Optimizing the Pegylation of Interferon alfa2a

An optimal pegylated IFN for use in the treatment of hepatitis C infection would be absorbed in a sustained fashion, would be distributed predominantly to the liver and remain in the circulation and interstitial fluids, and would have a reduced clearance from the body compared to IFN. The pegylation of IFN would result in a less active molecule in vitro than that of the native endogenous protein, IFN, however; the in vivo pharmacological activity related to efficacy would be better than that of IFN because sustained therapeutic concentrations would be maintained throughout a one week dosing interval (Figure 2). Conceptually then, the size, branching and pegylation process needs to be optimized for each protein such that therapeutically active concentrations are maintained for the appropriate period of time.

The biochemical and pharmacological properties of a protein conjugate depend on the physiochemical properties of the PEG moiety, and the pegylation process (i.e., PEG molecular weight, linear or branched PEG structure, chemical method of attachment, number and location of PEG moieties attached to the protein). A PEG molecular mass of 40 to 60 KD (kilodaltons) substantially reduces the renal and cellular clearance of small protein molecules16' 17. Smaller pegylated proteins are filtered readily by the

Figure 2. Conceptual Serum Concentration Profile for an Optimized Pegylated Interferon

kidney. Branched chain pegylated proteins are more stable against enzymatic proteolysis than linear moieties. PEG chains attached at a single site on the protein may be less likely to influence in vitro specific activity as attachment at a single site is less likely to obscure the active binding site on the protein. The size and the structure of the PEG moiety may also result in a more sustained absorption that is mediated via the lymphatics and a more restricted distribution within the body where the PEG-protein conjugate is limited to the circulation and interstitial fluids.

The paradigm that was used to optimize the pegylation of IFN required a multidimensional approach (Figure 3). Each parameter was optimized based on the constraints of pegylation and the cost of goods. Based on clinical pharmacology work with the 5 kDa pegylated interferon, it was understood that sustained concentrations above a given effective concentration were needed for stimulation of endogenous effector proteins and maintaining

0 0

Post a comment