Engineered UniSePT signal peptide boosts biotherapeutic protein secretion and bioactivity in mammalian systems

The production of therapeutic proteins in mammalian cell-based expression systems often faces limitations due to inefficient protein secretion and reduced bioactivity, frequently caused by incompatible secretory signal peptides (SPs). Current standard-of-care SPs can lead to suboptimal yields, increasing production costs and hindering the accessibility of vital biotherapeutics. There is a critical need for a broadly applicable, robust signal peptide that can consistently enhance the secretion and overall production of diverse proteins of interest without compromising their functional integrity, addressing a key bottleneck in biopharmaceutical manufacturing.

Researchers engineered a novel, broadly applicable Unique Secretory signal PepTide, named UniSePT, by combining specific signal peptide sequences derived from β-casein (CSN2) and β-lactoglobulin (BLG) proteins found in Indian river buffalo. The team evaluated UniSePT's performance by fusing it to various therapeutic proteins and expressing them within mammalian cell-based systems. Its secretion efficiency was directly compared against commonly utilized signal peptides, including human serum albumin (HSA) SP and preproinsulin SP. Additionally, the study assessed the bioactivity of the produced therapeutic proteins and analyzed the cleavage variability of UniSePT to confirm its broad compatibility.

UniSePT demonstrated higher secretion efficiency compared to widely used signal peptides such as human serum albumin (HSA) SP and preproinsulin SP in mammalian expression systems. This enhanced secretion was a consistent finding across different therapeutic proteins tested. Importantly, the study confirmed that this improved secretion efficiency did not compromise the inherent bioactivity of the produced therapeutic proteins, ensuring their functional integrity. UniSePT also exhibited minimal cleavage variability, indicating its robust and broad compatibility with a diverse range of therapeutic protein targets. These combined attributes suggest UniSePT's potential to significantly improve the overall titer and quality of biotherapeutic production.

The newly developed UniSePT enhances both the titer and bioactivity of therapeutic proteins in mammalian expression systems, addressing a critical production bottleneck.