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If a "blacklist" is made for the genetic mutations of cancer cells, the two genes TP53 and RAS must be very high.
TP53 has always been a difficult problem that targeted therapy cannot overcome.
In the RAS gene family, although there is a small molecule targeted drug KRAS that has achieved initial success, it is only suitable for a very limited number of patients.
Successfully targeting these two genes will definitely be a milestone in cancer treatment.
The team of Professor Bert Vogelstein of Johns Hopkins University recently published three new research results in Science and its sub-journals Science Immunology and Science Translational Medicine, which is expected to become such a milestone.
The research team developed a new bispecific antibody against mutation-associated neoantigens (MANAs).
They can recruit T cells to successfully eliminate cancer cells after recognizing the "trace" left by mutant genes on the cell surface, which is reflected in animal experiments.
It has an excellent curative effect and successfully broke through the problem of TP53 and RAS that are difficult to target [1-3]! Combining, activating, and Boom antibody drugs are an important member of targeted therapy.
The most typical are various monoclonal antibodies, but it is very difficult to target TP53 and RAS with antibodies because they are rarely expressed on the cell surface.
Proteins are basically hidden in cells, and it is difficult for monoclonal antibodies to enter cells to exert inhibitory effects like small molecule drugs.
But if TP53 and RAS are mutated, the situation is different: the protein encoded by the mutated gene will be hydrolyzed by proteases in the cell, and the resulting polypeptide fragment will form a complex (pHLA) with the human leukocyte antigen (HLA) protein, and then be presented On the cell surface, it becomes a new antigen that can be recognized by the T cell receptor (TCR).
Such peptide fragments are the aforementioned MANAs, which also provide a target for the development of antibodies against cells with TP53 or RAS mutations.
However, under normal circumstances, the expression level of MANAs outside the cell is very low, and the number of copies on each cell may be different.
There are less than 10.To target such a small number of targets, antibodies are required to be fully upgraded in design to achieve true precision strikes.
It took more than 5 years for the research team to come up with the protagonist this time-a new type of bispecific antibody called "Diabody".
Unlike traditional "Y" shaped antibodies, this bispecific antibody does not have the Fc segment of the antibody in its design.
Instead, it combines the single-chain variable region fragment (ScFv) targeting the mutant protein and the activated T cell receptor CD3.
The ScFv (UCHT1) are connected together to form a single-stranded Diabody (scDb), the shape is like the following.
The structure is very fresh, right? In order to accurately target pHLA, the research team used phage display (Phase Display) technology to select appropriate ScFv from a library of higher affinity "TCR-mimic" (TCR-mimic) fragments.
For example, in the development of TP53, the most common mutation TP53- For scDb of R175H, a fragment called H2 is used.
This H2 can highly specifically bind to TP53-pHLA, and then activate T cell immune response, and will not bind to the pHLA of the wild-type TP53 protein of normal cells, so it was selected for the development of scDb for TP53 and for different types of RAS Mutation, ScFv is replaced by R2, L2, etc.
with high affinity.
H2-ScDb's principle of action 3 That is to say, scDb can be flexibly designed and combined according to the purpose of treatment.
This is reflected in three different papers published this time: In the main issue of Science, the research team tested the therapeutic effect of H2-scDb in mice with multiple myeloma models (with the TP53-R175H mutation) .
The effect of H2-scDb is clear at a glance.
No matter whether low or high doses are used, the tumors of mice are significantly reduced, but if CRISPR is used to knock out the TP53 gene, or if human-derived T cells are not injected, then H2-scDb will not The effect proves that the target site and T cell immune response are indispensable for its onset. On the left is a normal multiple myeloma model.
The tumor shrinking effect is obviously better than that of knocking out TP53 on the right.
The "Science Immunology" paper shows that scDb targeting RAS mutations can also accurately identify and reconcile even when the antigen level is very low.
Eliminate lung cancer and pancreatic cancer cells with KRAS G12V or RAS Q61 mutations; the "Science Translational Medicine" paper allowed scDb to target T-cell cancers, and the test results were also very satisfactory.
To say that there are any shortcomings of this kind of ScDb, it is because of the lack of the Fc segment of the antibody, their stability in the blood is poor, and the clearance speed is faster.
If you want to maintain the therapeutic concentration, you have to give the patient continuous pumping.
In addition, ScDb uses ScFv also needs to be "customized" according to the specific types of TP53 or RAS mutations in patients [4].
However, being able to break the curse of TP53 "unable to make medicine" has already made many experts very happy.
Compared with the immature KRAS small molecule targeted drugs, the role of ScDb in activating the immune response may be more effective in terms of efficacy.
One chip.
A comment published in the same period of "Science" pointed out that in the future, ScDb combined with new therapies such as immune checkpoint inhibitors, oncolytic viruses, tumor vaccines, etc.
, is also expected to achieve breakthroughs in immunotherapy.
It is hoped that these ideas can quickly enter the clinical research stage, and in actual combat Further optimize and upgrade it. References: 1.
Hsiue EHC, Wright KM, Douglass J, et al.
Targeting a neoantigen derived from a common TP53 mutation[J].
Science, 2021, 371(6533).
2.
Douglass J, Hsiue EHC, Mog BJ, et al.
Bispecific antibodies targeting mutant RAS neoantigens[J].
Science Immunology, 2021, 6(57).
3.
Paul S, Pearlman AH, Douglass J, et al.
TCR beta chain-directed bispecific antibodies for the treatment of T- cell cancers[J].
Science Translational Medicine, 2021.
4.
https://immunology.
sciencemag.
org/content/6/57/eabd5515 Head image source: Pixabay Author of this article | Tan Shuo
TP53 has always been a difficult problem that targeted therapy cannot overcome.
In the RAS gene family, although there is a small molecule targeted drug KRAS that has achieved initial success, it is only suitable for a very limited number of patients.
Successfully targeting these two genes will definitely be a milestone in cancer treatment.
The team of Professor Bert Vogelstein of Johns Hopkins University recently published three new research results in Science and its sub-journals Science Immunology and Science Translational Medicine, which is expected to become such a milestone.
The research team developed a new bispecific antibody against mutation-associated neoantigens (MANAs).
They can recruit T cells to successfully eliminate cancer cells after recognizing the "trace" left by mutant genes on the cell surface, which is reflected in animal experiments.
It has an excellent curative effect and successfully broke through the problem of TP53 and RAS that are difficult to target [1-3]! Combining, activating, and Boom antibody drugs are an important member of targeted therapy.
The most typical are various monoclonal antibodies, but it is very difficult to target TP53 and RAS with antibodies because they are rarely expressed on the cell surface.
Proteins are basically hidden in cells, and it is difficult for monoclonal antibodies to enter cells to exert inhibitory effects like small molecule drugs.
But if TP53 and RAS are mutated, the situation is different: the protein encoded by the mutated gene will be hydrolyzed by proteases in the cell, and the resulting polypeptide fragment will form a complex (pHLA) with the human leukocyte antigen (HLA) protein, and then be presented On the cell surface, it becomes a new antigen that can be recognized by the T cell receptor (TCR).
Such peptide fragments are the aforementioned MANAs, which also provide a target for the development of antibodies against cells with TP53 or RAS mutations.
However, under normal circumstances, the expression level of MANAs outside the cell is very low, and the number of copies on each cell may be different.
There are less than 10.To target such a small number of targets, antibodies are required to be fully upgraded in design to achieve true precision strikes.
It took more than 5 years for the research team to come up with the protagonist this time-a new type of bispecific antibody called "Diabody".
Unlike traditional "Y" shaped antibodies, this bispecific antibody does not have the Fc segment of the antibody in its design.
Instead, it combines the single-chain variable region fragment (ScFv) targeting the mutant protein and the activated T cell receptor CD3.
The ScFv (UCHT1) are connected together to form a single-stranded Diabody (scDb), the shape is like the following.
The structure is very fresh, right? In order to accurately target pHLA, the research team used phage display (Phase Display) technology to select appropriate ScFv from a library of higher affinity "TCR-mimic" (TCR-mimic) fragments.
For example, in the development of TP53, the most common mutation TP53- For scDb of R175H, a fragment called H2 is used.
This H2 can highly specifically bind to TP53-pHLA, and then activate T cell immune response, and will not bind to the pHLA of the wild-type TP53 protein of normal cells, so it was selected for the development of scDb for TP53 and for different types of RAS Mutation, ScFv is replaced by R2, L2, etc.
with high affinity.
H2-ScDb's principle of action 3 That is to say, scDb can be flexibly designed and combined according to the purpose of treatment.
This is reflected in three different papers published this time: In the main issue of Science, the research team tested the therapeutic effect of H2-scDb in mice with multiple myeloma models (with the TP53-R175H mutation) .
The effect of H2-scDb is clear at a glance.
No matter whether low or high doses are used, the tumors of mice are significantly reduced, but if CRISPR is used to knock out the TP53 gene, or if human-derived T cells are not injected, then H2-scDb will not The effect proves that the target site and T cell immune response are indispensable for its onset. On the left is a normal multiple myeloma model.
The tumor shrinking effect is obviously better than that of knocking out TP53 on the right.
The "Science Immunology" paper shows that scDb targeting RAS mutations can also accurately identify and reconcile even when the antigen level is very low.
Eliminate lung cancer and pancreatic cancer cells with KRAS G12V or RAS Q61 mutations; the "Science Translational Medicine" paper allowed scDb to target T-cell cancers, and the test results were also very satisfactory.
To say that there are any shortcomings of this kind of ScDb, it is because of the lack of the Fc segment of the antibody, their stability in the blood is poor, and the clearance speed is faster.
If you want to maintain the therapeutic concentration, you have to give the patient continuous pumping.
In addition, ScDb uses ScFv also needs to be "customized" according to the specific types of TP53 or RAS mutations in patients [4].
However, being able to break the curse of TP53 "unable to make medicine" has already made many experts very happy.
Compared with the immature KRAS small molecule targeted drugs, the role of ScDb in activating the immune response may be more effective in terms of efficacy.
One chip.
A comment published in the same period of "Science" pointed out that in the future, ScDb combined with new therapies such as immune checkpoint inhibitors, oncolytic viruses, tumor vaccines, etc.
, is also expected to achieve breakthroughs in immunotherapy.
It is hoped that these ideas can quickly enter the clinical research stage, and in actual combat Further optimize and upgrade it. References: 1.
Hsiue EHC, Wright KM, Douglass J, et al.
Targeting a neoantigen derived from a common TP53 mutation[J].
Science, 2021, 371(6533).
2.
Douglass J, Hsiue EHC, Mog BJ, et al.
Bispecific antibodies targeting mutant RAS neoantigens[J].
Science Immunology, 2021, 6(57).
3.
Paul S, Pearlman AH, Douglass J, et al.
TCR beta chain-directed bispecific antibodies for the treatment of T- cell cancers[J].
Science Translational Medicine, 2021.
4.
https://immunology.
sciencemag.
org/content/6/57/eabd5515 Head image source: Pixabay Author of this article | Tan Shuo
