Biomedical Engineering Reference
In-Depth Information
16
DEVELOPMENT OF LATENT CYTOKINE
FUSION PROTEINS
L
ISA
M
ULLEN
,G
ILL
A
DAMS
,R
EWAS
F
ATAH
,D
AVID
G
OULD
,A
NNE
R
IGBY
,M
ICHELLE
S
CLANDERS
,
A
POSTOLOS
K
OUTSOKERAS
,G
AYATRI
M
ITTAL
,S
ANDRINE
V
ESSILLIER
,
AND
Y
UTI
C
HERNAJOVSKY
Bone and Joint Research Unit, William Harvey Research Institute, Barts and The London Medical School, London, UK
16.1 Introduction
16.2 Description of concept
16.3 Limitations of the latent cytokine technology
16.4 Generation of latent cytokines
16.5 Applications and potential clinical indications
16.6 Alternatives/variants of approach
16.7 Challenges (production and development)
16.8 Conclusions and future perspectives
Acknowledgments
References
therapeutic intervention can then consist of either the cyto-
kine itself or cytokine antagonists.
However, cytokines have a remarkably complex biology,
and there are a number of characteristics of these molecules
that must be considered prior to any attempt to use them as
therapeutic agents. First, cytokines are pleiotropic, meaning
that they have the ability to interact with not one, but a variety
of cellular targets. In practice, this means that cytokines have
different effects on a wide variety of cells. Second, cytokines
share an attribute known as redundancy, which describes the
fact that the same biological function can be exerted by several
distinct cytokines. The third characteristic of cytokines that is
abundantly clear is that these potent signaling molecules do
not function in isolation. Indeed, these proteins are known to
function as networks or cascades of interacting factors, which
are able to affect the synthesis of other cytokines.
So, how do these characteristics of cytokines affect their
potential use as therapeutics? The fact that these molecules
are not only secreted by, but also recognized by a wide
variety of both immune and nonimmune cells means that
systemic administration can result in a number of
undesirable side-effects. The redundant nature of cytokines
also means that blocking of a particular cytokine may not
necessarily have the desired affect on a pathological condi-
tion. There is also the possibility that blocking or augment-
ing a specific cytokine may result in unpredictable outcomes
due to unforeseen effects on other cytokine pathways.
A further complication of the use of cytokines as ther-
apeutics lies in the paracrine and autocrine manner in which
these molecules function. Cytokines are local mediators
that are designed to exert biological effects in their local
16.1
INTRODUCTION
Cytokines are mediators of cell-cell communication. The
majority of cytokines are low molecular-weight glycopro-
teins that play key roles in a wide range of biological
processes, including the regulation of immunity, inflamma-
tion, and hematopoiesis [1]. These soluble hormone-like
proteins are a key component of the immune system,
regulating lymphocyte turnover, differentiation, and activa-
tion. Hence, it is unsurprising that in chronic pathological
conditions, the cytokine network is deregulated.
Therefore, given the importance and central role of
cytokines in health and disease, it has long been recognized
that these proteins may be developed as therapeutics. To
develop cytokine-based therapies, it must first be established
whether the cytokine of interest has a beneficial or harmful
effect in the pathophysiological situation under scrutiny. The
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