Cell culture additives and their use for increased bioprotein production from cells

Abstract

The invention relates to a method of increasing protein biomolecule production in which a) a cell that produces a heterologous protein biomolecule is cultured, and b) an Additive and/or a source of the Additive is added to the culture medium in an amount sufficient to (i) increase a total yield of the heterologous protein biomolecule secreted into the cell culture media and/or (ii) increase a specific cellular productivity of the heterologous protein biomolecule secreted into the cell culture media.

What is claimed is: 
     
         1 . A bioreactor comprising a source of Nitric Oxide gas or a source of a chemical capable of forming Nitric Oxide, wherein the bioreactor is configured for and adapted to provide the Nitric Oxide or chemical capable of forming Nitric Oxide to a cell culture medium within the bioreactor. 
     
     
         2 . The bioreactor of claim  19 , wherein the bioreactor is configured for and adapted to commercial scale production of a heterologous protein biomolecule of at least 1000 mg/L per a cell culture batch or per a single, substantially contiguous cell culture production run. 
     
     
         3 . The bioreactor of claim  20 , wherein the bioreactor further comprises:
 a) a Nitric Oxide sensor configured to and adapted for measuring the Nitric Oxide levels in the cell culture medium in the bioreactor,   b) a Nitric Oxide gas injector and/or a chemical injector operably connected to a supply of a chemical source of Nitric Oxide, and   c) a computer with a communication link to the Nitric Oxide sensor and electronically connected to the injector(s) of b), the computer specifically programmed to receive the Nitric Oxide sensor reading and modulate the injector(s) to maintain the Nitric Oxide concentration in the cell culture medium within a pre-determined concentration range and/or set point.   
     
     
         4 . The bioreactor of claim  21 , wherein the pre-determined concentration range is 0.1-10 nanomolar of Nitric Oxide solublized in the cell culture medium. 
     
     
         5 . A method of operating the bioreactor of claim  19 , comprising the step of providing the Nitric Oxide gas, and/or a chemical capable of forming Nitric Oxide, to the cell culture medium within the bioreactor.