化学修飾蛋白性薬剤

抄録

The disadvantages of protein drugs lie in short circulation time (blood) and immunological side effects ranging in severity from mild allergic reaction to anaphylactic shock. Chemical modification of protein drugs with synthetic macromolecules can eliminate some of drawbacks of the proteins and give them new functions. Non toxic and non-immunogenic synthetic polymer, polyethylene glycol (PEG) such as 2-[O-methoxypoly(ethylene glycol)]-4, 6-dichloro-s-triazine (activated PEG₁) or 2, 4-bis[O-methoxy-poly(ethylene glycol)]-6-chloro-s-triazine(activated PEG₂), has been extensively used as a modifying reagent. Recently, PEG-derivatives with a comb-shaped form were explored by us, which are copolymers of polyethylene glycol derivative and maleic anhydride, with the molecular weight of 13, 000 and 100, 000 (activated PM₁₃ and activated PM₁₀₀). The modifications of asparaginase (136 kD) and bovine serum albumin (BSA, 67 kD) by PEGs (activated PEG₁ and activated PEG₂) with chain shaped-form and PMs(activated PM₁₃ and activate PM₁₀₀) with comb-shaped form are introduced in relation to the physiological and immunological functions. Both PM₁₀₀-asparaginase and PM₁₀₀-BSA have the reduced immunoreactivities with lower degree of modifications and with higher enzymic activities in comparison with PM₁₃- or PEG-asparaginases and PM₁₃- or PEG-BSAs. Furthermore, the half-life of asparaginases modified with both activated PEG₂ and PM₁₀₀ is prolonged about 20 times in comparison with non-modified asparaginase. General advantages of PEG-protein drugs seem to be the reduction of immunogenicity or antigenicity, prolongation of clearance time, increasing of solubility, and high stability in biomedical field. Now, more than 50 proteins have been modified with PEG or PEG derivatives for the purpose of therapy of various diseases.