摘要:

Musculoskeletal injuries have a significant human and financial impact on society. In particular, fractures that lead to delayed union or even nonunion represent a serious clinical challenge for which few treatment options are available. The multiple surgical procedures often needed are associated with patient morbidity and reduced quality of life. Biotechnological advances have made possible a host of potential treatments for enhancing and accelerating the repair of bone. By stimulating the body’s own healing mechanisms, clinical outcomes may be improved while also containing procedural costs. Biotherapeutics may take the form of proteins, genes or cells that can be used to treat the injury. Protein biotherapeutics have received the greatest attention. Using recombinant DNA techniques, growth factors that play important roles in bone development and repair are being produced. By delivering exogenous growth factors to the site of injury in an appropriate manner, bone formation can be stimulated. Although individual proteins have been the primary focus of investigation, combinations of biomolecules can have additive, and perhaps synergistic, effects. Alternatively, genes coding for osteotropic growth factors can be delivered to the site of injury. Expression of the gene effectively results in localised delivery of the growth factor. Delivery of cells having osteogenic potential can also result in bone formation. Furthermore, it may be possible to obtain additional benefits by combining biotherapeutic approaches, such as by introducing cells genetically modified to overexpress therapeutic proteins of interest. Although biotherapeutics have great potential for stimulating bone repair, only a limited number of treatments have been approved by governmental regulatory agencies for clinical use. Bone morphogenetic activity was initially described in 1965, but not until 2001 and 2002 did two protein biotherapeutics, utilising bone morphogenetic proteins 2 and 7, receive approval for commercial distribution. Gene- and cell-based therapies are in a comparatively early stage of development.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Neuroendocrine cells and other secretory cell types are able to store secretory proteins in a concentrated form for extended periods until the release of large quantities of protein is triggered. The proteins are stored in dense core secretory granules. The dense cores of these granules are made up of large, insoluble aggregates that form by self-association. These aggregates solubilise rapidly into monomeric proteins in their native conformations when released from the cells by exocytosis of secretory granules. Formation of aggregates is an early event in secretory granule formation in at least some cell types. The function of secretory granules containing protein aggregates varies, depending upon the contents. This may occur because recognition of an aspect, such as a surface motif, of the aggregate facilitates correct assembly of the membrane proteins necessary for transport and exocytosis of the granules.Understanding the principles necessary for aggregation of protein hormones may help in the formulation of proteins for clinical use. Formation of aggregates of human prolactin has been investigated both in cells and in solution. In cells, the aggregation of human prolactin requires a mildly acidic pH, and is slowed in the presence of a membrane-permeable chelator of zinc. In solution, the aggregation of human prolactin at mildly acidic pH and physiological concentrations of Zn2+resembles that which occurs in cells if the reaction is performed with macromolecular crowding, which will mimic the conditions in cells. The factors causing protein aggregation and the extent to which aggregation plays a role in secretory granule formation are likely to vary with the protein and cell type. Further understanding of the principles involved in forming these aggregates that readily disassociate may enhance the ability to formulate protein preparations. Knowledge of the exact residues involved in the protein : protein interfaces in the aggregates of secretory granule proteins may lead to the ability to use small molecules to interfere with self-association and to regulate the storage of secretory granule proteins.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

The construction and use of Class I human leucocyte antigen (HLA) tetramers has, for the first time, allowed the direct enumeration of CD8+T lymphocytes specific for the antigen of interest. Tetramer staining can be combined with functional assays of antigen-specific T cells measuring their production of intracellular cytokines after short-term stimulation with antigen. The advantages of flow cytometric tetramer-based assays are their short turn-around time and their amenability to standardisation. Currently, their main limitation is that only a limited number of Class I HLA tetramers are available. This situation may bias the information derived from such studies. Nevertheless, clinically useful information has been obtained in tetramer-based studies of the regeneration of cytomegalovirus (CMV) and Epstein-Barr virus (EBV)-specific CD8+T cells after allogeneic stem cell transplantation (SCT).Following myeloablative cytoreductive therapy and SCT, a period of deep cellular immunodeficiency follows until the donor-derived immune system has sufficiently regenerated. As a result of the lack of immunosurveillance, endogenous viruses such as CMV and EBV may reactivate and cause disease. In order to prevent these complications, pre-emptive therapeutic interventions are made, in which antiviral treatment is administered based on frequent viral load measurements. In this way, overtreatment associated with prophylactic strategies is reduced; however, a subgroup of patients developing recurrent reactivations and/or disease remains. Interventions aimed at the prevention of graft versus host disease (GVHD) and the reduction of its severity greatly reduce the rate of (virus-specific) T-cell reconstitution and hence, increase the frequency and severity of viral reactivations. Specifically, T-cell depletion of SCT and the use of antithymocyte globulin as part of the conditioning regimen reduces the (virus-specific) T lymphocytes transferred with the graft, which otherwise would have contributed to the first phase of T-cell regeneration post-SCT. Consequently, patients whose CMV- and EBV-specific CD8+T cells fail to regenerate to levels detectable by tetramer-based flow cytometry during the first 3–6 months post-SCT were at highly increased risk for CMV disease and EBV+B-lymphoproliferative disease, respectively. Furthermore, delayed reconstitution of the CD4+T-cell compartment results in the lack of adequate help for the generation of sufficient antiviral CD8+T cells. Conversely, adoptive immunotherapy using CMV- or EBV-specific T cells results in the swift restoration of virus-specific T-cell immunity and the reduction of viral load, unless corticosteroids have to be administered to treat concurrent GVHD. Studies have shown the clinical utility of tetramer-based immune monitoring in the setting of allogeneic SCT and indicate that such assays, extended by functional studies of the virus-specific T cells, may constitute a valuable extension of current viral load monitoring strategies.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

For molecular targeted cancer therapies to fulfill their promise in cancer treatment, innovative approaches are required to overcome significant obstacles that exist in the clinical development of these agents. Positron emission tomography (PET) is a functional imaging technology that allows rapid, repeated, noninvasive,in vivoassessment and quantification of many biological processes and in some cases molecular pathways targeted by these therapies. It is highly sensitive, with the capacity to detect subnanomolar concentrations of radiotracer and provides superior image resolution to conventional nuclear medicine imaging with gamma cameras. Novel PET radiotracers have been developed that allow visualisation of a variety of processes including tumour metabolism, cell proliferation, apoptosis, hypoxia and blood flow. Furthermore, specific molecular targets including cellular receptors can be identified using radiolabelled receptor ligands or specific monoclonal antibodies. Improvements in imaging technology leading to the development of small-animal PET scanners, with resolution capable of imaging commonly used mouse models of cancer, will enable PET to play an important role in preclinical proof-of-principle drug studies. Such improvements will also facilitate the validation of imaging protocols that can be readily translated to studies in humans. The greatest utility of PET in the development of molecular targeted therapeutics, however, lies in clinical studies, where PET may play a valuable role in a number of situations. These include selection of patients for therapy through noninvasive identification of the presence of specific molecular targets, pharmacokinetic studies with labelled drugs and pharmacodynamic evaluations of biological parameters to select the optimal biological dose, and assessment of response to therapies.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

ObjectiveTo review the efficacy of the ribosomal immunostimulant Ribomunyl®in preventing upper and lower respiratory tract infections.Design and settingReview of studies of 3 and 6 months’ duration comprising part of the international registration file.PatientsData from 2117 patients (1215 children and 902 adults); ribosomal immunostimulant n = 1062, placebo n = 1055.ResultsNineteen randomised, double-blind, placebo-controlled clinical trials were performed between 1983 and 1994 in Europe. In children with ear-nose-throat (ENT) infections, 3 months’ ribosomal immunostimulant treatment significantly decreased the mean number of recurrences (27–68% reduction), and reduced the duration of infection (28–66% reduction) and antibacterial requirement (29–60% reduction). Ribosomal immunostimulant was similarly effective in children with ENT and bronchopulmonary infections, reducing the mean number of recurrences by 32–61% compared with placebo. In children with otitis media, ribosomal immunostimulant reduced recurrences by 10–53% and also reduced the duration of infection, antibacterial use and local surgery requirement. Results obtained from studies of 6 months’ duration confirmed or extended these results. In adult patients with ENT or mixed respiratory infections, ribosomal immunostimulant produced similar reductions to those seen in children for recurrent infections (54–78% reduction), duration of infection (42–79% reduction) and antibacterial use (38% reduction).ConclusionsThese results clearly demonstrate that ribosomal immunostimulant is effective in preventing and in reducing upper and lower respiratory tract infections in children and adults.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Atlizumab [Actemra™,MRA] is a humanised anti-interleukin-6 receptor monoclonal antibody. It was originated by the Japanese company Chugai Pharmaceutical and is being developed for the treatment of rheumatoid arthritis, Crohn’s disease, multiple myeloma and the lymphoproliferative disorder giant lymph node hyperplasia (Castleman’s disease).In October 2002, a majority share (50.1%) in Chugai Pharmaceutical was acquired by Roche. Nippon Roche was merged into Chugai Pharmaceutical, which is now Roche’s exclusive pharma representative in Japan. The relationship between Chugai Pharmaceutical and Roche has been defined through a jointly agreed governance agreement, by which Chugai Pharmaceutical will be an autonomously managed company. Chugai Pharmaceutical is now Roche’s exclusive pharma representative in Japan and will have rights to develop and market Roche products in Japan. As part of the transaction, Roche gained rights of first refusal for licencing, marketing or co-developing any Chugai Pharmaceutical products which are available for partnering.In the first quarter of 2003, Chugai Pharmaceutical and Roche formed an agreement to co-develop and co-promote atlizumab. The companies will co-promote the drug in the UK, France and Germany. Roche will co-develop and promote atlizumab worldwide, except in Japan, South Korea and Taiwan. Chugai Pharmaceutical has retained co-promotion rights in the US, Italy and Spain.Atlizumab completed phase II development for giant lymph node hyperplasia in Japan in 2002, where it has been granted orphan drug status. In April 2003, a regulatory filing was submitted in Japan for use of atlizumab in the treatment of giant lymph node hyperplasia.In May 2000, Chugai Pharmaceutical and the US company Protein Design Labs reached an agreement whereby Chugai Pharmaceutical will receive nonexclusive, worldwide licences for an undisclosed number of its antibody targets under Protein Design Labs’ antibody humanisation patents. One of the targets included is the human interleukin-6 receptor. Chugai Pharmaceutical will pay Protein Design Labs $US6.04 million in signing and licencing fees. Chugai Pharmaceutical will also pay annual maintenance fees and royalties on any future product sales.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

CPH 82 [Reumacon®] is a purified semi-synthetic lignan glycoside derivative of the medicinal herbPodophyllum emodiwhich inhibits microtubules. It has been jointly developed by the Swedish company Conpharm and the Swiss company Analytecon SA. It has potential for the treatment of rheumatoid arthritis.The Swedish company Meda is licencing the drug and has taken over responsibility from Conpharm for development and documentation. Meda has obtained exclusive marketing rights for Reumacon®worldwide, except in China and some other Asian countries. Meda plans to form partnerships with other companies in the marketing of Reumacon®.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS

摘要:

Somatomedin-1 binding protein-3 [insulin-like growth factor-1 binding protein-3, SomatoKine®] is a recombinant complex of insulin-like growth factor-1 (rhIGF-1) and binding protein-3 (IGFBP-3), which is the major circulating somatomedin (insulin-like growth factor) binding protein; binding protein-3 regulates the delivery of somatomedin-1 to target tissues.Somatomedin-1 binding protein-3 has potential as replacement therapy for somatomedin-1 which may become depleted in indications such as major surgery, organ damage/failure and traumatic injury, resulting in catabolism. It also has potential for the treatment of osteoporosis; diseases associated with protein wasting including chronic renal failure, cachexia and severe trauma; and to attenuate cardiac dysfunction in a variety of disease states, including after severe burn trauma.Combined therapy with somatomedin-1 and somatomedin-1 binding protein-3 would prolong the duration of action of somatomedin-1 and would reduce or eliminate some of the undesirable effects associated with somatomedin-1 monotherapy. Somatomedin-1 is usually linked to binding protein-3 in the normal state of the body, and particular proteases clip them apart in response to stresses and release somatomedin-1 as needed. Therefore, somatomedin-1 binding protein-3 is a self-dosing system and SomatoKine®would augment the natural supply of these linked compounds.Somatomedin-1 binding protein-3 was developed by Celtrix using its proprietary recombinant protein production technology. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on June 1 2000.Insmed and Avecia, UK, have signed an agreement for the manufacturing of SomatoKine®and its components, IGF-1 and binding protein-3.CGMP clinical production of SomatoKine®and its components will be done in Avecia’s Advanced Biologics Centre, Billingham, UK, which manufactures recombinant-based medicines and vaccines with a capacity of up to 1000 litres. In 2003, manufacturing of SomatoKine®is planned to move to Avecia’s larger facility with a capacity of 10 000 litres.Somatomedin-1 binding protein-3 was originally licenced to Welfide for Japan. On October 1 2001, Welfide Corporation merged with Mitsubishi-Tokyo Pharmaceuticals to form Mitsubishi Pharma Corporation. The new company is a subsidiary of Mitsubishi Chemical.In April 2003 Insmed initiated a named patient programme in Europe, that will make available somatomedin-1 binding protein-3 for the treatment of growth hormone insensitivity syndrome (GHIS) – Laron syndrome. The treatment of patients was initiated in Scandinavia, with authorisation pending in several other European countries. Somatomedin-1 binding protein-3 will be made available to those GHIS patients who, in the opinion of their doctor, may benefit from IGF-1 therapy. At precommercial scale quantities, the drug will be available on a limited basis. Safety data generated from the named patient programme will be used to support marketing applications in 2004.A phase II dose-ranging study in children with GHIS was completed at Saint Bartholomew’s and the Royal London School of Medicine, London, UK. A single dose of somatomedin-1 binding protein-3 delivered the same amount of IGF-1 as two daily injections of unbound IGF-1. There were no adverse events reported.GHIS is a genetic condition in which patients do not produce adequate quantities of IGF because of a failure to respond to the growth hormone signal. This results in a slower growth rate and short stature.Insmed has acquired an exclusive licence to Pharmacia’s regulatory filings concerning yeast-derived IGF-1. These filings were used by Pharmacia to receive marketing approvals in several European countries and also in the investigational New Drug Application with the US FDA. This licence will facilitate the development of SomatoKine®for the treatment of children with GHIS.In January 2003, Insmed announced positive results from a double-blind, placebo-controlled, dose-ranging study of SomatoKine®in adolescent patients with type 1 diabetes mellitus receiving insulin therapy. The study was conducted at the University of Cambridge, Cambridge, UK, under the supervision of Professor D. Dunger.It has also been granted orphan drug status for the treatment of GHIS – Laron syndrome in the US and in Europe.Celtrix has been granted 11 US patents for its recombinant protein production technology, which it used for developing somatomedin-1 binding protein-3. Subsequently, Celtrix was acquired by Insmed Pharmaceuticals on June 1 2000. Following the acquisition, Insmed announced that it intends to maintain the US rights to Celtrix’s products portfolio. These US patents will expire between 2010 through 2017.Insmed is holding a US patent (expires in 2019) for the use of SomatoKine®in the treatment of both type 1 and type 2 diabetes mellitus.

ISSN:1173-8804    

出版商:ADIS    

年代:2003

数据来源: ADIS