▉ Guide

Monoclonal antibodies, mRNA/DNA vaccines, CAR-T cells, and other popular biological products play an important role in disease prevention and treatment. Most of these technologies originated in the 1980s, both independently and collaboratively developing to safeguard human health. Today, I would like to briefly introduce the development of monoclonal antibody drugs (mAbs) in the form of Q&A. These drugs play a crucial role in the treatment of autoimmune diseases and cancer.

▉ 1：What are mAbs?

Monoclonal antibodies (mAbs) are highly uniform antibodies produced by B cells that only target a specific antigenic epitope. A "Y" - shaped immunoglobulin used to identify and eliminate foreign substances such as bacteria, viruses, etc. A single B cell can only encode one type of antibody in its lifetime. Typically, natural antibodies consist of two heavy chains (H chain) and two light chains (L chain). Long heavy chain and relatively high molecular weight; Short light chain and relatively small molecular weight; A monomer molecule formed by disulfide bonds and non covalent bonds between chains.

The entire antibody can be further divided into two parts: the constant region (C region) and the variable region (V region). It is precisely because there are various pathogens and viruses in nature, and there are many different immunogens on their surfaces, that antibodies need to recognize them, and the variable region of their "Y" - shaped structure is correspondingly diverse. Among them, a small portion of the amino acid sequence within the variable region is highly susceptible to mutations, known as the hypervariable region. The amino acid sequence of the hypervariable region determines the specificity of the antibody binding to the corresponding antigen.

▉ 2：What is the most important technique in mAbs preparation?

It is a hybridoma technology developed in 1975. Thanks to this technology, mAbs have been extensively prepared for basic research and possess clinical translational capabilities, ushering in a new era of monoclonal antibody drug development. The general principle is to fuse B lymphocytes with bone marrow cells to form hybridoma cells that can survive for a long time in vitro and secrete immune proteins. By cloning, a monoclonal line derived from a single hybridoma cell can be obtained, known as a hybridoma cell line, which produces antibodies targeting the same antigen binding site.

▉ 3：What are the four stages of mAbs development?

The development of monoclonal antibodies has gone through four stages: mouse derived monoclonal antibodies, human mouse chimeric monoclonal antibodies, humanized monoclonal antibodies, and fully humanized monoclonal antibodies. The first stage of mouse derived antibodies has a strong immunogenicity, causing a super strong immune response in the body. Therefore, the following three stages of development aim to make the antibodies more humanized and minimize immune reactions as much as possible.

▉ 4：What are the basics and directions of mAbs development?

The development of mAbs drugs is based on an understanding of the pathogenesis of specific diseases and a clear understanding of the role of specific proteins and molecules in the pathogenic process. If the above two points are met, mAbs drugs will become a good treatment option. The direction of mAbs drug development includes not only the development of new products, but also the development of new indications for existing drugs.

▉ 5：What are the general categories of mAbs drugs?

Therapeutic mAbs can be roughly divided into three categories:

1. Directly treating diseases with naked antibodies. It mainly functions in the field of cancer treatment through several mechanisms, namely mediating the ADCC pathway; Targeting cancer cells to induce apoptosis; Targeting the tumor microenvironment; Targeting immune checkpoints, etc.

2. Improve antibody therapy efficacy through additional modifications. Such as immune cytokine conjugation, ADC, Radiopharmaceuticals coupling, bispecific antibodies, immunoliposomes, etc.

3. Multiple targeting, such as bispecific antibodies.

▉ 6：Which field currently has the most mAbs products?

The FDA has approved 79 therapeutic mAbs for marketing, of which 30 are used for cancer treatment. MAbs targets are becoming increasingly widespread, with cancer, immunology, and hematological diseases dominating. Most mAbs have multiple indications, at least one of which is associated with cancer. It includes lymphoma, myeloma, melanoma, glioblastoma, neuroblastoma, sarcoma, colorectal cancer, lung cancer, breast cancer, ovarian cancer, head and neck cancer, etc. Therefore, there are the most mAbs products available for treatment in the field of cancer. In 2018, the United States approved 12 mAbs, most of which were approved for non cancer indications, reflecting the high approval rate of mAbs as a treatment for other diseases.

▉ 7：When did the first mAbs appear?

In 1986, the US FDA approved the first monoclonal antibody drug, the active ingredient muromonab-CD3 (commonly known as Orthoclone OKT31986-2010). Originally developed, produced, and sold by Janssen Cilag, it is the only approved mouse monoclonal antibody drug on the market. It is mainly used as an immunosuppressant to suppress rejection reactions during organ transplantation. Due to its early development and being the only monoclonal antibody drug not named according to the WHO monoclonal antibody naming convention. Due to the serious side effects of the drug and the impact of similar drugs on subsequent market launches, the market has been shrinking day by day. The manufacturer delisted it in 2010 (the market circulation date was July 30, 2011). Since the launch of Orthoclone OKT3, there have been significant changes in antibody preparation technology. The current antibody drugs have high specificity and minimal side effects in order to meet market demand.

▉ 8：How many mAbs are there and how fast have they developed in recent years?

There are at least 570 therapeutic mAbs undergoing clinical trials worldwide. As of December 2019, the US FDA has approved 79 therapeutic mAbs, and this number is still significantly increasing. The development rate can be felt through the node numbers. Between 2008 and 2017, 48 mAbs were approved, and as of the end of 2017, 61 mAbs were available for clinical use. According to official website data, 18 new antibodies were approved between 2018 and 2019. Therapeutic mAbs are becoming increasingly important in the field of disease treatment. Over the past 25 years, mAbs have become the primary treatment for various diseases. The advancement of technology has made mAbs discovery and development faster and more efficient.

▉ 9：How big is mAbs oil-water?

In the 21st century, biopharmaceuticals are gradually surpassing chemical drugs and occupying the pharmaceutical market. In 2018, 8 out of the top 10 drugs sold globally were biopharmaceuticals. In the past five years, antibody drugs have also been among the top sellers in the pharmaceutical market. In 2018, the global therapeutic monoclonal antibody market was valued at 115.2 billion US dollars, which increased to 150 billion US dollars by the end of 2019 and is expected to reach 300 billion US dollars by 2025. Therapeutic antibody drugs have developed explosively and have been approved for the treatment of various human diseases, including cancer, autoimmune, metabolic and infectious diseases. In 2018, multiple monoclonal antibody products had annual sales exceeding 3 billion US dollars, with an additional 6 products exceeding 6 billion US dollars (adalimumab, nivolumab, pembrolizumab, trastuzumab, bevacizumab, rituximab). Among them, adalimumab (adalimumab) set a record for the highest sales of biopharmaceuticals, with nearly 19.9 billion US dollars.

▉ 10：Which companies dominate the current mAbs market?

Although the mAbs market has enormous growth potential, new companies are unlikely to gain a significant share. At present, the mAbs market is mainly dominated by 7 companies, with 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 remaining companies accounting for 13%.

References:

https://jbiomedsci.biomedcentral.com/articles/10.1186/s12929-019-0592-z