Alex Brown
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The immune system comprises various cells such as T cells and natural killer cells that detect and destroy foreign substances. However, some cancer cells can evade detection and destruction by inhibiting these cells' activities. One such mechanism employed by cancer cells is the high expression of programmed death-ligand 1 (PD-L1), which binds with programmed cell death protein 1 (PD-1) on T cells to suppress their activity. Researchers have developed an antibody-based technology called proteolysis targeting chimeras (PROTACs) to overcome this mechanism by degrading PD-L1 and, consequently, activating T-cell responses.
PROTACs is a novel approach to degrade specific target proteins instead of just inhibiting them. The technology involves two parts: a ligand for the target protein and a ligand for an E3 ubiquitin ligase enzyme. The ligand for the target protein directs the PROTAC to the desired protein, and the ligand for the E3 ubiquitin ligase enzyme brings the E3 ligase enzyme close to the target protein. The E3 ubiquitin ligase enzyme transfers ubiquitin, a protein that marks proteins for degradation, from a donor molecule to the target protein. When the target protein has enough ubiquitin molecules, it is degraded by the proteasome.
Antibody-based PROTACs are PROTACs that contain an antibody as the targeting ligand. Antibodies are proteins produced by B-cells to bind to specific molecules called antigens. They have a high binding affinity, specificity, and stability, making them ideal targeting ligands for PROTACs.
PD-L1 is a transmembrane protein that is expressed on various cancer cells, including breast, lung, and bladder cancer. Previous studies have shown that blocking PD-L1 and PD-1 interaction using antibodies can activate T cells and cause tumor regression. However, these antibodies only inhibit PD-L1 activity and do not degrade it.
In 2019, researchers at GlaxoSmithKline (GSK) developed an antibody-based PROTAC against PD-L1. The PROTAC contains an anti-PD-L1 antibody as a targeting ligand and a ligand for an E3 ubiquitin ligase. The researchers tested the PROTAC in vitro and observed that it reduced the PD-L1 protein level in several cancer cell lines. Importantly, the degradation of PD-L1 by the PROTAC was more effective than that of an anti-PD-L1 antibody alone.
To test the PROTAC's efficacy further, the researchers studied its effects on the immune system in vivo using a mouse model. The researchers implanted mice with a breast cancer cell line that expresses PD-L1 and tested the PROTAC's effects on tumor growth and the immune system. They observed that the PROTAC reduced the PD-L1 protein level in the tumor tissue and increased the number of T cells infiltrating the tumor, which resulted in a reduction in tumor growth.
Antibody-based PROTACs technology is a novel approach to degrade specific proteins, including PD-L1, and activate the immune system against cancer cells. GSK's successful development of an anti-PD-L1 antibody-based PROTAC that can degrade PD-L1 and activate T cells in vitro and in vivo represents an important milestone in the fight against cancer. This technology can also be applied to other cancer targets and has the potential to cause fewer side effects and achieve better treatment outcomes than current therapies. Further studies are required to optimize the technology and evaluate its safety and efficacy in human patients.
Introduction
The immune system comprises various cells such as T cells and natural killer cells that detect and destroy foreign substances. However, some cancer cells can evade detection and destruction by inhibiting these cells' activities. One such mechanism employed by cancer cells is the high expression of programmed death-ligand 1 (PD-L1), which binds with programmed cell death protein 1 (PD-1) on T cells to suppress their activity. Researchers have developed an antibody-based technology called proteolysis targeting chimeras (PROTACs) to overcome this mechanism by degrading PD-L1 and, consequently, activating T-cell responses.
Antibody-Based PROTACs Technology
PROTACs is a novel approach to degrade specific target proteins instead of just inhibiting them. The technology involves two parts: a ligand for the target protein and a ligand for an E3 ubiquitin ligase enzyme. The ligand for the target protein directs the PROTAC to the desired protein, and the ligand for the E3 ubiquitin ligase enzyme brings the E3 ligase enzyme close to the target protein. The E3 ubiquitin ligase enzyme transfers ubiquitin, a protein that marks proteins for degradation, from a donor molecule to the target protein. When the target protein has enough ubiquitin molecules, it is degraded by the proteasome.
Antibody-based PROTACs are PROTACs that contain an antibody as the targeting ligand. Antibodies are proteins produced by B-cells to bind to specific molecules called antigens. They have a high binding affinity, specificity, and stability, making them ideal targeting ligands for PROTACs.
Successful Degradation of PD-L1 by Antibody-Based PROTACs Technology
PD-L1 is a transmembrane protein that is expressed on various cancer cells, including breast, lung, and bladder cancer. Previous studies have shown that blocking PD-L1 and PD-1 interaction using antibodies can activate T cells and cause tumor regression. However, these antibodies only inhibit PD-L1 activity and do not degrade it.
In 2019, researchers at GlaxoSmithKline (GSK) developed an antibody-based PROTAC against PD-L1. The PROTAC contains an anti-PD-L1 antibody as a targeting ligand and a ligand for an E3 ubiquitin ligase. The researchers tested the PROTAC in vitro and observed that it reduced the PD-L1 protein level in several cancer cell lines. Importantly, the degradation of PD-L1 by the PROTAC was more effective than that of an anti-PD-L1 antibody alone.
To test the PROTAC's efficacy further, the researchers studied its effects on the immune system in vivo using a mouse model. The researchers implanted mice with a breast cancer cell line that expresses PD-L1 and tested the PROTAC's effects on tumor growth and the immune system. They observed that the PROTAC reduced the PD-L1 protein level in the tumor tissue and increased the number of T cells infiltrating the tumor, which resulted in a reduction in tumor growth.
Conclusion
Antibody-based PROTACs technology is a novel approach to degrade specific proteins, including PD-L1, and activate the immune system against cancer cells. GSK's successful development of an anti-PD-L1 antibody-based PROTAC that can degrade PD-L1 and activate T cells in vitro and in vivo represents an important milestone in the fight against cancer. This technology can also be applied to other cancer targets and has the potential to cause fewer side effects and achieve better treatment outcomes than current therapies. Further studies are required to optimize the technology and evaluate its safety and efficacy in human patients.
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Alex Brown
