Monoclonal antibody therapy in experimental allergic encephalomyelitis and multiple sclerosis

Experimental autoimmune encephalomyelitis (EAE) is a T-cell-mediated demyelinating disease of the central nervous system that has been used as an animal model for multiple sclerosis (MS). Based on the exciting results in EAE, a number of novel immunotherapies employing biotechnological products, rather than conventional immunosuppressants, are being developed for the treatment of MS. In this review, we delineate the rationale for monoclonal antibody (MAb) therapy in EAE and MS and summarize the various levels at which immune intervention was performed. For each approach, we discuss the role of MAbs at the level of lymphocyte and cytokine networks, chemokines, and adhesion molecules or their receptors.     

骨关节炎的单克隆抗体治疗

背景:在骨关节炎的发病过程中有大量炎症因子产生,针对炎症因子的抗体最近成为了研究热点。目的:概述治疗骨关节炎单克隆抗体的最新研究进展,为临床治疗骨关节炎提供参考。方法:利用计算机检索CNKI、万方、PubMed及Web of Science数据库2006年1月至2020年5月的相关文章,检索词为“骨关节炎,单克隆抗体,炎症因子,osteoarthritis,monoclonal antibodies,inflammatory factors”。查阅相关文章,最终共纳入69篇文献进行结果分析。结果与结论:①骨关节炎是一种炎症性、退行性疾病,与传统非类固醇类抗炎药相比,单克隆抗体因其靶向性好、不良反应小的特点,在治疗骨关节炎疼痛方面已显示出良好效果;②部分单克隆抗体会加大患者关节置换的风险,因此药物选择应当因人而异;③随着研究的不断深入,会有更多针对不同靶点的单克隆抗体产生,为临床治疗骨关节炎提供更多选择。     

淋巴瘤的单克隆抗体治疗

 淋巴瘤的抗淋巴细胞表面抗原单克隆抗体（单抗）靶向治疗是近年肿瘤特异性免疫治疗研究中进展较快并取得较大成功的一个领域。其中抗B淋巴细胞（B细胞）表面CD20抗原的利妥昔单抗（rituximab，美罗华）用于人类治疗已有10年之久，是治疗各种B细胞淋巴瘤的关键药物之一。单抗对淋巴瘤有高度敏感性且毒副作用较小，现正用于成千上万的淋巴瘤患者。它对免疫系统的调理作用使得它也被应用于其他血液系统疾病（如血小板减少性紫癜和冷球蛋白血症）以及非血液系统疾病（如风湿性关节炎和其他自身免疫病）。但关于其使用的最佳治疗方案，以及是否要与其他治疗方法联合使用，还没有定论。本文对单抗治疗淋巴瘤的原理和临床治疗方案的研究现状做一综述。...     

Treatment of allergic asthma with monoclonal anti-IgE antibody. rhuMAb-E25 Study Group

BACKGROUND: Immune responses mediated by IgE are important in the pathogenesis of allergic asthma. A recombinant humanized monoclonal antibody (rhuMAb-E25) forms complexes with free IgE and blocks its interaction with mast cells and basophils. We studied the efficacy of rhuMab-E25 as a treatment for moderate-to-severe allergic asthma. METHODS: After a 4-week run-in period, we randomly assigned 317 subjects (age range, 11 to 50 years) who required inhaled or oral corticosteroids (or both) to receive either placebo or one of two regimens of rhuMAB-E25: high-dose rhuMAb-E25 (5.8 microg per kilogram of body weight per nanogram of IgE per milliliter or low-dose rhuMAb-E25 (2.5 microg per kilogram per nanogram of IgE per milliliter) intravenously on days 0 (half a dose), 4 (half a dose), and 7 (full dose) and then once every 2 weeks thereafter for 20 weeks. For the first 12 weeks of the study, the subjects continued the regimen of corticosteroids they had received before enrollment. During the following eight weeks, the doses of corticosteroids were tapered in an effort to discontinue this therapy. The primary outcome measure was an improvement in the asthma symptom score at 12 weeks, according to a 7-point scale, in which a score of 1 indicated no symptoms and a score of 7 the most severe symptoms. RESULTS: A total of 106 subjects were assigned to receive a high dose of rhuMAb-E25, 106 were assigned to receive a low dose, and 105 were assigned to receive placebo. At base line, the mean asthma symptom score was 4.0. After 12 weeks of therapy, the mean (+/-SE) scores were 2.8+/-0.1 in the high-dose group (P=0.008) and 2.8+/-0.1 in the low-dose group (P=0.005), as compared with 3.8+/-0.1 in the placebo group. At 20 weeks, the mean scores were 2.7+/-0.1 in both the high-dose group (P=0.048) and the low-dose group (P=0.14), as compared with 2.9+/-0.1 in the placebo group. More subjects in the two rhuMAb-E25 groups were able to decrease or discontinue their use of corticosteroids than in the placebo group, but only some of the differences were significant. After 20 weeks, serum free IgE concentrations decreased by a mean of more than 95 percent in both rhuMAb-E25 groups. The therapy was well tolerated. After 20 weeks, none of the subjects had antibodies against rhuMAb-E25. CONCLUSIONS: A recombinant humanized monoclonal antibody directed against IgE has potential as a treatment for subjects with moderate or severe allergic asthma.     

Pollution and allergic airways disease

The incidence of allergic diseases has increased dramatically over recent years in most industrialized countries of the world. Air pollution from motor vehicles has been implicated as one of the factors that are responsible for this increase. Epidemiological studies carried out in different geographical regions in the world have shown a significant and consistent association between ambient levels of pollutants and increased asthma and rhinitis symptoms. Recent human and animal exposure studies, as well as laboratory-based studies, have demonstrated that diesel particles, ozone and nitrogen dioxide induce an inflammatory response that involves various inflammatory cells, mediators and adhesion molecules, which could contribute to worsening of the allergic disorders. The present review describes our current understanding of the mechanisms by which pollutants such as diesel exhaust and ozone enhance the underlying allergic inflammatory response, and possibly explain the associations between pollutants and increasing allergic diseases noted in epidemiological studies.     

Peptide-based immunotherapy: a novel strategy for allergic disease

The T-cell component of the antigen-specific immune response is the target of various novel interventions to modify chronic immunologic disorders, such as allergic diseases. Recent clinical trials have evaluated the safety and efficacy of therapeutic vaccines consisting of short, synthetic, allergen-derived peptides, corresponding to T-cell epitopes from the eliciting antigen. The main advantage of such an approach is the reduction in systemic, immunoglobulin E-mediated adverse events compared with existing whole allergen immunotherapy, often referred to as 'allergy shots'. T-cell peptide epitopes, although capable of inducing immunologic tolerance, are short linear structures that have reduced ability to cross-link mast cell- and basophil-bound immunoglobulin E. The precise mechanism of tolerance induction remains incompletely defined. However, recent data indicate that peptide therapy induces/expands a population of antigen-specific regulatory T-cells. A novel form of treatment combining efficacy with a substantially decreased occurrence of adverse events is likely to have a major impact on the management and prevalence of allergic diseases. Furthermore, the principles of epitope-specific therapy hold promise for the development of therapeutic vaccines for the treatment of autoimmune diseases.     

Omalizumab, anti-IgE recombinant humanized monoclonal antibody, for the treatment of severe allergic asthma

BACKGROUND: A recombinant humanized anti-IgE mAb, omalizumab, forms complexes with free IgE, blocking its interaction with mast cells and basophils; as a consequence, it might be effective in the treatment of asthma. OBJECTIVE: The purpose of this study was to evaluate the efficacy and safety of omalizumab in the treatment of inhaled corticosteroid-dependent asthma. METHODS: In this phase III, double-blinded, placebo-controlled trial, 525 subjects with severe allergic asthma requiring daily inhaled corticosteroids were randomized to receive placebo or omalizumab subcutaneously every 2 or 4 weeks, depending on baseline IgE level and body weight. Inhaled corticosteroid doses were kept stable over the initial 16 weeks of treatment and tapered during a further 12-week treatment period. RESULTS: Omalizumab treatment resulted in significantly fewer asthma exacerbations per subject and in lower percentages of subjects experiencing an exacerbation than placebo treatment during the stable steroid phase (0.28 vs 0.54 [P =.006] and 14.6% vs 23.3% [P =.009], respectively) and during the steroid reduction phase (0.39 vs 0.66 [P =.003] and 21.3% vs 32.3% [P =.004], respectively). Beclomethasone dipropionate reduction was significantly greater with omalizumab treatment than with placebo (median 75% vs 50% [P <.001]), and beclomethasone dipropionate discontinuation was more likely with omalizumab (39.6% vs 19.1% [P <.001]). Improvements in asthma symptoms and pulmonary function occurred along with a reduction in rescue beta-agonist use. Omalizumab was well tolerated, with an adverse-events profile similar to that of placebo. CONCLUSION: The addition of omalizumab to standard asthma therapy reduces asthma exacerbations and decreases inhaled corticosteroid and rescue medication use.     

Bicistronic expression plasmid encoding allergen and anti-IgE single chain variable fragment antibody as a novel DNA vaccine for allergy therapy and prevention

Several approaches have been applied in order to alleviate the difficulties allergic patients are suffering from. Among them DNA vaccination and anti-IgE antibody have shown promising results. Herewith, a combination of both strategies is proposed to minimize IgE production while inducing high levels of blocking IgG and strong Th1 immune responses. A bicistronic expression plasmid including an internal ribosomal entry site (IRES) can express both, allergen and a single chain variable fragment (scFv) antibody against human IgE within antigen presenting cells (APCs) including B cells. Presentation of allergen derived peptides via MHC I and MHC II stimulates specific Th1 responses resulting in high levels of IFN-gamma and IgG. Anti-IgE scFv antibody binds to newly synthesized IgE molecules within B cell cytoplasm and also to free serum IgE, thereby inhibiting attachment of IgE to its receptors on basophils and mast cells. Also, IgE-anti-IgE complex functions as blocking antibody and neutralizes allergens entering the body. Additionally, anti-IgE scFv antibody binds to membrane bound IgE (mIgE) on B cells and interferes with IgE expression. Using assays, such as enzyme linked immunosorbent assay (ELISA), IgG and IgE production in response to this expression system can be evaluated. Also, rat basophil leukemia cell assay (using RBL-2H3 cells) can show the amount of functional IgE in sera as basophil mediator release is regarded as an indicator of the allergic hypersensitive reactions. The proposed approach may result in high levels of blocking IgG and low levels of IgE secretion from B cells. Additionally, it can inhibit activity of IgE in degranulation of basophils and mast cells.     

IgE inhibition as a therapy for allergic disease

Monoclonal antibodies are potentially useful therapeutic agents in a variety of immunologically mediated diseases, since they offer the theoretical advantage of selectively targeting the mediators of the immuno-pathogenesis. It has been well established that IgE antibody synthesized by the immune system plays a pivotal role in the cascade of biochemical events leading to the allergic reaction. The aim of these studies was to eliminate IgE with a monoclonal antibody as the approach for treatment of atopic disease. To this end, a murine monoclonal antibody (MAE11) directed against IgE was identified which had all of the properties necessary to interfere with IgE responses. To avoid the problems of antigenicity associated with chronic administration of murine antibodies MAE11 was humanized. The best of several humanized variants, version 25 (rhuMAb-E25), was selected for clinical trials in allergic asthma and seasonal allergic rhinitis. In a series of phase I safety studies, rhuMAb-E25, by single or multidose administrations, was shown to be very well tolerated. Phase II studies were then designed to determine whether elimination of serum IgE, as a result of rhuMAb-E25 administration, had a significant impact on allergic symptoms. Results of these clinical trials establish the involvement of IgE in the pathophysiology of rhinitis and asthma and suggest a novel treatment for allergic disease.     

Monoclonal antibody therapy and laboratory medicine

Monoclonal antibodies (mAbs) therapies have been introduced to the many kinds of malignancies. Rituximab (Rituxan), a chimeric anti-CD20 monoclonal antibody, has improved clinical outcome in the patients with B cell non-Hodgkin's lymphoma (NHL) as a single agent as well as combination with chemotherapies including CHOP and stem cell transplantation. The efficacy has been reported in the patients with follicular lymphoma as well as aggressive NHL. The expression of CD20 should be confirmed by immunopathological staining or flow cytometry before the treatment. Gemtuzumab ozogamicin (Mylotarg), calicheamicin conjugates of anti-CD33 mAb, has been introduced in the treatment of AML. CD33 is not expressed by immature pluripotent stem cells even though expressed on myeloid progenitor cells. Mylotarg is internalized via CD33, however, detouched calicheamicin might be pumped out by multi-drug resistant related p glycoprotains (p-gp). The expression of CD33 and p-gp should be analyzed by flow cytometry before the treatment. We should give another caution to tumor-lysis syndrome and veno-occlusive disease.     

Evaluation of long-term safety of the anti-IgE antibody, omalizumab, in children with allergic asthma.

OBJECTIVE: To evaluate the long-term effects of the anti-IgE antibody omalizumab in children with asthma. METHODS: This was a 28-week, double-blind, randomized, placebo-controlled trial with a 24-week open-label extension. In the core trial 225 children (ages 6 to 12 years) with moderate-to-severe allergic asthma requiring inhaled beclomethasone dipropionate (BDP) received omalizumab every 2 or 4 weeks, and 109 received placebo. BDP dosage was stable for weeks 1 to 16, then reduced during weeks 17 to 24 using strict safety criteria. The lowest dose for optimal asthma control was maintained for 4 more weeks. During the 24-week extension, all patients (n = 309) received open-label omalizumab in addition to other asthma medications. One-year safety data were analyzed. RESULTS: The incidence of adverse events in patients treated with omalizumab for 52 weeks was similar to those treated for 28 weeks in the core trial, which was generally comparable with placebo. In the 52-week omalizumab group, upper respiratory tract infection and headache were the most frequently reported adverse events (47.1% and 42.7%, respectively). Eleven patients (4.9%) reported urticaria, which resolved spontaneously or with antihistamine, except for 1 patient who was discontinued because of severe urticaria. No anaphylactic reactions or adverse events suggestive of serum sickness or immune complex formation occurred. No anti-omalizumab antibodies were detected in any of the children. There is no evidence that new or more serious adverse events occur with long-term omalizumab treatment. CONCLUSIONS: Long-term treatment with omalizumab is safe and well tolerated in children with allergic asthma.     

Monoclonal antibody therapy for the induction of transplantation tolerance

There are three ways in which monoclonal antibodies could be used to facilitate the induction of tolerance to foreign tissues after organ transplantation. First, depleting monoclonal antibodies could be directed against the T cells responsible, thereby reducing their number and acting to non-specifically immunosuppress the patient. This is generally not sufficient to allow tolerance induction in the T cells which repopulate the periphery. Second, depleting monoclonal antibodies could be used to remove donor passenger leukocytes and antigen-presenting cells from the donor organ, which may both reduce immunogenicity and increase the chance of tolerance induction. Third, non-depleting, but functionally blocking, monoclonal antibodies to T cell molecules such as CD4 and CD8 can allow the specific induction of transplantation tolerance in mouse models, an approach which might be applicable to man, not only for organ transplantation, but also in the treatment of autoimmune diseases. These three approaches are, in time, likely to complement each other in clinical practice. Monoclonal antibodies can be tailored to each approach by choosing appropriate specificities and isotypes, and further refinements can be made where necessary by making monovalent or humanised antibodies. The application of each of these approaches to clinical therapy is described.     

Monoclonal antibody therapy in the treatment of Reye's syndrome.

A role for lipopolysaccharides (endotoxins, LPS) in 7 the pathogenesis of Reye's syndrome (RS) has previously been suggested. Impairment of hepatic LPS clearance can lead to systemic endotoxemia as previous studies by this and other laboratories have suggested for several hepatic disorders including RS. Systemic LPS may mediate many of the clinical findings associated with RS by eliciting monokines such as tumor necrosis factor-alpha, interleukin-1, interleukin-6, and interleukin-8. Monoclonal antibody therapy directed at LPS, and monokines may represent a novel approach to the treatment of RS.     

Omalizumab, an anti-IgE antibody, in the treatment of adults and adolescents with perennial allergic rhinitis.

BACKGROUND: Treatment with omalizumab, an anti-IgE antibody, improves symptoms and quality of life in patients with seasonal allergic rhinitis but has not previously been investigated in patients with perennial symptoms. OBJECTIVE: To investigate the efficacy, safety, and tolerability of omalizumab in the treatment of perennial allergic rhinitis (PAR). METHODS: Two hundred eighty-nine patients (aged 12 to 70 years) with moderate-to-severe symptomatic PAR were randomized to 16 weeks' double-blind subcutaneous treatment with either placebo (n = 145) or omalizumab (at least 0.016 mg/kg/IgE [IU/mL] per 4 weeks; n = 144). The primary efficacy variable was the mean daily nasal severity score, as determined from patient daily diary cards. Secondary efficacy variables included use of rescue antihistamine, rhinoconjunctivitis-specific quality of life (RQoL), and patients' evaluation of treatment efficacy. Safety and tolerability were evaluated from adverse event reports and laboratory safety parameters. RESULTS: Throughout 16 weeks of treatment, the mean daily nasal severity score was significantly lower in omalizumab-treated patients than with placebo (P < 0.001). The improvement in symptoms when taking omalizumab was paralleled by a reduction in use of rescue antihistamine (P < or = 0.005 overall) and improved RQoL relative to placebo. Patients' evaluation of treatment efficacy significantly favored omalizumab over placebo (P = 0.001). Omalizumab therapy was well tolerated. There were no safety concerns. CONCLUSIONS: Omalizumab was safe and well tolerated in the treatment of patients with PAR, providing effective control of symptoms and improved RQoL while simultaneously minimizing reliance on rescue antihistamines.