Xie Yuli: The development trend of new biomedical technologies

Drug development is complex and complex, and simple is simple, in fact, it is two parts: one is to understand the biological mechanism behind the occurrence and development of diseases, and the other is to find the means

01 Focus on biology from the perspective of physics to develop drugs

01 Focus on biology from the perspective of physics to develop drugs

For decades, we have studied the chemical reactions of biological macromolecules, or the interactions

Last year, Dr Roger Perlmutter, former Chief Scientific Officer (CSO), in collaboration with Professor Eric Betzig, a Nobel laureate in the invention of the fluorescence microscope at Bell Labs in the United States, founded Eikon, a company that observes the trajectory of proteins in the living cell state through fluorescence microscopy, that is, the spatiotemporal changes of proteins inside the cell, to see how the trajectory of proteins in normal and pathological states differs

So we can see that some companies in the U.

02 Biological phase transformation, a track that is gradually getting hot

It is worth mentioning that in biological research from the perspective of physics, there is one area that is developing very quickly - biological phase transformation (or phase separation/biocoagulant).

But until recently, the phenomenon has become particularly hot, and as some techniques have evolved, researchers have begun to revisit some of the findings

Although China's biomedical industry has made great strides in development in recent years and has made some achievements in the production of new drugs, there is still a big gap compared with the United States, especially in cutting-edge and revolutionary fields

Specifically

Without biological phase separation, we can't think of it at all, and we can't talk about making drugs, and with such a discovery, we know how to screen chemical drugs that can be enriched in small droplets

03 New biomedical technology with each passing day

Next, I will introduce technical means, that is, how to intervene in various life activities

Be forward-looking

Next, I summarize the characteristics

First, simulate the mode of regulation of the organism itself

Another example - KRAS target, previously thought to belong to the "incurable" target, like a slippery ball without a "pocket", it is difficult to do with traditional small molecules, but now through the covalent reaction, researchers can induce a "pocket" on it, which opens the door

Another example that everyone may know - PROTAC, which is actually a regulation

Recently, Arvinas, the leading company that proposed PROTAC, has made some preliminary data in the clinic, such as at least degrading the target, and we can also see some simple efficacy, so the whole track is very hot, whether it is academia or industry

2.

The more classical gene therapy refers to the gene transmitting genes into the human body through AAV to express a certain protein, but the current gene therapy is more extensive, including gene therapy such as small nucleic acids, gene editing, etc.

Above I summarized the development process of nucleic acid drugs, and the field of small nucleic acids has experienced several ups and downs

Compared with other new technologies, I think the development of nucleic acid drugs will be faster, because it is more like traditional drugs, small nucleic acids are actually chemical drugs, which can be synthesized chemically
.
At present, there may be more than a few hundred nucleic acid projects under investigation worldwide (excluding the COVID-19 vaccine projects
under investigation).
Sales of such drugs are expected to exceed $
10 billion by 2025.
So, I think it will soon become the third largest drug type after small molecules and monoclonal antibodies, and it will develop faster than in the field of cells and gene editing
.
Everyone may have heard of
mRNA technology because of the rise of the new crown vaccine.
We summarize in one sentence: it is protein substitution, and all protein drugs can theoretically be replaced
by mRNA.
mRNA can replace monoclonal antibodies, and can also be applied to regenerative medicine, because many transcription factors are also protein molecules, and such drugs do not need GMP workshops, directly hit the small dose of mRNA to the human body, you can express itself, equivalent to moving the protein factory to the human body
.
But it also has shortcomings, when it is a vaccine, as long as a small amount of mRNA can stimulate the human immune response, and as a therapeutic protein is not the same, it needs to be in the right place, express the right protein, but also need to be correctly modified, so it is much rare, so mRNA technology for therapeutic proteins, there is no substantial breakthrough
.

So, I think it will soon become the third largest drug type after small molecules and monoclonal antibodies, and it will develop faster than in the field of cells and gene editing
.
But it also has shortcomings, when it is a vaccine, as long as a small amount of mRNA can stimulate the human immune response, and as a therapeutic protein is not the same, it needs to be in the right place, express the right protein, but also need to be correctly modified, so it is much rare, so mRNA technology for therapeutic proteins, there is no substantial breakthrough
.

Programmatic pharma also has the potential to achieve true drug customization, which is relatively simple in design and can develop a drug
for you for a single patient.
For traditional medicine, this is almost impossible, but new technologies such as nucleic acids can do it
.
In fact, for the first time in the history of the US FDA, the drug developed for a patient was approved, and two FDA executives also wrote a review in the journal: Suppose when such a single-patient era comes, what should we regulate? The article explains how patients and doctors will become partnerships
.
The safety, efficacy and clinical statistical significance of the drug will no longer exist
.
A series of problems such as who has the final say and how to pay for product quality control show that the single-patient era will change
the entire regulatory model.
Of course, this technology is still very early, and I think with the development of new technologies, it is possible to achieve drug customization
on a large scale within ten years.
Gene editing techniques
are also involved in nucleic acid drugs.
Among them, CRISPR/Cas9 technology won the Nobel Prize in 2020 and is also the most classic of gene editing technologies, and many technologies are continued
from here.
Currently, it also has some visible proof-of-concept data clinically, so it has a high valuation
.
Gene editing companies founded by Zhang Feng, David Liu and other "big bulls" in the gene editing industry have also been listed on the NASDAQ, so gene editing is a very hot field
in terms of investment and entrepreneurship.

04 Interchange, combination and upgrading of drug forms

04 Interchange, combination and upgrading of drug forms

A new trend in the development of pharmaceutical technology is the interchange, combination and upgrading
of drug forms.
Drug form swapping can occur between a variety of drug forms, such as small molecules, monoclonal antibodies, siRNAs, and more of a concern for gene editing
.
The exchange of drug forms may have different biological effects
.

In the development of tumor drugs, two different interchange mechanisms can even be combined to achieve the effect
of overcoming drug resistance.
For example, a small molecule inhibitor of HER2 is combined with HER2 monoclonal
antibody.
This is a cost-effective technological innovation direction
.
In addition, combinatorial innovations
can be made between different drug forms.
Combinatorial innovation refers to exploring the new nature of its emergence by combining multiple single technologies
.
This direction is particularly suitable for Chinese companies to innovate, because it is relatively difficult to innovate from 0 to 1 at present, and the advantage of combined innovation is that its single technology has generally been published in the public domain, will not be restricted by patents, and the cost performance will be relatively high
.

This direction is particularly suitable for Chinese companies to innovate, because it is relatively difficult to innovate from 0 to 1 at present, and the advantage of combined innovation is that its single technology has generally been published in the public domain, will not be restricted by patents, and the cost performance will be relatively high
.

A very classic example is the recent more concerned DS-8201, which is an antibody-conjugated (ADC) drug that targets HER2, and recently, it has achieved great success, it has a good effect on solid tumors, and the therapy for breast cancer and non-small cell lung cancer has been approved, especially for breast cancer with low expression in HER2
.
What is the structure of the DS-8201? The figure above shows that its ADC is divided into three parts: monoclonal antibodies, connecting agents, and small molecule toxins
.
These three things have existed for a long time, the first three through more than ten years of polishing, after continuous optimization and combination, and finally made such a very revolutionary drug
.
As can be seen from this example, many times the innovation of drugs is the innovation of technical science, which is a certain difference
between this and basic research.
Articles on DS-8201 were only published in small journals with low impact factors, not cell and nature, but that did not prevent it from becoming a revolutionary drug
.
The technical sciences are very trivial, there is no theoretical guidance, it requires constant polishing and experimentation, patience and craftsmanship, so I often joke that the DS-8201 is only available to
the Japanese.
This is worth learning from
many of our innovators and biomedical companies.
Sometimes we will say that China's original is not good, basic research is not good, in fact, it is not necessarily, like the research and development of DS-8201 technology does not need any basic original innovation, and many original drugs approved in recent years are not obtained by
basic research.
Although basic research is very important for the entire biomedical field, it may not be necessary for specific companies
.
We must clarify the relationship between innovation and basic research, as well as the relationship between science and technology, in order to make innovations
suitable for us in a targeted manner.
Another example of combinatorial innovation is bispecific antibodies
.
At present, monoclonal antibody is already a relatively mature technology, but monoclonal antibody drugs have a limitation, it is a biological macromolecule, can not penetrate the cell membrane, generally can only act on the receptors on the surface of the cell membrane, which leads to the bottleneck it faces: lack of targets, homogenization competition is very fierce, want to solve the problem of too few high-quality targets, you need to carry out target combination innovation, such as making double antibodies and multiple antibodies
.

Although basic research is very important for the entire biomedical field, it may not be necessary for specific companies
.
We must clarify the relationship between innovation and basic research, as well as the relationship between science and technology, in order to make innovations
suitable for us in a targeted manner.
Lack of targets, homogenization competition is very fierce, to solve the problem of too few high-quality targets, you need to carry out target combination innovation, such as making double antibodies and multi-antibodies
.

The classic bi-antibody of a bispecific antibody is actually a cell binder, similar to a molecular glue, pulling two types of cells together
.
For example, pulling T cells together with tumor cells and letting T cells "kill" tumor cells, the classic dual antibody is Genentech's BiTE antibody drug
.
Of course, now the concept of double antibody has been expanded
.
For any molecule that contains two binding sites, such as binding to two different targets on the same cell, or even different epitopes of the same target, we call it a dual antibody
.
Dual antibodies also produce some new properties, which we call "More is different"
.
Dual antibody technology is now particularly popular, and the Johnson & Johnson EGFR/MET dual antibody approved last year is a particularly famous star molecule
.
In fact, its design is very simple, EGFR variant is a non-small cell lung cancer driver gene, MET amplification is also, target it to two targets, you can increase efficacy, overcome drug
resistance.

What is the difference between EGFR/MET dual antibody technology and the combination of two monoclonal antibodies? In fact, the two antibodies in the same molecule will emerge many new properties, to EGFR / MET as an example, EGFR and MET affinity is different, EGFR affinity is weak, MET affinity is stronger, is 40 times the EGFR, the advantage of the combination of the two is that in normal tissue, MET expression is relatively low, at this time it alone the effect is equivalent to EGRF monoclonal antibody, the binding force is relatively weak, the side effects will be relatively small, but in the tumor cells, MET will be highly expressed, The effect at this point is equivalent to an ADC, pulling the molecule near
the tumor cell.
But this is not the most important, EGFR/MET dual antibody also has an immune effect called ACDT, that is, it can combine with macrophages, produce cell gnawing, and suck the c-MET and EGFR of tumor cells into macrophages
.
This is sometimes not possible with the combination of two monoclonal antibodies, and it is precisely the largest
number of macrophages in non-small cell lung cancer.
Therefore, the combination of various characteristics of the double antibody makes it a very successful drug
.
The emergence of dual antibodies determines its success, which provides a good example
for us to do double antibody research.
In addition, the more complex combination platform is the
cell.
Cells are like aircraft carriers, like the pluripotent stem cells (iPSCs) that everyone pays more attention to now, and the well-known CAR-T treatment
.

CAR-T is the T cell through gene editing to install a "radar", that is, antibodies, the antibody and T cells combined together, so that the antibody recognizes the specific receptor or antigen on the tumor, pulls the T cells and tumor cells together, and then "kills"
the tumor cells.
Of course, CAR-T now faces a variety of challenges, such as CAR-T is now only more effective on blood tumors, but less effective on solid tumors, the main reason may be that it can not enter the solid tumor, or it may not
work biologically.
Another challenge is that CAR-T is a living drug that produces and controls its chemical composition (CMC) completely differently
.
From the very beginning, patients have to draw blood, store, and reinfuse, and the cost of a set of processes is very high, so it is also very
challenging in commercialization.
But in response to various challenges, various biotech companies are doing some new research to find breakthroughs
.
There may be some major breakthroughs at a certain point in the near future, and a breakthrough at any one point is likely to lead to some revolutionary drugs
.

But in response to various challenges, various biotech companies are doing some new research to find breakthroughs
.
There may be some major breakthroughs at a certain point in the near future, and a breakthrough at any one point is likely to lead to some revolutionary drugs
.

For solid tumors, a variety of cell therapies are being tried, in addition to CAR-T, but also TCR-T
.
In view of the problem that CAR-T cannot enter the solid tumor, the TILs that have entered the tumor can be separated, so that it can play the function of
homing.

At the same time, since last year, NK cells have also received attention, because NK cells are more like drugs, it has more gentle, versatile and other characteristics, less side effects, shorter
half-life.
On the other hand, it is relatively lethal, so it sometimes needs to be administered multiple times like traditional drugs
.
One of the biggest benefits of NK is that it is different from CAR-T, and it does not need to be made into an allogeneic (a patient can only correspond to a specific CAR-T, there is no general-purpose CAR-T with better results), NK cells can induce pluripotent stem cell production, so that batch production can be carried out, more like traditional drugs, and it is also expected to reduce costs
。 Some people will also ask: NK cells have a short half-life, need to be administered multiple times, and the cost has not become higher? The answer to this question is actually more complicated, but in the field of NK, the American Fate company recently released some clinical data, although not so amazing, but from the data point of view is still good, now NK has also become a more important direction of
cell therapy.
In addition to cells, oncolytic viruses are also a technology portfolio platform
.
Oncolytic viruses have been on the market before, but the effect is very poor
.
Today, by combining its technologies, oncolytic viruses can selectively kill tumor cells on the one hand, and as a delivery platform on the other hand, to express PD-1 and various cytokines
.

05 Empowering technology for drug discovery - artificial intelligence

05 Empowering technology for drug discovery - artificial intelligence

As an enabling technology in many fields, artificial intelligence makes us wonder whether artificial intelligence technology can bring some changes to the biopharmaceutical field.
In recent years, artificial intelligence as a particularly hot field, there are also many
financing and companies related to it.
However, it is not short of controversy within the biomedical industry: "Is artificial intelligence really that magical?" "Can AI really make a substantial difference to pharmaceuticals?" "The controversy over artificial intelligence can be described as a matter of opinion, the wisdom of the wise, no matter what, artificial intelligence as an enabling tool, the successful application in other fields is obvious to everyone, in the field of biomedicine may be no exception
.
" However, due to the characteristics of the biomedical field, the application of artificial intelligence in this field may not be as simple as in other industries, but it will not be as pessimistic as many people say, and it needs to be viewed
with a relatively open mind.
But I have to admit that the progress in the field of artificial intelligence is very rapid
.
In the field of chemical synthesis, for example, the University of Liverpool in the United Kingdom published a cover article in Nature, designing a chemical robot to complete 668 experiments
in 8 days.

However, due to the characteristics of the biomedical field, the application of artificial intelligence in this field may not be as simple as in other industries, but it will not be as pessimistic as many people say, and it needs to be viewed
with a relatively open mind.

The pace of labor is much slower, and an experienced chemist can only do about a dozen chemical reaction experiments
a week.
It is foreseeable that automation and intelligence in chemical synthesis will arrive earlier than in the pharmaceutical field, and will soon be commercialized
.
At present, the automation of semi-automatic laboratories and the synthetic design of artificial intelligence have been commercialized
.
If technology continues to advance, commercial products of fully automated robotics will most likely emerge in as little as five years, which will greatly accelerate the efficiency of chemical synthesis and empower the discovery
of small molecule drugs.
In addition, we pay more attention to the progress of artificial intelligence in the field of biology, such as The DeepMind company under Google has developed software to predict the three-dimensional structure of proteins, which shows that artificial intelligence has really penetrated into the molecular level
.

As we all know, it is not easy to analyze the structure of a protein by traditional methods, such as a well-done structural biologist, who may only be able to make a few protein structures per year, but artificial intelligence can quickly predict the three-dimensional structure of proteins based on gene sequences, and its promotion of biological development will be self-evident
.
DeepMind's latest achievement is that they have predicted the structure of almost all proteins on Earth and made a database
.
Although their accuracy is certainly not enough, their accuracy is completely comparable to that of cryo-EM in the laboratory for the prediction of simple proteins
.
Of course, the conformation of biology is dynamic, there are all kinds of protein interactions, as well as interactions with small molecules, which is a very complex process, so these simple protein structure predictions have not yet had a revolutionary impact on
the pharmaceutical field.
But importantly, it brings with it a noteworthy expectation, like when the train was first invented, it ran slower than a horse-drawn carriage, but it ran faster and faster behind it, and we can't rashly conclude that the train is not going to work just because it was slow at first, and
so is artificial intelligence technology.
The impact of artificial intelligence on pharmaceuticals may not be stormy, but there will be silent changes in moisturizers at various points, and eventually from quantitative to qualitative changes, such as in the process of pharmaceutical research, it can assist drug design, find literature, promote the efficiency of chemical synthesis, find targets, etc
.
Until one day, after all these points are connected, a revolutionary change
may occur.
But when will this day come? No one knows
.
It may come overnight, or it may come in 100 years, and this disruptive technology is difficult to predict
.
06 Innovation of drug delivery technology

Of course, the conformation of biology is dynamic, there are all kinds of protein interactions, as well as interactions with small molecules, which is a very complex process, so these simple protein structure predictions have not yet had a revolutionary impact on
the pharmaceutical field.
The impact of artificial intelligence on pharmaceuticals may not be stormy, but there will be silent changes in moisturizers at various points, and eventually from quantitative to qualitative changes, such as in the process of pharmaceutical research, it can assist drug design, find literature, promote the efficiency of chemical synthesis, find targets, etc
.
06 Innovation of drug delivery technology

For so many new technologies just introduced, from the practical level, the most critical one is drug delivery
.
As early as 2003, when RNA drugs were most concerned, they ignored its delivery problems
.
RNA is difficult to deliver to the human body, the genetic material of many viruses is RNA, the human body is impossible to actively let such viruses enter, nature has designed a multi-layer firewall
.
Therefore, how RNA drugs enter the human body is the most critical problem for all new nucleic acid technologies
.

Therefore, scientists like Zhang Feng and Liu Ruqian, who do gene editing, are developing their own delivery technology, which shows that delivery technology is very important and very lacking
.
In terms of delivery systems, there is a lipid nanoparticle (LNP) technology, and now there are various studies to try to improve its delivery efficiency, or to do the selectivity of target organs, and many researchers are constantly pondering it
.
I think liver targeting is the most mature and best technology at the moment, but it also has a flaw: after the receptor on the liver cell brings the nucleic acid into the cell, it enters the endocytosis
.
But the polarity of nucleic acids is very strong, can not come out of the endophagus, so the general efficiency is very low, that is, only a few molecules can escape from ten thousand molecules
.
Therefore, if someone can study this mechanism clearly and improve the efficiency, even if it becomes 10%, then this field will also undergo revolutionary changes, because once this technology is available, the dose of medication will drop a lot, the corresponding excipients will be much less, and this result may even win the Nobel Prize
.
Of course, there are also companies that have tried, such as ArrowHead, which once used a bee toxin to punch holes in the endocytosis to let small nucleic acids come out, but punching holes in the endocytosis will lead to increased
drug toxicity.
So far, there has been no accurate escape mechanism for small nucleic acid molecules, and there are also small companies listed on naslaq, claiming that they have found some laws, but so far they have not seen reliable data
.
Another idea is to simulate nature, such as exosome delivery, which is the small bubble secreted by our cells and contains many RNA and proteins, whether it can use its homing function
.
In addition, red blood cells do not have nuclei, whether it can be used as a drug carrier, in addition, platelets and the like can also do such attempts
.
Many companies in Europe and the United States are studying these very novel delivery technologies
.
Dyno, founded by George Church, is experimenting with aisling with AAV proteins to create an AAV protein
that humans never thought of.
Similarly, a company founded by another Harvard professor is also conducting research in this area, and there is a FlagShip-incubated company, Ring Therapeutics, which is working on the delivery of
new viruses.

Dr.
Xie Yuli introduced

Dr.
Xie Yuli introduced

CEO and founder
of Micro Biomedical Technology (Shanghai) Co.
, Ltd.
He graduated from the Department of Chemistry of Nankai University, ph.
D.
from Shanghai Institute of Materia Medica, Chinese Academy of Sciences, and postdoctoral fellow
from Columbia University.
He has worked in research institutions and pharmaceutical companies such as Columbia University School of Medicine, Yangtze River Pharmaceutical, Japan's Otsuka Pharmaceutical and WuXi AppTec, and in 2017 and 2018, he founded the biomedical companies Suzhou Andi ling and Shanghai Weijing and served as THE CEO
.

Dr.
Yuli Xie has more than 20 years of experience in drug discovery and project management, and is familiar with new targets and cutting-edge technologies, as well as regulations, policies and markets
.
In his spare time, he actively participates in and organizes industry activities, and serves as the vice president of the Suzhou Institute of Pharmaceutical Innovation of the Shanghai Institute of Materia Medica of the Chinese Academy of Sciences, the professor of the Course of Yihong Business School of Shenyang Pharmaceutical University, and the editorial board of "Pharmaceutical Progress", and his published popular science articles and reviews have been praised by the
biomedical industry.