Mechanisms of Action and Overview of OKT3

OKT3 is a murine monoclonal antibody of the immunoglobulin IgG2a isotype. The target of OKT3, CD3, is a 17-20 kilodalton (kD) molecule that is part of a multimolecular complex found only on mature T cells and medullary thymocytes. This complex is uniquely situated next to the T-cell receptor for antigen. An interaction between T cells, OKT3, and monocytes causes T-cell activation (mitogenesis) in vitro. Because of the unique association between the antigen receptor and CD3, antibodies that react with CD3 block T-cell receptor function and vice versa. Thus, OKT3 blocks both the generation and function of cytotoxic T cells. After an initial dose of OKT3, T cells virtually disappear from the circulation within minutes to hours. During treatment with OKT3, T cells bearing the usual array of surface molecules (CD2, CD4, CD8) reappear in the peripheral blood circulation but these cells are devoid of the OKT3 target molecule, CD3. Within 48 hours of discontinuing OKT3, the normal array of surface molecules including CD3 is found again on all T cells. The selective removal of CD3 by internalization is thought to be the key mechanism of action of OKT3. Comodulation of the antigen receptor with CD3 explains the immunoblocking action of OKT3 in vivo. Experience with a second or third treatment with OKT3 indicates that OKT3 is ineffective clinically if the CD3 target molecule is not modulated. OKT3 has been found to be effective for induction of immunosuppression and for treating initial and steroid-resistant rejections.