Abstract: An antibody is an immunoglobulin produced by the plasma cells in response to antigenic stimulation. It can specifically recognize and react with corresponding antigenic substances. Antibodies are the most wonderful molecules in the body. They are hugely diverse. Any exogenous substance that is regarded as an “exotic” by the human immune system, such as bacteria, viruses or toxins, can cause antibodies to be produced in the body, thus preventing and treating them. As a biomolecule with targeting, monoclonal antibodies have always been one of the hotspots of concern, and are widely used to treat tumors, viral infections and anti-graft rejection. However, the clinical application of murine monoclonal antibodies is limited by the induction of human anti-mouse antibodies, low tumor infiltration, low affinity and short half-life. With the development of molecular biology technology and its penetration into various disciplines, the modification of antibodies by genetic manipulation technology can be applied to the treatment of various diseases. The humanization of antibodies has become the development trend of therapeutic antibodies, and various antibody derivatives are also emerging. They overcome the application limitations of the antibodies themselves from different angles and provide a tool for treating human diseases. This article briefly introduces the basic principles, characteristics and research progress of therapeutic antibodies.
Antibody drug research history
The initial use of antibodies for disease treatment dates back more than a century. At the end of the 19th century, anti-diphtheria or tetanus toxin serum was used for early passive immunization of infected children, and the serum was obtained from animals immunized with diphtheria or tetanus toxin. At the beginning of the 20th century, P. Ehrlich proposed the idea of using antibodies as “magic bullets” to specifically track and kill pathogenic microorganisms and tumor cells. However, due to the complexity and heterogeneity of the polyclonal serum components, and the human body’s immune rejection of heterologous proteins, its clinical application is greatly limited.
With the rapid development of modern biotechnology and the deep understanding of the molecular structure and gene structure of antibodies, the development of antibody drugs has entered the stage of genetic engineering antibodies, and monoclonal antibodies (abbreviated as monoclonal antibodies) have become a therapeutic drug. In the late 1880s, the emergence of human-mouse chimeric antibodies was constructed by retaining the variable region sequences of mouse antibodies and replacing the constant region sequences of mouse antibodies with the constant region sequences of human antibodies.
In recent years, the successful preparation and application of various genetically engineered antibodies, as well as the significant increase in the level of antibody production, have led to the development of antibody drugs in a new stage of rapid development. At present, 28 therapeutic antibody products have been used in clinical applications, mainly for the treatment of tumors, autoimmune diseases, chronic inflammatory reactions, organ transplant rejection and viral infections.
Mechanism of therapeutic antibody action
The basic unit of an antibody is a symmetric structure consisting of four peptide chains, including two identical heavy chains and two identical light chains. The heavy and light chains are composed of a variable region and a constant region, respectively. The complementarity determining regions (CDRs) in the variable regions are directly involved in the diversity of antibody and antigen binding, while the structure of the constant regions is related to the biological activity of the antibody. In a few cases, the antibody binds to the antigen and can directly protect the body, such as neutralizing the toxicity of the toxin with the antibody, but in most cases it is necessary to inactivate or eliminate the foreign antigen through the effector function. In addition, the effect and mechanism of action of therapeutic antibodies are directly dependent on the antigenic determinant it recognizes. For example, anti-CD20 antibodies that treat non-Hodgkin’s B cell lymphoma can affect the function of ion channels on the cell membrane, thereby modulating B cells.
Progress in the study of therapeutic antibodies for tumor therapy
u Chimeric antibody
Chimeric antibody is the earliest successfully prepared genetically engineered antibody. The chimeric antibody is obtained by splicing the V region gene of the murine antibody and the c region gene of the human antibody, and the obtained chimeric gene is ligated to the human expression vector, and then the chimeric antibody can be obtained after transfecting the myeloma cells. Because it reduces the composition of the mouse, it reduces the adverse reactions caused by murine antibodies and helps to improve the efficacy.
u Completely humanized antibody for tumor therapy
On the basis of human and mouse chimeric antibodies, people have further used transgenic technology to prepare fully humanized antibodies. The method is to transfer the human antibody gene into the animal with defective gene by transgenic or transchromosomal technology, and the animal expresses the human antibody. Among the FDA-approved antibodies, Trastuzumab, Panitumumab, Bevacizumab, and Ipilimumab are such antibodies.
u Single-chain antibody for tumor therapy
The single-chain antibody is composed of an antibody heavy chain variable region and a light chain variable region linked by a short peptide of 15–20 amino acids (1inker). scFv can retain its antigen binding activity well, and has the characteristics of small molecular weight, strong penetrability and weak antigenicity. Based on these advantages of scFv, it is a hot research topic in the field to design bispecific antibodies that recognize two different epitopes at the same time, or to fuse them with toxins or immunopro-apoptotic molecules for anti-tumor therapy.
Prospects for therapeutic antibodies
Because of the high specificity, strong affinity and good therapeutic effect of therapeutic antibodies, antibody drugs have become the first-line drugs for cancer treatment. Although antibody therapy has shown bright application prospects, the currently approved antibody drugs are still in cancer treatment. There are more restrictions. In addition, we also need to note that most antibodies have certain side effects during application, partly due to insufficient target specificity, and partly due to human and mouse chimeric antibodies and humanized antibodies. It can cause a certain non-specific immune response, and part of it may be that tumor cells produce an alternative pathway to promote their own growth. Despite these problems, the potent anti-tumor effects exhibited by therapeutic antibodies are still attracting attention, and because of the low degree and probability of their side effects, they are still in an acceptable range. The more attention, more and more people have begun to invest in related research, coupled with the continuous development of translational medicine, more and more antibody drugs are coming out of the laboratory for clinical anti-tumor treatment. Therefore, we have every reason to believe that therapeutic antibodies will play a more important role in the anti-tumor arena.