What Is a VEGF Antibody?
Antibodies are secreted by plasma cells transformed from B lymphocytes, and each B lymphocyte strain can only produce one of its proprietary antibodies against a specific epitope. This kind of antibody produced from a single cell line is called monoclonal antibody (McAb), or monoclonal antibody for short. The first generation of monoclonal antibodies was prepared by Koehler and Milstein in 1975. It is derived from mouse B-cell hybridomas, but the human immune system can recognize mouse-derived monoclonal antibodies, so its application is greatly limited. In 1982, Levy prepared a monoclonal antibody against tumor cells in patients with B lymphoma, which achieved good results. Subsequently, genetic engineering was used to produce human or humanized monoclonal antibodies and chimeric monoclonal antibodies. The construction method of human-mouse hybridoma was reported in 1984, and the first clinical trial was conducted in 1987, 1986. The United States FDA approved the anti-CD3 monoclonal antibody OKT3 for transplant rejection. In 1995, 17-1A mouse monoclonal antibody was marketed in Europe for the treatment of colorectal cancer. In recent years, monoclonal antibody treatment drugs have developed rapidly, and some have been used clinically. [1]
- Antibodies are secreted by plasma cells transformed from B lymphocytes, and each B lymphocyte strain can only produce one of its proprietary antibodies against a specific epitope. This kind of antibody produced from a single cell line is called monoclonal antibody (McAb), or monoclonal antibody for short. The first generation of monoclonal antibodies was prepared by Koehler and Milstein in 1975. It is derived from mouse B-cell hybridomas, but the human immune system can recognize mouse-derived monoclonal antibodies, so its application is greatly limited. In 1982, Levy prepared a monoclonal antibody against tumor cells in patients with B lymphoma, which achieved good results. Subsequently, genetic engineering was used to produce human or humanized monoclonal antibodies and chimeric monoclonal antibodies. The construction method of human-mouse hybridoma was reported in 1984, and the first clinical trial was conducted in 1987, 1986. The United States FDA approved the anti-CD3 monoclonal antibody OKT3 for transplant rejection. In 1995, 17-1A mouse monoclonal antibody was marketed in Europe for the treatment of colorectal cancer. In recent years, monoclonal antibody treatment drugs have developed rapidly, and some have been used clinically. [1]
Monoclonal Antibody Drugs I. Classification of Monoclonal Antibody Drugs
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- Monoclonal drugs are generally divided into: monoclonal antibody agents for treating diseases (especially tumors), anti-tumor monoclonal antibody conjugates, and monoclonal antibodies for treating other diseases. The target of the monoclonal antibody agent is usually a cell-surface disease-related antigen or a specific receptor. Such as: the first monoclonal antibody drug rituximab approved by the US FDA for the treatment of tumors; antitumor monoclonal antibody conjugates, or immunoconjugates (Immunoconjugate), are composed of monoclonal antibodies and therapeutic substances (such as: Radionuclide, toxin, drug, etc.), including radioimmunoconjugate, immunotoxin, chemoimmunoconjugate, and enzyme-conjugated monoclonal antibody conjugate, photosensitizer-conjugated monoclonal antibody conjugate, etc. .
Monoclonal antibody drugs
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1 Monoclonal antibody drug 1. Monoclonal antibody drug as a tumor treatment agent
- ( 1 ) Rituximab
- B cells play an important role in the formation of autoimmune diseases. CD20 is a surface antigen expressed during the differentiation of pre-B cells into mature lymphocytes, and is involved in regulating the growth and differentiation of B cells. Rituximab (Melohua) is a human and mouse chimeric monoclonal antibody against the CD20 antigen. It is the first monoclonal antibody approved by the FDA for clinical treatment. After entering the human body, it can specifically bind to CD20 and cause B cells to lyse, thereby inhibiting B cell proliferation and inducing apoptosis of mature B cells without affecting the original B cells. It can kill lymph by mediating antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct effects caused by the binding of antibodies to CD20 molecules, including inhibiting cell growth, changing the cell cycle, and apoptosis. Tumor cells.
- Because rituximab drugs can increase the sensitivity of tumor cells to chemotherapy, the advantage of rituximab drugs is that they are used in conjunction with other therapeutic drugs and treatments. Clinical studies have shown that melanovir has good efficacy and safety in treating tumors alone or in combination with chemotherapy, but there are still certain toxic and side effects. Clinical research conducted by Xia Zhongjun and others: 34 patients with confirmed indolent lymphoma received chemotherapy with rituximab. The total effective rate was 92.3%, and the complete response rate was 60.0%. The main adverse reaction was myelosuppression. Other adverse reactions included nausea and vomiting, mild hair loss and impaired liver function. Zhang Xiaoyan and other 5 patients with CD20-positive non-Hodgkin's lymphoma (NHL) underwent 5 rituximab combined with autologous peripheral blood stem cell transplantation (APBSCT). The results showed that all patients were resistant to It has been well received, and hematopoietic reconstruction is achieved within 8-11 days after implantation, which shows that rituximab combined with APBSCT is a well-tolerated and effective method for CD20-positive NHL.
- ( 2 ) Trastuzumab
- Trastuzumab is a recombinant humanized IgG monoclonal antibody directed against HER-2 / neu. It can specifically recognize the cell surface protein HER-2 regulated by Her-2, leaving it to enter the cell membrane through endocytosis. In the nucleus, it inhibits the signal transduction mediated by it, thus playing a role in treating tumors. The US FDA approved its listing in 1999, and in 2002 in China. A large number of clinical data have confirmed that trastuzumab alone has an effective rate of 21% for breast cancer, and its combined use with chemotherapy has significantly improved survival time. According to reports, the European trastuzumab adjuvant therapy trial has studied the efficacy of trastuzumab in patients with HER-2 positive breast cancer with or without lymph node positive, of which 1 group was given trastuzumab for 1 year. Anti-treatment, the other group served as a control. Compared with the control group, the trastuzumab-treated 1-year group reduced the risk of recurrence by 46%. There was no significant difference in the overall survival rate between the two groups, indicating that trastuzumab is used to treat HER-2 positive breasts after adjuvant chemotherapy. Cancer patients significantly prolonged the disease-free survival of patients. Trastuzumab has also been clinically studied in China. Shen Kunwei et al. Treated 42 patients with stage II-A invasive breast cancer with paclitaxel combined with trastuzumab for 24 weeks. As a result, the complete remission rate in the neoadjuvant chemotherapy group was 26.3% In the neoadjuvant chemotherapy combined with trastuzumab group, 65.2%, it can be seen that breast cancer chemotherapy combined with trastuzumab for HER-2 overexpression can significantly improve the complete response rate.
- ( 3 ) Allenzumab
- Alendizumab is a humanized, non-binding monoclonal antibody that targets the CD52 antigen of normal and abnormal B lymphocytes. CD52 is widely distributed in normal B lymphocytes, T lymphocytes, monocytes, and macrophages. The surface of cells and B lymphocytes and T lymphoma cells is particularly abundant on the surface of chronic lymphocytic leukemia cells. After binding to target cells with CD52, it causes cell death through host effector complement-dependent cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and apoptosis. As a monoclonal antibody with a unique mechanism of action, alenduzumab has a very good therapeutic effect on various malignant tumors derived from B and T cells.
- British scientists used alendizumab and rituximab to treat patients with recurrent lymphoma, and the overall response rate was 52%, of which 8% was a complete response, indicating that the combined use of alendizumab and rituximab is Safe and feasible. In the treatment of other T-cell malignancies: 22 patients with stage III-IV cutaneous T-cell lymphoma (mycosis granulomatosis and Sezary syndrome) were intravenously infused with Alenjuz for 12 weeks. Good curative effect, the total effective rate is 55%. Among them, the total effective rate of patients with erythrodermic disease reached 69%, and that of plaque or skin tumors reached 40%. Alenduzumab combined with other drugs and chemotherapy has a significant effect on tumors. However, clinical studies have shown that there are some common complications, such as hypotension, chills, fever, nausea, vomiting, shortness of breath, bronchospasm, rash, fatigue, dyspnea, headache, diarrhea, infection, etc.
- ( 4 ) Cetuximab
- Cetuximab is an IgG1 monoclonal antibody and is an epidermal growth factor receptor antagonist. It can specifically bind to epidermal growth factor receptor (EGFR) expressed on the surface of normal cells and a variety of tumor cells and competitively block it. EGF binds to other ligands, such as alpha-transforming growth factor (TGF-a). It keeps the cell cycle in G1 phase by increasing the cell cycle inhibitor p27kip; increases Bax expression and decreases bcl-2 expression, induces cancer cell apoptosis; it also reduces matrix metalloproteinases and vascular endothelial growth factor (VEGF) production . Related experiments show that cetuximab can inhibit the proliferation of tumor cells that overexpress EGFR, but it has no antitumor effect on tumor cells lacking EGFR expression. It has also been found that combination of cetuximab with chemotherapy is better than chemotherapy alone.
- In the study of cetuximab combined with chemotherapy, the BOAD trial is the most famous. EGFR was overexpressed in 82% of 576 patients with advanced colorectal cancer (ACRC). Two treatments were adopted. The first group was treated with cetuximab combined with irinotecan; the second group was treated with cetuximab alone. Compared with cetuximab alone, the combination effect of cetuximab and irinotecan is better than single use, with effective rates of 23% and 11%, disease control rates of 56% and 32%, and disease progression. The median time was 4.1 and 1.5 months, the median survival time was 8.6 and 6.9 months, and cetuximab did not increase the side effects of chemotherapy. The above clinical experiments show that cetuximab can overcome the resistance of irinotecan in patients with ACRC and significantly improve the quality of life. Side effects of cetuximab include: acne-like rash, weakness, abdominal pain, nausea, vomiting, leukopenia, and allergic reactions. Among them, acne-like rash is the most common adverse reaction. The rash is mainly distributed on the face and upper trunk, which may be caused by cetuximab disturbing the epidermal physiology of EGF.
- ( 5 ) Bevacizumab
- Bevacizumab is a humanized monoclonal antibody against VEGF. It neutralizes VEGF to block its binding to receptors on endothelial cells, making tumor cells unable to obtain nutrients and oxygen, which plays a role in treating tumors. Presta et al. Chimeric the complementarity-determining region of mouse anti-human VEGF clone antibody (muMABVEGF) A.4.6.1 to the constant region framework of human IgG1 and modified the corresponding amino acid residues to form a human-mouse chimeric VEGF single Anti, still 7% of the amino acids are derived from mouse antibodies. Experiments show that bevacizumab is safe and effective for treating tumors.
- Zheng Hang and others explored the efficacy of bevacizumab combined with irinotecan in the treatment of metastatic colon cancer. The effective rate of bevacizumab combined with irinotecan in 90 patients was 43.3%, and the concentration of serum tumor markers was treated. Significant changes before and after. This shows that bevac combined with irinotecan has a higher disease control rate in the treatment of metastatic colon cancer. The latest results of bevacizumab were reported at the annual meeting of the American Society of Clinical Oncology in 2005.Bevacizumab combined with irinotecan and cisplatin were used as first-line treatment for patients with metastatic gastric cancer or adenocarcinoma of the gastroesophageal junction. Renal marrow suppression, gastrointestinal reactions, etc. caused by the original irinotecan and cisplatin, as well as adverse reactions caused by bevacizumab include embolism, gastric perforation, etc.
2 Monoclonal antibody drug 2, antitumor monoclonal antibody conjugate
- (1) Radioimmunoconjugate
- Radioimmunotherapy (RIT) uses a monoclonal antibody as a carrier and a radionuclide as a warhead. The antibody specifically binds to tumor cell-associated antigens, and targets radioactive nuclei that generate high-energy rays to tumor cells to achieve near-term tumor response. Irradiation treatment from a distance. RIT uses a radionuclide-carrying monoclonal antibody to specifically bind to the site of the lesion, reducing damage to normal tissues. 90Y-ibri-tumomab is the first radioimmunoagent approved by the FDA for clinical use, and is mainly used in patients with relapsed lymphoma or in patients with poor response to rituximab alone.
- (2) Immunotoxin
- Immunotoxin is a tumor treatment drug obtained by covalently linking a tumor-selective monoclonal antibody and a modified polypeptide toxin by chemical or genetic engineering methods. Immunotoxin can be internalized by binding to tumor cell surface receptors or target antigens on the cell surface, and then inhibiting cellular protein synthesis intracellularly, leading to tumor cell death. There are many types of toxins, such as plant toxins, bacterial toxins, and animal toxins. The most widely cited is diphtheria toxin in plant toxins. The US FDA has approved the recombinant immunotoxin ONTAK (DAB389-IL2) of diphtheria toxin and interleukin 2 for the treatment of human skin T cell lymphoma.
- (3) Chemical immunoconjugate
- Monoclonal antibody is a good drug-targeting carrier. It connects chemical drugs with monoclonal antibodies to form chemical immune conjugates through special functional groups on the drug molecule such as hydroxyl, thiol, amino, etc. The toxic effect of normal tissues selectively exerts its therapeutic effect. Drugs often coupled with monoclonal antibodies include doxorubicin, daunorubicin, pingyangmycin, boanmycin, mitomycin, neocarcinin, and methotrexate.
3 Monoclonal antibody drugs3 . Application of monoclonal antibody drugs in other diseases
- Monoclonal antibody drugs have not only achieved good results in the treatment of tumors, but also achieved some effects in the treatment of other diseases, for example; omalizumab significantly reduces free IgE levels by combining with free IgE, Blocks the binding of IgE to mast cells and basophils, preventing the release of inflammatory mediators. It can significantly improve the symptoms, lung function and quality of life of asthma patients, reduce the number of exacerbations of asthma, reduce the amount of glucocorticoids, safe to use, and well tolerated. The formation of tubes can inhibit the adhesion of Candida albicans to epithelial cells and endothelial cells and reduce the invasion of Candida albicans. Rituximab also has a good therapeutic effect on rheumatoid and systemic lupus erythematosus. Infliximab can reduce clinical symptoms such as pain, morning stiffness, and joint swelling in patients with rheumatoid arthritis by up to 60%. Other studies have shown that infliximab infusion can quickly and significantly relieve the symptoms of joints and skin lesions in patients with refractory psoriasis and arthritis. Digestive diseases such as liver disease have good curative effects, and have good safety within the recommended treatment range.
Monoclonal Drugs III. Outlook
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- Monoclonal antibody drugs occupy an important position in biotechnology pharmaceuticals, and have gradually become the main direction of development in the field of biomedicine. From the global market point of view, antibody drugs have become the focus of competition in the international pharmaceutical industry, and mergers and acquisitions have become a shortcut for international pharmaceutical giants to quickly cut into the antibody industry. In addition, 75% of antibody drugs currently on the market will expire in 2015, which also provides opportunities for Chinese biopharmaceutical companies to intervene in antibody drugs. Monoclonal drug therapy mainly uses its targeting to interfere with various pathways in the occurrence and development of the disease, or to activate the host's immunity to the disease. With the continuous development of biomedicine, there will be more targeted monoclonal antibodies and more effective "warheads", bringing greater hope for patients.