Dual anti-war is coming!

Since the world’s first mouse-derived monoclonal antibody drug Muromonab OKT3 for the treatment of renal transplant rejection was approved by the US FDA in 1986, the monoclonal antibody has grown from the first-generation mouse-derived monoclonal antibody (momab) and the first mouse-derived monoclonal antibody (momab) for 35 years.
The second-generation human-mouse chimeric monoclonal antibody (ximab), the third-generation humanized monoclonal antibody (zumab), and the fourth-generation fully humanized monoclonal antibody (mumab)
.

In recent years, antibody drugs accounted for 1/5 of the new drugs approved by the FDA each year
.

01 The era of "Baikang" has come

The total annual sales of global antibody drugs are reported to have exceeded 160 billion U.
S.
dollars, and several "super blockbuster drugs" with annual sales of more than 5 billion U.
S.
dollars have been born
.

Bi-antibody usually refers to the bispecific antibody (bsAb, Bispecific Antibody) with two specific antigen binding sites, which can interact with target cells and functional cells at the same time, thereby enhancing the killing of target cells
.

Most of the dual-antibody drugs choose tumors as indications.
Tumors account for up to 90% of the indications, of which solid tumors account for 59% and hematological tumors account for 29%; followed by autoimmune diseases, accounting for about 8% ; The remaining indications include ophthalmic diseases (AMD), rare diseases (hemophilia) and so on
.

Corresponding to the full bloom of monoclonal antibodies, the current approved products of double antibodies lag far behind those of monoclonal antibodies
.

Compared with monoclonal antibodies, double antibodies add a specific antigen binding site, so they have stronger specificity, can more accurately target tumor cells and reduce off-target toxicity, but double antibody drug development is more complicated and technical barriers.
The adaptability requirements for technology platform and target selection have also increased
.

Due to the difficulty in early development and expression of bispecific antibodies, poor stability, and complex production processes; a large number of different bispecific antibody molecules need to be screened before the drug molecules are determined, and the R&D cost is significantly higher than that of antibodies; Structural biology, antibody engineering, and screening strategies.
Therefore, companies with strong R&D capabilities are likely to win the competition in the development of dual-antibody drugs
.

There are more than one hundred bi-antibody drugs in the international multi-center clinical stage around the world.
About 120 bi-specific antibodies are in different stages of clinical development, but only 4 products have been approved for marketing
.

The four products currently approved for marketing are Removab, Blincyto, Hemlibra and Rybrevant
.

On May 21, the FDA accelerated the approval of the EGFR/c-Met dual antibody Rybrevant (amivantamab-vmjw) developed by Johnson & Johnson's Janssen Pharmaceuticals for the treatment of patients with epidermal growth factor receptor (EGFR) confirmed by the FDA-approved test Patients with locally advanced or metastatic non-small cell lung cancer (NSCLC) with exon 20 insertion mutations, these patients have disease progression during or after platinum-based chemotherapy.
It is the fourth dual antibody marketed in the world, which is far from the previous dual antibody.
It has been approved for listing for 4 years
.

02 Monoclonal antibodies look at the target, double antibodies look at the platform

The target of a drug is a biomolecule and its specific binding site that have important physiological or pathological functions and can be combined with the drug to produce pharmacological effects
.

It is reported that there are currently over a thousand monoclonal antibodies in the world, and antibody drugs corresponding to about 400 targets are under development or are already on the market
.

Targets of commercialized antibody products in the world are relatively concentrated.
Among them, PD-1/L1 ranks first, followed by CD20, TNF, HER2, CGRP/CGRPR, VEGF/VEGFR, IL-6/IL-6R, IL -23 Popular targets such as p19, EGFR, and CD19
.

Compared with the monoclonal antibody, the target is more important, and the double antibody is more focused on the platform
.

Bispecific antibodies can generally be divided into non-IgG-like double antibodies without Fc region and IgG-like double antibodies with Fc region
.

A non-IgG-like double antibody without an Fc region is a double antibody that combines multiple antibody fragments on a molecule without an Fc region
.
Its advantages mainly include strong tissue penetration ability, simple structure, lack of Fc fragments, only play a therapeutic effect through antigen binding, low immunogenicity, etc.
, but there is a short half-life
.

The first-generation bispecific antibody is a non-IgG-like double antibody without an Fc region.
Its typical representative is Amgen/Micromet's BiTE (Bispecific T-cell Engager).
It has a simple structure and is formed by connecting two scFvs, but has disadvantages.
Obviously, the half-life is short (only 2 hours) and the expression level is low
.
Because of the short half-life, a pump has to be used for continuous administration in clinical practice
.
Fortunately, the clinical dosage of BiTE is low, less than one-tenth of the dosage of ordinary antibodies, which virtually solves the problem of mass production
.
After overcoming various difficulties, the first recombinant bispecific antibody Blinatumomab (CD3/CD19 BiTE) was finally approved by the FDA for listing in the United States in December 2014.
The indication is lymphocytic leukemia.
The sales in 2020 will be US$421 million.
, Ling Teng Pharmaceutical introduced this product in China
.

An IgG-like double antibody with an Fc region is a form in which two specific binding units are combined in a single polypeptide or a single HL pair is used to obtain a fragment-based Fc fusion protein format antibody fragment and a conventional antibody molecule
.
Its advantages mainly include the recirculation mechanism of FcRn to increase the half-life of the drug and the effects of ADCC, CDC, and ADCP.
The disadvantage is that there is a mismatch between the light and heavy chains
.

In the 1990s, Genentech's Paul Carter team invented a bispecific antibody with an Fc region IgG-like double antibody knob-into-hole (KiH) structure, which became a typical representative of the second generation of bispecific antibodies
.
The second-generation bispecific antibody has a structure and stability similar to that of natural IgG, and has also been greatly improved in terms of expression and downstream processing
.
Roche/Chugai's Emicizumab (target factor IX and factor X bsAb) using ART-Ig technology was approved by the FDA in November 2017 to become the second bispecific antibody to be marketed in the United States
.
The indication is hemophilia A, and its sales in 2020 will be US$2.
287 billion
.

Mismatch refers to the non-complementarity between the bases on one strand of DNA and the corresponding bases on the other strand
.
In the double helix structure of DNA, there is always a principle that adenine (A) pairs with thymine (T), and guanine (G) pairs with cytosine (C)
.
If A is paired with C or G, or T is paired with G or C, a base mismatch occurs
.

The mismatch of heavy and light chains of IgG-like double antibodies with Fc region poses a greater challenge to the preparation process
.
In the structure of the monoclonal antibody, since the two heavy chains and the two light chains have exactly the same amino acid composition, there is only one structure after the combination of the four chains
.
However, the four polypeptide chains of the double antibody, including two heavy chains and two light chains, have different structures, and 16 possible structural combinations can be randomly generated when combined
.
Since there is only one target product, this means that the remaining products of the mismatch are invalid products or even by-products, which makes it difficult to separate the target product, and the production process is complicated in the final industrialization, the production cost is high, and the product efficiency of the dual antibody is Low, high impurity protein
.

In addition, the Fc fragment is immunogenic and may cause tumor-independent T cell activation.
In extreme cases, it may cause a "cytokine storm risk", and the Fc region usually needs to be engineered
.

In response to the short half-life of non-IgG-like double antibodies without Fc region and IgG-like double antibodies with Fc region and the mismatch of heavy and light chains, global pharmaceutical giants have designed double antibody technology platforms
.

Non-IgG-like double antibody technology platforms without Fc fragments mainly include Amgen’s BiTE platform, Sanofi’s Nanobody platform, MacroGenics’ DART platform, Affimed’s TandAbs platform, and CytomX’s platform
.
On the whole, there are not many products that can enter the clinical stage of non-IgG-like double antibody technology platforms without Fc fragments
.

BiTE (Bispecific T-cell Engager, bispecific T cell adapter) was developed by the German company Micromet
.
In 2012, Micromet was acquired by Amgen, which acquired BiTE technology
.
Blincyto (Blinatumomab) is a dual-antibody drug developed based on the BiTE platform.
It will be launched in China in December 2020, and BeiGene has Chinese rights and interests
.

In response to the short half-life problem, Amgen further designed the half-life extended (HLE) BiTE molecule
.
Unlike BiTE, HLE BiTE integrates the Fc structure into BiTE.
The essence is to convert non-IgG-like double antibody molecules without Fc end into double antibody molecules with Fc end, increase the molecular weight of the double antibody and use FcRn in the circulation to extend the drug’s effectiveness.
Half-life
.
Currently, drugs using HLE BiTE molecules such as AMG160 (CD3/PSMA), AMG199 (CD3/MUC17), AMG427 (CD3/FLT3), AMG757 (CD3/PSMA), AMG910 (CD3/CLDN18.
2), etc.
are in the clinical stage
.

In March 2021, Amgen terminated the clinical trials of three dual antibody products, namely AMG701 (BCMA/CD3), AMG 673 (CD33/CD3) and AMG 596 (EGFRIII/CD3)
.
Among them, AMG701 and AMG 673 are half-life extended (HLE) BiTE molecules, and the progress of AMG701 has reached clinical phase II and has been cut down
.

The termination of AMG701 and AMG 673 reminds companies under research to a certain extent: the risk of activating T cells must be carefully considered, and the extension of the half-life of the dual anti-body must be cautious!

Although AMG 673 (CD33/CD3) has been discontinued, the AMG 330 on the original BITE product line is still insisting, and it is also the only product currently in the clinical development stage on the original BITE product line of Amgen
.
Generally speaking, batch products developed on the same R&D platform usually have common shortcomings.
For the time being, the shortcomings of the original BITE platform are still affecting the R&D of HLE-BiTE
.

Although Amgen listed Blinatumomab after acquiring the BITE technology platform, the performance of Blinatumomab was average, and only one product on the original BITE product line was struggling
.
This shows that Amgen's acquisition of Micromet in 2012 for US$1.
16 billion in cash was a big loss
.
I thought that Amgen had taken the lead in the field of anti-doubles.
At present, it seems that the track has been selected correctly, but the technology platform has been bought in the wrong way
.

It is worth noting that after Amgen stopped the development of the dual anti-AMG701, Pfizer announced in May this year that the phase II clinical trial of the BCMA/CD3 dual anti-elranatamab MagnetisMM-3 of AMG701 was caused by 3 weeks of nerve damage.
Suspend the recruitment of patients
.
The response rate of elranatamab in the previous phase 1 clinical trial was as high as 83%, and the phase II trial was originally planned as the main basis for the accelerated approval of the market
.

BCMA is one of the most important targets of MM, and it is also the second target of CAR-T, a highly risky therapy that has a marketed product
.
The only targets that can withstand CAR-T bombing are CD19 and BCMA
.
CD3 is one of the component receptors of the TCR complex on the surface of T cells.
CD3 is one of the targets of 2 of the 3 double antibodies currently on the market.
Put the target point
.

It remains to be seen whether the target combination of BCMA/CD3 will be a dead group
.

Table product enters the clinical stage of the double antibody platform

For IgG-like double antibodies with Fc fragments, the technology platforms mainly include Roche’s KiH platform and CrossMab platform, AbbVie’s DVD-ig platform, Eli Lilly’s Orthogonal Fab IgG platform, and Zymeworks Inc’s EFECT platform
.
As the development of dual-antibody drugs continues to heat up, a number of domestic pharmaceutical companies have also established dual-antibody technology platforms, such as the YBODY platform of Youzhiyou, the FIT-Ig platform of Anmai Bio, and the FIT-Ig platform of Corning Jereh.
biological medicine out of Wuxibody platform, Jun real biological TEAC, and platinum medicine HBICETM platform
.

In 2020, Innovent and Roche reached a US$2 billion cooperation to develop universal CAR-T therapies and TCB bispecific antibodies
.
In November of the same year, Roche initiated the first clinical trial of the dual antibody Glofitamab in China, which was derived from Roche's TCB technology platform
.

BeiGene introduced the HER2-targeting bispecific antibody zanidatamab (ZW25) from Zymeworks at the end of 2018, and applied for clinical application in China in 2020
.
In November of the same year, Zymeworks announced that the FDA granted its zanidatamab breakthrough drug designation for use in previously treated patients with biliary tract cancer with amplified HER2 gene
.

The platform based on the world's fourth bispecific antibody Rybrevant is the DuoBody® technology platform
.
In July 2012, Genmab, headquartered in Copenhagen, Denmark, established a partnership with Janssen Biotech, Inc.
to create and develop bispecific antibodies using Genmab's DuoBody® technology platform
.
The production and development of Rybrevant will follow the license agreement between Janssen and Genmab for the use of the DuoBody® technology platform
.

In August 2016, Gilead and Genmab reached a cooperation agreement and will pay Genmab a maximum of more than US$300 million (including an upfront payment of US$5 million and a milestone payment of US$277 million) to use the latter’s DuoBody platform to develop HIV treatments.
Bispecific antibody drugs, but as of 2021, no products are in clinical practice
.

On June 10, 2020, AbbVie and Genmab announced that they have reached a partnership to jointly develop Genmab’s three next-generation bispecific antibody products, including the CD3/CD20 bi-antibody epcoritamab (currently undergoing B-cell non-Hodgkin’s lymphoma Clinical trial), CD37 double epitope double antibody GEN3009, CD3/5T4 double antibody
.

In May 2021, Novo Nordisk's Mim8 was approved for clinical use in China
.
Similar to the world's first hemophilia A bispecific antibody emicizumab developed by Roche, Mim8 is also a bispecific antibody targeting FIXa and FX to mimic the effects of FVIII in humans
.
Mim8 was developed using Genmab's Duobody platform.
The anti-FIXa and anti-FX antibodies were initially screened respectively, and then multiple system mutation optimization iterations were performed.
More than 30,000 bispecific antibodies were analyzed in total, and more than 40,000 were early screened with Emicizumab.
The workload of this combination is even worse
.

03 Combination therapy has become a new way for double antibodies?

Also facing setbacks in 2021 is the dual anti-star PD-L1/TGF-β dual anti-M7824, and in 2021 it can be described as the Waterloo of M7824
.
On March 16, German Merck announced that its PD-L1/TGF-β double antibody M7824 (bintrafusp alfa) in the second-line treatment of cholangiocarcinoma failed to reach the primary endpoint and failed
.

Previously, on January 15, the phase II study of M7824 treatment of patients with solid tumors who received immune checkpoint inhibitors (ICB) and microsatellite highly unstable (MSI-H)/mismatch repair defects (dMMR) did not show The anti-tumor activity has ended in failure
.
Five days later, M7824 again failed to challenge Keytruda's Phase III study of non-small cell lung cancer, and failed to reach the preset end point of PFS
.

At present, many domestic pharmaceutical companies have followed up the layout of the PD-L1/TGF-β double antibody combination, including Junshi Bio, Hengrui Pharmaceutical, Chuangsheng Group, Pumis Bio, Youzhiyou Bio, Nanjing Weilizhibo Bio, The clinical trial application (IND) for the original PD-1/TGFβ double antibody JS201 of Junshi Biopharmaceuticals, Lepu Biotech, etc.
, was accepted by the NMPA just last month
.

Currently, the popular target combination of double antibodies under research is PD-L1/CTLA-4, because the combination therapy of monoclonal antibodies has been recognized by the guidelines: Ipilimumab (CTLA-4) and Nivolumab launched by BMS Anti-(PD-1) combination therapy can greatly improve the ORR of subjects
.
In the United States, the FDA has approved the simultaneous use of nivolumab and ipilimumab for the first-line treatment of renal cell carcinoma (RCC) (April 2018), and high microsatellite instability (MSI-H) or dMMR ( Second-line treatment for colorectal cancer (CRC) with mismatch repair defects (July 2018)
.

Combination therapy may increase the rate of adverse reactions, and double antibodies are expected to reduce the rate of adverse reactions
.

In a Phase III clinical study called CheckMate 067, the proportion of grade 3-4 adverse reactions in the PD-1 monotherapy group was 22%, and the proportion of grade 3-4 adverse reactions in the CTLA-4 monotherapy group was 28.
%, and the rate of grade 3-4 adverse reactions in the combination group (O drug + Y drug) increased to 59%
.
The AK104 (PD-1/CTLA-4) clinical study of Kangfang Biology shows that the safety of AK104 is equivalent to that of PD-1 or PD-L1 monotherapy, which is significantly lower than the toxicity of combination therapy
.
Corning Jerry is very likely to become the first company listed on the domestic market in this target combination
.