Incite lymphocytes on the tumor
Antibodies identified cancer cells with a common mutation by replacing one amino acid
Vera Mukhina, N+1
With the help of bispecific antibodies, scientists managed to destroy cancer cells with the most common mutation in the p53 gene, which are especially poorly recognized by the immune system. Despite the fact that there is very little protein with a mutated site on the surface of cancer cells, bispecific antibodies successfully find them in vitro and in vivo in mice and activate T cells to destroy them. In theory, this approach, published in the journal Science (Hsiue et al., Targeting a neoantigen derived from a common TP53 mutation), may be useful in the treatment of other cancers with complex mutations.
There are a lot of mutations that can trigger the process of turning a cell into a malignant tumor. They often change the work of genes regulating cell division and the accuracy of DNA copying, and these can be both oncosuppressor genes and proto-oncogenes. In the case of proto-oncogenes, their activity increases, they become more noticeable to the body and can be used as targets for immunotherapy. Oncosuppressors are present in the cell at a low level and T cells specific for this mutation - the main cancer fighters – are difficult to find.
There are various ways to increase the attentiveness of T cells, one of which is bispecific antibodies. These are synthetic antibodies that are able to recognize two different antigens at once and stick to them. The idea is that an antibody that recognizes both T cells and the wrong piece of immunosuppressor simultaneously glues the patient and the immune cells, triggering the activation mechanism of the latter. Until today, several expensive anti-cancer drugs have been made on the basis of bispecific antibodies and tried to use them in the fight against HIV.
Emily Han-Chung Hsiue and her colleagues from Johns Hopkins University applied this technology to capture the broken protein p53, the main regulator of the cell cycle. They created antibodies that should recognize the variant of this protein with the most common mutation (R175H, in which arginine at position 175 is replaced by histidine), and do not touch the normal variant of the protein. The second target of these antibodies is cytotoxic T cells. The connection with them includes an immune response, T-cells secrete granzymes and perforins and the cancer cell dies from their effects. If the antibody confuses a healthy cell with a sick one, the immune system will turn against the body, therefore, the accuracy of the recognition of the cancer antigen by the antibody plays a very important role.
The regions of the p53 protein that distinguish between healthy and diseased cells can be demonstrated by a cancer cell at the receptors of the main histocompatibility complex (HCGS), where they can be seen by immune cells. Scientists have selected two variants of antibodies that can recognize this complex. The specificity of recognition in one of the antibodies was lower – it sometimes confused healthy and mutant variants, so another, more accurate variant was chosen for further analysis.
The joint cultivation of T cells with cells of four cancer lines with the desired mutation showed that, indeed, in the presence of bispecific antibodies, T cells exhibit cytotoxicity and destroy cancer cells, and this happens even when there is very little mutant protein.
The general mechanism of bispecific antibodies and their effectiveness against different cancer lines. The strength of the effect – the amount of interferon released by T cells - directly depended on the presence of the desired mutation in p53 (R175H+/–), the concentration of antibodies (H2-scDb) and the expression of HLA receptors by cancer cells. A drawing from an article in Science.
You can see how this happens in a short cartoon – VM.
In vivo testing also yielded encouraging results: in mice implanted with human myeloma cells, bispecific antibodies stimulated the effective work of T-killers against cells with mutant p53, which generally led to a decrease in tumors.
Bispecific antibodies have their strengths and weaknesses. Unlike CAR-T lymphocytes, a similar well–known variant of immune therapy, they are universal and are not made anew for each patient. At the same time, these antibodies do not know how to reproduce themselves in the body, and throughout the course it is necessary to replenish their supply from the outside. As in the case of CAR-T therapy with bispecific antibodies can lead to a cytokine storm, but – judging by the results of recent work – this can be avoided by blocking the release of one of the cytokines.
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