Over the past 20 years, monoclonal antibodies have gradually become the backbone of cancer treatment. From the initial application of mouse monoclonal antibodies with limited value to the new CAR-T technology occured recently, researchers have been constantly exploring improvements and innovations. The following section mainly introduces the use of monoclonal antibodies in cancer treatment from four aspects.
Cancer cell targeted therapy: Malignant tumor cells express some antigens that are different from normal healthy cells. These antigens can be used as good targets for monoclonal antibodies. In vitro and animal experiments have shown that antibodies directed against these targets can cause apoptosis, and through complement-mediated cytotoxicity (CMC) and antibody-dependent cell-mediated cytotoxicity dependent cellular cytotoxicity (ADCC) kills target cells. However, in different clinical experiments, it is still to be studied which mechanism is more important.
Changes in host response: VEGF and other vascular endothelial growth factors promote angiogenesis in tumors and provide a superior growth environment for tumors. Therefore, antibodies that inhibit angiogenesis by inhibiting VEGF, such as Bevacizumab, have become effective anti-cancer drugs. However, because they cannot directly act on cancer cells, such antibody drugs are usually used in combination with other cytotoxic drugs. Another method is T cell checkpoint blockade (T cell checkpoint blockade). In T cell immunity, the co-regulation of ligands and receptors plays an important role in the activation and suppression of tumor-specific T cells. Precisely controlled T cell checkpoints affect the immune system's response and avoid excessive activation of the immune system. Monoclonal antibodies that inhibit these checkpoints are called checkpoint blocking antibodies. They can induce a stronger tumor immune response and allow the response to last longer. Currently commonly used antibodies include CTLA4 Ipilimumab and PD1 antibodies pembrolizumab and nivolumab. The PD1 antibody has shown very good results in the initial clinical trials of Hodgkin's lymphoma.
Transporting cytotoxic molecules: In recent years, "smart bombs" have been used to describe this series of monoclonal antibodies that transport cytotoxic molecules to cancer cells. These molecules include radioimmunoconjugates, small cytotoxic molecules and cytokines in the immune system. Radioactive elements are used to label antibodies for tumor diagnosis and treatment. Lymphoma is a cancer that is more suitable for radiation therapy. The drugs currently approved by the FDA are ibritumomab tiuxetan and tositumomab. Antibody-drug conjugates (antibody-drug conjugates) are the most promising anticancer drugs recently developed. It couples cytotoxic drugs with specific antibodies to increase specificity while better killing tumor cells. In addition, immune cytokines such as IL-2 and GM-CSF are also used in combination with antibodies to target tumor cells and change the tumor microenvironment.
Remodeling T cells: T cell immunity plays a key role in tumor immunity. There are currently two major categories of methods that allow T cells to no longer be restricted by MHC molecules that recognize antigens by T cell receptors. The first type of method is a bispecific antibody. As the name implies, it can target cells as well as bind immune effector cells, such as T cells and NK cells. At present, the bispecific antibody blinatumomab against CD19 antigen has been approved by the FDA, and more antibodies are still under development. The second type of method is chimeric antigen receptor T cells (chimeric antigen receptor T cells), namely the famous CAR-T cells. These modified T cells contain specific antibody variable regions and T cell activation motifs that can attack cells expressing specific antigens. CAR-T cells can divide and grow, and maintain tumor cell specificity. At present, CAR-T cell therapy has achieved very significant effects in clinical trials. Although the accompanying cytokine storm will bring some risks, but the use of cytokine antibodies can mitigate its negative effects. The experience of the CAR-T experiment is still accumulating, and this technology will gradually mature in the future.
Cancer cell targeted therapy: Malignant tumor cells express some antigens that are different from normal healthy cells. These antigens can be used as good targets for monoclonal antibodies. In vitro and animal experiments have shown that antibodies directed against these targets can cause apoptosis, and through complement-mediated cytotoxicity (CMC) and antibody-dependent cell-mediated cytotoxicity dependent cellular cytotoxicity (ADCC) kills target cells. However, in different clinical experiments, it is still to be studied which mechanism is more important.
Changes in host response: VEGF and other vascular endothelial growth factors promote angiogenesis in tumors and provide a superior growth environment for tumors. Therefore, antibodies that inhibit angiogenesis by inhibiting VEGF, such as Bevacizumab, have become effective anti-cancer drugs. However, because they cannot directly act on cancer cells, such antibody drugs are usually used in combination with other cytotoxic drugs. Another method is T cell checkpoint blockade (T cell checkpoint blockade). In T cell immunity, the co-regulation of ligands and receptors plays an important role in the activation and suppression of tumor-specific T cells. Precisely controlled T cell checkpoints affect the immune system's response and avoid excessive activation of the immune system. Monoclonal antibodies that inhibit these checkpoints are called checkpoint blocking antibodies. They can induce a stronger tumor immune response and allow the response to last longer. Currently commonly used antibodies include CTLA4 Ipilimumab and PD1 antibodies pembrolizumab and nivolumab. The PD1 antibody has shown very good results in the initial clinical trials of Hodgkin's lymphoma.
Transporting cytotoxic molecules: In recent years, "smart bombs" have been used to describe this series of monoclonal antibodies that transport cytotoxic molecules to cancer cells. These molecules include radioimmunoconjugates, small cytotoxic molecules and cytokines in the immune system. Radioactive elements are used to label antibodies for tumor diagnosis and treatment. Lymphoma is a cancer that is more suitable for radiation therapy. The drugs currently approved by the FDA are ibritumomab tiuxetan and tositumomab. Antibody-drug conjugates (antibody-drug conjugates) are the most promising anticancer drugs recently developed. It couples cytotoxic drugs with specific antibodies to increase specificity while better killing tumor cells. In addition, immune cytokines such as IL-2 and GM-CSF are also used in combination with antibodies to target tumor cells and change the tumor microenvironment.
Remodeling T cells: T cell immunity plays a key role in tumor immunity. There are currently two major categories of methods that allow T cells to no longer be restricted by MHC molecules that recognize antigens by T cell receptors. The first type of method is a bispecific antibody. As the name implies, it can target cells as well as bind immune effector cells, such as T cells and NK cells. At present, the bispecific antibody blinatumomab against CD19 antigen has been approved by the FDA, and more antibodies are still under development. The second type of method is chimeric antigen receptor T cells (chimeric antigen receptor T cells), namely the famous CAR-T cells. These modified T cells contain specific antibody variable regions and T cell activation motifs that can attack cells expressing specific antigens. CAR-T cells can divide and grow, and maintain tumor cell specificity. At present, CAR-T cell therapy has achieved very significant effects in clinical trials. Although the accompanying cytokine storm will bring some risks, but the use of cytokine antibodies can mitigate its negative effects. The experience of the CAR-T experiment is still accumulating, and this technology will gradually mature in the future.