Use of a structured kinetic model of antibody synthesis and secretion for optimization of antibody production systems: II. Transient analysis.

The dynamic behavior of the monoclonal antibody (MAb) secretory pathway is studied by transient simulations using our previously developed structured kinetic model for antibody synthesis and secretion by hybridoma cells. The response of the secretory pathway to blocks in specific pathway steps and step changes in characteristic pathway parameters is presented in order to gain a better understanding of pathway dynamics and identify possible rate-limiting steps in the pathway. Model simulations suggest that the step of antibody assembly in the endoplasmic reticulum (ER) is a very good candidate for a rate-limiting step in the antibody secretory pathway in fast-growing hybridoma cells, whereas translation of the heavy and light chains is most likely rate-limiting in slowly growing or stationary phase cells. Transient simulation results are compared with experimentally observed transient changes in specific antibody secretion rates and used to suggest strategies for optimizing antibody secretion in large-scale production systems.