Monoclonal Antibodies: Targeted Therapytherapy N
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Educational Forum Monoclonal antibodies: Targeted therapytherapy N. Gupta, A. Srivastava ABSTRACT In an ongoing quest to improve the therapeutic arsenal against cancer, a fourth weapon Intas Biotechnology/Oncology, Plot other than surgery, chemotherapy and radiotherapy has emerged, i.e. targeted therapy. No. 423/P/A/GIDC, Sarkhej Bavla Targeted therapy includes, tyrosine kinase receptor inhibitors (small molecule inhibitors Highway, Moraiya, Tal: Sanand, Ahmedabad-382 210. India like imatinib, gefitinib, erlotinib), angiogenesis inhibitors (bevacizumab), proteasome inhibitors (bortezomib), biological response modifiers (denileukin diftitox) and Received: 2.2.2006 monoclonal antibodies (MAbs). The remarkable specificity of MAbs as targeted therapy Revised: 3.3.2006 makes them promising agents for human therapy. Not only can MAbs be used Accepted: 6.6.2006 therapeutically to protect against disease, they can also be used to diagnose a variety of illnesses, measure serum protein and drug levels, type tissue and blood and identify Correspondence to: infectious agents and specific cells involved in immune response. About a quarter of all Neera Gupta biotech drugs in development are MAbs, and about 30 products are in use or being E-mail: investigated. As a majority of the MAbs are used for the treatment of various [email protected] hematological and nonhematological malignancies, their role in cancer is discussed. KEY WORDS: Antibodies, chemotherapy, immunity, malignancy. .com). Introduction 1. Tyrosine kinase receptor inhibitor: There are different types of tyrosine kinase receptors in the body, one family being ‘Targeted therapy’ is a general term that refers to a the human epidermal receptor (HER) family. medication or drug that targets a specific pathway by attacking The members of the family are: or blocking important targets. The targets themselves are.medknow HER1 (also called as epidermal growth factor receptor typically various molecules (or small particles) in the body that [EGFR]) are known or suspected to play a role in various diseases. HER2 (also called ErbB2 or HER2/neu) One long-held dream is that the specificity of immune HER3 (also called ErbB3) mechanisms could be harnessed against tumor(www cells. HER4 (also called ErbB4) Monoclonal antibodies (MAbs) are so called because they arise EGFR inhibitors include small molecule inhibitors: gefitinib from a single cell type. They act by recognizing the protein on for non-small cell lung cancer and erlotinib for metastatic the surface of the cellThis and then PDFa lock site onto is hostedit. available They are produced by forMedknow freerenal download cell Publications carcinoma. from in the laboratory from a single clone and recognize only one Imatinib, the first commercially available tyrosine kinase antigen. MAbs are typically made by fusing a normally short- inhibitor for clinical use which targets platelet derived lived antibody producing β-cell to a rapidly dividing cell, such growth factor receptor (PDGF-R), was found to inhibit a as cancer cell (often referred to as ‘immortal cell’). The constitutively active fusion product arising from the resulting hybrid cell, or hybridoma, multiplies rapidly; creating Philadelphia chromosome of chronic myeloid leukemia. It a clone that produces large quantity of the antibodies. also inhibits c-kit and PDGF-R which are mutated in In 1975, Kohler and Milstein first fused lymphocytes to numerous solid tumors such as gastrointestinal stromal produce a cell line, which was both immortal and a producer tumors , lung cancer, prostate cancer, breast cancer, of specific antibodies. The two scientists were awarded the gliomas and seminoma. Nobel Prize for Medicine in 1984 for the development of this 2. Angiogenesis inhibitor includes bevacizumab, a vascular ‘hybridoma.’ The value of hybridomas to the field was not truly endothelial growth factor receptor inhibitor used in appreciated until about 1987, when MAbs were regularly treatment of metastatic colorectal cancer, metastatic renal produced in rodents for diagnostics. cell carcinoma, multiple myeloma and prostate cancer. Targeted therapies 3. Proteasome inhibitor: Proteasome is a structure inside the cell which breaks down proteins that have been labeled to Several classes of compounds included in targeted therapy undergo degradation and recycling. By binding part of the are as follows: proteasome, a drug can inhibit the breakdown of some of 390 Indian J Pharmacol | December 2006 | Vol 38 | Issue 6 | 390-396 Monoclonal antibodies these proteins that have been marked for destruction. Table 1 Bortezomib, a proteasome inhibitor, is used in multiple myeloma patients on whom other therapies failed. Monoclonal antibodies approved in various indications 4. Biological response modifier: Denileukin is diftitox used in Drug Indications Year non- Hodgkin’s lymphoma. of approval 5 Monoclonal antibodies (MAbs): Some specific areas of MAbs uses are as follows: Abciximab (Reopro) Acute coronary syndrome 1994 1. Inhibition of allo-immune reactivity: In case of organ Basiliximab (Simulect) Organ transplantation 1998 transplantation, MAbs are used to provide Daclizumab (Zenapax) Organ transplantation 1997 Eculizumab Dermatomyositis, nephritis 2000 immunosupression by antagonism of IL-2 or by the Epratuzumab SLE 2005 elimination of activated T-cells. Infliximab (Remicade) Crohn’s disease, RA 1998 2. Inhibition of autoimmune reactivity: Infliximab is used Omalizumab (Xolair) Bronchial asthma 2004 in the treatment of Crohn’s disease and rheumatoid Muronomab (OKT3) Organ transplantation 1986 arthritis. Rituximab is also used in the treatment of Palivizumab Viral infection 1998 rheumatoid arthritis. 3. Antiplatelet activity: Coronary intervention in ischemic cardiac disease disrupts the intimal layer of the vessel antibody used, it could be chimeric antibodies or humanized and aggravates platelet aggregation, leading to antibodies. Another approach involves genetically engineered thrombosis. Glycoprotein IIb/IIIa receptor blocker is a mice that produce more human-like antibodies. clear target for MAbs, in the prevention and treatment Engineered MAbs have the advantages of decreased of this disease. immunogenicity, enhanced half-life and optimized specificity. 4. Infectious diseases: MAbs is being used for the treatment Some of the MAbs approved for various indications (except of respiratory syncytial virus (RSV) infection in cancers) are shown in Table 1. premature infants with bronchopulmonary disease. MAbs in cancer Several drugs are in the pipeline for the treatment of infective diseases. One possible treatment for cancer involves MAbs that bind 5. Cancer therapy: MAbs that bind cancer cell-specific only to cancer cell-specific antigen which induce an antigen induce an immunological response on the target immunological response in the target (cancer) cell. Such MAbs cell. Another strategy for antitumor therapy is to target could also .com).be modified to deliver toxins, radioisotopes, the receptors of growth factors like EGF and VEGF. cytokines or other active conjugates. It is also possible to design bispecific antibodies that can bind through their Fab regions MAbs of different origin to both the target antigen and to a conjugate or effecter cell. � Murine MAbs: are obtained from murine hybridomas In fact, every intact antibody can bind to cell receptors or other produced by fusion of B-lymphocytes from immunized proteins with its Fc region. mice or rats with murine myeloma cells. .medknowMost of the therapeutic antibodies act differently in cancer: � Chimeric antibodies: The antibody combines the 1. Induce lysis of cancer cells by altering host-immune antigen-binding parts (variable regions) of the mouse response,e.g. rituximab, alemtuzumab antibody with the effector parts (constant region) of a 2. Bind with extracellular domains of the receptors involved human antibody, e.g. infliximab, rituximab(www and in cell growth and proliferation, e.g. trastuzumab, abciximab. cetuximab, bevacizumab � Humanized antibody: It combines only with the amino 3. Deliver radioisotopes to cancer cells: The antibodies are acids formingThis the antigen PDFa bindingsite is sitehosted available (the hyper variableby forMedknow freeconjugated download Publications to radioactive from substances to deliver regions), of a mouse (or rat) antibody part of the human radioactivity to cancer cells, e.g. tositumomab (conjugated antibody molecule, thus replacing its own hypervariable with I131, Ibritumomab [conjugated with Y90 and In111 ]) regions. Examples of humanized antibodies are 4. Deliver cytotoxic molecule: The antibody is conjugated to daclizumab, vitaxin, gemtuzumab ozogamicin, a cytotoxic molecule that kills the cancer cells, eg. trastuzumab and omalizumab. The advantage of human gemtuzumab, calicheamicin. MAbs is their potential to cause less immunogenic The MAbs that are available for the treatment of various reactions. cancers are shown in Table 2 and 3. Recombinant engineered MAbs MAbs for hematological malignancies Various approaches to overcome the problem of The treatment of hematological malignancies has been immunogenicity have been tried. One approach is to take the largely based on chemotherapy and radiotherapy. Although DNA that encodes the binding portion of monoclonal mouse improvement in response and survival rates has been seen antibodies and merge it with human antibody-producing DNA. over the years, poor response or relapses occur in a significant A mammalian cell culture is used to express