It's about to usher in the launch period!

01.
Introduction to Double Antibodies

01.
Introduction to Double Antibodies

According to the 2021 global best-selling drug list, 4 of the top 10 global best-selling drugs in 2021 are antibody drugs, and 9 of the top 20 are monoclonal antibody drugs.
Market performance, antibody-drug conjugates, bispecific antibodies and other antibody types have gradually become the key targets of corporate research and development
.

The main structure of monoclonal antibodies is composed of two symmetrical light chains and heavy chains.
Bispecific antibodies are usually artificially synthesized.
Antibodies with two specific antigen binding sites at the same time can be compared with traditional monoclonal antibodies by targeting.
, has the characteristics of stronger targeting, lower toxicity but high technical barriers to R&D and production
.

Bispecific antibodies are usually divided into IgG diabodies (containing FC fragments) and non-IgG diabodies (without FC fragments) according to the presence or absence of FC fragments, and IgG diabodies are further divided into symmetric IgG diabodies according to whether they are symmetrical or not.

IgG double antibodies contain FC fragments, which are closer in structure 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.

Table 1: Comparison of IgG and non-IgG diabodies

Source: Flint Creation Arranged based on public information

02.
Representative double antibody technology platform

02.
Representative double antibody technology platform

Since the double antibody is formed by the combination of two different light and heavy chains, there are 16 combinations
.

However, only 12.

(1) IgG double antibody technology platform

(1) IgG double antibody technology platform

As IgG double antibodies are more prone to light and heavy chain mismatches, the platform mainly solves such problems
.

1.
KIH and Cross Mab technology platform

1.
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 small amino acid on the other chain mutates.
It becomes a large amino acid, 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

2.
DuoBody Technology Platform

2.
DuoBody Technology Platform

Bispecific antibodies are obtained by swapping the Fab arms of two mAbs 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.

(2) Non-IgG double antibody technology platform

(2) Non-IgG double antibody technology platform

Due to the lack of FC fragments, non-IgG double antibodies cannot bind to FcRn, so the half-life is generally short.
Each technology platform mainly promotes the clinical application of non-IgG double antibodies by prolonging the half-life
.

1.
BITE Technology Platform

1.
BITE Technology Platform

In this platform, 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.
cells and induce T cells to kill tumor cells
.

And because the molecular weight of the double antibody fragment is small, the penetration rate of tumor cells is greatly improved.

2.
TandAb Technology Platform

2.
TandAb Technology Platform

A two-peptide antibody composed of four ScFv fragments developed by Affimed.
The peptide chains are arranged in the order of VL1-VH2-VL2-VH1 from the N-terminus to the C-terminus, and the two peptide chains form a homodimer connection , the molecular weight of the antibody synthesized by this technology is about 100kd, which can significantly prolong the half-life compared with the molecular weight of 50kd of ordinary non-IgG double antibody
.

03.
Research and development of double-antibody drugs

03.
Research and development of double-antibody drugs

At present, four double-antibody products have been launched in the world.
The first drug catulumumab is a T-cell redirecting antibody, and the approved indication is cancerous ascites
.

However, the drug was delisted in 2017 due to poor sales performance

The research on bispecific antibodies by domestic enterprises is progressing rapidly
.

According to incomplete statistics, there are 65 drugs entering the clinical trial stage, two-thirds of which are for tumor treatment

Table 2: Representative companies and drugs of domestic double-antibody R&D

Source: Flint Creation Arranged based on public information

04.
Double antibody industry chain

04.
Double antibody industry chain

Since there are currently no double-antibody drugs on the market in China, the industry chain of double-antibody drugs 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 are the type of bioreactor and culture conditions.
Since the metabolic level of bispecific antibodies may change during the cell growth process, it is necessary to evaluate the conditions that are conducive to cell metabolism.

.
At the same time, since bispecific antibodies are prone to cause aggregation, higher requirements are placed on the purification of antibodies, resulting in a decrease in yield
.
Due to the existence of numerous heavy and light chains, the analytical method needs to be improved.
Simple gel analysis is no longer sufficient, and more sensitive analytical methods need to be developed
.

05.
Summary

05.
Summary

It is predicted that by 2024, the domestic market of double-antibody drugs will reach 5 billion yuan
.
The domestic double-antibody drug R&D target layout is differentiated and the degree of homogeneity is low.
Antibody R&D focuses on optimizing the production process 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 stage of bispecific antibodies is expected to usher in a breakthrough in the market in the near future
.