Summary

The advent of biopharmaceuticals in current medicine brought enormous benefits to the treatment of life-threatening human diseases (e.g., cancer, diabetes and neurodegenerative disorders), and improved the well-being of many people worldwide. The global portfolio of these therapeutic products include proteins and antibodies, nucleic acids, and cell-based products, and continues to expand at a rapid pace - approvals in the period 2015-2018 essentially double the typical five-yearly historical approval pace (G. Walsh, Nat. Biotechnol., 36:1136-1145, 2018) -, representing a significant share of the entire market of pharmaceuticals.

Innovation in the (bio)pharmaceutical industry has been driven towards the development of cost-effective manufacturing processes, envisaging the delivery of products in high quantity, with superior quality (purity), and high specificity, with the ultimate goal of benefiting patients. Progress in this direction have resulted from the application of novel technologies in the upstream stage (high-throughput, single-use devices, statistical optimization of media and fermentation conditions, QbD, and continuous processing), while at the downstream level, chromatography has evolved through the development of new resins and ligands, coupled with advances in process modelling, operating and control strategies.

An emerging trend is the application of alternative solvents such as ionic liquids and deep eutectic solvents, in which their structure and physicochemical properties can be tuned to address unmet needs in (bio)pharmaceutical research. These compounds may be derived from natural and reneawable sources and hold great promise in the development of efficient, sustainable and cost-effective biopharmaceuticals purification processes.

This Entry Collection aims to provide the latest progresses achieved in pharmaceuticals bioprocessing. We welcome submissions of original research, comprehensive reviews and perspectives, including, but not limited, to the following fields:

- Upstream processing (genetic engineering, systems biology, difficult-to-express proteins, expression conditions, Quality by Design approaches, process analytical technologies);

- Chromatographic purification methods (process modelling and control, continuous bioprocessing, design and characterization of resins and ligands, new formats);

- Alternative purification methods (aqueous biphasic systems, filtration, crystallization, precipitation);

- Application of neoteric solvents in upstream and downstream stages;

- Analytical characterization of biopharmaceuticals (stability, post-translational modifications, biological activity, immunogenicity); 

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Entries
Topic Review
Accum™ Technology
Compromised activity is a common impediment for biologics requiring endosome trafficking into target cells. In cancer cells, antibody-drug conjugates (ADCs) are trapped in endosomes or subsequently pumped extracellularly, leading to a reduction in intracellular accumulation. In subsets of dendritic cells (DCs), endosome-engulfed antigens face non-specific proteolysis and collateral damage to epitope immunogenicity before proteasomal processing and subsequent surface presentation. Accum™ is a novel biotechnology exemplifying, in its initial concept, the need to circumvent the biological challenges of ADCs.
  • 404
  • 29 Jul 2022
Topic Review
Stem Cell-Derived Extracellular Vesicles in Bone Defects
The repair of critical bone defects is a hotspot of orthopedic research. With the development of bone tissue engineering (BTE), there is increasing evidence showing that the combined application of extracellular vesicles (EVs) derived from mesenchymal stem cells (MSCs) (MSC-EVs), especially exosomes, with hydrogels, scaffolds, and other bioactive materials has made great progress, exhibiting a good potential for bone regeneration. 
  • 369
  • 29 Jul 2022
Topic Review
Management of Chronic Spontaneous Urticaria Using Anti-IgE Antibodies
Chronic spontaneous urticaria (CSU) considerably alters patients’ quality of life, often for extended periods, due to pruriginous skin lesions, impaired sleep, unexpected development of angioedema, and failure of conventional treatments in properly controlling signs and symptoms. Although the production of specific immunoglobulin E (IgE) antibodies against certain allergens is not a characteristic of the disease, treatment with omalizumab, a monoclonal anti-IgE antibody, proved efficient and safe in patients with moderate to severe chronic spontaneous urticaria uncontrolled by H1-antihistamines. Ligelizumab, a high-affinity monoclonal anti-IgE antibody, may also efficiently relieve symptoms of unresponsive chronic urticaria to standard therapies. 
  • 958
  • 27 Jul 2022
Topic Review
Dual-Targeting Chimeric Antigen Receptor T-Cell Therapy
Single-targeted chimeric antigen receptor (CAR) T cells tremendously improve outcomes for patients with relapsed/refractory hematological malignancies and are considered a breakthrough therapy. However, over half of treated patients experience relapse or refractory disease, with antigen escape being one of the main contributing mechanisms. Dual-targeting CAR T-cell therapy is being developed to minimize the risk of relapse or refractory disease. Preclinical and clinical data on five categories of dual-targeting CAR T-cell therapies and approximately fifty studies were summarized to offer insights and support the development of dual-targeting CAR T-cell therapy for hematological malignancies. The clinical efficacy (durability and survival) is validated and the safety profiles of dual-targeting CAR T-cell therapy are acceptable, although there is still room for improvement in the bispecific CAR structure. It is one of the best approaches to optimize the bispecific CAR structure by boosting T-cell transduction efficiency and leveraging evidence from preclinical activity and clinical efficacy.
  • 611
  • 01 Aug 2022
Topic Review
Anticoagulatory and Procoagulatory Effects of Cannabinoids
Abnormal blood coagulation or coagulopathy is a common manifestation of many pathological conditions. It occurs when there is an imbalance between the activities of the coagulation system and the fibrinolytic system, leading to excessive or impaired intravascular blood clot formation, which can disturb blood flow causing ischemia or hemorrhage in the affected tissues. A growing body of evidence has demonstrated blood coagulation abnormalities in association with cannabinoid use, suggesting the involvement of the endogenous cannabinoid system (ECS) in modulating blood coagulation. However, the evidence in the literature has been controversial on whether cannabinoids promote or inhibit blood coagulation. 
  • 859
  • 25 Jul 2022
Topic Review
Regulating Reactive Oxygen Species Concentrations in Plant Cells
Environmental factors, such as high light intensity, adverse temperature, drought, or soil salinity, are summarized as abiotic stresses and discriminated from biotic stresses that are exerted by pathogens and herbivores, for instance. It was an unexpected observation that overproduction of reactive oxygen species (ROS) is a common response to all kinds of stress investigated so far. ROS are important messengers in cell signaling, but exceeding a concentration threshold causes damage. This requires fine-tuning of ROS production and degradation rates. In general, there are two options to control cellular ROS levels, (I) ROS scavenging at the expense of antioxidant consumption and (II) enzyme-controlled degradation of ROS. As antioxidants are limited in quantity, the first strategy only allows temporarily buffering of a certain cellular ROS level. This way, it prevents spells of eventually damaging ROS concentrations. 
  • 975
  • 28 Jul 2022
Topic Review
Icariin and Its Derivates
There has been considerable interest in icariin (ICA) and its derivates, icariside II (ICS) and icaritin (ICT), due to their wide range of potential applications in preventing cancer, cardiovascular disease, osteoporosis, delaying the effects of Alzheimer’s disease, treating erectile dysfunction, etc.
  • 646
  • 22 Jul 2022
Topic Review
Redox Disturbance and Inflammation during General Anesthesia
Worldwide, the prevalence of surgery under general anesthesia has significantly increased, both because of modern anesthetic and pain-control techniques and because of better diagnosis and the increased complexity of surgical techniques. Apart from developing new concepts in the surgical field, researchers and clinicians are now working on minimizing the impact of surgical trauma and offering minimal invasive procedures due to the recent discoveries in the field of cellular and molecular mechanisms that have revealed a systemic inflammatory and pro-oxidative impact not only in the perioperative period but also in the long term, contributing to more difficult recovery, increased morbidity and mortality, and a negative financial impact. Detailed molecular and cellular analysis has shown an overproduction of inflammatory and pro-oxidative species, responsible for augmenting the systemic inflammatory status and making postoperative recovery more difficult. Moreover, there are a series of changes in certain epigenetic structures, the most important being the microRNAs.
  • 358
  • 21 Jul 2022
Topic Review
JAMM Deubiquitinating Enzymes in Disease
Deubiquitinating enzymes (DUBs) are a group of proteases that are important for maintaining cell homeostasis by regulating the balance between ubiquitination and deubiquitination. As the only known metalloproteinase family of DUBs, JAB1/MPN/Mov34 metalloenzymes (JAMMs) are specifically associated with tumorigenesis and immunological and inflammatory diseases at multiple levels. The far smaller numbers and distinct catalytic mechanism of JAMMs render them attractive drug targets. Several JAMM inhibitors have been successfully developed and have shown promising therapeutic efficacy. 
  • 711
  • 22 Jul 2022
Topic Review
Brain Cancer Chemotherapy Using Monoclonal Antibody Conjugates
Central nervous system (CNS) drug delivery into the brain across the endothelium is difficult due to the blood-brain barrier (BBB), which is composed mainly of tight junctions and efflux transporters, such as multiple drug resistance 1 (MDR1) (P-glycoprotein). On the other hand, the development of anti-cancer drugs is a challenging task due to their frequent off-target side effects and the complicated mechanisms of cancer pathogenesis and progression. Brain cancer treatment options are surgery, radiation therapy, and chemotherapy. It is difficult to remove all tumor cells, even by surgical removal after a craniotomy. Accordingly, innovative brain cancer drugs are needed. Currently, antibody (Ab) drugs that show high therapeutic effects are often used clinically. Furthermore, antibody-drug conjugates (ADCs), such as trastuzumab deruxtecan, an anti-HER2 (human epidermal receptor 2) ADC with low-molecular cancer drugs through the suitable linker, have been developed. In the case of trastuzumab deruxtecan, it is internalized into cancer cells across the membrane via receptor-mediated endocytosis. Moreover, it is reported that drug delivery into the brain across the BBB was carried out via receptor-mediated transcytosis (RMT), using anti-receptor Abs as a vector against the transferrin receptor (TfR) or insulin receptor (InsR). Thus, anti-TfR ADCs with cancer drugs are promising brain cancer agents due to their precise distribution and low side effects.
  • 773
  • 20 Jul 2022
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