[Transfer] The fourth wave of revolution: antibody drug research and development opening the "Neptune Plan"

[Transfer] The fourth revolutionary wave of the pharmaceutical industry: antibody drug research and development opening the "Neptune Plan"

Source: amino observation/Fang Taozhi

"Under the leadership of Domatomic drugs, the pharmaceutical industry will usher in the fourth revolutionary wave."

In 2020, Professor Raymond J. Deshaies gave predictions in a paper published by Nature magazine.

Today, the fourth revolutionary wave has begun.

As the most important branch of Doxoma drugs, the development of multi -anti -drugs is in full swing. Since the beginning of the year to the present, the number of explosions of the number of double anti -drugs in the world has exceeded more than ten years.

In fact, global pharmaceutical companies have long been not satisfied with the "two boats".

Overseas, Pharmaceutical companies such as Sanofi, Johnson & Johnson, HarpoON have led the "Neptune Plan"; many pharmaceutical companies including Doul Biology, Jiahe Biology, and Baili Pharmaceuticals are also participating in it.

The most dreamy, or Baili Pharmaceutical. Earlier, Zhu Yi, chairman of Baili Pharmaceutical, said in an interview with the media that he had developed "five anti" research and development.

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

/ 01 /

From monoclonal to five resistance, the rise

In the past 30 years, antibody drugs have completely changed the treatment of the disease. At present, the FDA has approved the listing of over 100 monoclonal drugs, covering tumors and autoimmune diseases in the treatment field.

However, because the disease is essentially complex and originated from various factors and media, the eyes of the biopharmaceutical industry have long been aimed at two or more specific molecules.

As mentioned above, only in the field of tumor treatment, double resistance has burst completely, and more antibody drugs such as three -resistant and four -resistant targets are also in full swing. At present, more than 30 three -specific antibody candidates around the world are under research.

Of course, the "Neptune" is not aimless to spread the net.

On the contrary, their purpose is very clear. It is hoped that the different mechanisms in immunotherapy can play a role, including but not limited to bridge immune cell bridges, collaborative activation / blocking immune signal pathways, and increased tumor antigen selectivity.

In the actual application process, multi -anti -drugs can indeed achieve the effect of 1+1 greater than 2.

For example, the traditional 4-1BB monoclonal resistance, because the target target exists in the tissues of the body, is difficult to balance the safety and efficacy of the drug, which makes it difficult to develop.

The emergence of dual anti-technology has changed the fate of 4-1BB targets. Multi -resistance can accurately target specific tumor cells by adding a arm to reduce toxicity.

At present, 4-1BB targets are mostly developed in dual-resistance and multi-resistance.

Cornerstone Pharmaceuticals/NUMAB, CREScendo/Biontech deploy 4-1BB triple resistance, and Belle Pharmaceuticals has a 4-1BB four resistance.

Of course, whether it is dual -resistant or three -resistance or even four resistance, it must be proved that in terms of existing treatment standards, it provides further improvement evidence, or it is safer, more effective, or more convenient to use. This is the most basic requirement for innovation. Essence

Back to the current wave of anti -R & D, there are also challenges outside the lively.

/ 02 /

Several anti -anti -anti -resistances do not necessarily twist a thigh

The number of antibodies and clinical benefits cannot be used for equal number. In practice, the most popular "double resistance" field has not been developed, and there are not few examples of turning over.

For example, an ABT-122 dual resistance developed by Abervi-developed AL-17 and TNF-ɑ is used to treat rheumatoid arthritis.

In the initial clinic, this drug showed effectiveness and safety, and was once considered to be the successor of the medicine Wang Xiumele. However, in the later clinic, ABT-122 did not show the strength better than Adam monoclonal resistance.

This is not a case. In the field of tumors, the most well-known case of double anti-rollover, or the PD-L1/TGFβ dual-resistant developed by Merck in Germany.

Theoretically, by blocking the two signal channels of PD-L1 and TGF-β, it can not only relieve immunosuppressiveness, but also enhance the body's immune killing ability. It can be described as a strong combination. However, in the actual clinical, the clinical trials of M7824 were defeated and could not defeat the K -drug single medicine.

This is not difficult to understand. For some targets that have not been padded, we do not fully understand its single -action mechanism, let alone what kind of chemical reactions will occur between the collisions between the two targets.

For the research and development of multi -anti -drug, the biggest benefit is that there are enough choices. As mentioned above, more than 100 monoclonal drugs have been approved. Based on a clear mechanism, different arrangements and combinations may bring better results.

But this will also be a challenge for multi -anti -drugs. How to determine the order of the binding of the target and the receptor, the ratio of different receptors to control, how to choose the affinity between the target, how to control the toxicity, etc., there are no standard templates. Essence

Not only is it at the level of efficacy, but more resistance to safety can not necessarily be guaranteed, because at the same time, multiple targets may stimulate unexpected toxic and side effects. For example, a highly stimulating immune system may trigger cytokine release syndrome.

In the development of double resistance, safety issues are common, and the road to research and development of tri -resistance and four resistance will inevitably be more difficult. Researchers at the regenerative element have stated that although people are more and more interested in tri -resistance, cocktail combination therapy may achieve similar or better results.

/ 03 /

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

The challenge of multi -resistance is not only in the research and development link, but also the difficulty of industrialization. Even after the early design is completed, it is still troublesome to resist production and manufacturing later.

For example, the production capacity of multi -anti -drug is a problem. The interaction between multiple factors such as a flexible structural heterogeneous and potential gathering molecules, temperature, etc. will affect the multi -antican molecular space folding and the overall stability of the molecule.

Due to the extremely high variability, any unpredictable factor may make Duo Anti -large -scale production challenges.

It's like drawing two molecules on a piece of paper, and it is easy to assemble them correctly, but during the manufacturing process, these multi -anti -molecules may gather, precipitates, and poor expressions.

Because of this, some researchers believe that manufacturing capabilities will be the core factor of restricting some pharmaceutical companies in the field of anti -resistance.

Another key challenge is how to produce limited or neglected by -products and high -quality polytomotomy antibodies of impurities.

During the preparation of dual antidote, due to the mismatch between the heavy chain and light chain of the two original antibodies, it will produce an impurities that are difficult to separate, which will cause drug development and purification to become extremely difficult. In the research and development of drugs such as tri -resistance and four -resistance, it will face greater challenges.

Therefore, pharmaceutical companies need to continuously improve the expression and purification methods to obtain high output, produce the minimum unnecessary species, and simplify production methods.

However, compared with traditional monocyte -specific antibodies, we know very little about the development characteristics of multi -anti -therapy drugs. Therefore, although more anti -R & D, it is still a long way to go.

Of course, if anyone can solve these problems first, it will undoubtedly run the fourth wave of revolution in the pharmaceutical industry.

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