Section Review Biologicals & Immunologicals: Matrix metalloproteinases and malignant disease: Recent developments

One important proteolytic event during metastasis and angiogenesis appears to be the degradation of basement membrane components. A specific class of extracellular matrix (ECM) degrading metallo-enzymes, the matrix metalloproteinases (MMPs), also known as the matrixins, are thought to have a critical role in the creation of the proteolytic defect in basement membrane type IV collagen that allows tumour cells to escape from their primary site. The expression of matrixin proteases has been linked with many physiologic and pathologic processes involving ECM turnover. A number of correlative and functional studies suggest that the action of MMPs is required during tumour invasion and progression, as well as angiogenesis. The correlative studies have demonstrated overexpression of MMPs in many human cancer tissues at both the protein (immunoperoxidase) and mRNA (in situ hybridisation) levels. Functional studies have used endogenous inhibitors (Tissue Inhibitors of Metalloproteinases, TIMPs) or synthetic MMP inhibitors to block tumour cell invasion or metastasis formation. MMPs have also been implicated in the cell-surface proteolysis that modulates the adhesive behaviour of neoplastic cells. Therefore, targeting the activity of MMPs may provide a clinically useful mechanism for blocking local invasion and the metastatic spread of cancer cells. Results from a variety of studies indicate that mechanism-based inhibitors for MMPs can be developed and exploited in the clinical setting. This strategy has been utilised for the development of MMP inhibitors as substrate analogues have been modified to target selectively reactive moieties at the active site of MMPs.     

Overview: Biologicals & Immunologicals: Recombinant vaccines: technology and applications

Recombinant DNA technology, combined with the current understanding of antigen processing and recognition, provides a wide selection of possible approaches for vaccine development. The selection of a particular vaccine approach can thus be based on the desired outcome. Modern vaccinologists can select from a range of vaccines including subunits, purified proteins or polysaccharides, proteins made by recombinant methods in vitro, live vectors, or polynucleotides. Therefore, the treatment can be tailored according to the immune response desired and the safety, efficacy, and availability of the wild-type organism or naturally produced antigen. This article aims to review several of the recent advances and major patent applications in this area.     

Section Reviews: Biologicals & Immunologicals: Recent advances in non-viral gene therapy

Gene therapy is beginning to emerge as a safe and potentially effective means to treat human disease, and offers new opportunities to tackle conditions for which no satisfactory treatments have yet been developed. Current approaches rely upon either viral or non-viral vehicles to deliver the therapeutic gene, however, despite encouraging clinical data, it is realistic to expect that further advances are required if any are to be developed, manufactured and used in clinical practice. Non-viral gene therapy is attractive because, in general, it offers the potential to developed a synthetic, generic delivery vehicle, as well as safety and simplicity. However, a host of biological barriers exist, such as cell targeting and entry, intracellular trafficking, and maintenance and controlled expression of the therapeutic gene, which need to be overcome. Recently, non-viral gene therapy research has been an area of considerable innovation, with significant progress being made to address these issues. This review focuses on recent and potential advances to non-viral gene delivery systems and the strategies to ensure therapeutic genes are maintained and expressed in vivo Although further basic research is required, non-viral approaches promise to be an integral, if not major, component of future human gene therapy practice.     

Overview: Biologicals & Immunologicals; Biomolecule libraries,arrays and molecular diversity

In the last five years there has been an explosion of interest in the methods for creating and screening diverse molecular libraries. This interest has been driven by commercial competitive pressures, particularly but not exclusively from the pharmaceutical industry, coupled with major advances in chemical, molecular biological and screening technology. The field is still in its infancy and, although its literature is in exponential growth, much of the key data, particularly that relating to proprietary technologies, remains out of the public domain. Patenting issues in the field are complex and relatively little can be gleaned from the few patents that have, as yet, been published. This short review sets out to capture the current breadth and potential of the field by focusing largely on primary literature; it can be anticipated that a corresponding growth in the patent literature is imminent.     

Recent developments in macrolide antimicrobial research

Clarithromycin and azithromycin, which are more acid-stable than erythromycin A (EM), have been widely prescribed for the treatment of respiratory tract infections because of their high efficacy and safety. However, these macrolide antibiotics are only weakly active against pathogens with an efflux gene (mef) and are inactive against pathogens with a methyltransferase-inducible gene (erm) and constitutively resistant organisms. To address the drug resistance issue, tremendous efforts have been devoted to the modification of the macrolide structure. As a consequence, several types of decladinosyl derivatives, such as ketolide and acylides, have been recognized to be effective against mef-type resistant streptococci and methylase-inducible staphylococci. It has also been recognized that derivatives containing certain 11-, 6- or 4 -tethered aryl substituents, such as telithromycin (HMR 3647), cethromycin (ABT-773) and CP-544372, are effective against erm(B)-type resistant streptococci. Telithromycin was recently approved in several European countries for the treatment of respiratory tract infections and cethromycin is now in the final stage of clinical study. Macrolide antibiotics have been modified to address the issues of acid-instability and inactivity against resistant strains. In this review, we will summarize the progress in the macrolide research area and discuss the desirable features of the next generation macrolide antibiotics.     

Monthly Update: Biologicals & Immunologicals: Small molecule cytokine inducers

It is now widely accepted that the renin–angiotensin system (RAS) not only contributes to pathological mechanisms involved, e.g. in hypertension or hypertensive and diabetic end-organ damage, but also harbors a “protective arm” represented mainly by two receptors, the AT2 (angiotensin type 2) receptor and the Mas receptor, both mediating tissue-protective and pro-regenerative actions. Several compounds are currently in preclinical and clinical development, which aim at targeting the “protective RAS” by agonism on the AT2 or the Mas receptor. In a recent issue of Expert Opinion on Investigational Drugs Koen Verdonk and co-authors review the physiology and patho-physiology of the AT2 receptor and discuss potential future clinical indications and putative adverse effects of AT2 receptor agonists. This article comments the review by Verdonk et al., suggests some additional possible indications, and particularly re-reviews whether there is preclinical in vivo evidence for adverse effects of AT2 receptor agonists.     

Section Review Biologicals & Immunologicals: Advances in antibody engineering

Our ability to genetically modify antibody molecules has been dramatically enhanced by a number of technological breakthroughs, including the ability to rapidly and easily clone the variable region genes, and the development of good expression systems. In addition phage display technology has given a new impetus to the field by allowing the isolation and modification of novel antibodies. This paper reviews these important areas, and describes some of the more common genetic constructs that have been produced. Such recombinant molecules are entering clinical trials more frequently and will become increasingly important as diagnostic and therapeutic agents.     

Editorial Biologicals & Immunologicals: Patenting combinatorial libraries and associated technologies

The advent of combinatorial chemistry in all its manifestations has the potential to change radically the patenting strategies of all pharmaceutical organisations. This editorial reviews recent progress over the past three years.     

Review Biologicals & Immunologicals: Intellectual property rights in biotechnology

The development of intellectual property rights for biotechnology has occurred in a series of complex and often contentious steps. By granting many of the first patents for genetically engineered organisms and biological molecules, the US has played a leading role in shaping policy worldwide. This article reviews the role of patents in the development of biotechnology and discusses the new challenges posed by the integration of genomics into the drug discovery process.     

Section Review: Biologicals & Immunologicals: Gene therapy for haemophilia

Recently, there has been significant progress on the development of a gene therapy protocol for the treatment of haemophilia. Expression of physiologic levels of both human factors VIII and IX has been achieved in animal models, and correction of the disease phenotype has been demonstrated in haemophilia B dogs. Various durations of clotting factor expression in vivo have been observed. Adenoviral vector-mediated expression of therapeutic levels of human factor IX has been sustained for at least ten months in mice. Although research achievements have been substantial, several obstacles impede progress toward clinical trials. Improvements in gene transfer vehicles and delivery methods are needed to ensure safe and efficacious gene therapy. Specific issues currently under investigation include the persistence of clotting factor expression, procedures which allow re-administration of therapy, and host immune responses to treatment.     

Biologicals & Immunologicals: Process for categorising nucleotide sequencing populations

The nature of the invention relates to a method of “sorting” populations of nucleic acids, especially for use as templates for large scale sequencing studies such as those currently being pursued in the Human Genome Project. The invention permits “indexing” of nucieic acids, and facilitates the selection of individual sequences at will, thus obviating the problem of sequencing the same nucleic acid fragment several times. The latter case is often found in the current piecemeal approach to microdissection of the human genetic complement.     

Biologicals & Immunologicals: Stimulation of antitumour T-cell response using anti-idiotypic antibodies

The essence of this Jenner application is a biological method of stimulating the immune system in its defence against the growth and multiplication of tumour cells. No experimental data are provided, although the authors make a well reasoned argument as to the feasibility of the 'invention'. A reference is made to a US patent [101] issued 1 October 1991, as a forerunner to the present application, which describes the peritope of an antitumour antibody.     

Section Reviews: Biologicals & Immunologicals: Pharmacological attenuation of chemotherapy-induced oral mucositis

Mucositis is a common, dose-limiting complication in patients receiving cancer chemotherapy, which derives from cytotoxic insult to the oral epithelial cell population. While a number of treatments which palliate the symptoms associated with ulcerative mucositis are available, they do not effectively treat the underlying mucosal injury. Recently, therapeutic approaches utilising cytokines to stimulate healing or prevent damage to the oral mucosa have been described. Here we review current progress in reducing the incidence and severity of oral mucositis in cancer patients. The circumvention of oral and gastrointestinal mucositis should allow dose or schedule intensification, with a goal to effect increases in long-term survival in patients with cancers responsive to high-dose or accelerated-cycle chemotherapy.     

Therapeutic potential of macrolide immunosuppressants in dermatology

Dermatologists are frequently presented with inflammatory dermatoses that are responsive to treatment with immunomodulating drugs. Corticosteroids, particularly when applied topically, have been the mainstay of treatment in the past. Their undoubted efficacy, however, has been undermined by problems with repeated use including tachyphylaxis and side effects such as skin atrophy and hypertension. Macrolide immunosuppressive drugs, originally used for prophylaxis of organ transplant rejection, have been shown to be effective in the treatment of inflammatory dermatoses. The original drugs used in dermatology in this class have their own limitations including poor absorption when used topically and their distinct side-effect profiles. A search for other immunosuppressive macrolide antibiotics has led to the development of new agents, which have enhanced profiles for the treatment of skin disease. This review discusses the main dermatoses that may be targeted by this class of drugs and summarises the topical and systemic macrolides either currently in use, in clinical trials or preclinical development.     

Leading Article Biologicals & Immunologicals: Immunological adjuvants: Mechanisms of action and clinical applications

Adjuvants are a neglected aspect of vaccine formulations, prudent choice of which can enhance the immune response both quantitatively and qualitatively. This review details the evolution and current range of adjuvants, particularly those in clinical trials. The components of different adjuvants are outlined and the manner in which they are thought to work is discussed. Antigen processing is an essential requirement of any immune response and these mechanisms are discussed in the context of adjuvant action.