Abstract: Herein are reported modified mammalian cells wherein the expression of the MYC gene and one or more of the BAK, BAX, SIRT-1 and ICAM-1 genes has been reduced or eliminated as well as methods for the recombinant production of a heterologous polypeptide using a modified mammalian cell according to the current invention. Further reported are use of the reduction of the expression of the genes for increasing volumetric productivity, increasing cell volume, increasing viability and increasing the possible cultivation time without cell split.

Abstract: Herein is reported a method for generating a recombinant mammalian cell expressing a heterologous polypeptide and a method for producing a heterologous polypeptide using said recombinant mammalian cell, wherein in the recombinant cell the expression of the endogenous SIRT-1 gene has been reduced. It has been found that the knockout of the sirtuin-1 gene (SIRT-1) in mammalian cells, e.g. such as CHO cells, improves recombinant productivity and reduces lactate production by the cells. Additionally, it has been found that the viability decline at the end of a fed-batch fermentation is reduced.

Abstract: Herein is reported a method for generating a recombinant mammalian cell expressing a heterologous polypeptide and a method for producing a heterologous polypeptide using said recombinant mammalian cell, wherein in the recombinant cell the expression of at least the endogenous gene MYC has been reduced. It has been found that the knockout of at least the endogenous gene MYC in mammalian cells, e.g. such as CHO cells, improves recombinant productivity by the cells.