Humanization of the murine anti-human CD3 monoclonal antibody OKT3

Article type: Research Article

Authors: Adair, John R.^a; | Athwal, Diljeet S.^a | Bodmer, Mark W.^a | Bright, Susan M.^a | Collins, Alexander M.^b | Pulito, Virginia L.^b | Rao, Patricia E.^b; | Reedman, Roweena^a | Rothermel, Annette L.^b | Xu, Danlin^b | Zivin, Robert A.^b; | Jolliffe, Linda K.^b

Affiliations: [a] Celltech Ltd., 216 Bath Road, Slouth, Berks SL1 4EN, UK | [b] R. W. Johnson Pharmaceutical Research Institute, Route 202, Raritan, NJ 08869, USA

Correspondence: [] Correspondence and reprint requests to: Robert A. Zivin, Ph.D., Biotechnology Drug Discovery, R.W. Johnson Pharmaceutical Research Institute, 1000 Route 202, Raritan, NJ 08648, USA.

Note: [] Current address of John R. Adair, Scotgen Biopharmaceutical Inc., Kettock Lodge, Campus 2, Aberdeen Science and Technology Park, Aberdeen, AB22 SGU, UK.

Note: [] Current address of Patricia E. Rao, ImmuLogic Pharmaceutical Corp., 610 Lincoln St., Waltham, MA 02154, USA.

Abstract: OKT3 is a murine monoclonal antibody which recognizes an epitope on the e-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 1.4×109 M−1 compared with 1.2×109 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.

Keywords: CDR-grafting, antibody humanization OKT3, transplantation, immunosuppression

DOI: 10.3233/HAB-1994-51-206

Journal: Human Antibodies, vol. 5, no. 1-2, pp. 41-47, 1994