Custom-Tailored Pharmacokinetics and Pharmacodynamics via Chemical Modifications of Biotech Drugs

Custom-Tailored Pharmacokinetics and Pharmacodynamics via Chemical Modifications of Biotech Drugs 

The first and the second approaches have provided some positive results but, unfortunately, they depend upon the structure of the protein. Typical examples of sequence modifications to improve stability and pharmacokinetics are the preparation of humanized antibodies, where part of the mouse sequence is substituted by the human form, and the granulocyte colony-stimulating factor muteins, where up to seven amino acids are substituted. Examples of truncated sequence proteins with improved characteristic are the 7-36 analogues of glucagon-like peptides or the 1-29 sequence growth hormone-releasing factor [1, 2]. 

The third approach has provided several successful results, though its application is usually limited to low molecular-weight peptides or non-peptide drugs. The liposome formulations, however, suffer from difficulties of storage or reconstruction and unpredictable distribution. Immobilization into insoluble polymeric particles is difficult in the case of structured proteins, as it normally involves the use of organic solvents. Moreover, protein denaturation and degradation may occur 

Most of these polymers have multi-functional character, which results in cross-linked heterogeneous products. In contrast, monomethoxy polyethylene glycol (PEG) presents only one reactive terminal group per polymer chain. Once PEGy-lated with these compounds, the protein acquires a brush-like shape, with the hydrophilic PEG chains extended from the protein to the solvent. 

For this reason, although the first polymer-protein conjugates used clinically were streptokinase conjugated to dextran [8] and neocarzinostatins linked to succinic acid-co-maleic anhydride [5], from the 1980s onwards PEG became the polymer of choice, and all products that subsequently appeared on the market were based on this reagent. 

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