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The development history and types of antibody engineering drugs

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Antibody Engineering comprises in vitro selection and modification of human antibodies, including humanization of mouse antibodies for therapy, diagnosis, and research. It holds the potential for creating antibodies with multiple specificities, greater affinity for their targets, and fewer side effects. In this article, the development history and types of antibody engineering drugs are talked.

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  1. Antibodies as therapeutic agents

An antibody is an immunoglobulin molecule with a specific amino acid sequence induced by an antigen, synthesized and secreted by lymphocytes (plasma cells). An antibody can bind to an antigen such as a bacterium, a virus or a toxin, and neutralize and remove the harmful substance by the following three or one of the following methods: a. directly inactivates the antigen; b. the immune effector cells phagocytose and destroy it; c. it is weakened by the surface of the antigen and thus be easily damaged by complement. The study of antibodies as therapeutic agents has been going on for a century. The lateral chain theory proposed by Ehrlich laid the foundation for immunology and immunotherapy. He believes that the surface of the cell has specific receptor molecules (or side chains) that bind only to specific groups in the toxin molecule; if the cells survive with the toxin, they will produce excess side chains. Some of the side chains are released into the blood, which is an anti-toxin. This is what is now called an antibody. Ehrlich uses organic arsenic compounds to treat syphilis and introduces the term "magic bullet" in the field of chemotherapy to strengthen the strategies and goals of specific therapies. As early as 1895, it was reported that Hericourt and Richet injected cancer cells into animals to produce antiserum for the treatment of cancer patients, and the symptoms of the patients were significantly improved. In the early 20th century, many researchers repeated the above tests, but failed to obtain a definite therapeutic effect, and sometimes even produced serious side effects. Later studies have found that antisera contain a large number of different kinds of antibodies, which are directed against different antigens on the surface of cancer cells, and these antigens are also present in normal tissue cells. Therefore, the cross-reactivity of antibodies with normal tissues may lead to serious consequences. Antiserum has long been effective in neutralizing exogenous toxins such as snake venom, but has not been effective in the treatment of tumors and other diseases.

  1. Monoclonal antibody

In 1975, Köhler and Milstein used B lymphocyte hybridoma technology to prepare monoclonal antibodies (MAb). Monoclonal antibodies have high specificity, uniform properties and are easy to mass produce. A variety of monoclonal antibodies can be prepared in vitro by cell engineering, which is an epoch-making advance in antibody production. It is especially important that monoclonal antibodies have high specificity for the corresponding antigens and homogeneity of the antibody molecules, which can greatly reduce cross-reactivity with normal tissues in vivo, and bring new hope for the treatment of diseases by using antibodies, especially for treating tumors. At that time, some people called it "magic bullet", and it is expected that monoclonal antibodies can specifically attack pathogenic cells or pathogens without causing toxic side effects. In the past 20 years, monoclonal antibodies have been widely used in the diagnosis of diseases, and make much breakthroughs have despite many obstacles. To distinguish, an antibody previously prepared by immunizing an animal with an antiserum pathway is referred to as a polyclonal antibody, or a conventional antibody.

  1. Genetically engineered antibodies

Since the monoclonal antibodies prepared by the B lymphocyte hybridoma technique are mostly murine, the human anti-mouse antibody (HAMA) reaction can be induced in the human body, which limits the application of the monoclonal antibody as a therapeutic agent in humans. In order to overcome the heterologous reaction of murine monoclonal antibodies, in the mid-1980s, researchers explored the genetic engineering of mouse-derived monoclonal antibodies to prepare humanized antibodies. For example, they spliced the variable region of mouse Ig to the constant region of human Ig or modified the CDR region of the murine Ig to the human Ig. At the same time, considering the treatment of solid tumors with intact antibodies, the molecules are too large to penetrate the extracellular space into the deep tumor, so genetic engineering methods are used to miniaturize antibody molecules, such as single-chain antibodies (scFv), diabody, minibody, etc. The establishment and development of antibody library technology can directly clone the gene of specific antibody in the prokaryotic cell system by genetic engineering method, which greatly promotes the preparation and research and development of novel genetic engineering antibodies. Antibody engineering has become a key technology to promote the development of antibody drugs.

  1. Immunoconjugates and fusion proteins

The molecular structure and function of the antibody has two sides. One is the specific binding to the antigen and is completed by the variable region. The second is the effect function triggered by binding to the antigen, which is completed by the constant region. In order to enhance the effector function of antibody drugs, especially tumor antibody drugs, and to enhance their killing effect on tumor cells, an effector molecule or a "warhead" substance is commonly used to chemically connect with an antibody to prepare an immunoconjugate. The specificity of the antibody is utilized as a targeting vector; the "target" is used to kill tumor target cells. There are three main types of substances used as "warheads", namely radionuclides, chemotherapeutics and toxins. These "warhead" substances are linked to antibodies, which constitute radioimmunoconjugates, chemical immunoconjugates and immunotoxins, respectively. A fusion protein can be produced by a genetic engineering method, and the antibody portion of the fusion protein is generally a single-chain antibody scFv; the portion corresponding to the "warhead" is generally a toxin fragment, a cytokine or a peptide drug.

The monoclonal antibodies, antibody fragments, genetically engineered antibodies, and immunoconjugates described above can be collectively referred to as antibody-based drugs, also known as monoclonal antibody therapeutics. Such antibody drugs are prepared by a cell engineering method or a genetic engineering method or a combination of two methods, and may also be referred to as an antibody engineering drug.

  1. Antibody drugs for clinical application

The development of antibody drugs has a prominent position in the field of biotechnology drugs. The number of antibody drugs currently in preclinical and clinical research stages is among the highest in biotechnology drugs. The variety of antibody drugs in research and development is versatile, and the diseases that may be used for treatment include cancer, viruses and other infectious diseases, cardiovascular diseases and immune system diseases, among which cancer treatment is the first.


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