Monoclonal Antibodies in
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.