## 1 Introduction  
The demand for monoclonal antibodies has significantly increased in recent years, mainly due to new applications in therapy, but also for clinical diagnoses and highly specific purification processes [1, 2]. In this regard, the capacity of mammalian cells to perform complex post-translational modifications to yield biologically active proteins has led to their preferential use for biopharmaceuticals production. About 70-80% of all biopharmaceuticals, including monoclonal antibodies, viral vaccines and gene therapy vectors, are produced in mammalian cells. Among the top ten selling protein biopharmaceuticals in 2014, six were antibodies or antibody-derived proteins. It is therefore not surprising that in 2016, monoclonal antibody-based drug production using mammalian cell-based systems almost doubled that of 2010 [1, 3]. In recent years, monoclonal antibodies industrial manufacturing has been based on mammalian cell lines such as hybridoma, among others [3; 4; 5; 6]. Mammalian cell-based processes present important limitations regarding apoptosis: the accumulation of metabolic byproducts (i.e., lactate and ammonia) up to cytotoxic concentration, and the depletion of essential nutrients, which triggers apoptosis (programmed cell death) [7]. The prevention of apoptosis during cell growth has a critical effect on the productivity of the final process, as an increase of cell life-span results in an increase in the synthesis and accumulation of the product of interest, since cells remain productive for a longer time, even after the exponential cell growth phase [8]. Moreover, more robust cell lines which are less sensitive to apoptosis make it possible to design high cell density culture strategies based on consistently low nutrient concentrations in narrower ranges [9]. In recent years, strategies to generate stress-resistant cell lines preventing apoptosis have been focused on blocking the apoptotic transduction pathways [10; 11]. Although different pathways control the activation of signaling cascades of cell apoptosis activation, many of the apoptosis signals converge on the mitochondria, which stores numerous molecules that activate apoptosis [7]. The most widely used strategy to prevent apoptosis has been the overexpression of bcl-2 or bcl-xL genes, which inhibits the release of pro-apoptotic molecules from the mitochondria [10; 12]. This strategy has been successfully applied in different mammalian cell lines, such as CHO or hybridoma, showing higher viabilities and improved robustness in cell culture [13; 14; 15; 16]. The expression of mcl-1, another antiapoptotic gene with mechanism similar to that of bcl-2/bcl-xL, has also shown good results [17]. Another approach has been to directly target the caspase cascade, expressing X-linked inhibitor of apoptosis (XIAP) or cytokine response modifier CrmA, which both act to directly inhibit the caspases [18]. The expression of different viral proteins has also been reported to have antiapoptotic effects in hybridoma cell cultures, such as ksblc-2 from [PERSON]'s sarcoma-associated herpesvirus [19] and bhrf-1 from Epstein-Barr virus [20]. Furthermore, the downregulation of the pro-apoptotic genes Bak, Bax and Casp3 has been shown to reduce apoptosis in CHO cells [21]. Additionally, antiapoptotic genes have been shown to have an effect on metabolism, although this is not yet fully understood [22; 23]. This is remarkable, as cell-based processes present an important limitation regarding metabolism: deregulation of the uptake of substrates (i.e., high consumption rates of mainly glucose and glutamine), linked to the secretion and accumulation of lactate and ammonia as byproducts of metabolism [24]. The reduction of the secretion and accumulation of lactate remains a hot topic in the biomanufacturing industry.