Co-stimulatory blockade with belatacept in kidney transplantation

Chopra, Bhavna; Sureshkumar, Kalathil K

doi:10.1517/14712598.2014.896332

Cited by 11 publications

(8 citation statements)

References 18 publications

(19 reference statements)

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“…Costimulatory modulators, such as B7-1 and B7-2, are expressed on the surface of antigen-presenting cells and serve to regulate T-cell-mediated immunity (43). Consequently, they have been primarily utilized for their immunomodulatory effects in kidney transplantation and other systemic anti-inflammatory disorders (7,33). Interestingly, B7-1 is also expressed in podocytes and is significantly increased in models of podocyte injury (41).…”

Section: Abataceptmentioning

confidence: 99%

The podocyte as a direct target for treatment of glomerular disease?

Mallipattu

2016

American Journal of Physiology-Renal Physiology

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The Centers for Disease Control and Prevention estimates more than 10% of adults in the United States, over 20 million Americans, have chronic kidney disease (CKD). A failure to maintain the glomerular filtration barrier directly contributes to the onset of CKD. The visceral epithelial cells, podocytes, are integral to the maintenance of this renal filtration barrier. Direct podocyte injury contributes to the onset and progression of glomerular diseases such as minimal change disease (MCD), focal segmental glomerular sclerosis (FSGS), diabetic nephropathy, and HIV-associated nephropathy (HIVAN). Since podocytes are terminally differentiated with minimal capacity to self-replicate, they are extremely sensitive to cellular injury. In the past two decades, our understanding of the mechanism(s) by which podocyte injury occurs has greatly expanded. With this newfound knowledge, therapeutic strategies have shifted to identifying targets directed specifically at the podocyte. Although the systemic effects of these agents are important, their direct effect on the podocyte proves to be essential in ameliorating glomerular disease. In this review, we highlight the mechanisms by which these agents directly target the podocyte independent of its systemic effects.

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Section: Abataceptmentioning

confidence: 99%

The podocyte as a direct target for treatment of glomerular disease?

Mallipattu

2016

American Journal of Physiology-Renal Physiology

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“…DN is also associated with an increased cardiovascular mortality. Immunologic derangement is the cornerstone of pathogenesis of CKD [1]. Of course, both primary kidney disease and secondary kidney disease dwell in this process, including DN [2].…”

Section: Introductionmentioning

confidence: 99%

Mechanistic Insight and Management of Diabetic Nephropathy: Recent Progress and Future Perspective

Xue

Gui

Zheng

et al. 2017

Journal of Diabetes Research

109

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Diabetic nephropathy (DN) is the most serious microvascular complication of diabetes and the largest single cause of end-stage renal disease (ESRD) in many developed countries. DN is also associated with an increased cardiovascular mortality. It occurs as a result of interaction between both genetic and environmental factors. Hyperglycemia, hypertension, and genetic predisposition are the major risk factors. However, the exact mechanisms of DN are unclear. Despite the benefits derived from strict control of glucose and blood pressure, as well as inhibition of renin-angiotensin-aldosterone system, many patients continue to enter into ESRD. Thus, there is urgent need for improving mechanistic understanding of DN and then developing new and effective therapeutic approaches to delay the progression of DN. This review focuses on recent progress and future perspective about mechanistic insight and management of DN. Some preclinical relevant studies are highlighted and new perspectives of traditional Chinese medicine (TCM) for delaying DN progression are discussed in detail. These findings strengthen the therapeutic rationale for TCM in the treatment of DN and also provide new insights into the development of novel drugs for the prevention of DN. However, feasibility and safety of these therapeutic approaches and the clinical applicability of TCM in human DN need to be further investigated.

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“…4,5 This CD80/CD86-CD28/CTLA-4 regulatory network represents substantial opportunities for therapeutic intervention, either for immunosuppressive approaches blocking positive signaling through CD28 or immunostimulatory approaches blocking downregulatory functions of CTLA-4. To date, there are 3 marketed biologics targeting this network: (1) abatacept, a wild-type CTLA4-Ig fusion protein for rheumatoid arthritis; 6,7 (2) belatacept, a modified CTLA4-Ig with improved CD80/CD86 ligand-binding affinity for kidney transplantation 8,9 ; and (3) ipilimumab, an anti-CTLA-4 monoclonal antibody for melanoma.…”

mentioning

confidence: 99%

A Phase 1 Dose‐Escalation Study of ASP2409, a Selective T‐Cell Costimulation Inhibitor, in Stable Rheumatoid Arthritis Patients on Methotrexate Therapy

Zhang

Kernstock

Karrer

et al. 2016

Clinical Pharm in Drug Dev

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ASP2409 represents a new class of CTLA4-Ig molecules with higher binding avidity and selectivity to CD86. This first-in-human study was to assess the safety, tolerability, pharmacokinetics (PK), and pharmacodynamics of ASP2409 in stable rheumatoid arthritis patients on methotrexate therapy with a randomized, double-blind, placebo-controlled dose-escalation study design. Patients were enrolled and randomized in each of 8 dose-escalation cohorts ranging from 0.001 to 3.0 mg/kg to receive either ASP2409 or placebo in a sequential manner. Escalation to higher dose levels occurred in the absence of dose-limiting toxicity. A total of 57 patients completed the study. ASP2409 showed nonlinear PK over the dose range of 0.01 to 3.0 mg/kg following a single intravenous administration, indicating target-mediated drug disposition. Area under the concentration-time curve (AUC) and maximum concentration (Cmax ) increased at a greater than dose-proportional rate. The half-life of ASP2409 increased dose dependently and ranged from 1.57 to 6.68 days. ASP2409 showed a dose-dependent increase in the extent and duration of CD86 receptor occupancy. There were no clinically relevant safety issues up to a single dose of 3.0 mg/kg. No maximum tolerated dose was reached. The incidence and duration of antidrug antibodies did not correlate with adverse events. ClinicalTrials.gov identifier: NCT02171143.

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Co-stimulatory blockade with belatacept in kidney transplantation

Cited by 11 publications

References 18 publications

The podocyte as a direct target for treatment of glomerular disease?

The podocyte as a direct target for treatment of glomerular disease?

Mechanistic Insight and Management of Diabetic Nephropathy: Recent Progress and Future Perspective

A Phase 1 Dose‐Escalation Study of ASP2409, a Selective T‐Cell Costimulation Inhibitor, in Stable Rheumatoid Arthritis Patients on Methotrexate Therapy

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