In 1982, Humulin (human insulin), the world's first recombinant drug, was approved for marketing. This is a milestone in the development of drug access from chemical synthesis or extraction of Chinese medicine to biotechnological access, and it also marks the beginning of a rapidly developing era in the field of biopharmaceuticals. In 1986, the FDA approved Orthoclone OKT3, the first therapeutic monoclonal antibody drug, which kicked off the development of monoclonal antibody drugs. Today, more than 30 years have passed since biopharmaceuticals. With the improvement of humanization of monoclonal antibodies, the efficacy of monoclonal antibodies has been better played. Up to now, monoclonal antibodies have been approved to treat a variety of diseases and become an important part of biomedicine.
1. What are monoclonal antibody drugs?
Monoclonal antibodies (mAbs) are highly homogeneous antibodies produced by a single B-cell clone that only target a specific antigen epitope. They are usually prepared by hybridoma technology. The main idea of mAbs is to target specific molecules through the specificity of specific antigens based on disease-related targets and their signaling pathways. It can be reversible and high-affinity binding to the target through non-covalent interaction, causing blocking or activation, and then regulating the downstream biological effects to produce drug effects and/or side effects. As a kind of biological targeted drug, monoclonal antibody has the advantages of strong specificity, high target selectivity, and small side effects. It has been successfully used in the treatment of tumors, autoimmune diseases, ophthalmic diseases, transplant rejection, and rare diseases.
2. The Development of Monoclonal Antibody Drugs
Monoclonal antibody drugs have mainly experienced four generations of development:
2.1 Mouse monoclonal antibody
In 1890, German microbiologist Belling discovered diphtheria antitoxin (the earliest discovered antibody) and won the first Nobel Prize in medicine for it. In the long historical process since then, scientists have a deeper understanding of the antibody. In 1975, C. Milstein and G. Kohler created the hybridoma technology and prepared the first mouse-derived monoclonal antibody OTK3 (Ortholone) for the treatment of renal transplantation rejection, which pioneered the human use of hybridoma technology to produce monoclonal antibodies. The drug was declared on the market in 1986. However, the research and development of antibody drugs have been at a low ebb due to the fact that the mouse-derived monoclonal antibodies will be recognized as exogenous proteins by the immune system after entering the human body, and then produce human anti-mouse antibody reactions, resulting in reduced drug efficacy and a variety of adverse reactions in the human body, even life-threatening in severe cases.
2.2 Chimeric monoclonal antibody
In order to overcome this defect, scientists began to try to humanize mouse-derived monoclonal antibodies by genetic engineering technology. In 1984, Morrison et al. successfully constructed the first generation of mouse "chimeric antibody" by splicing the variable region of murine monoclonal antibody with the constant region of human antibody. The degree of human origin of the chimeric antibody can reach 60%. Although the chimeric antibody can maintain the specificity and affinity of the parental antibody to a certain extent, its murine variable region will still cause rejection in human body and interfere with the curative effect.
2.3 Humanized monoclonal antibody
Thus, in 1986, the first human-derived monoclonal antibody, also known as CDR transplantation antibody, was successfully constructed. This humanized monoclonal antibody consists of human IgG framework, with only three mouse-derived complementarity determining regions (CDR), and can be more than 90% humanized. In 1998, the world's first human-derived monoclonal antibody, Palivizumab, was put on the market. In the same year, star monoclonal antibody, Trastuzumab, was put on the market. Today, the total number has reached more than 10.
2.4 Fully humanized monoclonal antibody
However, the pursuit of excellence has never stopped. With the in-depth study of monoclonal antibodies, a variety of distinctive antibody screening techniques have emerged. Among them, the phage display technology developed in the 1990s laid the foundation for the production of fully human antibody drugs. In 2002, the world's first fully humanized monoclonal antibody "star product"-Adalimumab was listed in the United States. The drug is mainly used for the treatment of autoimmune diseases, and has been successively approved for more than 17 different indications. Because of the widely recognized efficacy and safety, the drug has been listed in more than 90 countries around the world.
In recent years, there have been a series of milestones in the field of antibody drugs. A variety of new monoclonal antibodies, such as antibody-drug conjugates (ADCs), bispecific and multi-specific antibodies, antibody fusion proteins, and small molecule antibodies, bloom together, which make monoclonal drugs have more durable vitality and brighter development prospects.
3. Monoclonal Antibody Drug Market
Through the above, we have learned about the "past and present life" of monoclonal antibody drugs. From unknown in the early 1990s to now becoming a high-profile bioengineering drug in the global pharmaceutical research and development pipeline, monoclonal antibody drugs have become increasingly mature in all aspects, from technical improvement to target development, from clinical research to commercialization strategy. Since the beginning of the 21st century, global biomedicin has entered a new era. Monoclonal antibody, as the fastest growing sector in the pharmaceutical market, has grown faster than chemical drugs. It can be said that monoclonal antibody drugs can change and promote the layout and development of modern medicine and pharmaceutical industry more than any other category of drugs.
By the end of 2021, the FDA had approved a total of 93 therapeutic monoclonal antibody products, of which tumors were the most important indications, followed by musculoskeletal diseases, skin and connective tissue diseases, infectious diseases (including COVID-19), and blood and lymphatic system diseases . As the "leader" of fully human monoclonal antibody, Adalimumab has indications such as rheumatoid arthritis, ankylosing spondylitis, ulcerative colitis, psoriasis, juvenile idiopathic arthritis, hidradenitis suppurativa, uveitis, Crohn's disease, etc., and has been creating a miracle of drug sales for many years. From 2012 to 2020, Adalimumab has ranked the top of the global prescription drug sales, known as the "drug king". In 2021, the sales of Adalimumab exceeded the $20 billion mark for the first time, and it was the highest sales of the drug except for the COVID-19 vaccine of Pfizer and BioNTech.
In addition, the targeting of monoclonal antibodies to important GPCR (Gprotein-coupled receptor) targets is a continuing focus of drug developers, as evidenced by the number of projects in the global pipeline and the increasing number of GPCR antibodies that have successfully entered clinical development in the past decade. There are now more than 170 active programs targeting 76 GPCR targets, but only two approved GPCR-targeting monoclonal antibodies.
4. Popular Research Targets of Monoclonal Antibody Drugs
Drug targets are the sites where drugs bind to biological macromolecules of the body, which can regulate physiological function or achieve the purpose of treating diseases by specifically binding to specific drugs. The following table lists the popular targets for research and development in the monoclonal antibody field.
5. How can monoclonal antibodies treat diseases?
Monoclonal antibodies have been particularly successful in the treatment of tumors and autoimmune diseases, so how do they work?
Monoclonal antibody drugs are administered primarily as injections to patients alone or in combination with other cancer treatments. Each mab drug has one or more modes of action depending on the antigen against which it is directed. Some monoclonal antibodies are able to bind directly to and kill cancer cells because they can target specific receptors in the cell, a process known as targeted therapy. For example, trastuzumab, which is used to treat HER2-positive breast cancer and gastric cancer, binds to the HER2 receptor on cancer cells and inhibits the interaction of growth factors with tumor cells, thereby arresting cancer cell growth and, in some cases, causing them to regress completely.
Other monoclonal antibodies help improve the immune system's response to cancer cells, these drugs are called immunotherapy. For example, Nivolumab, which is used to treat a variety of cancers, including lung cancer, kidney cancer, melanoma, lymphoma, and some head and neck cancers, targets the PD-1 receptor. But the immunotherapy drugs overpower the immune system and cause it to attack normal tissues, potentially causing serious side effects such as inflammation of the colon or lungs. To control the inflammation associated with this immunotherapy, steroids can be given. If steroids do not work, some patients may receive another monoclonal antibody to reduce inflammation.
6. Monoclonal Antibody Drugs and Diseases
Systemic lupus erythematosus (SLE) is an autoimmune inflammatory connective tissue disease involving multiple organs that occurs frequently in young women, and it belongs to rheumatic diseases. At present, the exact etiology of SLE is still unclear, and a large number of studies have shown that genetic, endocrine, infectious, immune abnormalities and some environmental factors may be related to the pathogenesis of SLE. Anifrolumab is a human immunoglobulin Glk antibody that binds to type I interferon (IFN) receptor. The results of Richard Furie  have shown that Anifrolumab can inhibit the signal transduction of IFN type I by blocking its biological activity, thus reducing the annual recurrence rate of SLE patients, prolonging the first recurrence time and reducing the recurrence times. On August 2, 2021, the FDA approved Anifrolumab, developed by Astrazeneca, for the treatment of adults with moderate-to-severe systemic lupus erythematosus who had received standard therapy.
Cytokine storm of the human immune system is considered to be one of the causes of acute respiratory failure and even death in COVID-19 patients. Cytokine storm refers to the phenomenon that a variety of cytokines such as TNF-α, IL-1, IL-6, IFN-α, IFN-β, MCP-1, etc. are rapidly produced in large quantities in body fluids after infection with microorganisms. Thus, the course of COVID-19 can be improved with the use of monoclonal antibodies that block major cytokine storm mediators . Anakinra is a recombinant IL-1 receptor antagonist (IL1RA) that has been recommended for the treatment of rheumatoid arthritis. On November 11, 2022, Sobi North America, a subsidiary of Orphan Biovitrum AB, Sweden, announced that the FDA has issued an Emergency Use Authorization (EUA) for Kineret (Anakinra) injection, Its use is permitted for the treatment of high-risk hospitalized patients with COVID-19. Such patients include those with pneumonia who require supplemental oxygen and those at risk for progression to severe respiratory failure. Previously, clinical studies have shown that Anakinra can reduce inflammation in patients with COVID-19 .
Allergic asthma is an important type of bronchial asthma, accounting for 60%-80% of bronchial asthma, and its main feature is the increase of serum IgE level and specific IgE level. IgE produced by B lymphocytes can activate mast cell high-affinity receptors (FcεR I) and other inflammatory cell low-affinity receptors (FcεR I, CD23), leading to the release of inflammatory mediators and causing allergy. Omalizumab binds IgE, thereby blocking the binding of IgE to FcεR I in mast cells and preventing their activation by allergens. Omalizumab is the world's first approved targeted therapy for the treatment of moderate to severe allergic asthma. It was first marketed globally in 2003 and has been approved in 96 countries.
6.4 Transplant rejection
Transplant rejection refers to the immune system to attack, destroy and eliminate the foreign tissue or organ as a "foreign component". Rituximab, as a monoclonal antibody against CD20, can effectively deplete B lymphocytes and treat various autoimmune diseases. The anti-human leukocyte antigen and anti-ABO antibody can be effectively reduced when it is used in transplantation patients. Studies have shown that Rituximab can improve severe hormone resistance and antibody-mediated rejection after renal transplantation .
6.5 Nipah virus
Nipah virus (NiV) is a new zoonosis virus, belonging to paramyxoviridae, which can cause a wide range of vasculitis. Infected people have fever, severe headache, meningitis and other symptoms, which has brought serious harm to people and animals. At present, there are no vaccines or treatments approved for human use, and only one monoclonal antibody, m102.4, has entered clinical trials. m102.4 is a cross-reactive, neutralizing humanized monoclonal antibody that recognizes and blocks the ephrin receptor-binding site on the G glycoprotein. m102.4 has been shown to treat Nipah virus infection in ferrets and nonhuman primates .
Dyslipidemia is an important and modifiable risk factor for atherosclerotic cardiovascular disease (ASCVD). Hyperlipidemia or dyslipidemia has long been a health concern, and various guidelines have emphasized the importance of controlling blood lipid levels to prevent heart disease. Although statins have been found to be highly effective in treating low-density lipoprotein cholesterol (LDL-C), 40% of patients still have residual cardiovascular risk. Evolocumab, a PCSK9 inhibitor, proved to be highly effective in lowering LDL-C and other lipid parameters, with a clear increase in cardiovascular benefits and few side effects .
Targeted antibody drugs define a new concept of "tumor therapy", involving a variety of tumor-related signaling pathways and targets. For example, in the treatment of solid tumors, the most common action targets of monoclonal antibodies include programmed cell death protein 1/ programmed cell death protein ligand (PD-1/PD-L1), human epidermal growth factor receptor (EGFR), vascular endothelial growth factor (VEGF), and others.
Immunotherapy is one of the important mechanisms by which monoclonal antibodies attack tumor cells. It refers to the inhibition of highly expressed immune checkpoint molecules to enhance the immune function and recover the recognition ability of T cells in the process of tumor occurrence and development, thereby eliminating or slowing the development process of tumor. Among them, the active PD-1/PD-L1 inhibitors have been proved to be effective in recent years tumour Hot spot of immunotherapy research. To date, several PD-1/PD-L1 antibody drugs have been marketed, such as Nivolumab and Pembroke, which are mainly used for the treatment of melanoma and non-small cell lung cancer. The efficacy for renal cell carcinoma, bladder carcinoma and Hodgkin's lymphoma is still in large-scale clinical trials. Other PD-L1 inhibitors such as Avelumab, Durvalumab, and Atezolizumab have been approved for the treatment of urothelial carcinoma. For more information on PD-1 and PD-L1, click on the https://www.cusabio.com/c-20955.html.
 Kinch M S, Kraft Z, Schwartz T. Monoclonal antibodies: trends in therapeutic success and commercial focus[J]. Drug discovery today, 2022.
 Furie R, Morand E F, Askanase A D, et al. Anifrolumab reduces flare rates in patients with moderate to severe systemic lupus erythematosus[J]. Lupus, 2021, 30(8).
 Kirillova A, Lado A, Blatt N. Application of Monoclonal Antibody Drugs in Treatment of COVID-19: a Review[J]. BioNanoScience, 2022.
 Giulio C, Giacomo D L, Corrado C, et al. Interleukin-1 blockade with high-dose anakinra in patients with COVID-19, acute respiratory distress syndrome, and hyperinflammation: a retrospective cohort study[J]. The Lancet Rheumatology, 2020, 2(6).
 Becker Y T, Becker B N, Pirsch J D, et al. Rituximab as Treatment for Refractory Kidney Transplant Rejection[J]. American Journal of Transplantation, 2015, 4(6):996-1001.
 Mire C E , Yee-Peng C , Viktoriya B , et al. A Cross-Reactive Humanized Monoclonal Antibody Targeting Fusion Glycoprotein Function Protects Ferrets Against Lethal Nipah Virus and Hendra Vi rus Infection[J]. The Journal of Infectious Diseases(Supplement_4):Supplement_4.
 Alhajri L, Alhadhrami A, Almheiri S, et al. The efficacy of evolocumab in the management of hyperlipidemia: a systematic review[J]. Ther Adv Cardiovasc Dis, 2017, 11(5):155-169.
CUSABIO team. Monoclonal Antibody Drugs Overview. https://www.cusabio.com/c-21097.html