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-PA6, consisting of the second kringle and protease domains, was compared to that of the native-sequence protein (nt-PA) in rhesus monkeys. Antibody responses were compared in groups of eight monkeys that were treated by i.v. injection twice, 1 month apart, using doses and regimens chosen 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 bolus. 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 1/8, 3/8, and 6/8 monkeys treated with mt-PA6, nt-PA as a bolus, or nt-PA as a bolus + infusion, respectively. Several monkeys were selected to determine whether circulating tPA antibody altered the pharmacokinetics of mt-PA6. Clearance was found to decrease without affecting peak blood levels as antibody concentrations increased from 0.02 to 100 micrograms/ml. In contrast, the peak blood level was reduced by 99% at an antibody concentration of 152 micrograms/ml in a monkey that had been exposed to mt-PA6 in adjuvant 14 months previously. Further, only the serum from this and three other hyperimmunized monkeys inhibited the enzymatic activity of tPA in vitro. It is concluded that mt-PA6 is not more immunogenic than nt-PA in rhesus, and that low levels of antibody are more likely to influence the pharmacokinetic properties of tPA than to inhibit its enzymatic activity. It is unlikely that mt-PA6 would present a serious immunogenic risk in humans.
Zwickl
C M
CM
Toxicology Research Laboratories, Lilly Research Laboratories, Greenfield, Indiana 46140, USA.
Hughes
B L
BL
Piroozi
K S
KS
Smith
H W
HW
Wierda
D
D
D000818:Animals; D000906:Antibodies / Q000494:pharmacology*; D000917:Antibody Formation; D007114:Immunization; D008253:Macaca mulatta; D010960:Plasminogen Activators / Q000097:blood* / Q000276:immunology* / Q000493:pharmacokinetics; D011994:Recombinant Proteins
D000906:Antibodies; D011994:Recombinant Proteins; D010960:Plasminogen Activators