Competing for the fourth revolutionary wave in the pharmaceutical industry: antibody drug research and development opens the "Neptune Plan"

"Led by multi-specific drugs, the pharmaceutical industry will usher in the fourth revolutionary wave.

In 2020, Professor Raymond J.

Now, the fourth revolutionary wave has begun to

As the most important branch of multi-specific drugs, the research and development of multi-antibody drugs is in full swing

In fact, global pharmaceutical companies have long been dissatisfied with the "two boats", and the research and development of three antibodies and four antibodies has long been on the road

Overseas, pharmaceutical companies such as Sanofi, Johnson & Johnson, and Harpoon have led the "Neptune Plan"; On the domestic side, a number of pharmaceutical companies, including Doyle Biologics, Jiahe Biologics, and Baili Pharmaceutical, are also involved

The most dreamed, or Baili Pharmaceutical

So, in the fourth wave of revolution in the pharmaceutical industry, who can really win by quantity?

/ 01 /

From monoclonal antibodies to five antibodies, the rise of the "multi-resistance war"

Over the past 30 years, antibody drugs have revolutionized the way diseases are treated

However, because diseases are inherently complex and stem from a variety of factors and mediators, the biopharmaceutical industry has long set its sights on molecules

As mentioned above, in the field of tumor treatment alone, dual antibodies have completely exploded, and the research and development of antibody drugs with more targets such as three antibodies and four antibodies is also in full swing

Of course, "Aquaman" is not aimless to cast a net

On the contrary, their purpose is very clear, hoping to play a role through different mechanisms in immunotherapy, including but not limited to bridging immune cell bridging, synergistic activation/blocking of immune signaling pathways, increasing tumor antigen selectivity, etc

In the process of practical application, multi-antibody drugs can indeed achieve the effect

For example, traditional 4-1BB monoclonal antibodies, because the target target is widely present in various tissues of the body, it is difficult to balance the safety and efficacy of drugs, resulting in difficulty in becoming a drug

The emergence of dual antibody technology has changed the fate of

At present, around the 4-1BB target, most of them are developed

CStone Pharmaceuticals/Numab and Crescendo/BioNtech laid out the three antibodies of 4-1BB, and Baili Pharmaceutical laid out the four antibodies
of 4-1BB.

Of course, whether it is a double antibody or a triple antibody or even a quadruple antibody, it must be proved that the existing treatment standards provide evidence of further improvement, which is either safer, more effective, or more convenient to use, which is the most basic requirement of
innovation.

Returning to the current wave of multi-resistance research and development, there are challenges in addition to the
bustle.

/ 02 /

Several arms of the multi-resistance do not necessarily allow one thigh of the monoclonal antibody to be twisted

There is no equivalence
between the number of stacked antibodies and the clinical benefit.
In actual clinical practice, the most popular "double antibody" field of research and development, the example of overturning is not small
.

For example, AbbVie developed an ABT-122 dual antibody that targets IL-17 and TNF-ɑ for the treatment of rheumatoid arthritis
.

In the early clinical stages, the drug demonstrated efficacy and safety, and was once regarded as the successor of the drug king Humira
.
However, in the later clinical stage, ABT-122 did not show a superior strength
to adalimumab.

This is not an isolated case
.
In the field of oncology, the most well-known double anti-rollover case is the PD-L1/TGFβ double antibody
developed by Merck in Germany.

Theoretically, by blocking the two signaling pathways of PD-L1 and TGF-β, it can not only release immunosuppression, but also enhance the body's immune killing ability, which can be described as a strong combination
.
However, in the actual clinic, the clinical trial of M7824 has lost four consecutive times and cannot defeat the K drug single drug
.

This is not difficult to understand
.
For some uninmedicated targets, we don't fully understand their single-action mechanisms, let alone what kind of chemical reactions arise from the collision between two targets
.

The biggest benefit for multi-antibody drug development is that there are enough options
.
As mentioned above, there are more than 100 monoclonal antibodies approved alone
.
Based on the clear mechanism, different permutations and combinations may lead to better results
.

But this will also be a challenge for multi-antibody
drugs.
How to determine the order of binding between targets and receptors, how many ratios of different receptors to control, how to choose the affinity between targets, how to control toxicity, etc.
, there is no standard template, which requires pharmaceutical companies to use time to explore
.

Not only in terms of efficacy, but also in terms of safety, multi-resistance is not necessarily guaranteed, because targeting multiple targets at the same time may trigger unexpected toxic side effects
.
For example, high stimulation of the immune system may trigger cytokine release syndrome
.

In the development of dual antibodies, safety problems are not uncommon, and the research and development of three and four antibodies will inevitably be more difficult
.

Regeneration researchers have said that although people are increasingly interested in tri-antibodies, cocktail combination therapy may achieve similar or better results
.

/ 03 /

In addition to the "blind box" drug research and development, industrialization is also a challenge

The challenge of multi-antibody drugs lies not only in the research and development process, but also in the difficulty of industrialization
.
Even after the early design is completed, the later multi-resistance production and manufacturing is still a troublesome thing
.

For example, the amplification of the capacity of multi-antibody drugs is a problem
.
The interaction between multiple factors such as flexible structural isomers and potential aggregate molecules, temperature, etc.
, will affect the spatial folding of multi-antibody molecules and the overall stability
of molecules.

Due to the extremely high variability, any unforeseen factor may make multi-resistance expansion of large-scale production challenge.

It's like drawing two molecules on a piece of paper and assembling them correctly, but in the manufacturing process, these multi-antibody molecules may accumulate, precipitate, poorly expressed, and fall apart for various reasons
.

For this reason, some researchers believe that manufacturing capacity will be the core factor
that limits some pharmaceutical companies from making a big difference in the field of multi-resistance.

Another key challenge is how to produce high-quality multispecific antibodies with limited or negligible by-products and impurities
.

In the preparation of dual antibodies, due to the mismatch between the heavy and light chains of the two original antibodies, impurities that are difficult to separate will be generated, which will make drug development and purification extremely difficult
.
In the development of drugs such as tri-antibodies and tetra-antibodies, there will be greater challenges
.

Therefore, pharmaceutical companies need to continuously improve expression and purification methods to produce the minimum number of unwanted species and simplify production methods while obtaining high yields
.

But we know very little
about the development properties of multi-antibody therapy drugs compared to traditional monospecific antibodies.
Therefore, although the research and development of multi-resistance is hot, there is still a long way to go
before it is truly successful.

Of course, if anyone can take the lead in solving these problems, it will undoubtedly be able to run away from the fourth revolutionary wave of
the pharmaceutical industry.