Pharmacodynamics of Rituximab in Kidney Transplantation

Genberg, Helena; Hansson, A.; Wernerson, Annika; Wennberg, Lars; Tydén, G

doi:10.1097/01.tp.0000296122.19026.0f

Cited by 46 publications

(41 citation statements)

References 19 publications

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“…+ cells rapidly fell in numbers even after a single dose of Rituximab, and completely depleted after all four doses (Figure 5), as previously reported in adults (53,54 …”

Section: Immunological Outcomes Depletion and Repopulation Of Periphesupporting

confidence: 67%

A Randomized, Prospective Trial of Rituximab for Acute Rejection in Pediatric Renal Transplantation

Zarkhin¹,

Li²,

Kambham

et al. 2008

American Journal of Transplantation

132

113

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We report 1-year outcomes of a randomized study of Rituximab versus standard-of-care immunosuppression (Thymoglobulin and/or pulse steroids) for treatment of biopsy confirmed, acute transplant rejection with B-cell infiltrates, in 20 consecutive recipients (2-23 years). Graft biopsies, with Banff and CADI scores, CD20 and C4d stains, were performed at rejection and 1 and 6 months later. Peripheral blood CMV, EBV and BK viral loads, graft function, DSA, immunoglobulins, serum humanized antichimeric antibody (HACA) and Rituximab, and lymphocyte counts were monitored until 1 year posttreatment. Rituximab infusions were given with a high index of safety without HACA development and increased infections complications. Rituximab therapy resulted in complete tissue B-cell depletion and rapid peripheral B-cell depletion. Peripheral CD19 cells recovered at a mean time of ∼12 months. There were some benefits for the recovery of graft function (p = 0.026) and improvement of biopsy rejection scores at both the 1-(p = 0.0003) and 6-month (p < 0.0001) follow-up biopsies. Reappearance of C4d deposition was not seen on follow-up biopsies after Rituximab therapy, but was seen in 30% of control patients. There was no change in DSA in either group, independent of rejection resolution. This study reports safety and suggests further investigation of Rituximab as an adjunctive treatment for B-cell-mediated graft rejection.

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“…+ cells rapidly fell in numbers even after a single dose of Rituximab, and completely depleted after all four doses (Figure 5), as previously reported in adults (53,54 …”

Section: Immunological Outcomes Depletion and Repopulation Of Periphesupporting

confidence: 67%

A Randomized, Prospective Trial of Rituximab for Acute Rejection in Pediatric Renal Transplantation

Zarkhin¹,

Li²,

Kambham

et al. 2008

American Journal of Transplantation

132

113

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“…Although anti-CD20 therapy can efficiently deplete B-cells in the blood, a number of reports suggest a potential incomplete depletion in lymphoid organs (32)(33)(34)(35). This issue raises the question of whether pancreatic B-cells are depleted, and it is likely that the current ongoing trial will not clarify this issue due to the impossibility of performing pancreatic biopsies.…”

Section: Anti-cd22 Immunotherapy In Diabetesmentioning

confidence: 79%

Targeting CD22 Reprograms B-Cells and Reverses Autoimmune Diabetes

et al. 2008

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OBJECTIVES-To investigate a B-cell-depleting strategy to reverse diabetes in naïve NOD mice. RESEARCH DESIGN AND METHODS-We targeted the CD22 receptor on B-cells of naïve NOD mice to deplete and reprogram B-cells to effectively reverse autoimmune diabetes.RESULTS-Anti-CD22/cal monoclonal antibody (mAb) therapy resulted in early and prolonged B-cell depletion and delayed disease in pre-diabetic mice. Importantly, when new-onset hyperglycemic mice were treated with the anti-CD22/cal mAb, 100% of B-celldepleted mice became normoglycemic by 2 days, and 70% of them maintained a state of long-term normoglycemia. Early therapy after onset of hyperglycemia and complete B-cell depletion are essential for optimal efficacy. Treated mice showed an increase in percentage of regulatory T-cells in islets and pancreatic lymph nodes and a diminished immune response to islet peptides in vitro. Transcriptome analysis of reemerging B-cells showed significant changes of a set of proinflammatory genes. Functionally, reemerging B-cells failed to present autoantigen and prevented diabetes when cotransferred with autoreactive CD4 ϩ T-cells into NOD.SCID hosts. Most individuals affected by type 1 diabetes exhibit multiple features associated with impaired B-cell function, including autoantibodies against a variety of islet cell antigens (6,7). Data from different groups using NOD mice, the best animal model for the study of type 1 diabetes, have confirmed the importance of B-cells in the onset of diabetes (2-4,8,9). NOD mice that are deficient in B-cells have been shown to be protected from autoimmune diabetes (3,10,11) and are deficient in the development of a T-cell response to major autoantigens (such as 65-kDa glutamate decarboxylase) (3,10,11). In humans, the production of autoantibodies to islet antigens is well documented as an early indicator of disease onset (12). These observations render B-cell targeting a particularly attractive and novel strategy for the treatment of type 1 diabetes (13-15). Unfortunately, this strategy has not been fully described in naïve NOD mice. Only recently did a publication show the positive effects of an anti-CD20 -based B-cell-depleting strategy in transgenic NOD mice expressing the humanized CD20 receptor on B-cells (8). Interestingly, use of B-cell depletion as a therapy for human autoimmune disease (16 -20), including in patients with new-onset type 1 diabetes, is ongoing (21,22). CONCLUSIONS-TargetingWe made use of a newly developed reagent (anti-CD22 calicheamicin-conjugated monoclonal antibody [anti-CD22/cal mAb]) that efficiently depletes mature B-cells in mice (13) to establish a therapeutic approach for type 1 diabetes. Our main hypothesis was that depleting B-cells by targeting CD22 should prevent diabetes onset and restore normoglycemia in newly hyperglycemic NOD mice. Furthermore, we hypothesize that our approach will generate a pool of reemerging B-cells that may function to regulate the autoimmune response in vivo, establishing a state of long-term tolerance toward autoantigens. RESEA...

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“…Because B cell depletion is a recognized PD marker for rituximab activity (Genberg et al 2006(Genberg et al , 2007 and rituximab is an anti-CD20 mAb with the potential to compete for binding with the anti-CD20 reagent used for immunophenotyping, additional B cell subsets were also characterized by flow cytometry: CDÀCD20þCD40þ (mature B cells), CD3ÀCD19þ (immature and mature B cells), and CD3ÀCD40þ (immature and mature B cells). The relative percentage of each phenotype was multiplied by the absolute total lymphocyte count from the hematology analysis to calculate absolute (cells/mL) values for each lymphocyte subset.…”

Section: Comparative Lymphocyte Immunophenotyping and Pharmacodynamicmentioning

confidence: 99%

Comparative Nonclinical Assessments of the Proposed Biosimilar PF-05280586 and Rituximab (MabThera®)

Ryan

Sokolowski

et al. 2014

Toxicol Pathol

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Comparative nonclinical studies were conducted with the proposed biosimilar PF-05280586 and rituximab-EU (MabThera 1 ). In side-by-side analyses, peptide maps and complement-dependent cytotoxicity assay results were similar. Sexually-mature cynomolgus monkeys were administered PF-05280586 or rituximab-EU as a single dose of 0, 2, 10, or 20 mg/kg on day 1 and observed for 92 days (single-dose study) or as 5 weekly injections of 0 or 20 mg/kg and necropsied on day 30, the day after the 5th dose, or on day 121 (repeat-dose study). The pharmacokinetic and pharmacodynamic profiles for both molecules were similar. Marked depletion of peripheral blood B cells 4 days after dosing was followed by near or complete repletion (single-dose study) or partial repletion (repeat-dose study). In the single-dose study, anti-drug antibodies (ADA) were detected by day 29 in all animals administered PF-05280586 or rituximab-EU and persisted through day 85, the last day tested. In the repeat-dose study, ADA were detected on day 121 in 50% of animals administered PF-05280586 or rituximab-EU. Both molecules were well tolerated at all doses. In all endpoints evaluated, PF-05280586 exhibited similarity to rituximab-EU.

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Pharmacodynamics of Rituximab in Kidney Transplantation

Cited by 46 publications

References 19 publications

A Randomized, Prospective Trial of Rituximab for Acute Rejection in Pediatric Renal Transplantation

A Randomized, Prospective Trial of Rituximab for Acute Rejection in Pediatric Renal Transplantation

Targeting CD22 Reprograms B-Cells and Reverses Autoimmune Diabetes

Comparative Nonclinical Assessments of the Proposed Biosimilar PF-05280586 and Rituximab (MabThera®)

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