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Belatacept

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https://www.readbyqxmd.com/read/27932157/belatacept-and-eculizumab-for-treatment-of-calcineurin-inhibitor-induced-thrombotic-microangiopathy-after-kidney-transplantation-case-report
#1
J Merola, P S Yoo, J Schaub, J D Smith, M I Rodriguez-Davalos, E Tichy, D C Mulligan, W Asch, R Formica, M Kashgarian, S Kulkarni
Thrombotic microangiopathy (TMA) after kidney transplantation is an uncommon and challenging cause of graft dysfunction and is associated with early graft loss. An idiosyncratic endothelial reaction to calcineurin inhibitors (CNIs) has been implicated as a frequent cause of TMA. This reaction is marked by uncontrolled activation of complement and subsequent cellular destruction. Usual therapy consists of withdrawal of the inciting drug and plasmapheresis to minimize levels of circulating complement. Recently, eculizumab, a monoclonal antibody to complement component C5, has been used for the treatment of atypical hemolytic uremic syndrome...
November 2016: Transplantation Proceedings
https://www.readbyqxmd.com/read/27932109/risk-evaluation-and-outcome-of-pneumocystis-jirovecii-pneumonia-in-kidney-transplant-patients
#2
S Brakemeier, M Dürr, F Bachmann, D Schmidt, J Gaedeke, K Budde
Pneumocystis jirovecii pneumonia (PJP) affects immunocompromised patients. As a result of effective prophylaxis in the 1st months after kidney transplantation, PJP is increasingly diagnosed in the long term after transplantation. The present study evaluates course and outcome of PJP in a single transplant center from 2010 to 2015. Twenty-three patients presented with PJP at a mean of 53.7 ± 50.2 months after transplantation. Of these, 3 patients underwent ABO-incompatible (ABO-i) living-donor transplantation and 3 patients were treated with the use of belatacept...
November 2016: Transplantation Proceedings
https://www.readbyqxmd.com/read/27889299/safety-and-efficacy-outcomes-3-years-after-switching-to-belatacept-from-a-calcineurin-inhibitor-in-kidney-transplant-recipients-results-from-a-phase-2-randomized-trial
#3
Josep M Grinyó, Maria Del Carmen Rial, Josefina Alberu, Steven M Steinberg, Roberto C Manfro, Georgy Nainan, Flavio Vincenti, Charlotte Jones-Burton, Nassim Kamar
BACKGROUND: In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss. STUDY DESIGN: 36-month follow-up of the intention-to-treat population. SETTING & PARTICIPANTS: CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1...
November 23, 2016: American Journal of Kidney Diseases: the Official Journal of the National Kidney Foundation
https://www.readbyqxmd.com/read/27888551/selective-targeting-of-high-affinity-lfa-1-does-not-augment-costimulation-blockade-in-a-nonhuman-primate-renal-transplantation-model
#4
K P Samy, D A Anderson, D J Lo, M S Mulvihill, M Song, A B Farris, B S Parker, A L MacDonald, C Lu, T A Springer, S C Kachlany, K A Reimann, T How, F V Leopardi, K S Franke, K D Williams, B H Collins, A D Kirk
Costimulation blockade (CoB) via belatacept is a lower morbidity alternative to calcineurin inhibitor (CNI)-based immunosuppression. However, it has higher rates of early acute rejection. These early rejections are mediated in part by memory T cells, which have reduced dependence on the pathway targeted by belatacept, and increased adhesion molecule expression. One such molecule is Leukocyte Function Associated Antigen (LFA)-1. LFA-1 exists in two forms, a commonly expressed, low-affinity form, and a transient, high-affinity form, expressed only during activation...
November 26, 2016: American Journal of Transplantation
https://www.readbyqxmd.com/read/27881707/a-cd80-biased-ctla4-ig-fusion-protein-with-superior-in-vivo-efficacy-by-simultaneous-engineering-of-affinity-selectivity-stability-and-fcrn-binding
#5
Julie Douthwaite, Jacques Moisan, Cyril Privezentzev, Blagoje Soskic, Shereen Sabbah, Suzanne Cohen, Andie Collinson, Elizabeth England, Catherine Huntington, Ben Kemp, Li Zhuang, Suzanne Hudak, D Gareth Rees, Debbie Goldberg, Chris Barton, Linda Chang, Inna Vainshtein, Meina Liang, Laurie Iciek, Philip Ambery, Mark Peakman, Tristan J Vaughan, Tim I M Tree, David M Sansom, Michael A Bowen, Ralph R Minter, Lutz Jermutus
Affinity- and stability-engineered variants of CTLA4-Ig fusion molecules with enhanced pharmacokinetic profiles could yield improved therapies with the potential of higher efficacy and greater convenience to patients. In this study, to our knowledge, we have, for the first time, used in vitro evolution to simultaneously optimize CTLA4 affinity and stability. We selected for improved binding to both ligands, CD80 and CD86, and screened as dimeric Fc fusions directly in functional assays to identify variants with stronger suppression of in vitro T cell activation...
November 23, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27861289/the-effect-of-asp2409-a-novel-cd86-selective-variant-of-ctla4-ig-on-renal-allograft-rejection-in-nonhuman-primates
#6
Shinsuke Oshima, Erik E Karrer, Yuka Kawato, Masashi Maeda, Hidehiko Fukahori, Susumu Tsujimoto, Jun Hirose, Koji Nakamura, Takanori Marui, Fujiko Takamura, Takahisa Noto, Steven J Chapin, Yasutomo Fujii, Margaret Neighbors, Sridhar Viswanathan, Bruce H Devens, Yasuyuki Higashi
BACKGROUND: Blockade of CD28-mediated T cell costimulation by a modified cytotoxic T lymphocyte-associated antigen 4 (CTLA4-Ig), belatacept, is a clinically effective immunosuppressive therapy for the prevention of renal allograft rejection. Use of belatacept-based calcineurin inhibitor-free immunosuppression, however, has demonstrated an increased frequency of cellular rejection episodes and immunosuppression-related safety issues relative to conventional regimens. Furthermore, belatacept typically requires infusion for its administration chronically, which may present an inconvenience to patients...
December 2016: Transplantation
https://www.readbyqxmd.com/read/27847589/belatacept-conversion-in-african-american-kidney-transplant-recipients-with-severe-renal-dysfunction
#7
Heather S Snyder, Benjamin T Duhart, Amy G Krauss, Vinaya Rao
OBJECTIVES: Conversion from calcineurin inhibitor-based maintenance immunosuppression to belatacept in kidney transplant recipients has been demonstrated to improve renal function while maintaining efficacy against rejection. However, conversion studies to date have excluded patients with an estimated glomerular filtration rate < 35 mL/min/1.73 m(2). METHODS: We describe two patients with an estimated glomerular filtration rate < 30 mL/min/1.73 m(2) who underwent conversion from maintenance calcineurin inhibitor to belatacept...
2016: SAGE open medical case reports
https://www.readbyqxmd.com/read/27742385/costimulatory-blockade-and-use-of-mtor-inhibitors-avoiding-injury-part-2
#8
REVIEW
David Wojciechowski, Flavio Vincenti
Kidney transplantation immunosuppression relies on a calcineurin inhibitor backbone. Calcineurin inhibitors have reduced early-acute rejection rates but failed to improve long-term allograft survival. Their nephrotoxicity has shifted the focus of investigation to calcineurin inhibitor-free regimens. Costimulation blockade with belatacept, a second generation, higher avidity variant of CTLA4-Ig, has emerged as part of a calcineurin inhibitor-free regimen. Belatacept has demonstrated superior glomerular filtration rate compared with calcineurin inhibitors albeit with an increased risk of early and histologically severe rejection...
September 2016: Advances in Chronic Kidney Disease
https://www.readbyqxmd.com/read/27742383/immunosuppression-minimization-and-avoidance-protocols-when-less-is-not-more
#9
Rohini Prashar, K K Venkat
Kidney transplantation is well established as the best treatment option for end-stage kidney disease. It confers not only a better quality of life but also a significant survival advantage compared to dialysis. However, despite significant improvement in short-term kidney transplant graft survival over the past three decades, long-term graft survival remains suboptimal. Concerns about the possible contribution of chronic calcineurin inhibitor (CNI) nephrotoxicity to late allograft failure and other serious adverse effects of currently used immunosuppressive agents (especially corticosteroids) have led to increasing interest in developing regimens which may better preserve kidney allograft function and minimize other immunosuppression-related problems without increasing the risk of rejection...
September 2016: Advances in Chronic Kidney Disease
https://www.readbyqxmd.com/read/27662596/immunosuppressive-effect-of-asp2408-a-novel-cd86-selective-variant-of-ctla4-ig-in-rats-and-cynomolgus-monkeys
#10
Shinsuke Oshima, Yasutomo Fujii, Erik E Karrer, Fujiko Takamura, Steven J Chapin, Margaret Neighbors, Sridhar Viswanathan, Bruce H Devens, Yasuyuki Higashi, Hidekazu Mizuhara
The CTLA4-Ig fusion proteins abatacept and belatacept inhibit CD28-mediated T cell activation by binding CD80 (B7-1) and CD86 (B7-2) costimulatory ligands and are clinically proven immunosuppressants used for rheumatoid arthritis and renal transplantation, respectively. Abatacept and belatacept preferentially bind CD80, yet CD86 has been implicated as the dominant ligand for CD28-mediated costimulation of T cells. We investigated the immunosuppressive effects of ASP2408, a novel CTLA4-Ig with CD86 selectivity and high potency created by directed evolution methods...
September 19, 2016: International Immunopharmacology
https://www.readbyqxmd.com/read/27598231/asp2409-a-next-generation-ctla4-ig-versus-belatacept-in-renal-allograft-survival-in-cynomolgus-monkeys
#11
L Song, A Ma, H Dun, Y Hu, Y Fujii, F Kinugasa, S Oshima, Y Higashi, P Daloze, H Chen
Belatacept is the first costimulatory blockade agent approved for maintenance immunosuppression in kidney transplant recipients. Clinical results have indicated that belatacept is associated with superior renal function and improved metabolic profile. However, higher incidence of acute rejection and PTLD are the shortcomings of this agent. In this study, ASP2409, a new CTLA4-Ig possessing 14-fold higher in vitro CD86 binding affinity than belatacept, was tested for renal allograft survival in cynomolgus monkeys...
September 6, 2016: American Journal of Transplantation
https://www.readbyqxmd.com/read/27591335/costimulation-blockade-in-autoimmunity-and-transplantation-the-cd28-pathway
#12
Andrew B Adams, Mandy L Ford, Christian P Larsen
T cell activation is a complex process that requires multiple cell signaling pathways, including a primary recognition signal and additional costimulatory signals. TCR signaling in the absence of costimulatory signals can lead to an abortive attempt at activation and subsequent anergy. One of the best-characterized costimulatory pathways includes the Ig superfamily members CD28 and CTLA-4 and their ligands CD80 and CD86. The development of the fusion protein CTLA-4-Ig as an experimental and subsequent therapeutic tool is one of the major success stories in modern immunology...
September 15, 2016: Journal of Immunology: Official Journal of the American Association of Immunologists
https://www.readbyqxmd.com/read/27578428/immunosuppressive-therapy-for-kidney-transplantation-in-adults-a-systematic-review-and-economic-model
#13
Tracey Jones-Hughes, Tristan Snowsill, Marcela Haasova, Helen Coelho, Louise Crathorne, Chris Cooper, Ruben Mujica-Mota, Jaime Peters, Jo Varley-Campbell, Nicola Huxley, Jason Moore, Matt Allwood, Jenny Lowe, Chris Hyde, Martin Hoyle, Mary Bond, Rob Anderson
BACKGROUND: End-stage renal disease is a long-term irreversible decline in kidney function requiring renal replacement therapy: kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation, followed by immunosuppressive therapy (induction and maintenance therapy) to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES: To review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect(®), Novartis Pharmaceuticals UK Ltd) and rabbit anti-human thymocyte immunoglobulin (rATG) (Thymoglobulin(®), Sanofi) as induction therapy, and immediate-release tacrolimus (TAC) (Adoport(®), Sandoz; Capexion(®), Mylan; Modigraf(®), Astellas Pharma; Perixis(®), Accord Healthcare; Prograf(®), Astellas Pharma; Tacni(®), Teva; Vivadex(®), Dexcel Pharma), prolonged-release tacrolimus (Advagraf(®) Astellas Pharma), belatacept (BEL) (Nulojix(®), Bristol-Myers Squibb), mycophenolate mofetil (MMF) (Arzip(®), Zentiva; CellCept(®), Roche Products; Myfenax(®), Teva), mycophenolate sodium (MPS) (Myfortic(®), Novartis Pharmaceuticals UK Ltd), sirolimus (SRL) (Rapamune(®), Pfizer) and everolimus (EVL) (Certican(®), Novartis) as maintenance therapy in adult renal transplantation...
August 2016: Health Technology Assessment: HTA
https://www.readbyqxmd.com/read/27557331/immunosuppressive-therapy-for-kidney-transplantation-in-children-and-adolescents-systematic-review-and-economic-evaluation
#14
Marcela Haasova, Tristan Snowsill, Tracey Jones-Hughes, Louise Crathorne, Chris Cooper, Jo Varley-Campbell, Ruben Mujica-Mota, Helen Coelho, Nicola Huxley, Jenny Lowe, Jan Dudley, Stephen Marks, Chris Hyde, Mary Bond, Rob Anderson
BACKGROUND: End-stage renal disease is a long-term irreversible decline in kidney function requiring kidney transplantation, haemodialysis or peritoneal dialysis. The preferred option is kidney transplantation followed by induction and maintenance immunosuppressive therapy to reduce the risk of kidney rejection and prolong graft survival. OBJECTIVES: To systematically review and update the evidence for the clinical effectiveness and cost-effectiveness of basiliximab (BAS) (Simulect,(®) Novartis Pharmaceuticals) and rabbit antihuman thymocyte immunoglobulin (Thymoglobuline,(®) Sanofi) as induction therapy and immediate-release tacrolimus [Adoport(®) (Sandoz); Capexion(®) (Mylan); Modigraf(®) (Astellas Pharma); Perixis(®) (Accord Healthcare); Prograf(®) (Astellas Pharma); Tacni(®) (Teva); Vivadex(®) (Dexcel Pharma)], prolonged-release tacrolimus (Advagraf,(®) Astellas Pharma); belatacept (BEL) (Nulojix,(®) Bristol-Myers Squibb), mycophenolate mofetil (MMF) [Arzip(®) (Zentiva), CellCept(®) (Roche Products), Myfenax(®) (Teva), generic MMF is manufactured by Accord Healthcare, Actavis, Arrow Pharmaceuticals, Dr Reddy's Laboratories, Mylan, Sandoz and Wockhardt], mycophenolate sodium, sirolimus (Rapamune,(®) Pfizer) and everolimus (Certican,(®) Novartis Pharmaceuticals) as maintenance therapy in children and adolescents undergoing renal transplantation...
August 2016: Health Technology Assessment: HTA
https://www.readbyqxmd.com/read/27552251/use-of-a-cocktail-probe-to-assess-potential-drug-interactions-with-cytochrome-p450-after-administration-of-belatacept-a-costimulatory-immunomodulator
#15
Daphne Williams, Xiaolu Tao, Lili Zhu, Michele Stonier, Justin D Lutz, Eric Masson, Sean Zhang, Bishu Ganguly, Zoe Tzogas, Susan Lubin, Bindu Murthy
Therapeutic proteins that are cytokine modulators can alter cytochrome P450 (CYP) pathways. Belatacept is a recombinant fusion protein and selective co-stimulation modulator for preventing kidney transplant rejection. This open-label study investigated the effect of belatacept on cytokine levels and on the pharmacokinetics of caffeine, losartan, omeprazole, dextromethorphan and midazolam, as CYP probe substrates after oral administration of the Inje cocktail in healthy volunteers. Twenty-two evaluable subjects received the Inje cocktail on Days 1, 4, 7 and 11 and belatacept infusion on Day 4...
August 23, 2016: British Journal of Clinical Pharmacology
https://www.readbyqxmd.com/read/27525642/costimulation-blockade-in-kidney-transplantation-beyond-belatacept
#16
Lionel Rostaing, Paolo Malvezzi
No abstract text is available yet for this article.
December 2016: Transplantation
https://www.readbyqxmd.com/read/27517137/current-status-of-costimulatory-blockade-in-renal-transplantation
#17
David Wojciechowski, Flavio Vincenti
PURPOSE OF REVIEW: The review will focus on the impact and current status of costimulatory blockade in renal transplantation. RECENT FINDINGS: The mainstay of immunosuppression in kidney transplantation is calcineurin inhibitors (CNIs) which have reduced acute rejection rates but failed to improve long-term allograft survival. Their cardiometabolic side-effects and nephrotoxicity have shifted the focus of investigation to CNI-free regimens. Costimulation blockade with belatacept, a second generation, higher avidity variant of cytotoxic T-lymphocyte associated protein 4 has emerged as part of a CNI-free regimen...
November 2016: Current Opinion in Nephrology and Hypertension
https://www.readbyqxmd.com/read/27514317/experience-with-belatacept-rescue-therapy-in-kidney-transplant-recipients
#18
Susanne Brakemeier, Dennis Kannenkeril, Michael Dürr, Tobias Braun, Friederike Bachmann, Danilo Schmidt, Michael Wiesener, Klemens Budde
In kidney transplant recipients with chronic graft dysfunction, long-term immunosuppression with calcineurin inhibitors (CNIs) or mTOR inhibitors (mTORi) can be challenging due to adverse effects, such as nephrotoxicity and proteinuria. Seventy-nine kidney transplant recipients treated with CNI-based or mTORi-based maintenance immunosuppression who had CNI-induced nephrotoxicity or severe adverse events were switched to belatacept. Mean time from transplantation to belatacept conversion was 69.0 months. Mean estimated glomerular filtration rate (eGFR) ± standard deviation at baseline was 26...
August 12, 2016: Transplant International: Official Journal of the European Society for Organ Transplantation
https://www.readbyqxmd.com/read/27500470/the-knife-s-edge-of-tolerance-inducing-stable-multilineage-mixed-chimerism-but-with-a-significant-risk-of-cmv-reactivation-and-disease-in-rhesus-macaques
#19
H B Zheng, B Watkins, V Tkachev, S Yu, D Tran, S Furlan, K Zeleski, K Singh, K Hamby, C Hotchkiss, J Lane, S Gumber, A B Adams, L Cendales, A D Kirk, A Kaur, B R Blazar, C P Larsen, L S Kean
Although stable mixed-hematopoietic chimerism induces robust immune tolerance to solid organ allografts in mice, the translation of this strategy to large animal models and to patients has been challenging. We have previously shown that in MHC-matched nonhuman primates (NHPs), a busulfan plus combined belatacept and anti-CD154-based regimen could induce long-lived myeloid chimerism, but without T cell chimerism. In that setting, donor chimerism was eventually rejected, and tolerance to skin allografts was not achieved...
August 8, 2016: American Journal of Transplantation
https://www.readbyqxmd.com/read/27472094/costimulation-blockade-in-kidney-transplantation-an-update
#20
Paolo Malvezzi, Thomas Jouve, Lionel Rostaing
In the setting of solid-organ transplantation, calcineurin inhibitor (CNI)-based therapy remains the cornerstone of immunosuppression. However, long-term use of CNIs is associated with some degree of nephrotoxicity. This has led to exploring the blockade of some costimulation pathways as an efficient immunosuppressive tool instead of using CNIs. The only agent already in clinical use and approved by the health authorities for kidney transplant patients is belatacept (Nulojix), a fusion protein that interferes with cytotoxic T lymphocyte-associated protein 4...
November 2016: Transplantation
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