Current Opinion in Molecular Therapeutics最新文献

This review describes the advances in malaria antigen discovery and vaccine development using the long synthetic peptide platforms that have been made available during the past 5 years. The most recent technical developments regarding peptide synthesis with the optimized production of large synthetic fragments are discussed. Clinical trials of long synthetic peptides are also reviewed. These trials demonstrated that long synthetic peptides are safe and immunogenic when formulated with various adjuvants. In addition, long synthetic peptides can elicit an antibody response in humans and have demonstrated inhibitory activity against parasite growth in vitro. Finally, new approaches to exploit the abundance of genomic data and the flexibility and speed of peptide synthesis are proposed.

TRU-015, being developed by Trubion Pharmaceuticals Inc and Pfizer Inc, is an intravenously administered anti-CD20 IgG fusion protein for the treatment of rheumatoid arthritis. TRU-015 depletes B-cells from the peripheral blood in vitro, and can mediate complement-and antibody-dependent cellular cytotoxicity. TRU-015 was well tolerated in patients with rheumatoid arthritis in phase I and II clinical trials, and demonstrated an efficacy profile similar to other biological agents approved for rheumatoid arthritis. At the time of publication, phase II trials were ongoing in patients with rheumatoid arthritis. TRU-015 could represent a novel therapy for the treatment of rheumatoid arthritis, although the efficacy, safety profile and advantages of this compound compared with existing therapeutic options would need to be established in phase III trials. In addition, this agent also may be useful to the treatment of B-cell neoplasms and autoimmune diseases.

DNA vaccines are versatile and safe, but limited immunogenicity has prevented their use in the clinical setting. Experimentally, immunogenicity may be enhanced by the use of new delivery technologies, by coadministration of cytokines and pathogen-associated molecular patterns, or by fusion of antigens into molecular domains that enhance antigen presentation. More specifically, the immunogenicity of DNA vaccines may benefit from increased protein synthesis, increased T-cell help and MHC class I presentation, and the addition of a range of specific cytokines and pathogen-associated molecular patterns that increase activation of the innate immune system. Importantly, viral-vectored vaccines that act through the induction of one or more of these factors also may benefit from cytokine coadministration and increased antigen presentation. In order to increase immunogenicity to the level achieved with viral-vectored vaccines, various synergistic components may need to be incorporated into DNA vaccines. From the perspective of the future clinical use of DNA vaccines, it has been suggested that antigen presentation should be improved and cytokine coadministration attempted. However, even with these modifications, it is likely that the primary use of DNA vaccines may be as primers for viral-vectored vaccines, rather than as single agents. This review discusses the approaches used to enhance DNA vaccine immunogenicity, with a primary focus on fusion strategies that enhance antigen presentation.

Although androgen deprivation is the standard of care for advanced prostate cancer, patients with metastatic disease eventually progress to a castration-resistant state. The available options for secondary therapy are hormonal therapy and chemotherapy. Significant potential remains for the development of alternative approaches, which can improve survival with early treatment but do not cause the toxicities associated with chemotherapy. The field of immunotherapy for prostate cancer has recently made significant progress, and data from several clinical trials demonstrating the efficacy of this type of therapy have been reported. These reports include data from randomized controlled trials with sipuleucel-T (Dendreon Corp) and with PROSTVAC-VF-TRICOM (NCI/BN ImmunoTherapeutics Inc), both of which resulted in improvements in overall survival in patients with advanced prostate cancer. Although these results are encouraging, there are many unresolved questions regarding immunotherapy, including the best clinical setting for immunotherapy, the definition of relevant clinical and immunological endpoints, and the potential combination of immunotherapies with other treatments. This review discusses the most promising recent developments in vaccine therapy for prostate cancer, as well as the challenges remaining to be addressed.

Angiogenesis is essential for development and tissue repair, and is controlled by a balance of inhibitors and promoters. Overactive angiogenesis promotes tumor progression and other chronic disorders, including diabetic retinopathy and rheumatoid arthritis. The discovery of angiogenesis inhibitors has resulted in a promising therapeutic approach to these diseases. However, the benefits of anti-angiogenic drugs have been modest, stimulating interest in developing more effective approaches by combining anti-angiogenic therapy with other therapeutics. Oncolytic virotherapies are attractive therapeutics for cancer, but virotherapy alone has had similar problems to anti-angiogenic therapy, with few examples of clinical efficacy. This review summarizes the progress of the emerging field of combinations of anti-angiogenic therapy and virotherapy, and highlights future challenges in experimental and translational research that need to be addressed in order for these therapeutics to advance into the clinic.

Advances in proteomics technologies, in particular the parallel development of highly sensitive mass spectrometers and accurate protein quantitation technologies, have allowed the detection and accurate measurement of low abundance proteins in bodily fluids and tissues. Furthermore, the application of these technologies in biomedical research has led to the identification of proteins and genes with expression patterns that change as a consequence of disease; detection and quantitation of these proteins and genes could provide valuable information for disease diagnosis and prognosis. For example, cell-surface protein expression can change in diseased cells. These proteins may then be secreted or shed from the cell surface; the levels of these proteins in blood or urine could provide valuable information for the diagnosis of disease and disease severity. The focus of this review is the methods by which proteomics-based technologies can be applied to characterize cell-surface proteins and to measure changes to expression levels in diseased states; the review also discusses the soluble counterparts of these surface proteins in the blood; these proteins could be important diagnostic and/or prognostic indicators of disease.

The human genome is characterized by structural variations, in addition to having expansive areas of tandem repeat sequences and SNPs. Copy number variations (CNVs) in the human genome are the result of insertions, deletions, duplications and complex multisite variants, affecting approximately 10 to 12% of the genome and covering a higher number of nucleotides than SNPs. Several methods are used for the detection of CNVs, including approaches based on hybridization, such as arrays, PCR amplification, FRET and sequencing. These methods can identify microscopic structural variations (> or = 3 Mb in size), as well as submicroscopic structural variations (approximately 1 kb to 3 Mb in size). CNVs can affect drug metabolism and disease susceptibility. Therefore, the effect of variations in the copies of genes on the efficacy and toxicity of therapeutic agents needs to be well established at both pharmacokinetic and pharmacodynamic levels prior to the use of these agents clinically. This review evaluates the techniques for detecting the CNVs available at the time of publication, citing examples from the application of CNVs in clinical pharmacogenetics.

Amsterdam Molecular Therapeutics BV is developing alipogene tiparvovec (Glybera, AMT-011, AAV1-LPLS447X), a Ser(447)X variant of the human lipoprotein lipase (LPL) gene (LPLSer(447)X) in an adeno-associated virus vector, as a potential intramuscular gene therapy for the treatment of LPL deficiency. Familial LPL deficiency is a rare, autosomal-recessive disorder of lipoprotein metabolism that is characterized by severe hypertriglyceridemia with episodes of abdominal pain, acute pancreatitis and eruptive cutaneous xanthomatosis. The lack of functional LPL in patients with LPL deficiency causes an accumulation of triglyceride (TG)-rich lipoproteins in the plasma. The LPLSer(447)X variant is associated with decreased levels of plasma TGs and increased HDL cholesterol concentrations compared with wild-type LPL. Preclinical studies evaluating alipogene tiparvovec in a mouse model of LPL deficiency demonstrated a long-term, dose-dependent correction of the lipid abnormalities. The first clinical trials in patients with LPL deficiency appear promising, with a significant decrease in the levels of plasma TGs observed in the first 3 months following the administration of alipogene tiparvovec, and an increase in local LPL activity and protein levels observed after 6 months. In addition, a decrease in pancreatitis frequency was observed during a 3-year follow-up period. At the time of publication, a phase II/III trial in patients with LPL deficiency, being conducted to further support the submission of an MAA to the EMEA for alipogene tiparvovec, was ongoing. The compound is also under investigation for the treatment of type V hyperlipoproteinemia, Syndrome X and non-alcoholic steatohepatitis.

Targeted mAbs to VEGFR and EGFR are well-established therapies for the treatment of colorectal cancer. The costs and toxicities associated with these novel treatments are not insignificant, and therefore molecular markers that predict treatment efficacy are needed to individualize the therapy administered to each patient. Recent data in this research field support KRAS mutation testing to guide the selection of EGFR inhibitors for the treatment of colorectal cancer. This review discusses the evidence that KRAS mutation analysis can indicate a beneficial response to EGFR inhibitors, and the potential and limitations of other mutations in the VEGF and EGF signaling pathways as predictive molecular markers in this setting.

RNAi is the process of sequence-specific, post-transcriptional/transcriptional gene silencing through siRNA. RNAi is a popular method of controlling gene expression and has potential in the development of drugs for several diseases, such as various types of cancer and viral infections. Gene therapy for asthma has already been developed and has demonstrated promising results in animal models. Recent progress in delivering siRNA to the respiratory system has also improved the therapeutic feasibility of RNAi for asthma. In this review, the mechanism, as well as the general strategies and problems associated with the application of RNAi in vivo, are discussed, focusing on the possibility of applying RNAi to alleviate airway inflammation in allergic asthma. Data from studies with siRNA against molecules involved in allergic responses are summarized, and the potential and limitations of RNAi as a novel therapeutic approach are discussed.