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Recent Advances of Nanotechnologies for Cancer Immunotherapy Treatment
Published in Loutfy H. Madkour, Nanoparticle-Based Drug Delivery in Cancer Treatment, 2022
mAb belonging to the IgG class has been widely studied for cancer immunotherapy [378]. mAb mediates tumor cell depletion by binding to a specific surface antigen at the cancer cells, triggering antigen-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC), which are both dependent on the host immune system. mAb targeting the immune checkpoint has been developed to improve the antitumor immune response [379]. For example, Ipilimumab (Yervoy®) and Tremelimumab (CP-675,206) bind to CTLA-4 receptor in T cells and block the inhibitory function against the costimulatory receptor CD28, thereby enhancing the T cell-DC interaction and reducing the number of Treg [165,180,380]. Nivolumab (Opdivo®), Pidilizumab (C-011), and Pembrolizumab (Keytruda®) target the programmed death signal-1(PD-1) receptor, another negative regulator on the T-cell surface that reduces the interaction with TAAs. Blocking the PD-1 receptor results in enhanced activation of T cells and decreased Treg infiltration to the tumor [381]. Among other immune mAbs, Daclizumab (Zinbryta®), an anti-CD25 mAb [382]; Dacetuzumab, an anti-CD40 mAb [383]; and Durvalumab (Imfinzi®) [384] and Avelumab (Bavencio®) [385], as anti-PD-L1 mAbs, are currently approved or in last stages of clinical trials for cancer immunotherapy.
Escherichia coli Expression Systems
Published in Yoshikatsu Murooka, Tadayuki Imanaka, Recombinant Microbes for Industrial and Agricultural Applications, 2020
Tatsurou Shibui, Kenji Nagahari
The CHO cells are the most popular eukaryotic host for producing the proteins of eukaryotic origin by recombinant DNA techniques [28], This host is also effective in the production of whole-antibody molecules, as well as the Fab fragments [12], secreting the active molecule into the medium, and obviating the refolding processes that are necessary with E. coli. However, the expression level is low and the medium cost for culturing the eukaryotic cells is very high compared with that for E. coli cells. Yeast is one of the candidates for the heterologous protein expression system. Simultaneous expression of the Fd (truncated heavy chain) and light chain gene in Saccharomyces cerevisiae resulted in secretion of a properly folded and assembled Fab fragment that bound to target cancer cells [14]. This was accomplished by simultaneous expression of the mature light-chain gene and the heavy-chain gene. In S. cerevisiae cells, glycosylation is different from that of the eukaryotic cells. This may be why the yeast-derived whole antibody has the same antibody-dependent cellular cytotoxicity (ADCC) activity, but lacks the complement-dependent cytotoxicity (CDC) activity, shown by the lymphoid cell-derived antibody [13]. Many eukaryotic proteins have now been produced in E. coli expression systems. Escherichia coli, as a host, has several advantages over other hosts. It is easy to handle, fast in growth rate, and a large amount of biochemical and genetic background knowledge is available, all of which facilitate the use of E. coli.
Product Quality and Process
Published in Wei-Shou Hu, Cell Culture Bioprocess Engineering, 2020
The list of quality attributes derived from the QTPP can be rather long, as seen in the example shown in Table 4.4. However, not all the attributes identified are critical and must be controlled within a range to minimize the risk of negatively affecting clinical outcomes (Panels 4.12 and 4.13). The task of identifying the CQAs among all the attributes typically takes place during product and process development, and before the manufacturing process is established and process and clinical data is available. The selection relies heavily on the knowledge of past products and processes, as well as the understanding of the mechanism of action (MOA) of the product. A literature review on the MOA of the new candidate drug is performed and a knowledge database on experience from similar products is surveyed. For example, if the mechanism of a monoclonal antibody product is to block receptor sites, attributes that enhance antibody-dependent cellular cytotoxicity (ADCC) and complement-dependent cytotoxicity (CDC) may not be important for efficacy. As a result, fucosylation at the Fc region may not be considered a CQA. On the other hand, if the MOA is ADCC, the level of fucosylation of the glycan in the Fc region might be selected as a CQA.
Enhancement of anti-TNFα monoclonal antibody production in CHO cells through the use of UCOE and DHFR elements in vector construction and the optimization of cell culture media
Published in Preparative Biochemistry & Biotechnology, 2021
Chinh Chung Doan, Nguyen Quynh Chi Ho, Thi Thuy Nguyen, Thi Phuong Thao Nguyen, Dang Giap Do, Nghia Son Hoang, Thanh Long Le
Adalimumab is a typical tumor necrosis factor-α (TNFα) blocker that has been approved for the treatment of severe rheumatoid arthritis, psoriasis, ankylosing spondylitis, and moderate to severe Crohn’s disease.[1] Adalimumab is the first fully human recombinant monoclonal antibody (mAbTNFα) with a high binding affinity to TNFα.[2,3] Compared to other recombinant monoclonal TNFα antibodies, including etanercept or infliximab, adalimumab has a stronger binding affinity and neutralizes both soluble and transmembrane TNFα; it potentially kills TNFα-expressing cells through antibody-dependent cell-mediated cytotoxicity (ADCC) or/and complement-dependent cytotoxicity (CDC).[2,4–6] Furthermore, adalimumab causes less adverse immunogenic reactions than etanercept or infliximab in humans, making it suitable for the long-term treatment of chronic diseases.[2] Adalimumab has a longer circulation half-life (about 10–20 days) than that of etanercept (about 3–5 days) and infliximab (about 5–9 days). Therefore, patients can conveniently inject adalimumab every other week.[3,7] Among originator drugs, Humira, the brand name of the original adalimumab medicine, is frequently at the top of the selling record,[7] indicating the importance of this prescribed drug.