Over-Production of Therapeutic Growth Factors for Articular Cartilage Regeneration by Protein Production Platforms and Protein Packaging Cell Lines

Abstract

This review article focuses on the current state-of-the-art cellular and molecular biotechnology for the over-production of clinically relevant therapeutic and anabolic growth factors. We discuss how the currently available tools and emerging technologies can be used for the regenerative treatment of osteoarthritis (OA). Transfected protein packaging cell lines such as GP-293 cells may be used as “cellular factories” for large-scale production of therapeutic proteins and pro-anabolic growth factors, particularly in the context of cartilage regeneration. However, when irradiated with gamma or x-rays, these cells lose their capacity for replication, which makes them safe for use as a live cell component of intra-articular injections. This innovation is already here, in the form of TissueGene-C, a new biological drug that consists of normal allogeneic primary chondrocytes combined with transduced GP2-293 cells that overexpress the growth factor transforming growth factor β1 (TGF-β1). TissueGene-C has revolutionized the concept of cell therapy, allowing drug companies to develop live cells as biological drug delivery systems for direct intra-articular injection of growth factors whose half-lives are in the order of minutes. Therefore, in this paper, we discuss the potential for new innovations in regenerative medicine for degenerative diseases of synovial joints using mammalian protein production platforms, specifically protein packaging cell lines, for over-producing growth factors for cartilage tissue regeneration and give recent examples. Mammalian protein production platforms that incorporate protein packaging eukaryotic cell lines are superior to prokaryotic bacterial expression systems and are likely to have a significant impact on the development of new humanized biological growth factor therapies for treating focal cartilage defects and more generally for the treatment of degenerative joint diseases such as OA, especially when injected directly into the joint.

Recombinant Spider Silk Bioinks for Continuous Protein Release by Encapsulated Producer Cells

“…1f,2a,g,4 Chemical and genetic modification of biologicals, their direct or particle-loaded encapsulation in hydrogels, or gene-based therapy (in vivo gene transfer) for therapeutic drug delivery is a current solution to overcome these problems. 1f,2a,g,4d, 5 Further promising approaches to overcome the limitations discussed above could be the matrix-free injection of drugproducing cells (combination of gene and cell therapy) 6 or the implantation of matrix-encapsulated cells directly in the target tissue. 7 In general, it must be distinguished between temporary applications, where only short-living, non-reproducible producer cells are injected locally, 6 and matrix-based cell delivery applications such as cell-containing capsules or other 3D constructs.…”

“…8 used cell type, as stable protein expression, successful scale-up, and long-term production should be guaranteed. 6,9 Nowadays, many protein-based therapeutic targets (antibodies, fusion proteins, cytokines) are synthesized in mammalian and even human cells, which typically enable high product quality and have the potential to express large and complex biopharmaceuticals. 2e,6,9b,c,10 Especially, for human-derived producer cells, additional advantages ensuring advanced protein folding, secretion, and post-translational modifications are guaranteed as well as minimizing the risk of immunogenic reaction.…”

“…Further promising approaches to overcome the limitations discussed above could be the matrix-free injection of drug-producing cells (combination of gene and cell therapy) or the implantation of matrix-encapsulated cells directly in the target tissue . In general, it must be distinguished between temporary applications, where only short-living, non-reproducible producer cells are injected locally, and matrix-based cell delivery applications such as cell-containing capsules or other 3D constructs . In the latter case, matrix-encapsulated, proliferating producer cells should be injected or implanted locally for long-term production of a biological directly at the target tissue of interest .…”

Neuroscience and Neuroimmunology Solutions for Osteoarthritis Pain: Biological Drugs, Growth Factors, Peptides and Monoclonal Antibodies Targeting Peripheral Nerves

“…Biological treatments that target OA, attenuate catabolic activity and promote articular cartilage repair include purified or recombinant growth factors, including fibroblast growth factor 18 (FGF-18), also known as Sprifermin [52][53][54], bone morphogenic protein 7 (BMP7) [55,56], transforming growth factor β1 (TGF-β1) [57][58][59], neuropeptides [60,61], humanized mAbs that target NGF and vascular endothelial growth factor (VEGF) (i.e., tanezumab (Pfizer) and fasinumab (Teva/Regeneron) against NGF and bevacizumab (Genentech/Roche) and ranibizumab (Genentech/Roche) against VEGF) [62][63][64][65][66], gene and cell therapy incorporating allogeneic cells and protein production platforms that overproduce produce growth factors (i.e., Kolon TissueGene's TissueGene-C, overproducing TGF-β1) [67][68][69][70][71] (Figure 2). A detailed discussion of each of these areas and intra-articular therapies is way beyond the scope of this communication and readers are directed to several comprehensive reviews [72][73][74][75].…”

“…TissueGene-C, developed by the US-based company Kolon TissueGene is another exciting development in cell and gene therapy specifically developed for the treatment of knee OA [69]. In this unique product, transfected and irradiated protein packaging cell lines are used as "cellular factories" for the production of therapeutic TGF-β1.…”