ANTI-IDIOTYPIC AND NON-ANTI-INDIOTYPIC ANTIBODIES TO OKT3 ARISING DESPITE INTENSE IMMUNOSUPPRESSION

Abstract

The frequency, timing, and specificity of the humoral antibody response to a murine monoclonal antibody (OKT3, IgG_2a) were measured in 21 consecutive renal allograft recipients. These patients received i.v. OKT3, 1–5 mg/day for 10–20 days as treatment for acute graft rejection. Maintenance immunosuppression consisted of azathioprine and corticosteroids. Using three different assays, n antibody response was detected in 75% of the 20 patients with adequate samples. The ELISA assay of the overall IgM and IgG reactivity to OKT3 revealed that IgM anti-OKT3 in 50% of the patients, reaching a peak 20–33 days after the last dose of OKT3 The IgM preceeded the IgG in most cases (p2a) or anti-Leu4 (another anti-T3), and the blocking activity remained after affinity absorption with normal mouse IgG. Using this assay, 60% of the pateints made an anti-Id response. One made only anti-Id, and several had anti-Id at times when other reactivities were undetectable. Antibodies to non-idiotypic, presumably isotypic, determinants represented on OKT8 occurred in only 44%, while other reactivity (OKT4; IgG_2bk) was less common (12%) and weaker. While no adverse allergic reactions occurred in this group of patients, the anti-Id antibodies, which are a prominent feature of the immune response to this and probably other monoclonal antibodies, can block their therapeutic effectiveness and can arise despite intense immunosuppression. This response may require the use of different idiotypes for prolonged or repeated courses o therapy and may be the major obstacle to the use of human monoclonal antibodies.