我国生物医药企业发展建议

近年来,国外生物医药产业发展迅速,在发达国家,生物医药产品在药品市场中已占有了重要地位,哺乳动物细胞表达的产品已经占据生物医药的主流地位。相比之下,我国生物医药品种主要采用简单的大肠杆菌、酵母表达技术,技术难度较高的哺乳动物细胞药品与国外差距显著,因此,哺乳动物表达的生物药品将成为国内生物医药企业的重要发展机会。多年来,鉴于我国从发达国家获得生物技术转让少,国内生物医药发展需立足于自主研发,建立高效的研发技术平台,选择合适的开发项目,促进企业的发展。     

海洋生物制药现状及展望

现代生物技术在制药产业中发挥了重要作用,海洋生物技术的出现和发展推动了海洋生 物药物的研究,是今后生物技术药物的发展方向。综述了生物技术在海洋药物开发中的应用,并 展望了新世纪海洋生物制药的前景。     

美国、欧盟和中国生物技术药物的比较

按照相同表达系统表达的相同氨基酸序列的产品视为同种产品,而不同表达系统表达的相同氨基酸序列的产品视为不同产品的原则,归纳总结了美国、欧盟和中国已批准上市的生物技术药物。美国FDA批准的以基因工程产品、抗体工程产品和细胞工程产品为主要代表的生物技术药物共79种(18种为大肠杆菌表达,8种为酵母表达,53种为哺乳动物细胞培养生产),其中基因重组蛋白质药物为64种。欧盟批准了49种基因重组酶、激素或细胞因子,11种基因重组治疗性抗体和5种基因重组疫苗。在欧美60％-70％的产品由哺乳动物细胞表达。中国批准了27种生物技术药物。比较了美国、欧盟和中国生物制药的特点。     

2014 年热门生物技术公司的研发动态

FierceBiotech 网站报道了2014 年最热门的16 家生物技术公司,其涉足生物制药、体外诊断以及医疗器械研发等热门医疗领域,其中多家公司与包括葛兰素史克、罗氏、拜耳、默克等公司在内的制药巨头展开合作,值得医疗行业的投资者关注。对这16 家热门生物技术公司的研发重点、主打产品的适应证/ 用途、合作伙伴、并购交易信息进行归纳总结,旨在为新一代生物技术药物的深入研发提供参考。     

全球生物制药产业发展态势

传统化学制药的黄金时代结束,新化学药品数量下降,而生物技术药物已成为当今最活跃和发展最迅速的领域。随着基因组和蛋白质组研究的深入,越来越多与人类疾病发展相关的靶标被确定,生物制药将有更多的机会获得突破性进展。综述了全球生物制药产业发展的几个态势,主要有：（1）全球生物制药产业的研究成果数量增长迅速;（2）生物制药依然是生物技术产业的重点领域,生物技术药物市场发展规模逐渐扩大,市场集中度高,主要集中于美国和大的跨国公司;（3）生物技术新药在新药研发中的比重越来越大,逐渐成为新药研发主流;（4）生物制药企业间通过加强联盟,来增强新药研发能力和降低新药研发成本;（5）各国政府均重视生物制药产业的发展,出台一系列相关政策。（6）生物疫苗、基因工程药物和基因药物具有良好的市场前景。     

Biopharmaceuticals in China

The biopharmaceutical industry, whose products are produced mainly by recombinant DNA technology, antibody technologies and cytotechnology, is the most important sector in industrial biotechnology, and is one of the most rapidly growing high-tech industries. The global market for biopharmaceuticals had been growing at annual growth rates of 15-33% over the last 8 years, and sales exceeded 55 billion dollars in 2005. This review presents an overview of the Chinese biopharmaceutical industry, listing the global top-selling biopharmaceuticals in 2005, and briefly describes the major biotech drugs approved by the Chinese State Food and Drug Administration, such as recombinant cytokines, therapeutic antibodies, recombinant vaccines, and gene therapy products.     

生物制药的现状和未来（二）：发展趋势与希望

随着基因组和蛋白质组研究的深入,越来越多的与人类疾病发展相关的靶标被确定,使得我们能够研发更精确的药物来防治这些疾病。这意味着生物制药将有更多机会获得突破性进展,最终将使更多更好的生物技术药物被批准上市。综述了生物制药发展的几个趋势,主要有:(1)哺乳动物细胞表达的产品将在相当长的时间内占统治地位;(2)治疗性抗体将会是生物制药领域第二次创新高潮;(3)越来越多分子量大、结构复杂的功能蛋白将被开发成生物技术药物,尤其是用于治疗遗传性疾病的药物;(4)对已批准上市的生物技术药物的化学修饰尤其是PEG化以改善药物性能;(5)通过某些药物的定点突变获得第二代新生物技术药物,如胰岛素、EPO和t-PA的突变体;(6)组织工程、细胞治疗和基因治疗充满了机遇和挑战。     

Transgenic plants as factories for biopharmaceuticals

Plants have considerable potential for the production of biopharmaceutical proteins and peptides because they are easily transformed and provide a cheap source of protein. Several biotechnology companies are now actively developing, field testing, and patenting plant expression systems, while clinical trials are proceeding on the first biopharmaceuticals derived from them. One transgenic plant-derived biopharmaceutical, hirudin, is now being commercially produced in Canada for the first time. Product purification is potentially an expensive process, and various methods are currently being developed to overcome this problem, including oleosin-fusion technology, which allows extraction with oil bodies. In some cases, delivery of a biopharmaceutical product by direct ingestion of the modified plant potentially removes the need for purification. Such biopharmaceuticals and edible vaccines can be stored and distributed as seeds, tubers, or fruits, making immunization programs in developing countries cheaper and potentially easier to administer. Some of the most expensive biopharmaceuticals of restricted availability, such as glucocerebrosidase, could become much cheaper and more plentiful through production in transgenic plants.     

Biotech in Russia

Cover illustration: Matryoshkas (Russian wooden nesting dolls). This special issue on “Biotech in Russia” is edited by Prof. Mikhail Rabinovich. It features Reviews and Research Articles on state of the art biotech research and biopharmaceutical economy. Image © Sigrid Mehren     

The cost-effectiveness of biopharmaceuticals: A look at the evidence

Due to the increasing availability and costs of biopharmaceuticals, policymakers are questioning whether they provide good value relative to other health interventions and many are increasingly relying on cost-utility analyses (CUAs) to supplement decision-making. Analyzing data from the Tufts Medical Center Cost-Effectiveness Analysis Registry, this study critically reviewed the cost-utility literature for biopharmaceuticals and compared their value to other health interventions. Of 2,383 studies in the registry through 2009, biopharmaceutical CUAs comprised the sixth largest category of interventions at 11%. Characteristics of biopharmaceutical articles were similar to other CUAs; however, they displayed slightly better quality. The median cost-effectiveness ratio of biopharmaceuticals was less favorable (i.e., higher) than other interventions, though many seem to provide value for money. A logistic regression showed that among biopharmaceuticals the cost-effectiveness of industry-sponsored studies and products that treat infectious diseases were significantly more likely to be favorable (less than the overall median), while cancer and neurological treatments were significantly less likely.Key words: biopharmaceuticals, cost-effectiveness, cost-utility analysis, value for money, quality adjusted life-year, economic analysis     

Cell‐specific biomarkers and targeted biopharmaceuticals for breast cancer treatment

Breast cancer is the second leading cause of cancer death among women, and its related treatment has been attracting significant attention over the past decades. Among the various treatments, targeted therapy has shown great promise as a precision treatment, by binding to cancer cell‐specific biomarkers. So far, great achievements have been made in targeted therapy of breast cancer. In this review, we first discuss cell‐specific biomarkers, which are not only useful for classification of breast cancer subtyping but also can be utilized as goals for targeted therapy. Then, the innovative and generic‐targeted biopharmaceuticals for breast cancer, including monoclonal antibodies, non‐antibody proteins and small molecule drugs, are reviewed. Finally, we provide our outlook on future developments of biopharmaceuticals, and provide solutions to problems in this field.     

Production of recombinant proteins in serum-free media

The advantages of serum-free culture for the manufacture of recombinant biopharmaceuticals from mammalian cells are reviewed. The process favoured is fed-batch serum-free cell culture. This process is applicable to the majority of cell lines, is practical on the large scale, gives the lowest manufacturing cost, and can b e carried out without the use of any serum.The advantages of serum-free culture for the manufacture of recombinant biopharmaceuticals from mammalian cells are reviewed. The process favoured is fed-batch serum-free cell culture. This process is applicable to the majority of cell lines, is practical on the large scale, gives the lowest manufacturing cost, and can be carried out without the use of any serum.     

Alternative non-antibody scaffolds for molecular recognition

Originally proposed one decade ago, the idea of engineering proteins outside the immunoglobulin family for novel binding functions has evolved as a powerful technology. Several classes of protein scaffolds proved to yield reagents with specificities and affinities in a range that was previously considered unique to antibodies. Such engineered protein scaffolds are usually obtained by designing a random library with mutagenesis focused at a loop region or at an otherwise permissible surface area and by selection of variants against a given target via phage display or related techniques. Whereas a plethora of protein scaffolds has meanwhile been proposed, only few of them were actually demonstrated to yield specificities towards different kinds of targets and to offer practical benefits such as robustness, smaller size, and ease of expression that justify their use as a true alternative to conventional antibodies or their recombinant fragments. Currently, the most promising scaffolds with broader applicability are protein A, the lipocalins, a fibronectin domain, an ankyrin consensus repeat domain, and thioredoxin. Corresponding binding proteins are not only of interest as research reagents or for separation in biotechnology but also as potential biopharmaceuticals, especially in the areas of cancer, autoimmune and infectious diseases as well as for in vivo diagnostics. The medical prospects have boosted high commercial expectations, and many of the promising scaffolds are under development by biotech start-up companies. Although some issues still have to be addressed, for example immunogenicity, effector functions, and plasma half-life in the context of therapeutic use or low-cost high-throughput selection for applications in proteomics research, it has become clear that scaffold-derived binding proteins will play an increasing role in biotechnology and medicine.     

Gene amplification and vector engineering to achieve rapid and high-level therapeutic protein production using the Dhfr-based CHO cell selection system

Demand is increasing for therapeutic biopharmaceuticals such as monoclonal antibodies. Achieving maximum production of these recombinant proteins under developmental time constraints has been a recent focus of study. The majority of these drugs are currently produced in altered Chinese hamster ovary (CHO) cells due to the high viability and the high densities achieved by these cells in suspension cultures. However, shortening the process of developing and isolating high-producing cell lines remains a challenge. This article focuses on current expression systems used to produce biopharmaceuticals in CHO cells and current methods being investigated to produce biopharmaceuticals more efficiently. The methods discussed include modified gene amplification methods, modifying vectors to improve expression of the therapeutic gene and improving the method of selecting for high-producing cells. Recent developments that use gene targeting as a method for increasing production are discussed.     

Considerations in assessing the developmental and reproductive toxicity potential of biopharmaceuticals

This report discusses the principles of developmental and reproductive toxicity (DART) testing for biopharmaceuticals. Biopharmaceuticals are large-molecular-weight proteins or peptides produced by modern biotechnology techniques incorporating genetic engineering and hybridoma technologies. The principles of DART testing for biopharmaceuticals are similar to those for small-molecule pharmaceuticals and in general follow the regulatory guidance outlined in International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) document S5(R2). However, because many biopharmaceuticals are species-specific, alternate approaches may be needed to evaluate DART potential as outlined in ICH S6. For molecules that show species-specific cross-reactivity restricted to non-human primates (NHP), some aspects of DART may require NHP testing. For biopharmaceuticals that are uniquely specific and only active on intended human targets or human and chimpanzee targets, surrogate molecules that cross-react with the more traditional rodent species may need to be developed and used for DART testing. Alternatively, genetically modified transgenic animals may also need to be considered. Surrogate molecules and transgenic animals may also be considered for DART testing even if the biopharmaceutical is active in NHPs in order to reduce the use of NHPs. Because of the unique properties of biopharmaceuticals, a case-by-case approach is needed for DART and general toxicity evaluation, which requires consideration of specific product attributes including biochemical and biophysical characteristics, pharmacological activity, and intended clinical indication. Birth Defects Res (Part B), 33:176–203, 2009. © 2009 Wiley-Liss, Inc.     

Oleosin fusion expression systems for the production of recombinant proteins

For the production of recombinant proteins, product purification is potentially difficult and expensive. Plant oleosins are capable of anchoring onto the surface of natural or artificial oil bodies. The oleosin fusion expression systems allow products to be extracted with oil bodies. In vivo, oleosin fusions are produced and directly localized to natural oil bodies in transgenic plant seeds. Via the oleosin fusion technology the thrombin inhibitor hirudin has been successfully produced and commercially used in Canada. In vitro, artificial oil bodies have been used as “carriers” for the recombinant proteins expressed in transformed microbes. In this article, plant oleosins, strategies and limitations of the oleosin fusion expression systems are summarized, alongside with progress and applications. The oleosin fusion expression systems reveal an available way to produce recombinant biopharmaceuticals at large scale.     

巴西农业生物技术年报

巴西是世界上第二大植物生物技术农作物生产国。预计在2011-2012年间种植生物技术农作物的面积将增加16%。种植面积的增加主要归因于巴西增加了生物技术玉米事件的审批,并为农民提供信贷补贴。本报告还提供了最新数据用以反映新的贸易信息和政府资源。     

Coexistence, North American style: regulation and litigation

Globally, biotech crops have left a legacy of success and some notable failures due to regulatory and litigious barriers to entry, with a pipeline of potentially beneficial biotech agricultural products lined up and awaiting approval. Compared with traditional agriculture, these crops provide significant health benefits to environmental and human health benefits, including organic systems. While the rest of the world has increased acreage of biotech crops at a steady annual rate of 10%, North America-the birthplace of most biotech crops-has reached a critical turning point in its regulatory evolution. Biotech crops can play a major role in creating a more sustainable agricultural landscape, which is increasingly well-documented, but future commercial use may be hampered by regulation and litigation that place organic and non-GMO agriculture on a pedestal, which could force many biotech crops into containment. If producers of biotech crops are required to prevent their crops from contaminating these other, high premium specialty crops through migration, innovation in agricultural biotechnology will suffer (as the European experience with agricultural biotechnology clearly demonstrates).     

Probable ways for spreading domestic chicken genes from Asia to Russia: analysis of the genogeographic studies of A.S. Serebrovskii

The unique material of A.S. Serebrovsky's gene-geographic studies, most of which is kept at the Archives of the Russian Academy of Sciences, was analyzed and summarized. A comparison of 58 populations of the domestic chicken was conducted. These populations were described by Serebrovsky and his coworkers in 23 regions of the former USSR from 1926 to 1933. On the dendrogram constructed on the basis of a comparison between the frequencies of 14 genes of the domestic chicken, three major clusters can be detected. Russian populations formed a separate cluster. Ukrainian populations clustered with some North-Caucasian populations. The Bashkir chicken populations were shown to be unique. A parallel change in frequencies of some gene pairs (termed by Serebrovsky "gene parallelism") was studied. As a result, three pathways for spreading domestic chickens from Asia to Russia were suggested: through Europe, the Caucasus, and Central Asia.