摘要:

Anticalins are a novel class of engineered ligand-binding proteins that are prepared from lipocalins – conventional plasma proteins in humans – via targeted random mutagenesis and selection against prescribed haptens or antigens. The first anticalins were selected to bind to small ligands, such as the cardioactive drug digoxin. Recently, libraries that also permit the generation of anticalins with high affinities and specificities for protein targets, especially disease-related cell-surface receptors, have been constructed. Anticalins are much smaller than antibodies or their antigen-binding fragments, lack glycosylation as well as immunological effector functions, and consist of a single, stably folded polypeptide chain. Thus, they offer benefits as biopharmaceuticals in several areas of medical therapy, for example as receptor antagonists or as effective antidotes against toxic compounds.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

The idiotypic determinants of B-cell lymphomas, formed by cell-specific rearrangement of the immunoglobulin genes, are unique and are therefore a suitable target against which to direct immunotherapy. Recent advances in our understanding of the fundamental mechanisms behind an effective immune response, coupled with advances in genetic engineering techniques, have led to a renewed interest in immunotherapy. Early clinical studies have confirmed the immunogenicity of the idiotypic antigen in patients with lymphoma. This review discusses the different methods of idiotypic vaccination currently under investigation in the clinic, including protein, genetic, and cellular vaccines. Protein vaccines are the most clinically advanced, with phase III trials of idiotypic protein linked to GM-CSF currently underway. DNA vaccines are easier to produce but to date only appear to be weakly immunogenic in man. Dendritic cell vaccines have shown promise but their use may be limited by the complexity of this approach. This review also highlights other approaches not yet in the clinic but that have shown promise in the laboratory, such as viral vaccines and T-cell therapy.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

The etiology of multiple sclerosis (MS) is incompletely understood, and evidence suggests there may be more than one underlying cause in this disorder. Furthermore, this complex and heterogeneous autoimmune disease shows a high degree of clinical variability between patients. Therefore, in the absence of a single therapeutic target for MS, it is difficult to apply conventional drug design strategies in the search for new treatments. We review the potential mechanisms of action of several effective therapies for MS that are currently available or in development. The effects of each treatment are described in terms of their actions on key processes in a five-step model of MS pathogenesis. Conventional immunosuppressants targeting intracellular ligands (e.g. mitoxantrone) have broad cytotoxic effects on B cells, T cells, and macrophages. This suppresses the pathogenic immune response in MS with high efficacy but is also associated with high toxicity, limiting the long-term use of these agents. Monoclonal antibodies (e.g. natalizumab and alemtuzumab) are a new generation of immunosuppressants that act on immune-cell surface ligands. These agents have narrower immunosuppressive actions and different safety profiles compared with conventional immunosuppressants. Immunomodulators (interferon-β and glatiramer acetate), which shift the immune balance toward an anti-inflammatory response, are at the frontline of treatments for MS. Immunomodulators have targeted actions on the immune system, but affect a greater number of immunopathogenic processes than monoclonal antibodies. Given the inherent heterogeneity of MS, such treatments, which act at many levels of the disease, may achieve the best clinical results. Using our understanding of the interplay between mechanism of action and clinical effects in MS therapies may help us to better design and select new treatments for the future.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Radioimmunotherapy (RIT) is among the newest modalities for treating the diverse neoplasms known as non-Hodgkin lymphomas (NHLs). The first RIT agent approved by the US FDA was yttrium-90 (90Y) ibritumomab tiuxetan in February 2002. This radioimmunoconjugate consists of the monoclonal IgG1 antibody ibritumomab (the murine parent of rituximab) bound to the chelator tiuxetan and linked by a stable thiourea covalent bond to the β-emitting radionuclide90Y. RIT with90Y ibritumomab tiuxetan is completed in 7–9 days on an outpatient basis, with only minimal (universal) precautions required. The dosing of90Y ibritumomab tiuxetan is based on patient weight and platelet count, after normal biodistribution with indium-111 ibritumomab tiuxetan has been confirmed. Treatment with90Y ibritumomab tiuxetan has produced high response rates and long-term benefits in patients with relapsed or refractory follicular and low-grade NHL, including those in whom rituximab therapy has failed. Its toxicity is primarily hematologic, with the hematologic nadirs generally occurring at 7–9 weeks after treatment. Severe infections are uncommon, with infrequent need for supportive measures such as administration of growth factors and transfusions of blood components. There is little nonhematologic toxicity with RIT and it is generally related to infusion-associated reactions. Clinical trials are investigating ways of increasing the efficacy of RIT. In particular, using RIT earlier in the course of treatment of NHL appears to be a promising approach and has been shown to produce better results than when it is used later. Ongoing research is needed to maximize the efficacy of RIT and minimize adverse events, with the goal of developing a multimodality approach that combines RIT with other biologic agents and possibly chemotherapy as frontline treatment to improve the outcomes in patients with NHL.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Subcutaneous recombinant interferon-β-1a (Rebif®) 22 or 44µg three times weekly is a valuable option in the first-line treatment in patients with relapsing-remitting multiple sclerosis. It has shown benefits on outcome measures related to relapses, progression of disability, and magnetic resonance imaging in clinical trials. A significant efficacy advantage for subcutaneous interferon-β-1a three times weekly over intramuscular interferon-β-1a 30µg once weekly was shown at 24 and 48 weeks. The most common adverse events are generally mild and clinically manageable. Considering both direct and indirect comparative clinical trial data, an assessment suggests that subcutaneous interferon-β-1a 44µg three times weekly has the best benefit-to-risk values of the available disease-modifying drugs used to treat relapsing-remitting multiple sclerosis.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS

摘要:

Darbepoetin alfa (Aranesp®, Nespo®) is an amino acid substituted analog of human erythropoietin (EPO) that promotes erythrocyte survival, proliferation, and differentiation. Approved in Europe and the US for the treatment of anemia associated with chronic kidney disease (CKD), it is characterized by delayed clearance and a more prolonged elimination half-life than recombinant human erythropoietin (rhEPO; epoetin alfa and beta), permitting an extended interval between doses.Darbepoetin alfa is generally well tolerated, and clinical trials of 20–52 weeks' duration have demonstrated the efficacy of subcutaneous and intravenous administration at 1- or 2-week intervals in the initial treatment of anemia associated with CKD both in dialysis patients and in patients not yet on dialysis. Trials of up to 52 weeks' duration demonstrated that in the majority of patients with CKD, treatment with darbepoetin alfa at up to 4-week intervals maintained hemoglobin (Hb) levels established by prior erythropoietic treatment, while in patients undergoing dialysis, intravenous or subcutaneous darbepoetin alfa administered at 1- or 2-week intervals was noninferior to rhEPO administered once, twice, or three times per week in maintaining established Hb levels.

ISSN:1173-8804    

出版商:ADIS    

年代:2005

数据来源: ADIS