CD25 mAb

Wdien administered on the day of renal transplantation, both anti-CD25 mAbs were highly effective in reducing the frequencies of first rejection episodes or graft loss (by approximately 20 to 30%) (29-32). Moreover, the number of rejection episodes subjected to antibody therapy was reduced by about 50% as compared with placebo. The safety profile of both mAbs was similar to that of placebo, at least within the first 6 to 12 months after administration. In particular, neither infections nor malignancies were found to be increased in incidence, and... 

Anti-CD25 mAbs are also useful in the therapy of other allografts, such as liver transplantation and bone marrow transplantation (34, 35) and may also prove beneficial in other disorders, such as rheumatoid arthritis and systemic lupus erythematosus (see Section VI.)... 

The exact mechanism of action of the anti-CD25 mAbs is not completely understood but likely results from the binding of the anti-CD25 mAbs to the IL-2 receptor on the surface of activated, but not resting, T cells. Significant depletion of T cells does not appear to play a major role in the mechanism of action of these mAbs. Therapy with the anti-IL-2R mAbs is thought to result in a relative decrease of the expression of the a chain, either from depletion of coated lymphocytes or modulation of the a chain secondary to decreased expression or increased shedding. 

The chimeric human/murine (basiliximab and dacluzi-mab) or murine (inolimomab) monoclonal antibodies are specifically directed against a part (CD25) of the interleukin-2 (IL-2) receptor. Binding of one of these antibodies to CD25 thereby displaces physiological IL-2 and prevents proliferation of activated T-lymphocytes. 

Hall BM, Chen J, Robinson C, Xy H, et al. 2002. Therapy with mab to CD25 blocks function of CD4+CD25+ T regulatory cells which maintain transplantation tolerance. Nephrology. 7 A111-A111. 

Zenapax daclizumab (1997) Anti-CD25 (IL-2R) (mAb-IgGl) Acute organ rejection Not done... 

Basiliximab is a chimeric (murine/human) MAb (also known as CD25 antigen) on the surface of activated T-lymphocytes the calculated MW of the glycoprotein is 144 kDa. 

Several antibody-based products are indicated for non-cancer applications. Zena-pax, for example, is used for the prevention of acute kidney transplant rejection. The product is a humanized mAb that specifically binds the a-chain (also known as CD25 or Tac) of the IL-2 receptor. This receptor is expressed on the surface of activated lymphocytes. It acts as an antagonist of the receptor, thus blocking the binding of IL-2 that in turn prevents the stimulation of lymphocytes mediating organ rejection. 

Switzerland basiliximab antibody Simulect Humanized murine MAb directed against CD25 (lL-2 receptor) Immuno- suppressant... 

Daclizumab Zenapax Hoffmann La Roche humanized mAb CD25 kidney transplant rejection 1997 IgGl 14%... 

Basiliximab Simulect Novartis chimeric mAb CD25 kidney transplant rejection 1998 IgGl <2%... 

Immunomodulatory, Immunosupressant. Humanized IgGl Mab that binds to the human IL-2R (anti-CD25). Composite of 90% human (IgGl constant plus variable framework regions of the Eu myeloma Ab) and 10% murine Ab (CDR) sequences. 

Later we shall review the extensive literature that exists for monoclonal antibody therapy in animal models both as immunosuppressants and agents to induce antigen-spedfic immunological tolerance and yet, as already stated, only mAbs to CDS and CD25 (IL-2 receptor) are licensed for transplantation in humans. These two targets for therapy may not even be the best choices based on experimental data, so why have they had such relative success ... 

The literature for describing the use of mAbs to CD25 in rodent studies is relatively small when one considers this specificity is a target for human transplantation. Predominantly models of heart or kidney transplantation are described where significant delays in allograft rejection were observed (81-83). 

The few examples of skin transplantation show only modest effects on survival at best (84). Unlike mAb to CD4 and CDS the induction of tolerance as a therapeutic procedure could not be routinely accomplished, though long-term survival was demonstrated in a proportion of rats receiving kidney allografts (83). However, animals with intact transplants were not tested for tolerance by re-grafting. Several studies in rodents demonstrated synergy with sub-therapeutic doses of cyclosporin and this is probably the most important feature when one considers that mAb to CD25 is used as an adjunct to triple therapy (4, 82). 

Indeed if one does ever evoke regulatoiy T cells in a clinical setting such a treatment may well be counterproductive since such cells are almost certainly CD25". A much longer period of time will be necessary to determine if current use of these mAbs will lead to improved graft and patient survival at five years. 

Anti-CD3 mAb treatment 437 Monoclonal antibodies to CD4 and CDS 440 Monoclonal antibodies to CD25 (IL-2 receptor) 442 Blockade of co-stimulation through CD40 and CD28 pathways 443 T cell depletion 444 Summary 445 References 445... 

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