美国食品和药物管理局刚批准首个转基因动物表达的药 ATryn，人类终于有了第一个转基因动物生产的药物上市用于临床。该药品是从经过基因修饰奶山羊分泌出的羊奶中提取纯化，它是用于治疗一种被称为遗传性抗凝血酶缺乏症的疾病。

这种药物是由美国一家生物技术公司GTC Biotherapeutics ，这种药物的上市标志着转基因动物药物真正迈入产业化时代。记得20年前，笔者在做博士论文时，就看到当时这家美国生物技术公司类似试验获得成功的报道，当时觉得非常惊讶和兴奋，动物居然可以成为活的生物反应器，为人类生产昂贵的药物。

生物技术太神奇了

没想到从实验动物的初步成功到药物上市，走了二十多年漫长的路。这家公司就在离自己做论文的实验室10多英里处，后来还有同学去那家公司工作。公司是Genezye旗下的公司，为了分担风险和募集资金，母公司还特意剥离了这家公司单独在NASDAQ单独上市。

尽管后来这家公司花费巨大财力物力，不断取得工艺突破和临床研究进展，但公司的产品就是迟迟上不了市。因为全世界没有这种先例，用转基因动物来替代生物发酵和细胞培养的大工厂化生产生物药。正因为缺乏操作和审批指南，使得该产品的研制过程格外艰难曲折。

几个星期前，美国食品和药物管理局遗传工程动物制药相关问题发布了一套规章和报批指南。使得审批这类药物有章可循，有了明显的审批和操作的程序和方向，给转基因动物生产药物带来美好的前景。欧洲药监部门的专家本周刚逆转过去持否定态度，也开始推荐 ATryn药物的上市，看来GTC Biotherapeutics 在经历这么多年曲折，终于要扬眉吐气后，开始腾飞了。

纽约时报最近列举了几个正在开发中的通过转基因动物手段生产的药物：一家名为Pharming药业的公司正计划申请一种批准的药物，是在转基因兔的奶中表达和提取的，用于治疗某种遗传性蛋白质缺陷症；而另一家公司也在研制一种转基因山羊表达的药物，用于治疗神经毒气中毒的患者。

第一个转基因药物获准上市和FDA出台具体申报指南，这是生物技术产业的一大成就和里程碑式的突破，让科学界和转基因领域的研究者受到极大鼓舞。但不是所有人都欢迎这样的科学进步和成果转化。美国有不少民间组织和动物保护组织竭力反对转基因动物的商业化，他们不希望众生动物被遗传工程手段修饰后被用于商业化生产药物，有的干脆对动物用于生命科学研究都持反对意见。

但转基因动物生产药物实践的的支持者说，这种药物生产手段可稳定地供应某些重要或稀缺药物，可以更环保和经济地生产更便宜和更容易获得的药物。 不需要投资好多亿美元设立庞大的工厂，您需要生产多少药，你就培育多少转基因动物，通过动物奶分泌提取，省略了许多的废物和污染带来的麻烦，这种新型的制药方式很有前途。

Certainly, for the company as a whole, this is a tremendous validation.

THOMAS E. NEWBERRY,
GTC BIOTHERAPEUTICS VICE PRESIDENT OF CORPORATE COMMUNICATIONS

FDA批准世界首个转基因动物生产的药物ATryn®

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GTC Biotherapeutics ("GTC", NASDAQ: GTC and OVATION Pharmaceuticals, Inc. announced today that the U.S.
FoodandDrugAdministration (FDA) approved ATryn® (Antithrombin [Recombinant]) for the prevention of peri-operative and peri-partum thromboembolic events in hereditary antithrombin deficient patients.It is not indicated for treatment of thromboembolic events in hereditary antithrombin deficient patients. ATryn is the first ever transgenically produced therapeutic protein

and the first recombinant antithrombin approved in the U.S. Along with the approval of ATryn, the FDA's Center for Veterinary Medicine also approved GTC's New Animal Drug Application, the first of its kind to regulate genetically engineered animals.

This is now required for a recombinant technology used to develop transgenic animals, such as the goatsthatproducerecombinant antithrombin.

GTC has granted OVATION the right to market ATryn in the U.S. and pursue further clinical development. The companies expect ATryn to be available in the second quarter of 2009.

People with hereditary antithrombin deficiency are at increased risk for venous thromboembolic events, including pulmonary embolism and deep vein thrombosis, which can be life-threatening, particularly in high risk situations. Antithrombin is a natural anticoagulant that plays an important role in controlling the formation of blood clots.

Purifiedrecombinantantithrombin has the same amino acid sequence as antithrombin derived from human plasma.

The approval of ATryn marks a significant milestone in the development of this innovative recombinant technology and delivers a new therapeutic option to benefit hereditary antithrombin deficient patientswhoareundergoingsurgeryorchildbirthprocedures," said Geoffrey F. Cox, Ph.D., GTC's Chairman and Chief Executive Officer.

Advancing this novel technology from the early days of demonstrating its capability to the daily practice of producing a safe and efficacious product for the U.S. and the European Union, is a testament to the persistence and capabilityofouremployees."

ATryn was developed to provide a safe and consistent supply of recombinant antithrombin.

With FDA approval of ATryn, we can help ensure that patients with hereditary antithrombin deficiency, a rare clottingdisorder associated with severe complications, have access to much needed therapy," said Jeffrey S. Aronin, OVATION President andChief Executive Officer. "Bringing ATryn to market gives us the opportunity to make a meaningful difference in the lives of people with this rare disorder and is consistent with Ovation's mission of addressing unmet medical needsofsmallpatientpopulations."

The safety and efficacy of ATryn was established in clinical studies conducted in hereditary antithrombin deficient patients with a history of thromboembolic events in the U.S., Europe and Canada. During these studies, ATryn was shown to prevent the formation of clinically overt thromboembolic events. Post-marketing studies will be performed toassesssafetyandimmunogenicity after repeat dosing.

The prevalence of hereditary antithrombin deficiency in the general population is approximately one in 2,000 to one in 5,000. Half these patients may experience a thrombosis before 25 years of age and, based on a study, up to 85 percent may suffer a thromboembolic event by age 50.

About ATryn

ATryn is the first recombinant antithrombin product approved in the world and the first antithrombin product that has been approved through the centralized procedure in the European Union. It is now also the first recombinant antithrombin product approved by the FDA.

Important Safety Information

ATryn is contraindicated in patients with known hypersensitivity to goat and goat milk proteins. Allergictypehypersensitivity reactions, including anaphylaxis are possible. If these reactions occur during administration, treatment must be discontinued immediately and emergency treatment should be administered.

The anticoagulant effect of drugs that use antithrombin to exert their anticoagulation may be altered when ATryn is added or withdrawn. To avoid excessive or insufficient anticoagulation, coagulation tests suitable for the anticoagulant used (e.g., aPTT and anti-Factor Xa activity) are to be performed regularly, at close intervals, and in particular in the first hours following the start or withdrawal of ATryn. Additionally, patients must be monitored for the occurrenceofbleedingorthrombosis in such situations.

The serious adverse reaction that has been reported in clinical studies is hemorrhage (intra-abdominal, hemarthrosis and post procedural). The most common adverse events reported in clinical trials at a frequency of ? 5% are hemorrhage and infusion site reaction.

For more information including full prescribing information go to www.ovationpharma.com.

About Transgenic Production

The process for producing ATryn involves scientists inserting DNA for the human antithrombin protein into a single-celled goat embryo. This embryo is implanted into a surrogate doe. The resulting transgenic offspring are able to produce highlevels of antithrombin in their milk.

This protein is collected and purified from the milk to produce ATryn, which is administered to patients by intravenous infusion.

About GTC Biotherapeutics

GTC Biotherapeutics develops, supplies, and commercializes therapeutic proteins produced through transgenic animaltechnology. In addition to ATryn, GTC is developing a portfolio of recombinant human plasma proteins with known therapeutic properties.
These proteins include recombinant forms of human coagulation factors VIIa, VIII, and IX, which are being developed for the treatment of hemophilia, and alpha-1 antitrypsin.

GTC also has a monoclonal antibody portfolio that includes a monoclonal antibody to CD20 and a monoclonal antibody to CD137. GTC's intellectual property includes a patent in the United States through 2021 for the production of any therapeutic protein in the milk of any transgenic mammal. GTC's transgenic production platform is particularly well suitedtoenablingcosteffective development of proteins that are difficult to express in traditional recombinant production systemsaswellasproteins that are required in large volumes. Additional information is available on the GTC web site, www.gtc-bio.com .

This press release contains forward-looking statements as defined in the Private Securities Litigation Reform Act of 1995, including without limitation statements regarding the commercial launch of ATryn in the U.S. and the prospects for further clinical development of ATryn. Such forward-looking statements are subject to a number of risks, uncertainties and other factors that could cause actual results to differ materially from future results expressed or implied by such statements.
Factors that may cause such differences include, but are not limited to, the risks and uncertainties discussed in GTC's most recent Annual Report on Form 10-K and its other periodic reports filed with the Securities and Exchange Commission, including the uncertainties associated with dependence upon the actions of collaboration partners and regulatory agencies.

GTC cautions investors not to place undue reliance on the forward-looking statements contained in this release.

These statements speak only as of the date of this document, and GTC undertakes no obligation to updateorrevisethestatements, except as may be required by law.

About OVATION Pharmaceuticals

OVATION is a fast growing ***aceutical company that develops and commercializes medically necessary therapies to satisfyunmet medical needs for patients with severe illnesses. Headquartered in Deerfield, Ill., with products available in more than 85 countries, OVATION is committed to having a significant impact on patients' lives through its focus on centralnervous system (CNS), hematology/oncology, and hospital-based therapies. The company expects five new launches over the next three years, fueled largely by its late-stage CNS pipeline, which is one of the most robust in the industry. OVATION has been recognized for excellence in the global pharmaceutical and biotechnology industries with the 2006 and 2007 "Pharma Company of the Year" award from Scrip magazine for small to mid-sized enterprises. More information about the company, its products and full prescribing information may be found at www.ovationpharma.com .

欧洲药监部门专家组逆转先前决定，改为推荐批准ATryn上市

Reversal boosts ATryn prospects

European panel now recommends GTC anti-clotting drug’s surgical use

By Lisa Eckelbecker TELEGRAM & GAZETTE STAFF

leckelbecker@telegram.com

FRAMINGHAM — A European drug regulation committee reversed itself yesterday and recommended that a GTC Biotherapeutics Inc. anti-clotting drug drawn from the milk of genetically altered goats be approved for use in surgical patients.

The move clears away another hurdle for ATryn, a long labored-over drug that could become the world’s first human medicine produced in genetically engineered, or transgenic, animals. It also boosts GTC, which saw its stock tumble in February after European regulators said the company’s studies were insufficient to approve the drug.

Certainly, for the company as a whole, this is a tremendous validation,” said Thomas E. Newberry, vice president of corporate communications.

GTC stock, which trades under the symbol GTCB, nearly doubled in value yesterday, rising 83 cents, to $1.81, on the Nasdaq Stock Market.

ATryn’s key ingredient is recombinant human antithrombin, a blood protein that blocks one of the body’s clottingsubstances. GTC has developed goats that carry the human gene for antithrombin. Female goats with the gene produce the protein in their milk, and the protein can be extracted and purified for use in human treatments.

The company operates a farm in Charlton for genetically altered, or transgenic, goats.

Final approval to sell ATryn could come from the European Commission in about three months, according to GTC. The initial European market for ATryn would be surgical patients with an inherited antithrombin deficiency, a relatively small population that regulators estimate could total one in every 3,000 to 5,000 patients.

Yet ATryn could be a foot in the door for GTC as it seeks to widen the use of ATryn and the acceptance of transgenic medicines. GTC is working with LEO Pharma A/S to develop ATryn in Europe as a treatment for clotting in sepsis patients who have acquired an antithrombin deficiency, a market with an estimated 220,000 Europeans a year.

GTC is also conducting U.S. studies of ATryn in an effort to seek Food and Drug Administration approval in mid-2007.

Rodman & Renshaw analyst Navdeep S. Jaikaria, who yesterday raised his rating on GTC stock to “outperform,” told clients in a note that ATryn approval was “in fact a milestone achievement for GTCB. This is the first time ever that a transgenic goat product is approved for any indication, which serves to validate GTCB’s proprietary technology platform.”

In a written release issued yesterday in London, the European Medicines Agency Committee for Medicinal Products for Human Use said it had initially considered GTC’s patient studies too small. The studies contained information on five surgical patients and nine women in childbirth. At first, the committee disregarded the data from the pregnant women and told GTC it had not provided data on at least 12 patients, as required.

The European committee also questioned manufacturing changes that GTC made after the data had been collected.

GTC asked the committee to re-examine the data, and the committee convened a panel of European experts on blood and blood clotting. Yesterday, the committee reported that it concluded it could use the data from all the patients because all faced the risk of blood clotting, but it restricted the drug’s use to nonpregnant patients.

The committee also reported that manufacturing changes made by GTC were slight and that “the benefits of ATryn outweigh its risks.”

Regulators have been cautious about the use of animals to produce medicines, even as many researchers have devoted their careers to the field and companies have labored on limited funding to advance the technology, said Eric W. Overstrom, professor and head of the department of biology and biotechnology at Worcester Polytechnic Institute.

The whole concept of a bioreactor, an animal-based bioreactor, this will really push that forward now,” Mr. Overstrom said. “If they’re (GTC) the first ones in, then I think you’re going to see a rollout, a domino effect.”

News of GTC’s advance raised the price of at least one other transgenics company. Shares of Pharming Group NV of the Netherlands rose 15 percent, to 3.71 euros, in European trading.

GTC has long collaborated with corporate partners interested in exploring new production methods, such as Abbott Laboratories and Bristol-Myers Squibb. The company has also worked, with government backing, on a malaria vaccine that could be produced in goat milk.

An approval in Europe, however, could bolster GTC’s ability to raise money and attract partners. The company ended the first quarter of this year on April 2 with a net loss of $8.5 million, or 14 cents a share, and a cash cushion of $15.6 million.

Mr. Newberry of GTC said the European recommendation allows the company to look at a variety of new options.

“Clearly, with this sort of validation, ‘Great science, but can you do anything with it?’ is a long way to being answered,” he said.

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jinwsapa edited on 2009-02-07 11:32

三年内中国也有望推出首个转基因动物生产的药物

“借”转基因动物的乳腺，不花大钱，就能保质保量地生产人类稀缺的药用蛋白质，好比建了一座大型制药厂。各国科学家正铆足了劲推进这项临床试验。中国工程院院士、上海医学遗传研究所所长曾溢滔，两年前在上海举行的第九期院士讲坛上预测，中国首个转基因动物生产的药物有望在2011年左右上市。

制药成本大大降低

借助转基因动物生产药物，具有成本低、效益高、产量高、无公害等优点，可大大降低制药成本和投资风险。有人算过，若用其他工艺生产1克药用蛋白质，成本需800～5000美元，而利用转基因动物只需0.02～0.5美元。以防治A型血友病的凝血因子Ⅷ为例，美国目前的需求总量是120克，如从血浆中提取，需要120万升血浆，由1200万人次捐血；而由转基因动物“代劳”，只需1.2头转基因牛就够了。

在转基因动物体内建“药厂”，乳腺是最佳“厂址”。因为乳汁不会进入体内循环，不会影响转基因动物本身的新陈代谢；而且，从乳汁中提取蛋白，产量高、生物活性稳定。

新药研发时间缩短

同时，转基因动物也可促使药物开发成倍“提速”。目前，一种新药从研制开发、通过药审直到上市，约需10～15年的周期；用转基因动物生产药物，周期仅5年左右。荷兰PHP公司用转基因牛生产具有抗菌作用的乳铁蛋白，预计每年从牛奶生产出的营养奶粉的销售额是50亿美元。英国罗斯林研究所研制成功的转基因羊的乳汁中含有可治疗肺气肿病的a[,1]——抗胰蛋白酶，这种羊奶每升可售6000美元，1头转基因小羊可售30万美元。

我国正在临床试验

据曾院士介绍，我国目前已有乳铁蛋白、白蛋白、凝血因子等进入临床试验阶段，新药有望在“十一五”期间上市。究竟哪种转基因药物率先上市，还得由临床疗效说了算。在上海奉贤的奉新动物实验场，转基因羊的乳汁中已有了治疗B型血友病的凝血因子Ⅸ，研究工作正在展开。

按照转基因动物经典技术路线，药物蛋白基因先被显微注射入供体动物受精卵，再通过移植进入受体动物输卵管。转基因动物幼崽初生后，就得接受分子生物学检测，其间手术不断，转基因的成功率仅1%～5%。上海医学遗传研究所的科研人员另辟蹊径，将分子生物“选秀”提前至胚胎囊胚阶段，使转基因羊的成功率明显提高。

Drugs from genetically engineered animals poised to debut in US

Friday, January 23, 2009

By Kristen Minogue

Medication from genetically engineered animals could appear as early as next month if, as anticipated, the Food and Drug Administration approves ATryn, a blood thinner made from the milk of genetically engineered goats.

An FDA committee gave a green light to the drug, manufactured by Framingham, Mass.-based GTC Biotherapeutics, on Jan. 9. The European Commission already approved the drug in August 2006, and the FDA could formally approve it for sale in the U.S. as soon as Feb. 7.

If the agency approved it, the drug could help treat patients with a rare blood-clotting disorder called hereditary antithrombin deficiency.

ATryn is just one of several drugs from gentically engineered animals that could start appearing on the market soon.

Transgenic animals are probably going to be the drug stores of the future,” said biologist Bryan Pickett, who works with genetically engineered zebra fish at Loyola University of Chicago.

The FDA guidelines for such drugs, released on Jan. 15, outlined a much more stringent review process for genetically engineered animal products than cloned animal products. Unlike clones, which are supposed to be genetically identical to animals that already exist, genetically engineered animals have DNA from other organisms, often other species, inserted into their genome. Milk and meat from cloned cows, pigs and goats received a blanket approval from the FDA in January 2008.

The FDA evaluates every different "recombinant DNA construct "– foreign DNA inserted into an animal – on a case-by-case basis. Developers who want to market products from transgenic animals have to submit a new animal drug application to the FDA. Approval can take up to 10 months.

So far the only genetically engineered animals for sale in the U.S. are a glow-in-the-dark zebra fish sold in pet stores and laboratory animals like mice. The FDA hasn’t received any applications for genetically engineered meat.

Consumers are wary of the new technology. Of the 28,000-plus comments the FDA received on the draft guidelines last fall, the overwhelming majority opposed genetic engineering.

But that isn’t stopping developers, according to University of Illinois at Urbana-Champaign biologist Matthew Wheeler, who co-authored a report on the animals’ potential benefits last June.

Wheeler's report showed genetically engineered animals are popping up in dozens of sectors, including:

New Medicines – ATryn may become the first transgenic animal-produced drug to hit U.S. markets, but it’s not the only one that’s been developed. Researchers have created milk from genetically engineered sheep and pigs that can treat a rare type of hemophilia. Another strain of genetically altered pigs secretes milk with a hormone to help anemia patients produce more red blood cells.

Eco-friendly Animals – Researchers created the Enviropig in 2001, a pig that can excrete 60 percent less phosphorus than normal pigs, reducing pollution. Scientists at the National University of Singapore engineered the GloFish, a fluorescent zebra fish now sold in the U.S., to detect water pollution.

Human-Animal Transplants – Some have greeted this as the solution to the organ shortage problem. Transgenic pig hearts have lasted in baboons for up to six months. Researchers also hope insulin-producing pig cells could help diabetes patients and transgenic pig livers could act as temporary transplants while patients wait for permanent replacements.

Animal Health – Genetically engineered dairy cows are already able to begin resisting mastitis, an infection that decreases milk production, by secreting the bacteria-killer lysostaphin into their milk. Other possibilities include creating cows resistant to mad cow disease and brucellosis, a bacterial disease that can be transferred to humans.

Pickett said the risk of releasing potentially dangerous genetic materials is very low. But at the same time he respects the FDA’s regulation.

Meanwhile researchers are trying to calm any fears consumers may have about genetic engineering.

“I think all scientists really are for responsible, compliant and responsible, drug policy,” Pickett said.

©2001 - 2009 Medill Reports - Chicago, Northwestern University.

The use of transgenic systems in pharmaceutical research

Michael R. Snaith

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http://bfgp.oxfordjournals.org/cgi/reprint/1/2/119

Associate Director of AstraZeneca Transgenics and Comparative Genomics at AstraZeneca since 2000. Previously, he worked as a Senior Research Scientist for Glaxo Wellcome.

Jan Törnell

Director of Transgenics and Comparative Genomics at AstraZeneca since 1996. In 1998, he was appointed Professor of Physiology at Gothenburg University.

Dr Jan Törnell, AstraZeneca Transgenics and Comparative Genomics, AstraZeneca R&D, S-431 83 Mölndal, Sweden Tel: +46 31 776 2469 Fax: +46 31 776 3700 E-mail: Jan.Tornell@astrazeneca.com

Those pharmaceutical companies whose goal is to generate novel innovative drugs are faced with the challenge that only a fraction of the compounds tested in clinical trials eventually become a registered drug. This problem of attrition is compounded by the fact that the clinical trial or development stage is by far the most costly phase of bringing a new drug to market, consuming around 80 per cent of the total spend. Transgenic technology represents an attractive approach to reducing the attrition rate of compounds entering clinical trials by increasing the quality of the target and compound combinations making the transition from discovery into development. Transgenic technology can impact at many points in the discovery process, including target identification and target validation, and provides models designed to alert researchers early to potential problems with drug metabolism and toxicity, as well as providing better models for human diseases. In target identification, transgenic animals harbouring large DNA fragments can be used to narrow down genetic regions. Genetic studies often result in the identification of large genomic regions and one way to decrease the region size is to do complementation studies in transgenic animals using, for example, inserts from bacterial artificial chromosome (BAC) clones. In target validation, transgenic animals can be used for in vivo validation of a specific target. Considerable efforts are being made to establish new, rapid and robust tools with general utility for in vivo validation, but, so far, only transgenic animals work reliably on a wide range of targets. Transgenic animals can also be used to generate better disease models. Predictive animal models to test new compounds and targets will significantly speed up the drug discovery process and, more importantly, increase the quality of the compounds taken further in the research and development process. Humanised transgenic animals harbouring the human target molecule can be used to understand the effect of a compound acting on the human target in vivo. Also, models mimicking human drug metabolism will provide a means of assessing the effect of human-specific metabolites and of understanding the pharmacokinetic properties of potential drugs. In toxicology studies, transgenic animals are providing more predictive models. A good example of this are those models routinely used to look for carcinogenicity associated with new compounds.

Keywords: Transgenic mice, drug discovery, target validation, disease models, safety models

国际重组蛋白药物的市场和研发趋势分析

重组蛋白药物也称rDNA药物，不包括重组疫苗、单克隆抗体药物（抗体药物的市场和研发趋势另有文章详述[1]）、检测用重组蛋白和生化提取的天然蛋白，也不包括仿制药物。重组蛋白药物虽然仅占全球处方药市场的7-8%左右，但是发展非常迅速，尤其到了21世纪其发展更是进入黄金时节，1989年的销售额为47亿美元，2001年为285亿美元，2004年达到347亿美元[2]，2005年约410亿美元，是1989年的9倍。相对小分子药物，重组蛋白药物生产条件苛刻、服用复杂和价格昂贵，但对于有些疾病的治疗是不可替代的。绝大部分重组蛋白药物是人体蛋白或其突变体，以弥补某些体内功能蛋白的缺陷或增加人体内蛋白功能为主要作用机理，其安全性显著大于小分子药物，因而具有较高的批准率，同时，重组蛋白药物的临床试验期要短于小分子药物，专利保护相对延长，给制药公司更长的独家销售时间[3]。这些特点成为重组蛋白药物研发的重要动力。从重组蛋白药物市场的地理分布角度，美国和欧洲占有全球市场的81%[4]。重组蛋白药物研发公司6强（Amgen, Biogen IDEC, Johnson & Johnson，Eli Lily，Novo Nordisk和Roche）全部来自美国或欧洲，占有75%市场份额[2]。从新药上市的数量和速度看，美国居首位，这与美国拥有较自由的药物价格环境以及医生接受新药的需求和高速度有明显关系。欧洲近几年发展也较快，率先批准上市了转基因动物（羊）生产的重组人抗凝血酶（美国GTC生物治疗公司）[5]，以及第一个重组蛋白药物的仿制药物（Biosimilar，通用名生物药，下通称重组药物仿制药）[6，7]，后者结束了多年来重组蛋白药物是否能有仿制药的争论。鉴于美国和欧洲实际上主导着全球市场，分析其市场和研发趋势，也就能准确把握重组蛋白药物整体发展的脉搏。专家们对“新”重组蛋白药物的定义不尽相同，所以，不同文献中的新重组蛋白药物统计数量可能存在较大的差别。

本文以在美国和/或欧洲新上市的重组蛋白药物注册品名为准（以下通称重组药物），计有82个，包括15个“重磅***”，后者2005年销售额即达278亿美元，占销售总额的66%。目前的研发重点在于解决生产能力不足、更加合理的改变重组药物结构和给药途径多样化。尽管重组药物发展面临着种种挑战，但是我们认为该市场会持续发展，并在2020年前后到达峰值，那时将可能有新的替代治疗大量获准上市。剩下短短的十几年也许是我们发展重组药物的最后和最佳机会。

一、上市重组药物的销售情况分析

本文借用经济学“市场细分”的方法，从重组药物种类的销售入手，比分析适应症的市场规模能更直观地反映市场发展趋势。根据功能和性质，重组药物可分8类16种。促红细胞生成素Procrit最为畅销，近5年销售额近180亿美元；融合蛋白Enbrel销售增长最快，2005年的销售额是2001年的4.3倍，达36.5亿美元。（注：下文中括号：制药公司及与药物商品名对应的重组蛋白化学名称）

1、多肽类激素药：
 （1）人胰岛素，适应症是糖尿病。1982年第一个重组人胰岛素Humulin (Eli Lilly)上市，目前共有12种制剂（Novo Nordisk的8个速效、中效和长效重组胰岛素突变体在此仅计为1个），包括3个“重磅***”，Humulin（野生型胰岛素）、Humalog (Eli Lilly，胰岛素突变体)、Lantus (Anvents，胰岛素突变体)，2005年重组人胰岛素的销售额至少达75亿美元[14,16,18]。
 （2）人生长激素，适应症是生长激素缺陷、发育障碍和AIDS相关耗竭病。1985年第一个重组人生长激素Protropin(Genetech) 上市,现有8个品种。重组人生长激素的主要产品Nutropin/Protropin等在2005年的销售总额约为13亿美元[10，18，23]。
 （3）卵泡刺激激素（3个）和其他激素（7个），适应症是是不育症、调节排卵、更年期骨质酥松等，尚未形成很大的市场。

2、人造血因子：
 （1）重组人促红细胞生成素，适应症是贫血。1989年上市第一个重组人促红细胞生成素Epogen(Amgen)，现有的5个产品中4个是“重磅***”，Aranesp(Amgen，Epoetin α突变体)、Neorecormon(Roche，野生型Epoetin β)、Procrit(Johnson & Johnson，野生型Epoetin α)和Epogen(野生型Epoetin α)，2005年销售合计为91.5亿美元。
 （2）粒细胞/单核细胞集落刺激因子GM-CSF，适应症是癌症或癌症化疗引发的感染预防和治疗。仅有的3个产品2个是“重磅***”，Neulasta(Amgen,PEG化的GM-CSF)和Neupogen(Amgen, GM-CSF突变体)，2005年销售总额为35亿美元。
 （3）其他造血相关因子（5个），适应症主要是儿童发育不良以及恶性血液病或糖尿病的并发症。

3、人细胞因子：
 （1）α干扰素，适应症为慢性病毒性肝炎和某些癌症。1986年第一个重组人α干扰素Roferon(Huffman-La Roche)上市,现有5个同类产品，其中2个（组）为“重磅***”，一是Pegasys（Roche，PEG化的重组人α干扰素-2a）,另一组是Schering Plough的PEG-Intron A/Intron A，2005年销售额合计约21.6亿美元。
 （2）β干扰素，适应症为多发性硬化症（MS）。3个产品都是重磅***，Rebif(Serono，野生型β干扰素1a)、Avonex(Biogen, 野生型β干扰素1a)和Betaferon/Betaseron (Schering AG, β干扰素1a突变体)，销售额合计40亿美元[19]。
 （3）其他细胞因子（4个），包括白细胞介素1、2和11的突变体，适应症为肿瘤化疗引起的血小板减少症、肾细胞癌和慢性肉芽肿疾病等[20]。

4、人血浆蛋白因子：
 （1）重组人凝血因子VIII，适应症是血友病A。最早上市的为Recombinate (Baxter和Genetics,野生型)，现有5个同类产品，最畅销的是Kogenate（Bayer，野生型）及Advate（Baxter，野生型），2005年销售分别为8亿[21]和6亿美元[22]。
 （2）重组人凝血因子VII，仅上市NovoSeven(Novo Nordisk)，适应症是血友病和止血，2005年的销售额近10亿美元，2006年上半年销售增长19%。
 （3）重组人凝血因子IX，仅Renefix (Genetics)1个，适应症是血友病B。
 （4）组织血浆酶原激活物tPA，最早上市的为Activase(Genetech), 现有4个品种，适应症是急性心肌梗死，2005年市场规模为6-8亿美元[23]。
 （5）C反应蛋白，适应症是严重败血症，仅Xigris(Eli Lilly)1个。（6）重组人抗凝血酶（ATryn）是2006年批准的、第一个由转基因动物（羊）生产的重组药物。

5、人骨形成蛋白（2个）：是最年轻的一组，第一个产品2001年批准上市。Wyeth的成骨蛋白2005年销售额达2.4亿美元[17]，适应症为急性胫骨骨折、脊椎愈合和促进骨愈合等。

6、重组酶：适应症为先天性酶缺陷的替代治疗。1993年第一个重组酶Pulmozyme(Genetech)上市，适应症是肺纤维化，2005年的销售6亿美元[23]，共有 8个不同重组酶产品。

7、融合蛋白：是为数很少的以抑制为作用机理的重组药物，仅有3个。1998年批准的Enbrel(Amgen)是TNF受体和IgG的Fc片段的融合蛋白，含934个氨基酸，适应症为风湿性关节炎，为“重磅***”，近5年的销售额约100亿美元。1999年上市的免疫毒素Ontak（Ligand）[24]，适应症是皮肤T细胞淋巴瘤（CTCL），是缺失细胞结合域的白喉毒素与IL-2的N端133个氨基酸的融合蛋白。2003年上市的Amevive（Biogen Idec）[25]是LEF-3的CD2与IgG的Fc片段的融合蛋白，适应症是牛皮癣。

8、外源重组蛋白：外源蛋白能够用于人的疾病治疗，这在单克隆抗体药物发展过程中已经得到了验证。但是，至今批准上市的只有1个重组水蛭素（hirudin）[20]，适应症为血栓性疾病。

重组药物最大的一类是重组人促红细胞生成素，近5年销售总额近430亿美元；以后依次是重组胰岛素（除“重磅***”外，总销售额用Novo Nordisk的相应产品销售额进行调整，因为该公司占有胰岛素市场的近50%份额）、β干扰素、GM-CSF、融合蛋白Enbrel以及α干扰素。由于重组血浆蛋白中没有单一“重磅***”，所以没有列入“重磅***”中进行比较，但其在2005年的总销售额已达到30亿美元[18，21-23]。

时隔5年，占市场前3位的重组药物名次没有发生变化，只是由于Enbrel的快速增长导致各自的份额有所下降，Enbrel在2005年已上升至与GM-CSF并列第四名，α干扰素降至第六位。重组人促红细胞生成素的适应症已经从肾衰性贫血扩大至癌症或癌症化疗引起的贫血，并已有大量临床证据说明重组人促红细胞生成素能够促进癌症病人的生活质量[26]，其领头羊位置在未来5年将更加稳固。重组胰岛素占市场份额下降，但今年上市的肺吸入型胰岛素以及长效胰岛素和基础胰岛素等会支持市场不会下滑。β干扰素治疗MS将受到抗体药物和小分子药物的挑战，发展可能会受到抑制。GM-CSF在临床使用中能够有效降低癌症化疗导致的中性粒细胞下降引发的感染，长效GM-CSF