摘要:

Gene therapy is an interesting approach for the correction of defective genes, the treatment of cancer and the introduction of immunomodulatory genes. Various techniques for gene transfer into cells or tissues have been developed within the last decade; these can be divided generally into viral and nonviral gene transfer systems. Nonviral techniques include the liposome- or gene gun-mediated introduction of therapeutic genes; however, the efficiency of gene transfer by these applications is still very low. In contrast, viruses have optimised their strategies for efficient infection of virtually any cell type in a mammalian organism. The genetic modification of genomes from different virus families (Adenoviridae, Retroviridae, Herpesviridae) led to the development of gene therapy vectors with a similar capacity to infect cells or tissues as that of wild type viruses. In contrast to wild type viruses, gene therapy vectors are engineered to transfer therapeutic genes into the target cells or tissues. In addition, they have lost their capacity for replication in target cells, because of the removal of essential genes, which allows replication only in specialised packaging cell lines engineered for the production of recombinant viruses.Despite considerable progress over the past decade in the generation of gene transfer systems with reduced immunogenic properties, the remaining immunogenicity of many gene therapy vectors is still the major hurdle, preventing their frequent application in clinical trials.Recombinant adenoviruses have been shown to be promising vectors for gene therapy, since they are able to transduce both quiescent and proliferating cells very efficiently. However, a major disadvantage of adenoviral vectors lies in the activation of both the innate and adaptive parts of the recipient’s immune system when appliedin vivo. The inflammatory responses induced by adenovirus particles can be very strong and can be fatal in patients treated with these adenoviral constructs. Therefore, many experiments have been performed in the effort to prevent these inflammatory responses mediated by adenoviral particles. The depletion of cell populations responsible for these inflammatory responses as well as the application of immunosuppressive drugs have been investigated. Moreover, the generation of less immunogenic adenoviral vectors by further genetic modification within the adenoviral genome has led to vectors with reduced immunogenic properties. Both strategies to reduce inflammatory responses against adenoviral particles are discussed in this review.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Solid organ transplantation during the past 30 years has developed from an experimental procedure into routine clinical practice. The current repertoire of immunosuppressive agents has made a major contribution to transplant survival; however, problems in different areas still need to be overcome.Several gene polymorphisms are supposed to influence immunosuppressive therapy and susceptibility to rejection. Therefore, a priority of transplant biologists is to estimate individual patient risk and to characterise the genetic profile of patients in need of a transplant in order to optimise the use of a scarce resource such as organs from cadaver donors, and to avoid serious drug-induced adverse effects. Polymorphisms in genes encoding tumour necrosis factor-α (TNFα), interleukin (IL)-6, IL-10, interferon-γ (IFNγ), transforming growth factor-β (TGFβ) and thiopurine S-methyltransferase (TPMT) can have significant effects on an individual’s risk of rejection, as well as their ability to tolerate immunosuppressive therapy. Genotyping of known polymorphisms in these genes may in the future contribute to our ability to individualise immunosuppressive therapy in organ transplant recipients.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

The ultimate goal of current chlamydial vaccine efforts is to utilise either conventional or modern vaccinology approaches to produce a suitable immunisation regimen capable of inducing a sterilising, long-lived heterotypic protective immunity at mucosal sites of infection to curb the severe morbidity and worldwide prevalence of chlamydial infections. This lofty goal poses tremendous challenges that include the need to clearly define the relevant effectors mediating immunity, the antigens responsible for inducing these effectors, the anti-chlamydial action(s) of effectors, and establishment of the most effective method of vaccine delivery. Tackling these challenges is further compounded by the biological complexity of chlamydia, the existence of multiple serovariants, the capacity to induce both protective and deleterious immune effectors, and the occurrence of asymptomatic and persistent infections. Thus, novel molecular, immunological and genetic approaches are urgently needed to extend the frontiers of current knowledge, and develop new paradigms to guide the production of an effective vaccine regimen. Progress made in the last 15 years has culminated in various paradigm shifts in the approaches to designing chlamydial vaccines. The dawn of the current immunological paradigm for antichlamydial vaccine design has its antecedence in the recognition that chlamydial immunity is mediated primarily by a T helper type1 (Th1) response, requiring the induction and recruitment of specific T cells into the mucosal microenvironment. Additionally, the ancillary role of humoral immune response in complementing the Th1-driven protective immunity, through ensuring adequate memory and optimal Th1 response during a reinfection, has been recognised. With continued progress in chlamydial genomics and proteomics, select chlamydial proteins, including structural, membrane and secretory proteins, are being targeted as potential subunit vaccine candidates. However, the development of an effective adjuvant, delivery vehicle or system for a potential subunit vaccine is still an elusive objective in these efforts. Promising delivery vehicles include DNA and virus vectors, bacterial ghosts and dendritic cells. Finally, a vaccine still represents the best approach to protect the greatest number of people against the ocular, pulmonary and genital diseases caused by chlamydial infections. Therefore, considering the urgency and the enormity of these challenges, a partially protective vaccine preventing certain severe sequelae would constitute an acceptable short-term goal to controlChlamydia. However, more research efforts and support are needed to achieve the worthy goal of protecting a significant number of the world’s population from the devastating consequences of chlamydial invasion of the human mucosal epithelia.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

A growing number of studies suggest a key role of nitric oxide (NO) derived from the inducible NO synthase (iNOS) isoform as a signalling molecule leading to acute organ transplant rejection. Current theory suggests that NO targets certain tissue proteins for nitrosylation or nitration leading to inhibition of enzyme/protein function and to cell death via apoptosis. Gene expression of iNOS and formation of nitrotyrosine residues have been confirmed in biopsies of rejecting grafts in humans. Experimental attempts to delay graft rejection by treatment with iNOS enzyme inhibitors have yielded conflicting results. An alternative strategy to alter rejection mediated by NO is to scavenge and/or neutralise the actions of excess NO, thereby by-passing the inhibition of iNOS enzyme activity. This review summarises recent laboratory evidence that new experimental NO scavengers/neutralisers have potential value to prolong graft survival. To date, various metal-based NO scavenging/neutralising compounds have been shown to enhance cardiac allograft survival in the absence of immunosuppression. When used in combination with low-dose cyclosporin, these agents produce a synergistic action to enhance graft survival or even to produce ‘permanent graft survival’ under certain prolonged drug regimens. A portion of this benefit may be accounted for by the property of some of these compounds to display immunosuppressant and anti-inflammatory activityin vivo. These properties are based on findings including the following: (i) attenuating cell infiltration into the graft; (ii) attenuating activation of NFκB (a transcription factor important for upregulation of various inflammatory genes); (iii) attenuating cyclin D3 gene expression (a marker of cell proliferation; (iv) antagonising autoimmune activation (as determined by attenuated cytokine gene expression in splenocytes isolated from treated animals but stimulated for several daysex vivoin mixed lymphocyte cultures).

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Intravenous immunoglobulins (IVIg) are therapeutic preparations of normal human immunoglobulin (Ig) G obtained from pools of blood from more than 1000 healthy donors, and exert immunomodulatory effects in autoantibody-mediated and T-cell-mediated autoimmune disorders and systemic inflammatory diseases. IVIg mechanisms of action in autoimmune diseases have been extensively analysed during the last 15 years and include the following: (i) interaction of the IgG Fc fragment with Fc receptors on leucocytes and endothelial cells; (ii) interaction of infused IgG with complement proteins; (iii) monocyte and lymphocyte modulation of synthesis and release of cytokines and cytokine antagonists; (iv) modulation of cell proliferation and reparation; (v) neutralisation of circulating autoantibodies; (vi) selection of immune repertoires; and (vii) interaction with other cell-surface molecules on T and B lymphocytes.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Bacteriophages (phages) are viruses of bacteria that can kill and lyse the bacteria they infect. After their discovery early in the 20th century, phages were widely used to treat various bacterial diseases in people and animals. After this enthusiastic beginning to phage therapy, problems with inappropriate use and uncontrolled studies and ultimately the development of antibacterials caused a cessation of phage therapy research in the West. However, a few institutions in Eastern Europe continued to study and use phages as therapeutic agents for human infections. The alarming rise in antibacterial resistance among bacteria has led to a review of the Eastern European studies and to the initiation of controlled experiments in animal models. These recent studies have confirmed that phages can be highly effective in treating many different types of bacterial infections. The lethality and specificity of phages for particular bacteria, the ability of phages to replicate within infected animal hosts, and the safety of phages make them efficacious antibacterial agents. Although there are still several hurdles to be overcome, it appears likely that phage therapy will regain a role in both medical and veterinary treatment of infectious diseases, especially in the scenario of emerging antibacterial resistance.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Background and ObjectivesLeucocyte β2 integrin adhesion receptors are hypothesised as a therapeutic target to modify immune responses to ischaemia-reperfusion injury that may be detrimental to recovery in a variety of disease states. Two phase I studies were designed to evaluate the pharmacokinetics, immunogenicity and safety of rhuMAb CD18, a humanised monoclonal antibody F(ab’)2fragment to the CD18 receptor, in normal healthy human volunteers.Study Design and MethodsThe first study evaluated six escalating doses of rhuMAb CD18 (0.06, 0.12, 0.25, 0.5, 1.0, 2.0 mg/kg) in 36 subjects given two intravenous (IV) bolus injections 12 hours apart. In the second study, 16 subjects received IV doses of 1.0 and 2.0 mg/kg as a single dose or as two doses given 12 hours apart. Study endpoints were rhuMAb CD18 serum pharmacokinetics, change in white blood cell (WBC) count, and safety and tolerability. The two studies enrolled a total of 53 subjects.ResultsSerum concentration-time profiles demonstrated a monophasic decline and were best characterised by a one-compartment pharmacokinetic model. At the doses administered, the volume of distribution approximated the serum volume (range of means: 42 to 58 ml/kg). The serum clearance decreased with increasing dose until becoming consistent at doses of 0.5 to 2.0 mg/kg (range of means: 3.1 to 5.0 ml/h/kg). At doses of 0.5 to 2.0 mg/kg, the mean elimination half-life ranged from 7.0 to 9.6 hours. WBC counts increased at doses of above 0.06 mg/kg, returning to within 20% of predose values by day 7. Antibodies to rhuMAb CD18 were not detected at day 28. Mild-to-moderate adverse events were observed in both the placebo and treated groups, and were limited to flu-like symptoms. One subject experienced a serious adverse event (febrile reaction) and recovered with minimal intervention. There was no evidence of an increase in infection in subjects who received rhuMAb CD18.ConclusionsUpon IV bolus administration, rhuMAb CD18 serum concentration-time data fit a one-compartment pharmacokinetic model. At doses of 0.5 to 2.0 mg/kg, the pharmacokinetics were linear and the half-life ranged from 7.0 to 9.6 hours with a volume of distribution that approximated the serum volume. No antibodies to rhuMAb CD18 were detected. A transient, dose-dependent increase in the WBC count was observed, consistent with the expected effect of rhuMAb CD18 on leucocyte demargination. No increase in infection was observed. rhuMAb CD18 administered by IV bolus was well tolerated, with the exception of one febrile reaction.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

All drugs appearing in the Adis Profile Summary table have been selected based on information contained inR&D Insight™,1a proprietary product of Adis International. The information in the profiles is gathered from the world’s medical and scientific literature, at international conferences and symposia, and directly from the developing companies themselves. The emphasis of this section inBioDrugsis on the clinical potential of new drugs, and selection of agents for inclusion is based on products in late phase clinical development that have recently had a significant change in status.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Antigenics is developing a therapeutic cancer vaccine based on heat-shock proteins (HSPs)1. The vaccine [HSPPC-96, Oncophage®] is in a pivotal phase III clinical trial for renal cancer at 80 clinical sites worldwide. The trial is enrolling at least 500 patients who are randomised to receive surgical removal of the primary tumour followed by out-patient treatment with Oncophage®or surgery only. This study was initiated on the basis of results from a pilot phase I/II study and preliminary results from a phase II study in patients with renal cell cancer. In October 2001, Oncophage®was designated as a fast-track product by the Food and Drug Administration in the US for the treatment of renal cell carcinoma.Oncophage®is in phase I/II trials in Italy for colorectal cancer (30 patients) and melanoma. The trials in Italy are being conducted at the Istituto dei Tumouri, Milan (in association with Sigma-Tau). Preliminary data from the phase II trial for melanoma was presented at the AACR-NCI-EORTC International Conference in Florida, USA, in October 2001.Oncophage®is also in a phase I/II (42 patients) and a phase II trial (84 patients) in the US for renal cell cancer, a phase II trial in the US for non-Hodgkin’s lymphoma (35 patients), a phase II trial in the US for sarcoma (20-35 patients), a phase I/II trial in the US for melanoma (36 patients), and phase I/II trials in Germany for gastric (30 patients) and pancreatic cancers. A pilot phase I trial in patients with pancreatic cancer began in the US in 1997 with 5 patients enrolled. In November 2000, Antigenics announced that this trial had been expanded to a phase I/II study which would now include survival as an endpoint and would enroll 5 additional patients. The US trials are being performed at Memorial Sloan-Kettering Cancer Center and the M.D. Anderson Cancer Center. The trials in Germany are being carried out at Johannes Gutenberg-University Hospital, Mainz.Oncophage®is an autologous vaccine consisting of purified complexes of tumour-derived HSPs linked to tumour antigen peptides. When these HSPPC are readministered to a patient following surgery or biopsy of the tumour, the antigenic tumour peptides are expressed on the surface of potent antigen-presenting cells of the immune system, such as macrophages and dendritic cells. This stimulates a much more powerful anti-tumour immune response than that generated by expression of the same antigens by the tumour cell. Thus, Antigenics autologous HSP technology is attractive because it is highly specific for individual patients and circumvents the need for identification of specific antigens for individual cancers (i.e. it does not require definition of the antigenic epitopes on cancer cells) and it overcomes the immune tolerance associated with various tumours. Oncophage®is manufactured in a 10-hour process from surgically resected autologous tumour. A minimum of 1-3g of tumour tissue is required to produce enough Oncophage®for a course of treatment. The major limiting factor for producing Oncophage®from a particular cancer is the ability to purify HSP from that cancer. From clinical studies to date, Antigenics has been able to produce HSP from 100, 98, 90, 71 and 30% of colorectal carcinoma, renal cell carcinoma, melanoma, gastric cancer and pancreatic cancer tumours, respectively. The low success rate with pancreatic cancers is because of the high concentration of proteases in that tissue type.HSPs are a family of highly conserved proteins present in the cells of all organisms. They function as molecular chaperones, assisting the correct folding of polypeptides and aiding intracellular protein transport. In addition, HSPs associate with a broad range of peptides derived from intracellular protein degradation, including antigenic peptides produced in tumour cells.Antigenics has exclusively licensed worldwide rights to its HSP immunotherapeutic complexes from Mount Sinai School of Medicine and Fordham University in the USA. On 3 November 1998, Antigenics was issued a US patent (5,830,464) covering immunotherapy in which antigen-presenting cells are isolated and mixed with heat shock protein-antigen complexes purified from patients’ tumours. The patent was issued to Fordham University, New York, US, who subsequently licensed it to Antigenics.Antigenics has an agreement with Sigma Tau, under the terms of which the latter company will fund 2 clinical trials in return for an option to market Oncophage®in Italy, Portugal, Spain and Switzerland. Antigenics also has an agreement with Medison for marketing of Oncophage®in Israel.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS

摘要:

Collateral Therapeutics and Schering AG in Germany are developing a gene therapy product, GENERXTMfor coronary artery disease.1Based on the terms of the agreement, Schering or its affliates will be responsible for conducting and financing phase II/III clinical trials which are currently underway in the US and Europe. In particular, Berlex Labs (the US subsidiary of Schering AG), is involved in developing the gene therapy in the US.GENERXTMis an angiogenic gene therapy which triggers the production of a protein that stimulates new blood vessel growth providing an alternative route for blood to bypass clogged and blocked arteries in the heart. GENERXTMinvolves a one-time, non-surgical delivery of an adenovirus vector containing the human fibroblast growth factor-4 (FGF-4) into coronary arteries via a standard catheter. The FGF-4 gene was licensed from New York University.Collateral Therapeutics has been granted a US patent for ‘gene transfer-mediated angiogenesis therapy’ for the nonsurgical administration of angiogenic genes for coronary and peripheral vascular disease. The patented technology has been licensed from the University of California. Collateral and Berlex have initiated pivotal phase IIb/III trials with GENERXTMin the US and Europe. The US-based study will evaluate the safety and efficacy of GENERXTMin patients with stable exertional angina due to coronary artery disease. The European-based study will evaluate patients with advanced coronary artery disease who are not considered candidates for interventions such as angioplasty and bypass surgery and/or patients who are unlikely to have positive outcomes from such interventions. Both studies, of a multicentre, randomised, double-blind and placebo-controlled design, will evaluate 2 dose levels of GENERXTMwhich will be non-surgically administered to the heart via intracoronary infusion through a standard cardiac catheter. Collateral also plans to develop a non-surgical gene therapy product using the FGF-4 gene for the treatment of patients with heart failure. In a blinded placebo-controlled study in a pig model of pacing-induced heart failure, intracoronary delivery of human FGF-4 expressed in an adenovirus vector showed significant improvement in regional cardiac function and a reduction in the size of the heart over a 3-week study period. If these results translated favourably to humans, FGF-4 gene therapy may be a therapeutic option for patients with dilated heart failure. Collateral Therapeutics has also announced a research collaboration with Targeted Genetics on the use of viral vectors to deliver therapeutic genes in cardiovascular disease. Under the terms of the agreement, Targeted Genetics and Collateral Therapeutics each have the option to collaborate further to use Targeted Genetics’ recombinant adeno-associated viral vector to treat congestive heart failure. In such an event, Targeted Genetics would be responsible for constructing and manufacturing the vector, and Collateral Therapeutics will fund the costs of future collaboration. Either party may terminate this agreement at any time upon 30 days prior written notice.

ISSN:1173-8804    

出版商:ADIS    

年代:2002

数据来源: ADIS