Rice creates human serum albumin, a larger market and a more difficult challenge

There are many answers to this question. However, what Aminojun wants to talk about today is the role of rice production drugs.

That's right, rice can not only be eaten, but also used to prepare a variety of drugs, 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, heavy bleeding, surgical blood loss, and even treat the new crown.

In China, the dosage of human hemoglobulin is very large. According to Frost & Sullivan data, the batch issuance of serum albumin in Chinese 2021 was about 645.2 tons. However, this drug is very dependent on imports, and the proportion of serum albumin imported in 2021 is about 60%.

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

However, decades of efforts have not succeeded. This time, Heyuan Biotechnology, which is impacting the IPO of 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 Biology succeed?

01

Brain-opening technology

Genetic engineering, recombinant proteins, everyone is familiar with it. In the 20th century, the development of genetic engineering technology opened a brilliant chapter in recombinant protein drugs.

In 1982, the first recombinant protein drug - recombinant human insulin was launched, followed by recombinant human growth hormone and various recombinant human cytokines and other important drugs were launched one after another, and the development and marketing of these recombinant protein drugs promoted the rapid development of biological drugs.

But they are all obtained by using genetic engineering technology to modify "engineered bacteria" or "engineered cells", "rice hematopoiesis", which to many people still sounds incredible.

This is nothing new, though. In other words, plant synthetic biology is not a new technology, it has been around for decades.

In 1, the world's first genetically modified plant, tobacco containing antibiotic antibodies, was successfully cultivated in the United States.

The first plant into which the human serum albumin gene entered was also tobacco, but the expression efficiency was too low; Later, it was expressed in potatoes and other plants, which was limited by problems such as low expression efficiency and incorrect structure of recombinant proteins, and the effect was also unsatisfactory.

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

That is, recombinant human albumin must undergo proper folding, assembly, and post-translational modification to have its specific structure and function. Therefore, the key is to choose a suitable expression system.

Scientists have worked 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, recombinant human serum albumin that takes the "conventional" technical route of cells and yeast has experienced more twists and turns. In 2007, the recombinant human serum albumin developed by Mitsubishi Tanabe Pharmaceutical was successfully approved for marketing. Unfortunately, this drug has not changed the scarcity of human serum albumin, because its clinical trial data is suspected of falsification, and it was withdrawn from the market two years after it was launched.

Fortunately, there are still pharmaceutical companies on this road.

In China, the fastest recombinant human serum albumin player is Heyuan Biotechnology. At present, its recombinant human serum albumin has entered phase III clinical trials. It is worth noting that unlike most recombinant proteins produced by yeast, Heyuan Bio's recombinant human serum albumin is produced using rice.

In order to make human serum albumin more suitable for synthesis in rice seeds, Heyuan Bio modified and optimized the human serum albumin gene, and at the same time formed a new gene with a rice seed-specific promoter, and used Agrobacterium to transfer the new gene into the rice genome to obtain transgenic rice plants.

Due to the use of rice seed-specific components, it instructs human serum albumin genes to be synthesized only in rice. With the plant, the next step is to grow rice on a large scale, and then extract and purify human serum albumin.

In other words, Heyuan Bio uses rice seeds as bioreactors to specifically express various recombinant proteins and small molecule polypeptides in rice seeds, and stores them in the proteosome in a targeted manner to avoid degradation of the target recombinant protein by cytoplasmic protease attack, and finally obtain a highly expressed recombinant protein.

Although the recombinant human serum albumin of Heyuan Biotechnology is ahead in China, the development of this product is not smooth overseas.

02 

Technology with great potential

In 2020, Ventria Bioscience, the old owner of Yang Daichang, the founder of Heyuan Biotechnology, sued Heyuan Bio for infringement of its own recombinant human serum albumin patent.

After two years, in September 2022, the ITC made a final ruling of investigation, confirming that Heyuan Biotech infringed on the Ventria patent and had excluded Heyuan Biologics' infringing products from the US market.

However, ITC also leaves a way for Heyuan Biologics to survive, that is, recombinant human serum albumin products with polymer content higher than 2% in Heyuan Bio's recombinant human serum albumin products does not involve infringement.

The matter did not rest there. Ventria Bioscience again appealed the outcome. Regardless of the final outcome of this patent war, falling into a patent dispute is definitely not good news for Heyuan Biotechnology's future road to sea.

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

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

The role of the former is that it can specifically express various recombinant proteins and peptides; The function of the latter is to extract the protein and purify the target protein of the obtained recombinant protein, and finally obtain the desired product.

Based on this technology platform, in addition to recombinant human serum albumin, Heyuan Biologics has also laid out a variety of plant-derived products in its pipeline, including recombinant human lactoferrin lysozyme oral liquid HY1002 and plant-derived α1-antitrypsin HY1003 for injection have also entered the clinic.

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

Take Heyuan Bio's fist product, recombinant human serum albumin.

At present, the price of human blood albumin on the market is not cheap, even after collection, the price of human serum albumin is still maintained at 300-600 yuan / 10 grams. And if plant-derived recombinant human serum albumin can be successful, things will be different.

According to Heyuan Biotechnology, the company can produce about 1 grams of serum albumin in 10 kg of rice, and after achieving large-scale production, 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 is also more advantageous. The potential risk of infectious diseases such as chronic hepatitis B, AIDS and unknown viruses in human blood, and even after purification, it is difficult to guarantee that the virus will not be introduced into the product, but plant-derived recombinant human serum proteins do not have this concern.

According to the prospectus of Heyuan Biotechnology, in 2020, the domestic human serum albumin therapy market reached 258.570 billion yuan, and ten years later, this market is expected to grow to <> billion yuan.

Moreover, due to patents and technical barriers, there are fewer companies in the world involved in the recombinant human serum albumin track. In addition to Heyuan Biotechnology, only two domestic players' products are in the clinical stage, the domestic Shanghai Enretics recombinant human albumin injection has completed phase II clinical trials, and Shenzhen Proji recombinant human serum albumin injection is in the first phase of clinical trials.

It seems that this is a wide enough blue ocean, if Heyuan Bio's recombinant human serum albumin injection can really be successfully approved for marketing, then, with the advantages of low price and safety, it will inevitably have the opportunity to get a piece of today's human serum albumin market.

Not only is the potential market considerable, but the valuation growth of Heyuan Biotech is also considerable. In this IPO of the Science and Technology Innovation Board, the company plans to issue 8945.14 million shares and raise 35.02 billion yuan. Based on this calculation, the post-issuance valuation reached 140 billion yuan. In September 2022, Heyuan Biotech completed a new round of capital increase of 9 million yuan, with a post-investment valuation of 5.56 billion yuan. In less than two years, valuations have increased by 51%.

But the ideal is very full, the reality is very skinny, and with the opportunity is the challenge.

03 

A road that no one has traveled

The research and development of plant molecular medicine technology has been for nearly 30 years, and the industrialization of plant molecular medicine technology has been developing slowly due to its problems such as low expression, complex purification process and difficulty in scale. To date, no recombinant serum albumin of plant origin has been successfully approved for marketing.

To put it bluntly, whether plant molecular drugs can be beaten or not, no one knows. Because the road taken by Heyuan Biology is a road that no one has walked.

In fact, at the beginning of his business, founder Yang Daichang was also questioned because of the level of purification and research direction, swinging between making excipients or injections. In the end, the company decided to generate revenue through excipient products while aiming for more difficult pharmaceutical injection grades.

In 2021, Heyuan Biorecombinant Human Serum Albumin (pharmaceutical excipient grade, culture medium grade and other products) earned 1711.2021 million yuan. However, this is a drop in the bucket for its R&D investment. In 7521, Heyuan Biotech's R&D investment was <>.<> million yuan.

The market's greater concern than R&D investment may be whether this road that no one has traveled can really work?

In terms of purification process, according to the prospectus, the purity of injection-grade recombinant human albumin should be more than 99.9999%, and host cell impurities are required to be safe. This is also the main area of excipient-grade and clinically injectable grade recombinant human albumin. Excipient grades do not need to achieve 99.9999% purity like injection grades.

This is due to the relatively large clinical dose of human albumin, and for the body's immune system, milligram or microgram level bio-derived impurities may be fatal. You may be thinking that continuous purification always meets the purity requirements.

But there is also the issue of cost to consider. If the cost of recombinant human albumin exceeds that of human blood albumin, how can there be a cost advantage. How to obtain high-quality recombinant human albumin at low cost is one of the core issues in the development of this product.

Another example is the issue of scale, from overseas experience, despite efforts by researchers and companies to draw a line between traditional GM foods/feeds and plant-based synthetic organisms, the latter is still embroiled in escalating conflicts between the food industry, regulators, environmental groups, the media, politicians and the public.

There are also many companies that have fallen victim to conflicts, such as SemBioSys Genetics, whose biosimilar insulin is in phase I/II clinical trials. Monsanto, Bayer, Dow, and Syngenta withdrew.

Until today, researchers and businesses have been eager to promote the economic benefits of plants, seeking balanced measures between the environment, economy and technology.

Of course, setbacks and risks are frequent visitors on the road to new drug development. This does not change the trend of new drugs forward, just as genetic engineering greatly promotes the development of biological drugs, and in retrospect, groundbreaking research is the technical trigger point, which has led to an explosion of scientific research.

Today, more and more cutting-edge biotech platform technologies are maturing. Cell and gene therapies, mRNA, protein degradants, multispecific antibodies, and antibody-drug conjugates are crossing from uncertain territory to near-defined therapeutic domains.

This time the new crown epidemic has accelerated the industrialization of mRNA technology. The success of the new crown vaccine has increased the confidence of mRNA players around the world in the future of the technology.

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

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

In any case, we look forward to the day when human albumin is no longer in short supply.