The double antibody research and development track is hot! Cinda and other nuggets exceed 200 billion market

Recently, the bispecific antibody drug market has been heaty: Akeso Biologics and Summit Therapeutics reached an overseas licensing deal of up to 5 billion US dollars for bispecific antibody product AK112, and Wuhan Youzhiyou Biotechnology, a domestic bispecific antibody research and development company, submitted an IPO application.
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Driven by the favorable market, bispecific antibody drugs have also ushered in a boom
in research and development.
At present, there are about 80 bispecific antibodies in the clinical stage in China, Innovent Biologics, CSPC Holdings, Roche, etc.
have 4 or more products under development, Hengrui Pharmaceutical's SHR-1701, BeiGene's Zanidatamab and other 13 products are in phase III clinical trials, based on CD47/PD-L1 target bispecific antibodies are the most popular, 5 products are undergoing clinical trials.
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In view of the urgent problems in the clinical research and development of bispecific antibodies, CDE has formulated a series of guiding principles to guide enterprises to carry out bispecific antibody clinical research and development
more scientifically.

Source: CDE official website bispecific antibody (BsAb, hereinafter referred to as "bispecific antibody") is an artificial antibody prepared by cell fusion, recombinant DNA, protein engineering and other technologies, which can specifically bind two antigens or two different epitopes
of the same antigen at the same time or successively.


As a class of "monotherapy" with dual functions, bispecific antibodies are different from related monoclonal antibodies and different from the combination of monoclonal antibodies
.
The clinical research and development ideas and technical requirements of monoclonal antibody antitumor drugs are relatively mature, but bispecific antibody drugs for multiple epitopes have special considerations in clinical research and development due to their special structure and function
.


In summary, the "Technical Guidelines for Clinical R&D of Bispecific Antibody Antitumor Drugs" provides three key reference points for relevant R&D enterprises: (1) it is generally believed that the pharmacodynamic or biological mechanism of action of bispecific antibodies mainly includes:

bridging cells, bridging receptors, and bridging factors;

(2) In terms of treatment, compared with monoclonal antibodies, bispecific antibodies may have potential advantages such as mediating the killing of immune cells by immune cells, enhancing the activation of immune cells, blocking dual-target signals to prevent drug resistance, and mediating stronger endocytosis;

(3) Bispecific antibodies may exist in a mixed state of biologically active and inactive forms, in addition to multiple domains, mediating clinical efficacy in different ways, therefore, the selection of the optimal dosing strategy for bispecific antibodies needs to consider target binding associated with the two targets, as well as the impact
of binding kinetics on efficacy and safety.


9 global models and 3 domestic models, the bispecific antibody field has broad

prospects compared with traditional monoclonal antibodies, the advantage of bispecific antibodies is that they have more accurate targeting and stronger therapeutic effects, and theoretically bispecific antibodies can play the role
of "1+1>2".
It is precisely because of its huge therapeutic potential that bispecific antibody drugs have broad prospects and gradually become the "new favorite"
of new drug research and development and investment.


Global bispecific antibody approval for marketing

Source: Minai.
com's new version of the database currently has a total of

9 bispecific antibody drugs approved for marketing worldwide, including Roche's emezelizumab and Faricimab, Amgen Biologics' belintoumab, Fresenius Kabi's catuxumab, Akeso's cardunelimab, Johnson & Johnson's Amivantamab, Boehringer Ingelheim's ozolizumab, etc
.
Among them, Roche's emezelizumab, Amgen Biologics' belintoumab and Akeso's cardunilimab have landed
in the Chinese market.


In recent years, the sales trend of emizumab and belintoumab in China's three major terminal markets (: 10,000 yuan)

Source:

Roche's emezelizumab and Amgen Biologics' Belintoumab were approved by the NMPA in November 2018 and December 2020, respectively, and were included in the priority review
as "new varieties, dosage forms and specifications of pediatric drugs that meet the physiological characteristics of children".
According to data from Minai.
com, the sales of the above products in the six major markets of China's three major terminals in 2021 will be close to 100 million yuan, with a year-on-year increase of 13.
67% and 79.
52%
respectively.


Akeso's cardunilimab was approved by the NMPA in June 2022 for the treatment of patients with relapsed or metastatic cervical cancer who have failed previous platinum-containing chemotherapy, and is the first PD-1/CTLA-4 bispecific immunotherapy drug in China and the world's first, and it is also a popular anti-tumor drug
in 2022.


Nearly 80 models of double antibodies under research are ready to go, Cinda, Hengrui.
.
.

In
recent years, with the successful listing of a number of bispecific antibody drugs and the continuous advancement of biopharmaceutical technology, bispecific antibody drugs have begun to enter a stage of rapid development, and the popularity of research and development continues to rise
.
According to Minai.
com, nearly 80 bispecific antibody drugs in China are currently in the state of clinical application and above research and development, and more than 37 domestic pharmaceutical companies have participated in the layout
.


Domestic pharmaceutical companies that are in the clinical trial stage with 3 or more bispecific antibody drugs

Source: Minai.
com New Drug R&D Database

In terms of quantity, Innovent Biologics is a "leader" in the field of bispecific antibody research and development, with a total of 8 products in the clinical trial stage, of which IBI-302 is intended for the treatment of wet age-related macular degeneration, and IBI-318 is intended to be used for the treatment of T-cell lymphoma and skin cancer has entered phase II.
clinical trials
.
Pumis Biotechnology (Zhuhai) has 6 bispecific antibodies in the clinical trial stage, of which 2 antitumor drugs PM-8001 and PM-8002 have entered phase II.
clinical trials
.
In addition, pharmaceutical companies with 3 or more bispecific antibody drugs in the clinical trial stage include Roche (4 models), CSPC Holdings (4 models), Johnson & Johnson (3 models), Sichuan Baili Tianheng Pharmaceutical (3 models), and Yiming Onke Biotechnology (3 models).



Domestic bispecific antibody research situation

 
Note: Only statistics apply for clinical and above stage

source: Minainet new drug research and development database

From the perspective of target research and development popularity, CD47/PD-L1 is the most popular combination
of bispecific antibodies under research in China 。 CD47/PD-L1 dual antibody can activate both natural immunity and acquired immunity dual pathways, enhance the targeted recognition of tumors by the immune system, and synergistically fight tumors.
It can also target CD47 and PD-L1 on tumors at the same time, accurately navigate and target tumor tissues, and reduce toxicity, which can be described as "strong cooperation, safe and effective"
.
At present, there are 5 CD47/PD-L1 dual antibodies in the clinical trial stage in China, including Mabwell's 6MW-3211, Qilu Pharmaceutical's QL-401, Bio-Thea's BAT-7104, Innovent Biologics' IBI-322 and Hangzhou Shangjian Biologics' SG-12473, of which Mabwell's 6MW3211 (acceptance number: CXSL2101058) has made rapid progress and has entered phase II clinical trials
.


From the analysis of R&D progress, 13 bispecific antibodies, including Hengrui Pharmaceutical's SHR-1701, BeiGene's Zanidatamab, Akeso's Ivonescimab, and Corning Jerry's KN-046, are undergoing phase III clinical trials, and production will be just around
the corner.
Among them, Hengrui Pharmaceutical's SHR-1701 is the fastest PD-L1/TGFB bispecific antibody in research and development, and if the drug is successfully approved, it is expected to become the "first-in-class"
of similar products.
BeiGene's Zanidatamab, a HER2 dual antibody, has previously been granted breakthrough therapy designation by the FDA for patients with biliary tract cancer (BTC) amplified by the HER2 gene, and orphan drug designation for the treatment of biliary and gastric cancer, which is expected to further promote the domestic marketing process
.


Sales of anti-tumor and immunomodulatory agents in China's three major terminal markets in recent years (: million yuan)

Source: Minai Grid Bureau database

From the perspective of treatment categories, anti-tumor and immunomodulatory agents are the majority, and a total of 71 drugs are undergoing clinical research; There are 3 sensory system drugs, 2 blood and hematopoietic system drugs, 1 digestive system and metabolic drug, and 1 systemic anti-infective drug, all of which have entered the clinical trial stage
.
According to data from Minai.
com, the sales scale of anti-tumor and immunomodulators in the six major markets of China's three major terminals exceeded 200 billion yuan in 2021, a year-on-year increase of 12.
52%, and it is expected to reach a new high
in 2022.


Three key points to help R&D enterprises break through the hot bispecific antibody drug research and development track, how should Chinese pharmaceutical companies break through

and achieve curve transcendence? The author believes that we can start from three aspects: "target screening, process improvement, and R&D acceleration":

(1) Focusing on biological mechanisms and target screening dual targets will cause more complex mechanisms of action, which may bring potential unknown safety risks, and these risks are difficult to predict
in preclinical research 。 Researchers must have a deep understanding of the paired targets, screen out the appropriate bispecific antibody infrastructure, and meet various indicators of affinity and pharmacokinetics, and the less structural changes the bispecific antibody has more suitable stability and solubility, and it is easier to achieve the effect of "1+1>2
".


(2) Improve antibody development and process technology At the technical level, the technical difficulty of bispecific antibodies lies in structural design and chain matching, which is not a problem that can be solved by combining two monoclonal antibodies, with the State Food and Drug Administration's guidance for clinical needs, the past intention to develop bispecific antibodies through simple combination of the era no longer exists
。 The general trend of clinical demand will force the dual antibody platform of R&D enterprises to have the characteristics of easy follow-up drug development, as well as stable and efficient antibody technology; At the process level, continuous optimization of the structure will facilitate the purification
of bispecific antibodies.


(3) Shortening the R&D cycle, winning the first opportunity for product commercialization Any market, any product, and winning the first-mover advantage is crucial, and the field of dual antibodies is no exception
.
Therefore, the selected drug candidates should meet multiple criteria for clinical trials and development, namely clinical efficacy, high safety, appropriate pharmacodynamic/pharmacokinetic parameters, good physicochemical properties, scalable production, and low immunogenicity
.
Biantibodies with excellent properties can obviously reduce the difficulty of CMC (chemistry, manufacturing and control of drugs) development and shorten the development cycle, and win the opportunity
for product commercialization.


Conclusion Bispecific

antibody drugs are upgraded products of monoclonal antibody drugs, and have gradually become an important development direction
of tumor and immunotherapy drugs.
At present, many global and domestic pharmaceutical companies attach great importance to the research and development of bispecific antibody drugs, and the types of drugs that have been developed and entered the clinic are increasing
.
In clinical research and development, we need to pay attention to the risk control, optimal dosing strategy, immunogenicity, and biomarker development of the first human clinical trial
.
With the approval of bispecific antibody drugs and the approval of more indications for bispecific antibodies, data forecasts show that the global market size of bispecific antibodies will exceed 50 billion yuan
in 2025.
Under the situation that the market prospects are getting better, it is obviously indispensable
for latecomers to break through on the hot double antibody track, reduce homogeneous competition, and seek differentiated products.


Source: Minainet database, CDE official website Note: Minai.
com "China's three major terminal 6 major market drug competition pattern", the statistical scope is: urban public hospitals and county-level public hospitals, urban community centers and township health centers, urban physical pharmacies and online pharmacies, excluding private hospitals, private clinics, village clinics, excluding county and rural pharmacies; The above sales are calculated
based on the average retail price of the product at the terminal.
Data statistics as of December 9, if there are any omissions, welcome to correct!