Monoclonal Antibodies in
Anti-inflammatory Therapy
INTRODUCTION
For decades corticosteroids and other immunomodu-latory agents have been
the cornerstone of therapy for inflammatory conditions. These other
immuno-modulatory agents are often referred to as disease-modifying
anti-rheumatic drugs (DMARDs), which include not only anti-metabolites like
methotrexate, azathioprine and leflunomide, but also gold salts,
D-penicillamine, some “antimalarials” (chloroquine and hydroxychloroquine), as
well as sulfasalazine. The successful development of targeted biologic agents,
specifically monoclonal antibodies and recom-binant receptor fusion proteins,
as anti-inflammatory therapies for allergic and autoimmune diseases over the
past decade has not only revolutionized options for patients with these
disorders, but also begun to further elucidate the underlying pathology. Though
at
present there are only a handful of approved biologics for these chronic
immunologic diseases, this area of pharmaceutical research and development is
rapidly growing.
The currently approved targeted therapies for autoimmune disorders
either block the tumor necrosis factor alpha (TNF-a ) or interleukin-1 (IL-1) pathway, block lymphocyte activation or
migration, or directly deplete lymphocyte subsets. For allergic inflamma-tory
conditions (allergic asthma), there is currently only one approved targeted
therapy, omalizumab (Xolair ), which acts by neutralizing soluble
immu-noglobulin E (IgE). Although the potential risk-to-benefit ratio is always
of central importance in making therapeutic decisions, the acceptable
thresholds for potential safety risks is substantially different in these
chronic inflammatory conditions as compared to more acutely life-threatening
settings (like cancer and organ transplantation), where some of these types of
immunomodulatory agents were first used. Besides the safety considerations, demonstration
of therapeu-tic efficacy in these chronic inflammatory conditions also poses
different challenges than for cancer or transplantation, because most of these
disease courses wax and wane with episodic flares and spontaneous recoveries
that complicate interpretation of efficacy in the short term. The hope for
these newer therapies is that they will in fact provide safer and more
tolerable therapeutic opportunities that can be used earlier in the course of
disease to not only maintain control over the episodic disease flares, but also
prevent the less reversible organ damage posed in the long-term from
uncontrolled chronic inflammation.
There are already several agents with approvals for use in one or more
specific forms of autoimmune arthritis including: rheumatoid arthritis (RA),
juvenile rheumatoid arthritis (JRA), psoriatic arthritis (PsA), and ankylosing
spondylitis (AS). Several agents are also nowapproved for use in one or more
forms of inflammatory bowel disease, including fistulizing and/or non-fistuliz-ing
Crohn’s disease (CD), and/or ulcerative colitis (UC). A few agents are approved
for use in plaque psoriasis (PP) and only one targeted biologic treatment is
approved for use in relapsing, remitting multiple sclerosis (RRMS). Also, as
mentioned above, there is currently only one approved targeted agent for use in
allergic asthma.
Though the list of indications continues to grow for these agents and
newer agents every year, this chapter will focus on describing approved
biologic therapies for only a few of the major inflammatory disease areas in
order to provide a solid introduction, but without attempting to be exhaustive.
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