Alemtuzumab induction and belatacept maintenance in marginal pathology renal allografts

Sparkes, Tracy; Ravichandran, Bharath; Opara, Onumara; Ugarte, Richard; Drachenberg, Cinthia B.; Philosophe, Benjamin; Bromberg, Jonathan S.; Barth, Rolf N.

doi:10.1111/ctr.13531

Cited by 3 publications

(2 citation statements)

References 27 publications

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“…The combination of induction therapy with T-cell-depleting drugs and belatacept has been tested in several studies, with various outcomes. In one study, alemtuzumab induction followed by tacrolimus or belatacept led to a similar incidence of AR [58]. In another study, patients treated with T-cell-depleting induction therapy (either rabbit antithymocyte globulin [rATG] or alemtuzumab) followed by belatacept were compared with patients treated with rATG induction followed by tacrolimus [59].…”

Section: Clinical Outcomes Of De Novo Use Of Belatacept In Kidney Tramentioning

confidence: 99%

Costimulation Blockade in Kidney Transplant Recipients

Zwan

Hesselink

Hoogen

et al. 2019

Drugs

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Costimulation between T cells and antigen-presenting cells is essential for the regulation of an effective alloimmune response and is not targeted with the conventional immunosuppressive therapy after kidney transplantation. Costimulation blockade therapy with biologicals allows precise targeting of the immune response but without non-immune adverse events. Multiple costimulation blockade approaches have been developed that inhibit the alloimmune response in kidney transplant recipients with varying degrees of success. Belatacept, an immunosuppressive drug that selectively targets the CD28-CD80/CD86 pathway, is the only costimulation blockade therapy that is currently approved for kidney transplant recipients. In the last decade, belatacept therapy has been shown to be a promising therapy in subgroups of kidney transplant recipients; however, the widespread use of belatacept has been tempered by an increased risk of acute kidney transplant rejection. The purpose of this review is to provide an overview of the costimulation blockade therapies that are currently in use or being developed for kidney transplant indications.

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Section: Clinical Outcomes Of De Novo Use Of Belatacept In Kidney Tramentioning

confidence: 99%

Costimulation Blockade in Kidney Transplant Recipients

Zwan

Hesselink

Hoogen

et al. 2019

Drugs

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“…Antagonistic CTLA-4 antibodies, such as ipilimumab, increase immune activation and are successfully used in tumor therapy [8,9], whereas agonistic CTLA-4 fusion proteins, like commercially available belatacept and abatacept, act immunosuppressive. Treatment with belatacept has been shown to prevent rejection of allografts, particularly renal transplants [10,11], and abatacept is used to treat rheumatoid arthritis [12,13].…”

Section: Introductionmentioning

confidence: 99%

Preventive CTLA-4-Ig Treatment Reduces Hepatic Egg Load and Hepatic Fibrosis inSchistosoma mansoni-Infected Mice

Sombetzki

Rabes

Bischofsberger

et al. 2019

BioMed Research International

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Background. Hepatic fibrosis and granuloma formation as a consequence of tissue entrapped eggs produced by female schistosomes characterize the pathology of Schistosoma mansoni infection. We have previously shown that single-sex infection with female schistosomes mitigates hepatic fibrosis after secondary infection. This was associated with an increased expression of cytotoxic T-lymphocyte-associated protein-4 (CTLA-4), known as a negative regulator of T cell activation. Based on these findings, we hypothesized that administration of agonistic CTLA-4-Ig (Belatacept) is capable to prevent and/or treat hepatic fibrosis during schistosomiasis. Methods. Mice were infected with 50 S. mansoni cercariae and CTLA-4-Ig, or appropriated control-Ig was administered for 4 weeks. Preventive treatment started 4 weeks after infection, before onset of egg production, and therapeutic treatment started 8 weeks after infection when hepatic fibrosis was already established. Results. When given early after infection, livers of CTLA-4-Ig-treated mice showed significantly reduced collagen deposition and decreased expression of profibrotic genes in comparison to controls. In addition, administration of CTLA-4-Ig suppressed the inflammatory T cell response in infected mice. If therapy was started at a later time point when fibrogenesis was initiated, CTLA-4-Ig had no impact on hepatic fibrosis. Conclusion. We could demonstrate that an early preventive administration of CTLA-4-Ig suppresses effector T cell function and therefore ameliorates liver fibrosis. CTLA-4-Ig administration after onset of egg production fails to treat hepatic fibrosis.

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New Developments and Therapeutic Drug Monitoring Options in Costimulatory Blockade in Solid Organ Transplantation: A Systematic Critical Review

de Graav,

Udomkarnjananun,

Baan

et al. 2024

Therapeutic Drug Monitoring

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Purpose: In this review, the authors summarized the latest developments in costimulatory blockade to prevent rejection after solid organ transplantation (SOT) and discussed possibilities for future research and the need for therapeutic drug monitoring (TDM) of these agents. Methods: Studies about costimulatory blockers in SOT in humans or animal transplant models in the past decade (2014–2024) were systematically reviewed in PubMed, European Union clinical trials (EudraCT), and ClinicalTrials.gov. Results: Seventy-five registered clinical trials and 58 published articles were found on costimulation blockade of the CD28-CD80/86, CD40-CD40L, and OX40-OX40L pathways. Belatacept, an antagonist of the CD28-CD80/86 pathway, is the only approved costimulatory agent in SOT, hence accounting for most of the research. Other identified costimulatory blocking agents included abatacept and CD28 antagonists tegoprubart, dazodalibep, and TNX-1500. Although tegoprubart was unsuccessful in pancreas transplantation in nonhuman primates, trials in human kidney transplantation are underway. Dazodalibep trials faced recruitment challenges. TNX-1500 was unsuccessful in animal studies and is currently not pursued in humans. After discontinuation of iscalimab (CD40-CD154 pathway antagonist) in SOT, the alternatives, bleselumab and KPL404, showed promising results in kidney transplantation and cardiac xenotransplantation. Studies on secondary costimulatory pathway antagonists, such as OX40-OX40L, have only used animal models. Despite the low interindividual variability in pharmacokinetics (PK) in all studied agents, TDM could be useful for optimizing dosing in PK/pharmacodynamic (PD) studies. Conclusions: The routine use of costimulation blockade in SOT is hindered by problems in efficacy compared with the standard of care. Costimulatory inhibitors could be combined in a calcineurin inhibitor-free regimen. Future PK/pharmacodynamic studies in costimulatory agents and personalized medicine could warrant TDM of these agents.

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Alemtuzumab induction and belatacept maintenance in marginal pathology renal allografts

Cited by 3 publications

References 27 publications

Costimulation Blockade in Kidney Transplant Recipients

Costimulation Blockade in Kidney Transplant Recipients

Preventive CTLA-4-Ig Treatment Reduces Hepatic Egg Load and Hepatic Fibrosis inSchistosoma mansoni-Infected Mice

New Developments and Therapeutic Drug Monitoring Options in Costimulatory Blockade in Solid Organ Transplantation: A Systematic Critical Review

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