BACKGROUND & AIMS: :Biologically active natural products are spontaneous medicinal entrants, which encourage synthetic access for enhancing and supporting drug discovery and development. Marine bioactive peptides are considered as a rich source of natural products that may provide long-term health, in addition to many prophylactic and curative medicinal drug treatments. The large literature concerning marine peptides has been collected, which shows high potential of nutraceutical and therapeutic efficacy encompassing wide spectra of bioactivities against a number of infection-causing agents. Their antimicrobial, antimalarial, antitumor, antiviral, and cardioprotective actions have achieved the attention of the pharmaceutical industry toward new design of drug formulations, for treatment and prevention of several infections. However, the mechanism of action of many peptide molecules has been still untapped. So in this regard, this paper reviews several peptide compounds by which they interfere with human pathogenesis. This knowledge is one of the key tools to be understood especially for the biotransformation of biomolecules into targeted medicines. The fact that different diseases have the capability to fight at different sites inside the body can lead to a new wave of increasing the chances to produce targeted medicines.

背景与目标： ：具有生物活性的天然产物是自发的药物，鼓励合成途径以增强和支持药物的发现和开发。海洋生物活性肽被认为是天然产物的丰富来源，除了许多预防和治疗性药物治疗外，还可提供长期健康。已经收集了有关海洋肽的大量文献，这些文献显示出对营养和治疗功效的高潜力，其中包括针对多种致病因子的广泛的生物活性。它们的抗微生物，抗疟疾，抗肿瘤，抗病毒和心脏保护作用已引起制药行业对新的药物制剂设计的关注，以治疗和预防多种感染。然而，许多肽分子的作用机理仍未开发。因此，在这方面，本文综述了几种干扰人类发病机理的肽化合物。该知识是要理解的关键工具之一，特别是对于将生物分子生物转化为靶向药物的方法。不同疾病具有在体内不同部位进行战斗的能力这一事实可以导致新一波增加生产靶向药物的机会的浪潮。

BACKGROUND & AIMS: :Age-related macular degeneration (AMD) is a condition that may cause blindness. The prevalence of the disease in the Western world is estimated at 1-2% of the population. Over the past decade, treatment of neovascular AMD has been shifting from destruction of newly formed blood vessels towards inhibitors that silence the vascular endothelial growth factor (VEGF) pathway. Such agents are often first-in-class biopharmaceuticals that benefit from the fact that they can be locally administered in an immune-privileged environment with slow clearance. These new VEGF pathway inhibitors have improved therapeutic effects over conventional treatment and have promoted the identification of novel targets for inhibition of AMD angiogenesis. This review describes the rationale behind the shift from conventional to current treatment options and discusses investigational, most notably biopharmaceutical, drugs that are in clinical trials. It also provides possible points for improvement of these treatments, specifically regarding their delivery.

背景与目标： ：与年龄有关的黄斑变性（AMD）是一种可能导致失明的疾病。据估计，该疾病在西方世界的患病率为人口的1-2％。在过去的十年中，新血管AMD的治疗已从破坏新形成的血管转向抑制血管内皮生长因子（VEGF）通路的抑制剂。此类试剂通常是一流的生物药品，这得益于它们可以在免疫特权较低的环境中以缓慢清除的方式局部给药的事实。这些新的VEGF途径抑制剂与常规治疗相比具有改善的治疗效果，并促进了抑制AMD血管生成的新靶标的鉴定。这篇综述描述了从常规治疗方案向当前治疗方案转变的基本原理，并讨论了临床试验中的研究性药物，尤其是生物制药。它还为改进这些治疗方法提供了可能的要点，特别是在治疗方面。

BACKGROUND & AIMS: OBJECTIVES:Infliximab is an anti-tumour necrosis factor-alpha (TNF-alpha) mouse-human IgG1/kappa antibody used to treat patients with rheumatoid arthritis (RA) and other inflammatory diseases. Unfortunately, response failure and side-effects due to immunogenicity of the drug are not rare. In this study, we have compared different methods of assessing drug levels and anti-infliximab antibodies (Abs) and analysed the character of these Abs in sera of RA patients treated with infliximab for 1.5-18 months. METHODS:Functional serum infliximab levels and anti-infliximab Abs were measured by fluid-phase RIAs using 125I-labelled ligands in combination with molecular size and affinity chromatography, and immune complex precipitation. RESULTS:Anti-infliximab Abs were predominantly IgG, 36% being IgG4, and half the immune complexes were lambda-light-chain-positive. Ab titres were associated with inhibition of TNF binding to the drug, and low trough levels of infliximab were most frequent in anti-infliximab Ab-positive sera. Cross-binding to two other anti-TNF drugs was not observed. Detection of anti-infliximab Abs by solid-phase RIA using cross-binding of plastic-fixed and soluble infliximab exhibited low sensitivity and the data were inconsistent with results obtained from binding of the Abs to soluble infliximab. CONCLUSIONS:Specific and neutralizing anti-infliximab antibodies develop in RA patients treated with infliximab, and that low trough levels of functional infliximab are associated with the presence of such antibodies. The most sensitive antibody assay involved binding to soluble and intact infliximab. Assessments of bioavailability and immunogenicity of anti-TNF biologicals may be used to optimize dose regimens and prevent prolonged use of inadequate therapy.

背景与目标： 目的：英夫利昔单抗是一种抗肿瘤坏死因子-α（TNF-alpha）小鼠-人类IgG1 / kappa抗体，用于治疗类风湿关节炎（RA）和其他炎症性疾病的患者。不幸的是，由于药物的免疫原性引起的反应失败和副作用并不罕见。在这项研究中，我们比较了评估药物水平和抗英夫利昔单抗抗体（Abs）的不同方法，并分析了接受英夫利昔单抗治疗1.5-18个月的RA患者血清中这些Abs的特征。
方法：采用125 I标记的配体，结合分子大小和亲和层析，通过免疫相沉淀法，通过液相RIA法测定功能性血清英夫利昔单抗和抗英夫利昔单抗的抗体水平。
结果：抗英夫利昔单抗主要为IgG，36％为IgG4，一半的免疫复合物为λ轻链阳性。 Ab滴度与TNF结合药物的抑制作用有关，在英夫利昔单抗Ab阳性血清中英夫利昔单抗的低谷水平最常见。没有观察到与其他两种抗TNF药物的交叉结合。通过固相和可溶性英夫利昔单抗的交叉结合通过固相RIA检测抗英夫利昔单抗抗体具有较低的灵敏度，且数据与Abs与可溶性英夫利昔单抗的结合结果不一致。
结论：在英夫利昔单抗治疗的RA患者中出现了特异性和中和的抗英夫利昔单抗抗体，并且功能性英夫利昔单抗的低谷水平与此类抗体的存在有关。最敏感的抗体测定涉及与可溶性和完整英夫利昔单抗的结合。抗TNF生物制剂的生物利用度和免疫原性的评估可用于优化剂量方案并防止长期使用不足的疗法。

BACKGROUND & AIMS: :Plant cells are ideal bioreactors for the production and oral delivery of vaccines and biopharmaceuticals, eliminating the need for expensive fermentation, purification, cold storage, transportation and sterile delivery. Plant-made vaccines have been developed for two decades but none has advanced beyond Phase I. However, two plant-made biopharmaceuticals are now advancing through Phase II and Phase III human clinical trials. In this review, we evaluate the advantages and disadvantages of different plant expression systems (stable nuclear and chloroplast or transient viral) and their current limitations or challenges. We provide suggestions for advancing this valuable concept for clinical applications and conclude that greater research emphasis is needed on large-scale production, purification, functional characterization, oral delivery and preclinical evaluation.

背景与目标： 植物细胞是用于生产和口服递送疫苗和生物制药的理想生物反应器，无需昂贵的发酵，纯化，冷藏，运输和无菌递送。植物疫苗已经开发了二十年，但没有一个疫苗已经超过了I期。但是，目前有两种植物生物药物正在通过II期和III期人体临床试验。在这篇综述中，我们评估了不同植物表达系统（稳定的核和叶绿体或瞬时病毒）的优缺点及其当前的局限性或挑战。我们提供了一些建议，以推动这一有价值的概念在临床上的应用，并得出结论，需要在大规模生产，纯化，功能表征，口服给药和临床前评估方面给予更多的研究重点。

BACKGROUND & AIMS: :It was clear from the number of attendees and the broad spectrum of organizations represented at this conference, that effective formulation development for biopharmaceuticals is a critical and timely issue. From DNA-based products to antibodies, vaccines to therapeutics, administered by every route known to medicine, formulation plays a critical role in the ultimate success of biopharmaceutical products. It was obvious from the various case studies presented that effective formulation development is not often achieved as an organization enters into drug development. In fact, systematic pre-formulation work was stressed by most speakers as an effective use of company resources. In order to develop successful formulations, it is essential that appropriate analytical information is collected, that excipients are systematically evaluated, and that the developer understands the basis of stability of the drug product. In all cases, this means understanding product instability, including the physicochemical and thermodynamic basis for instability. Drugs such as therapeutic antibodies, which may require large doses to achieve the desired pharmacological effect, require ever more advanced formulation development to achieve concentrations in the 100-mg/ml range. Potent drugs, such as gene therapies and DNA vaccines, require formulation development in order to achieve effective delivery and expression. On aggregate, it is apparent that there is much to learn in formulation development, from each other as well as in the unexplored territory ahead. This conference provided an excellent forum for the exchange of ideas and information regarding effective formulation development for biopharmaceuticals.

背景与目标： ：从与会的人数和参加此次会议的众多组织中可以明显看出，有效开发生物制药制剂是一个关键而及时的问题。从基于DNA的产品到抗体，从疫苗到治疗剂，通过医学上已知的每种途径进行给药，制剂在生物制药产品的最终成功中都起着至关重要的作用。从提出的各种案例研究中可以明显看出，随着组织参与药物开发，往往无法实现有效的制剂开发。实际上，大多数发言者都强调系统化的预制定工作是对公司资源的有效利用。为了开发成功的制剂，必须收集适当的分析信息，对赋形剂进行系统评估，并且开发人员必须了解药品稳定性的基础，这一点至关重要。在所有情况下，这都意味着要了解产品的不稳定性，包括不稳定性的物理化学和热力学基础。可能需要大剂量才能达到所需药理作用的药物（例如治疗性抗体），需要开发更先进的制剂才能达到100 mg / ml的浓度。强有力的药物，例如基因疗法和DNA疫苗，需要开发配方才能实现有效的传递和表达。总体而言，很明显，在配方开发方面，彼此之间以及在未来的未开发领域中，还有很多值得学习的东西。这次会议为交流有关生物药物有效制剂开发的思想和信息提供了一个极好的论坛。

BACKGROUND & AIMS: :This Special issue, Biopharmaceuticals - discovery, development and manufacturing is edited by Alois Jungbauer and Klaus Graumann and includes articles on various aspects of the development of biopharmaceuticals. Topics covered include the importance of antigen presentation in creating and selecting binding molecules, G-protein-coupled receptors as drug targets, and continuous downstream processing.

背景与目标： ：本期特刊《生物制药-发现，开发和制造》由Alois Jungbauer和Klaus Graumann编辑，其中包括有关生物制药开发各个方面的文章。涵盖的主题包括抗原呈递在创建和选择结合分子，G蛋白偶联受体作为药物靶标以及持续下游加工中的重要性。

BACKGROUND & AIMS: :Biopharmaceuticals (BPs) represent a rapidly growing class of approved and investigational drug therapies that is contributing significantly to advancing treatment in multiple disease areas, including inflammatory and autoimmune diseases, genetic deficiencies and cancer. Unfortunately, unwanted immunogenic responses to BPs, in particular those affecting clinical safety or efficacy, remain among the most common negative effects associated with this important class of drugs. To manage and reduce risk of unwanted immunogenicity, diverse communities of clinicians, pharmaceutical industry and academic scientists are involved in: interpretation and management of clinical and biological outcomes of BP immunogenicity, improvement of methods for describing, predicting and mitigating immunogenicity risk and elucidation of underlying causes. Collaboration and alignment of efforts across these communities is made difficult due to lack of agreement on concepts, practices and standardized terms and definitions related to immunogenicity. The Innovative Medicines Initiative (IMI; www.imi-europe.org), ABIRISK consortium [Anti-Biopharmaceutical (BP) Immunization Prediction and Clinical Relevance to Reduce the Risk; www.abirisk.eu] was formed by leading clinicians, academic scientists and EFPIA (European Federation of Pharmaceutical Industries and Associations) members to elucidate underlying causes, improve methods for immunogenicity prediction and mitigation and establish common definitions around terms and concepts related to immunogenicity. These efforts are expected to facilitate broader collaborations and lead to new guidelines for managing immunogenicity. To support alignment, an overview of concepts behind the set of key terms and definitions adopted to date by ABIRISK is provided herein along with a link to access and download the ABIRISK terms and definitions and provide comments (http://www.abirisk.eu/index_t_and_d.asp).

背景与目标： 生物药物（BPs）代表了快速增长的一类经过批准和研究的药物疗法，为促进多种疾病领域的治疗做出了重要贡献，包括炎性和自身免疫性疾病，遗传缺陷和癌症。不幸的是，对BP的有害的免疫原性应答，尤其是那些影响临床安全性或功效的免疫原性应答，仍然是与这一重要药物类别相关的最常见的负面作用。为了管理和减少不良免疫原性的风险，临床医生，制药行业和学术界科学家参与了以下工作：解释和管理BP免疫原性的临床和生物学结果，改进描述，预测和减轻免疫原性风险的方法以及阐明潜在的免疫原性。原因。由于缺乏对与免疫原性有关的概念，实践以及标准化术语和定义的共识，使得跨这些社区的工作难以进行协作和统一。创新药物倡议（IMI； www.imi-europe.org），ABIRISK联盟[抗生物制药（BP）免疫预测和降低临床风险的临床意义； www.abirisk.eu]由领先的临床医生，学术科学家和EFPIA（欧洲制药工业和协会联合会）成员组成，旨在阐明根本原因，改进免疫原性预测和缓解方法，并围绕与免疫原性相关的术语和概念建立通用定义。预计这些努力将促进更广泛的合作，并为管理免疫原性带来新的指导方针。为了支持一致性，此处提供了ABIRISK迄今为止采用的一组关键术语和定义背后的概念概述，以及访问和下载ABIRISK术语和定义并提供注释的链接（http://www.abirisk.eu /index_t_and_d.asp）。

BACKGROUND & AIMS: BACKGROUND:The COVID-19 pandemic had infected more than 3.5M people around the world and more than 250K people died in 187 countries by May 2020. The causal agent of this disease is a coronavirus whose onset of symptoms to death range from 6 to 41 days with a median of 14 days. This period is dependent on several factors such as the presence of comorbidities, age and the efficiency of the innate or adaptive immune responses. The effectors mechanisms of both types of immune responses depend on the pathogen involved. In the case of a viral infection, the innate immune response may approach the harmful virus through pattern recognition receptors inducing an antiviral state. On the other hand, the adaptive immune response activates antibody production to neutralize or eliminate the virus. Phenolics are plant secondary metabolites with many biological activities for plants and humans against infection. Chemical modification of proteins may enhance their biological properties; thus, a protein of medical interest, for instance, a viral protein can be used as scaffold to build a biopharmaceutical conjugated or complexated with phenolics exhibiting structural complexity or biological activities to achieve effective phenolic-protein-based therapeutics like vaccine adjuvant complexes, immunogen conjugates, and antiviral conjugates. CONCLUSION:Pharmaceutical biotechnology applies the principles of biotechnology to develop biopharmaceuticals for protein-based therapeutics; such as adjuvants, recombinant proteins, monoclonal antibodies, and antivirals. As neither a vaccine nor a treatment for COVID-19 is currently available, this manuscript focuses on insights from pharmaceutical biotechnology into phenolic biopharmaceuticals against COVID-19.

背景与目标： 背景：到2020年5月，COVID-19大流行已感染了全球超过350万人，并在187个国家中超过25万人死亡。该病的病因是冠状病毒，其症状发作至死亡的范围为6至41。天，中位数为14天。这个时期取决于多种因素，例如合并症的存在，年龄以及先天性或适应性免疫反应的效率。两种类型的免疫反应的效应子机制均取决于所涉及的病原体。在病毒感染的情况下，先天的免疫反应可能通过诱导抗病毒状态的模式识别受体接近有害病毒。另一方面，适应性免疫应答激活抗体产生以中和或消除病毒。酚类物质是植物的次生代谢产物，对植物和人类具有抵抗感染的许多生物学活性。蛋白质的化学修饰可以增强其生物学特性；因此，医学上感兴趣的蛋白质，例如病毒蛋白质可以用作支架，以构建与酚类化合物结合或复合的生物药物，所述酚类化合物表现出结构复杂性或生物学活性，以实现有效的基于酚类蛋白质的疗法，如疫苗佐剂复合物，免疫原结合物和抗病毒偶联物。
结论：药物生物技术应用生物技术原理开发基于蛋白质的治疗药物。例如佐剂，重组蛋白，单克隆抗体和抗病毒药。由于目前尚无针对COVID-19的疫苗或治疗方法，因此该手稿着重介绍了从药物生物技术到针对COVID-19的酚类生物药物的见解。

BACKGROUND & AIMS: :Although toxicology studies should always be conducted in pharmacologically relevant species, the specificity of many biopharmaceuticals can present challenges in identification of a relevant species. In certain cases, that is, when the clinical product is active only in humans or chimpanzees, or if the clinical candidate is active in other species but immunogenicity limits the ability to conduct a thorough safety assessment, alternative approaches to evaluating the safety of a biopharmaceutical must be considered. Alternative approaches, including animal models of disease, genetically modified mice, or use of surrogate molecules, may improve the predictive value of preclinical safety assessments of species-specific biopharmaceuticals, although many caveats associated with these models must be considered. Because of the many caveats that are discussed in this article, alternative approaches should only be used to evaluate safety when the clinical candidate cannot be readily tested in at least one relevant species to identify potential hazards.

背景与目标： ：尽管毒理学研究应始终在药理学上相关的物种中进行，但许多生物药物的特异性可能会给鉴定相关物种带来挑战。在某些情况下，即当临床产品仅在人类或黑猩猩中具有活性，或者如果临床候选者在其他物种中具有活性，但是免疫原性限制了进行彻底安全性评估的能力，则可以使用替代方法来评估生物药品的安全性必须考虑。替代方法，包括疾病的动物模型，转基因小鼠或替代分子的使用，可以提高对物种特异性生物药物进行临床前安全性评估的预测价值，尽管必须考虑与这些模型相关的许多警告。由于本文讨论了许多警告，因此仅当无法在至少一个相关物种中对临床候选者进行便捷测试以识别潜在危害时，才应使用替代方法来评估安全性。

BACKGROUND & AIMS: :Despite the wide occurrence of crystallization in the pharmaceutical industry, deep understanding and fine control of the process remain a tricky issue. Nevertheless, the successful manufacturing of finished pharmaceutical products, as well as the structural determination of biopharmaceuticals, depend on the size, form, shape and purity of the crystals. The ability of substrates with precise chemistry and topological features to induce nucleation has been thoroughly assessed during the recent years. This paper reviews the major advances and discoveries in controlling small molecule drug and protein crystallization by means of engineered surfaces. By designing superficial properties and morphology, it has been possible to tune the polymorph outcome, shorten the nucleation induction time, impose specific crystal shapes, control the crystal size and carry out crystallization at very low supersaturation levels. Such achievements underline the potential of surface-induced crystallization to provide an ideal platform for the study of the nucleation process and gain control over its stochastic nature.

背景与目标： ：尽管在制药行业中发生了广泛的结晶，但是对过程的深入了解和精细控制仍然是一个棘手的问题。然而，成品药品的成功生产以及生物药品的结构确定取决于晶体的大小，形式，形状和纯度。近年来，已经对具有精确化学和拓扑特征的底物诱导成核的能力进行了全面评估。本文综述了通过工程表面控制小分子药物和蛋白质结晶的主要进展和发现。通过设计表面性质和形态，可以调节多晶型物的结果，缩短成核诱导时间，施加特定的晶体形状，控制晶体尺寸并以非常低的过饱和水平进行结晶。这些成就强调了表面诱导结晶的潜力，为研究成核过程和获得对其随机性的控制提供了理想的平台。

BACKGROUND & AIMS: :PEGylation (the covalent binding of one or more polyethylene glycol molecules to another molecule) is a technology frequently used to improve the half-life and other pharmaceutical or pharmacological properties of proteins, peptides, and aptamers. To date, 11 PEGylated biopharmaceuticals have been approved and there is indication that many more are in nonclinical or clinical development. Adverse effects seen with those in toxicology studies are mostly related to the active part of the drug molecule and not to polyethylene glycol (PEG). In 5 of the 11 approved and 10 of the 17 PEGylated biopharmaceuticals in a 2013 industry survey presented here, cellular vacuolation is histologically observed in toxicology studies in certain organs and tissues. No other effects attributed to PEG alone have been reported. Importantly, vacuolation, which occurs mainly in phagocytes, has not been linked with changes in organ function in these toxicology studies. This article was authored through collaborative efforts of industry toxicologists/nonclinical scientists to address the nonclinical safety of large PEG molecules (>10 kilo Dalton) in PEGylated biopharmaceuticals. The impact of the PEG molecule on overall nonclinical safety assessments of PEGylated biopharmaceuticals is discussed, and toxicological information from a 2013 industry survey on PEGylated biopharmaceuticals under development is summarized. Results will contribute to the database of toxicological information publicly available for PEG and PEGylated biopharmaceuticals.

背景与目标： PEG化（一种或多种聚乙二醇分子与另一种分子的共价结合）是一种经常用于改善蛋白质，肽和适体的半衰期以及其他药物或药理特性的技术。迄今为止，已经批准了11种PEG化生物药物，并且有迹象表明，还有更多的药物正在非临床或临床研究中。在毒理学研究中看到的不良反应主要与药物分子的活性部分有关，与聚乙二醇（PEG）无关。在此处呈现的2013年行业调查中，在11种已批准的11种PEG化生物药物中有5种在17种药物中，有10种在组织学上在某些器官和组织的毒理学研究中观察到了细胞空泡化。尚无单独归因于PEG的其他影响的报道。重要的是，在这些毒理学研究中，主要发生在吞噬细胞中的空泡化与器官功能的变化没有联系。本文是通过行业毒理学家/非临床科学家的共同努力撰写的，旨在解决PEG化生物药物中大PEG分子（> 10千道尔顿）的非临床安全性的问题。讨论了PEG分子对PEG化生物药品的整体非临床安全性评估的影响，并总结了2013年有关正在开发的PEG化生物药品行业调查的毒理学信息。结果将有助于公开可用于PEG和PEG化生物制药的毒理学信息数据库。

BACKGROUND & AIMS: :Subcutaneous (SC) injection is becoming a more common route for the administration of biopharmaceuticals. Currently, there is no reliable in vitro method that can be used to anticipate the in vivo performance of a biopharmaceutical formulation intended for SC injection. Nor is there an animal model that can predict in vivo outcomes such as bioavailability in humans. We address this unmet need by the development of a novel in vitro system, termed Scissor (Subcutaneous Injection Site Simulator). The system models environmental changes that a biopharmaceutical could experience as it transitions from conditions of a drug product formulation to the homeostatic state of the hypodermis following SC injection. Scissor uses a dialysis-based injection chamber, which can incorporate various concentrations and combinations of acellular extracellular matrix (ECM) components that may affect the release of a biopharmaceutical from the SC injection site. This chamber is immersed in a container of a bicarbonate-based physiological buffer that mimics the SC injection site and the infinite sink of the body. Such an arrangement allows for real-time monitoring of the biopharmaceutical within the injection chamber, and can be used to characterize physicochemical changes of the drug and its interactions with ECM components. Movement of a biopharmaceutical from the injection chamber to the infinite sink compartment simulates the drug migration from the injection site and uptake by the blood and/or lymph capillaries. Here, we present an initial evaluation of the Scissor system using the ECM element hyaluronic acid and test formulations of insulin and four different monoclonal antibodies. Our findings suggest that Scissor can provide a tractable method to examine the potential fate of a biopharmaceutical formulation after its SC injection in humans and that this approach may provide a reliable and representative alternative to animal testing for the initial screening of SC formulations.

背景与目标： ：皮下（SC）注射正在成为生物药物给药的一种更为普遍的途径。当前，没有可靠的体外方法可用于预期用于SC注射的生物药物制剂的体内性能。也没有一种动物模型可以预测体内的结果，例如人类的生物利用度。我们通过开发称为Scissor（皮下注射部位模拟器）的新型体外系统来满足这一未满足的需求。该系统对生物药物在从SC注射后从药物制剂的状态转变为皮下组织的稳态状态时可能经历的环境变化进行建模。 Scissor使用基于透析的注射腔室，该腔室可以合并各种浓度和脱细胞细胞外基质（ECM）成分的组合，这些成分可能会影响生物药物从SC注射部位的释放。该腔室浸入一个基于碳酸氢盐的生理缓冲液的容器中，该缓冲液模仿了SC注射部位和身体的无限深处。这样的布置允许对注射室内的生物药物进行实时监控，并且可以用于表征药物的物理化学变化及其与ECM成分的相互作用。生物药物从注射室向无限的水槽隔室的运动模拟了药物从注射部位的迁移以及血液和/或淋巴毛细血管的吸收。在这里，我们介绍了使用ECM元素透明质酸和胰岛素以及四种不同单克隆抗体的测试制剂对Scissor系统的初步评估。我们的发现表明，剪刀式剪可提供一种易于处理的方法来检查生物药物制剂在人体中的SC注射后的命运，并且这种方法可为动物试验中SC制剂的初步筛选提供可靠且有代表性的替代方法。

BACKGROUND & AIMS: :The freezing step plays a central role in reaching the most stringent requirements of quality, homogeneity and standardization of freeze-dried products. In this paper, a systematic procedure has been proposed to obtain a quantitative estimation of the pore-size variability of lyophilized products resulting from uncontrollable variations of the nucleation temperature. This procedure consisted in collecting the nucleation temperature from a statistically significant number of samples and correlating each nucleation temperature to the corresponding product morphology, using a mathematical model, to obtain a statistical description of the lyophilized product structure. This approach can also be used to obtain an estimation of the variability of the mass transfer resistance to vapor flow and, finally, of the drying time. Two different freezing configurations, i.e., conventional and suspended-vial freezing, have been used as case studies since they can produce significantly different freezing rates.

背景与目标： ：冷冻步骤在达到冷冻干燥产品的质量，均质性和标准化最严格的要求中起着核心作用。在本文中，已经提出了一种系统的程序来获得对由于成核温度的不可控制的变化而导致的冻干产品的孔径变化的定量估计。该程序包括从统计学上大量的样品中收集成核温度，并使用数学模型将每个成核温度与相应的产品形态相关联，以获得冻干产品结构的统计描述。该方法也可以用于获得传质阻力对蒸气流的变化以及最终的干燥时间的变化的估计。案例研究使用了两种不同的冷冻配置，即常规冷冻和小瓶冷冻，因为它们可以产生明显不同的冷冻速率。

BACKGROUND & AIMS: :Antiphospholipid syndrome (APS) is an autoimmune disease that is characterized by arterial and/or venous thrombosis and/or recurrent pregnancy losses. Obstetric APS (OAPS) is considered as a distinct entity from vascular APS (VAPS). In the absence of any additional disease, APS is designated as primary (PAPS), while the term secondary APS (SAPS) is used when other diseases are associated. Catastrophic APS (CAPS) is characterized by the rapid development of multiple thrombosis in various vital organs. The presence of antiphospholipid antibodies (aPL Abs) is considered as a laboratory criterion for APS diagnosis. aPL Abs cause an increase in systemic and decidual TNF-alpha levels in experimental model of APS (eAPS), while paradoxically, administration of TNF-alpha blockers has been associated with de novo synthesis of aPL Abs in patients with various autoimmune diseases. While eAPS provides evidence for the fact that application of TNF-alpha blockers has beneficial effects, lack of randomized prospective studies is the main obstacle for consideration of TNF-alpha blockers administration as a therapeutic option not for all, but at least for selected cases of APS patients despite compelling evidence for detrimental roles of TNF-alpha for both VASP and OAPS. This article represents a review of previously published reports on detrimental roles of TNF-alpha in APS, reports on the application of anti-TNF-alpha agents in eAPS and articles that reported de novo synthesis of aPL Abs induced by biopharmaceuticals against TNF-alpha.

背景与目标： ：抗磷脂综合症（APS）是一种自身免疫性疾病，其特征是动脉和/或静脉血栓形成和/或反复流产。产科APS（OAPS）被认为是与血管APS（VAPS）不同的实体。在没有任何其他疾病的情况下，将APS称为原发性（PAPS），而在与其他疾病相关的情况下使用术语继发性APS（SAPS）。灾难性APS（CAPS）的特征在于各种重要器官中多发性血栓形成的快速发展。抗磷脂抗体（aPL Abs）的存在被认为是诊断APS的实验室标准。在APS（eAPS）实验模型中，aPL Abs导致全身和蜕膜TNF-α水平增加，而自相矛盾的是，在患有各种自身免疫性疾病的患者中，TNF-α阻滞剂的给药与aPL Abs的从头合成有关。尽管eAPS为使用TNF-α阻滞剂产生有益作用这一事实提供了证据，但缺乏随机的前瞻性研究是考虑将TNF-α阻滞剂作为治疗选择的主要障碍，但并非对所有患者（至少对于某些病例）尽管有令人信服的证据表明APS患者对VASP和OAPS都具有TNF-α的有害作用。本文代表对先前发表的有关TNF-α在APS中的有害作用的报道的综述，有关抗TNF-α药剂在eAPS中的应用的报道，以及报道了由生物药物诱导的针对TNF-α的aPL Ab的从头合成的文章。

BACKGROUND & AIMS: :The market of therapeutic glycoproteins (including coagulation factors, antibodies, cytokines and hormones) is one of the profitable, fast-growing and challenging sectors of the biopharmaceutical industry. Although mammalian cell culture is still expensive and technically complex, the ability to produce desired post-translational modifications, in particular glycosylation, is a major issue. Glycans can influence ligand binding, serum half-life as well as biological activity or product immunogenicity. Aiming to establish a novel production platform for recombinant glycoproteins, the human TE671 cell line was investigated. Since the initial analysis of cell membrane proteins showed a promising glycosylation of TE671 cells for biotechnological purposes, we focused on the recombinant expression of two model glycoproteins of therapeutical relevance. The optimization of the cell transfection procedure and serum-free expression succeeded for the human serine protease inhibitor alpha-1-antitrypsin (A1AT) and the hematopoietic cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF). N-glycan analyses of both purified proteins by matrix-assisted laser desorption/ionization time-of-flight (MALDI-TOF) mass spectrometry provided first fundamental insights into the TE671 glycosylation potential. Besides protein specific pattern, strong distinctions - in particular for N-glycan fucosylation and sialylation - were observed depending on the medium conditions of the respective TE671 cell cultivations. The cell line's ability to synthesize complex and highly sialylated N-glycan structures has been shown. Our results demonstrate the TE671 cell line as a serious alternative to other existing human expression systems.

背景与目标： ：治疗性糖蛋白（包括凝血因子，抗体，细胞因子和激素）市场是生物制药行业中盈利，快速增长且充满挑战的行业之一。尽管哺乳动物细胞培养仍然昂贵并且技术上复杂，但是产生期望的翻译后修饰，特别是糖基化的能力是主要问题。聚糖可影响配体结合，血清半衰期以及生物学活性或产物免疫原性。为了建立重组糖蛋白的新型生产平台，研究了人TE671细胞系。由于对细胞膜蛋白的初步分析显示，出于生物技术目的，TE671细胞有希望的糖基化作用，因此我们集中于两种具有治疗意义的模型糖蛋白的重组表达。人丝氨酸蛋白酶抑制剂α-1-抗胰蛋白酶（A1AT）和造血细胞因子粒细胞巨噬细胞集落刺激因子（GM-CSF）的细胞转染程序和无血清表达的优化成功。通过基质辅助激光解吸/电离飞行时间（MALDI-TOF）质谱对两种纯化蛋白进行N-聚糖分析，为了解TE671糖基化潜力提供了基础知识。除了蛋白质特异的模式，还根据各自的TE671细胞培养的培养基条件，观察到了很强的区别-特别是N-聚糖岩藻糖基化和唾液酸化。已经显示出细胞系合成复杂和高度唾液酸化的N-聚糖结构的能力。我们的结果证明TE671细胞系可作为其他现有人类表达系统的替代品。