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Chapter: Pharmaceutical Biotechnology: Fundamentals and Applications : Monoclonal Antibodies in Solid Organ Transplantation

Rituximab - Specific Agents Used In Solid Organ Transplant

Rituximab is a monoclonal antibody directed at the CD20 cell surface protein. Rituximab is currently FDA approved for the CD20 positive forms of Non-Hodgkin’s lymphoma and refractory rheumatoid arthritis.

Rituximab

 

Rituximab is a monoclonal antibody directed at the CD20 cell surface protein. Rituximab is currently FDA approved for the CD20 positive forms of Non-Hodgkin’s lymphoma and refractory rheumatoid arthritis. The CD20 protein is expressed on all B-cells, from pre-B-cells to activated B-cells. This protein is not expressed on hematopoetic stem cells, plasma cells, or T-lympho-cytes (Tobinai, 2003). The CD20 protein is a calcium channel and is responsible for B-cell proliferation and differentiation (Tobinai, 2003). Early monoclonal anti-bodies developed against CD20 revealed that anti-body binding did not result in modulation of activity or shedding of the surface protein, making the development of a humanized anti-CD20 antibody rational (Tobinai, 2003). Rituximab was originally developed to treat B-cell lymphomas, as the vast majority of malignant B-cells express the CD20 receptor. Following continuously infused, high doses of engineered anti-CD20 monoclonal antibodies clear-ance of CD20 positive cells occurred within 4 hours of administration (Press et al., 1987). Circulating B-cell clearance was immediate; however, lymph node and bone marrow B-cell clearance was dose-dependent.

 

Rituximab was initially used in solid organ transplant recipients to treat post-transplant lympho-proliferative disorder (PTLD). Post-transplant lym-phoproliferative disorder is a malignancy that develops following exposure to high levels of T-cell depleting immunosuppression (see the section “Immunologic Targets: Rational Development/Use of Monoclonal Antibodies in Organ Transplant”). Under normal physiologic conditions, both the hu-moral and cellular immune systems work in concert to fight infection. In addition, cytotoxic T-lymphocytes survey the body for malignant cells. Current immu-nosuppression and induction therapy is focused ondecreasing communication and proliferation of T-lymphocytes which may lead to unopposed B-cell proliferation. Certain B-cells which are transfected with Ebstein Barr virus, or other viruses, may go onto unopposed cellular differentiation leading to PTLD. This disorder was first reported in two renal transplant recipients who developed “immunoblastic sarcomas” of the central nervous system (Matas et al., 1976). The incidence of post-transplant malignancy, specifically PTLD, increased as the number of solid organ transplants increased. Specific agents linked to the development of PTLD included OKT3 and rabbit anti-thymocyte globulin (Swinnen et al., 1990). The initial treatment for PTLD is a reduction in maintenance immunosuppression, to allow T-cell surveillance to resume and aid in the destruction of malignant cells. Rituximab was initially used in the 1990’s to target B-cell specific forms of PTLD that did not involve the central nervous system (Faye et al., 1998; Cook et al., 1999; Davis, 2004). The molecular size of rituximab precludes its use for central nervous system tumors. Administration of rituximab in patients with periph-eral lymphomas resulted in clearance of malignant B-cells for up to 12 months (Davis, 2004). Rituximab is currently used alone or in combination with chemo-therapy for severe or refractory PTLD.

 

Rituximab has also been employed as a desensi-tizing agent (see the section “Monoclonal Antibodies Administered Pre-transplant”) prior to solid organ transplant. Doses of 375 mg per m2 administered prior to transplant enabled transplantation across ABO incompatible blood types and transplantation of highly sensitized patients. Often rituximab is given in combination with other immunosuppressants to halt the production of new B-lymphocytes and prevent the formation of new plasma cells. Desensitization protocols involve administration of pooled immunoglobulin followed by plasmapheresis to remove donor specific antibody complexes. Rituximab is administered following the course of plasmapheresis for two reasons: (i) rituximab is removed by plasmapheresis and (ii) rituximab only targets B-lymphocytes, not the plasma cells currently secreting antibody. Therefore, timing of administra-tion is crucial to the success of the desensitization protocol.

 

 

Following transplant, rituximab is also used for the treatment of acute, refractory antibody-mediated rejection. Antibody-mediated rejection is character-ized by host recognition of donor antigens followed by T-cell proliferation and antigen presentation to B-cells. B-cells then undergo clonal expansion and differentiation into mature plasma cells which secrete anti-donor antibody. This immune process may occur before or after transplantation. Often the presence of antibodies against donor tissue is discovered priorto transplant, during final cross-match, thus prevent-ing hyperacute rejection. Unfortunately, in some cases low levels of antibody or memory B-cells exist which can facilitate antibody-mediated rejection within the first several weeks following transplant. Rituximab, therefore, is used to induce apotosis of the B-cells producing or capable of producing antibodies against the allograft. Unfortunately, the CD20 receptor is absent on mature plasma cells, therefore, rituximab can only stop new B-cells from forming. Plasmapheresis is necessary to remove antibodies produced by secreting plasma cells. The optimal number of doses and length of therapy necessary to suppress antibody mediated rejection is unknown.

 

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Pharmaceutical Biotechnology: Fundamentals and Applications : Monoclonal Antibodies in Solid Organ Transplantation : Rituximab - Specific Agents Used In Solid Organ Transplant |


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