A protein chimera strategy supports production of a model “difficult‐to‐express” recombinant target

Due in part to the needs of the biopharmaceutical industry, there has been an increased drive to generate high quality recombinant proteins in large amounts. However, achieving high yields can be a challenge as the novelty and increased complexity of new targets often makes them ‘difficult‐to‐express’. This study aimed to define the molecular features that restrict the production of a model ‘difficult‐to‐express’ recombinant protein, Tissue Inhibitor Metalloproteinase‐3 (TIMP‐3). Building from experimental data, computational approaches were used to rationalize the redesign of this recombinant target to generate a chimera with enhanced secretion. The results highlight the importance of early identification of unfavourable sequence attributes, enabling the generation of engineered protein forms that bypass ‘secretory’ bottlenecks and result in efficient recombinant protein production.