Recombinant proteins are genetically altered proteins with a new combination of genes made from cloned DNA sequences that typically encode a protein or enzyme with a known function. The new DNA sequences may or may not be present normally in an organism. They are created through genetic engineering, also known as recombinant DNA technology or splicing. They can be produced in bulk quantities with recombinant DNA technology.
Recombinant proteins have significant clinical importance in areas such as enzymes, antibodies, and hormones. There are currently over 200 protein drugs available commercially, across a growing variety of pathologies, and even more are currently in development and being evaluated in clinical trials and preclinical studies.
Expression systems from non-mammalian sources, like yeast and bacteria, have huge success in biopharmaceutical production because of their low costs, high yields, and convenience. However, these organisms are limited in their success in producing complex and large protein therapeutics because they require significant human-specific post-translational modifications (PTMs) and appropriate protein folding without the formation of aggregates. In 1986, a mammalian cellular recombinant therapeutic known as tissue plasminogen factor (tPA) facilitated the rise of biopharmaceutical production from mammalian cell lines. This change in source organism was especially important for medicine, as seven of the main ten selling medications in 2019 were manufactured with recombinant gene expression produced from mammalian cell lines. These cell lines are successful because they can add PTMs that closely resemble those found in human molecules. The proteins can fold properly, a vital requirement in protein function.
The major drawback of mammalian cells in the application of recombinant protein therapies is their high cost per mg of protein produced. Current researchers have great interest in finding methods to improve protein yields and reduce production costs.
A Novel Approach
One recent study evaluated the possibility of reaching these goals through direct engineering of cellular transition machinery by introducing an R98S point mutation into ribosomal protein L10, a catalytically essential protein. The R98S point mutation on ribosomal protein L10 is the substitution of serine for arginine at residue 98, a mutation found in pediatric T-cell lymphoblastic leukemia. Previous studies suggested that the RPL10-R98S mutation has the potential to increase recombinant protein production in mammalian cells. The current study uses the previous results to further evaluate the potential of this mutation to decrease proteasomal activity while enhancing the translation rate and accuracy.
RPL10-R98S Mutation Effects
The results show that RPL10-R98S has advantageous effects on protein translation efficiency and fidelity. It can also reduce proteasomal activity, the molecule responsible for breaking down proteins by breaking down the peptide bonds. The study demonstrated a protein production yield gain between 1.7- to 2.5-fold. However, these benefits are strongly affected by the cell type. Though further research is required to fully understand how different factors will affect RPL10-R98S, the results found in this study suggest that it is a viable method to increase output and decrease the production cost of mammalian line recombinant proteins.
Future Implications
Recombinant proteins play a part in growth factors, recombinant hormones, blood clotting, and tumor necrosis. They also have implications for treating many diseases, including congestive heart failure, diabetes, hepatitis, Crohn’s disease, and cerebral apoplexy. For these reasons, finding a method that results in lower cost and higher production volume for mammalian line recombinant proteins could have far-reaching effects on global health.
