Therapeutic antibodies: successes, limitations and hopes for the future

With more than 20 molecules in clinical use, monoclonal antibodies have finally come of age as therapeutics, generating a market value of $11 billion in 2004, expected to reach $26 billion by 2010. While delivering interesting results in the treatment of several major diseases including autoimmune, cardiovascular and infectious diseases, cancer and inflammation, clinical trials and research are generating a wealth of useful information, for instance about associations of clinical responses with Fc receptor polymorphisms and the infiltration and recruitment of effector cells into targeted tissues. Some functional limitations of therapeutic antibodies have come to light such as inadequate pharmacokinetics and tissue accessibility as well as impaired interactions with the immune system, and these deficiencies point to areas where additional research is needed. This review aims at giving an overview of the current state of the art and describes the most promising avenues that are being followed to create the next generation of antibody-based therapeutic agents.This article is part of a themed section on Vector Design and Drug Delivery. For a list of all articles in this section see the end of this paper, or visit: http://www3.interscience.wiley.com/journal/121548564/issueyear?year=2009     

Safety and secondary pharmacology: successes, threats, challenges and opportunities

This review summarises the lecture of Dr Tim Hammond, recipient of the Distinguished Service Award of the Safety Pharmacology Society, given on 20 September 2007 in Edinburgh. The lecture discussed the rationale behind the need for optimal non-clinical Safety and Secondary Pharmacology testing; the evolution of Safety and Secondary Pharmacology over the last decade; its impact on drug discovery and development; the value of adopting an integrated risk assessment approach; the translation of non-clinical findings to humans and finally the future challenges and opportunities facing these disciplines.     

Targeting CDK2 in cancer: challenges and opportunities for therapy

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New drug targets for cholera therapy

Intestinal infection with Vibrio cholerae results in secretory diarrhea with potentially massive fluid losses and volume depletion. Morbidity and mortality associated with cholera remain a major problem in the developing world despite the success of oral rehydration therapy. New research aiming to inhibit cholera toxin binding to receptors in the intestine provides an attractive strategy for cholera therapy. Together with anti-secretory agents, including inhibitors of enkephalinase and of the cystic fibrosis transmembrane conductance regulator, new treatment options for managing severe diarrhea in cholera could soon be available.     

Tyrosine kinases as targets in cancer therapy - successes and failures

Protein kinases play a crucial role in signal transduction and also in cellular proliferation, differentiation and various regulatory mechanisms. The inhibition of growth-related kinases, especially tyrosine kinases, might therefore provide new therapies for diseases such as cancer. Due to the enormous progress that has been made in the past few years in the identification of the human genome, in molecular and cell biology technologies, in structural biology and in bioinformatics, the number of receptor and non-receptor tyrosine kinases that have been identified as valuable molecular targets has greatly increased. Currently, more than 20 different tyrosine kinase targets are under evaluation in drug discovery projects in oncology. The progress made in the crystallisation of protein kinases, in most cases complexed with ATP-site-directed inhibitors, has confirmed that the ATPbinding domain of tyrosine kinases is an attractive target for rational drug design; more than 20 ATP-competitive, low molecular weight inhibitors are in various phases of clinical evaluation. Meanwhile, clinical proof-of-concept (POC) has been achieved with several antibodies and small molecules targeted against tyrosine kinases. With Herceptin, Glivec and Iressa (registered in Japan), the first kinase drugs have entered the market. This review describes the preclinical and clinical status of low molecular weight drugs targeted against different tyrosine kinases (e.g., epidermal growth factor receptor [EGFR], vascular endothelial growth factor receptor [VEGFR], platelet-derived growth factor receptor [PDGFR], Kit, Fms-like tyrosine kinase [Flt]-3), briefly describes new targets, and provides a critical analysis of the current situation in the area of tyrosine kinase inhibitors.     

Osteoporosis: challenges and new opportunities for therapy

Osteoporosis is a chronic disease that affects a large number of both men and women and is characterized by a decrease in bone mass, as well as weakened bones. It causes a significant amount of morbidity and mortality in patients and is often only diagnosed after a fracture occurs. This review will highlight recent advances in the development of novel anabolic approaches for treatment of osteoporosis, such as parathyroid hormone (PTH), calcium sensing receptor modulators, statins and prostanoid receptor agonists. Selected antiresorptive targets (cathepsin K inhibitors and vitronectin receptor antagonists) will also be surveyed.     

TRAIL in cancer therapy: present and future challenges

Since its identification in 1995, TNF-Related apoptosis-inducing ligand (TRAIL) has sparked growing interest in oncology due to its reported ability to selectively trigger cancer cell death. In contrast to other members of the TNF superfamily, TRAIL administration in vivo is safe. The relative absence of toxic side effects of this naturally occurring cytokine, in addition to its antitumoural properties, has led to its preclinical evaluation. However, despite intensive investigations, little is known in regards to the mechanisms underlying TRAIL selectivity or efficiency. An appropriate understanding of its physiological relevance, and of the mechanisms controlling cancer cells escape from TRAIL-induced cell death, will be required to optimally use the cytokine in clinics. The present review focuses on recent advances in the understanding of TRAIL signal transduction and discusses the existing and future challenges of TRAIL-based cancer therapy development.     

TRAIL in cancer therapy: present and future challenges

Since its identification in 1995, TNF-related apoptosis-inducing ligand (TRAIL) has sparked growing interest in oncology due to its reported ability to selectively trigger cancer cell death. In contrast to other members of the TNF superfamily, TRAIL administration in vivo is safe. The relative absence of toxic side effects of this naturally occurring cytokine, in addition to its antitumoural properties, has led to its preclinical evaluation. However, despite intensive investigations, little is known in regards to the mechanisms underlying TRAIL selectivity or efficiency. An appropriate understanding of its physiological relevance, and of the mechanisms controlling cancer cells escape from TRAIL-induced cell death, will be required to optimally use the cytokine in clinics. The present review focuses on recent advances in the understanding of TRAIL signal transduction and discusses the existing and future challenges of TRAIL-based cancer therapy development.     

Predictive models for nanotoxicology: current challenges and future opportunities

Characterizing the risks posed by nanomaterials is extraordinarily complex because these materials can have a wide range of sizes, shapes, chemical compositions and surface modifications, all of which may affect toxicity. There is an urgent need for a testing strategy that can rapidly and efficiently provide a screening approach for evaluating the potential hazard of nanomaterials and inform the prioritization of additional toxicological testing where necessary. Predictive toxicity models could form an integral component of such an approach by predicting which nanomaterials, as a result of their physico-chemical characteristics, have potentially hazardous properties. Strategies for directing research towards predictive models and the ancillary benefits of such research are presented here.     

New strategies for cancer gene therapy: Progress and opportunities

1. To date, cancer persists as one of the most devastating diseases worldwide. Problems such as metastasis and tumour resistance to chemotherapy and radiotherapy have seriously limited the therapeutic effects of existing clinical treatments.
2. To address these problems, cancer gene therapy has been developing over the past two decades, specifically designed to deliver therapeutic genes to treat cancers using vector systems. So far, a number of genes and delivery vehicles have been evaluated and significant progress has been made with several gene therapy modalities in clinical trials. However, the lack of an ideal gene delivery system remains a major obstacle for the successful translation of regimen to the clinic.
3. Recent understanding of hypoxic and necrotic regions within solid tumours and rapid development of recombinant DNA technology have reignited the idea of using anaerobic bacteria as novel gene delivery systems. These bacterial vectors have unique advantages over other delivery systems and are likely to become the vector of choice for cancer gene therapy in the near future.
4. Meanwhile, complicated tumour pathophysiology and associated metastasis make it hard to rely on a single therapeutic modality for complete tumour eradication. Therefore, the combination of cancer gene therapy with other conventional treatments has become paramount.
5. The present review introduces important cancer gene therapy strategies and major vector systems that have been studied so far with an emphasis on bacteria-mediated cancer gene therapy. In addition, exemplary combined therapies are briefly reviewed.     

Targeting cancer: the challenges and successes of structure-based drug design against the human purinome

Purine-binding proteins are of critical importance to all living organisms. Approximately 13% of the human genome is devoted to coding for purine-binding proteins. Given their importance, purine-binding proteins are attractive targets for chemotherapeutic intervention against a variety of disease states, particularly cancer. Modern computational and biophysical techniques, combined together in a structure-based drug design approach, aid immensely in the discovery of inhibitors of these targets. This review covers the process of modern structure-based drug design and gives examples of its use in discovery and development of drugs that target purine-binding proteins. The targets reviewed are human purine nucleoside phosphorylase, human epidermal growth factor receptor kinase, and human kinesin spindle protein.     

Polymer conjugates as therapeutics: future trends, challenges and opportunities

OBJECTIVE: Clinical proof of concept for polymer conjugates has already been achieved over the last 30 years, with a family of polymer-protein conjugates reaching the market and an exponentially growing list of polymer-drug conjugates currently in clinical trials. However, many challenges and opportunities still lie ahead, providing scope to develop this platform technology further. METHODS: The delivery of new anticancer agents aimed at novel molecular targets and their combination, the development of both new polymeric materials with defined architectures and the treatment of diseases other than cancer are the most exciting and promising areas. The latest advances and future trends in the polymer conjugate field will be presented in this article, providing an insight into their potential in the clinics and offering a wide range of research approaches within the scientific community. RESULTS/CONCLUSION: Polymer therapeutics is a rapidly emerging field with exponentially growing opportunities to achieve medical treatments with highly enhanced therapeutic value.     

Restoring BMPRII functions in pulmonary arterial hypertension: opportunities,challenges and limitations

Introduction: Pulmonary arterial hypertension (PAH) is a cardiopulmonary disorder in which mechanical obstruction of the pulmonary vascular bed is largely responsible for the rise in pulmonary arterial pressures. The discovery of heterozygous BMPR2 germline mutations as critical predisposing factors together with a remarkable progress in our understanding of the pathogenic mechanisms have helped identify the significant and complex roles of the BMPRII axis in PAH. However, their precise contributions to the condition are still incompletely understood.

Areas covered: This review aims to assemble and discuss the cellular actions of BMPs together with the possible clinical applications and prospects for their use in the near future.

Expert opinion: Although major advances have been made, several questions remain unanswered regarding development of efficacious therapies targeting the BMPRII axis in PAH. Specifically, the reasons why BMPRII signaling is reduced in PAH and how the alterations influence or even drive the pathogenesis need to be understood. Because the BMPRII axis is ubiquitously expressed and exhibits a wide variety of functions in organ regeneration and homeostasis, a better understanding of the overall risk-benefit ratio of these strategies with long-term follow-up is needed. This knowledge will lay the foundation for discovery of innovative therapeutics for PAH.     

Potential chemotherapeutic targets for Japanese encephalitis: current status of antiviral drug development and future challenges

Introduction: Japanese encephalitis (JE) remains a public health threat in Asia. Although several vaccines have been licensed, ～ 67,900 cases of the disease are estimated to occur annually, probably because the vaccine coverage is low. Therefore, effective antiviral drugs are required to control JE. However, no licensed anti-JE drugs are available, despite extensive efforts to develop them.

Areas covered: We provide a general overview of JE and JE virus, including its transmission cycle, distribution, structure, replication machinery, immune evasion mechanisms and vaccines. The current situation in antiviral drug development is then reviewed and future perspectives are discussed.

Expert opinion: Although the development of effective anti-JE drugs is an urgent issue, only supportive care is currently available. Recent progress in our understanding of the viral replication machinery and immune evasion strategies has identified new targets for anti-JE drug development. To date, most candidate drugs have only been evaluated in single-drug formulations, and efficient drug delivery to the CNS has virtually not been considered. However, an effective anti-JE treatment is expected to be achieved with multiple-drug formulations and a targeted drug delivery system in the near future.     

New drug candidates and therapeutic targets for tuberculosis therapy

Despite advances in chemotherapy and the BCG (Bacillus Calmette-Guérin) vaccine, tuberculosis remains a significant infectious disease. Although it can be cured, the therapy takes at least 6-9 months, and the laborious and lengthy treatment brings with it dangers of noncompliance, significant toxicity and drug resistance. The increasing emergence of drug resistance and the problem of mycobacterial persistence highlight the need to develop novel TB drugs that are active against drug resistant bacteria but, more importantly, kill persistent bacteria and shorten the length of treatment. Recent new and exciting developments in tuberculosis drug discovery show good promise of a possible revolution in the chemotherapy of tuberculosis.