The Effects of FK778 in Combination With Tacrolimus and Steroids: A Phase II Multicenter Study in Renal Transplant Patients

Vanrenterghem, Yves; Hooff, J van; Klinger, Marian; Włodarczyk, Zbigniew; Squifflet, Jean‐Paul; Mourad, Georges; Neuhaus, P.; Jurewicz, Adam; Rostaing, Lionel; Charpentier, B; Pączek, Leszek; Kreis, Henri; Chang, Rin; Lc, Paul; Jm, Grinyo; Short, Colin D.

doi:10.1097/01.tp.0000132562.54089.62

Cited by 65 publications

(32 citation statements)

References 14 publications

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“…[28][29][30] Furthermore, FK778 demonstrates inhibition of cytomegalovirus replication in animal and in vitro models. 7 In this study, we have shown for the first time that FK778 is safe and effective in preventing immunologic corneal graft rejection in rats.…”

Section: Discussionmentioning

confidence: 97%

“…[1][2][3][4][5][6] The substance has been found to be effective and safe in a phase II study in renal transplantation in humans. 7 As the mechanism of graft rejection in solid organ transplantation differs considerably from those in corneal transplantation, it is necessary to evaluate the efficacy of FK778 in preventing corneal graft rejection in an animal model.…”

Section: Introductionmentioning

confidence: 99%

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The new malononitrilamide immunosuppressant FK778 prolongs corneal allograft survival in the rat keratoplasty model

Birnbaum

Schwartzkopff

Scholz

et al. 2007

Eye

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Section: Discussionmentioning

confidence: 97%

Section: Introductionmentioning

confidence: 99%

The new malononitrilamide immunosuppressant FK778 prolongs corneal allograft survival in the rat keratoplasty model

Birnbaum

Schwartzkopff

Scholz

et al. 2007

Eye

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“…FK778 exerts beneficial effects in different experimental transplantation models, including suppression of acute and chronic allograft and xenograft rejection (1,3). In addition, clinical trials proved that FK778 is safe, well tolerated and reduces the incidence of acute rejection in human kidney transplant recipients (4).…”

Section: Introductionmentioning

confidence: 99%

Cellular growth inhibition by FK778 is linked to G1 arrest or S phase accumulation, dependent on the functional status of the retinoblastoma protein

Hoppe‐Seyler

Weigand²,

Lohrey³

et al. 2009

Int J Mol Med

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Abstract.The malononitrilamide FK778 is a novel immunosuppressive agent with antiproliferative activities. To gain insight into the molecular mechanism of FK778-mediated growth inhibition, we analyzed cells which differ in their p53 status and functionality of retinoblastoma protein (pRb). FK778 acted as a broad inhibitor of cell proliferation independent of the p53 or pRb status. However, the mechanism of FK778-mediated growth inhibition differed, leading either to cell cycle arrest in G1, or cell accumulation in S phase. This differential response was linked to the phosphorylation status of pRb. In addition, since FK778 was reported to exhibit antiviral activities, we analyzed the effect of FK778 on the growth stimulatory human papillomavirus (HPV)-16 and -18 E7 genes. Although growth of HPV-positive cells was strongly inhibited by FK778, we did not observe significant effects on viral E7 expression, indicating that the antiproliferative effect is not linked to an antiviral activity of FK778.

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“…19 The first clinical data showed that FK778 is safe and well tolerated and reduced the incidence rate of acute rejection in human renal transplant recipients. 5 The immunomodulatory effects of FK778 on human T cells have not been studied in detail before. In this study, we have investigated the tolerance-promoting potential of FK778 with an emphasis on CD4 ϩ T cells, since these cells play a crucial role in the regulation of the immune response directed against the allograft.…”

Section: Introductionmentioning

confidence: 99%

“…5 FK778 is a synthetic analog of the active metabolite of leflunomide, A77 1726. FK778 has a much shorter half-life than the parent drug, making it suitable for use in transplantation settings.…”

Section: Introductionmentioning

confidence: 99%

The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+CD25− T cells

Kreijveld

Koenen

Hilbrands

et al. 2006

Blood

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The induction of transplantation tolerance involves a T-cell-mediated process of immune regulation. In clinical transplantation, the use of immunosuppressive drugs that promote or facilitate this process would be highly desirable. Here, we investigated the tolerance-promoting potential of the immunosuppressive drug FK778, currently under development for clinical therapy. Using a human allogeneic in vitro model we showed that, upon T-cell receptor (TCR) triggering, FK778 induced a regulatory phenotype in CD4 ؉ CD25 ؊ T cells. Purified CD4 ؉ CD25 ؊ T cells primed in the presence of FK778 showed hyporesponsiveness upon restimulation with alloantigen in the absence of the drug. This anergic state was reversible by exogenous interleukin-2 (IL-2) and was induced independent of naturally occurring CD4 ؉ CD25 ؉ regulatory T cells. Pyrimidine restriction was a crucial requirement for the de novo induction of regulatory activity by FK778. The FK778-induced anergic cells showed suppressor activity in a cell-cell contactdependent manner; were CD25 high , CD45RO ؉ , CD27 ؊ , and CD62L ؊ ; and expressed cytotoxic T-lymphocyteassociated antigen-4 (CTLA-4), glucocorticoid-induced tumor necrosis factor receptor (GITR), and FoxP3. The cells revealed delayed p27 kip1 degradation and enhanced phosphorylation of STAT3. In conclusion, the new drug IntroductionThe use of immunosuppressive agents after solid-organ transplantation is crucial for the prevention of transplant rejection. In the past few decades, potent immunosuppressive regimens have been developed, currently leading to 1-year graft survival rates exceeding 85%. 1 However, in the long run, a considerable number of grafts are lost, mainly due to chronic rejection. Moreover, the continuous suppression of the immune system increases the risk for infections and malignancies. Therefore, the preferable approach to improve transplantation outcome is the induction of transplant tolerance: the acceptance of the graft in the absence of chronic immunosuppression. 2 Tolerance induction is believed to involve, at least in part, a T-cellmediated process of immune regulation. 3 Indeed, animal studies have revealed that regulatory T (Treg) cells form an intricate part of the tolerance-maintaining network. 4 Consequently, it is crucial that immunosuppressive drugs, administered to prevent acute graft rejection, do not interfere with the development of Treg cells. The ideal drug should not only inhibit effector T-cell function, but also enhance or facilitate Treg-cell function.FK778 is an immunosuppressive drug currently under development for use in organ transplantation. 5 FK778 is a synthetic analog of the active metabolite of leflunomide, A77 1726. FK778 has a much shorter half-life than the parent drug, making it suitable for use in transplantation settings. These compounds belong to the malononitrilamides (MNAs), a family of lowmolecular-weight substances structurally different from other currently applied drugs. 6 Their primary mode of action is the restriction of the de novo pyrimid...

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The Effects of FK778 in Combination With Tacrolimus and Steroids: A Phase II Multicenter Study in Renal Transplant Patients

Abstract: FK778 is pharmacologically active, well-tolerated, and safe. To fully benefit from this promising new drug, FK778 dosing will be optimized in subsequent studies.

Cited by 65 publications

References 14 publications

The new malononitrilamide immunosuppressant FK778 prolongs corneal allograft survival in the rat keratoplasty model

The new malononitrilamide immunosuppressant FK778 prolongs corneal allograft survival in the rat keratoplasty model

Cellular growth inhibition by FK778 is linked to G1 arrest or S phase accumulation, dependent on the functional status of the retinoblastoma protein

The immunosuppressive drug FK778 induces regulatory activity in stimulated human CD4+CD25− T cells

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