Susan Margaret Bright

Humanization of the murine anti-human CD3 monoclonal antibody OKT3

OKT3 is a murine monoclonal antibody which recognizes an epitope on the epsilon-subunit within the human CD3 complex. OKT3 possesses potent immunosuppressive properties in vivo and has been proven effective in the treatment of renal, heart and liver allograft rejection. Despite its efficacy, significant problems remain associated with OKT3 therapy, i.e. T-cell activation and the anti-murine antibody response. To address the problem of the anti-murine antibody response we have constructed humanized versions of OKT3. One of the humanized derivatives, gOKT3-7 incorporating the OKT3 complementarity determining regions plus a small number of alterations to the human framework, has an affinity of 1.4 x 10(9) M-1 compared with 1.2 x 10(9) M-1 for the murine OKT3. A humanized antibody (gOKT3-1) incorporating only the CDRs from OKT3 was found to be functionally inactive, confirming the requirement for nonCDR substitutions. gOKT3-7 retains the ability of mOKT3 to induce T cell proliferation in vitro and appears to be a good candidate for further development for in vivo therapy.

Monthly Update Biologicals & Immunologicals Progress with humanised antibodies - An update

(1995). Monthly Update: Biologicals & Immunologicals: Progress with humanised antibodies - An update. Expert Opinion on Investigational Drugs: Vol. 4, No. 9, pp. 863-870.

From laboratory to clinic: the development of an immunological reagent

Access to a wide range of high quality and increasingly sophisticated reagents and equipment has underpinned the great surge of knowledge in basic immunology and the growing interest in clinical immunointervention. In this article, the first in an occasional series on immunological research and development in industry, Sue Bright and colleagues outline the key steps in a development programme to take a humanized monoclonal antibody into the clinic. The procedures involved in developing such reagents, particularly for clinical use, are long and require considerable ingenuity and scientific creativity.