The Human Immune Response to the OKT3 Monoclonal Antibody Is Oligoclonal

Abstract

The availability of highly specific and homogeneous antibodies to human T cells by the hybridoma technique has elicited new interest in the clinical use of antibodies to lymphocytes as immunosuppressive agents. OKT3 is the murine monoclonal antibody that has been the most widely used in clinical transplantation to induce immunosuppression. This antibody recognizes a membrane molecular complex, exclusively present on mature human T lymphocytes, which is tightly linked to the T-cell antigen receptor. The long-term therapeutic use of murine monoclonal antibodies in vivo is hampered by the intense antibody response that occurs in most human patients. Thus, when administered alone, OKT3 manifests its immunosuppressive activity only during the 10 to 15 days that precede the onset of sensitization. The results presented here show, by use of isoelectrofocusing, that the antibody response to OKT3, already reported to be restricted in its specificity (only anti-isotypic and anti-idiotypic antibodies are produced), is in addition oligoclonal. This restriction of the anti-monoclonal response may suggest that an efficient way to circumvent the sensitization problem would be to administer consecutively different monoclonal antibodies presenting the same specificity but distinct idiotypes.

Examination of a role for idiotypy in the disease remission of a long-term survivor of adult T cell leukemia treated with anti-Tac antibody

“…The cc␣Id thus appears to reflect a dominant monoclonal response in vivo against the anti-Tac idiotype. In contrast, the immune response to the OKT3 monoclonal antibody has been shown to be oligoclonal in most patients, 44 expressing both anti-isotypic and anti-idiotypic antibodies despite immunosuppressive therapy, although one patient, like ours, was shown to make only anti-idiotypic antibodies. 8 As discussed above, anti-idiotypic Ab2 antibodies may mimic antigen (Tac) in ligand binding or may themselves serve as immunogen for the production of Ab3 antibodies that mimic the original Ab1 (MAT) in binding antigen (Figure 1).…”

Cross-reactive and pre-existing antibodies to therapeutic antibodies—Effects on treatment and immunogenicity

“…[69][70][71] Antibodies formed in response to treatment with murine therapeutic antibodies appear to be a combination of anti-idiotype antibodies and anti-isotype antibodies, the latter partly isotypespecific. 1,72 This suggests that in addition to the idiotype, several immunodominant sites exist on the constant domains of the heavy chains of murine antibodies. Absence of these determinants in humanized antibodies explains in part their reduced immunogenicity.…”

“…1 This led to the development of methods to include human sequence in antibody therapeutics, and thus potentially reduce immunogenicity. Chimeric antibodies were developed by replacing the murine constant domains by human constant domains.…”

Inhibition of Arteriosclerosis by T-Cell Depletion in Normocholesterolemic Rabbits Immunized With Heat Shock Protein 65

“…Without additional application of prednisolone, the rapid depletion of T lymphocytes by intravenous application of anti-CD3 mAb would wane within Ϸ2 weeks. 22 Ten animals served as untreated controls. All experimental animal procedures were done in accordance with institutional guidelines.…”