The target layout is low in homogeneity and the market competition pattern is good

In 2021, the monoclonal antibody drug market will perform well, and the research and development of antibody-conjugated drugs and bispecific antibodies will receive more attention from pharmaceutical companies
.
Bispecific antibodies are usually artificially synthesized.
They are antibodies with two specific antigen binding sites at the same time.
Compared with traditional monoclonal antibodies, they have stronger targeting and lower toxicity, but have higher technical barriers to R&D and production
.
According to the presence or absence of Fc fragments, bispecific antibodies can be divided into IgG diabodies (containing Fc fragments) and non-IgG diabodies (without Fc fragments)
.
IgG double antibodies can be further divided into symmetrical IgG double antibodies and asymmetric IgG double antibodies
.
IgG double antibodies are structurally close to natural antibodies and have lower antigenicity
.
The Fc fragment can bind to the FcRn receptor in circulating blood and avoid being hydrolyzed by lysozyme and has a longer half-life
.
At the same time, IgG double antibodies have Fc-mediated effector functions, such as antibody-dependent cell-mediated cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC) and antibody-dependent cell-mediated phagocytosis (ADCP) )
.
In addition, the Fc segment contains A/G protein, which can be used for antibody purification by affinity chromatography
.
However, IgG double antibodies also have disadvantages such as low tumor penetration rate and high light and heavy chain mismatch rate
.
Non-IgG double antibody has simple structure, simple preparation process, small molecular weight and high tumor penetration rate, but it has the disadvantages of short half-life and no Fc fragment-mediated effect
.
Representative Double Antibody Technology Platform Double antibody is formed by combining two different light and heavy chains
.
There are 16 combinations of two different light and heavy chains, and only 12.
5% ​​of the antibodies formed by this random combination are sufficient to bind the bispecific antigenic site
.
Mismatches between light and heavy chains will result in high protein impurities and low yields of dual antibodies
.
In response to the mismatch between light and heavy chains, bispecific antibody R&D companies have developed different technical platforms for IgG and non-IgG double antibodies.

.
IgG class double antibody technology platform IgG class double antibody is more prone to light and heavy chain mismatch problems than non-IgG class double antibody, and related technology platforms are mainly devoted to solving such problems
.
KIH and Cross Mab technology platform KIH technology first proposed a method to solve the problem of heavy chain mismatch.
By changing the amino acids on the two heavy chain structures respectively, the large amino acid on one chain is mutated into a small amino acid, and the corresponding other amino acid is mutated.
Small amino acids on a chain are mutated into large amino acids, and the mutated sites form convex and concave structures, respectively, thereby forming heterodimers through electrostatically directed pairing
.
This approach prevents over 90% of the heavy chain mismatch problem, but not light chain mismatches
.
After that, Roche improved and formed Cross Mab technology on the basis of this platform, that is, the Fc part of the two antibodies forms a heterodimer through KIH technology, and at the same time, the light and heavy chains of the Fab segment of one of the antibodies are exchanged to form the correct light chain binding
.
●DuoBody technology platform This technology obtains bispecific antibodies by exchanging the Fab arms of two monoclonal antibodies targeting different epitopes
.
The Fab arm swap reaction is the result of a disulfide isomerization reaction and a CH3 domain dissociation-association, in which the heavy chain disulfide bond in the hinge region of the parent antibody is reduced, and the resulting free cysteine ​​interacts with the other parent antibody.
The cysteine ​​residues of the antibody molecule form inter-heavy chain disulfide bonds, while the CH3 domain of the parent antibody is released and reformed by dissociation-association
.
Amivantamab developed by Xi'an Janssen uses this platform technology to target both C-MET and EGFR receptors
.
Non-IgG double antibody technology platform Due to the lack of Fc fragment, non-IgG double antibody cannot bind to FcRn, so the half-life is generally short.
Each technology platform mainly promotes the clinical application of non-IgG double antibody by prolonging the half-life.

.
●BITE technology platform This platform is Amgen uses linker to connect two ScFV fragments in series, one ScFV fragment targets the CD3 target of T cells, and the other ScFV fragment targets tumor cells, and the concatenated double antibody fragments can bind to tumors at the same time cells and T cells, and induce T cells to kill tumor cells
.
Due to the smaller molecular weight, the permeability of the double antibody fragment to tumor cells is greatly improved
.
The currently marketed dual-antibody fragment drug blinatumomab uses this technology, but its half-life is only 2 hours
.
In response to this shortcoming, Amgen has improved the HLE-BITE technology based on this technology - by connecting Fc fragments, the half-life can be significantly extended to more than 44 hours
.
●TandAb technology platform This technology is developed by Affimed Company.
The molecular weight of the synthesized antibody is about 100kd.
Compared with ordinary non-IgG double antibody, it can significantly prolong the half-life
.
Research and development of double-antibody drugs and industrial development At present, there are 4 double-antibody products on the market in the world.
The first drug on the market is catulumumab developed by Lingteng Medicine.
This product is a T-cell redirecting antibody, and the approved indication is cancer.
Sexual ascites
.
The drug was approved by the European Medicines Agency (EMA) in 2009, but was withdrawn in 2017 due to poor market performance
.
Recently, Lingteng Pharma has restarted the marketing process of the drug worldwide.
So far, Phase I/II clinical trials for bladder cancer patients have been launched in China, and Phase III clinical trials for gastric cancer have been launched in South Korea and other places.
also approved
.
The second dual-antibody drug on the market is the non-IgG drug blinatumomab developed by Amgen.
The approved indication is B-cell leukemia.
BeiGene has obtained the authorization to introduce the drug
.
The third bispecific antibody drug on the market is Roche's emilacizumab, which brings together factor IXa and factor X needed to activate the natural coagulation cascade, helping people with hemophilia A restore blood coagulation Features
.
In November 2018, emeclizumab was listed in China through the priority review process for the routine preventive treatment of hemophilia A patients with coagulation factor VIII inhibitors (congenital coagulation factor VIII deficiency).
Prevent bleeding or reduce the frequency of bleeding
.
The fourth drug is Johnson & Johnson's Amivantamab, which is approved for the treatment of patients with EGFR exon 20 insertion mutation-positive non-small cell lung cancer
.
Domestic pharmaceutical companies have made rapid progress in the research on bispecific antibodies
.
According to incomplete statistics, there are more than 60 kinds of bispecific antibody drugs in clinical trials, two-thirds of which are indicated for tumor treatment
.
In addition, there are also double antibody products in the fields of immunity, blood, and ophthalmology
.
Bispecific antibody targets are mainly combined in the following ways: simultaneously targeting two tumor cell signaling pathway proteins to exert synergistic therapeutic effects; bridging immune cells and tumor cell signaling pathway proteins (also known as T cell redirection); Dual immunomodulatory effects; immune checkpoint targets and tumor signaling targets cooperate with each other
.
At present, the industrial chain of double-antibody drugs in China is concentrated in the middle and upper reaches
.
Many companies reduce R&D costs through R&D outsourcing services.
The main factors affecting the upstream industry are the type of bioreactor and culture conditions (the metabolic level of bispecific antibodies may change during the cell growth process, and it is necessary to evaluate the conditions conducive to cell metabolism.
)
.
At the same time, since bispecific antibodies are easy to form aggregates, higher requirements are placed on the purification of antibodies, and the yield will be correspondingly reduced
.
In addition, there are many cases of heavy and light chains, and simple gel analysis is no longer sufficient, and more sensitive analytical methods need to be developed
.
At present, the target distribution of double-antibody drug R&D in China is low in homogeneity.
Antibody R&D focuses on optimizing production processes and solving adverse reactions such as cytokine storms
.
There are few domestic technology platforms with intellectual property rights and mature technology, and the overall market presents a good competition pattern
.
With the continuous advancement of clinical trials of bispecific antibody drugs, the domestic clinical research stage of bispecific antibodies is expected to usher in a breakthrough in the market in the near future
.
(Flint Creation Feed)