Monoclonal antibodies in oncology
Cancer immunotherapy: monoclonal antibodies
Anna Petrenko, Copper NewsThe history of cancer immunotherapy has come a long way: from the first "miraculous" healings to the first vaccines.
Recently, many drugs of this direction have already appeared in cancer therapy, and scientists predict that there will be even more of them.
All the molecules of the body are under the supervision of the immune system. Substances that should not be in a healthy body usually cause an immune response and are destroyed if possible. The immune response is expressed in the mass production of special proteins – antibodies that bind to such substances – antigens. Among the most well-known antigens are parts of bacteria and viruses, pollen, foreign molecules during transplantation and tumor antigens expressed only by cancer cells.
Unfortunately, the immune system is not always able to recognize or destroy the tumor. Neoplasm cells also have a whole list of ways of masking. In addition, the tumor is not homogeneous, but heterogeneous, that is, it consists of cells with different phenotypes, which further complicates the task for both drugs and internal defense systems of the body. Immunotherapy marks cancer cells and makes them visible to immune cells, directly kills regenerated cells or strengthens the immune system as a whole. Some medications can even prevent the appearance of the disease by teaching the body in advance to fight a certain type of cancer.
I. TYPES OF CANCER IMMUNOTHERAPYThe concept of "immunotherapy" includes three main groups of drugs:
- Anti-cancer vaccines cause an immune response against a specific tumor or work proactively.
- Nonspecific immunotherapy generally strengthens the immune system and helps it fight the disease.
- And finally, monoclonal antibodies (mAt or mAbs) are variants of immune system proteins created by scientists in laboratories. They are so called because they are produced by clone cells derived from a single progenitor cell.
II. MONOCLONAL ANTIBODIES FOR CANCER THERAPYMonoclonal antibodies differ not only in their target target, but also in the way they fight cancer cells.
They will be divided into two large groups: conjugated and unconjugated. The former act on their own, the latter are targeted (targeted) to convey to cancer cells what scientists have "hung" on them – for example, a medicine.
The first monoclonal bodies used by scientists were mouse ones. But, since they were alien to the human body, their introduction itself could provoke an immune response. In this regard, scientists have begun to replace those parts of animal mAt proteins that do not bind to the target antigen with human ones. The first such developments were called "chimeric" antibodies – by analogy with the ancient Greek monster Chimera. Further efforts were aimed at reducing the number of mouse antibody sites and, accordingly, increasing the number of human ones. The next generation of drugs created as a result of this are humanized mats, to which the immune system already reacts weakly. Finally, there are now fully human antibodies.
Unconjugated monoclonal antibodiesUnconjugated monoclonal antibodies are used most often.
In most cases, they attach to a specific antigen on cancer cells and "tag" them for the immune system. For example, alemtuzumab (Campath) is used to treat some patients with chronic lymphocytic leukemia. The drug binds to CD52 on lymphocytes and attracts cells of the immune system.
Rituximab (Rituxan) was invented for the treatment of B-cell lymphoma. It targets the CD20 protein, which is expressed only by blood B cells. After exposure to the drug, the total number of B cells decreases: both tumor and healthy. The body produces new healthy cells instead of destroyed ones, so the absolute and relative number of cancer cells is reduced.
Another group of mAt blocks growth factor receptors. Growth factors are signaling molecules of normal and degenerate cells that provoke division. Overexpression of their receptors or amplification of the corresponding gene allows cancer cells to divide many times faster than healthy ones. Cetuximab (Erbitux), approved for the treatment of colon cancer and head and neck cancer, targets the epidermal growth factor receptor (EGFR) of cancer cells. Trastuzumab (Herceptin) is widely used in HER2+ breast and stomach cancers. These mats block the enzymatic activity of the HER2 receptor of human epidermal growth factor 2 (human epidermal growth factor receptor).
Another mechanism of action is the inhibition of angiogenesis – the germination of new vessels. In order to get more nutrition and oxygen, tumors secrete various factors that cause the formation of new vessels within "walking distance" of the neoplasm. Monoclonal bodies targeting vascular growth factors can block signals from cancer cells or destroy an existing vascular network.
An example is ramucirumab (Cyramza), approved by the FDA in 2014 as a second-line treatment for advanced stomach cancer. The drug blocks the vascular endothelial growth factor receptor-2 (VEGF2) on blood vessel cells.
Conjugated monoclonal antibodiesConjugated monoclonal antibodies are mAt combined with radioactive particles or chemotherapy drugs.
Using such a complex design, doctors can direct medicine or radiation directly to cancer cells and at the same time reduce damage to healthy tissues. For example, the drug ibritumomab (Zevalin) is approved for non-Hodgkin's lymphoma. The monoclonal body is labeled with yttrium-90 and binds to CD20 B cells. Ado-trastuzumab emtansin (Kadcyla) is approved for the treatment of HER2+ breast cancer. After binding to the receptor, the cell captures the mAt, which then releases chemotherapeutic molecules.
Another type is bispecific mAt. They consist of parts of two different monoclonal antibodies and, consequently, bind to two antigens at once. For example, blinatumomab (Blincyto) is used to treat certain types of acute lymphoblastic leukemia. One part of the drug binds to CD19 of some leukemia and lymphoma cells, and the other to CD3 on T cells of the immune system. Thus, when the MATE has contacted both sites at once, the T-cell turns out to be reduced nose to nose with the cancer cell and can attack it.
III. NEW DEVELOPMENTSScientists are now creating and testing new forms of mAt: more specific to new antigens, conjugated with new particles or molecules, with fewer side effects.
For example, in 2013, a new ESK1 MAT was created, targeting the oncogenic WT1 protein, which is located not on the surface, but inside the cell. WT1 is overexpressed in leukemia, myeloma, breast, ovarian, colon and rectal cancers. The drug is in preclinical studies for the treatment of leukemia.
Researchers from the University of California (University of California) in the same year announced a humanized mAt that directly kills cells of chronic lymphocytic leukemia. Cells of this type of tumor express a high level of CD44 on the surface, which is targeted by the drug. As scientists say, the effect on normal B cells is small.
Conjugation of mAt with selenium increases the effectiveness of treatment in patients with resistance to chemotherapy, as Texas Tech University showed in 2014.
Some patients do not respond to mAt treatment, or they develop resistance to such therapy. But scientists are also struggling with this. Researchers from the University of Southampton (University of Southampton) and the Swedish biotech company BioInvent this year showed one of the mechanisms of such resistance: some cancer cells can absorb the MATE and thus avoid a collision with the immune system. The new antibody BI-1206 does not allow this to be done, and the effectiveness of the drug increases due to binding to the Fc-gamma-RIIB receptor. The prospects of development have already been shown in preclinical models and the drug is expected to be tested in clinical trials.
Not spared the treatment of the MAT and our younger brothers. There is evidence that almost every second dog over the age of 10 develops cancer. Therefore, scientists from Vienna last year for the first time used antibodies to treat cancer in dogs.
Portal "Eternal youth" http://vechnayamolodost.ru13.05.2015