Modifications of therapeutic proteins: challenges and prospects

Abstract

The production of therapeutic proteins is one of the fastest growing sectors of the pharmaceutical industry. However, most proteins used in drug therapy require complex post-translational modifications for efficient secretion, drug efficacy and stability. Common protein modifications include variable glycosylation, misfolding and aggregation, oxidation of methionine, deamidation of asparagine and glutamine, and proteolysis. These modifications not only pose challenges for accurate and consistent bioprocessing, but also may have consequences for the patient in that incorrect modifications or aggregation may lead to an immune response to the protein therapeutic. This review provides examples of analytical and preventative advances that have been devised to meet these challenges, and insights into how further advances can improve the efficiency and safety in manufacturing recombinant proteins.

Human immunoglobulin allotypes

“…These issues have been explored in numerous review articles. [1][2][3][4] Whilst the above parameters that might predispose antibodies to be immunogenic are widely recognized, and appropriate steps taken to monitor and control them, the consequences of administration to diverse human populations is less well developed. Human populations exhibit multiple genotypes and phenotypes, and one would not wish to add structural differences due to polymorphisms to the inherent propensity for rP/rGP products to exhibit structural heterogeneity.…”

Scale-down studies for assessing the impact of different stress parameters on growth and product quality during animal cell culture

“…Therefore, any change in charge has to be attributed to deamidation, which introduces an additional negative charge to the antibody and generates acidic species, decreasing the protein's isoelectric point (Liu et al, 2008). These factors have been found sensitive to process condition (Jenkins, 2007) and the isoelectric point might reasonably be expected to have fallen after repeated exposure to elevated osmolality and pH during alkali addition to the PFR. Yet, the variation in mean isoelectric point across the various experimental conditions in Table 3 is insignificant, the difference between the mean Ip of each run and the control mean (here called ΔIp control) being within the expected error range for the technique as experienced at MedImmune.…”

“…Consistency of glycoform is a major consideration when assessing protein quality for therapeutic purposes (Jenkins, 2007;Godoy-Silva et al, 2009a;2009b). As can be seen, the small variation in glycoforms between the differing experimental conditions to which the cells were exposed is quite random and typical of that found in industrial historical data.…”

Physiology and Pathology of Cytokine: Commercial Production and Medical Use

“…Despite the fact that recombinant human IFN-γ is not glycosylated [17], its biological activity is not afected. It is used for the treatment of chronic granulomatous disease ( Table 4).…”