A mutant streptokinase lacking the C-terminal 42 amino acids is less reactive with preexisting antibodies in patient sera.
Streptokinase (SK) is an efficacious thrombolytic drug for the treatment of myocardial infarction. Because of its immunogenicity, patients receiving SK therapy develop high anti-SK antibody (Ab) titers, which might provoke severe allergic reactions and neutralize SK activity. In this report we studied the reactivity of a synthetic 42-residue peptide resembling SKC-2 C-terminus with patient sera. SKC-2(373-414) peptide was recognized by 39 and 64% of patients, before and after SKC-2 therapy, respectively. An SKC-2 deletion mutant (mut-C42), lacking the same 42 C-terminal residues, was constructed and expressed in Escherichia coli. Recognition of mut-C42 by preexisting Abs from patient sera was 51 and 68% of reactivity to SKC-2, as assessed by direct binding and competition assays, respectively. For most of the patients, mut-C42-neutralizing activity titer (NAT) significantly decreased with respect to SKC-2-NAT. This study opens the possibility of producing a less immunogenic variant of SK, which could constitute a preferred alternative for thrombolytic therapy.
Torréns
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Division of Pharmaceutical, Centro de Ingeniería Genética y Biotecnología, Havana, Cuba. Isis@cigb.edu.cu
Ojalvo
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Seralena
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D000485:Allergens / Q000737:chemistry / Q000276:immunology; D000907:Antibodies, Bacterial / Q000097:blood / Q000276:immunology*; D000942:Antigens, Bacterial / Q000737:chemistry / Q000276:immunology; D001667:Binding, Competitive; D004797:Enzyme-Linked Immunosorbent Assay; D006801:Humans; D016056:Immunodominant Epitopes / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D009203:Myocardial Infarction / Q000188:drug therapy / Q000276:immunology; D009500:Neutralization Tests; D010446:Peptide Fragments / Q000138:chemical synthesis / Q000737:chemistry / Q000235:genetics / Q000276:immunology; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000276:immunology / Q000302:isolation & purification; D017384:Sequence Deletion / Q000235:genetics*; D013300:Streptokinase / Q000737:chemistry* / Q000235:genetics / Q000276:immunology* / Q000627:therapeutic use; D015912:Thrombolytic Therapy
D000485:Allergens; D000907:Antibodies, Bacterial; D000942:Antigens, Bacterial; D016056:Immunodominant Epitopes; D010446:Peptide Fragments; D011994:Recombinant Proteins; D013300:Streptokinase