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Challenges and prospects for monoclonal antibodies in China.

INTRODUCTION

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.

FUTURE OUTLOOK

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.

ACKNOWLEDGEMENT

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.

Email: haohu@umac.mo
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Title Annotation:Original Article
Author:Shi, Honghao; Chen, Meiwan; Shi, Yunzhen; Hu, Hao; Wang, Yitao
Publication:Journal of Commercial Biotechnology
Article Type:Report
Geographic Code:9CHIN
Date:Apr 1, 2013
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