Antibodies are secreted by plasma cells transformed from B lymphocytes, and each B lymphocyte strain can only produce one type of
antibody specific to one specific antigenic determinant. This antibody produced from a single cell line is called a monoclonal antibody (McAb), or monoclonal antibody for short. The first-generation monoclonal antibody was prepared by Koehler and Milstein in 1975. It was derived from mouse B-cell hybridoma, but the human immune system can recognize murine monoclonal antibody, so its application is greatly limited. In 1982, Levy prepared a monoclonal antibody against tumor cells of patients with B lymphoma, and achieved good results. Subsequently, the method of 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 carried out in 1987. In 1986 The US FDA approved the anti-CD3 monoclonal antibody OKT3 for transplant rejection. In 1995, the 17-1A mouse monoclonal antibody was launched in Europe for the treatment of colorectal cancer. In recent years, monoclonal antibody therapy has developed rapidly, and some of them have been used in clinical practice.
Classification of monoclonal antibody drugs
Monoclonal antibody drugs are generally divided into: monoclonal antibody drugs for the treatment of diseases (especially tumors), anti-tumor monoclonal antibody conjugates, and monoclonal antibodies for the treatment of other diseases. The target of monoclonal antibody agents is usually disease-related antigens or specific receptors on the cell surface. For example: rituximab, the first monoclonal antibody drug approved by the US FDA for the treatment of tumors; anti-tumor monoclonal antibody conjugates, or immunoconjugates, which are composed of monoclonal antibodies and therapeutic substances (such as: Radionuclides, toxins and drugs, etc.) are composed of two parts, including radioimmunoconjugates, immunotoxins, chemical immunoconjugates, in addition to enzyme-conjugated monoclonal antibody conjugates, photosensitizer-conjugated monoclonal antibody conjugates, etc. .
Commonly used monoclonal antibody drugs in clinic
Monoclonal Antibody Drugs as Cancer Therapeutics
(1) Rituximab
B cells play an important role in the development of autoimmune diseases. CD20 is a surface antigen expressed during the differentiation of pre-B cells to mature lymphocytes and is involved in regulating the growth and differentiation of B cells. Rituximab (Rituximab) is a human-mouse chimeric monoclonal antibody against the CD20 antigen and is the first monoclonal antibody approved by the FDA for clinical treatment. After entering the human body, it can specifically bind to CD20 to cause B cell lysis, thereby inhibiting B cell proliferation and inducing apoptosis of mature B cells, but does not affect original B cells. It can kill lymphocytes by mediating antibody-dependent cytotoxicity (ADCC), complement-dependent cytotoxicity (CDC), and direct effects caused by antibody binding to CD20 molecules, including inhibition of cell growth, cell cycle changes, and apoptosis. tumor cells.
Since rituximab can improve the sensitivity of tumor cells to chemotherapy, the advantage of rituximab is that it can be used in combination with other therapeutic drugs and treatment methods. Clinical studies have shown that Rituxan alone or in combination with chemotherapy has good efficacy and safety in the treatment of tumors, but there are still certain toxic and side effects. A clinical study conducted by Xia Zhongjun et al.: 34 patients with diagnosed indolent lymphoma received chemotherapy with rituximab, the total effective rate was 92.3%, and the complete remission rate was 60.0%. The main adverse reaction is bone marrow suppression, other adverse reactions include nausea and vomiting, mild hair loss and liver function impairment. Zhang Xiaoyan et al conducted 5 times of rituximab combined with autologous peripheral blood stem cell transplantation (APBSCT) in 4 cases of CD20 positive non-Hodgkin lymphoma (NHL) patients. The results showed that all patients were resistant to rituximab. Hematopoietic reconstitution was achieved within 8-11 days after implantation, indicating 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 against HER-2/neu, which can specifically recognize the cell surface protein HER-2 regulated by Her-2, allowing it to leave the cell membrane and enter through internal phagocytosis. In the nucleus, it inhibits the signal transduction mediated by it, thereby playing a role in the treatment of tumors. The US FDA approved its listing in 1999, and it was listed in my country in 2002. A large number of clinical data confirmed that the effective rate of trastuzumab for
breast cancer was 21%, and its combined application with chemotherapy significantly improved the survival time. The European Trastuzumab Adjuvant Therapy Trial was reported to investigate the efficacy of trastuzumab in patients with HER-2-positive breast cancer with or without node-positive breast cancer, in which arm 1 was given 1 year of trastuzumab Anti-treatment, the other group served as control. Compared with the control group, the 1-year trastuzumab treatment group reduced the risk of recurrence by 46%, and the overall survival rate of the two groups was not significantly different, indicating that trastuzumab is used for the treatment of HER-2-positive breast cancer after adjuvant chemotherapy. cancer patients, significantly prolonging the disease-free survival of patients. my country has also conducted clinical research on trastuzumab. Shen Kunwei et al. treated 42 patients with stage II-IIIA invasive breast cancer with paclitaxel combined with trastuzumab for 24 weeks. The results showed that the complete remission rate in the neoadjuvant chemotherapy group was 26.3%. In the neoadjuvant chemotherapy combined with trastuzumab group, the rate was 65.2%. It can be seen that for HER-2 overexpressed breast cancer chemotherapy combined with trastuzumab can significantly improve the complete remission rate.
(3) Alemtuzumab
Alemtuzumab is a humanized, unconjugated 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. cells and on the surface of B lymphocytes and T lymphoma cells, especially on the surface of chronic lymphocytic leukemia cells. After binding to target cells with CD52, it leads to cell death through mechanisms such as complement-dependent cytotoxicity (CDC), antibody-dependent cytotoxicity (ADCC), and apoptosis of host effectors. As a monoclonal antibody with a unique mechanism of action, alemtuzumab has a good therapeutic effect on various malignant tumors derived from B and T cells.
British scientists used alemtuzumab and rituximab in the treatment of patients with relapsed lymphoma, and the overall response rate was 52%, of which 8% were complete remissions, indicating that the combined use of alemtuzumab 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 fungoides and Sezary syndrome) were given intravenous infusion of alenzumab for 12 weeks. Good curative effect, the total effective rate is 55%. Among them, the total effective rate is 69% in patients with erythroderma, and 40% in patients with flaky plaques or skin tumors. Alemtuzumab combined with other drugs and chemotherapy has a significant effect in the treatment of 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, an IgG1 monoclonal antibody, is an epidermal growth factor receptor antagonist that can specifically bind to and competitively block epidermal growth factor receptor (EGFR) expressed on the surface of normal cells and various tumor cells. Binding of EGF and other ligands such as alpha-transforming growth factor (TGF-alpha). It makes the cell cycle stay in the G1 phase by increasing the cell cycle inhibitor p27kip; increases the expression of Bax and reduces the expression of bcl-2, induces apoptosis of
cancer cells; it also reduces the production of matrix metalloproteinases and vascular endothelial growth factor (VEGF) . Relevant experiments have shown that cetuximab can inhibit the proliferation of tumor cells that overexpress EGFR, but has no anti-tumor effect on tumor cells lacking EGFR expression. It is also found that the combination of cetuximab and chemotherapy is better than chemotherapy alone.
Among the studies on 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 regimens were used for treatment. The first group was treated with cetuximab combined with irinotecan; the second group was treated with cetuximab alone. Compared with cetuximab alone, the combination of cetuximab and irinotecan has better efficacy than single use, the effective rates are 23% and 11%, respectively, the disease control rate is 56% and 32%, and the disease progression The median times were 4.1 and 1.5 months, and the median survival times were 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 ACRC patients to irinotecan, and the quality of life is significantly improved. Toxic side effects of cetuximab include; acne-like rash, weakness, abdominal pain, nausea, vomiting, leukopenia, and allergic reactions. Among them, acne-like rash was the most common adverse reaction, and the rash was mainly distributed on the face and upper trunk, which may be caused by cetuximab interfering with the epidermal physiology of EGF.
(5) Bevacizumab
Bevacizumab is a humanized monoclonal antibody against VEGF, which mainly neutralizes VEGF to block its binding to receptors on endothelial cells, so that tumor cells cannot obtain nutrients and oxygen, and plays a role in tumor therapy. Presta et al. chimeric the complementarity-determining region of mouse anti-human VEGF clone antibody (muMABVEGF) A.4.6.1 with the constant region of human IgG1, and modified the corresponding amino acid residues to form a human-mouse chimeric VEGF monoclonal antibody. Antibodies, still 7% of the amino acids are derived from murine antibodies. Experiments have shown that bevacizumab is safe and effective for the treatment of tumors.
Zheng Hang et al. explored the efficacy of bevacizumab combined with irinotecan in the treatment of metastatic colon cancer. Among 90 patients, the effective rate of a group of 90 patients treated with bevacizumab combined with irinotecan was 43.3%. There are significant changes before and after. This suggests that bevac combined with irinotecan has a higher disease control rate in the treatment of metastatic colon cancer. The latest research results of bevacizumab were reported at the annual meeting of the American Society of Clinical Oncology in 2005. The first-line treatment of patients with metastatic gastric cancer or gastroesophageal junction adenocarcinoma with bevacizumab combined with irinotecan and cisplatin showed that the adverse reactions of the treatment were in addition to The original irinotecan and cisplatin-induced renal myelosuppression, gastrointestinal reactions, etc., and the adverse reactions caused by bevacizumab, including embolic disease, gastric perforation, etc.
2. Antitumor monoclonal antibody conjugates
(1) Radioimmunoconjugates
Radioimmunotherapy (RIT) uses monoclonal antibodies as carriers and radionuclides as warheads. The antibodies specifically bind to tumor cell-related antigens and target the radionuclides that produce high-energy rays to tumor cells to achieve close proximity to tumors. Internal beam radiation therapy. RIT utilizes radionuclide-carrying monoclonal antibodies to specifically bind to the lesion site, reducing damage to normal tissue. 90Y-ibri-tumomab is the first FDA-approved radioimmunoassay for clinical use, mainly for patients with relapsed lymphoma or patients who have not responded well to rituximab alone.
(2) Immunotoxin
Immunotoxin is a tumor therapeutic drug which is formed by chemically or genetically engineering a tumor-selective monoclonal antibody and a modified polypeptide toxin covalently linked. Immunotoxins can be internalized after binding to tumor cell surface receptors or target antigens on the cell surface, thereby inhibiting cellular protein synthesis in the cell, leading to tumor cell death. There are many kinds of toxins, such as plant toxins, bacterial toxins, and animal toxins, of which the most widely cited is diphtheria toxin in plant toxins. The US FDA has approved the immunotoxin ONTAK (DAB389-IL2), a recombinant diphtheria toxin and interleukin 2, for the treatment of human cutaneous T-cell lymphoma.
(3) Chemical immunoconjugates
Monoclonal antibody is a good targeting carrier for drugs. Through special functional groups on the drug molecule such as hydroxyl, sulfhydryl, amino, etc., the therapeutic drug is connected with the monoclonal antibody to form a chemical immunoconjugate, which avoids the drug’s effect on other drugs. Toxic effects of normal tissues, selective therapeutic effects. Drugs that are often coupled with monoclonal antibodies include doxorubicin, daunorubicin, pingyangmycin, boanmycin, mitomycin, neocarcinstatin, methotrexate, and the like.
3. Application of monoclonal antibody drugs in other diseases
Monoclonal antibody drugs have achieved good efficacy not only in the treatment of tumors, but also in the treatment of other diseases. For example, omalizumab significantly reduces the level of free IgE by binding to free IgE, Block the binding of IgE to mast cells and basophils to prevent 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, and reduce the dosage of glucocorticoids. It is safe to use and has good tolerance. Mab03.2C1C2 can inhibit Candida albicans buds in vitro Tube formation, thereby inhibiting the adhesion of Candida albicans to epithelial cells and endothelial cells, and reducing the invasive power of Candida albicans. Rituximab is also a good treatment for rheumatoid and systemic lupus erythematosus. Infliximab can reduce clinical symptoms such as pain, morning stiffness, and joint swelling by up to 60% in patients with rheumatoid arthritis. Another study showed that infliximab infusion can quickly and significantly relieve symptoms of joint and skin lesions in patients with refractory psoriasis and arthritis. Digestive system diseases such as liver disease have good curative effect, and the safety is good within the recommended treatment range.
