Monoclonal antibodies immunosuppressive

Nonspecific immunosuppressive therapy in an adult patient is usually through cyclosporin (35), started intravenously at the time of transplantation, and given orally once feeding is tolerated. Typically, methylprednisone is started also at the time of transplantation, then reduced to a maintenance dose. A athioprine (31) may also be used in conjunction with the prednisone to achieve adequate immunosuppression. Whereas the objective of immunosuppression is to protect the transplant, general or excessive immunosuppression may lead to undesirable compHcations, eg, opportunistic infections and potential malignancies. These adverse effects could be avoided if selective immunosuppression could be achieved. Suspected rejection episodes are treated with intravenous corticosteroids. Steroid-resistant rejection may be treated with monoclonal antibodies (78,79) such as Muromonab-CD3, specific for the T3-receptor on human T-ceUs. Alternatively, antithymocyte globulin (ATG) may be used against both B- and T-ceUs. 

Murine monoclonal antibodies reacting with CD4, which is solely located on T-helper lymphocytes and monocytes/macrophages, may also be suited for immunosuppression. 

Treatment for PTLD is still controversial however, the most common treatment options include reduction of immunosuppression, chemotherapy,11,82 and anti-B cell monoclonal antibodies.79... 

Antibodies have and likely will find additional use in transplantation-related medicine. In general, cell-mediated immunological mechanisms are responsible for mediating rejection of transplanted organs. In many instances, transplant patients must be maintained on immunosuppressive drugs (e.g. some steroids and, often, the fungal metabolite cyclosporine). However, complications may arise if a rejection episode is encountered that proves unresponsive to standard immunosuppressive therapy. Orthoclone OKT-3 was the first monoclonal antibody-based product to find application in this regard. 

Basiliximab is a mouse/human chimeric monoclonal antibody with specificity and high affinity for the a-subunit of the IL-2 receptor. The antibody acts as an lL-2Ra antagonist and inhibits lL-2-mediated activation and proliferation of T l)unphocytes. It is indicated for the prevention of acute organ rejection in adult and paediatric renal transplant recipients in combination with other immunosuppressive agents like cyclosporin, azathioprine, mycophenolate mofetU... 

Pharmacology Daclizumab is an immunosuppressive, humanized IgGI monoclonal antibody produced by recombinant DNA technology that binds specifically to the alpha subunit (Tac subunit) of the human high-affinity interleukin-2 (IL-2) receptor that is expressed on the surface of activated lymphocytes. Daclizumab is a composite of human (90%) and murine (10%) antibody sequences. 

Muromonab-CD3 (Orthoclone OKT3) [Immunosuppressant/ Monoclonal Antibody] WARNING Can cause anaphylaxis monitor fluid status Uses Acute rejection following organ transplantation Action Murine Ab, blocks T-cell Fxn Dose Per protocol Adults. 5 mg/d IV for 10-14 d Peds. 0.1 mg/kg/d IV for 10-14 d Caution [C, /-] w/ Hx Szs, PRG, uncontrolled HTN Contra Murine sensitivity, fluid overload Disp Inj SE Anaphylaxis, pulm edema, fever/chills w/ 1st dose (premedicate w/ stCToid/APAP/antihistamine) Interactions t Effects W/ immunosuppressives t effects OF live virus vaccines t risk of CNS effects encephalopathy W/ indomethacin EMS Monitor for S/Sxs of Infxn monitor resp Fxn, known to... 

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. 

Contraindications Concurrent use of immunosuppressive agents, hypersensitivity to any murine or humanized monoclonal antibody preparation... 

The first monoclonal antibody—OKT3 or Orthoclone—was designed to be immunosuppressive and to reduce the likelihood of transplant rejection. Now monoclonal antibodies are used to treat a wide range of diseases, including arthritis, certain kind of cancers, and microbial and viral infections. 

A. General description Muromonab-CD3 is a murine monoclonal antibody (MW 150 kDa) to the CD3 antigen of human T cells. It functions as an immunosuppressant. The antibody is a biochemically purified IgG2a immunoglobulin... 

In the management of transplants, ALG and monoclonal antibodies can be used in the induction of immunosuppression, in the treatment of initial rejection, and in the treatment of steroid-resistant rejection. There has been some success in the use of ALG and ATG plus cyclosporine to prepare recipients for bone marrow transplantation. In this procedure, the recipient is treated with ALG or ATG in large doses for 7-10 days prior to transplantation of bone marrow cells from the donor. Residual ALG appears to destroy the T cells in the donor marrow graft, and the probability of severe graft-versus-host syndrome is reduced. 

Immunosuppressive monoclonal antibody with singular specificity to CDS antigen of human T cells... 

Class Immunosuppressive chimeric monoclonal antibody, specifically binds to and blocks the interleukin-2 receptor alpha chain on the surface of activated T- lymphocytes... 

The major classes of immunosuppressive drugs employed in clinical practice to avoid tissue rejection include calcineurin inhibitors, target of rapamycin (TOR) inhibitors, sphingosine-1 -phosphate receptor (S1P-R) modulators, cytotoxic agents, glucocorticoids and monoclonal antibodies. These drugs need to be used on a lifelong basis and have major undesirable side effects. 

The monoclonal antibodies used as immunosuppressive agents in tissue transplantation include muromonoab-CD3, daclizumab and basiliximab. Muromonoab-CD3 binds to a specific site on CD3 receptors and interferes with the ability of the TCR to bind the antigen and also inhibits CD3 receptor-dependent signal transduction mechanisms, all of which result in immune suppression. Both daclizumab and basiliximab are monoclonal antibodies directed against IL-2 receptors and consequently inhibit IL-2-dependent responses after tissue transplantation, resulting in immune suppression. The monoclonal antibodies used as immunosuppressive agents are described in detail in Chapter 5. 

Buhaescu I, Segall L, Goldsmith D, Covic A. New immunosuppressive therapies in renal transplantation monoclonal antibodies. JNephrol. 2005 18 529-536. 

Treatment with available anti-TN F-a inhibitors can be associated with the development of antibodies to the administered biologies [10]. The incidence is reported to be higher in patients receiving infliximab (13 to 60%), the chimeric monoclonal antibody containing a murine variable region, compared with the incidences reported for the fusion protein etanercept (<5 %) or the fully human antibody, adalimumab (-12% as monotherapy). The observed incidence of antibody formation is reduced by concomitant immunosuppressive therapies, such as methotrexate. Lower efficacy and higher incidences of infusion-related reactions have been reported in antibody-positive patients receiving infliximab [80]. 

Tang, S. C., Hewitt, K., Reis, M. D., and Berinstein, N. L. (1996). Immunosuppressive toxicity of CAMPATH1H monoclonal antibody in the treatment of patients with recurrent low grade lymphoma. Leuk. Lymphoma 24, 93-101. 

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