Challenges and prospects for monoclonal antibodies in China.
In 2010, cancer replaced cardiovascular disease as the world's deadliest disease, taking 7 million lives every year. (1) In China millions of people suffer from the disease. (2), (3) In the search for a drug to prolong survival and relieve pain with fewer side effects for rising cancer patient population, the monoclonal antibody (Mab) is attracting tremendous attention from industry and academia. (4), (5)
Based on immunological principles and relying on antibody in vitro amplification techniques to produce therapeutic antibodies primarily for tumor therapy, Mabs are the most important element in the bio-pharmaceutical system. (6), (7) T he ability of Mabs to recognize specific targets (such as tumor cells and pathogenic microorganisms) can be exploited to enhance the diagnosis, prevention, and treatment of diseases. (8) For example, in the treatment of tumors, Mab drugs can target the cancer cells, gather around them, block their growth, and shrink the cancerous parts. (9), (10) As a result, a low-dose treatment of low toxicity can be achieved. A Mab is like a biological missile in the human body that is constantly looking for the receptor. (11) Once it finds a cancerous cell, cohesion, combination, and blocking the growth of the cancer cell take place. (12) As a result, the major therapeutic areas of Mabs are in cancer treatment, which accounts for more than 40% of Mab sales. (13)
Compared with small molecule drugs, the biggest advantage of Mab products is their accuracy. (14), (15) They can simultaneously treat a specific target, with minimal side effects, and enhance efficacy. The mechanisms of Mab treatment can be divided into two categories: one is the combination of Mab itself with the target protein, followed by use of the human immune system to clear the target protein; and the other is the combination of Mab with a therapeutic small molecule drug or radio-therapy drug, thereby directing the drug towards lesions and achieving specific therapeutic purposes. (16), (17)
As a result, with the development of biotechnology, many pharmaceutical giants and emerging biopharmaceutical firms invested more and more resources and efforts in Mabs, which has led to notable development of Mab products to market. (18), (19) Recently, in the first decade of the 21st century, Chinese pharmaceutical companies have put much emphasis on Mabs, and have already realized much advancement in technology and product development of Mab. (20), (21)
CHINESE CONTEXT FOR MAB
With its rising economy and huge population, China is becoming a more influential pharmamerging market for global pharmaceutical industry. Especially cancer has been a major disease threating people health in China, and the incidence rate of cancers including lung cancer, liver cancer, stomach cancer, colorectal, esophagus, and breast cancer keeps rising in the past decade. (22) Such kind of increasing patient population with considerable consumption capability provides unique opportunities for Mab products. It is estimated the Mab market in China will grow to 32.5-65 billion yuan by 2015. (23)
Attracted by the enlarging Chinese market foreign Mab producers try to introduce their Mab products into China. Until now nine Mab products of foreign companied are listed in China (see Table 1). Among these nine Mabs five are humanized products, showing that foreign companies are using their most advanced Mab products to obtain market control. In fact before 2006 the whole Mab market in China is mostly dominated by foreign Mab products.
Table 1: Background information on nine foreign Mab products in China Non-proprietary Firm Market Type of Target name time antibody Daclizumab Roche 2001 Humanized CD-25 Rituximab Roche 2001 Mosaic CD-20 Trastuzumab Roche 2003 Humanized HER-2 Basiliximab Novartis 2003 Mosaic CD-25 Cetuximab Merck 2006 Mosaic EGFR Infliximab Johnson & 2007 Mosaic TNF-[alpha] Johnson Bevacizumab Roche 2010 Humanized VEGF Adalimumab Abbott 2010 Humanized TNF-[alpha] Etanercept Amgen 2010 Humanized TNF-[alpha] Non-proprietary Therapeutic areas name Daclizumab Kidney graft-rejection Rituximab Non-Hodgkin's lymphoma, Rheumatoid-like arthritis, Trastuzumab Mammary cancer Basiliximab Kidney graft-rejection Cetuximab Colorectal cancer Infliximab Rheumatoid-like arthritis, ankylosing spondylitis Bevacizumab Colorectal cancer Adalimumab Rheumatoid-like arthritis Etanercept Rheumatoid-like arthritis, ankylosing spondylitis
Because of their distinguished medical efficacy, the foreign Mab products are widely accepted by physicians in China. But Mab products are not included into the National Social Security and have to be paid by patients themselves. Consequently foreign Mab producers generally concentrate on the high-end market in China.
Realizing the great medical and financial value of Mab, the central and local governments in China have tried to support the development of Mab, especially through providing research funding to universities and academic institutes. Consequently laboratory research and development of Mabs is fairly strong in China. According to the number of patent applications to the State Intellectual Property Office of China, applications for Mabs grew by more than 5,000 (up to 2011), as shown in Table 2, indicating good technology development as well.
Table 2: Mab patent applications in China up to 2011 Patents for Utility Appearance Invention inventions model patent authorization patent Has patent right 1005 136 0 1005 No patent right 1912 40 1 317 Under review 2314 0 0 0 Total 5231 176 1 1322
The Mab patent applications in China mainly focus on anti-cancer and biological toxin detection. From academic point of view, monoclonal technology in China is not far behind world leaders in this area due to its world-class gene technology researchers. Currently, Mab technology in China is keeping pace with its foreign counterparts (mainly in the USA). Nevertheless more than 50% applications among all the Mab patent applications in China are from universities and academic institutes rather than firms, implying possible lag between academia and industry. (24)
DOMESTIC MAB PRODUCTS
The domestic Mab producers are also taking efforts to enter into this market and have obtained 20% of the Mab market in China from global pharmaceutical companies. Now there are seven Mab products are manufactured and marketed by domestic producers (see Table 3). Unlike its chemical drugs that struggle in the generic market, some Chinese Mab products have already taken a leading position. Among the seven listed Mab products three Mab products are humanized. Since it began focusing on products with minor side effects, Shanghai CP Guojian Pharma has marketed two humanized products. Meanwhile, Biotech Pharma, in collaboration with a Cuban group, has produced Taixinsheng[R] and the humanized level is as high as 95%, which makes Taixinsheng[R] a leading Mab product in the market.
Table 3: Background information on seven domestic Mab products Non-proprietary Firm Market Type of Target name time antibody Mouse anti-human Wuhan 1999 Murine T lymphocytes CD3 antigen of T Institute CD3 lymphocytes for of injection Biological Products Anti-human Asia Space 2004 Murine IL-8 interleukin-8 pharma cream Recombinant human Shanghai CP 2006 Humanized TNF-a tumor necrosis Guojian factor-receptor Pharma Recombinant Shanghai CP 2011 Humanized TNF-a humanized anti-CD25 Guojian injection Pharma Iodine [131|] tumor Shanghai 2007 Murine Nucleus of necrosis therapy Meien tumor cells injection Biotech Iodine [131|] Huasun 2007 Murine HAb18G/CD147 metuximab Biotech injection Nimotuzumab Biotech 2008 Humanized EGFR injection Pharma Non-proprietary Therapeutic name areas Mouse anti-human Protects CD3 antigen of T against the lymphocytes for rejection of injection certain organ transplants Anti-human Psoriasis interleukin-8 vulgaris cream Recombinant human Moderate and tumor necrosis severe active factor-receptor rheumatoid arthritis Recombinant Organ humanized anti-CD25 transplant injection rejection Iodine [131|] tumor Lung cancer necrosis therapy injection Iodine [131|] Lung cancer metuximab injection Nimotuzumab HNSCC, injection colorectal cancer
Three Mab products in China are used to treat cancer, but only one of them is a humanized product; the other two are used for the treatment of lung cancer and are murine. Perhaps because the survival of individuals diagnosed with lung cancer is brief, it is not necessary for China's existing research organizations to continue humanized research. Consequently, compared with foreign products that are almost humanized, China still adheres to its own technology path.
Aiming to catch-up the frontiers of international Mab products, the Chinese producers try to acquire Mab technologies from diversified sources: three Mabs are input from overseas; one is from domestic university; and the other three Mabs are from self-development. As Table 4 shows, the Chinese producers also have innovatively developed the various characteristics of Mabs based on the original Mab technologies input from outside to distinguish themselves from current Mabs in the market.
To support these Mab projects, the Chinese producers have to make use of varied financing models to cover the huge Mab development cost and meet the requirements of different types of stakeholders (see Table 4). The Chinese government provides strong finance support by direct investment or indirect investment through state-owned enterprises. Some domestic private pharmaceutical companies and venture capitals also have interest on Mab projects but feel hesitant about investment required and failure risk.
Table 4: Technological characteristics of Mab products in China Non-proprietary Technology source Technological name characteristics Mouse anti-human Self-development A pioneer in the CD3 antigen of T Chinese Mab market; lymphocytes for direct effect on T injection cells that play a major role in organ transplant rejection. Anti-human Input from Canada To introduce the interleukin-8 world's first cream therapeutic Mab for external use; convenient Recombinant human Self-development Similar to the tumor necrosis world's factor-receptor best-selling Mab (Enbrel) and has fewer side-effects Recombinant Self-development High humanization; humanized can be used alone anti-CD25 or as combination injection therapy with other drugs. Ilodine [131|] Input from US The first lung tumor necrosis cancer irradiation therapy injection immune targeted therapy in the world; significant effect on patients with advanced lung cancer that failed to respond to radiotherapy and chemotherapy. Iodine [131|] Input from domestic The world's first metuximab university Mab injection radioimmunoassay targeted drug for liver cancer. Nimotuzumab Input from Cuba Highly humanized; injection targets the epidermal growth factor receptor (EGFR) Non-proprietary Financing name model Mouse anti-human Investment CD3 antigen of T from lymphocytes for government injection Anti-human Joint interleukin-8 venture cream Recombinant human Investment tumor necrosis from factor-receptor state-owned enterprises Recombinant Investment humanized from anti-CD25 state-owned injection enterprises Iodine [131|] Venture tumor necrosis capital from therapy injection US and domestic Iodine [131|] Investment metuximab from domestic injection private enterprise Nimotuzumab Joint venture injection between China and Cuba government
CONSTRAINTS OF MAB DEVELOPMENT IN CHINA
Because of the increasing number of cancer patients, researchers are confident that Mabs have a promising future. However, there are several technical constraints that are affecting the development of Mabs throughout the world, including limitations to the number of drug targets, restricted biological diffusion, limitations to administration routes, and species-specific issues (see Table 5). (25) These four aspects are also the main bottlenecks restricting the development of Mabs in China.
Table 5: Four technological bottlenecks to Mab development Technological Detailed description bottleneck Limited drug Mab is specific. Each Mab can only bind targets to one target or the cell types of one disease. Biological Mab is a large protein molecule that diffusion cannot enter solid tumors. It has good limitations efficacy in suppressing surface tumor cells. Species-specific Humanized antibody really can minimize side effects and allergic reactions but has a long R&D time. However, it is not necessary for some malignancies with a short survival period. Route of The human body will metabolize drugs administration during the administration process. There limitation are considerable limitations to drug absorption. Meanwhile, some Mab molecules of large size could not penetrate through certain body tissues and organs.
Despite Chinese strengths in technological development, the introduction of few innovative Mabs to the market may imply a lack of cooperation between enterprises and research institutes. Compared to foreign companies, China has its own difficulties in the development of Mabs (as shown in Figure 1).
In addition, several other troublesome problems constrain the development of Mab in China. The main direction of Mab R&D in China is still following that of foreign countries (mainly USA). Nevertheless, a major problem restricting the development of the Chinese pharmaceutical companies is lack of finance, which might be attributed to the small size of these pharmaceutical firms in China. This fundamental problem prevents China from making greater progress in R&D in Mabs.
The second but most vital problem is the production processes. The production of biological products is very different from that of chemical drugs. Mab production processes have strict production requirements. In addition, an antibody used in cell culture technology and production requires precise controls. A slight mistake will cause the whole production process to fail. Currently, foreign Mab production fermentation tanks and other equipment have a scale above 3000 L, but in China the highest attainable scale is 2500 L (Biotech Pharma). (26) Consequently, China's production output lags far behind that of the more sophisticated pharmaceutical companies. (27)
Finally the price of Mabs constrains the Mab development in China. Because of their huge R&D investment and higher production cost the price of Mab products in China remains at a high level that can't be easily afforded by ordinary patients, which limits the sales of Mab products in the less developed areas of China where cancer incidence rate is much higher.
By the year 2020, bio-medicines are expected to completely replace chemical products. (28) As a key component of biological drugs, Mab is a primary prerequisite for achieving this goal. (29) New breakthroughs are expected to solve the four previously mentioned global technology bottlenecks. The Chinese pharmaceutical sector also looks forward to contributing to the development of Mab.
According to a systematic analysis of the technological and economic environment, several solutions for China's own R&D and production technology bottlenecks can be suggested. In R&D, Chinese pharmaceutical firms should be encouraged to cooperate with universities, colleges, and other agencies, not only to reduce R&D cost and time, but also to improve technological innovation capabilities. A production-learning-research system can effectively promote technological innovations in Mabs. Cooperation partners should not be confined to China, but should also include foreign advanced scientific research institutions, such as the cooperation on Taixinsheng[R] between Biotech Pharma and its Cuban partner as well as the cooperation on Enboke[R] between Asia Space Pharmaceutical (Dalian) and Anogen-Yes Biotech Laboratories (Canada). In addition, licensing of antibody technology that has already been developed by a foreign laboratory can help to develop China's Mab market. Some Chinese pharmaceutical enterprises have already realized this and are making efforts in this regard (e.g., Qilu Pharmaceutical).
In production areas, Chinese biopharmaceutical factories ought to expand production capabilities and solve the problem of low production yields. Otherwise, even if the technology becomes readily available, it still cannot be industrialized and might never be profitable. Today, most domestic production equipment is purchased from foreign countries, which offers great opportunities for domestic enterprises to enhance the strength of their own production. Moreover, China's Mab firms should focus more on raw material selection: Biotech Pharma offers a good example in this field.
The global biopharmaceutical market is undergoing tremendous change. China possesses some unique potential advantages, especially in fields of cutting-edge research such as genomics and stem cell research. Having recognized the value of these technologies, the Chinese government is providing financial support to create a healthy environment for the biopharmaceutical industry. Particularly the planning inclusion of cancer treatment into National Social Security may provide greater opportunities for Mabs in China. With the development of Mabs, Chinese pharmaceutical companies are expected to devise their own technology map and business model with their own solutions.
We are grateful for the funding support from University of Macau (MYRG160(Y1-L1)-ICMS12-HH).
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Received: November 21, 2012; Revised: March 9, 2013
Honghao Shi is a member of program staff for China Global Fund TB program at the Center for Certification of Drug, State Food and Drug Administration in China. His research interests are in business model and medicinal administration.
Meiwan Chen is currently an assistant professor in State Key Laboratory of Quality Research in Chinese Medicine, University of Macau. Her research interests are in research and development of drug delivery systems.
Yunzhen Shi is a master student of Medicinal Administration at Institute of Chinese Medical Science at University of Macau. She is interested in contract research organization (CRO) in China.
Hao Hu joined the Institute of Chinese Medical Science at University of Macau in 2007. His research interests are in sectoral innovation of biopharmaceutical and Chinese Medicine, and pharmaceutical technology analysis and forecasting.
Yitao Wang is a founder and director of Institute of Chinese Medical Science at University of Macau. He is also the founding director of State Key Laboratory of Quality Research in Chinese Medicine, University of Macau.
Correspondence: Hao Hu, Institute of Chinese Medical Science, University of Macau, Macau.
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|Title Annotation:||Original Article|
|Author:||Shi, Honghao; Chen, Meiwan; Shi, Yunzhen; Hu, Hao; Wang, Yitao|
|Publication:||Journal of Commercial Biotechnology|
|Date:||Apr 1, 2013|
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