 Home > Active Ingredient News > Drugs Articles > PD-1 R&D experience, ADC is not applicable to the first field

PD-1 R&D experience, ADC is not applicable to the first field

 Last Update: 2022-11-26
 Source: Internet
 Author: User

Tags

high index lenses disadvantages

morgellons disease treatment

Search more information of high quality chemicals, good prices and reliable suppliers, visit www.echemi.com

☆ In the R&D interview, many companies agreed
with the "recommended enterprises to carry out extensive exploratory research" mentioned in the "Technical Guidelines for Clinical R&D of Anti-tumor Antibody Conjugate Drugs (Draft for Comments)" recently issued by the Center for Drug Evaluation (CDE) of the State Food and Drug Administration.
They all said that the transition from small molecules, antibodies to antibody drug conjugates (ADCs) is a one-dimensional to three-dimensional change, in which there are a lot of unknowns to explore
.
Therefore, the fast-follow strategy adopted by PD-1 antibodies, ADCs are not applicable
.

The current ADC research and development in China, the situation is similar to the PD-1 antibody a few years ago, and large and small companies are rushing up
.
According to the data disclosed by the company, the top 10 companies in the local ADC pipeline have nearly 80 ADCs under development, and their products are mainly concentrated in a few targets such as Her2
.
In addition to small and medium-sized biotechnology companies, large companies such as Kelun, Hengrui, Qilu, and Shiyao have also entered the market
.

At present, most of the ADC products of domestic companies are in the preclinical or early clinical research stage
.
In this context, the release of the draft of the "Technical Guidelines for Clinical R&D of Anti-tumor Antibody Conjugate Drugs" (hereinafter referred to as the "Draft Guidelines") issued by the Center for Drug Review (CDE) of the State Food and Drug Administration is considered to help the industry make comprehensive planning for ADC research and development in advance and help developers fill in the omissions in research design
.

Alan, Senior Vice President of Suzhou Yilian Biotechnology and CEO of Yilian Biologics Dr.
Xu mentioned that it is necessary to further clarify that the scope of application of the guidelines is cytotoxicity-based ADCs, "There are some ADC products, the payload is other types of molecules, such as immune agonists, oligonucleotides, etc.
, these products and common cytotoxic ADCs as the payload, there is a big difference
in clinical development.
" ”

Why not follow the PD-1 path?

From an industry perspective, the most direct reason for CDE's release of the draft guidelines is that ADC characteristics are complex, and the design of different technology platform products has its own characteristics
.
Data has been shown that ADC characteristics differ significantly
from each other even to the same target.

Even with the same target, the characteristics of ADCs differ significantly from each other

For example, Daiichi Sankyo, Kelunbotai, Zhejiang Pharmaceutical, Rongchang Biotechnology, etc.
all have Her2 ADC is under research, and compared with the published clinical data, it can be seen that there are great differences
in efficacy and toxicity spectrum of multiple products.
The draft guidelines also mention that differences in efficacy may be observed on the same target ADC, such as a drug treatment that is effective in HER2-positive breast cancer, but no significant clinical benefit is achieved in patients with HER2-positive gastric cancer.
The other drug is effective
in patients with HER2-positive breast cancer and gastric cancer.

Industry insiders said that similar phenomena
were rarely observed on PD-1 antibodies in the past.
"Although there are some differences in sequence between different PD-1 antibodies, the observed efficacy range and toxicity spectrum are very similar
.
Previously, many domestic PD-1 inhibitors were completed in phase I clinical studies, and they quickly started registration studies by drawing on the research and development experience of foreign products, and the final results also proved that there was little difference in safety and efficacy data between them
.
”

However, ADCs are intertwined due to various design factors, and there is great uncertainty
in characteristics.
Design considerations include targets, antibodies, linkers, payloads, and ligation strategies, such as whether the target is expressed in normal tissues, whether high-affinity or low-affinity antibodies are used, whether toxins are used with high-toxicity or low-toxicity types, whether the design has a low endocytosis effect or a high endocytosis effect, and the stability of the linker
.
These factors are intertwined and affect the whole body
.

There is great uncertainty in the characteristics, and these factors are intertwined and affect the whole body

In view of this, the interviewed companies all mentioned that the R&D process should fully understand the advantages and disadvantages of their own product design, such as bystander effect, target affinity, toxin characteristics, etc.
, and should not arbitrarily learn from the research results of the same target product, but should carry out extensive exploratory research
.

For example, the creation
of the bystander effect.
At present, when Daiichi Sankyo explains the efficacy advantages of its product DS8201, it is more due to this
.
However, Dr.
Ting Xu, chairman of Corning Jerry, said: "If you look at the early published literature of Daiichi Sankyo, you will find that it has repeatedly mentioned that DS8201 has an immunoactivating effect
on the tumor microenvironment.
”

The industry has not yet reached a conclusive conclusion
on how ADC products can better play the bystander effect.
Alan Xu said that the bystander effect is also affected by multiple factors, in addition to the lipophilic nature of the small molecule toxin itself, the hydrophilic and hydrophobic properties of the linker, and the release mechanism of the small molecule also affect the bystander effect, so it is necessary to consider the linker, toxin and other factors in combination
.

He also mentioned that at present, Yilian Bio is exploring new ways to enhance the bystander effect, in addition to allowing ADC to target tumor cell targets, while using the specificity in the tumor microenvironment, including targets in the microenvironment, specific acidity and alkalinity, etc.
, so that some toxins do not need to be released after entering the cell through intracellular phagocytosis, but can be directly released
in the tumor microenvironment.

In addition, the toxicity spectrum of ADC is also related
to various factors such as target, half-life, antibody modification, whether the linker is easy to break, and toxin properties.
Hence Alan Xu mentioned that the adverse reactions that may occur in the research should be fully explored in preclinical research, and through translational medical research, it should be clear in advance
.
In addition, in the process of clinical research, if new problems are found, the sponsor must also have a good safety control awareness and response plan
.

Alan In his past work, Xu has experienced rare adverse reactions during the upgrade process of ADC technology platform
.
At that time, the company's early product development adopted non-fixed-point coupling technology, and at the same time, it was trying to develop and upgrade fixed-point coupling technology, and for this purpose, it specially established a new technology platform and developed several ADC projects for different targets, one of which was advanced to the phase I clinical stage
.

"While R&D was moving forward methodically, non-clinical research found a serious adverse reaction
that might have been overlooked before.
" Alan Xu said
.

"In one of the GLP studies, monkeys developed pulmonary fibrosis after medication
.
At first, it was thought that it was target-related toxicity, but since then repeated monkey experiments and GLP studies using multiple different target projects developed on the same platform have observed the same lung phenomenon
in monkeys.
”Alan Xu said, "At this time, the fixed-point coupling platform technology was highly suspected to be a factor in the safety problems in the GLP study, and the company immediately suspended all clinical studies, and finally the first project study enrolled only one patient at a low dose with no serious consequences
.
" ”

This incident has been a reminder for Alan Xu to pay special attention to the unique security risks
that ADC platform technology can create.

Extensive exploration of enterprise ADC R&D strategies

The draft guidelines refer to "extensive exploratory research", which is also understood by enterprises to mean that ADC R&D should pursue differentiation as much as possible to avoid homogenization again, which will also help promote the internationalization
of product development.

Differentiated R&D can start with dosing regimen exploration
.
The draft guidelines mention that "rational dosing strategy is a key factor affecting the benefit risk characteristics of ADC drugs, and it is necessary to explore the PK/PD of ADC drugs and components and their relationship
with the efficacy and safety of drugs as much as possible.
" ”

Dosing regimen exploration

"Traditional oncology clinical research has explored the maximum tolerated dose (MTD), which can guide the later clinical development of drugs
.
However, for ADCs, MTD is only a framework for dose exploration, and it is more important to find out whether the clinical recommendation to optimize the dosing regimen, such as using multiple low-dose administrations compared to one-time high-dose administration, can achieve better safety and tolerability
under the premise of comparable efficacy.
”Alan Xu mentioned
.

MTD is only a framework for dose exploration and, more importantly, for finding clinical recommendations to optimize dosing regimens

Historically, ADC drugs have been brought back to life
by changing the dosing regimen.

The world's first commercially available ADC Gemtuzumab ozogamicin targeted for acute myeloid leukemia (AML).

Its first approved dosing regimen was 9 mg/m2, After 14 days, the drug was repeated once, and the result was a number of black box warnings added by the FDA because it may lead to serious adverse reactions such as hepatic venous occlusive disease, and it was withdrawn from the market
in 2010.

But then, Gemtuzumab ozogamicin changed the medication regimen and was successfully approved again in 2017, the new drug regimen used 1, 4, 7 days of 3mg/m2 administration, due to the better safety, the newly approved product is suitable for AML patients over 60 years old who are not suitable for chemotherapy to ordinary adult and even pediatric patients
.
Other studies have also found that the drug can fully occupy the CD33 target with a dose of 2mg/m2, and combined with the half-life of the drug, choosing a low dose and short interval administration is a better dosing regimen
.

In actual research, ADC dose exploration is difficult
.
When the ADC enters the human body, it will be cracked into three parts, each of which has different PK/PD characteristics
.
Alan Xu said that it is necessary to consider the index setting of monitoring and detection in advance, fully understand the PK/PD of each component of ADC, and then understand the relationship between PK/PD of each component and clinical efficacy and safety, at the same time, the ADCC effect and immunogenicity of macromolecular antibodies cannot be ignored
.

At present, there are also companies that show product differentiation through
new technology development.
Many domestic ADC research and development are based on the first Sankyo DS8201 and its technology platform as a benchmark, but in fact, DS8201 also has imperfections, especially in terms of
security.
The DS8201 has been found to cause interstitial pneumonia in multiple indications, which is a black box warning by the FDA, and similar phenomena
have been observed in other target ADCs developed on the same platform.

Xu Ting mentioned that the current ADC realizes the connection between toxins and antibodies, mainly using sulfhydryl-based antibody coupling reaction, or lysine-based antibody conjugation reaction
.
Sulfhydryl-based conjugation opens the 4 pairs of disulfide bonds on the antibody to attach the toxin, so the drug-antibody conjugation ratio (DAR) of a homogeneous conjugated product is usually 8
.
However, the maleimide-sulfhydryl reaction of the sulfhydryl coupling process is a reversible reaction, so it is easy to have toxin shedding, and free toxins enter the body, which increases the possibility of
adverse reactions.

Corning Jerry has developed a new ADC coupling technology platform to address this issue
.
It allows the sugar molecules on the surface of the antibody to connect with the toxin, using the biological orthogonal reaction plus Click reaction, the toxin is connected to the glycan group of the antibody, the technology can also adjust the number of coupling of toxins through the modification of the sugar structure, and the coupling control
of 1~4 loads can be achieved at present.

"In preclinical studies, we found that DS8201 was half of the toxins shed after 3 weeks in plasma, but the products produced by our ADC platform have very little toxin shedding, and no interstitial pneumonia has been observed in monkey studies, and the new coupling technology is expected to achieve better product stability
.
" Xu Ting mentioned
.

At present, Corning Jerry uses this technology platform to develop bispecific antibody ADCs targeting different target positions of Her2 JSN003, which has started phase I clinical trials in Australia and enrolled multiple patients, will obtain more safety and efficacy data
in clinical studies in the future.

Domestic companies have cooperated more closely with international companies in the research and development of ADC new drugs, and since last year, a number of products have been authorized
to the outside world.

In August last year, Remegen and Seagen reached a vedicitumab licensing agreement, with a down payment of US$200 million and a milestone payment of up to US$2.
4 billion, setting a new record
for the amount of overseas licensing of Chinese single drugs.
This year, Kelun Pharmaceutical has twice joined hands with Merck to grant the global development rights of two ADC drugs, including Trop2-ADC, to Merck, with a total transaction value of more than US$2.
2 billion
.
In addition, a number of ADC drugs developed by Duoxi Biologics and CSPC Jushi Biologics have been authorized
to the outside world.

For emerging biopharmaceutical companies, Yilian Biotech is also negotiating technology platform cooperation
with related companies at home and abroad.
"This allows us to carry out a more comprehensive technology exploration and apply the platform technology to more targets and diseases, and at the same time reduce the research and development costs
of the company's products.
" Alan XU said
.

This article is an English version of an article which is originally in the Chinese language on echemi.com and is provided for information purposes only. This website makes no representation or warranty of any kind, either expressed or implied, as to the accuracy, completeness ownership or reliability of the article or any translations thereof. If you have any concerns or complaints relating to the article, please send an email, providing a detailed description of the concern or complaint, to service@echemi.com. A staff member will contact you within 5 working days. Once verified, infringing content will be removed immediately.