Autoimmune disease monoclonal antibodies

The first mouse monoclonal antibody specific for human CD3 was produced in 1979 and named orthoclone OKT3. Aside from its use in the laboratory, OKT3 became the first anti-CD3 antibody to be utilized in transplantation medicine, but its wider application was hampered by its immunogenic and mitogenic properties (reviewed in [6]). Consequently, humanized and engineered anti-CD3 antibodies were developed to circumvent these limitations (Table 1). Since T cells and the TCR are involved in many immunological diseases, it is not surprising that the application of CD3 antibodies is not restricted to the field of transplantation. For example, CD3 antibodies are tested in clinical studies of diseases such as autoimmune diabetes (type 1 diabetes), immune-mediated inflammatory arthritis and inflammatory bowel disease [7]. 

Priliximab (cM-T412) is an anti-CD4 chimeric monoclonal antibody that was evaluated in the clinic for the treatment of autoimmune diseases. Priliximab binds to CD4 on the surface of T cells and leads to a profound and sustained decrease in circulating CD4+ T cells decreased counts have been reported to be below normal levels at 18 and 30 months following single- and multiple-infusions.81 Similar findings were observed in preclinical studies in chimpanzees.82 The administration of priliximab was also associated with a cytokine-release syndrome that caused transient fever, myalgia, chills, headache, nausea, and/or hypotension that was accompanied by an increase in serum IL-6. Although evidence of efficacy was observed in clinical trials for CD, the... 

In December 1991, a project team was formed to develop fhe anfi-CD20 antibody. Acfually, two teams were formed at the same time, one to lead the development of anfi-CD4 and fhe ofher to lead fhe developmenf of anfi-CD20. Anfi-CD4, an antibody fhaf affecfs helper T cells, was fhought to have incredible potential to affect multiple autoimmune diseases, which were thought to be dependent on helper T cells. The autoimmune diseases included rheumatoid arthritis, and possibly, allergic asthma — both diseases with enormous markets and without effective treatmenf options. A nondeplefing modified version of fhe anfi-CD4 monoclonal antibody was still under consideration for additional clinical frials in 2005. 

Monoclonal antibodies directed against specific antigens such as CD3, CD4, CD25, CD40, IL-2 receptor, and TNF-a (discussed below) much more selectively influence T-cell subset function. The high specificity of these antibodies improves selectivity and reduces toxicity of the therapy and alters the disease course in several different autoimmune disorders. 

A major application of monoclonal antibodies is in clinical assays for drugs, bacterial and viral products, tumor antigens, hormones, and other circulating proteins. Their use in conjunction with immunoassays (Box 31-C) has provided increased specificity and sensitivity. Another major application is to observe binding of antibodies to specific proteins by electron microscopy. The location of specific receptor proteins can be established - as can the locations of ribosomal proteins and many other cellular components (Fig. 29-1). Monoclonal antibodies to acetylcholine receptors have been shown to induce symptoms of myasthenia gravis (Box 31-D), supporting the autoimmune origin of that disease. 1 Monoclonal antibodies specific for such a small hapten as mercuric ion have been isolated.k... 

Coles AJ, Wing M, Smith S, Coraddu F, Greer S, Taylor C, Weetman A, Hale G, Chatteqee VK, Waldmann H, Compston A. Pulsed monoclonal antibody treatment and autoimmune thyroid disease in multiple sclerosis. Lancet 1999 354(9191) 1691-5. 

Therapeutic monoclonal antibodies are widely recognized to be a most promising means to treat an increasing number of human diseases, including cancers and autoimmunity. To a large extent, the efficacy of monoclonal antibody treatment is because IgG antibodies have greatly extended persistence in vivo. However, conventional rodent models do not mirror human antibody pharmacokinetics. The key molecule responsible for the extended persistence antibodies is the major histocompatibility complex class I family Fc receptor, FcRn. We describe human FcRn transgenic mouse models and how they can be exploited productively for the preclinical pharmacokinetic evaluation of therapeutic antibodies. 

VI. Monoclonal Antibody Therapy in Rheumatologic and Autoimmune Diseases... 

In the 1980s, monoclonal antibodies were hailed as magic bullet therapeutics for the treatment of cancer, autoimmune disorders, and infectious diseases. Humanized monoclonal antibodies (MAbs) are now succeeding as drugs where mouse MAbs failed. Fully humanized MAbs are in the development pipeline, and therapeutic-biospecific MAbs are extending the versatility of nature s magic bullets. Several MAbs are now FDA-approved drugs (Table 2). Several MAbs are also in development (Table 3).3... 

EAE is traditionally regarded as a prototypic TH-1 CD4+ T-cell mediated autoimmune disease of the CNS. However, other cells of the immune system play important roles in the neuropathogenesis of this disorder. Defining the precise role of various cell types in EAE is complicated by the diverse and heterogeneous nature of EAE model systems. Recently, a new class of T-cells, TH-17 cells, has been shown to regulate inflammation in EAE. This unique subset of T helper cells produce IL-17 and develops along a pathway that is distinct from that of TH-1 and TH-2 cell differentiation (Park et al., 2005). It has been demonstrated that neutralization of IL-17 with IL-17-receptor-Fc-protein or an IL-17 monoclonal antibody ameliorates the disease course of EAE (Hofstetter et al., 2005). The production of IL-17 requires upstream activation of IL-23, and neutralizing antibodies specific for... 

Anti-CD4 monoclonal antibodies are used to treat various autoimmune diseases, such as rheumatoid arthritis, asthma, and psoriasis (1-3). Keliximab (rINN) (IDEC CE9.1) is a human-cynomolgus monkey chimeric (prima-tized) antibody with specificity for human and chimpanzee CD4. Clenoliximab (rINN) is an immunoglobulin G4 derivative of keliximab. These antibodies induce a more than 80% down-regulation of CD4 molecules on the surface of T lymphocytes. 

Perosa F, Scudeletti M, Imro MA, Dammacco F, Luccarelli G, Indiveri F. Anti-CD4 monoclonal antibody (mAb) and anti-idiotypic mAb to anti-CD4 in the therapy of autoimmune diseases. Clin Exp Rheumatol 1997 15(2) 201-10. 

Isaacs JD, Burrows N,Wing M, Keogan MT, Rebello PR, Watts RA, Pye RJ, Norris P, Hazelman BU HaleG, Waldmann H Humanized anti-CD4 monoclonal antibody therapy of autoimmune and inflammatory disease, Clin Exp immunol 1997,110 158-166... 

Nevertheless, the potential for autoimmune disease would clearly exist if one considers the polyspecificity of immune recognition molecules such as B cell receptors, antibodies, T cell receptors and MHC molecules. Further, the polyspecificity of immune receptors is also able to transcend the biochemically defined classes of biomolecules. For instance, the monoclonal antibody SYA/J6 has been demonstrated to have a dual specificity, binding a specific carbohydrate or a specific peptide with comparable affinity.68 Detailed analysis of the interatomic interactions between the antibody combining site and either the carbohydrate or the peptide antigens demonstrated that functional mimicry is possible without exact structural mimicry. This example underlines the case that it is not possible to predict with certainty whether the molecular surfaces of all potentially cross-reactive epitopes, whether of foreign or self molecules, will, or will not, be able to bind to a specific antibody. 

Recent reviews Hst more than 400 biotechnology-based pharmaceutical formulations either registered in clinical trials or undergoing review by the regulatory agencies for the treatment of nearly 150 diseases including cancer, infectious diseases, autoimmune diseases, and AIDS/HIV (1,2). Biotechnology-based pharmaceuticals already on the markets include recombinant blood factors, recombinant hormones, cytokines, vaccines, monoclonal antibody-based products, and therapeutic enzymes. 

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