Activation of human T cells by FcR nonbinding anti-CD3 mAb, hOKT3gamma1(Ala-Ala)

J Clin Invest. 2003 Feb;111(3):409-18. doi: 10.1172/JCI16090.


Dimeric Fc receptor (FcR) nonbinding anti-CD3 antibodies have been developed to minimize toxicities associated with classical anti-CD3 monoclonal antibodies (e.g., OKT3). Studies with murine analogs of non-FcR-binding antibodies have shown reduced mitogenicity compared to OKT3. In a trial of an FcR nonbinding humanized anti-CD3 mAb hOKT3gamma1(Ala-Ala) for treatment of patients with type 1 diabetes, we found significant increases in IL-10 and IL-5 in the serum of 63% and 72% of patients, respectively, and TNF-alpha and IL-6 levels that were lower than those previously reported following OKT3 therapy. The activation signal delivered by hOKT3gamma1(Ala-Ala) was associated with calcium signaling and cytokine production by previously activated human cells in vitro. However, the production of IL-10, compared to IFN-gamma on a molar basis, was greater after culture with hOKT3gamma1(Ala-Ala) than with OKT3. Flow cytometric studies confirmed that OKT3 induced IFN-gamma and IL-10 production, but hOKT3gamma1(Ala-Ala) induced only detectable IL-10 production in CD45RO(+) cells. Moreover, in vivo, we found IL-10(+)CD4(+) T cells after drug treatment. These cells were heterogeneous but generally CD45RO(+), CTLA-4(-), and expressed CCR4. A subgroup of these cells expressed TGF-beta. Thus, the non-FcR binding anti-CD3 mAb, hOKT3gamma1(Ala-Ala) delivers an activation signal to T cells that is quantitatively and qualitatively different from OKT3. It leads to the generation of T cells that might inhibit the autoimmune response and may be involved in the beneficial effect on beta cell destruction in Type 1 diabetes.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Antibodies, Monoclonal / metabolism
  • CD3 Complex / biosynthesis*
  • Calcium / metabolism
  • Diabetes Mellitus, Type 1 / drug therapy*
  • Flow Cytometry
  • Humans
  • Interleukin-6 / biosynthesis
  • Leukocyte Common Antigens / biosynthesis
  • Lymphocyte Activation*
  • Muromonab-CD3 / chemistry*
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Receptors, Fc / metabolism
  • Signal Transduction
  • Time Factors
  • Tumor Necrosis Factor-alpha / biosynthesis


  • Antibodies, Monoclonal
  • CD3 Complex
  • Interleukin-6
  • Muromonab-CD3
  • Receptors, Fc
  • Tumor Necrosis Factor-alpha
  • Leukocyte Common Antigens
  • Protein Tyrosine Phosphatase, Non-Receptor Type 1
  • Calcium