Rheumatoid arthritis monoclonal antibodies

Anticytokine antibodies Infliximab Chimeric (mouse/human) monoclonal antibody against TNEa. Effective in the treatment of severe forms of rheumatoid arthritis where it can halt disease progression, or inflammatory bowel disease (EBD). 

Adalimumab (Humira ) is a folly human anti-TNF monoclonal antibody that is mainly used in combination with methotrexate to treat rheumatoid arthritis in adults [3]. Meanwhile, it is also used against arthritis of psoriasis and ankylosing spondylitis. Its therapeutic value in Crohn s disease is under clinical trial. 

Haringman JJ, Gerlag DM, Smeets TJ, et al. A randomized placebo controlled trial with an anti-MCP-1 (CCL2) monoclonal antibody in patients with rheumatoid arthritis [Abstract 519], Arthritis Rheum 2004 50(Suppl) S238. 

The most widely studied therapeutic proteins produced in plants include monoclonal antibodies for passive immunotherapy and antigens for use as oral vaccines [40]. Antibodies against dental caries, rheumatoid arthritis, cholera, E. coli diarrhea, malaria, certain cancers, Norwalk virus, HIV, rhinovirus, influenza, hepatitis B virus and herpes simplex virus have been produced in transgenic plants. However, the anti-Streptococcus mutans secretory antibody for the prevention of dental caries is the only plant-derived antibody currently in Phase II clinical trials [40]. Until recently, most antibodies were expressed in tobacco, potato, alfalfa, soybean, rice and wheat [9], It has been estimated that for every 170 tons of harvested tobacco, 100 tons represents harvested leaves. A single hectare could thus yield 50 kg of secretory IgA [3, 41]. Furthermore, it has been estimated that the cost of antibody production in plants is half that in transgenic animals and 20 times lower than in mammalian cell cul-... 

Embrel (Wyeth) Monoclonal antibody based (treatment of rheumatoid arthritis) 1.3... 

Humira (EU USA also sold as Trudexa in EU) (adalimumab r (anti-TNF) human monoclonal antibody created using phage display technology Cambridge Antibody Technologies Abbott (USA) Abbott (EU) Rheumatoid arthritis... 

Moreland, L.W. et al., Treatment of refractory rheumatoid arthritis with a chimeric anti-CD4 monoclonal antibody, Arthritis Rheum., 36 307, 1993. 

Figure 7.9. FcyRI expression in blood and synovial-fluid neutrophils. Neutrophils were isolated from the blood (trace ii) and synovial fluid (trace iii) of a patient with rheumatoid arthritis. Expression of CD64 (FcyRI) was then measured by FACS analysis. Trace (i) indicates the fluorescence distribution of a non-immune isotype control monoclonal antibody. Similar results were obtained in 6 out of 11 patients with rheumatoid arthritis.

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. 

Tumor Necrosis Factor There are two types of tumor necrosis factor TNF-a and TNF- 8. Of the two, TNF-a has been studied in more detail. TNF-a is a 157 amino acid polypeptide. It is a mediator of immune regulation, including the activation of macrophages and induction of the proliferation of T cells. Another TNF-a function is its cytotoxic effects on a number of tumor cells. Recent research, however, concentrates on its property in the stimulation of inflammation, particularly in the case of rheumatoid arthritis. Clinical trials are being conducted with drugs to block TNF-a with anti-TNF-a monoclonal antibodies. These antibodies target the excessive levels of TNF-a in the synovial fluid of joints and provide relief to sufferers of rheumatoid arthritis (Exhibit 4.10). 

TGN1412 (CD28-SuperMAb) is a humanized monoclonal antibody that binds and acts as an agonist for the CD28 receptor of the immune system s T cell. It is intended to treat B cell chronic lymphocytic leukemia (B-CLL) and rheumatoid arthritis. 

Maini, R. N., Breedveld, E. C., Kalden, J. R., et al. (1998) Therapeutic efficacy of multiple intravenous infusions of anti-tumor necrosis factor alpha monoclonal antibody combined with low-dose weekly methotrexate in rheumatoid arthritis. Arthritis and Rheumatism. 41, 1552-1563. 

Keystone, E. C., Kavanaugh, A. E., Sharp, J. T., et al. (2004) Radiographic, cUnical, and functional outcomes of treatment with adaUmumab (a human anti-tumor necrosis factor monoclonal antibody) in patients with active rheumatoid arthritis receiving concomitant methotrexate therapy a randomized, placebo-controUed, 52-week trial. Arthritis and Rheumatism. 50, 1400-1411. 

Barrera, P., Joosten, L. A., den Broeder, A. A., van de Putte, L. B., van Riel, P. L., and van den Berg, W. B. (2001) Effects of treatment with a fully human anti-tumour necrosis factor alpha monoclonal antibody on the local and systemic homeostasis of interleukin 1 and TNFalpha in patients with rheumatoid arthritis. Annals of the Rheumatic Diseases. 60, 660-669. 

Examples of antibodies in the market include trastuzumab (anti-HER2 monoclonal antibody), rituximab, natalizumab (x4-integiin antibody), abciximab, infiximab (targets TNF-a in Crohn s disease and rheumatoid arthritis), alemtuzumab, adalimumab (TNF-a antibody for the treatment of rheumatoid arthritis) and efalizumab (anti-CDlla monoclonal antibody for the treatment of psoriasis)Rituximab is a mouse/human chimeric anti-CD20 monoclonal antibody used for the treatment of various l)unphoid malignancies. As CE)20 antigen is found on the surface of... 

A variety of medical conditions are now believed to be caused or exacerbated by overproduction of certain cytokines in the body. A variety of pro-inflammatory cytokines, including IL-6 and IL-8 as well as TNF, have been implicated in the pathogenesis of both septic shock and rheumatoid arthritis. Inhibiting the biological activity of such cytokines may provide effective therapies for such conditions. This may be achieved by administration of monoclonal antibodies raised against the target cytokine, or administration of soluble forms of its receptor which will compete with cell surface receptors for cytokine binding. 

Adalimumab is a recombinant, fully human antitumor necrosis factor monoclonal antibody approved in the US and Europe for the treatment of adult patients with moderate to severe, active rheumatoid arthritis. It has to be injected subcutaneously. The most common side effects of adalimumab are injection site reactions. Adalimumab increases the risk of rare serious infections. Rare side effects include worsening or initiation of congestive heart failure, a lupus-like syndrome, a promotion of lymphoma, medically significant cytopenias, and worsening or initiation of a multiple sclerosis like neurological disease. 

Infliximab is a monoclonal antibody against TNF-a (see Chapter 26, Section III.d.1). It has been approved for the treatment of psoriasis, Crohn s disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and ulcerative colitis. Similar immunosuppressants are etanercept, and adali-mumab. 

Mecfianism of Action A monoclonal antibody that binds specifically to tumor necrosis factor (TNF) alpha, blocking its interaction with cell surface TNF receptors, Tfier-apeutic Effect Reduces inflammation, tenderness, and swelling of joints slows or prevents progressive destruction of joints in rheumatoid arthritis. 

Some drugs situations are frankly confusing and need to be explored in greater depth. For example, tumor necrosis factor (TNF) is produced in the body as a natural defense against the many spontaneous tumors that arise in the body and has been suggested as a treatment for cancer, which may very well be effective under some conditions. However, TNF is also believed to be involved in the pain associated with rheumatoid arthritis, and monoclonal antibodies with specific activity against TNF are now on the market. The use of TNF is therefore a complex issue and needs to be evaluated with considerable care. 

Ten years ago monoclonal antibodies (MAb) were of considerable interest but faded after clinical and commercial failures. Further clinical and laboratory testing revealed that only humanized MAb were likely to be of any benefit in a human patient. From a practical standpoint this research developed, and humanized MAb were launched onto the market, with success in the treatment of several diseases including rheumatoid arthritis. These developments justify a chapter on the subject in this book. 

Many attempts have been made to link monoclonal antibodies specific for antigenic determinants on cancer cells to protein toxins such as ricin (Box 29-A). It is hoped that this may provide an effective way of carrying toxins into cancer cells/ 1 r Therapeutic human monoclonal antibodies are already in use as antirejection drugs for kidney transplantation, for treatment of rheumatoid arthritis, Crohn disease, and for some types of cancer/... 

Maini, R., St. Clair, E. W., Breedveld, F., Furst, D., Kalden, J., Weisman, M., Smolen, J., Emery, P. 1999. Infliximab (chimeric anti-tumor necrosis factor alpha monoclonal antibody) versus placebo in rheumatoid arthritis patients receiving concomitant methotrexate a randomised phase HI trial. Attract study group. Lancet 354 1932-1939. 

TNF-rt effects cellular function via activation of specific membrane-bound TNF receptors (TNFRi, TNFR2). Administered soluble TNF receptors, by combining with soluble TNF-, can inhibit the effects of the endogenous cytokine. Monoclonal anti-TNF antibodies can, in theory, cross-link TNF receptors on the cell surface and inhibit T cell and macrophage function. Three drugs interfering with TNF- have been approved for the treatment of rheumatoid arthritis. 

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