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Monoclonal antibodies in renal transplantation: a review

OKT3 is the first anti-CD3 monoclonal antibody available for treatment in humans. Over the last few years it has proven to be a very powerful immunosuppressive agent in renal transplantation. Clinical studies have shown that OKT3 is superior to high-dose steroids as first-line treatment for acute renal allograft rejection. Furthermore, it is comparable to antithymocyte globulin (ATG) in treating steroid-resistant rejection and is also effective as rescue treatment in ATG-and antilymphocyte globulin-(ALG-) resistant rejection. Despite its excellent rejection-reversal rate, OKT3 treatment is followed by a substantital percentage of re-rejections, most of which respond well to steroids. In the early post-transplantation period, a prophylactic course of OKT3 is very effective in preventing acute rejections, and in this respect it is probably equivalent to ATG. Indirect evidence exists that a prophylatic course of OKT3 may be beneficial in immunologically high-risk patients and in patients with delayed graft function. However, more clinical studies are required to answer the question whether OKT3 should be given as induction treatment, as first-line treatment, or as rescue treatment. To answer this question, the side effects of OKT3 should also be taken into account. First-dose-related side effects, although frequent and disturbing, are usually transient and seldom life-threatening, provided overhydration has been corrected and steroids have been given before the first administration. These side effects are attributed to the release of cytokines as a result of T-cell activation or lysis. After exposure of patients to OKT3 an increased incidence of infections and malignanies has been reported. However, it is not yet clear whether this is due to OKT3 as such, or whether it merely reflects the total burden of immunosuppression. Xenosensitization represents an important limitation to OKT3 treatment, although a second or third course can still be effective in patients with low antibody titers. The precise immunosuppressive mechanism of anti-CD3 monoclonal antibodies is yet unknown. Monitoring of patients treated with OKT3 revealed CD3 and/or T-cell antigen receptor depletion and immunological incompetence of remaining T cells. More clinical data are required to establish the correct dose and duration of OKT3 treatment. In conclusion, OKT3 is a powerful immunosuppressive agent but its real value in renal transplantation remains to be determined. A practical approach may be to reserve it for the treatment of steroid-resistant rejections. Research strategies for the development of new monoclonal antibodies for future use in renal transplant patients should be aimed at evading the major hazards of OKT3 treatment, namely side effects and xenoimmunization. Many promising monoclonal antibodies are currently under study: theoretically, anti-CD3/TCR monoclonal antibodies that are not mitogenic (such as CLB-T3/4.A, BMA 031, T10.B9.1A-31A, and OKT3 F[ab']2 fragments) may be expected to cause less immediate toxicity than OKT3. However, their immunosuppressive properties still have to be established. Monoclonal antibodies that are reactive with more restricted T-cell markers such as the interleukin-2 receptor (33B3.1 and anti-Tac), CD4 (BL4), and CD8 (Leu 2a) are generally better tolerated than OKT3. On theoretical grounds they may also be expected to cause fewer long-term complications. However, their immunosuppressive properties also remain to be established. In patients with high titers of anti-idiotypic antibodies to OKT3, WT 32 and perhaps RIV 9 and T10B9.1A–31A may be good alternatives.