POLYMER CONJUGATES OF INTERFERON-BETA WITH ENHANCED BIOLOGICAL POTENCY

摘要

Methods are provided for the synthesis of polymer conjugates of cytokines an d receptor-binding antagonists thereof, especially a non glycosylated interfer on- beta, which conjugates retain unusually high biological potency. Preparation of polymer conjugates according to the methods of the present invention diminishes or avoids steric inhibition of receptor-ligand interactions that commonly results from the attachment of polymers to receptor-binding regions of cytokines, as well as to agonistic and antagonistic analogs thereof. The invention also provides conjugates and compositions produced by such methods . The conjugates of the present invention retain a high level of biological potency compared to those produced by traditional polymer coupling methods that are not targeted to avoid receptor-binding domains of cytokines. In assays in vitro, the biological potency of the conjugates of non-glycosylate d interferon-beta of the present invention is substantially higher than that o f unconjugated interferon-beta and is similar to that of interferon-beta-1a th at is glycosylated. The conjugates of the present invention also exhibit an extended half-life in vivo compared to the corresponding unconjugated cytokine. The present invention also provides kits comprising such conjugate s and/or compositions, and methods of use of such conjugates and compositions in a variety of diagnostic, prophylactic, therapeutic and bioprocessing applications, including treatment of multiple sclerosis.