Biotechnology Medicine Research Articles

SA-49, a Novel Aloperine Derivative, Induces MITF-Dependent Lysosomal Degradation of PD-L1

Programmed death-ligand 1 (PD-L1) is a T-cell inhibitory checkpoint molecule that suppresses antitumor immunity. Anti-PD-L1 antibodies have shown remarkable promise in treating tumors, but the patient response rate is low. Small-molecule checkpoint inhibitors blocking PD-L1 function are urgently needed. Here we reported that SA-49, a novel aloperine derivative, decreased the expression of PD-L1 in NSCLC cells and enhanced the cytotoxicity of co-cultured T and NK cells. Importantly, we found lysosomal pathway contributed to SA-49-mediated down-regulation of PD-L1. SA-49 increased the biogenesis of lysosome and promoted translocation of PD-L1 to lysosome for proteolysis, which was associated with nuclear translocation of MITF. SA-49-induced MITF translocation acted through activation of PKCα and subsequently suppression of GSK3β activity. Furthermore, SA-49 suppressed Lewis tumor xenograft growth by activating immune microenvironment in C57BL/6 mice. Our data demonstrate that SA-49 can be used to regulate PD-L1 in cancer cells and trigger its degradation by activating lysosome function. Funding Statement: This work was supported by grants from National Natural Science Foundation of China (81773782, 81473248 and 81621064) and CAMS Major Collaborative Innovation Project (2016-12M-1-011). Declaration of Interests: The authors have declared no conflicts of interest. Ethics Approval Statement: The animal procedures were carried out with the approval of the Animal Ethics Committee of the Institute of Medicinal Biotechnology, Chinese Academy of Medical Sciences.

An Untapped Resource in the Spotlight of Medicinal Biotechnology: The Genus Scutellaria.

This review is intended to draw the attention of pharmaceutical and biotechnological communities to the untapped potential of the Scutellaria genus. Skullcaps, as they are more widely known, are found in one of the oldest materia medica in the world, that of ancient Chinese pharmacology, and their numerous wide range of medicinal bioactivities have been studied both in vivo and in vitro. For thousands of years, chemical compounds from the Scutellaria species have been safely used as antitumor, antibacterial, antiviral, anti-inflammatory, antioxidant or hepatoprotective factors. As these effects are well known, reflected in the presence of Scutellaria plants in national pharmacopoeias, it is clear that the plant has yet enormous unexploited potential. The European pharmacological market has turned to the resources of Scutellaria only in the last two decades, and although the construction and clinical processing of a new drug is a long process, the general impression is that very few medical products in pharmacies have been inspired by the phytochemistry of skullcaps. This paper presents the current state of knowledge on the wealth of Scutellaria chemical compounds with treatment applications, its tissue culture and biotechnological achievements, especially in the context of the production of secondary metabolites.

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ASIA – The first Greater Bay Area biotechnology and translational medicine international collaboration. ASIA – New insight on therapeutic treatment for mental disorders. OCEANIA – Multiple chronic diseases leave patients with adversely high costs. AMERICAS – Measuring the risks and rewards of drug development. AMERICAS – Ketone drink could help diabetics by lowering blood sugar.

BIOSIMILARS, PRODUCED USING THE RECOMBINANT DNA TECHNOLOGY

The review presents materials on the scientific principles underlying the development, preclinical and clinical research, registration and control of the safety of biosimilar medicines produced using genetic engineering techniques. The number of biosimilars used in the clinic, defined as «biosimilars», is steadily increasing. The features of biotechnological preparations are presented, that requires a special approach to assessing the newly developed preparation evidence of similarity with the original (reference) preparation. To ensure the effectiveness and safety of their use, the procedure for registration of such medicines is determined by the regulatory framework governing the requirements for proof of similarity with previously approved biological medicinal products. The data concerning the differences in the nature and scope of studies at the stages of quality assessment, preclinical and clinical development of biosimilar and original drugs are performed. The issues related to extrapolation of clinical trial results and the issues of medicines interchangeability are reported. The modern information on international experience of biosimilar medicines registration, scientific achievements and regulatory requirements concerning evidence of similarity in assessing the quality, effectiveness and safety of biosimilar biotechnological medicines («biosimilars») has been reported.

Mycoplasma Clearance and Risk Analysis in a Model Bioprocess.

Mycoplasmas are a type of bacteria that lack cell walls and are occasional cell culture contaminants. In a biotechnology setting, because they can pass through 0.2 μm filters, mycoplasmas could pose a potential patient safety hazard if undetected contaminants from the production culture were not completely removed by downstream biotechnology manufacturing. In this study we investigated the ability of typical commercial monoclonal antibody purification operations to clear and kill mycoplasmas, using Acholeplasma laidlawii as a model organism. Our spike/removal studies have shown that protein A column chromatography clears about 4-5 log10 Column regeneration effectively prevents A. laidlawii column carryover between chromatography runs. Moreover, low-pH hold steps, typically implemented after protein A purification, effectively kill A. laidlawii using either pH 3.8 glycine or acetate solutions (LRV ≥5.30 and ≥4.57, respectively). Solvent/detergent treatment, used in some processes instead of low-pH hold, also completely kills highly concentrated A. laidlawii (LRV ≥5.95).LAY ABSTRACT: Biotechnology medicines need to be free from contaminating microorganisms such as mycoplasmas, a type of bacteria that can cause disease in humans (e.g., walking pneumonia). Here we show that some monoclonal antibody manufacturing steps can effectively clear and/or kill Acholeplasma laidlawii, a model mycoplasma species used in our study. This provides an additional level of safety assurance of biotechnology medicines for patients.

Biotechnology in medicine

Biotechnology in medicine

Characterization of Protein Aggregating Tungstates: Electrospray Mass Spectrometry Analysis of Extracts from Prefilled Syringes and from Tungsten Pins Used in the Manufacture of Syringes.

Glass prefilled syringes are increasingly becoming a container of choice for storing and administering therapeutic protein products to patients. Tungsten leaching from a PFS is known to induce protein particle formation, and the source was traced to the tungsten pins used in the manufacturing process of the syringe barrels. Study of the tungstates present in extracts from both tungsten pins used in the syringe manufacturing process and from single syringes from various suppliers was undertaken. Electrospray mass spectrometry was chosen as a technique with the sensitivity to characterize tungstates at levels (∼1 ppm of elemental tungsten) observed in single syringes. Extraction solvents were chosen to simulate the range (pH 4.0-7.0) typically used for therapeutic protein formulation. A commercial product formulation buffer was also used as an extraction solution to characterize tungstate species used for tungsten spiking studies of protein. All pin and syringe extracts from various manufacturers were similar in regards to containing stable Na/K containing lacunary polytungstate ([W11O39](7-)) species, which were the main species present in syringe extracts and are different than the metatungstate ([W12O39](6-)) species identified in commercially available sodium polytungstate and as the main species in pin extracts. These stable Na/K containing polytungstates species present in pin and syringe extracts are likely formed during the glass manufacturing process at >400 °C and may have the capability to subsequently form larger polytungstate complexes. Glass prefilled syringes are a type of container used for storing and administering biotechnology medicines to patients. The manufacturing process for the syringes may lead to very low levels of the metal tungsten being present in the syringes, and thus in the medicine stored in the syringes. The presence of tungsten in certain biotechnology medicines has been shown to cause changes to the medicine. Understanding something that can cause a medicine to change is an important part of producing safe and effective medicines for patients. The study described in this article sought to increase understanding by characterizing the form of tungsten observed in syringes from a number of vendors. Study of the tungsten present in syringes from four vendors indicates the same form of tungsten is observed regardless of the vendor. The study also found that the form of tungsten differed from that expected.

배합사료의 부패 동안 발생하는 미생물학적 및 영양학적 변화

1 Department of Animal Science and Technology, Konkuk University, Seoul 05029, Korea Department of Animal Science, Gyeongsang National University, Jinju 52828, Korea Department of Medicinal Biotechnology, Dong-A University, Busan 49315, Korea 4 School of Biological Sciences, Chung-Ang University, Seoul 06974, Korea Department of Animal Science and Technology, Sunchon National University, Suncheon 57922, Korea National Institute of Animal Science, RDA, Wanju 55365, Korea

The Pharmaceutical Pricing and Reimbursement Information (PPRI) network – a decade of exchange of information and policy research?

Policy-makers throughout Europe and beyond have been working to develop and implement, and further adjust, the most appropriate mix of policy measures in pharmaceutical pricing and reimbursement to ensure equitable access to medicines despite limited budgets. The experience with policies in other countries is highly valuable information for them. In order to support policy-makers, the Pharmaceutical Pricing and Reimbursement Information (PPRI) network of competent authorities was established in 2005, with the aim to offer a platform for competent authorities of pharmaceutical pricing and reimbursement to exchange information and data and to establish a sustainable reporting system for country information. Within the decade of PPRI's existence, more than 60 country reports (information about medicines policies for the out-patient sector, hospital pharma reports, and integrated country profiles about the out-patient and the in-patient sectors) of 28 different countries and more than 60 country posters were produced. Comparative analyses were undertaken, e.g. in the PPRI report [1], the PHIS Hospital Pharma report [2] or in scientific articles [3-5]. A glossary [6] and indicators were developed and are regularly updated. These deliverables have been shared in the open domain (http://whocc.goeg.at/Publications/). In addition to these reports and tools, the instrument of PPRI network queries has proven its importance. A PPRI network query allows PPRI network members to ask for specific and quick information about a policy and situation in the other countries represented in the PPRI network [7]. In total, 319 PPRI queries have been launched until June 2015. The PPRI network is predominantly Europe-based. It has been growing over the years and currently comprises competent authorities for pharmaceutical pricing and reimbursement from 45 countries (thereof all 28 European Union Member States, another twelve European countries, and five non-European countries) as well as European and international institutions (European Commission, OECD, WHO, World Bank). Face-to-face meetings of the PPRI network are organised twice a year. The PPRI network is characterized by trust and mutual respect. The last decade has brought both new challenges (e.g. financial constraints due to the crisis, new premium-priced medicines) and opportunities (e.g. new policy tools such as managed-entry agreements, patent expiries of biotechnological medicines) for policy-makers. Participation in the PPRI network has supported them to deal with these developments and discuss possible solutions and collaborative approaches. In the light of on-going challenges, the PPRI network is well placed and prepared to continue playing its role as discussion and information exchange platform for the years to come.

Role of Pharmacovigilance in India: An overview

Pharmacovigilance (PV) plays a key role in the healthcare system through assessment, monitoring and discovery of interactions amongst drugs and their effects in human. Pharmaceutical and biotechnological medicines are designed to cure, prevent or treat diseases; however, there are also risks particularly adverse drug reactions (ADRs) can cause serious harm to patients. Thus, for safety medication ADRs monitoring required for each medicine throughout its life cycle, during development of drug such as pre-marketing including early stages of drug design, clinical trials, and post-marketing surveillance. PV is concerns with the detection, assessment, understanding and prevention of ADRs. Pharmacogenetics and pharmacogenomics are an indispensable part of the clinical research. Variation in the human genome is a cause of variable response to drugs and susceptibility to diseases are determined, which is important for early drug discovery to PV. Moreover, PV has traditionally involved in mining spontaneous reports submitted to national surveillance systems. The research focus is shifting toward the use of data generated from platforms outside the conventional framework such as electronic medical records, biomedical literature, and patient-reported data in health forums. The emerging trend in PV is to link premarketing data with human safety information observed in the post-marketing phase. The PV system team obtains valuable additional information, building up the scientific data contained in the original report and making it more informative. This necessitates an utmost requirement for effective regulations of the drug approval process and conscious pre and post approval vigilance of the undesired effects, especially in India. Adverse events reported by PV system potentially benefit to the community due to their proximity to both population and public health practitioners, in terms of language and knowledge, enables easy contact with reporters by electronically. Hence, PV helps to the patients get well and to manage optimally or ideally, avoid illness is a collective responsibility of industry, drug regulators, clinicians and other healthcare professionals to enhance their contribution to public health. This review summarized objectives and methodologies used in PV with critical overview of existing PV in India, challenges to overcome and future prospects with respect to Indian context.

Evolution and clinical application of microsurgery

Evolution and clinical application of microsurgery

Maßgeschneidertes Genom — Designer-Nukleasen im Einsatz

Designer nucleases are artificial proteins for the precise modification of complex genomes. The most commonly used platforms are zinc-finger nucleases (ZFNs), transcription activator-like effector nucleases (TALENs) and the clustered regularly interspaced short palindromic repeat (CRISPR)/Cas system. These powerful tools greatly facilitate the generation of plant and animal models for basic research, and harbor an enormous potential for applications in biotechnology and regenerative medicine.

The safety of biological medicines for rheumatoid arthritis.

Biotechnological medicines have improved the treatment of various diseases and the quality of life of patients [1]. The administration of a drug may lead to adverse events that may or may not be documented. These events affect disease progression and health expenditures [2]. Rheumatoid Arthritis (RA) is an autoimmune disease for which biotechnological medicines are prescribed. RA has serious economic impact. Especially, the annual cost of RA is 41 billion euros in the USA and 45 billion euros in Europe, which are increasing dramatically with appearance of an adverse event [3].

The Effects of Reforms, Price Cuts and Global Budget Implementation on Biotechnological Medicine Sales Which Have Annual Average Highest Amount Of Sales Between 2008-2013 In Turkey.

In 2003 Health Transformation Program and in 2006 Social Security Reform were launched in Turkey. At the end of the years 2009 and 2011 price cuts were done by the Government and between the years 2010-2012, there was a global budget implementation in Turkey. The top 100 medicines, annual average highest amount of sales of between 2008-2013, had one to four of the total pharmaceutical market value in 2013. We aimed to examine the status of biotech-medicines in the first 100 medicine’s and evaluate the effects of policy interventions on these medicine sales. While pharmaceutical sales data were obtained from the IMS Health-Turkey data base, prices and characteristics of medicines were obtained from the Turkish Medicine and Medical Devices Agency data bases. Each group (biotech/nonbiotech-medicines) was analyzed using TRAMO and SEATS method. 19 medicines are biotechnological. In 2009 compared to 2008 while biotech-medicines amount increased by 43.8%, nonbiotech-medicines amount increased by 14.2%. In subsequent years, an increase over the previous year is observed at lower rates for biotech-medicines. This total amount has decreased compared to previous years for nonbiotech-medicines. 2014 and 2015 for the consumption of biotechnological medicines was estimated to be around 9 million boxes, expenditure for 2014 of 1360 million Turkish Liras (TL) and 2015 million TL for the year 2015. On the other hand, non-biotechnological medicines consumption would be approximately 185 million boxes and for the year 2014 2225 million TL, for the year 2015 2280 million TL are projected. Biotechnological medicines have high unit costs and these costs are increasing compared to year to year. Policy interventions did not effected biotechnological medicine sales negatively. While big differences between the biotechnological and non-biotechnological medicine box sales will continue, the gap between the biotechnological and non-biotechnological medicines total amount will be closer.

Centella asiatica: from folk remedy to the medicinal biotechnology – a state revision

Centella asiatica or “gotu kola” has been used since long time ago as an ethno-pharmacological plant and supposed to be a potent medicinal plant for its various pharmacological effects favorable for human health. Many studies described the noteworthy protective effect of C. asiatica against numerous diseases. Biological activities of C. asiatica have been linked to the most major compounds in it. This state paper is a part of our ongoing research on C. asiatica, its activity, isolation of novel metabolites, and applying the biotechnological methods to improve this plant and its phytochemical activities.

Evaluation of Meat Used for Human Consumption in Latvia

Over the last decade in Latvia, the production levels of beef, pork and poultry meat have been dramatically reduced. The yearly meat consumption per capita in Latvia is about 60 kg. Traditionally, pig meat consumption is higher than consumption of bovine meat, which has higher production costs. Lower priced meat from European countries is imported and placed on the market in Latvia. The Research Institute of Biotechnology and Veterinary Medicine “Sigra”, Latvia, LUA, performs important research on meat quality and acquisition of safe and healthy food of animal origin. Cattle herds of meat breed are highly varied both from the aspect of animals and the quality of the sold meat produce. In meat of bovine animals, the settling of cholesterol on the blood vessel walls is precluded by 5.4-8.13% ω-3 and 12.97-16.27% ω-6 on average. The meat of the beef breed cattle contains wholesome proportions of proteins, fatty acids in quantities sufficient for humans, a relatively low cholesterol level (about 77 mg%) and good qualities of the culinary flavours and aromas. There are on-going research studies on the quality of meat of different pig breeds and their influencing factors, as well as on acquisition of meet in accordance with the consumer requirements. Extensive research is carried out also on the quality of broiler meat, with the target of acquisition of new quality meat. Assessment of the role of game meat in human consumption and the hygiene aspects of its acquisition are also included. Due to the development of heliculture in Latvia, the assessment of snail meat and its role in human consumption has also been launched.

Current status and considerations on biosimilar in China

Since the WHO “Guidelines on Evaluation of Similar Biotherapeutic Products (SBPs)” was published in April 2010[1], twenty two Countries and regions including EU and FDA have established their guidelines or guideline drafts on evaluation of biosimilar. In terms of the technical features, WHO guidelines are consistent with that of EU[2-4], head-to-head comparison exercise between SBP and reference biotherapeutic product (RBP) are required. In the prerequisite of quality similarity, the unnecessary or repeated non-clinical and/or clinical data might be reduced. Furthermore, extrapolation to other indications of the RBP may be possible. As for the FDA draft, requirements of interchangeability and substitution of SBP with RBP were introduced [5,6]. Guidelines of other developing countries generally used the WHO guidelines and the FDA guidance draft as blueprints to set up the technical requirements. These regulations and guidelines have far-reaching significance for each country’s biotechnology industry development and the availability and affordability of public medicine use. Up to now, there are not yet specified regulations for SBPs in China. Based on “The Provisions for Drug Registration (SFDA Order 28)” [7], Part I “Biological Products for Therapeutic Use” of the appendix 3 includes fifteen categories, three of them (7, 10 and 15) are related to SBPs. With respect to the technical requirements, there are no essential differences between China and WHO guidelines. However, our current regulations pay more attention to the requirements for the new drug approval. Consequently, some candidate SBPs products which might be suitable for abbreviated licensure pathway still need to experience the complete non-clinical and clinical studies. In addition, extrapolating to other indications is not allowed in our current regulations. Among the research projects of the Twelfth Five-Year Plan significant new drugs creation special, me too biothreapeutics are still the major part of the projects of biotechnology medicines. Therefore, accelerating the process of establishing our SBPs guidelines has great benefit for achieving the goal of ensuring the availability and affordability of public medicine and improving the development of our country’s biotechnology industry. Recently, our department has initiated the process of surveying the need to draft a specified SBP guideline. As some suggestions, due to very hard to obtain and very high costing of RBP would surely increase the difficulties of developing and evaluation of SBPs, how to define the requirement of RBP should be elaborately considered during the process of establishing our guidelines. Besides, special attention should be focused on how to perform the comparability exercise with RBP in the non-clinical and/or clinical study during the development of SBPs of therapeutic monoclonal antibodies. We believe that a SBPs guideline which considering both the actual situation of development of biomedicine in China and the general WHO framework would be established in the near future.

Medical Nanobiotechnology and Its Prospective

Medical nanobiotechnology, the application of combined nanotechnology and biotechnology in medicine has revolutionized our understanding of diagnosis and treatment of certain diseases. The field of nanobiotechnology has experienced unexpected advances throughout the last decade and as the result has attracted much attention from scientific communities and even public (1). We are at the edge of a new horizon in molecular medicine: convergence of these two disciplines has increased our ability to apply novel treatment tools and methods in cancer biology which were 20 years ago might have been difficult to imagine (Figure 1). Nanobiotechnology which invloves usage of defined nanoparticles i.e. metals, polymers, lipids and carbon with a potential to be conjugated with molecular markers to achieve unprecedented protocols like molecular targeting, molecular imaging, and directed diagnostic tools can contribute to optimize cancer treatment (1, 2). The major obstacle in cancer drug delivery is known to be selective drug delivery which might be overcome by Copyright c 2012 Kowsar Corp. All rights reserved.

Budget Impact Model of New Antiretroviral Biotechnology Medicines for Treatment of HIV/AIDS Patients in Bulgaria

ABSTRACTThe objective of the study is to evaluate the impact of the new highly active antiretroviral biotechnology medicines (tenofovir disoproxil, emtricitabin and darunavir) on the clinical centre health care budget for AIDS in 2011 for a one year time horizon. A computer simulated budget impact model is created to calculate the budget impact of the new biotechnology medicines as a difference among the cost of illness based on current practice monus the cost of illness based on new practice after the new medicines inclusion in the clinic. The cost of therapy is calculated as a sum of mean annual medicines cost for all patients on the therapeutic regime, yearly cost of physician's consultation, and laboratory tests.Two scenarios have been considered depending on the line of therapy—Ist line (140 patients in the current state and 20 in the new state) and IInd line (2 patients in the current state and 26 in the new state).The yearly cost per patient in the current state on Ist line therapy, which did not involve the use of the new biotechnology products varied between 3000 and 12 000 euro. In the new state the budget impact varies from 8000 to 13000 euro for treatment naïve patient, and for the switched—therapy patients it varies between 5000 and 13 000 euro. Thus the addition of the new medicines let to the increase in the yearly budget per patient with 1000 to 5000 euro.The IInd line therapy is usually started when adverse drug events or resistance against the first line therapy is observed. The addition of the new medicines increases total budget more evidently for the patients on first line therapy, than for the patients on IInd line.The budget impact of the new highly active antiretroviral therapy depends mainly on the new biotechnology medicines cost.

How much is the life of a cancer patient worth? A pharmaco-economic perspective

Countries struggle to accommodate the introduction of new effective cancer medicines, while containing costs. Our objective is to comment on several pharmaco-economic challenges involved in determining the value of cancer medicines by reviewing cost-effectiveness thresholds for cancer medicines in several countries and by discussing the cost-effectiveness of anti-cancer biotechnology and orphan medicines. A literature search was carried out of PubMed, Centre for Reviews and Dissemination databases, Cochrane Database of Systematic Reviews and EconLit up to August 2009. Health technology assessment agencies in England and Scotland are willing to incur a higher cost per quality-adjusted life year for cancer medicines than for other medicines. Risk-sharing arrangements have been implemented to optimize the value of cancer medicines. The cost-effectiveness of biotechnology medicines in cancer care is challenged by their high price, and depends on the ability to identify the most responsive target population, through use of suitable biomarkers. The evaluation of orphan medicines in cancer care needs to balance the absence of an alternative therapy for a life-threatening disease against the high cost-effectiveness ratio, and usually weak clinical data. Current strategies used to inform decisions on the funding of expensive anti-cancer medicines are commented on to highlight important issues and problems. Pharmaco-economic evaluation is an important tool for assessing the value of cancer medicines and to inform evidence-based decision making in cancer care. Value-judgments such as preferential consideration of anti-cancer medicines can then be made explicitly.