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The Clinical Pharmacokinetics of Therapeutic Monoclonal Antibodies and Their Application in Disease Treatment

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Therapeutic monoclonal antibodies are currently one of the hotspots in the development of new drugs. Compared with traditional small molecule drugs, their pharmacokinetic characteristics and formation mechanisms are very different. A full understanding of these mechanisms and characteristics can effectively guide Screening and development of monoclonal antibody drugs. Monoclonal antibody drugs provide ideal means for the prevention and diagnosis of human diseases, tumor positioning in vivo, preparation of targeted drugs, prevention of rejection of grafts, and development of new vaccines. Medicilon’s preclinical pharmacokinetic service department can design and carry out in vivo and in vitro pharmacokinetic tests according to customer needs, and provide customers with a complete set of pharmacokinetic evaluation and optimization services.

Clinical pharmacokinetics of therapeutic monoclonal antibodies

Because of its huge molecular weight, strong hydrophilicity and easy degradation by the gastrointestinal tract, monoclonal antibodies are not suitable for oral administration, and are usually administered by intravenous injection, subcutaneous injection, or intramuscular injection. Also because of the huge molecular weight, the rate of monoclonal antibody distribution to various tissues is usually slow, and the volume of distribution is small. Monoclonal antibodies are preferentially degraded by amino acids or polypeptides in some tissues, such as phagocytes in the blood or cells expressing target antigens. Monoclonal antibodies and endogenous immunoglobulins can bind to the protective FcRn receptor to avoid being degraded, thereby greatly prolonging the elimination half-life (up to 4 weeks). The in vivo kinetics of monoclonal antibodies present linear and non-linear characteristics, and the decisive factor lies in the metabolism and elimination mediated by the target antigen. Factors affecting the clearance process of monoclonal antibodies include target antigen levels, immune responses to antibody drugs, and patient demographic characteristics. In short, parenteral administration, small tissue distribution volume and long half-life constitute the most significant clinical pharmacokinetic characteristics of monoclonal antibodies.


The molecular weight of monoclonal antibody drugs is huge, so the ability to diffuse and distribute from the blood to peripheral tissues is very limited. The extravasation of drugs mainly includes convective transport of drugs in the bloodstream, and endocytosis and pinocytosis of endothelial cells. The therapeutic monoclonal antibody can bind to the target antigen with high affinity. Therefore, the interaction between the antibody and the antigen will affect the distribution of the drug. Although the antibody can bind to the target tissue with high affinity according to the predetermined design, the apparent volume of distribution should be large, but it is not actually observed. The huge molecular weight and strong hydrophilicity hinder the distribution of antibody molecules to other tissues, so that the volume of distribution is actually small, which is basically the same as the volume of plasma. Another reason for the small volume of distribution is the slow rate of tissue distribution and target antigen-mediated elimination. If the antigen targeted by the antibody is located in the tissue, the rate of distribution of the monoclonal antibody from the systemic circulation to the tissue is slow, and the volume of distribution is low, which will hinder the clinical efficacy. Existing people have put forward the hypothesis of “binding site barrier”, thinking that the presence of high concentrations of antigen around the tumor tissue prevents the distribution of antibodies to the center of the tumor. Because of these factors, the distribution of tumor tissue antibodies is very uneven. Due to the small amount of tumor penetration and unevenness, antibody administration should be done in divided doses rather than one-time administration: tumor reduction can greatly improve and change the blood flow speed, reduce the intercellular fluid pressure, so that the subsequent labeled antibody will reach the tumor tissue Inside.

Due to the huge molecular weight, the antibody prototype cannot be excreted in the urine, but is metabolized into peptides and amino acids, which are reused by the body to synthesize proteins, or excreted into the body through urine. The metabolism of endogenous IgG can be in various tissues and Performed in plasma. Using a physiologically-based pharmacokinetic model, the measurement results of the contribution of various organs to the elimination of endogenous IgG were 33% for skin, 24% for muscle, 16% for liver and 12% for intestine.

Monoclonal antibodies used for disease treatment mainly include the following categories.

(1) Monoclonal antibodies against cell surface molecules can inhibit the same immune response and are mainly used for the prevention and treatment of transplant rejection.

Morolizumab is the first murine monoclonal antibody approved by the FDA to prevent allograft rejection in kidney transplant patients.

(2) Anti-tumor monoclonal antibodies can be used for targeted therapy of tumors.

Tuximab (Rituxan) is the first monoclonal antibody approved for clinical treatment. It is a human-mouse chimeric monoclonal antibody directed against CD20 antigen after entering the human body, it can specifically bind to CD20 to cause B cell lysis, thereby inhibiting B cell proliferation and inducing mature B cell apoptosis, but does not affect the original B cell. Trastuzumab, which is subsequently marketed for breast cancer treatment, is a recombinant humanized IgG monoclonal antibody against HER22/neu, which can specifically recognize the cell surface protein HER22 regulated by Her22 and make it leave through endophagy. The cell membrane enters the nucleus and inhibits the signal transduction mediated by it, thus playing a role in the treatment of tumors. Alemtuzumab is a humanized, unconjugated monoclonal antibody. Its target is the CD52 antigen of normal and abnormal B lymphocytes. It has a good therapeutic effect on various malignant tumors derived from B and T cells. Both cetuximab and bevacizumab, which were launched in 2004, are aimed at the treatment of colorectal cancer.

(3) Application of monoclonal antibodies in other diseases.

Monoclonal antibody drugs have achieved good results not only in the treatment of tumors, but also in the treatment of other diseases. For example: Omalizumab significantly reduces the level of free IgEde by binding to free IgE, blocking the binding of IgE to mast cells and basophils, and preventing the release of inflammatory mediators. It can significantly improve the symptoms, lung function and quality of life of asthma patients, and reduce the number of asthma exacerbations.

Medicilon provides antibody drugs discovery, CMC research (API + formulation), pharmacodynamics research, PK study, safety evaluation and other services. As of the end of June 2023, Medicilon has successfully assisted in the clinical approval of 31 antibody drugs (8 approved by FDA and NMPA, 1 approved by NMPA and TGA, 1 approved by FDA, NMPA, and TGA) and has multiple antibody projects under development.

Research on new applications of monoclonal antibodies. It is expected to treat coronary heart disease.

An article published in the journal Nature pointed out: Anti-oxidant phospholipid (OxPL) antibodies can not only block the inflammatory response in mice by binding to oxidized phospholipids (OxPL) on the cell surface, even in a high-fat diet, Antibodies can also protect mice from arterial plaque formation, arteriosclerosis and liver disease, and extend their lifespan.

The latest clinical guidelines point out that the level of low-density lipoprotein in patients with atherosclerosis should be reduced to below 1.8mmol/L or below 50%, which fully illustrates the progression of low-density lipoprotein in atherosclerosis The key role! Oxidized phospholipids (OxPL) are expressed on the surface of low-density lipoproteins, apoptotic cells and a large number of cytokines secreted by foam cells, and can mediate the recognition of low-density lipoproteins by macrophages and vascular smooth muscle cells. Simply put, if oxidized phospholipids can be reduced, the harmful effects of low-density lipoproteins can be reduced.

In order to study the molecular biological mechanism of oxidized phospholipids and atherosclerosis, researchers used transgenic technology to transfer the anti-oxidized phospholipid antibody (E06) gene into mice, and constructed a plasma expressing high concentration of anti-oxidized phospholipid antibody in vivo. Mouse model. By giving these genetically modified mice and ordinary mice a high-fat diet, the researchers tried to discover the relationship between oxidized phospholipids and atherosclerosis. The results showed that compared with the control group, mice that express anti-oxidized phospholipid antibodies had a 28%-57% lower probability of developing atherosclerosis. At the same time, the antibody can significantly reduce the occurrence of valve calcification, fatty liver and liver inflammation.

With the rapid development of biotechnology, more and more monoclonal antibody drugs have been developed for clinical treatment. Undoubtedly, biotechnology drugs represented by monoclonal antibody drugs are a new trend in the development of new drugs in the future.

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