN-gamma, or IL-2. In parallel, we observed no functional interaction of the IgG2 mutant Abs with K562 cells, which express the IgG2-binding Fc receptor on their surface. Despite no measurable T cell activation, the mutant Abs could still modulate the CD3 complex. When coupled to a humanized anti-CD3, the IgG2 variant may provide a drug with less acute toxicity and immunogenicity, but may still retain potent immunosuppressive properties.
Cole
M S
MS
Protein Design Laboratories, Inc., Mountain View, CA 94043, USA.
Anasetti
C
C
Tso
J Y
JY
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D000915:Antibody Affinity; D017252:CD3 Complex / Q000276:immunology; D016207:Cytokines / Q000493:pharmacokinetics; D006801:Humans; D007127:Immunoglobulin Constant Regions / Q000235:genetics; D007141:Immunoglobulin Fc Fragments / Q000235:genetics / Q000502:physiology; D007074:Immunoglobulin G / Q000235:genetics*; D007143:Immunoglobulin Heavy Chains / Q000235:genetics; D007132:Immunoglobulin Isotypes / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects; D051379:Mice; D008934:Mitogens / Q000276:immunology / Q000494:pharmacology*; D016853:Muromonab-CD3 / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D016297:Mutagenesis, Site-Directed / Q000276:immunology; D017452:Receptors, IgG / Q000502:physiology; D011993:Recombinant Fusion Proteins / Q000276:immunology* / Q000494:pharmacology; D013601:T-Lymphocytes / Q000187:drug effects / Q000276:immunology*
D000276:Adjuvants, Immunologic; D017252:CD3 Complex; D016207:Cytokines; D007127:Immunoglobulin Constant Regions; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007132:Immunoglobulin Isotypes; D008934:Mitogens; D016853:Muromonab-CD3; D017452:Receptors, IgG; D011993:Recombinant Fusion Proteins