Assessment of Belatacept-Mediated Costimulation Blockade Through Evaluation of CD80/86-Receptor Saturation

Latek, Robert; Fleener, Catherine; Lamian, Vahideh; Kulbokas, Edward J.; Davis, Patricia M.; Suchard, Suzanne J.; Curran, Mark; Vincenti, Flavio; Townsend, Robert M.

doi:10.1097/tp.0b013e31819b5a58

Cited by 93 publications

(92 citation statements)

References 11 publications

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“…On the basis of previously published in vitro data, trough levels achieved with 4-wk dosing (reported in Table 5) would be expected to provide 84 to 85% CD86 receptor saturation, and trough levels achieved with 8-week dosing would be expected to provide 53 to 59%, consistent with what was seen in this study: 74 and 56%, respectively. 23 Although belatacept binds to both the CD86 and CD80 receptors, our assessment focused on CD86 receptors because only CD86 is constitutively expressed on monocytes, and saturation of these receptors more closely reflects inhibition of the alloresponse. 23 A limitation of this study is that our cohort was a nonrandomized, self-selected group of patients who did particularly well during the first year.…”

Section: Discussionmentioning

confidence: 99%

Five-Year Safety and Efficacy of Belatacept in Renal Transplantation

Vincenti

Blancho

Dürrbach

et al. 2010

Journal of the American Society of Nephrology

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Belatacept is a first-in-class co-stimulation blocker in development for primary maintenance immunosuppression. A Phase II study comparing belatacept with cyclosporine (CsA) for prevention of acute rejection and protection of renal function in kidney transplant recipients demonstrated similar efficacy and significantly higher measured GFR at 1 year for belatacept, but the incidence of posttransplantation lymphoproliferative disorder was higher. Here, we present the results for the extension of this trial, which aimed to assess long-term safety and efficacy of belatacept. Seventy-eight of 102 patients who were receiving belatacept and the 16 of 26 who were receiving CsA completed the long-term extension period. GFR remained stable in patients who were receiving belatacept for 5 years, and the incidences of death/graft loss or acute rejection were low. The frequencies of serious infections were 16% for belatacept and 27% for CsA, and neoplasms occurred in 12% of each group. No patients who were treated with belatacept and one patient who was treated with CsA developed posttransplantation lymphoproliferative disorder during the follow-up period. Serious gastrointestinal disorders occurred more frequently with belatacept (12% belatacept versus 8% CsA), and serious cardiac disorders occurred more frequently with CsA (2% belatacept versus 12% CsA). Pharmacokinetic analyses showed consistent exposure to belatacept over time. CD86 receptor saturation was higher in patients who were receiving belatacept every 4 weeks (74%) compared with every 8 weeks (56%). In conclusion, this study demonstrated high patient persistence with intravenous belatacept, stable renal function, predictable pharmacokinetics, and good safety with belatacept over 5 years.

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Section: Discussionmentioning

confidence: 99%

Five-Year Safety and Efficacy of Belatacept in Renal Transplantation

Vincenti

Blancho

Dürrbach

et al. 2010

Journal of the American Society of Nephrology

Self Cite

175

139

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“…Notably, estimated mean GFR at year 10 was similar for the belatacept 4‐weekly (67.0 mL/min per 1.73 m 2 ) and 8‐weekly (68.7 mL/min per 1.73 m 2 ) regimens. Although extended‐interval belatacept dosing during the maintenance phase has the potential to reduce healthcare costs and ease administrative burdens, 8‐weekly dosing may lead to trough levels of belatacept that result in reduced CD86‐receptor occupancy and, consequently, less efficacy in some patients 17. Collectively, the data suggest that belatacept 8‐weekly dosing may not be sufficient for all patients, if initiated 3−6 months posttransplant.…”

Section: Discussionmentioning

confidence: 99%

Ten-year outcomes in a randomized phase II study of kidney transplant recipients administered belatacept 4-weekly or 8-weekly

Vincenti

Blancho

Dürrbach

et al. 2017

American Journal of Transplantation

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In the phase II IM103‐100 study, kidney transplant recipients were first randomized to belatacept more‐intensive‐based (n = 74), belatacept less‐intensive‐based (n = 71), or cyclosporine‐based (n = 73) immunosuppression. At 3‐6 months posttransplant, belatacept‐treated patients were re‐randomized to receive belatacept every 4 weeks (4‐weekly, n = 62) or every 8 weeks (8‐weekly, n = 60). Patients initially randomized to cyclosporine continued to receive cyclosporine‐based immunosuppression. Cumulative rates of biopsy‐proven acute rejection (BPAR) from first randomization to year 10 were 22.8%, 37.0%, and 25.8% for belatacept more‐intensive, belatacept less‐intensive, and cyclosporine, respectively (belatacept more‐intensive vs cyclosporine: hazard ratio [HR] = 0.95; 95% confidence interval [CI] 0.47‐1.92; P = .89; belatacept less‐intensive vs cyclosporine: HR = 1.61; 95% CI 0.85‐3.05; P = .15). Cumulative BPAR rates from second randomization to year 10 for belatacept 4‐weekly, belatacept 8‐weekly, and cyclosporine were 11.1%, 21.9%, and 13.9%, respectively (belatacept 4‐weekly vs cyclosporine: HR = 1.06, 95% CI 0.35‐3.17, P = .92; belatacept 8‐weekly vs cyclosporine: HR = 2.00, 95% CI 0.75‐5.35, P = .17). Renal function trends were estimated using a repeated‐measures model. Estimated mean GFR values at year 10 for belatacept 4‐weekly, belatacept 8‐weekly, and cyclosporine were 67.0, 68.7, and 42.7 mL/min per 1.73 m2, respectively (P<.001 for overall treatment effect). Although not statistically significant, rates of BPAR were 2‐fold higher in patients administered belatacept every 8 weeks vs every 4 weeks.

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“…Egy szolúbilis fúziós protein, amely tartalmazza a humán CTLA-4 extracelluláris doménját és egy módosított humán IgG Fc doménját. A belatacept szelektíven a CD28-CD80/CD86 interakciót blokkolja, CD80-hoz tizedakkora koncentrációban már kötő-dik, de értékelhető biológiai hatást csak akkor vált ki, ha adott a CD86-kötődéshez szükséges koncentráció [14,15].…”

Section: A Kostimuláció Gátlásán Keresztül Ható Immunszuppresszánsokunclassified

Recent options in drug therapy after solid organ transplantation

2012

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A szervtranszplantáció ötvenéves történetében az immunszuppresszív terápia fejlődésének köszönhetően egyre jobb szerv-és betegtúlélési eredményekről számoltak be világszerte, azonban a bázisgyógyszereknek minősülő kalcineurin inhibitorok káros mellékhatásait, elsősorban a nephrotoxicitast mellőző vegyületek kifejlesztése csak az elmúlt két évtizedben zajlott. A gazdaszervezet számára idegennek minősülő implantált szerv a recipiensből komplex immunválaszt vált ki. A dolgozatban az immunválasz vázlatos áttekintését követően a szerzők bemutatják az új, eltérő tá-madáspontokon ható gyógyszereket. Ezek vagy már gyakorlati alkalmazásban lévő, vagy rövid időn belül esetlegesen forgalomba kerülő vegyületek, amelyek távlati lehetőségeket nyújtanak a kalcineurin inhibitorok leváltására. Kiemelt hangsúlyt kap a kostimulációs blokádon keresztül ható belatacept és az elmúlt években egyre nagyobb kutatási teret nyerő toleranciaindukció, mint jövőbeli lehetőség. Orv. Hetil., 2012Hetil., , 153, 1294Hetil., -1301. Kulcsszavak: szervátültetés, immunszuppresszió, kalcineurin inhibitor, kostimulációs blokád, toleranciaindukció Recent options in drug therapy after solid organ transplantationSolid organ transplantation has shown improvement in patient and graft survival rates due to the development of immunosuppression in the last fi fty years; however only the last two decades led to the development of new, baseline immunosuppressive drugs that avoid the unlikely side effects of calcineurin inhibitors, especially nephrotoxicity. The transplanted organ is foreign to the host and, therefore, it induces a complex immune response of the recipient. In this review, a brief outline of immune response is given, followed by the introduction of new immunosuppressive drugs acting via variant pathways. These are compounds which are already in use or becoming shortly available and are potential future alternatives for the calcineurin inhibitors. This paper highlights the role of co-stimulation blockade with belatacept and the recently even more intensively studied fi eld of tolerance induction. Orv. Hetil., 2012, 153, 1294-1301 Keywords: organ transplantation, immunosuppression, calcineurin inhibitor, co-stimulation blockade, tolerance induction (Beérkezett: 2012. február 12.; elfogadva: 2012. június 17.) Rövidítések APC = (antigen presenting cell) antigén-bemutató sejt; BKV = BK-vírus; CD = (cluster of differentiation) sejtfelszíni fehérjék jelölése; CMV = cytomegalovirus; CNI = kalcineurin inhibitor; CTLA4 = citotoxikus T-lymphocyta-antigén-4; DC = dentritikus sejt; EBV = Epstein-Barr-vírus; FDA = Food and Drug Administration; FKBP12 = (FK-binding protein 12) FK-kötő fehérje 12; FOXP3 = forkhead boksz p3, egyike a transzkripciós regulátor fehérjéknek; γ-IFN = gamma-interferon; GVH = graft versus host; HUS = hemolitikus urémiás szindróma; IDO = indolamin-2,3-dioxigenáz; IL = interleukin; IL-2R = interleukin-2-receptor; JAK3 = Janus activated kinase 3, citokinreceptorokhoz kötődő tirozinkinázok egyike; LFA-1 = limphocytafunkció-asszociált anti...

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Assessment of Belatacept-Mediated Costimulation Blockade Through Evaluation of CD80/86-Receptor Saturation

Cited by 93 publications

References 11 publications

Five-Year Safety and Efficacy of Belatacept in Renal Transplantation

Five-Year Safety and Efficacy of Belatacept in Renal Transplantation

Ten-year outcomes in a randomized phase II study of kidney transplant recipients administered belatacept 4-weekly or 8-weekly

Recent options in drug therapy after solid organ transplantation

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