Current
Topics in Medicinal Chemistry
ISSN: 1568-0266
Current Topics
in Medicinal Chemistry
Volume 6, Number 16, 2006
Contents
Immunomodulators in Medicinal Chemistry
and Drug Discovery
Guest Editor: Dr. Athanasia Mouzaki
Editorial Pp. 1655
Immunotherapeutic and Immunoregulatory
Drugs in Haematologic Malignancies Pp. 1657-1686
Gerassimos A. Pangalis, Marie-Christine Kyrtsonis, Theodoros
P. Vassilakopoulos, Maria N. Dimopoulou, Marina P. Siakantaris,
Christos Emmanouilides, Dimitris Doufexis, Sotirios Sahanas,
Flora N. Kontopidou, Christina Kalpadakis, Maria K. Angelopoulou,
Evangelia M. Dimitriadou, Styliani I. Kokoris and Panayiotis
Panayiotidis
[Abstract]
Monoclonal Antibodies in the Management of Solid
Tumors Pp. 1687-1705
Haralambos P. Kalofonos and Petros D. Grivas
[Abstract]
Anti-TNF-α
Antibody Therapies in Autoimmune Diseases Pp. 1707-1714
Kokona Chatzantoni and Athanasia Mouzaki
[Abstract]
Artificial Carriers: A Strategy for Constructing
Antigenic/ Immunogenic Conjugates Pp. 1715-1735
Maria Sakarellos-Daitsiotis, Dimitrios Krikorian,
Eugenia Panou Pomonis and Constantinos Sakarellos
[Abstract]
RNA-Mediated Therapeutics: From Gene Inactivation
to Clinical Application Pp. 1737-1758
Dimitra Kalavrizioti, Anastassios Vourekas, Vasiliki Stamatopoulou,
Chrisavgi Toumpeki, Stamatina Giannouli, Constantinos Stathopoulos
and Denis Drainas
[Abstract]
Regulatory T-Cells: Immunomodulators in Health
and Disease Pp. 1759-1768
Karen Scalzo, Magdalena Plebanski and Vasso Apostolopoulos
[Abstract]
Immunosuppresive Drugs in HIV Disease Pp.
1769-1789
Christos Argyropoulos and Athanasia Mouzaki
[Abstract]
Rethinking Target Discovery in Polygenic Diseases
Pp. 1791-1798
Christodoulos S. Flordellis, Antonis S. Manolis, Hervé
Paris and Andreas Karabinis
[Abstract]
Abstracts
[Back to top]
Editorial
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.
Athanasia Mouzaki
Division of Hematology,
Department of Internal Medicine,
Medical School,
University of Patras, Patras,
Greece
[Back to top]
Immunotherapeutic and Immunoregulatory Drugs in Haematologic
Malignancies
Gerassimos A. Pangalis, Marie-Christine Kyrtsonis,
Theodoros P. Vassilakopoulos, Maria N. Dimopoulou, Marina
P. Siakantaris, Christos Emmanouilides, Dimitris Doufexis,
Sotirios Sahanas, Flora N. Kontopidou, Christina Kalpadakis,
Maria K. Angelopoulou, Evangelia M. Dimitriadou, Styliani
I. Kokoris and Panayiotis Panayiotidis
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.
[Back to top]
Monoclonal Antibodies in the Management of Solid
Tumors
Haralambos P. Kalofonos and Petros D. Grivas
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 drug-activating 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.
[Back to top]
Anti-TNF-α
Antibody Therapies in Autoimmune Diseases
Kokona Chatzantoni and Athanasia Mouzaki
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.
[Back to top]
Artificial Carriers: A Strategy for Constructing
Antigenic/ Immunogenic Conjugates
Maria Sakarellos-Daitsiotis, Dimitrios Krikorian,
Eugenia Panou Pomonis and Constantinos Sakarellos
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.
[Back to top]
RNA-Mediated Therapeutics: From Gene Inactivation
to Clinical Application
Dimitra Kalavrizioti, Anastassios Vourekas, Vasiliki Stamatopoulou,
Chrisavgi Toumpeki, Stamatina Giannouli, Constantinos Stathopoulos
and Denis Drainas
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.
[Back to top]
Regulatory T-Cells: Immunomodulators in Health
and Disease
Karen Scalzo, Magdalena Plebanski and Vasso Apostolopoulos
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.
[Back to top]
Immunosuppresive Drugs in HIV Disease
Christos Argyropoulos and Athanasia Mouzaki
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.
[Back to top]
Rethinking Target Discovery in Polygenic Diseases
Christodoulos S. Flordellis, Antonis S. Manolis, Hervé
Paris and Andreas Karabinis
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.
|
