Directed molecular evolution (DME ) mutation, recombination and selection, the evolution towards the needs of the people of the direction of development. As in recent years in the field of biology of swift and violent development of a technology, DME can produce a more optimized protein drug candidates.
In 2005, 83% of the total amount of global drug sales are from small molecule drugs, biological drugs ( especially the therapeutic protein and monoclonal antibody ) sales accounted for only 15% of total global drug sales. However, according to the forecast, to 2010, small molecule drugs in pharmaceutical sales total amount proportion will decline to 76%, this was mainly due to the class of drugs is facing more and more challenge, especially from generic competition gradually increased; and biotechnology drugs than in 2010 but is expected to grow to 22%.
The competing drugs increase brings double trouble
Various data show that, in comparison with small drug molecules, although biotechnology drug market in the future growth potential is tremendous, but after 2010, the market will continue to expand rate but not with 2005~2010 between the years of strong growth to maintain synchronization, a large part of this was due to the emergence of biological generic drug. In addition, from including therapeutic proteins and monoclonal antibodies, biotechnology drugs will inevitably encounter their own rival gradually increased and "target target crowding ( target crowding ) " and other problems. In 2005~2010, there are 16 new monoclonal antibodies is listed, this will make the market of the monoclonal antibody drug increased from 30 to 46. In the same time, the therapeutic protein domain also will have 13 new drug is pushed to the market.
In addition to the market of biotechnology drug quantity will surge, likewise, by generic drug manufacturers and biotechnology drugs have the same target " similar products " will also appear in a large amount. These targets are more concentrated, such as CD20, CD22, CD30, TNF and VEGF etc.. Therefore, this has resulted in some target role in the field of drug relatively crowded situation.
In these targets are fields, the most crowded is anti rheumatoid arthritis field. Today, the United States of America Johnson company Remicade ( infliximab, infliximab ), Abbott Company ( adalimumab Humira adalimumab, Amgen ) and Enbrel ( etanercept, etanercept ) have become resistant to rheumatoid arthritis field trump treatment drugs. However, in the next few years, according to the treatment field in the research of other biotech drugs will have entered the market, such as for disease treatment adds several new options, but from another point of view, go situation can accelerate drug market saturation, thereby increasing the treatment areas of drug competition.
In view of this, the next 5 years, in the field of biotechnology drugs has a total of 29 new drugs will participate in the market competition in the ranks, and thus became the future market sales growth force. At the same time, the increase in the number of drugs and the field of competition focus also means in the market battle, drugs will also aggravate the competition between each other, coupled with the threat from biological generic drug, in " before the arrival, have after chase after arms " situation, the biotechnology drugs market for a more optimized a new generation of drugs demand becomes particularly strong, and the use of directed molecular evolution ( directed molecular evolution, referred to as DME ) for biotechnological drug life cycle control can realize the optimization is a new generation of drugs one of technology.
DME strategy optimization to produce a new generation of drugs
DME is also called laboratory evolution ( laboratory evolution ) or evolutionary biology technology ( evolutionary Biotechnology ), which aims to simulate the natural evolution mechanism in vitro ( mutation, recombination and selection ), the evolution towards the needs of the people of the direction of development. As in recent years in the field of biology of swift and violent development of a technology, DME can produce a more optimized protein drug candidates.
And at this stage of the protein optimization techniques are compared, the DME is available in the early structural and functional information is absent by application of a method. In some respects, also be considered for biotechnology drugs tailored combinatorial chemistry -- used instead of (or in addition to ) to existing information based optimization for biotechnology drugs method, can be used to explore the candidate protein medicine " protein sequence space ". It can be said, DME is probably the most able to interpret a new generation of biotech drugs and the most accurate technique, it than biosimilar drugs and other competing drugs bring threats to the market a greater impact, but also will be the biotechnology drugs in the market game to win an important hope.
As a kind of optimization method for protein drug candidates, DME showed great potential. It mainly have 3 kinds of modes available for commercial use. In a first mode for " competition ", in this mode, DME can lock the competition has listed biotechnology drugs and being developed in optimize breed, which is itself a product under development to provide useful help. The second model for " collaborative " mode, in this mode, DME can represent its companies ( usually for a major pharmaceutical company ) developed than the first generation of biotech drugs more optimization of a new generation of drugs. In return, its companies will usually pay DME a certain cost, thus obtaining DME technology is used to control the generation of the first biotech drug life cycle. The third model for " development mode", in this mode, the DME company is not locked listed biotechnology drugs, replace sb. Is the direct application of DME technology optimization in the research of novel protein drug candidates.
At this stage, DME company of two big leader -- the United States of America applied molecular evolution ( AME company, now a subsidiary of Eli Lilly and company ) and Maxygen, were respected " competition mode " and its application in drug R & D are themselves. AME says it is working to Johnson company Remicade and the Swiss company Roche and American Genentech company jointly developed by Rituxan (rituximab, rituximab ) optimization into a new generation of versions of the drugs, and Maxygen company now is riveting became sufficient strength to conquer G-CSF, is currently in the treatment of dominant position of the United States the company markets Neupogen.
The early bird catches great taste benefit
In addition to the " competition ", AME company also adopted the " cooperative mode " as a part of business strategy, which is mainly with the American biotechnology company MedImmune cooperation to achieve, to use the DME technology to optimize its resistance to respiratory syncytial virus ( RSV ) monoclonal antibody Synagis ( palivizumab ). The development of the cooperative outcome is the development of a new generation of monoclonal antibody against RSV Numax motavizumab ), which is expected to launch in 2008.
MedImmune company and AME company decided in 1999 to cooperate to complete the product Synagis optimization. In accordance with the contract, in the 10 years to pay the latter cooperative reward. Now, MedImmune has used DME technology to achieve a new generation of monoclonal antibody development, this is also the company and Synagis developers -- the United States Abbott Company for further cooperation to open a new situation, to further expand the market for sales of Numax.
Therefore, as a kind of can be used to control the biotechnology drug life cycle method, DME technology has great market prospect and commercial potential.
Domestic temporarily should " clever imitation "
At present, the domestic pharmaceutical industry is still undeveloped, generic drug in the pharmaceutical market in occupy an important position, especially in the R & D strength is weak, project repeat construction the phenomenon is serious, especially the lack of independent innovation products of biotechnology drugs, drug research and development have been out of the shadow of imitation.
At present, China's biomedical technology drugs to declare the seemingly active, actually belong to the independent innovation technology is rarely. According to statistics, in 2000, September ~2004 year in September, China had 108 registered number of approval of biological products were added to apply, but the main breeds only recombinant human interferon, recombinant human erythropoietin, recombinant human granulocyte colony-stimulating factor, recombinant human white blood cells, mediated by recombinant human growth hormone several species of. Reporting of clinical research on new drugs of the 175, the main breeds only split influenza virus vaccine, recombinant reteplase ( TPA ), recombinant human interferonβ-1b etc. Get a new drug certificate and documents the production of 230, but the main varieties are only human nerve growth factor, recombinant human basic fibroblast growth factor, recombinant human interleukin -11, recombinant human interleukin -2 and recombinant human tumor necrosis factor -NC several.
Compared with developed countries, China's biological laboratory technical level difference is not big, but in the industrialization of the gap is gradually increase -- when the world has 20 a variety of best-selling biological medicine, our country can produce 10 kinds of; now the world has 140 kinds of biological medicine, our country can only produce 10. The lack of independent intellectual property rights, subject to technical conditions and other factors, led to China's pharmaceutical enterprises in the overall lack of new drug innovation ability, thus in the present stage must be to produce generic drugs mainly to maintain the survival of enterprises. In order to less risk, each enterprise repeat production LED products are concentrated in the same market, resulting in vicious competition, greatly weakened the biological and pharmaceutical industry of China overall competitiveness.
Restricted by the conditions, if at this stage of China's biotechnology industry is temporarily unable to get rid of R & D dilemma to generics to survive as excusable word, so even in the pharmaceutical field, most of our pharmaceutical enterprises also lack the " clever imitation ". In fact, in the imitation process can also have independent intellectual property rights, the Japanese have a lot of good example: the use of so-called " nibble " policy, continue to introduce technology to be updated, improved, thereby surrounding the foreign basic patents, and created many with Japanese characteristics dependent patent. While in Japan it is through these wise and clever parodies of introduction, not only successfully promoted the rapid growth of the economy, and become one of the world recognized the patent one of big countries, continue to accumulate huge patent projects in turn for Japan to become the world economy big country laid certain foundation.
By other's faults, wise men correct their own. From these successful experience and reflection from abroad, a comprehensive understanding of biotechnology drug market has to DME technology forward movement, long a walk mechanical imitation route domestic pharmaceutical enterprises, thinking whether or not could be more open some?
