Human transferrin (hTf) is a serum glycoprotein involved in iron transport. We performed, for the first time, mathematical modeling of stably transfected insect Drosophila melanogaster S2 cell culture, a nonlytic plasmid-based system that secretes recombinant hTf under control of the copper sulfate-inducible Drosophila metallothionein promoter. Cell growth patterns at various inducer concentrations revealed that the specific growth rate of S2 cells was substantially reduced as the specific rate of recombinant hTf production increased, and recovered to some extent when recombinant hTf production was nearly stopped. Additionally, the time profiles of specific production rates exhibited a maximum in the early culture period. Longer times and lower values of the maximum specific production rate were observed at lower inducer concentrations, and shorter times and higher values at higher inducer levels. Although the proposed S2 cell culture model was slightly limited with regard to prediction of cell growth profile at the late stage, we ensured that it gave reasonable predictions of the dynamics of glucose consumption and recombinant hTf production and confirmed its validity through simulating other culture experiments under different conditions. The S2 model proposed in this study can contribute to the elucidation of cell culture dynamics, and optimization of each culture variable to enhance heterologous protein production. (c) 2005 Elsevier Inc. All rights reserved.