Monoclonal antibodies, mRNA/DNA vaccines, CAR-T cells, etc., are popular biological products nowadays, which play an important role in disease prevention and treatment. Most of these technologies originated in the 1980s, which are independent of each other and developed in concert to jointly protect human health.

What are mAbs?
Monoclonal antibody (mAb) is a highly uniform antibody produced by B cells that only targets a specific epitope, which is a "Y"-shaped immunoglobulin used to identify and remove foreign substances such as bacteria and viruses. A single B cell can only encode one antibody in its lifetime. Generally, natural antibodies are composed of two heavy chains (H chains) and two light chains (L chains). The heavy chain is longer with larger relative molecular weight, and the light chain is shorter with smaller relative molecular weight. The chains are connected by disulfide bonds and non-covalent bonds to form a monomer molecule.

The entire antibody can be further divided into two parts, the constant region (C region) and the variable region (V region). Since there are many different immunogens on the surface of various pathogens and viruses in nature, antibodies need to recognize them, and the variable region part of its "Y"-shaped structure is correspondingly ever-changing. Among them, a small part of the amino acid sequence in the variable region is prone to mutation, which is called hypervariable region. The amino acid sequence of the hypervariable region determines the specificity of the antibody binding to the corresponding antigen.

What is the core technology in the preparation of mAbs?
With the help of the hybridoma technology developed in 1975, it was possible to prepare mAbs in large quantities for basic research with linical transformation capabilities, thereby opening a new era of mAb drug development. The general principle is to fuse B lymphocytes and bone marrow cells to form hybridoma cells that survive long-term in vitro and secrete immune proteins. Through cloning, a monoclonal cell line derived from a single hybridoma cell, that is, a hybridoma cell line, can be obtained. The antibodies it produces are mAbs against the same antigen-binding site.

What are the four stages of mAbs development?
The development of monoclonal antibodies has gone through four stages, which are murine monoclonal antibodies (, human-mouse chimeric monoclonal antibodies, humanized monoclonal antibodies, and fully human monoclonal antibodies. In the first stage, the mouse-derived antibody has strong immunogen which causes severe immune response in the body. Therefore, the following three stages are to make the antibody more humanized and minimize the immune response.

What are the basis and target of mAb development?
The development of mAbs drugs is based on the understanding of the pathogenesis of specific diseases and the mode of action of specific proteins and molecules in the pathogenic process. In addition to new products, mAbs drug development also includes the discovery of new indications for existing drugs.

How are mAbs drugs categorized?
Therapeutic mAbs are roughly divided into three categories.
1. Antibodies that directly treat disease, which plays a role in the field of cancer treatment mainly through several mechanisms, namely mediating ADCC pathway, targeting cancer cells to induce apoptosis, targeting the tumor microenvironment, and targeting immune checkpoints.
2. Improve the therapeutic effect of antibody through additional modifications, such as immunocytokine coupling, ADC, radiopharmaceutical coupling, bispecific antibody, and immunoliposome.
3. Multiple targets, such as bispecific antibodies.

Which field has the most products?
The FDA has approved 79 therapeutic mAbs by now, 30 of which are for cancer treatment. The targets, mainly covering cancer, immunology, and hematology diseases, are becoming more and more extensive. Most mAbs have multiple indications, at least one of which is related to cancer, including lymphoma, myeloma, melanoma, glioblastoma, neuroblastoma, sarcoma, colorectal cancer, lung cancer, breast cancer, ovarian cancer, and head and neck cancer. In 2018, 12 mAbs were approved in the US, most of which were approved for non-cancer indications, which also reflects the high approval rate of them as treatment for other diseases.

When did the first mAb appear?
In 1986, the FDA approved the first monoclonal antibody drug, the active ingredient muromonab-CD3 (Orthoclone OKT3, 1986-2010). It was first developed, produced, and sold by Janssen-Cilag, the only mouse monoclonal antibody approved for marketing. As an immunosuppressant, it is mainly used to suppress rejection in organ transplantation. Due to its early development, it is also the only mAb drug that is not named in compliance with the WHO mAb naming rules. Due to the serious side effects and the impact of subsequent marketing of similar drugs, the market shrunk day by day. The manufacturer "delisted" it in 2010, and its market circulation ended on July 30, 2011. Significant changes have taken place in antibody preparation technology, making present antibody drugs have high specificity and low side effects to meet market demand.

How is the mAb development in recent years?
There are at least 570 therapeutic mAbs in clinical trials around the world. As of December 2019, the FDA has approved 79 therapeutic mAbs. Between 2008 and 2017, 48 were approved, and as of the end of 2017, 61 were available for clinical use. According to official data, between 2018 and 2019, 18 new antibodies were approved.

How is the profit?
In the 21st century, biological drugs gradually surpassed chemical drugs to occupy the pharmaceutical market. In 2018, 8 of the top 10 drugs sold globally were biologics. In the past five years, antibody drugs have also been among the best in the pharmaceutical market. The global therapeutic monoclonal antibody market is expected to reach 300 billion USD in 2025. The development of therapeutic antibody drugs has exploded, and they have been approved for the treatment of various human diseases, including cancer, autoimmune, metabolic, and infectious diseases.

Which companies occupy the market?
Despite the huge potential of the mAb, new companies are unlikely to get a large share. At present, the market is mainly occupied by 7 companies, Genentech (30.8%), AbbVie (20.0%), Johnson & Johnson (13.6%), Bristol-Myers Squibb (6.5%), Merck (5.6%), Novartis (5.5%), Amgen ( 4.9%), and the others accounted for 13%.

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