Current Topics in Medicinal Chemistry - Volume 6, Issue 16, 2006

One of the “Holy Grails” of modern medicine (and pharmaceutical companies alike) is to be able to “persuade” the immune system to treat all pathologies, that do not result from awry Mendelian genetics, specifically, without side effects and, most importantly, avoiding bystander destruction of healthy cells and tissues. These goals have not been achieved yet, but the tremendous progress that has been made in basic science has enabled us to understand better the ways the immune and the other physiological systems work, and how they interact with each other. Importantly, empirical data from published clinical trials of drugs, successful, partially successful or failed, have helped to clarify misconceptions of past years and, in turn, define new drug targets and/or re-assess old ones. Two striking examples that come to mind are (i) the realization that T regulatory cells are a separate entity of T-cells [1] that can be destroyed by immunomodulatory drugs that target activated T-cells expressing the high affinity interleukin-2 receptor (such as anti-IL2R monoclonal antibodies used in organ transplantation), with potentially detrimental long-term consequences for the patient and (ii) the recently publicized TGN1412 trial fiasco in which an anti-CD28 antibody, inadequately tested before entering into clinical trials, sent six healthy volunteers to the intensive care unit [2]. This issue includes eight reviews on current and experimental immunotherapeutic regiments for various diseases including neoplasias, autoimmune diseases and AIDS. The first three reviews cover the current immunomodulatory therapies for hematological malignancies, cancer and autoimmune diseases (with emphasis on antibodies, but also cytokines, proteasome inhibitors and thalidomide), that are becoming the treatments of choice in the clinic. The 4th review covers the design and synthesis of artificial carriers of peptide epitopes for the construction of antigenic and immunogenic conjugates, and their application in diagnostics and vaccine development. The 5th review deals with RNA-mediated therapeutics and their potential use for gene inactivation and therapy. The 6th review is an update on T regulatory cells which - as we now know- must be taken into consideration when immunomodulatory drugs are used and when designing “intelligent“ drugs to alter the balance of the immune response to treat disease. The 7th review recapitulates what is now known on the mode of action of traditional immunosuppressive drugs and T-cell activation pathways, and how this current knowledge can be exploited to (re)assess their use as adjunct drugs to treat HIV disease in various clinical settings. Finally, the last review invites us to rethink our ideas on drug targets in polygenic diseases. I learned a lot preparing this issue, and I thank the Editor for giving me the opportunity and the motivation to go through this process. REFERENCES [1] Regulatory T-cells. Nature Immunol., 6(4):327-361 (2005). [2] Tragic drug trial spotlights potent molecule: Study reveals risks of interfering with immune system. Nature News, published on line: 17 March 2006; doi:10.1038/news060313-17.

A better understanding of the biology and pathogenesis of hematological malignancies has led to the development of immunotherapeutic and immunoregulatory drugs. Many of these agents have revolutionized the current treatment modalities, while others are under investigation. Rituximab (anti-CD20 antibody) has been established as the gold standard of treatment for aggressive B-cell lymphomas in combination with CHOP and has shown significant activity as monotherapy in the treatment of indolent B-cell lymphomas. In follicular lymphomas the combination of Rituximab with chemotherapy improves the outcome compared to chemotherapy alone. CD 20-based radioimmunotherapy, with the advantage of the bystander effect, represents an additional therapeutic alternative in B-cell lymphomas and may produce tumor regression in Rituximab resistant patients. The anti-CD52 monoclonal antibody, alemtuzumab, further expands the armamentarium against lymphoid malignancies producing high response rates in these entities. Antibody-targeted chemotherapy such as gemtuzumab ozogamicin, consisting of an anti-CD33 antibody combined to calicheamicin, has shown efficacy in the treatment of refractory acute myeloid leukemia; exact indications, timing and dosing schedule for optimized efficacy remain to be determined. Interferons have proven significant activity in cutaneous lymphomas, hairy cell leukemia and chronic myelogenous leukemia by mechanisms that are not fully elucidated. Thalidomide, by acting as an immunomodulatory and antiangiogenic agent can modulate neoplastic cells microenvironment and lead to disease control in multiple myeloma as well as in numerous other hematological malignancies. Bortezomib, a proteasome inhibitor, displays significant anti-tumor activity, especially in multiple myeloma and lymphoproliferative disorders. The addition of these agents in therapeutic regimens has improved considerably the treatment of hematological malignancies.

Thorough understanding of the complex interactions between components of immunological response has led to the arousal of the concept of immune-mediated anti-cancer therapy. Although, the use of monoclonal antibodies (MAbs) in hematological malignancies met with success, therapy of solid tumors has been impeded by many obstacles. Some MAbs have increased the efficacy of treatment of certain tumors with acceptable adverse events. Trastuzumab, cetuximab and bevacizumab have become FDA approved for the treatment of breast and colorectal cancer, respectively. The dosing strategies, timing and schedule of antibody administration, duration of treatment are yet to be determined under specific circumstances. Combinations with other biologic agents, such as small-molecule inhibitors of the same pathway would be really useful. Multimodality approaches are based on synergistic effects observed with the combination of antibodies with chemotherapeutic drugs and/or radiotherapy. Immune-mediated effects may be further exploited with the use of bivalent (bispecific) molecules, while radioimmunotherapy via radiolabelling of the antibody is feasible. Modified recombinant antibodies could be applied for toxin delivery to tumor cells, while molecules fused with drugactivating enzymes can mediate prodrug therapy. Increased penetrability into tumors can also be achieved with novel antibody fragments. In the future, better selection of patient subpopulations with tumors overexpressing disease-related clinical biomarkers could result in an increase in both efficacy and specificity of antibody-based treatment.

Autoimmune diseases affect about 3% of the world population, more frequently women than men, and their incidence is attributed to an immune response of a genetically predisposed individual to an environmental pathogen, under the influence of inadequate immuno-regulatory mechanisms. Advances in understanding the cellular activity pathways and cytokine expression profiles have led to new therapeutic regiments, like soluble receptors, monoclonal antibodies and molecular mimetics that have been employed to enhance or replace conventional immunosuppressive therapies. Among new biologicals that have been developed to target defined pathways of the adaptive immune response are TNF-α inhibitors. TNF-α is a proinflammatory cytokine elevated in many autoimmune lesions, and its deregulation characterizes many autoimmune diseases. TNF-α seems to exhibit an immunoregulatory role that can alter the balance of T regulatory cells and orchestrate acute immunological responses. More than half a million autoimmune patients have received therapy with anti-TNF-α antibodies, usually because they were refractory to conventional treatments. This review offers an update on TNF-α-targeted therapies used in patients suffering from various autoimmune diseases, based on the current knowledge of disease pathogenesis, with emphasis on the efficacy and safety that clinical trials have shown until now.

The rational design of artificial carriers for anchoring multiple copies of B and/or T cell epitopes, built-in vaccine adjuvants and "promiscuous" T cell epitopes for the construction of conjugates as antigenic substrates or potent immunogens has been the stimulus of intensive efforts nowadays. The unambiguous composition, the reliability and the versatility of the production of reconstituted antigens or immunogens has found a great number of biochemical applications in developing immunoassays of high sensitivity, specificity and reproducibility and in generating site-specific antibodies for usage as human vaccine candidates. In this review are summarized different types of artificial carriers currently used as dendrimers bearing branching segments, multimeric core matrices and templates with built-in folding devices. Emphasis is given to the construction and application of a helicoid-type Sequential Oligopeptide Carrier (SOCn) developed in our laboratory. The beneficial structural elements of SOCn induce a favorable arrangement of the conjugated peptides, which also retain their initial "active" conformation, so that potent antigens and immunogens are generated.

The specific targeting and inactivation of gene expression represents nowdays the goal of the mainstream basic and applied biomedical research. Both researchers and pharmaceutical companies, taking advantage of the vast amount of genomic data, have been focusing on effective endogenous mechanisms of the cell that can be used against abnormal gene expression. In this context, RNA represents a key molecule that serves both as tool and target for deploying molecular strategies based on the suppression of genes of interest. The main RNA-mediated therapeutic methodologies, deriving from studies on catalytic activity of ribozymes, blockage of mRNA translation and the recently identified RNA interference, will be discussed in an effort to understand the utilities of RNA as a central molecule during gene expression.

Regulation of immune responses is crucial in order to maintain immunological self-tolerance. This is maintained in the periphery by a number of cell types that have the capacity to control and regulate immune responses, thus preventing reactivity to self while monitoring appropriate, non-exuberant responses to non-self-antigens. The various mechanisms of regulation will be discussed in this review together with how this knowledge could be used to develop better drugs and treatments for various diseases.

Hyper activation of the immune system has emerged as an important clinical marker of HIV disease progression to AIDS. During the chronic phase of the disease, chronic immune activation is linked to systemic CD4 T-cell depletion and eventual immune failure. Additionally, the HIV virus per se seems to engage in a form of molecular parasitism for host T-cell signaling pathways and transcription factors (e.g. NFAT). Targeting host T-cell factors that mediate immune activation in conjunction with HAART (Highly Active Antiretroviral Therapy) could be the basis of novel immune-modulatory regimens that avoid the development of mutant viral strains. Hence the three-signal model of T-cell activation provides a framework for the rational selection of immunomodulatory therapies in HIV disease. Within this framework we examine the immunosuppressive, and antiretroviral properties of NFAT (calcineurin) inhibitors (cyclosporine and tacrolimus), the purine rescue pathway inhibitor mycophenolate mofetil and sirolimus (rapamycin). The results of small clinical studies to date are reviewed and they suggest that immunosuppressive medications might be a safe and effective adjunct to HAART in stable HIV disease, when such medications are used in full doses. Finally, we discuss the potential implications of such therapies for solid organ transplantation in HIV patients.

Despite an extraordinary investment in R&D the yield of successful new drugs has been disproportionately low in recent years, suggesting that the whole process of drug development requires rethinking and reform. Most analyses on this issue focus on molecular target discovery considerations. Target identification is characterized by a surplus of potential targets, but there is a translational bottleneck primarily due to limitations of currently employed target validation platforms. Meanwhile, the clinical entities, to which treatments are directed, are also highly complex in terms of pathophysiologic mechanisms and manifestations. In the present study we discuss the limitations of current molecular target discovery approaches mainly in regard to selectivity and efficacy. We also describe the constraints imposed on drug development by the current diagnostic constructs and the tendency towards dissecting the complex clinical phenotypes to component intermediate phenotypes. Finally, we describe how the reconsideration of molecular and clinical targets in polygenic diseases may lead to new strategies of pharmacological intervention directed against component dysfunctions, rather than the whole complex phenotype. Such strategies involve the combination of single ligands that act selectively on multiple molecules involved in a particular disease, or the employment of “multi-targeted” drugs, i.e. single drug molecules that hit selectively multiple receptors sharing common binding sites.