P. R. U. B. Rebello

Phase I study of an engineered aglycosylated humanized CD3 antibody in renal transplant rejection

BACKGROUND The potential therapeutic benefits of CD3 monoclonal antibodies, such as OKT3, have been limited by their immunogenicity and their propensity to activate a severe cytokine release syndrome. This has constrained the clinical use of OKT3 to the treatment of acute rejection episodes of organ allografts. METHODS We have humanized a rat CD3 antibody and created a single amino acid substitution in position 297 of the IgG1 heavy chain to prevent glycosylation and, consequently, binding of the therapeutic antibody to Fc receptors and to complement. This antibody has been given as first line antirejection therapy in nine kidney transplant recipients with biopsy-proven acute rejection episodes. RESULTS None of the patients demonstrated any antiglobulin response nor any significant cytokine release syndrome. Seven of the nine showed evidence of resolution of their rejection, although some patients experienced re-rejection. CONCLUSIONS These findings suggest that CD3 antibodies can be engineered to lose their toxicity while retaining their potency as immunosuppressants. Nonactivating humanized CD3 monoclonal antibodies now merit further investigation in the management of transplant patients and in therapy of autoimmune diseases.

A simple method for measuring patient anti-globulin responses against isotypic or idiotypic determinants

A simple inhibition of capture enzyme-linked immunosorbent assay (IOC-ELISA) was developed which permitted the independent measurement of anti-idiotypic and anti-isotypic antiglobulins in serum samples from patients receiving therapeutic monoclonal antibodies.

Anti-globulin responses to rat and humanized CAMPATH-1 monoclonal antibody used to treat transplant rejection

BACKGROUND Antiglobulin responses are a significant limitation to the repeated use of murine monoclonal antibodies for treatment of transplant rejection. It is hoped that these might be largely overcome by using antibodies genetically engineered to resemble human antibodies. METHODS We have compared the responses in patients treated with the CD52 monoclonal antibodies CAMPATH-1G (rat IgG2b) or its humanized derivative, CAMPATH-1H (human immunoglobulin G1). RESULTS A majority of patients (15 of 17) made responses to the rat antibody, but there were no detectable responses to the humanized antibody (0 of 12). CONCLUSIONS Although anti-idiotype responses are theoretically possible against humanized therapeutic antibodies and are especially likely to be provoked by cell-binding antibodies, these data show that humanization offers a significant reduction in immunogenicity, potentially allowing repeat courses of treatment.