The potential improvement of thrombolytic therapy by targeting with bispecific monoclonal antibodies: why they are used and how they are made.
The generation of the proteolytic enzyme plasmin from its inactive precursor plasminogen, mediated by so called plasminogen activators, is the essential step in thrombolytic therapy. Plasmin is responsible for the degradation of the insoluble fibrin, the major component of a thrombus, to soluble fibrin degradation products. So far, the use of the more recently developed thrombolytic agents single-chain urokinase-type plasminogen activator (scu-PA) and tissue-type plasminogen activator (t-PA) were disappointing, mainly due to some of their negative properties in vivo, i.e., rapid inhibition and/or hepatic clearance. Besides some background information on the haemostatic balance; t-PA and scu-PA structure; and mechanisms of action, we here review some reported attempts to improve on these agents for thrombolytic therapy following various strategies. One of the more potential strategies, antibody-targeted thrombolytic therapy using bispecific monoclonal antibodies, is discussed somewhat more extensively, as are the several procedures that can be followed for bispecific antibody preparation.
Bos
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IVVO-TNO, Gaubius Laboratory, Leiden, The Netherlands.
Nieuwenhuizen
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W
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D005343:Fibrinolytic Agents / Q000008:administration & dosage*; D006801:Humans; D009154:Mutation; D015912:Thrombolytic Therapy / Q000379:methods*; D010959:Tissue Plasminogen Activator / Q000627:therapeutic use; D014568:Urokinase-Type Plasminogen Activator / Q000627:therapeutic use
D000911:Antibodies, Monoclonal; D005343:Fibrinolytic Agents; D010959:Tissue Plasminogen Activator; D014568:Urokinase-Type Plasminogen Activator