Rice-made human serum albumin, bigger market and tougher patent challenges

What else can rice be used for besides eating? There are many answers to this question. However, what Mr. Amino wants to talk about today is the role of rice in the production of drugs.

That's right, rice can not only be eaten, but also used to prepare various medicines, such as human serum albumin.

Human serum albumin is the most abundant protein in plasma, which can save the lives of some critically ill patients such as shock, hemorrhage, and surgical blood loss, and even treat the new crown.

In my country, the amount of human blood globulin is very large. According to Frost & Sullivan data, in 2021, the batch release volume of Chinese serum albumin will be about 645.2 tons. However, this drug is very dependent on imports. In 2021, imported human serum albumin will account for about 60%.

The reason is that the source of all currently available human serum albumin is plasma. Donated plasma alone cannot meet the huge domestic demand. Scientists can only find ways to produce human serum albumin on a large scale through genetic engineering.

However, decades of efforts have been unsuccessful. This time, Heyuan Biotechnology, which is hitting the IPO on the Science and Technology Innovation Board, has brought recombinant human serum albumin into people's attention again.

Its core product, plant-derived recombinant human serum albumin injection (OsrHSA), is recombinant human serum albumin extracted from rice, and has completed phase II clinical trials.

This is a road that no one has traveled. Will Heyuan Biotech succeed?

／ 01 ／Brain-opening technology

Everyone is familiar with genetic engineering and recombinant proteins. In the 20th century, the development of genetic engineering technology opened a brilliant chapter of recombinant protein drugs.

In 1982, the first recombinant protein drug—recombinant human insulin was launched, followed by important drugs such as recombinant human growth hormone and various recombinant human cytokines. The research and development of these recombinant protein drugs promoted the rapid development of biological drugs .

But they are all obtained by using genetic engineering technology to transform "engineering bacteria" or "engineering cells". "Rice hematopoiesis" sounds incredible to many people so far.

However, this is nothing new. In other words, plant synthetic biology is not a new technology, it has a history of decades.

In 1983, the world's first transgenic plant—tobacco containing antibodies to antibiotics—was successfully cultivated in the United States.

The first plant into which the human serum albumin gene was introduced was also tobacco, but the expression efficiency was too low; later, it was expressed in plants such as potatoes, but the effect was also unsatisfactory due to problems such as low expression efficiency and incorrect structure of the recombinant protein. .

As early as 1981, scientists successfully expressed recombinant human albumin in E. coli, but unfortunately, due to the lack of correct folding and post-translational modification processing, this recombinant albumin has no biological function.

That is to say, recombinant human albumin must undergo correct folding, assembly and post-translational modification in order to have its specific structure and function. Therefore, the key is to choose an appropriate expression system.

Scientists have worked so hard to develop prokaryotic expression systems, yeast expression systems, transgenic animal expression systems, and transgenic plant expression systems to produce recombinant human serum albumin.

Plant expression is not ideal, and recombinant human serum albumin, which takes "conventional" technical routes such as cells and yeast, has experienced more tortuous experiences. In 2007, recombinant human serum albumin developed by Mitsubishi Tanabe Pharmaceuticals was successfully approved for marketing. Unfortunately, this drug did not change the scarcity of human serum albumin, because its clinical trial data was suspected of falsification, and it was withdrawn from the market two years after it was launched.

Fortunately, there are still pharmaceutical companies insisting on this road.

In China, the fastest-growing recombinant human serum albumin player is Heyuan Biotech. At present, its recombinant human serum albumin has entered the third phase of clinical trials. It is worth noting that, unlike most recombinant proteins produced by yeast, Heyuan Biotech's recombinant human serum albumin is produced by rice.

Rice-made human serum albumin, bigger market and tougher challenge

In order to make human serum albumin more suitable for synthesis in rice seeds, Heyuan Biotech has transformed and optimized the human serum albumin gene, and at the same time combined it with a rice seed-specific promoter to form a new gene, using Agrobacterium to transfer the new gene into In the rice genome, a transgenic rice plant is obtained.

Due to the adoption of rice seed-specific elements, it can direct the synthesis of human serum albumin gene only in rice. With the plants, the next step is to grow rice on a large scale, and then extract and purify human serum albumin.

That is to say, Heyuan Bio uses rice seeds as a bioreactor, specifically expresses various recombinant proteins and small molecular polypeptides in rice seeds, and stores them in the protein body to avoid target recombinant proteins from being attacked by cytoplasmic proteases. degradation, and finally obtain highly expressed recombinant proteins.

Although the progress of Heyuan Biotech's recombinant human serum albumin is leading in China, the development of this product is not smooth overseas.

／02／Technology with great potential

In 2020, Ventria Bioscience, the former owner of Yang Daichang, the founder of Heyuan Biosciences, filed a lawsuit against Heyuan Biosciences to the US International Trade Commission (ITC), suing Heyuan Biosciences for infringing its patent on recombinant human serum albumin .

After two years, in September 2022, the ITC made a final investigation and confirmed that Heyuan Biotech infringed Ventria patents , and Heyuan Biotech’s infringing products have been excluded from the US market.

However, the ITC also left a way out for Heyuan Biotech, that is, recombinant human serum albumin products with a polymer content higher than 2% in Heyuan Biotech’s recombinant human serum albumin products do not involve infringement.

Things didn't stop there. Ventria Bioscience again appealed the result. No matter what the final outcome of this patent war is, falling into a patent dispute is definitely not good news for Heyuan Biotech's future overseas journey.

Fortunately, the imagination of Heyuan Biotechnology's plant-derived recombinant technology is not limited to this product.

Focusing on plant technology, Heyuan Biotechnology has established a rice endosperm cell bioreactor high-efficiency recombinant protein expression platform (OryzHiExp) and a downstream technology recombinant protein purification technology platform (OryzPur).

The function of the former is to specifically express various recombinant proteins and polypeptides; the function of the latter is to perform protein extraction and target protein purification on the obtained recombinant proteins, and finally obtain the desired product.

Based on this technology platform, in addition to recombinant human serum albumin, Heyuan Biological also has a variety of plant-derived products in its pipeline, including recombinant human lactoferrin lysozyme oral solution HY1002 and plant-derived α1-antitrypsin injection HY1003 Two products have also entered clinical trials.

Compared with current drugs, plant molecular drugs have many advantages, such as large-scale production, low cost, and better safety. As mentioned above, transgenic plants have long been used to develop new agricultural varieties and research on recombinant protein expression. Its biggest advantage is that it does not require a large amount of expensive medium, and only needs enough sunlight to produce a large amount of recombinant protein through photosynthesis.

Take the flagship product of Heyuan Biotechnology, recombinant human serum albumin, as an example.

At present, the price of human serum albumin on the market is not cheap. Even after the centralized procurement, the price of human serum albumin remains at 300-600 yuan per 10 grams. But if plant-derived recombinant human serum albumin can be successful, things will be different.

According to Heyuan Biotechnology, the company can produce about 10 grams of serum albumin per kilogram of rice. After large-scale production is realized, the production cost of recombinant human serum albumin will be much lower than the production cost of plasma isolated human serum albumin .

In terms of safety, recombinant human serum albumin also has more advantages. There are potential risks of infectious diseases such as chronic hepatitis B, AIDS and unknown viruses in human blood, and it is difficult to guarantee that the virus will not be brought into the product even after the purification process, while the recombinant human serum protein derived from plants does not have this serious concern .

According to the prospectus of Heyuan Biological, in 2020, the domestic human serum albumin therapeutic drug market will reach 25.8 billion yuan, and ten years later, this market is expected to grow to 57 billion yuan.

Moreover, due to patent and technical barriers, there are fewer companies in the world involved in recombinant human serum albumin. Apart from Heyuan Biotech, there are only two domestic players whose products are in the clinical stage. Domestic Shanghai Anruite recombinant human albumin injection has completed the second phase of clinical trials, and Shenzhen Proji recombinant human serum albumin injection is in the first clinical phase.

Rice-made human serum albumin, bigger market and tougher challenge

It seems that this is a blue ocean that is wide enough. If Heyuan Bio's recombinant human serum albumin injection can really be approved for marketing, then, with the advantages of low price and safety, it will definitely have the opportunity to start from today's human serum albumin injection. A slice of the albumin market.

Not only the potential market is considerable, but the valuation growth of Heyuan Bio is also considerable. In this Sci-tech Innovation Board IPO, the company plans to issue 89.4514 million shares and raise funds of 3.502 billion yuan. Based on this calculation, the valuation after the issuance will reach 14 billion yuan. In September 2022, Heyuan Biotech completed a new round of capital increase of 556 million yuan, with a post-investment valuation of 5.157 billion yuan. In less than two years, the valuation has increased by 171%.

But the ideal is full and the reality is very skinny. Along with opportunities are challenges.

/ 03 / A road no one has traveled

The research and development of plant molecular medicine technology has been carried out for more than 30 years. Due to the problems of low expression level, complicated purification process, and difficulty in scale-up, the industrialization of plant molecular medicine technology has been developing slowly. So far, no plant-derived recombinant serum albumin has been successfully approved for marketing.

To put it bluntly, no one knows whether plant molecular drugs can be used. Because the path that Heyuan Biotech took was a path that no one has traveled.

In fact, at the beginning of the business, the founder Yang Daichang was also questioned because of the level of purification and research direction, and he vacillated between making excipients or making injections. In the end, the company decided to aim at the more difficult pharmaceutical injection level while obtaining revenue through excipient products.

In 2021, Heyuan Bio's recombinant human serum albumin (pharmaceutical excipient grade, culture medium grade and other products) revenue will be 17.11 million yuan. However, this is a drop in the bucket for its R&D investment. In 2021, the R&D investment of Heyuan Biotech will be 75.21 million yuan.

Compared with R&D investment, the market's greater concern may be that this road that no one has traveled, can it really work?

In terms of purification process, according to the prospectus, the purity of injection-grade recombinant human albumin must be above 99.9999%, and the host cell impurities are required to be safe. This is also the main region for excipient grade and clinical injectable grade recombinant human albumin. Excipient grade does not need to be 99.9999% pure like injectable grade.

This is because human albumin is clinically used in relatively large doses, and milligram or microgram-level biological impurities may be fatal to the human immune system. You might think that continuous purification will always achieve the purity requirement.

But here also need to consider the issue of cost. If the cost of recombinant human albumin exceeds that of human serum albumin, what is the cost advantage? How to obtain high-quality recombinant human albumin at low cost is one of the core issues in developing this product.

Another example is the issue of scale. Judging from overseas development experience, despite the efforts of researchers and companies to draw a line between traditional genetically modified food/feed and plant synthetic biology, the latter is still involved in the food industry, regulatory agencies, environmental protection, etc. Amid escalating conflicts between organisations, media, politicians and the public.

There are also many companies that have become victims of the conflict, such as SemBioSys Genetics, whose biosimilar insulin is already in Phase I/II clinical trials. Monsanto, Bayer, Dow, and Syngenta all withdrew.

To this day, researchers and businesses have been eager to promote the economic benefits of plants, seeking a balance between environmental, economic and technological measures.

Of course, setbacks and risks are frequent visitors on the road to new drug development. This will not change the forward trend of new drugs, just as genetic engineering has greatly promoted the development of biological drugs. Looking back, pioneering research is the trigger point of technology, leading to the explosive growth of scientific research.

And today, more and more cutting-edge biotechnology platform technologies are maturing. Cell and gene therapy, mRNA, protein degradants, multispecific antibodies, and antibody-drug conjugates are moving from indeterminate territory to near-determined therapeutic territory.

This COVID-19 epidemic has accelerated the industrialization of mRNA technology. The success of the new crown vaccine has doubled the confidence of global mRNA players in the future of this technology.

This once again tells us that behind any major leap in scientific progress lies a little-known truth: Groundbreaking science doesn't seem to work until it is finally achieved.

So, will Heyuan Bio's plant-derived recombinant human serum albumin create a new historical leap or fall into the dust of history?

In any case, we all look forward to the day when there will be no shortage of human albumin.