The third-generation CD20 monoclonal antibody, Rituxi Dugu, who has been fighting for more than 20 years

In 1997, the first anti-CD20 monoclonal antibody rituximab (trade name: Rituxan) was approved for marketing, and the legend of rituximab began
.

In the next 25 years, the anti-CD20 mAb has developed to the third generation, but Rituxima is still the invincible defender
.

The second generation of swords is slanted, and it shines in the field of MS indications.
The third generation has the latest technology, but it failed in the head-to-head test with the first generation of rituximab
.

The only one who can defeat Rituxan is Rituxan itself, and the biosimilar drug of Rituxan has become the biggest threat to Rituxan
.

The birth of the legendary "Generation Eye" In the 1970s, chemotherapy became the first choice for the treatment of cancer, but in the face of lymphoma, chemotherapy was helpless
.

It has been found that the use of single-drug chemotherapy for lymphoma has a phenomenon of "increasing the dose but not increasing the effect", and the survival rate of lymphoma patients does not change when the dose of single-drug chemotherapy is increased
.

To save lymphoma patients, scientists have turned their attention to the inside of the human body
.

Using the mechanism by which the body's immune system kills cancer cells, it may be possible to find a way to defeat lymphoma
.

The advent of hybridoma technology has turned a new page in the history of human medicine
.

In vitro mass production of antibodies is achieved, and more importantly, the desired antibodies can be screened
.

The next step is to find the antigen used to customize the antibody, and this antigen is CD20
.

CD20 is a transmembrane phosphoprotein that is highly expressed on the surface of B cell-derived lymphoma, leukemia and other tumor cells
.

Although it is also expressed on the surface of normal B cells, it is only expressed on the surface of B cells in a specific period
.

B lymphocytes are differentiated from pluripotent stem cells in the bone marrow.
The developmental process includes four stages: progenitor B cells, pre-B cells, immature B cells and mature B cells
.

Mature B cells can go on to differentiate into plasma cells
.

CD20 is only expressed on pre-B cells and mature B cells, but not on hematopoietic stem cells, progenitor B cells and mature plasma cells
.

Therefore, although anti-CD20 antibodies will attack tumor cells by mistakenly killing normal mature B cells, progenitor B cells can then replenish mature B cells, and existing plasma cells can also support the normal operation of the immune system
.

The initial CD20 monoclonal antibody was hybridized with mouse B cells and myeloma cells.
When used in humans, it will produce a rejection reaction.
In addition, the mouse-derived monoclonal antibody has reduced activity and shortened half-life in the human body.
The therapeutic effect is greatly reduced.

.

IEDC, a company founded by Stanford University lymphoma treatment expert Ronald Levy, produced a human-mouse chimeric monoclonal antibody with both human and mouse parts through gene recombination technology, which is the birth of Rituxan
.

Rituxan pioneered targeted therapy for lymphoma
.

Rituxima said that the main reason for the amazing sales of Rituxan Wang is that it is really easy to use
.

Clinical studies have found that the use of rituximab in the treatment of lymphoma not only has a long survival period, but also is not easy to relapse
.

(Rituximab: no rituximab; 5-year survival rate = 65.
7% vs.
44.
6% (P < 0.
05); recurrence rate = 6.
4% vs.
22.
9% (P < 0.
01))
.

For lymphomas, rituximab can be said to be the catch-all, whether it is the aggressive type of DLBCL (diffuse large B-cell lymphoma) that progresses very rapidly, or the more slowly progressive type of follicular lymphoma, as well as some other lymphomas Small subtypes, rituximab combined with chemotherapy can effectively defeat cancer cells! In the lymphoma treatment recommendations of the CSCO (China Anti-Cancer Association Clinical Oncology Collaborative Professional Committee) authoritative guideline, rituximab is used in many lymphoma types, including diffuse large B-cell lymphoma, follicular lymphoma, mantle Cell lymphoma, marginal zone lymphoma, chronic lymphocytic leukemia,
etc.

Later, it was found that rituximab can not only treat B cell-derived lymphomas, but also treat autoimmune diseases such as multiple sclerosis and rheumatoid arthritis, because the B cells involved in these diseases also express the CD20 antigen
.

Rituxan has been the standard of care for certain types of non-Hodgkin lymphoma since its inception
.

The number of patients with Hodgkin's lymphoma is huge, with more than 500,000 new cases each year.
Coupled with the number of patients with some autoimmune diseases, the market size of CD20 monoclonal antibody has been established
.

In 2020, the global CD20 mAb market will reach 11.
3 billion US dollars, and the domestic market will be 3.
5 billion US dollars
.

In 2017, Rituxima entered the national medical insurance, further expanding the market size
.

And as rituximab has been explored for a variety of combination therapies, there is still room for further growth in sales
.

There are four mechanisms by which the third-generation anti-CD20 antibody rituximab kills cancer cells
.

The main killing mechanism is antibody-dependent cell-mediated cytotoxicity (ADCC): that is, after rituximab binds to cancer cells, it indicates the killing target to immune cells such as NK cells in the human body, and they solve the cancer.
cells
.

Complement-dependent cytotoxicity (CDC): When a part of rituximab binds to complement, it activates a series of complement-led mechanisms to form membrane attack complexes on the surface of cancer cells, breaking the cell membrane of cancer cells
.

Cancer cells that are "adhered" by rituximab will be limited in their proliferation and division, and may even directly enter the gate of apoptosis.
This is the third killing mechanism
.

The fourth mechanism is the changes in the cancer cell cycle, metabolic pathway, etc.
caused by rituximab binding, which can enhance the lethality of chemotherapeutic drugs to cancer cells
.

The efficacy of the first-generation CD20 monoclonal antibody is very good, but because mouse cells are used in the preparation process, whether it is murine or human-mouse chimeric antibody, there is a certain rejection reaction when used, and the side effects need to be improved
.

The representative product is Ritux, which is invincible all over the world
.

The second-generation CD20 monoclonal antibody is transformed by humanization or fully humanization, which reduces the immunogenicity, adverse reactions and side effects, but the specificity of the antibody and the affinity of antigen binding are reduced to a certain extent
.

The representative product is ofatumumab (trade name: Arzerra) from Genmab Inc, which was launched in the United States in 2009 for the treatment of chronic lymphocytic leukemia (CLL)
.

This is also the first fully human anti-CD20 mAb on the market
.

The third-generation CD20 monoclonal antibody is based on the second generation, and the Fc fragment of the antibody is modified by glycosylation to enhance the target binding force and enhance the ADCC (antibody-dependent cytotoxicity) effect
.

The representative product is Roche's own updated third-generation product otuzumab
.

The ADCC effect is stronger, and theoretically the lethality will be greater
.

The third-generation CD20 monoclonal antibody MIL62 of Beijing Tianguangshi Biotechnology Co.
, Ltd.
in China modifies the Fc fragment of the antibody through desalination and fucosylation, hoping to achieve a similar effect to Ortuzumab
.

In addition to Roche's rituximab, the weak Houlang-generation CD20 mAbs also include mouse-derived mAbs Tiimumab (trade name: Zewaling) and GSK's Tosilimumab (trade name: Bexxar)
.

However, only rituximab stood out and won a big victory, because both tilimumab and tosilimumab belong to radioimmunotherapy and need to be treated in a specialized nuclear medicine department.
The difficulty of promotion has led to both failure in business
.

GSK finally chose to give up tosilimumab, and the sales revenue of Zevalin continued to decline
.

Ofatumumab (trade name: Arzerra), the representative of the second-generation CD20 monoclonal antibody, was approved for the treatment of chronic lymphocytic leukemia (CLL) in 2009, and its sales fell sharply in 2016.
Another second-generation product this year The monoclonal antibody ibrutinib (Ibrutinib) is FDA-approved for the first-line treatment of CLL and competes with ofatumumab
.

Because the indications of both of them are limited to CLL, they do not threaten the sales and status of the first-generation rituximab
.

The second-generation anti-CD20 monoclonal antibody also includes Roche's humanized monoclonal antibody Ocrevus (trade name: Ocrevus)
.

Roche has made some breakthroughs with second-generation CD20 monoclonal antibody.
Orelizumab is the first product to receive a breakthrough therapy in the field of multiple sclerosis and was approved by the FDA in March 2017 for the treatment of relapsing multiple sclerosis (RRMS).
) and primary progressive multiple sclerosis (PPMS), which is currently the top-selling MS drug, reaching CHF 4.
326 billion in 2020
.

Although it has not been able to replace the position of the predecessors, it can be regarded as a monopoly in the field of MS
.

In 2015, the FDA granted orphan drug designation to the second-generation anti-CD20 monoclonal antibody veltuzumab in the field of immune thrombocytopenia
.

But the indication also determines that it also does not have the ability to threaten rituximab
.

What is the combat power of the third-generation anti-CD20 monoclonal antibody? The first is Roche's own third-generation humanized monoclonal antibody otuzumab (trade name: Gazyva, also known as GA101), which was approved by the FDA in 2013
.

Indications include: 1) Chlorambucil for the treatment of patients with previously untreated chronic lymphocytic leukemia; 2) Combined with bendamustine, second-line treatment of relapsed follicular lymphoma
.

In 2016, Roche announced the results of a head-to-head Phase 3 clinical trial of Gazyva and Rituxan in follicular lymphoma, which showed that Ortuzumab significantly improved patients with previously untreated follicular lymphoma.
The PFS (progression-free survival) of the trial met the primary clinical endpoint of the trial
.

Ortozhu won a game
.

However, in another phase 3 clinical trial, in the diffuse large B-cell lymphoma field, a head-to-head comparison of Ortuzumab and rituximab, its primary clinical endpoint (Octuzumab significantly prolonged the treatment of previously untreated DLBCL patients) PFS) was not achieved
.

Otuzumab unfortunately lost
.

The second-generation CD20 monoclonal antibody could not beat rituximab in terms of lymphoma indications and efficacy, and turned its attention to the field of multiple sclerosis
.

Although the third-generation Ortuzumab defeated rituximab head-to-head in the field of follicular lymphoma, it was defeated again in the field of diffuse large B lymphoma.
Another big win
.

Because in non-Hodgkin lymphoma, the highest proportion is diffuse large B lymphoma, accounting for about 30%, and the type of follicular lymphoma only accounts for about 25%
.

And 30-40% of patients with follicular lymphoma will transform into diffuse large B lymphoma over time
.

Therefore, the market field of diffuse large B lymphoma is the best in the world, and rituximab wins
.

 The only thing that can beat Rituxan is Rituxan.
Rituxan's record has attracted worldwide attention.
With the expiration of Rituxan's patent period, many companies are rushing to make Rituxan biosimilars
.

In 2016, Truxima, a rituximab biosimilar produced by the Korean pharmaceutical company Celltrion, was approved for marketing in Europe, and rituximab began to bloom all over the world
.

As the first cancer biosimilar to be marketed in Europe, Truxima has had a lot of success
.

At the end of 2021, Celltrion announced that Truxima’s market share in Europe has reached 40.
2%.
According to Celltrion officials, Truxima’s market share in European countries surpassed Roche for the first time as early as the fourth quarter of 2019
.

In February 2019, the domestic rituximab developed by Henlius was successfully listed in China.
Since then, China has had its own rituximab, breaking the pattern of foreign monopoly on rituximab
.

2014-2020 Hospital sales of rituximab and its analog samples (100 million yuan) Source: Tianfeng Securities Research Institute 2021 Q1 2021 Rituxix sample hospital sales ratio Source: 4 models approved by China Everbright Securities Research Institute Among the anti-CD20 monoclonal antibodies, rituximab-like drugs account for two, namely Hanlikang of Henlius and Dabohua of Innovent Bio
.

In addition, Shandong New Times Pharmaceutical, Chia Tai Tianqing, Hualan Bio, Ruckus Bio, Hisun Pharmaceutical, Shanghai Institute of Biological Products, etc.
are all deploying rituximab-like drugs
.

The homogenization competition is fierce, and how to solve the problem of involution and highlighting the characteristics of domestic rituximab-like drugs needs to be considered
.

In addition to similar drugs, there are also innovations based on rituximab.
Although China Cell's CD20 monoclonal antibody SCT400 is similar to rituximab, its structure has changed and can be regarded as an innovative drug
.

Affected by similar drugs, sales of rituximab began to decline
.

In 2017, the sales of rituximab broke a record of 7.
388 billion Swiss francs (RMB 48.
6 billion), and by 2020, the sales will only be 4.
223 billion Swiss francs
.

Sales of rituximab in China fell 23% in 2020
.

The third-generation anti-CD20 monoclonal antibody, the recombinant humanized monoclonal antibody MIL62 injection (abbreviation: MIL62), is the third-generation anti-CD20 monoclonal antibody independently developed by Beijing Tianguangshi Biotechnology Co.
,
Ltd.

It is China's first and currently the only third-generation anti-CD20 monoclonal antibody developed by a domestic pharmaceutical company that has entered Phase III clinical trials
.

According to Tianguangshi's prospectus, MIL62 seems to have better Fc binding ability and stronger ADCC effect when administered at low concentrations compared with rituximab and Ortuzumab
.

Smaller doses may mean fewer side effects
.

But these are only in vitro data, pending clinical results
.

On January 11th, the innovative class 1 CD20 monoclonal antibody zebetuzumab (trade name: Amreximab) independently developed by Borui Biosciences/Hisun Biotechnology was used for the initial treatment of CD20-positive diffuse large B-cell lymphoma (DLBCL).
) The marketing application for the indication was accepted by the NMPA
.

Compared with rituximab (rituximab), showed stronger ADCC activity, larger steady-state volume of distribution and lower serum drug exposure, more durable clearance of B cells and CD3+/CD8 + More durable activation of T cells
.

In a phase III confirmatory clinical study, zebetuzumab injection combined with CHOP was non-inferior to R-CHOP in ORR in newly treated patients with diffuse large B-cell lymphoma, and the CR rate was significantly higher at the end of treatment; In terms of long-term survival benefit, the 1-year PFS and OS of the zebetuzumab injection group showed a trend of being significantly better than that of the rituximab group; the 1-year PFS and OS had a trend of being significantly better than that of the rituximab group
.

The competition of the three generations of anti-CD20 antibodies is not over yet, and CD20-based double antibodies, ADCs, CAR-T, etc.
are also on the way
.

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