Monoclonal antibodies in the treatment of indolent lymphomas

Humanised monoclonal antibodies have transformed the treatment of patients with lymphomas. The first application of these new drugs appeared less than 10 years ago but currently a lymphoma patient will certainly receive at least one of them once or several times during the evolution of his/her disease. This review covers the use of these monoclonal antibodies alone or in combination with chemotherapy. Rituximab, an unconjugated anti-CD20 chimeric antibody, is certainly the most widely used but other unconjugated or radiolabelled monoclonal antibodies are catching up quickly. If there are randomised studies demonstrating the benefit of adding these drugs to the treatment of patients with lymphoma, very few studies have compared the activity of the different monoclonal antibodies. Many questions need to be answered before the best setting for these drugs will be known.     

Monoclonal antibodies in the treatment of autoimmune cytopenias

In recent years, clinical studies have been undertaken with selected monoclonal antibodies (MoAbs) in the treatment of several hematological diseases, especially in malignant disorders. However, some clinical observations indicate that MoAbs may be an important alternative for the conventional therapy of some autoimmune disorders. Two MoAbs directed against CD20 antigen (rituximab, Rituxan, Mabthera) and CD52 antigen (alemtuzumab, Campath-1H) seem to be especially useful for this purpose. Autoimmune cytopenias have been investigated in the last few years with positive preliminary results. Rituximab seems to be an effective and safe agent for the treatment of immune thrombocytopenias, autoimmune hemolytic anemia, cold agglutinin disease and pure red cell aplasia. Although the case series are small, rituximab seems to be an effective and safe agent for the treatment of these diseases. Clinical experience with alemtuzumab in patients with autoimmune cytopenias is even more limited than with rituximab. However, preliminary results indicate that further studies with this MoAb are warranted. A longer follow-up and the studies on larger number of patients are needed to determine the real value of these new approaches in autoimmune cytopenias. Recent experiences with the use of MoAbs in treatment of these diseases are the subject of this review.     

Monoclonal antibodies in the treatment of multiple myeloma

Despite recent advances in treatment that have significantly improved overall survival, multiple myeloma (MM) remains incurable. Although rituximab, the first monoclonal antibody (MAb) evaluated in MM treatment, provided only very limited benefit, research is ongoing into a number of other MAbs directed against a variety of MM‐related target antigens. Given the inherent immune dysfunction associated with MM, newer strategies that may enhance immune function in conjunction with antibodies may also provide a more fruitful clinical approach. Potential MAb targets in MM include growth factors and their receptors, other signalling molecules, and antigens expressed exclusively or predominantly on MM cells. MAb therapy involves a range of mechanisms, including antibody‐dependent cellular cytotoxicity, complement‐dependent cytotoxicity, interference with receptor‐ligand interactions, and MAb conjugation to radioisotopes or toxins. The antigens currently targeted in MM therapy are discussed, along with the development status of the corresponding MAb therapeutics. Elotuzumab, an anti‐CS1 MAb, has recently achieved clinically meaningful responses when combined with lenalidomide or bortezomib in patients with relapsed and relapsed/refractory MM. Other MAbs are also showing early promise. More ongoing clinical research is required to identify optimal combination regimens and biomarkers that may help predict response to specific MAb‐based combinations.     

Monoclonal antibodies in the treatment of hematologic malignancy

Methods to generate monoclonal antibodies to antigens of neoplastic cells have revolutionized our understanding of cancer cell growth and differentiation, diagnosis, and treatment. Monoclonal antibodies derived by immunizing animals (mostly mice) with mammalian cells or molecules have been critical reagents for the discovery and characterization of many key molecules involved in the behavior of neoplastic cells. Now, over 30 years later, monoclonal antibodies are widely used in the differential diagnosis of cancer and are key elements in the treatment of many forms of cancer. This review will focus on the roles that monoclonal antibodies play in the treatment of hematological malignancies. In particular, we will focus on acute myeloid leukemia and mature B-cell neoplasms.     

Monoclonal antibodies for treating cancer

PURPOSE: To assess the current status of in-vivo use of monoclonal antibodies for treating cancer. DATA IDENTIFICATION: Publications appearing between 1980 and 1988 were identified by computer searches using MEDLINE and CANCERLIT, by reviewing the table of contents of recently published journals, and by searching bibliographies of identified books and articles. STUDY SELECTION: More than 700 articles, including peer-reviewed articles and book chapters, were identified and selected for analysis. DATA EXTRACTION: The literature was reviewed and 235 articles were selected as relevant and representative of the current issues and future applications for in-vivo monoclonal antibodies for cancer therapy and of the toxicity and efficacy which has been associated with clinical trials. RESULTS OF DATA SYNTHESES: Approaches include using antibody alone (interacting with complement or effector cells or binding directly with certain cell receptors) and immunoconjugates (antibody coupled to radioisotopes, drugs, toxins, or other biologicals). Most experience has been with murine antibodies. Trials of antibody alone and radiolabeled antibodies have confirmed the feasibility of this approach and the in-vivo trafficking of antibodies to tumor cells. However, tumor cell heterogeneity, lack of cytotoxicity, and the development of human antimouse antibodies have limited clinical efficacy. Although the immunoconjugates are very promising, heterogeneity and the antimouse immune response have hampered this approach as has the additional challenge of chemically or genetically coupling antibody to cytotoxic agents. CONCLUSIONS: As a therapeutic modality, monoclonal antibodies are still promising but their general use will be delayed for several years. New approaches using human antibodies and reducing the human antiglobulin response should facilitate treatment.     

Monoclonal antibodies against EGFR in non-small cell lung cancer

Blockade of the epidermal growth factor receptor (EGFR) by monoclonal antibodies is a strategy to improve outcome in patients with non-small cell lung cancer. Cetuximab, a chimeric anti-EGFR monoclonal antibody, has been studied in combination with different chemotherapy protocols in both phase II and phase III trials in patients with advanced NSCLC. In the phase III FLEX trial, cetuximab added to cisplatin/vinorelbine resulted in an absolute overall survival benefit of 1.2 months compared to the same chemotherapy alone in patients with advanced EGFR-expressing NSCLC. In the second phase III trial, cetuximab added to carboplatin plus paclitaxed failed to improve progression-free survival but suggested a survival benefit similar to that seen in the FLEX trial. However, the benefit in survival reached statistical significance only in the FLEX trial. A meta-analysis that included patients from four randomized trials confirmed the efficacy of cetuximab when added to chemotherapy. Thus addition of cetuximab to platinum-based chemotherapy represents a new treatment option for patients with advanced NSCLC. Matuzumab and panitumumab have also been evaluated in phase II trials. Necitumumab is currently evaluated in combination with chemotherapy in two randomized phase III trials.     

Monoclonal antibodies

Serologic reagents have played an important role in the diagnosis, treatment, and epidemiology of infectious diseases. A new technology has been developed for generating homogeneous antibodies that can be produced in large amounts and are available indefinitely. This technique promises to increase the reliability and sensitivity of immunoassays and may even provide antibodies that can be used safely in vivo.     

Monoclonal antibodies in the treatment of immune thrombocytopenic purpura (ITP)

Immune thrombocytopenic purpura is characterized by antibody-mediated destruction of platelets and suboptimal platelet production. Initially the treatment of ITP includes corticosteroids, IgG-anti-D, and intravenous immunoglobulins. Splenectomy and monoclonal antibodies are usually considered for refractory and chronic ITP patients. There are new data suggesting that early administration of rituximab is important, and this antibody has been used as first-line therapy in adults. In this concise review the role of rituximab and other monoclonal antibodies is analyzed. These agents have the capability of sparing splenectomy and possibly curing the disease in some patients.     

Monoclonal antibodies in pediatrics: use in prevention and treatment

An update is provided on monoclonal antibodies (MAbs): concept, production, indications for the diagnosis and treatment of neoplastic diseases and autoimmune disorders, prevention of transplant rejection, and treatment of allergic diseases, autoimmune disease and other noninflammatory disorders such as coronary disease. Mention is also made of MAb use in the prevention of respiratory syncytial virus (RSV) infection. A more extensive account is provided of the use of MAb in B cell lymphomas (anti-CD20) and T cell leukemias (anti-IL-2 R). Likewise, mention is made of the use of MAbs in autoimmune disorders, such as anti-TNF-alfa in application to chronic arthritis, Crohn's disease and psoriasis, anti-C5 in the treatment of chronic arthritis, uveitis, systemic lupus erythematosus, and autoimmune hemolytic anemia. Anti-KT 3 MAb is used to treat acute rejection and graft versus host disease, while anti-IL-2 R alfa and anti-IL-2 R gamma are used for the prevention of acute transplant rejection. Anti-IgE MAb (omalizumab) is used to treat asthma and allergic rhinitis refractory to other treatments. Anti-L5 (mepolizumab), anti-IL-4, anti-TNF and anti-inflammatory cytokine mediator MAbs all have indications in asthma and severe allergic rhinitis, and in intense atopic dermatitis refractory to other treatments. As to the MAbs used for the prevention of RSV infection, mention is made of anti-epitope A of the F protein of the virus.     

Monoclonal antibodies in haematology

The development of methods for the production of monoclonal antibodies is having an important impact in the field of immunohaematology. Four separate areas are implicated. First, there is the use of monoclonal antibodies in blood transfusion, where antibodies within the ABO, Rh, Lewis, P, MN, Kell and Lutheran systems are available. Most of the monoclonal antibodies are of murine origin but the techniques for producing human monoclonal antibodies is now well established and this is especially valuable in the Rh system, with the production so far of anti-c, D, -E, -e and -G. Secondly, there is a great potential for the use of monoclonal anti-D to substitute for polyclonal anti-D in the prophylaxis of haemolytic disease of the newborn. The introduction of these antibodies will depend on clinical trials using both the IgG1 and IgG3 subclasses and on the ability to prepare antibody which is free of viruses and DNA. Thirdly, monoclonal antibodies are being used in basic research on red cell membranes to isolate and characterise blood group antigens. Finally, these antibodies are being used in bone marrow transplantation to purge the donor marrow of T-cells in order to reduce the incidence of graft-versus-host disease.     

Monoclonal antibodies of hybridomas

Among the most prominent biological advances of this century, the hybridoma technology stands out as providing the best tool for the analysis of complex antigens of pathogens and tumor cells. This technology will play a major role in the immunodiagnosis and treatment of infectious and malignant diseases. This review focuses on the most recent developments (1980-1981), with emphasis on human immunology.     

Monoclonal antibodies combined to chemotherapy for the treatment of patients with lymphoma

Humanized monoclonal antibodies have transformed the treatment of patients with lymphomas. The first application of these new drugs appeared less than 10 years ago but currently one patient will certainly receive them once or several time during the evolution of his disease. This review will cover the use of these monoclonal antibodies alone or in combination with chemotherapy. Rituximab, an unconjugated anti-CD20 chimeric antibody, is certainly the most widely used but other unconjugated or radiolabeled monoclonal antibodies catch up quickly. If there are randomized studies demonstrating the benefit of adding these drugs to the treatment of patients with lymphoma, very few studies have compared the activity of the different monoclonal antibodies. A lot of questions needs to be answered before the best setting of these drugs will be known.