A mutant streptokinase lacking the C-terminal 42 amino acids is less immunogenic.
Streptokinase (SK) is the most widely used compound for the treatment of myocardial infarction and the least expensive thrombolytic agent, but a drawback to its use is the widespread presence of anti-SK antibodies (Abs). Clinical failure of the activation of the fibrinolytic system by SK has been reported due to the presence of a high titer of anti-SK neutralizing Abs. Patients receiving SK therapy develop high anti-SK antibody titers, which might provoke severe allergic reactions. These Abs are sufficient to neutralize a standard dose of SK up to four years after initial SK administration. This is a clinical problem because of the increasing number of patients who have been treated once with SK for acute myocardial infarction (AMI) and are likely to require plasminogen activator treatment in the future. In previous in vitro studies, we have shown that a deletion mutant (mut-C42), lacking the 42 C-terminal residues, was significantly less antigenic when compared with the native molecule (SKC-2). In this study, 14 monkeys were subjected to treatment with SKC-2 and mut-C42 in order to compare their humoral response by determining SK neutralizing activity in monkey's sera. All monkeys developed anti-SKC-2 Ab titers, but in the case where treatment induced Abs directed against the C-terminus of SKC-2, neutralizing activity against the native protein was significantly higher than that developed against mutant SK mut-C42.
Torrèns
I
I
Division of Pharmaceutical, Centro de Ingenierià Genètica y Biotecnologìa, Havana, Cuba. isis@cigb.edu.cu
Ojalvo
A G
AG
Seralena
A
A
Hayes
O
O
de la Fuente
J
J
D000818:Animals; D002522:Chlorocebus aethiops; D005260:Female; D005343:Fibrinolytic Agents / Q000276:immunology* / Q000627:therapeutic use; D008297:Male; D009154:Mutation; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000276:immunology* / Q000627:therapeutic use; D015202:Protein Engineering; D017384:Sequence Deletion; D013300:Streptokinase / Q000235:genetics* / Q000276:immunology* / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy
D005343:Fibrinolytic Agents; D010446:Peptide Fragments; D013300:Streptokinase