A structured kinetic modeling framework for the dynamics of hybridoma growth and monoclonal antibody production in continuous suspension cultures

A structured kinetic model is developed to describe the dynamics of hybridoma growth and the production of monoclonal antibodies and metabolic waste products in suspension culture. The crucial details of known metabolic processes in hybridoma cells are incorporated by dividing the cell mass into four intracellular metabolic pools. The model framework and structure allow the dynamic calculation of the instantaneous specific growth rate of a hybridoma culture. The steady state and dynamic simulations of the model equations exhibit excellent agreement with experimentally observed trends in substrate utilization and product formation. The model represents the first to include any degree of metabolic detail and structure in describing a hybridoma culture. In so doing, it provides the basic modeling framework for incorporating further details of metabolism and can be a useful tool to study various strategies for enhancing hybridoma growth as well as viability and the production of monoclonal antibodies in suspension cultures.

[1]  P. Pedersen,et al.  Tumor mitochondria and the bioenergetics of cancer cells. , 1978, Progress in experimental tumor research.

[2]  W. Mckeehan,et al.  Glycolysis, glutaminolysis and cell proliferation. , 1982, Cell biology international reports.

[3]  D F Ollis,et al.  Transient kinetics of hybridoma growth and monoclonal antibody production in serum‐limited cultures , 1989, Biotechnology and bioengineering.

[4]  J. Birch,et al.  THE LARGE SCALE CULTIVATION OF HYBRIDOMA CELLS PRODUCING MONOCLONAL ANTIBODIES , 1985 .

[5]  M. L. Shuler,et al.  INVITED REVIEW ON THE USE OF CHEMICALLY STRUCTURED MODELS FOR BIOREACTORS , 1985 .

[6]  A G Fredrickson,et al.  Formulation of structured growth models. , 2000, Biotechnology and bioengineering.

[7]  L. Reitzer,et al.  The continuous growth of vertebrate cells in the absence of sugar. , 1981, The Journal of biological chemistry.

[8]  D. Hume,et al.  Aerobic glycolysis and lymphocyte transformation. , 1978, The Biochemical journal.

[9]  L. Reitzer,et al.  Evidence that glutamine, not sugar, is the major energy source for cultured HeLa cells. , 1979, The Journal of biological chemistry.

[10]  E. Newsholme,et al.  Glutamine metabolism in lymphocytes of the rat. , 1983, The Biochemical journal.

[11]  W. Bentley,et al.  A novel structured kinetic modeling approach for the analysis of plasmid instability in recombinant bacterial cultures , 1989, Biotechnology and bioengineering.

[12]  N. Connell,et al.  Transport of 6‐deoxy‐D‐glucose and D‐xylose by untransformed and SV40‐transformed 3T3 cells , 1982, Journal of cellular physiology.

[13]  S. Reuveny,et al.  Factors affecting cell growth and monoclonal antibody production in stirred reactors. , 1986, Journal of immunological methods.

[14]  A J Sinskey,et al.  Reduction of waste product excretion via nutrient control: Possible strategies for maximizing product and cell yields on serum in cultures of mammalian cells , 1986, Biotechnology and bioengineering.

[15]  B O Palsson,et al.  On the dynamic order of structured Escherichia coli growth models. , 1987, Biotechnology and bioengineering.

[16]  D. Brouty‐boye,et al.  Characteristics of the chemostat culture of murine leukemia L 1210 cells. , 1976, Experimental cell research.

[17]  Newsholme Ea,et al.  Metabolism in lymphocytes and its importance in the immune response. , 1985 .

[18]  D. Hume,et al.  Role and regulation of glucose metabolism in proliferating cells. , 1979, Journal of the National Cancer Institute.

[19]  M. Cornblath,et al.  Reciprocal regulation of glucose and glutamine utilization by cultured human diploid fibroblasts , 1978, Journal of cellular physiology.