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Professor Zhou Caicun: Lung cancer treatment and drug development

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Zhou Caicun

Director of the Institute of Oncology, School of Medicine, Tongji University

Consultant of Freehand Clinical R&D Club

On September 16, Professor Zhou Caicun, Director of the Cancer Research Institute of Tongji University School of Medicine and Advisor of Tongfreehand Clinical R&D Club, made a report entitled "Lung Cancer Treatment and Drug R&D" at the Tongfreehand President's Living Room activity - "The Disruption of Innovative Drugs and the Future of Biotech", which is organized
according to the content of the report.

The efficacy of targeted therapy and immunotherapy for lung cancer has reached a platform, and it is difficult
to go a little further on the existing basis.
So what should we focus on now? In drug research and development, there must be new biology, new drug research and development technology and drug discovery empowerment technology in order to keep up with the rhythm
of technological updates.
In the past, we found some targets, but they couldn't become drugs
.
With drug discovery enablement, the likelihood of off-the-shelf drugs, such as KRAS mutations
, increases.

Today, talking about the current status of lung cancer treatment drug research, in fact, the current status
of the entire tumor treatment drug research.
Lung cancer is not just a disease of the lungs, advanced lung cancer is a systemic disease
.
Being a lung cancer specialist is fortunate because all new methods are used
.

In the past 20 years, small molecule targeted drugs have been approved one after
another.
The study of targeted drugs is relatively simple
.
We find a pathway, inhibit it, and it may be effective for
the tumor.
But this pathway must be most important, specific, and safe
for tumors.
Otherwise, if the tumor dies and the person dies, there will
be no therapeutic value.

There are many ways to treat lung cancer, and as an expert in the treatment of lung cancer, I am very fortunate that many new treatments can be used, including targeted therapy, immunotherapy, etc
.
The current standard mode of first-line treatment for advanced NSCLC is still monoclonal antibody ± chemotherapy
.
In terms of the immune market, lung cancer accounts for at least half of the total
.
It also has better
efficacy than other types of tumors.
Immunomonotherapy or immunocombination chemotherapy has become the standard of first-line treatment for driver-negative advanced NSCLC, which is familiar
to everyone.

Oncology drug development is characterized by a short life cycle, especially lung cancer, which is fleeting
.
Treatment strategies are developing too quickly, increasing costs, and ramping up is rampant
.
Chinese can solve the phenomenon of clustering, the situation will be much
better.

For EGFR mutations, we have first, second and third generation targeted drugs, which started in 2001-2002 and are exactly 20 years
now.
The third generation of targeted drugs entered the market
last year.
In fact, the opportunity for the second generation of targeted drugs is very short, and the third generation of targeted drugs is
on the market just a few years later.
Targeted drugs are ultimately resistant
.
What should I do if I am resistant? The domestic approach is to continue to push forward for a certain target, but how is it done abroad?

Bispecific antibodies combined with third-generation targeted drugs as first-line drugs to treat EGFR-mutated NSCLC, these two together, the vast majority of tumors are
small.
The combination regimen was quickly approved in the United States for the treatment of
patients with failed EGFR TKIs.
The results of phase II clinical studies of bispecific antibodies combined with third-generation targeted first-line treatment of EGFR mutation patients with a small sample size showed that the ORR reached 100%, which is a rare efficacy
so far.

No matter how good the efficacy of targeted drugs, including the first, second and third generations, the effective rate is about
70%.
There are still many third-generation targeted drugs in China doing clinical research, and after approval, whether there are still market opportunities is a question
worth considering.

The development of fourth-generation targeted drugs faces the same problem
.
After development, there may be no more patients
.
The resistance mechanism of bispecific antibodies combined with third-generation targeted drugs is currently unknown, is there an EGFR C797X mutation?

This places high demands on every company's Chief Medical Officer (CMO), who must be forward-looking
.
To understand the situation of competitive products in the market, pay attention to the replacement of drugs, and see the market prospects
of products in at least 5 years.
If the situation is unfavorable, stop loss
in time.
Now many manufacturers are doing the fourth generation of targeted drugs, the biggest worry is that after the product is launched, there is no corresponding market, and patients with such targets can no longer be found
.

Therefore, our requirements for the fourth generation of targeted drugs are that they must have wide coverage, be effective against sensitive mutations, and have excellent efficacy with PFS for 30 months
.
With such a drug, the product market will be very large
.
In short, it is necessary to achieve the combination of industry, education and research, realize that new biological mechanisms are the source of drug innovation, and adopt new technologies, including simulating the regulation mode of organisms themselves, programmable medicine, and the exchange, combination and upgrading of drug forms
.
It is also necessary to be good at using drug discovery enabling technologies, such as: AI (artificial intelligence), drug delivery technology, chemical modification, etc
.

The efficacy of immunotherapy has reached a platform, and it is difficult
to go a little further on the existing basis.
So what should we focus on now? In drug research and development, there must be new biology, new drug technology and drug discovery empowerment technology in order to keep up with the pace
of technological updates.
In the past, we found some targets and tried many methods, but failed to develop effective drugs, which is difficult to become a drug
.
With drug discovery enablement, the likelihood of drugging against these targets increases
.

New biological mechanisms are the source of drug innovation, and in 2021, top journals published many important discoveries
with translational potential.
For example: cellular transcription factors ID3 and SOX4 that enhance CAR-T activity, CD93, DDR1, GABA receptors, COP1, RBM39, ELANE and CD161 that regulate immunity, B4GALT1, IL-27, HULC, GRP75, and DNPH1 that regulate metabolism, new kinase targets CLI1-LTK and TNK1, epigenetic targets METTL3 and NSD3, etc
.

CD93 is the latest published immune target by Professor Chen Lieping of Yale University
.
Studies have shown that blocking the CD93 pathway can reshape the vasculature of the tumor microenvironment, in addition to increasing the number of effector T cells and improving immunity, it can also improve the intratumoral penetration
of chemotherapy drugs.

In November 2021, the team of Li Rong of the University of Washington and An Zhiqiang of the University of Texas published in Nature about DDR1, a new target that regulates immune escape, and they found that DDR1 induces tissue collagen fibers to shield immune cells from entering tumors
.
Meanwhile, Parthenon, a company founded on this discovery, announced a $65 million Series A funding round to develop a "first-in-class" antibody drug
targeting DDR1.

In 2021, the US FDA approved 50 new drugs, many of which are new targets
.
The 21 First in Class drugs include Merck's HIF-2α inhibitor Belzutifan, Amgen's KRAS G12C inhibitor Sotorasib, and Johnson & Johnson's EGFR/c-Met bispecific antibody Amivantamab
.

In 2021, the FDA also urgently authorized or officially approved the new crown mRNA vaccine, neutralizing antibodies, and small molecule oral drugs Molnupiravir and Paxlovid
.

How to make innovative drugs? We should find innovative targets and innovate
from the source.
The manufacturer can't find the target, why? Some manufacturers just sit in the office to check the information, relying on the office to check the information can not find innovative drugs
.
Some manufacturers pay attention to animal testing, but animal testing of many products is effective, but it is not good to use people
.

The research and development of real drug mouths should come from clinical practice and do translational research
.
Human tumor tissue is required and clinical research centers
need to be coordinated.
Why can't manufacturers do it? Because the manufacturer has no human pathological tissue
.
The research and development of new drugs by pharmaceutical companies should be combined
with the production, education and research of hospitals.
(Note: This is in
line with the basic spirit of ICH E8 R1.
) ICH E 8 R1 requires that all Stakeholders be involved in the development of new drugs, including R&D, hospitals, investigators and patients.

We are now the best time
to innovate at the source.
In the past, it often took ten years for a product to go from the United States to China
.
Because the Chinese market is small, manufacturers must first occupy the US market, then to Europe, to Japan, and finally to China
.
The gap has now narrowed, with immunotherapy only 2 years
apart.
A large number of clinical studies of PD-(L)1 monoclonal antibody have been carried out in China, and many exploratory analyses
have also been carried out.
At the same time, no matter how good the product, there is acquired resistance
.
Finding a solution to acquired drug resistance is innovation
.
Many manufacturers are reluctant to spend money on exploratory and translational research, and are reluctant to collect specimens, but this is often the best way to
find new targets.

In recent years, a large number of new drug technologies
have emerged in the field of biomedicine.
Drug technology has been following the "central law" of life for a hundred years, covering proteins, nucleic acids and genes from the outside to the inside, including the earliest traditional drugs targeting proteins, the re-emerging nucleic acid drugs, and the latest gene therapy and gene editing that precisely manipulate RNA and DNA molecules
.
In addition to the classic small molecules, peptides, proteins, polysaccharides and nucleic acids, more complex living drugs
such as cells, viruses and intestinal bacteria have also emerged.

Another trend in the development of pharmaceutical technology is Programmable Medicine, and another trend in the development of pharmaceutical technology is the exchange, combination and upgrading
of drug forms.
Here are some of the new technologies:

1 Covalent inhibitors

Covalent inhibitors are a class of small organic molecules that can interact with specific target proteins and form covalent bonds, resulting in changes in protein conformation, thereby inhibiting protein activity
.
Protein modification by covalent inhibitors is usually irreversible, bringing long-lasting efficacy and differentiated regulatory methods, which have become a hot spot in the development of anti-tumor drugs, such as EGFR, BTK and KRAS G12C inhibitors
.
Previous covalent drugs were highly toxic due to lack of specificity
.

Today, we can design highly selective covalent inhibitors
based on the structure of the protein.
For example, a rationally designed acrylamide compound can react rapidly with the sulfhydryl group of cysteine only in the microenvironment of the target protein
.
Covalent inhibitors are small organic molecules that interact with specific target proteins and form covalent bonds, resulting in changes in protein conformation, thereby inhibiting protein activity
.

Although KRAS G12C inhibitors are approved in the United States, their efficacy is not ideal
.
PFS is prolonged with second-line chemotherapy, but there is little improvement
in OS.
Now many domestic manufacturers are also doing KRAS G12C inhibitors
.
What needs to be considered is whether you are going to do Me Too or Me Better
.
If there is no good effect, it is difficult to upgrade from a second-line treatment to a first-line treatment
.
For example, the current PFS of KRAS G12C inhibitors can reach 6.
5 months, but immunotherapy plus chemotherapy can reach 9 to 10 months
.

2 Protein degradation technology

Common protein degradation techniques are PROTAC (Arvinas, Nurix and Kymera) and molecular glue (Monte Rosa).

。 Relatively new technologies include cell membrane protein degradation technology LYTAC (Lycia) and extracellular protein degradation technology ATAC (Avilar) developed by Professor Carolyn Bertozzi of Stanford University, ATTEC (PAQ) developed by Professor Lu Boxun of Fudan University based on autophagy protein LC3, autophagy degradation AUTAC, chaperone-mediated protein degradation CHAMP (Juno Biologics), RIBOTA for RNA degradation, DUBTAC (Stablix), bifunctional degradation technology (Amphista) and antibody-conjugated degradation drug AnDC (Orum) that degrade DUB generally mimic the intrinsic protein degradation mechanism
of ubiquitination, autophagy and endocytosis.

Multi-level control is the basic law
of life.
Each link of the central law has a full range of regulations, including genes, epigenetic modifications, transcription and protein expression
.
Specific to the protein, the regulatory goals of drugs include protein synthesis, degradation, function, conformation and interaction with other life molecules
.
Moreover, the same target, different regulatory methods produce different
biology and phenotype.
Allosteric inhibitors that regulate protein conformation and PPIs that inhibit protein interactions have become popular small molecule drug technologies
in recent years.

Different from traditional protein function inhibitors, drugs that induce protein degradation are considered to have the advantages of overcoming drug resistance and increasing selectivity, and have become quite fashionable in
recent years.

Molecular glue is a classic example
of mimicking biological regulation.
As the name suggests, molecular glue refers to a class of compounds
that bind two protein molecules together.
When two molecules are close together, chemical reactions and biological effects
occur with each other.
For example, when one of the protein molecules is ubiquitin ligase, the molecular gel can cause ubiquitin modification of the other protein and degrade
through the proteasome pathway.
Plant auxin, i.
e.
indoleacetic acid, is a molecular gel
that degrades gene suppressor proteins through this principle.
Studies have found that the immunomodulatory drug lenalidomide and the anti-cancer drug Indisulam have similar mechanisms
of action.

PROTAC is a new small molecule technology
designed according to this principle to bring two proteins closer together and induce the degradation of the target protein.
Specifically, the ubiquitin-binding molecule (binder) is linked
to the target protein-binding molecule through a linker.
In this way, PROTAC molecules contain three parts, usually with a large molecular weight, which is no different from
conventional molecular glue in terms of mechanism of action.

In 2021, companies such as Arvinas, Nurix and Kymera have obtained preliminary clinical data
for PROTACs targeting targets such as AR/ER, BTK and IRAK4.
It can effectively degrade the target protein without significant side effects, but whether the efficacy is better than the existing small molecule inhibitors has yet to be clinically verified
.

Of course, the meaning of molecular glue is broader, pulling two proteins together does not necessarily have to occur protein degradation, but can also inhibit the function of
the target protein by forming a ternary complex structure.
For example, Revolution's molecular glue drug that inhibits KRAS G12C and G12D by recruiting endogenous proteins cyclophilin has recently had impressive preclinical data published
.
The principle of proximity is ubiquitous in nature and is widely used
in drug design.
The classic bispecific antibody is actually a "cell glue" technology, or cell engager
.

For example, Genentech's BiTE bispecific antibody binds to the antigen CD19 of tumor cells at one end and CD3 of T cells at the other end, pulling tumor cells and T cells together, allowing T cells to kill tumor cells
nearby.
Immunocore's newly approved TCR therapy Kimmtrak is similarly designed: binding to the T cell receptor CD3 at one end and a high-affinity TCR
that recognizes the tumor antigen GP100 at the other.
Recently, the Fu Yangxin team at Southwestern Medical Center in the United States reported a bispecific antibody targeting T cell CD3 and DC cell PD-L1, a novel design of bispecific antibodies that can induce a more durable anti-tumor immune response
.

Johnson & Johnson's EGFR/c-Met bispecific antibody and Roche's newly approved VEGF/Ang2 bispecific antibody target two targets
on the same cell.
In China, dozens of similar bispecific antibodies have entered the clinic for the
combination of different targets.
For example, Akeso recently announced the phase II data of PD-1/VEGF bispecific antibody combined chemotherapy for NSCLC, and the DCR reached 100%.

In theory, if the bispecific antibody combines two targets or different epitopes of the same target at the same time, it can greatly enhance the affinity of each other, which is somewhat similar to the "molecular glue" technology
.
In addition, monoclonal antibio-mediated cytotoxicity such as ADCC and CDC is essentially a "cytogel" effect, which is increasingly valued
in the design of anti-tumor drugs.

3 PROTAC technology: a tool for new drug development

PROTAC (PROteolysis TArgeting Chimera) is a drug development technology that uses the ubiquitin-proteasome system to degrade target proteins, and is also a technology
based on the Nobel Prize in Chemistry.
The PROTAC compound is structured as an E3 ubiquitin ligase ligand and a target protein ligand linked together by a specially designed "Linker" structure to form a triplet
.
PROTAC technology induces the target protein into the protein degradation system in the process of degrading cancer cells to inactivate cancer cells, and does not necessarily have to bind to the active site of the target protein to play a role, which makes it theoretically effective for most proteins, and at the same time it can also overcome the problems
of traditional small molecule drug resistance.

The protein degradation technology represented by PROTAC uses a natural "recycling system"
in the cell.
Specifically, this system is called the "ubiquitin-mediated protein degradation system," which means that cells label unwanted proteins with "ubiquitin" and then send them to the proteasome inside the cell for degradation
.
The degraded product can be reused
by the cell.
In 2004, three scientists who discovered the system were also awarded the Nobel Prize
in Chemistry.

Interestingly, the Nobel Prize in Chemistry press release that year was quite forward-looking that drugs developed based on this system could be expected to destroy unwanted proteins and thus treat a variety of diseases
.
This is the theoretical basis for
protein degradation technologies such as PROTAC.
Taking PROTAC technology as an example, new drug developers will design a class of bispecific molecules, one end binds to the disease-causing protein they want to destroy, and the other end binds to the E3 ligase, which plays an important role in the protein degradation process, and the two are connected
by a linker.
In theory, the new molecule can "pull" E3 ligase near the target disease-causing protein and add ubiquitin to them, prompting cells to degrade these proteins and treat diseases
.

In 2001, Professor Craig Crews of Yale University and Professor Ray Deshaies of the California Institute of Technology jointly published a landmark paper - they designed the first functional PROTAC molecule and successfully degraded the target protein to complete a proof
of concept.
However, the part of the molecule used to bind E3 ligase is a polypeptide, which greatly limits its application
.

Fourteen years later, the storm changed dramatically
.
In 2015, Professor Crews' research group first published several papers in a row, reporting on the high potential of PROTAC small molecules; Professor Jay Bradner, who was still at Dana Farber Cancer Institute at the time, published an article in Science about another selective PROTAC molecule
.
The mechanisms mentioned in these papers have been validated in other drugs, so they quickly attracted the attention
of new drug developers.
"The whole field exploded
.
" Professor Crews said
.

Years before the explosion in the field of protein degradation therapy, Professor Crews founded a forward-thinking company called Arvinas to accelerate the scientific transformation
of this technology.
The company pioneered two investigational therapies in the clinical stage, targeting protein receptors and estrogen receptors
.
These are two very mature targets, as long as they can be degraded, they can bring clinical benefits
to patients.
Today, Arvinas' corresponding investigational therapies have achieved very promising clinical data, which also makes the industry full of expectations in the field of
protein degradation.

The challenges
of PROTAC technology.
The mechanism of action, which seems clear and easy to understand on the surface, is not so simple
in actual research and development.
As with all emerging technologies, PROTAC technology presents some challenges
.
A Nature Biotechnology article points out that "pulling" E3 ligase near the target protein does not ensure that the latter can be degraded
.
In practice, a stable ternary structure must be formed between different molecules and ubiquitination
must be ensured smoothly.
In addition, even if proteins are successfully ubiquitinated, it does not mean that they will be successfully degraded
.

4 CRISPR-CAS9 gene editing technology

On October 7, 2020, the Royal Swedish Academy of Sciences has decided to award the 2020 Nobel Prize in Chemistry to Dr.
Emmanuelle Charpentier of the Max Planck Institute for Etiological Research in Germany and Dr.
Jennifer A.
Doudna of the University of California, Berkeley, for their contributions
to the field of gene editing.

Emmanuelle Charpentier was born in 1968 in Juvis-sur-Orvie
, France.
He received his Ph.
D.
from the Institut Pasteur in Paris, France in 1995 and is currently the director of
the Max Planck Pathogenology Research Office.
Jennifer A.
Doudna was born in 1964 in Washington, D.
C.

He received his Ph.
D.
from Harvard Medical School
in Boston in 1989.
Professor at the University of California, Berkeley, and researcher at
the Howard Hughes Medical Institute.

In 2002, when Emmanuelle Charpentier founded her own research group at the University of Vienna, she focused on one of the pathogens that had the greatest impact on humans: Streptococcus pyogenes
.
Every year, Streptococcus pyogenes infects millions of people, and common symptoms, including tonsillitis and pustules, tend to be easily cured
.
However, it can also damage soft tissues in the body and lead to the development
of life-threatening sepsis.
To better understand Streptococcus pyogenes, Charpentier wanted to thoroughly study how the bacteria's genes are regulated
.
This decision became the starting point for
gene-editing technology.

In 2006, a UC Berkeley research team led by Dr.
Jennifer Doudna was working on
the phenomenon of "RNA interference.
" For years, researchers thought they had mastered the basic functions of RNA, but then suddenly discovered many new types of small RNA molecules that help regulate gene activity
in cells.

CRSPR-Cas9 gene editing technology comes from bacteria and is essentially an application of
the principle of biological proximity.
sgRNA is equivalent to a molecular gel, which locates the target DNA with the Cas9 protein with DNA cutting ability according to the principle of base pairing, and obtains an efficient and controllable DNA cutting tool
.
Different Cas proteins, such as Cas13, have also been developed to extend editing techniques to RNA molecules
.

5 Nucleic acid technology - a kind of programmed pharmaceutical

The above gene editing technology is actually a kind of
programmed pharmaceutical.
Noubar Afeyan, founder of Flagship, interprets it as designing and developing drugs like computer programming to improve biological
certainty.
The concept is not new, it was proposed after the discovery of small interfering nucleic acids (siRNAs) more than 20 years ago, when there was optimism that small nucleic acid drugs
that could silence any disease gene could be designed and synthesized according to the principle of base pairing.

After humans completed genome sequencing in 2003, the concept of programmed pharmaceuticals drove the development of the first nucleic acid drugs, but due to the immaturity of delivery technology, it soon failed
.
Until 2018, nucleic acid drugs re-emerged under the impetus of nucleotide chemical modification technology, as well as LNP and GalNac delivery technology, and a large number of star companies
such as Ionis, Arrowhead, Dicerna, Alnylam, Moderna and BioNTech emerged.
At present, more than 20 nucleic acid drugs have been approved, and hundreds of clinical trials are in progress, becoming the third largest drug technology
after small molecules and monoclonal antibodies.

Nucleic acid technologies, including antisense nucleic acids, small nucleic acids, mRNA, etc.
, together with equally programmable DNA synthesis, gene therapy and gene editing, constitute the frontier of programmed pharmaceuticals and are sought after by top venture capital firms
.
In particular, mRNA vaccines have come to the fore in this once-in-a-century epidemic, further promoting the development of related technologies, and new technologies and start-ups are emerging one after
another.

Companies and technologies that received attention in 2021 include Stoke's "TANGO" antisense nucleic acid technology that activates gene expression, Avidity BioScience's first antibody-siRNA conjugate drug to enter the clinic, OliX's permeable membrane cp-asiRNA, Alnylam's dual-target siRNA, and Lilly's and MiNA's saRNA, Flagship's tRNA company Alltrna and IncRNA company Laronde, VaxEquity's self-scalable low-dose mRNA technology, and cutting-edge companies such as Orna, Laronde and Ring Code Biologics pioneered circular RNA technology that does not require the addition of a cap and tail structure
.

The fast and intuitive design of nucleic acid drugs based on base sequences and affordable production costs make drug customization or single-patient times possible
.

6 ADC (antibody drug conjugate)

A classic example of a combination of drug forms is a monoclonal antibody small molecule conjugate drug (ADC).

Drug technology combinations were originally designed to exploit strengths and avoid weaknesses, such as ADCs, which use the specificity of monoclonal antibodies to bring toxins into tumor tissues and reduce damage to normal tissues
.

Daiichi Sankyo's DS8201 represents a new trend in ADC technology: on the one hand, high DAR values and bystander effects make it possible
to have toxins and payloads with moderate activity and different mechanisms of action.
The door to innovation is thus opened and the range of loads available is greatly increased
.

For example, the coupling of monoclonal antibodies to small molecule immune agonists (ISAC, TLRs/STING, etc.
) has become a hot direction, but unfortunately the clinical data reported last year is not satisfactory (Bolt and Silverback).

It is biologically worth considering whether limiting the immune effect to the tumor microenvironment through ADC technology is the right direction
.

On the other hand, loads, monoclonal antibodies and even linkers can work synergistically to create new biology
.
For example, the toxin Dxd of DS8201 is thought to promote the expression of Her2 and can form a synergistic effect with the treatment of Her2 monoclonal antibody and the ADCC effect
.
Therefore, peptide conjugate drugs (PDCs) similar to ADCs, although increasing the tissue penetration ability of drugs, also lose the immune effect of monoclonal antibodies, and their advantages and disadvantages
need to be analyzed specifically.

Finally, conditionally activated antibodies (probodies) and bispecific antibodies are also common differentiating designs
for ADC drugs.
These designs further add to the complexity of the drug, and there is not much clinical data reported at present, which is in the proof-of-concept stage
.
Recent clinical data on CX-2029, the Probody conjugate drug co-developed by CytomX and AbbVie, has been quite negative, with an objective response rate (ORR) of only 18.
8%
in 16 NSCLC patients.

The road is simple, and the unknown risk of drugs with overly complex designs such as Probody is relatively large
.
It is worth mentioning that Harpoon's complex design of TriTAC CD3 bispecific antibody HPN424 is also not clinically
effective.
Xilio's so-called tumor microenvironment selectively activated monoclonal antibodies and inflammatory factor drugs have also entered clinical research in 2021, and no clinical data has been reported
.

Datopotamab Deruxtecan shows encouraging antitumor activity
in the treatment of solid tumors.
Datopotamab deruxtecan (Dato-DXd) is an antibody-conjugated drug formed by a humanized anti-TROP2 monoclonal antibody binding to a potent topoisomerase I inhibitor payload via a stable tetrapeptide-based cleavage linker
.
Dato-DXd observed antitumor activity
at different doses of 4-, 6-, and 8-mg/kg.
Most remissions were long-lasting, including a median duration of response of 10.
5 months
in the 6-mg/kg dose group.

7 Oncolytic virus

OVs are a class of viruses
that are natural or genetically engineered to selectively replicate in tumor tissue, thereby infecting and killing tumor cells or causing tumor cell lysis, but have no killing effect on normal tissue.
According to whether it has been genetically modified, it can be mainly divided into two categories: one is wild-type virus strains and natural weak virus strains, such as reovirus, Newcastle disease virus, etc.
; The other is a genetically modified virus that can only proliferate in tumor cells, mainly adenovirus, herpes simplex virus, vaccinia virus and measles virus
.

In fact, the discovery of OVs has a history of 100 years, which can be roughly divided into three stages: the discovery and application stage of wild virus strains (1904-1990), the development stage of genetically modified virus strains (1991-2000), and the stage of gene insertion and combination therapy synergy (21st century).

In the early 20th century, cases of remission or recovery of tumor patients with constant viral infections aroused the curiosity of researchers, and then the concept of oncolytic viruses and related research
were born.

In the mid-to-late 20th century, researchers began to use immunization or viral infection to treat cancer tumors with certain results
.
However, due to the limited technology at that time, the clinical practice mainly used natural weak virus strains (chickenpox virus, measles virus, etc.
), which have limited killing ability to tumor cells, easily activate the host immune system to be cleaned up, and easily cause related complications, and it is difficult for researchers to effectively control the pathogenicity of
the virus.
At that time, chemotherapy and radiotherapy showed subversive effects, making oncolytic treatment neglected and research underestimated
.

In the late 20th century, with the continuous development of virology and genetic engineering technology, researchers were able to modify viral genes, which greatly improved the efficacy, specificity and safety
of oncolytic viruses in tumor treatment.
After that, oncolytic viruses opened a new era of
tumor treatment.

Based on the above mechanism of action of oncolytic viruses, studies have found that the effect of combination therapy of oncolytic viruses is much higher than that of individual administration
in some cases.

8 CAR-T products

There are already many CAR-T products that have been approved for marketing abroad, but they are mainly for hematological
cancers.
CAR-T cell therapy for solid tumors has limited
efficacy in clinical trials.
However, once there is a breakthrough in the field of solid tumors, the market prospects are also great
.

9 AI (Artificial Intelligence) and Biomedicine

One way to integrate AI and biomedicine is to "hammer to find nails", that is, to develop AI technology first, and then try to solve a certain pain point
of biomedicine.
This method is more common
in this wave of AI pharmaceutical companies in China.
The founders are generally high-caliber students
from AI technology and graduated from prestigious universities.

These companies are generally equipped with experienced senior management teams in biopharmaceuticals, but their grasp of pharmaceutical pain points is relatively broad but not deep, usually including protein structure prediction, small molecule drug, antibody and nucleic acid sequence design, physicochemical properties and toxicity prediction.

A considerable number of companies do not have real core algorithms, and the phenomenon of homogenized competition is more serious
.

The trend in Europe and the United States in recent years is "nails looking for hammers", that is, the "AI+"
of new technologies.
The aforementioned Eikon company is to build big data for protein movement and then develop its own AI technology
.
On November 9, 2021, Arbor, founded by Zhang Feng, announced the completion of a $215 million Series B financing
.
The company mainly uses AI technology to screen for gene-editing enzymes, and has discovered dozens of DNA nucleases (Cas12h, Cas12i), RNA nucleases (Cas13d, Cas12g, III-E) and transposases (Tn7-Cas12k).

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