IMMUNOGENICITY OF TISSUE-PLASMINOGEN ACTIVATORS IN RHESUS-MONKEYS - ANTIBODY-FORMATION AND EFFECTS ON BLOOD LEVEL AND ENZYMATIC-ACTIVITY

The immunogenicity of a tissue-type plasminogen activator analog, mt-P A6, consisting of the second kringle and protease domains, was compare d to that of the native-sequence protein (nt-PA) in rhesus monkeys. An tibody responses were compared in groups of eight monkeys that were tr eated by iv injection twice, 1 month apart, using doses and regimens c hosen to mimic therapy (0.5 mg/kg mt-PA6 bolus, 1.25 mg/kg nt-PA bolus + infusion). An additional group was treated with a 0.5 mg/kg nt-PA b olus. A single positive response was obtained in a monkey treated with 0.5 mg/kg nt-PA after the primary injection. Following the secondary injection, responses were obtained in 118, 3/8, and 6/8 monkeys treate d with mt-PA6, nt-PA as a bolus, or nt-PA as a bolus + infusion, respe ctively. Several monkeys were selected to determine whether circulatin g tPA antibody altered the pharmacokinetics of mt-PA6. Clearance was f ound to decrease without affecting peak blood levels as antibody conce ntrations increased from 0.02 to 100 mu g/ml. In contrast, the peak bl ood level was reduced by 99% at an antibody concentration of 152 mu g/ ml in a monkey that had been exposed to mt-PA6 in adjuvant 14 months p reviously. Further, only the serum from this and three other hyperimmu nized monkeys inhibited the enzymatic activity of tPA in vitro. It is concluded that mt-PA6 is not more immunogenic than nt-PA in rhesus, an d that low levels of antibody are more likely to influence the pharmac okinetic properties of tPA than to inhibit its enzymatic activity. It is unlikely that mt-PA6 would present a serious immunogenic risk in hu mans. (C) 1996 Society of Toxicology