Application of ER Stress Biomarkers to Predict Formulated Monoclonal Antibody Stability.

For a therapeutic monoclonal antibody (mAb) to reach the clinic, the molecule must be produced at an appropriate yield and quality, then formulated to maintain efficacy and stability. The formation of subvisible particles (SVPs) can impact product stability and is monitored during formulation development; however, the potential of a mAb to form such species can be influenced throughout the whole bioprocess. The levels of intracellular endoplasmic reticulum (ER) stress perceived by Chinese hamster ovary (CHO) cell lines, the day of mAb harvest, and the relationship with subsequent product stability of two mAbs (denoted A and B), as determined by the SVP content after accelerated stability studies, are reported here. Here, it is shown that the propensity of mAb A to form SVPs can be predicted by transcript expression of biomarkers of cellular ER stress, heavy/light-chain transcript and polypeptide amounts, and harvest day. Further, mAb A material harvested on day 9 of culture was more stable, in terms of SVP formation, than material harvested on day 13. These data suggest that ER stress perceived by CHO cells can reflect the stability of a mAb, and that biomarkers of such stress could help define culture harvest time as a tool to control SVP formation in formulated mAbs.