Showing papers in "BioDrugs in 2008"
TL;DR: The chemical procedures and the conditions that have been used thus far to achieve PEGylation of biomedical molecules are reviewed and the importance of structure and size of P EGs, as well as the behavior of linear and branched PEGs are discussed.
Abstract: The term PEGylation describes the modification of biological molecules by covalent conjugation with polyethylene glycol (PEG), a non-toxic, non-immunogenic polymer, and is used as a strategy to overcome disadvantages associated with some biopharmaceuticals. PEGylation changes the physical and chemical properties of the biomedical molecule, such as its conformation, electrostatic binding, and hydrophobicity, and results in an improvement in the pharmacokinetic behavior of the drug. In general, PEGylation improves drug solubility and decreases immunogenicity. PEGylation also increases drug stability and the retention time of the conjugates in blood, and reduces proteolysis and renal excretion, thereby allowing a reduced dosing frequency. In order to benefit from these favorable pharmacokinetic consequences, a variety of therapeutic proteins, peptides, and antibody fragments, as well as small molecule drugs, have been PEGylated.
843 citations
TL;DR: Current options being explored include the development of humanized monoclonal antibodies to NGF or its tyrosine kinase receptor TrkA, and the sequestration of NGF using TrkAd5, a soluble receptor protein that binds NGF with picomolar affinity.
Abstract: Chronic pain presents a huge economic and social burden, with existing treatments largely unable to satisfy medical needs. Recently, studies have shown that nerve growth factor (NGF) is a major mediator of inflammatory and neuropathic pain, providing a new therapeutic target. Although originally discovered as a trophic factor for sympathetic and sensory neurons during development, it now appears that in adults, levels of NGF are elevated in many acute and chronic pain conditions. Furthermore, preclinical animal models of inflammatory and neuropathic pain also show increased NGF levels, while the sequestration of NGF alleviates the associated hyperalgesia. The molecular mechanisms involved are being elucidated. This review briefly examines pain signaling pathways and describes currently available analgesics. It then investigates the approaches taken in targeting NGF-mediated pain. Current options being explored include the development of humanized monoclonal antibodies to NGF or its tyrosine kinase receptor TrkA (also known as neurotrophic tyrosine kinase receptor, type 1 [NTRK1]), and the sequestration of NGF using TrkA domain 5 (TrkAd5), a soluble receptor protein that binds NGF with picomolar affinity. Administration of either antibodies or TrkAd5 has been shown to be effective in a number of preclinical models of pain, including cystitis, osteoarthritis, UV irradiation (sunburn), and skeletal bone pain due to fracture or cancer. Other possible future therapies examined in this review include small-molecule TrkA antagonists, which target either the extracellular NGF binding domain of TrkA or its intracellular tyrosine kinase domain.
170 citations
TL;DR: The specifics of FGF21 activities both in cell culture and in vivo, its potential as a target for diabetes, and insights into the molecular mechanisms of F GF21 metabolic actions will be discussed in this review.
Abstract: Fibroblast growth factor (FGF)-21 is a unique member of the FGF family, with several molecular characteristics that differ from classical FGFs and exhibiting a pharmacologic profile that includes a variety of metabolic responses in vitro and when tested in vivo in animal models. FGF21 represents a novel and attractive therapeutic agent for type 2 diabetes mellitus, because of its ability to modulate disease phenotype in preclinical settings without inducing any apparent adverse effects. Although FGF21 was discovered relatively recently, the understanding of its biology and therapeutic utility is rapidly evolving. A number of key metabolically linked molecules and pathways have been suggested to be involved in the mechanism of action of FGF21, depending on the specific target tissue/organ. Further research into these mechanisms should lead to important advances in the understanding of FGF21 biology and pave the way for novel therapeutic strategies. The specifics of FGF21 activities both in cell culture and in vivo, its potential as a target for diabetes, and insights into the molecular mechanisms of FGF21 metabolic actions will be discussed in this review.
120 citations
TL;DR: This article provides an overview of the design and construction of Fc-based cytokines, in both dimeric and monomeric forms and a novel approach to improve stability in serum, called AbDeg.
Abstract: The application of Fc (fragment crystallizable)-based cytokines (the fusion of the constant region of IgG to a cytokine of interest) as biotherapeutic agents to modulate inflammatory and immune responses has become increasingly popular in recent years. This is because in their monomeric form, cytokines are relatively small molecules with short serum half-lives, which necessitates frequent administration and thus limits their clinical utility. To rectify the problem, attempts have been made to improve the stability of these agents in vivo. This has been achieved through diverse strategies such as modification with polyethylene glycol (PEGylation) or by ligating the cytokine to protein moieties such as the constant heavy chain of IgG, known as the Fc fragment. The construction of Fc chimeric proteins has been shown to improve pharmacokinetics. However, since there is an inverse relationship between the size of molecules and the rate at which they diffuse through mucus, Fc fusion constructs potentially have a lower rate of diffusion. Consequently, a compromise is reached whereby Fc constructs are engineered to incorporate ligated cytokines in a monomeric form (one molecule of cytokine fused to a single Fc dimer) rather than in a dimeric form (two molecules of cytokine fused to a single Fc dimer). A recent and novel approach to improve stability in serum is a procedure that involves sheathing cytokines in protective protein covers called latency peptides. The enclosed cytokine is protected from degradation and allowed to act where needed when the outer peptide cover is removed. For some applications, a reduced serum half-life is desirable; for example, where there is a need to reduce IgG levels in antibody-mediated diseases. To achieve this goal, a strategy called AbDeg, which involves enhanced Ig degradation, has been devised. This article provides an overview of the design and construction of Fc-based cytokines, in both dimeric and monomeric forms. Several examples of recent applications of such constructs, which include cytokine antagonism, cytokine traps, gene therapy and drug delivery, are also discussed. Other antibody-engineered constructs such as Fab (fragment, antigen binding) and single chain Fv (fragment, variable) fusions are also briefly covered.
107 citations
TL;DR: The development of ranpirnase as a cancer chemotherapeutic agent is described, which involves binding to anionic components of the extracellular membrane, cytosolic internalization, and degradation of transfer RNA leading to apoptosis.
Abstract: Ranpirnase, a cytotoxic ribonuclease from the frog Rana pipiens, is the archetype of a novel class of cancer chemotherapeutic agents based on homologs and variants of bovine pancreatic ribonuclease (RNase A). Ranpirnase in combination with doxorubicin is in clinical trials for the treatment of unresectable malignant mesothelioma and other cancers. The putative mechanism for ranpirnase-mediated cytotoxicity involves binding to anionic components of the extracellular membrane, cytosolic internalization, and degradation of transfer RNA leading to apoptosis. The maintenance of ribonucleolytic activity in the presence of the cytosolic ribonuclease inhibitor protein is a key aspect of the cytotoxic activity of ranpirnase. The basis for its specific toxicity for cancer cells is not known. This review describes the development of ranpirnase as a cancer chemotherapeutic agent.
92 citations
TL;DR: The property identified that reflected the efficacies of the anti-TNFα agents etanercept, adalimumab, certolizumab pegol, and infliximab in CD was the ability to inhibit the cytokine production by monocytes that is induced by bacterial lipopolysaccharide, suggesting that this mode of action is important for efficacy in CD.
Abstract: Antibodies, having a high specificity for their particular target, are increasingly being used as therapeutic agents with functions including agonist, antagonist, and targeted drug delivery. The use of many biologic therapies, including antibody fragments, is generally limited by their rapid clearance from plasma. A commonly used approach to extend exposure to biologic therapies is the attachment of polyethylene glycol.Tumor necrosis factor (TNF)-alpha is a multifunctional cytokine involved in the regulation of immune responses. Elevated levels of TNFalpha are found in a wide range of diseases, including the chronic inflammatory conditions rheumatoid arthritis, psoriasis, and Crohn disease (CD). Anti-TNFalpha antibodies have proved highly efficacious in the treatment of these conditions. In addition, they have proved invaluable for investigating the role of TNFalpha in disease etiology. Based on evidence showing that neutralizing antibodies to TNFalpha were effective in animal models of CD, anti-TNFalpha antibody treatments were assessed in clinical trials. Interestingly, the anti-TNFalpha antibody etanercept proved ineffective at achieving remission in active CD despite potently neutralizing soluble TNFalpha. This indicated that an additional mode of action is also involved in the efficacy of the anti-TNFalpha agents adalimumab, certolizumab pegol, and infliximab in CD; one suggestion was apoptosis. However, etanercept, like adalimumab and infliximab, can induce apoptosis. Furthermore, certolizumab pegol (which has demonstrated efficacy in CD) does not cause complement-dependent cytotoxicity, antibody-dependent cell-mediated cytotoxicity, apoptosis, or necrosis of neutrophils, all measured in vitro. These functional differences observed with certolizumab pegol stem from its unique structure that does not include the crystallizable fragment (Fc) portion present in the other anti-TNFalpha agents, and the way in which it signals through membrane TNF. It is well established that bacteria are a major part of the inflammatory process in CD. The property identified that reflected the efficacies of the anti-TNFalpha agents etanercept, adalimumab, certolizumab pegol, and infliximab in CD was the ability to inhibit the cytokine production by monocytes that is induced by bacterial lipopolysaccharide. It may therefore be the case that this mode of action is important for efficacy in CD.
74 citations
TL;DR: It is speculated that calcitonin treatment will lead to a continuously positive bone balance in contrast with other antiresorptive agents currently on the market and thereby, in a physiologic manner, result in improved bone quality.
Abstract: Postmenopausal osteoporosis results from a continuous imbalance between bone resorption and bone formation, favoring bone resorption. An increasing number of treatments for osteoporosis are in development and on the market. A range of differences and similarities are found between these treatment options, and these need to be carefully evaluated before the initiation of treatment. This article summarizes data from in vitro and animal studies, as well as clinical trials, on the effect of calcitonin on bone turnover. Calcitonin was found to exert its antiresorptive effects via directly reducing osteoclastic resorption, and thus leads to an increase in bone mineral density and bone strength. Furthermore, calcitonin appears to mainly target the most active osteoclasts, and in contrast to most other antiresorptive agents it does not reduce the number of osteoclasts. Finally, in humans, while attenuating resorption, calcitonin treatment does not interfere markedly with bone formation, in contrast to other currently available antiresorptive agents. Thus, we speculate that calcitonin treatment will lead to a continuously positive bone balance in contrast with other antiresorptive agents currently on the market and thereby, in a physiologic manner, result in improved bone quality. Calcitonin is currently only available in injectable and nasal formulations. An oral formulation may, however, improve patient acceptance and compliance. Currently, several different routes are being pursued to identify an optimal oral formulation, of which the technology based on 5-CNAC is the most advanced. There are promising clinical data available for this formulation from both osteoarthritis and osteoporosis clinical trials, although the antifracture efficacy is not yet known.
72 citations
TL;DR: The mechanisms for insulin and particle uptake and translocation through the gastrointestinal tract, and the potential barriers to this are reviewed, the design of nanoparticulate carriers for the oral delivery of insulin is outlined, and prospects for its clinical application are presented.
Abstract: The design of strategies that improve the absorption of insulin through the gastrointestinal tract is a considerable challenge in the pharmaceutical sciences and would significantly enhance the treatment of diabetes mellitus. Several strategies have been devised to overcome physiologic and morphologic barriers to insulin absorption, including the inhibition of acidic and enzymatic degradation, enhancement of membrane permeability or widening of tight junctions, chemical modification of insulin, and the formulation of carrier systems. In particular, the concept of nanoparticulate carriers for oral insulin delivery has evolved through remarkable advances in nanotechnology. Investigations focused on uptake and translocation via Peyer’s patches have demonstrated high levels of nanoparticle absorption based on significant alterations in the glycemic response to various glucogenic sources. This paper reviews the mechanisms for insulin and particle uptake and translocation through the gastrointestinal tract, and the potential barriers to this, outlines the design of nanoparticulate carriers for the oral delivery of insulin, and presents prospects for its clinical application.
69 citations
TL;DR: The AS03-H5N1 vaccine as discussed by the authors is a split virion, inactivated vaccine containing H5 hemagglutinin antigen adjuvanted with a 10% oil-in-water emulsion-based adjuvant system (AS03).
Abstract: Although rare, influenza pandemics are a recurrent event, and influenza A/H5N1 is generally considered to be the most likely causative agent of the next pandemic. Vaccines are widely considered to be the first line of defense for protecting populations in advance of an influenza pandemic. Because it is not known beforehand which strain of influenza A/H5N1 virus could give rise to a pandemic, prepandemic vaccines that impart broad cross-reactive immunogenicity are required. In addition, low doses of H5 hemagglutinin are preferable in order to make antigen supplies go further towards meeting global demands for prepandemic vaccines.Prepandemic influenza vaccine H5N1 [Prepandrix(trade mark); AS03-H5N1 vaccine] is a split virion, inactivated vaccine containing H5 hemagglutinin antigen adjuvanted with a novel 10% oil-in-water emulsion-based adjuvant system (AS03). It is approved in the EU for use as an active immunization against H5N1 subtype influenza A virus (influenza A/H5N1 virus) in adults aged 18-60 years. The recommended dosage in this population is two doses of 0.5 mL containing 3.75 microg of H5 hemagglutinin, administered > or =21 days apart. Adjuvantation of H5N1 vaccine with AS03 allows for a reduction in the H5 hemagglutinin dose required to elicit an adequate immune response, and administration of two doses of the adjuvanted vaccine met all criteria for the licensure of influenza vaccines set out in European Committee for Proprietary Medicinal Products (CPMP) and US FDA documents. In two clinical trials, two doses of AS03-H5N1 vaccine containing 3.75 microg of H5 hemagglutinin induced an immune response in healthy volunteers aged 18-60 years against the homologous, clade 1 vaccine strain, A/Vietnam/1194/2004, and the heterologous, drifted, clade 2 nonvaccine strains, A/Anhui/1/2005, A/Indonesia/5/2005, and A/turkey/Turkey/1/2005. This cross-clade response persisted for > or =6 months following administration of the first vaccine dose in the majority of vaccine recipients. In addition, AS03-H5N1 vaccine protected against lethal challenge with A/Vietnam/1194/2004 or A/Indonesia/5/2005 in animal studies. The vaccine was generally well tolerated and adverse events were transient and predominantly of mild to moderate severity.AS03-H5N1 vaccine has demonstrated antigen dose-sparing properties and cross-clade reactive immunity in clinical trials and challenge studies in animal models. As a result, stockpiling AS03-H5N1 vaccine has the potential to protect populations against a pandemic caused by an influenza A/H5N1 virus and may represent an important measure in pandemic preparedness.
67 citations
TL;DR: An overview of roles played by selectins and integrins in lung inflammation is provided and recent clinical results (both failures and successes) in developing adhesion molecule antagonists are described, with specific emphasis on those targets that may have potential benefit in asthma and COPD.
Abstract: Chronic obstructive pulmonary disease (COPD) and asthma are inflammatory diseases of the lung where a hallmark feature is excessive leukocyte infiltration that leads to tissue injury. Cell adhesion molecules (e.g. selectins and integrins) play a key role in cell trafficking, and in the lung they regulate leukocyte extravasation, migration within the interstitium, cellular activation, and tissue retention. All selectin family members (including L-selectin, P-selectin, and E-selectin) and many of the β1 and β2 integrins appear to be important therapeutic targets, as numerous animal studies have demonstrated essential roles for these cell adhesion molecules in lung inflammation. Not surprisingly, these families of adhesion molecules have been under intense investigation by the pharmaceutical industry for the development of novel therapeutics. Integrins are validated drug targets, as drugs that antagonize integrin αIIbβ3 (e.g. abciximab), integrin αLβ2 (efalizumab), and integrin α4β1 (natalizumab) are currently US FDA-approved for acute coronary syndromes, psoriasis, and multiple sclerosis, respectively. However, none has been approved for indications related to asthma or COPD. Here, we provide an overview of roles played by selectins and integrins in lung inflammation. We also describe recent clinical results (both failures and successes) in developing adhesion molecule antagonists, with specific emphasis on those targets that may have potential benefit in asthma and COPD. Early clinical trials using selectin and integrin antagonists have met with limited success. However, recent positive phase II clinical trials with a small-molecule selectin antagonist (bimosiamose) and a small-molecule integrin α4β1 antagonist (valategrast [R411]), have generated enthusiastic anticipation that novel strategies to treat asthma and COPD may be forthcoming.
62 citations
TL;DR: Promising results from novel approaches based on the combination of systematically selected antigens have been reported, and combinatory vaccines target microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), a family of bacterial proteins that bind to human extracellular matrix components.
Abstract: Staphylococcal infections represent an enormous burden to the public health system in the US and worldwide. While traditionally restricted to the hospital setting, highly virulent strains have recently emerged that may cause severe, even fatal, disease in healthy adults outside healthcare settings. This situation, together with the increasing resistance to many antibacterials in a wide variety of staphylococcal strains, requires that vaccine development for staphylococcal diseases be re-evaluated. Finding a vaccine for staphylococci is not trivial, as protective immunity to staphylococcal infections does not appear to exist at a significant degree, which may be partly due to the fact that our immune system is in constant contact with staphylococcal antigens and many strains are commensal organisms on human epithelia. Furthermore, the most virulent species, Staphylococcus aureus, produces protein A, a powerful means to evade acquired host defense. While two high-profile vaccine preparations have failed clinical trials within the last few years, promising results from novel approaches based on the combination of systematically selected antigens have been reported. These combinatory vaccines target microbial surface components recognizing adhesive matrix molecules (MSCRAMMs), a family of bacterial proteins that bind to human extracellular matrix components. In addition, polysaccharide and other nonprotein antigens may represent suitable vaccine targets on the staphylococcal cell surface.
TL;DR: The present review focuses on the structural and functional characteristics of mAbs and their fragments, and also provides a walk through the most important methods used in antibody selection.
Abstract: Hybridoma fusion technology, proposed by Kohler and Milstein in 1975, started major developments in the field of monoclonal antibodies (mAbs). During the following 2 decades, their high potential as laboratory tools was rapidly exploited for biotechnology and biomedical applications. Today, mAbs represent over 30% of all biological proteins undergoing clinical trials and are the second largest class of biodrugs after vaccines. With the help of antibody engineering, mAbs have been reduced in size, rebuilt into multivalent molecules, and conjugated with drugs, toxins, or radioisotopes for the treatment of cancer, autoimmune disorders, graft rejection, and infectious diseases. Additionally, in the past few years, important advances have been made in the design, selection, and production of these new types of engineered antibodies. The present review focuses on the structural and functional characteristics of mAbs and their fragments, and also provides a walk through the most important methods used in antibody selection. In addition, the recent trends in antibody engineering for improving antibody clinical efficacy are also reviewed.
TL;DR: In a case series of approximately 400 SLE patients with refractory disease, with or without concomitant use of cyclophosphamide Epratuzumab, a humanized anti-CD22 monoclonal antibody that partially deplets B cells, has also been shown to reduce disease activity but not to decrease autoantibody levels in patients with moderately active SLE as discussed by the authors.
Abstract: Systemic lupus erythematosus (SLE) is a classic autoimmune disease characterized by a myriad of immune system aberrations, most likely resulting from pathogenic autoantibody production, immune complex deposition, and subsequent end-organ damage B cells play a key role in the pathogenesis; therefore, B-cell-targeted therapies, including B-cell depletion and blockage of B-cell survival factors such as B-lymphocyte stimulator (BLyS), are potential therapeutic targets for SLE In uncontrolled clinical trials from approximately 20 studies, rituximab--a mouse-human chimeric anti-CD20 monoclonal antibody that effectively depletes B cells--has been demonstrated to reduce disease activity and decrease serum autoantibodies, with a clinical response of 86% in a case series of approximately 400 SLE patients with refractory disease, with or without concomitant use of cyclophosphamide Epratuzumab, a humanized anti-CD22 monoclonal antibody that partially depletes B cells, has also been shown to reduce disease activity but not to decrease autoantibody levels in patients with moderately active SLE Randomized controlled phase I/II trials in patients with active SLE have documented that belimumab, a humanized anti-BLyS monoclonal antibody, reduces B-cell numbers, inhibits disease activity and decreases anti-double-stranded DNA autoantibody in SLE patients All these therapies are well tolerated, but accompanying infectious complications have been observed Other B-cell-targeted therapies such as 'humanized' monoclonal antibodies to CD20 (eg ocrelizumab) and agents that interrupt B-cell/T-cell interactions also have potential, and the efficacy of these, along with rituximab, belimumab and epratuzumab, needs to be determined by randomized controlled trials
TL;DR: Based on phase III results, a once-daily dasatinib regimen is considered optimal in chronic phase CML, while a twice-daily regimen continues to be recommended in accelerated phase, myeloid blast phase or lymphoid blastphase CML and Ph-positive ALL.
Abstract: Dasatinib is a small-molecule inhibitor of multiple tyrosine kinases, including BCR-ABL, SRC, c-KIT, ephrin A receptor and platelet-derived growth factor-beta receptor kinases, at nanomolar concentrations. In vitro, dasatinib is 325-fold more potent than imatinib against cells expressing wild-type BCR-ABL. The efficacy and tolerability of oral dasatinib has been established in the START phase II trials in adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who were intolerant or resistant to imatinib, and optimal dasatinib dosage regimens were identified in phase III randomized trials. In patients with chronic phase CML, the major cytogenetic response rate in the START-C trial (median follow-up 15.2 months) was 59% with dasatinib, and in the randomized START-R trial (median follow-up 15 months), was greater with dasatinib than with high-dose imatinib (52% vs 33%). Major hematologic response rates with dasatinib were 63% in patients with accelerated phase CML (follow-up > or =9 months; START-A trial), 34% in patients with myeloid blast phase CML and 35% in those with lymphoid blast phase CML (follow-up > or =12 months; START-B and START-L trials), and 41% in patients with Ph-positive ALL (follow-up > or =12 months; START-L trial). Based on phase III results, a once-daily dasatinib regimen is considered optimal in chronic phase CML (starting dosage 100 mg once daily), while a twice-daily regimen continues to be recommended in accelerated phase, myeloid blast phase or lymphoid blast phase CML and Ph-positive ALL (starting dosage 70 mg twice daily). Adverse events were frequent in patients treated with dasatinib, but most were mild to moderate in severity. Grade 3/4 adverse events were uncommon and were clinically manageable.
TL;DR: Pramlintide treatment is associated with improvements in markers of oxidative stress and cardiovascular risk and improved patient-reported treatment satisfaction, which make pramlintide an attractive option for the treatment of postprandial hyperglycemia in patients with diabetes using mealtime insulin.
Abstract: Pramlintide, the first member of a new class of drugs for the treatment of insulin-using patients with type 2 or type 1 diabetes mellitus, is an analog of the peptide hormone amylin. Amylin is co-secreted with insulin from pancreatic β cells and acts centrally to slow gastric emptying, suppress postprandial glucagon secretion, and decrease food intake. These actions complement those of insulin to regulate blood glucose concentrations. Amylin is relatively deficient in patients with type 2 diabetes, depending on the severity of β-cell secretory failure, and is essentially absent in patients with type 1 diabetes. Through mechanisms similar to those of amylin, pramlintide improves overall glycemic control, reduces postprandial glucose levels, and reduces bodyweight in patients with diabetes using mealtime insulin. Reductions in postprandial glucose and bodyweight are important, since postprandial hyperglycemia is associated with an increased risk of microvascular and macrovascular complications, and increased weight is an independent risk factor for cardiovascular disease. Pramlintide is generally well tolerated, with the most frequent treatment-emergent adverse event being mild to moderate nausea, which decreases over time. Pramlintide treatment is also associated with improvements in markers of oxidative stress and cardiovascular risk and improved patient-reported treatment satisfaction. These factors make pramlintide an attractive option for the treatment of postprandial hyperglycemia in patients with diabetes using mealtime insulin.
TL;DR: The HPV 16/18 vaccine was generally well tolerated and injection-site reactions were the most common vaccine-related adverse events reported.
Abstract: ▴ Cervarix™ is a prophylactic vaccine comprised of a mixture of virus-like particles derived from the L1 capsid proteins of human papillomavirus (HPV) types 16 and 18 formulated with the AS04 adjuvant system. It is administered by intramuscular injection as a three-dose vaccine regimen at 0, 1 and 6 months. The vaccine is indicated for the prevention of high-grade cervical intraepithelial neoplasia (CIN 2 and CIN 3) and cervical cancer causally related to HPV types 16 and 18.
▴ In randomized, double-blind, phase II or III trials in >19 000 women aged 15–25 years, the HPV 16/18 vaccine showed high efficacy in preventing CIN 2+ associated with HPV 16/18. Cross-protection against new incident or 6-month persistent HPV 45 or HPV 31 infection was also evident. Phase II follow-up was for at least 5.5 years, and the phase III interim analysis was at ≈15 months after the first vaccine dose.
▴ In a bridging study, in adolescent girls aged 10–14 years, the HPV 16/18 vaccine induced twice the already high antibody titres as it did in young women (aged 15–25 years). The immune response in older women (aged 26–55 years) at 24 months in another study was ≥8-fold higher than antibody levels reported in younger age groups. Anti-HPV 16/18 antibody responses were greater with an AS04-adjuvanted HPV 16/18 vaccine than with an aluminium salt-adjuvanted formulation.
▴ The HPV 16/18 vaccine was generally well tolerated and injection-site reactions were the most common vaccine-related adverse events reported.
TL;DR: The initial success in the application of ES cells to partially repair and improve myocardial function in experimental models of heart disease has been quite promising, however, multiple hurdles need to be crossed before the potential benefits ofES cells can be translated to the clinic.
Abstract: Cardiovascular diseases remain the leading cause of death worldwide, and the burden is equally shared between men and women around the globe. Cardiomyocytes that die in response to disease processes or aging are replaced by scar tissue instead of new muscle cells. Although recent reports suggest an intrinsic capacity for the mammalian myocardium to regenerate via endogenous stem/progenitor cells, the magnitude of such a response appears to be minimal and has yet to be realized fully in cardiovascular patients. Despite the advances in pharmacotherapy and new biomedical technologies, the prognosis for patients diagnosed with end-stage heart failure appears to be grave. While heart transplantation is a viable option, this life-saving intervention suffers from an acute shortage of cardiac organ donors. In view of these existing issues, donor cell transplantation is emerging as a promising strategy to regenerate diseased myocardium. Studies from multiple laboratories have shown that transplantation of donor cells (e.g. fetal cardiomyocytes, skeletal myoblasts, smooth muscle cells, and adult stem cells) can improve the function of diseased hearts over a short period of time (1-4 weeks). While long-term follow-up studies are warranted, it is generally perceived that the beneficial effects of transplanted cells are mainly due to increased angiogenesis or favorable scar remodeling in the engrafted myocardium. Although skeletal myoblasts and bone marrow stem cells hold the highest potential for implementation of autologous therapies, initial results from phase I trials are not promising. In contrast, transplantation of fetal cardiomyocytes has been shown to confer protection against the induction of ventricular tachycardia in experimental myocardial injury models. Furthermore, results from multiple laboratories suggest that fetal cardiomyocytes can couple functionally with host myocytes, stimulate formation of new blood vessels, and improve myocardial function. While it is neither practical nor ethical to test the potential of fetal cardiomyocytes in clinical trials, embryonic stem (ES) cells serve as a novel source for generation of unlimited quantities of cardiomyocytes for myocardial repair. The initial success in the application of ES cells to partially repair and improve myocardial function in experimental models of heart disease has been quite promising. However, multiple hurdles need to be crossed before the potential benefits of ES cells can be translated to the clinic. In this review, we summarize the current knowledge of cardiomyocyte derivation and enrichment from ES-cell cultures and provide a brief survey of factors increasing cardiomyogenic induction in both mouse and human ES cultures. Subsequently, we summarize the current state of research using mouse and human ES cells for the treatment of heart disease in various experimental models. Furthermore, we discuss the challenges that need to be overcome prior to the successful clinical utilization of ES-derived cardiomyocytes for the treatment of end-stage heart disease. While we are optimistic that the researchers in this field will sail across the hurdles, we also suggest that a more cautious approach to the validation of ES cardiomyocytes in experimental models would certainly prevent future disappointments, as seen with skeletal myoblast studies.
TL;DR: Investigation into adjunctive cytokine therapies for myocardial and peripheral muscle ischemia is warranted based on experimental evidence, and appropriate angiogenic cytokine therapy should provide benefits in both perfusion and hemodynamic function.
Abstract: Coronary artery and peripheral vascular disease are global health concerns with limited therapies. Currently available medical and surgical therapies for these disease processes are highly effective for only a fraction of patients. Extensive effort has been devoted to finding molecular therapies to enhance perfusion and function of ischemic myocardial and peripheral skeletal muscle. Angiogenic cytokines (fibroblast growth factor [FGF], vascular endothelial growth factor [VEGF], hepatocyte growth factor [HGF], placental growth factor, stromal cell-derived factor-1alpha) have shown theoretical and experimental promise in upregulating endogenous endothelial progenitor cell-mediated angiogenesis. Preliminary clinical trials have suggested improvements in myocardial and peripheral perfusion following therapy with FGF, VEGF, and HGF. Further studies on the efficacy of cytokine-mediated angiogenesis are required before widespread clinical application is possible. Investigation into adjunctive cytokine therapies for myocardial and peripheral muscle ischemia is warranted. Based on experimental evidence, appropriate angiogenic cytokine therapy should provide benefits in both perfusion and hemodynamic function.
TL;DR: Nanotechnology has also significantly impacted diagnostic intervention in cardiology, with the use of nanoparticles as contrast agents, for targeted biomedical imaging of vulnerable plaques, for detection of specific pathologic targets signaling the onset of atherosclerosis, and for tracking inflammatory events.
Abstract: Advances in the emergence of biological probes, materials, and analytical tools limited to the nanoscale size range, collectively referred to as 'nanotechnology', are increasingly being applied to the understanding and treatment of the major pathophysiological problems in cardiovascular medicine. Analytical techniques based on high-resolution microscopy and molecular-level fluorescence excitation processes capable of detecting nanoscale interactions have been used to elucidate cardiovascular pathology. Nanotechnology has also significantly impacted diagnostic intervention in cardiology, with the use of nanoparticles as contrast agents, for targeted biomedical imaging of vulnerable plaques, for detection of specific pathologic targets signaling the onset of atherosclerosis, and for tracking inflammatory events. Real-time nanoscale biosensors can be used to measure cardiovascular biomarkers, and nanopore sequencing has the potential to speed up the analysis of gene expression in cardiovascular disease. Potential therapeutic applications include the use of nanomaterials in cardiovascular devices, for delivery of drugs and bioactive molecules, or in novel technologies for reducing cholesterol accumulation and for dissolving clots.
TL;DR: Since wild-type mice were found to develop sufficient T-cell responses to codon regions 145–160 and 210–220, it is believed that there is a theoretical chance of a successful vaccination therapy, and the influence of the way the immunogen is presented has already been shown to be of major importance for the ensuing immune response.
Abstract: Prion diseases are transmissible neurodegenerative diseases of humans and animals. The prion agent consists of a misfolded protein, PrPSc (prion protein, scrapie form), of a glycosylphosphatidylinositol-anchored host protein, PrPC (PrP cellular form) of unknown function. During prion replication, PrPSc induces host PrPC to adopt its pathogenic conformation. Some PrPSc may aggregate to microscopically visible, extracellular prion plaques that stain for amyloid. The development of antiprion vaccines presents some challenges. While there is strong self-tolerance to an endogenous antibody response to PrPC and PrPSc, highly potent monoclonal antibodies (mAbs) have been raised in mice in which the prion protein gene has been deleted by gene targeting. These mAbs have been demonstrated to be antiprion-active in permanently scrapie-infected neuroblastoma (ScN2a) cells, primarily when bound to one of four epitopes (the octarepeat region, the region around codons 90-110, helix 1 region codons 145-160, and the extreme C-terminal codons 210-220). The mAbs directed against codon regions 90-110 or 145-160 are also antiprion-active in vivo, but only after intraperitoneal infection with prions, not intracerebral infection, suggesting their blood-brain barrier (BBB) impermeability. The challenge will be to make antibodies, or recombinant derivatives thereof, BBB permeable; this is preferably achieved by monovalent antibody fragments since divalent ones were found to be neurotoxic. Self-tolerance of wild-type animals to PrP immunizations was found to be of extrathymic origin. Even though antibodies raised in wild-type mice were found to display antiprion activity in ScN2a cells, these mice did not have significant extensions of incubation times when challenged intraperitoneally with prions. A general low affinity of these antibody responses to native surface-bound PrPC may account for this. Since wild-type mice were found to develop sufficient T-cell responses to codon regions 145-160 and 210-220, we believe that there is a theoretical chance of a successful vaccination therapy. The influence of the way the immunogen is presented has already been shown to be of major importance for the ensuing immune response, in that presentation of PrP with CpG oligodeoxynucleotides as adjuvant or viral packaging improved antibody responses. Major progress for active immunizations may therefore be expected in this field. Eradication programs will be one of the most important uses of active immunization protocols. For this purpose, vaccines will have to be inexpensive, easy to handle, and effective. In the short term, passive immunizations will likely be most promising for therapy of prion disease, including for human medical interventions. Active immunization protocols are less likely to succeed quickly, and will take years if not decades to be validated for domestic or free-ranging animals.
TL;DR: Besides the precise definition of the disease status of patients with prostate cancer, combinations of vaccine therapy with radiotherapy, chemotherapy, and/or hormonal therapy are approaches that look promising and deserve further investigation.
Abstract: Standard systemic treatment of prostate cancer today is comprised of antihormonal and cytostatic agents. Vaccine therapy of prostate cancer is principally attractive because of the presence of tumor-associated antigens such as prostate-specific antigen (PSA), prostatic acid phosphatase (PAP), prostate-specific membrane antigen (PSMA), and others. Most prostate cancer vaccine trials have demonstrated some activation of the immune system, limited clinical success, and few adverse effects.One strategy to overcome the problem of limited clinical success of vaccine therapies in prostate cancer could be strict patient selection. The clinical course of patients with prostate cancer (even in those with PSA relapse following surgery or radiotherapy with curative intention, or those with metastatic disease) can vary significantly. In patients with organ-confined prostate cancer, the most promising immunotherapeutic approach would be an adjuvant therapy following surgery or radiotherapy. Patients with PSA relapse following surgery or radiotherapy could also benefit from immunotherapy because tumor burden is usually low. However, most patients in prostate cancer vaccine trials had metastatic hormone-refractory prostate cancer (HRPC). High tumor burden correlates with immune escape phenomena. Nevertheless, 2 years ago, it was demonstrated, for the first time, that a tumor vaccine can prolong survival compared with placebo in patients with HRPC. This was demonstrated with the vaccine sipuleucel-T (APC-8015; Provenge), a mixture of cells obtained from the patient's peripheral blood by leukapheresis followed by density centrifugation and exposition. The Biologics License Application for this vaccine was denied by the US FDA in mid 2007, however, because the trial had failed to reach the primary endpoint (prolongation of time to tumor progression). Nevertheless, clinical trials with sipuleucel-T are ongoing, and the approach still looks promising. Another interesting approach is a vaccine made from whole tumor cells: GVAX. This vaccine is presently being studied in phase III trials against, and in combination with, docetaxel. The results from these trials will become available in the near future. Besides the precise definition of the disease status of patients with prostate cancer, combinations of vaccine therapy with radiotherapy, chemotherapy, and/or hormonal therapy are approaches that look promising and deserve further investigation.
TL;DR: Data from extensive worldwide experience with the refrigerator-stable version of the Varilrix vaccine is reviewed, including information derived from its use in over 10 000 individuals participating in clinical trials investigating its immunogenicity, efficacy, effectiveness, and safety, as well as postmarketing data including itsUse in universal mass vaccination programs.
Abstract: Without vaccination, chickenpox (varicella) will affect almost every person in the world during their lifetime. The burden of disease due to varicella is often unrecognized. Varilrix™ is a varicella vaccine derived from the Oka strain of varicella virus. The vaccine, as a frozen formulation, was licensed for use in 1984 and was the first commercially available varicella vaccine. It subsequently became the first refrigerator-stable varicella vaccine; its development commenced in 1991 and it has been licensed for use since 1994. Varilrix™ is indicated for use in high-risk groups, potentially immunocompromised individuals, and healthy subjects in many countries. This article reviews data from extensive worldwide experience with the refrigerator-stable version of the vaccine, including information derived from its use in over 10 000 individuals participating in clinical trials investigating its immunogenicity, efficacy, effectiveness, and safety, as well as postmarketing data including its use in universal mass vaccination programs. Sixteen years of clinical and postmarketing experience with the same formulation represents the longest and most extensive experience with a refrigerator-stable varicella vaccine worldwide. Varilrix™, in conjunction with the trivalent measles-mumps-rubella vaccine Priorix™, has also been the basis for clinical development of the tetravalent measles-mumps-rubella-varicella vaccine (Priorix-Tetra™).
TL;DR: Hoping trends reported in a number of pilot trials await validation in larger proof-of-principle trials that are now in progress, which lend direct support to the involvement of inflammatory myelin-reactive T cells in the MS disease process.
Abstract: T-cell vaccination (TCV) is a unique approach to induce immune regulation that may have importance in the treatment of autoimmune diseases, including multiple sclerosis (MS). TCV employs a classic vaccine strategy of injecting an attenuated form of the disease-causing agent — in this case, myelin-reactive T cells — that have been selected and expanded from each MS donor and then re-injected after irradiation to induce protective immunity. This anti-T-cell immunity consistently results in selective deletion or regulation of the targeted pathogenic T cells in vivo. Longitudinal studies have established that TCV is safe and often results in a reduced relapse rate and clinical stability or improvement, at least temporarily, in the majority of treated MS patients. These results lend direct support to the involvement of inflammatory myelin-reactive T cells in the MS disease process. However, these hopeful trends reported in a number of pilot trials await validation in larger proof-of-principle trials that are now in progress.
TL;DR: Following a single intravenous dose of recombinant factor VIIa in patients with hemophilia, the area under the plasma concentration-time curve generally increased in a dose-dependent fashion, and volume of distribution at steady state, clearance, elimination half-life, and mean residence time were generally independent of dose.
Abstract: Recombinant factor VIIa (NovoSeven®; also known as recombinant activated factor VII or eptacog alfa) is structurally similar to human plasma-derived coagulation factor VIIa, but is manufactured using DNA biotechnology. Recombinant factor VIIa interacts with thrombin-activated platelets to produce a thrombin burst leading to accelerated fibrin clot formation localized to the site of vascular injury. It is approved in many countries for use as an intravenous hemostatic agent in patients with congenital hemophilia with inhibitors, and also for acquired hemophilia, factor VII deficiency, and Glanzmann thrombasthenia in some countries. Studies have shown it to be effective and generally well tolerated when used intravenously to treat bleeding episodes or provide hemostatic cover during surgery in patients with congenital hemophilia with inhibitors, acquired hemophilia, factor VII deficiency or Glanzmann thrombasthenia. Based on available data, its efficacy in terms of patient-assessed response may be similar to that of activated prothrombin complex concentrate (aPCC), but treatment with a single 270 µg/kg dose of recombinant factor VIIa might reduce the need for rescue therapy compared with aPCC. Recombinant factor VIIa is not immunogenic in patients with hemophilia, does not produce an anamnestic response in hemophilia patients with inhibitors, and has very low thrombogenicity. It is recommended in guidelines as the treatment of choice for bleeds in patients with hemophilia B with high-responding inhibitors and for patients with factor VII deficiency, and is also a first-line therapeutic option for high-responder hemophilia A patients with inhibitors and those with acquired hemophilia. Cost data from pharmacoeconomic analyses support its use in hemophilia patients with inhibitors. Thus, recombinant factor VIIa is a valuable treatment option for patients with these rare, but potentially serious, bleeding disorders. Recombinant factor VIIa is a recombinant protein, similar in structure to coagulation factor VIIa derived from human plasma, but manufactured without using material of human origin. It has effects on both tissue factor-dependent and -independent coagulation. In particular, at pharmacologic concentrations, its main effect is to enhance thrombin generation on the surface of activated platelets, even in the absence of factors VIII and IX, which are deficient in patients with congenital hemophilia A and B, respectively. The thrombin induced by recombinant factor VIIa enhances platelet activation, fibrin formation, and inhibition of fibrinolysis. The effects of recombinant factor VIIa are localized to the site of vascular injury and it does not appear to enhance systemic activation of coagulation. Thrombotic events have been reported rarely. Antibodies to recombinant factor VIIa generally do not develop in patients with hemophilia, although there have been a few reports in patients with factor VII deficiency. Following a single intravenous dose of recombinant factor VIIa in patients with hemophilia, the area under the plasma concentration-time curve generally increased in a dose-dependent fashion. Volume of distribution at steady state, clearance, elimination half-life, and mean residence time were generally independent of dose in patients with hemophilia. Values for clearance were higher in pediatrie patients than in adults with hemophilia, and were also higher in patients with factor VII deficiency than in adults with hemophilia. In addition to a number of small controlled trials, therapeutic efficacy data for recombinant factor VIIa come from noncomparative studies, and compassionate- or emergency-use programs. The most widely used dosage in these studies was 90 µ-g/kg every 2–4 hours in patients with congenital hemophilia with inhibitors, acquired hemophilia or Glanzmann thrombasthenia, and 15–30 µ-g/kg in patients with congenital factor VII deficiency. Hemostatic efficacy was generally evaluated using a global assessment by the patient or the physician. Recombinant factor VIIa was effective at controlling mild to moderate bleeding episodes in patients with congenital hemophilia with inhibitors during home treatment in noncomparative studies, with efficacy rates of up to 93% after ≈2 doses. Early treatment was more likely to be associated with a successful outcome than late treatment. In double-blind or open-label comparative trials in hemophilia patients with inhibitors experiencing hemarth-roses, the effectiveness of a single dose of recombinant factor VIIa 270 µg/kg was similar to that of a standard regimen of 90 µg/kg every 3 hours. A single 270 µg/kg dose achieved successful hemostasis in >90% of patients with mild to moderate bleeding episodes after 9 hours without the need for additional hemostatic medication. Two open-label, crossover studies compared recombinant factor VIIa with aPCC in hemophilia patients with inhibitors. One study failed to demonstrate equivalency between the two treatments, possibly due to inadequate patient/bleed numbers. In the other study, patient-assessed treatment response did not differ significantly between recombinant factor VIIa (single dose of 270 µg/kg or standard regimen of three doses of 90 µg/kg at 3-hour intervals) and aPCC 75 U/kg; however, fewer patients required ‘rescue’ therapy with additional hemostatic agents after a single 270 µ-g/kg dose of recombinant factor VIIa than after aPCC. Based on data largely from the compassionate-use program, recombinant factor VIIa was effective in the treatment of major nonsurgical bleeds (e.g. life- or limb-threatening bleeds), and at producing and maintaining hemostasis during surgery, in patients with hemophilia with inhibitors. In a double-blind controlled trial in hemophilia patients with inhibitors undergoing surgical procedures, satisfactory hemostasis was achieved in 13 out of 14 patients (93%) treated with a standard regimen of recombinant factor VIIa. Data from a limited number of patients with acquired hemophilia, factor VII deficiency or Glanzmann thrombasthenia (mostly from the compassionate-use programs or patient registries) indicated that recombinant factor VIIa was also effective at treating surgical and nonsurgical bleeding in these patient groups. Efficacy rates were generally consistent with those seen in patients with congenital hemophilia. Recombinant factor VIIa is generally well tolerated and adverse events do not appear to be dose-related. Non-serious adverse events include nausea, fever, injection-site pain, skin rash and increased values for ALT, alkaline phosphatase and lactate dehydrogenase. The overall incidence of serious adverse events with recombinant factor VIIa is <1%. Serious events have included thrombotic events (e.g. myocardial infarction, stroke, pulmonary embolism, deep vein thrombosis, disseminated intravascular coagulation); however, they have generally occurred in patients with predisposing risk factors or in patients without hemophilia being treated for non-approved conditions. Recombinant factor VIIa has no risk for transmission of human pathogens, is not immunogenic, and does not induce an anamnestic response in patients with inhibitors. On-demand treatment with recombinant factor VIIa was associated with improvements in health-related quality of life relative to plasma-derived agents in a cost-utility study in hemophilia patients with inhibitors. Modelled cost analyses in this patient population found that on-demand treatment of mild to moderate bleeds with recombinant factor VIIa was cost neutral or cost saving relative to aPCC. Modelled cost analyses also showed that orthopedic surgery using recombinant factor VIIa to maintain hemostasis was generally cost saving over the medium to long term relative to not having surgery. Modelled analyses were performed from the healthcare payer perspective.
TL;DR: The predictive value of mutant KRAS for a lack of clinical benefit with panitumumab monotherapy was supported by results from an open-label extension of the phase III study and a large phase II study.
Abstract: Panitumumab is a fully human IgG2 monoclonal antibody that is highly selective for the epidermal growth factor receptor (EGFR), which is overexpressed in 25-77% of colorectal cancers and is often associated with a poor prognosis. Binding of panitumumab to EGFR reduces cell proliferation and mediator production, and induces apoptosis. In a comparative, phase III trial in adult patients with chemotherapy-refractory metastatic colorectal cancer, intravenous panitumumab 6 mg/kg every 2 weeks plus best supportive care (BSC) improved progression-free survival (PFS) [primary endpoint] and objective tumor response rate to a significantly greater extent than BSC alone. The improvement in PFS produced by panitumumab monotherapy was significantly greater in patients with non-mutated (wild-type) KRAS than in those with mutant KRAS (in whom no benefit from panitumumab was observed). Similarly, all patients experiencing a partial response had wild-type KRAS, while stable disease was achieved by more patients with wild-type KRAS than with mutant KRAS. The predictive value of mutant KRAS for a lack of clinical benefit with panitumumab monotherapy was supported by results from an open-label extension of the phase III study and a large phase II study. Although most patients treated with panitumumab experienced at least one adverse event, the incidence of severe adverse events resulting in discontinuation of treatment was relatively low. The most commonly reported treatment-related adverse events were skin-related toxicities, which reflect the mechanism of action of panitumumab.
TL;DR: Results of several large randomized trials have established omalizumab as an effective and well tolerated agent for use as add-on therapy in patients with severe persistent allergic asthma or those with moderate to severe disease.
Abstract: Omalizumab, a monoclonal antibody that targets circulating IgE, is approved as add-on therapy for adult and adolescent patients with severe allergic asthma in the EU and moderate to severe allergic asthma in the US. Several randomized, double-blind trials have demonstrated the therapeutic efficacy of subcutaneously administered omalizumab as add-on therapy in patients with allergic asthma. The INNOVATE study included only patients with severe persistent disease, and omalizumab was associated with a statistically significant relative reduction of 26% in the rate of clinically significant asthma exacerbations (primary endpoint) compared with placebo (after adjustment for an imbalance in the exacerbation history at baseline). Results for a number of secondary outcomes also significantly favored omalizumab over placebo. Two large studies in patients with moderate to severe allergic asthma showed that, compared with placebo, omalizumab was associated with statistically significant relative reductions of 41-58% in the mean number of asthma exacerbations (primary endpoint) during the trial. Omalizumab also significantly reduced asthma symptom scores and the use of inhaled corticosteroids and rescue medication. Moreover, all of these trials showed that omalizumab was associated with clinically and statistically significant improvements from baseline in overall asthma-related quality of life. In general, omalizumab was well tolerated in clinical trials. Most adverse events were mild or moderate in severity and occurred at a similar frequency among omalizumab and placebo recipients. Injection-site reactions were the most commonly reported adverse events in clinical trials with omalizumab. Although rare, anaphylactic reactions have occurred following administration of omalizumab, and appropriate precautions should be taken. Results of several large randomized trials, therefore, have established omalizumab as an effective and well tolerated agent for use as add-on therapy in patients with severe persistent allergic asthma (EU labeling) or those with moderate to severe disease (US labeling). In addition, international treatment guidelines acknowledge the importance of omalizumab as a treatment option in these difficult-to-treat patient populations.
TL;DR: The scientific basis for the development of glucagon-like peptide-1 (GLP-1) analogs is outlined, clinical experience gained so far is reviewed, and future expectations for long-acting forms of GLP- 1 analogs are discussed.
Abstract: Type 2 diabetes mellitus is characterized by insulin resistance, impaired glucose-induced insulin secretion, and inappropriately elevated glucagon levels which eventually result in hyperglycemia. The currently available treatment modalities for type 2 diabetes are often unsatisfactory in getting patients to glycemic goals, even when used in combination, and therefore many patients develop microvascular and macrovascular diabetic complications. Additionally, these treatment modalities are often limited by inconvenient dosage regimens and safety and tolerability issues, the latter including hypoglycemia, bodyweight gain, edema, and gastrointestinal intolerance. There is, therefore, a need for new and more efficacious agents, targeting not only treatment, but also prevention of the disease, its progression, and its associated complications. Recently, an entirely new therapeutic option for the treatment of type 2 diabetes has become available in the US (since October 2005) and in Europe (since May 2007): the incretin-based therapies. The incretin-based therapies fall into two different classes: (i) incretin mimetics, i.e. injectable peptide preparations with actions similar to the natural incretin hormones; and (ii) the incretin enhancers, i.e. orally available agents that inhibit the degradation of the incretin hormones in the body and thereby increase their plasma levels and biologic actions. This article focuses on the incretin mimetics and outlines the scientific basis for the development of glucagon-like peptide-1 (GLP-1) analogs, reviews clinical experience gained so far, and discusses future expectations for long-acting forms of GLP-1 analogs.
TL;DR: Past and current endeavors in the development of peptides that inhibit replication of HIV-1 and the role of peptide inhibitors in the search for new anti-HIV drugs are summarized.
Abstract: More than 2 decades of intensive research has focused on defining replication mechanisms of HIV type 1 (HIV-1), the etiologic agent of AIDS. The delineation of strategies for combating this viral infection has yielded many innovative approaches toward this end. HIV-1 is a lentivirus in the family retroviridae that is relatively small with regard to both structure and genome size, having a diploid RNA genome of approximately 9 kb, with only three major genes and several gene products resulting from alternate splicing and translational frameshifting. Most marketed drugs for treating AIDS are inhibitors of HIV-1 reverse transcriptase or protease enzymes, but new targets include the integrase enzyme, cell surface interactions that facilitate viral entry, and also virus particle maturation and assembly. The emergence of drug-resistant variants of HIV-1 has been the main impediment to successful treatment of AIDS. Thus, there is a pressing need to develop novel treatment strategies targeting multiple stages of the virus life-cycle. Research efforts aimed at developing successful means for combating HIV-1 infection have included development of peptide inhibitors of HIV-1. This article summarizes past and current endeavors in the development of peptides that inhibit replication of HIV-1 and the role of peptide inhibitors in the search for new anti-HIV drugs.
TL;DR: A novel approach in suppressing inflammation is to intervene in the mechanisms responsible for the migration of leukocytes into inflamed tissue by selective adhesion molecule inhibition, which could offer an alternative to the anti-TNF agent class in patients with moderate to severe Crohn disease.
Abstract: The last few years have been highlighted by further knowledge and optimism regarding the use of biologic therapy in Crohn disease. The introduction of anti-tumor necrosis factor (TNF) therapy into clinical practice in the form of the murine chimeric monoclonal antibody infliximab, and more recently the fully human monoclonal antibody adalimumab, has significantly advanced treatment for Crohn disease. Despite the introduction of the anti-TNF agents, 20-40% of patients will fail to respond to initial induction therapy, and of the initial responders only 60-70% will have a sustained response at 1 year. Therefore, there remains a significant unmet need in the treatment of patients with Crohn disease. A novel approach in suppressing inflammation is to intervene in the mechanisms responsible for the migration of leukocytes into inflamed tissue. One such method is by selective adhesion molecule inhibition. Several agents based on this strategy have been evaluated in the treatment of inflammatory bowel disease. It is expected that these agents will offer an alternative to the anti-TNF agent class in patients with moderate to severe Crohn disease.
TL;DR: Subgroup analyses in AVOREN suggested that interferon-alpha-2a dose reductions (to manage grade > or =3 adverse events attributable to the drug) did not compromise the efficacy of combination treatment with bevacizumab plus interfer on-alpha -2a.
Abstract: Bevacizumab, an anti-vascular endothelial growth factor recombinant humanized monoclonal antibody, directly inhibits tumor angiogenesis and hence tumor growth. First-line therapy with intravenous bevacizumab 10 mg/kg every 2 weeks plus subcutaneous interferon-alpha-2a 9 million international units three times weekly has been evaluated in two randomized, double-blind or open-label, multicenter phase III trials (AVOREN [n = 649] and CALGB 90206 [n = 732]). Bevacizumab combination therapy resulted in a median progression-free survival that was significantly (p or =3 adverse events attributable to the drug) did not compromise the efficacy of combination treatment with bevacizumab plus interferon-alpha-2a. The addition of bevacizumab to interferon-alpha-2a in AVOREN was generally well tolerated. No unexpected/new adverse events were observed; bevacizumab-associated toxicities were generally of mild intensity.