Current Pharmaceutical Biotechnology - Volume 4, Issue 1, 2003

Cytokines hold huge potential for the treatment of disease due to their often fundamental roles in development and homeostasis. However, it is this same primary biological function that can both cause disease through dysregulation as well as prevent their therapeutic use due to systemic consequences arising from this inherent pleiotropy. Molecularly, this can be explained through an understanding of the receptor system specific to each cytokine and the cells on which they are expressed. This knowledge has been exploited to yield muteins (mutated proteins) that exhibit selective, and sometimes novel, biological properties dependent upon receptor subunit usage. In some cases, these muteins have been evaluated in clinical trials and have been approved for clinical use; in most instances, however, these muteins are not suitable for therapeutic application due to intrinsic characteristics of the muteins themselves or the cellular and receptor system to which they are directed. Ultimately, molecular insight to the biological processes governing disease pathology underlies the successful application of mutein-based therapy. The clinical success enjoyed by a subset of these proteins signals the advent of a new mode of therapeutic protein development.

Excessive cell proliferation contributes to the pathobiology of human diseases with a high health and socioeconomic impact, including cancer and vascular occlusive diseases (e.g., atherosclerosis, in-stent restenosis, transplant vasculopathy, and vessel bypass graft failure). Recent advances in the understanding of the molecular networks governing the hyperplastic growth of tumors and vascular obstructive neointimal lesions have provided new perspectives for preventive and therapeutic strategies against these disorders.Mammalian cell proliferation requires the activation of several cyclin-dependent protein kinases (CDKs). Postranslational activation of CDKs is a complex process that involves their association with regulatory subunits called cyclins. The activity of CDK / cyclin holoenzymes is negatively regulated through their interaction with members of the CDK family of inhibitory proteins (CKIs). Moreover, over fifty low molecular weight pharmacological CDK inhibitors that target the ATP-binding pocket of the catalytic site of CDKs have been identified. In this review, we will discuss the use of pharmacological and gene therapy strategies against CDK / cyclins in animal models and clinical trials of cancer and cardiovascular disease.

Primary brain tumors including anaplastic astrocytomas and glioblastoma multiforme are difficult to treat because of their locally invasive nature and chemoradioresistance. Novel therapies are needed. One class of therapeutics is fusion proteins consisting of peptide toxins fused to brain tumor selective ligands. DAB389EGF is a fusion protein composed of the catalytic and translocation domains of diphtheria toxin fused via a His-Ala linker to human epidermal growth factor (EGF). DAB389EGF is selectively toxic to EGF receptor (EGFR) overexpressing cells. Close to half of all high-grade primary brain tumors have EGFR gene amplification and EGFR overexpression. With the use of convection-enhanced delivery (CED), DAB389EGF may be delivered locally at high concentrations to the brain tumor. CED would avoid many of the pharmacologic and toxicologic barriers which have limited effective use of this agent including rapid clearance from the circulation, high anti-diphtheria toxin antibody titers in the blood and toxicities to the liver and kidney. Both cell lines and animal models are available to assess the potential of this agent for brain tumor therapy. Since significant amounts of clinical grade DAB389EGF are available, some careful additional preclinical efficacy work should lead to testing of this agent in patients within the next few years.

The use of monoclonal antibodies has become routine in the research and diagnostic laboratories, but the potential of antibody molecules in public health and medical applications is still far from its maximum. Most infections begin at mucosal surfaces, and this is certainly not only a stroke of good fortune if mother's milk serves as a natural delivery vehicle for antibodies protecting the gastrointestinal tract of nursing infants. Mammary gland or other mucous secretions containing numerous antibody specificities provide an efficient mean to immediately protect a mucosal surface against pathogens, which have never been encountered by the host. From a public health perspective, topical passive immunization of mucosal surfaces with monoclonal antibodies can block entry and transmission of bacteria, viruses, fungi and parasites that infect humans, and thus defeat some key immune evasion strategies designed by many pathogens. The chief antibody on most mucosal surfaces is secretory immunoglobulin A (SIgA), a polypeptide complex comprising dimeric IgA, the connecting J chain, and the secretory component. The molecular stability, tetravalency, and strong antiinflammatory properties make SIgA particularly well suited to fulfill the function of passive protective immunity when applied exogenously to mucosal surfaces. The review will give an overview of the basic concepts underlying mucosal immunity, present the molecular mechanisms whereby SIgA prevents mucosal infections, cover the last advances in the topic of recombinant SIgA production, and examine how structure-function relationship in SIgA will help designing molecules with novel properties for passive immunotherapy.

Prophylactic vaccination against tuberculosis with BCG gained much of the credit for the decline of TB in Europe. However, with TB resurgent in many parts of the world, better vaccines are urgently needed. To improve on BCG, a rapid, rational approach to vaccine discovery is needed. Fortunately, advances in the fields of molecular biology and computer science have spawned new disciplines: Genomics, Proteomics and Transcriptomics are transforming the ways in which candidate vaccine antigens are discovered. In this review, we discuss how these new approaches have accelerated the pace of antigen discovery and vaccine development, and highlight some of the most promising new candidate vaccines and vaccine targets.