RECOMBINANT HUMAN TUMOR NECROSIS FACTOR RECEPTOR Fc FUSION PROTEIN(TNFR:Fc) THERAPY IN KIDNEY TRANSPLANT RECIPIENTS RECEIVING OKT3 INDUCTION THERAPY

Abstract

294 The monoclonal antibody OKT3 is widely used for induction and treatment of rejection in organ transplant recipients. However, initial doses of the drug are often associated with a cytokine-induced acute clinical syndrome (ACS), which appears to be primarily mediated by TNFα. Several approaches have been used to minimize OKT3-ACS symptoms including pretreatment with corticosteroids, IL-10, and anti-TNF monoclonal antibodies. This study examined the safety of a recombinant human TNF receptor Fc fusion protein(TNFR:Fc) administered post-operatively to kidney transplant recipients, and the ability of the drug to reduce OKT3-ACS symptoms. Methods: Sixteen renal allograft recipients undergoing OKT3 induction therapy were randomized into 4 groups of 4 patients each. All patients received intraoperatively IV azathioprine (Imuran) 3 mg/kg and methylprednisolone 3 mg/kg 1 hour prior to 2.5 mg IV OKT3. Daily IV dosing of 2.5 mg OKT3 was continued for 12 days and CsA was initiated when serum creatinine ≤3.0. The 3 treatment groups received TNFR:Fc (4, 8, or 16 mg/m2) 1 hour prior to OKT3 administration on days 0 and 3. ACS symptoms were assessed on post-transplant days 1 to 3 using a scoring system. Serum cytokine levels(IL-2, IL-4, IL-6, IFNγ, GM-CSF, endothelin-1, NO) were determined using ELISA, RIA, and colorimetry. Serum creatinine and C-reactive protein (CRP) levels were also followed. Results: For most parameters tested there were no differences between groups. Noteworthy findings are summarized:TableThe etiology of the higher incidence of infection in treated patients was unclear. The infections were minor, resolved, and typical of the patient population. The small size of the study and confounding factors such as gender and transplant type (cadaveric vs. living) likely contributed to the observed difference. There were no other differences in adverse event profiles between the two groups. Conclusion: This study suggests that TNFR:Fc is well tolerated by renal transplant patients receiving OKT3 induction therapy. TNFR:Fc therapy may offer some improvement in symptoms associated with OKT3-ACS. Considering the evidence implicating TNFα in the pathogenesis of acute rejection. TNFR:Fc may be a useful adjuvant immunomodulator in the subacute period (1 to 6 months) following transplant, allowing a reduction or earlier withdrawal of steroids.