Targeting Osteoporosis and Rheumatoid Arthritis by Active Vaccination Against RANKL
Chronic diseases like osteoporosis and rheumatoid arthritis (RA) represent a major burden for the society, both in terms of quality of life for the affected individuals and associated health care costs. Approximately 25–30% of postmenopausal women are affected by osteoporosis, and RA occurs in about 1% of the adult population worldwide, with numbers expected to rise substantially as the average life expectancy in western societies increases (Riggs, Khosla, and Melton 2002; Lawrence, Helmick, Arnett, et al. 1998). Conventional treatments – mainly bisphosphonates and selective estrogen modulators in the case of osteoporosis, and NSAIDs and DMARDs in the case of RA - are efficient, but dosing regimens are sometimes difficult and side effects are often considerable. Novel therapeutic approaches are aimed at blocking specifically the molecular interactions at the basis of the disease process. For the treatment of RA a number of monoclonal antibodies (mAbs) and other biologicals are now available which neutralize central inflammatory cytokines like TNF αor IL-1 or lead to depletion of diseasepromoting B cells. Likewise, a mAb specifically targeting the RANK-RANKL interaction is in development for the treatment of osteoporosis and has shown very promising results (McClung, Lewiecki, Cohen, et al. 2006). Although highly efficient, these biological therapies have several potential drawbacks, including the high cost of goods and the risk of generating neutralizing antibody responses, which might limit their long term efficacy. Expensive production of mAbs has important economical implications, since it often prevents the use of such drugs as first-line treatment. A point in case are mAbs directed against TNFα; due to their high production costs they cannot compete with e.g. methotrexate financially; consequently, such drugs cannot easily become first line treatment and mass products. This is particularly unfortunate in this case, since TNFα-blocking agents are the most important disease modifying drugs for the treatment of RA. Although the frequency of administration may be lower for mAbs directed against RANKL (McClung, Lewiecki, Cohen, et al. 2006; Bekker, Holloway, Rasmussen, et al. 2004), the problem remains similar and it will be difficult to treat osteoporosis patients early, before onset of severe symptoms, with such expensive biologicals. Hence, a need for convenient, disease modifying and cost-effective long term treatments for such chronic diseases still exists.
KeywordsRheumatoid Arthritis Osteoclast Precursor Active Vaccination Specific Antibody Titer Additional Cysteine Residue
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