Anti-rituximab Antibodies Research Articles

Neutralizing Anti-Rituximab Antibodies and Relapse in Membranous Nephropathy Treated With Rituximab.

Membranous Nephropathy (MN) is an autoimmune disease associated with antibodies against podocyte proteins: M-type phospholipase A2 receptor (PLA2R1) or thrombospondin type-1 domain-containing 7A (THSD7A) in 70 and 3% of patients, respectively. Antibody titer is correlated with disease activity: rising during active disease and decreasing before remission. Therefore, decreasing PLA2R1-Antibodies titer has become an important goal of therapy. Rituximab a chimeric monoclonal antibody induces remission in 60–80% of primary MN patients. All monoclonal antibodies such as rituximab can elicit antidrug antibodies, which may interfere with therapeutic response. We aim to analyze the relevance of anti-rituximab antibodies on the outcome of MN after a first course of rituximab. Forty-four MN patients were included and treated with two 1 g infusions of rituximab at 2-weeks interval. Anti-rituximab antibodies, CD19 count, and clinical response were analyzed. Then, we (i) analyzed the association of anti-rituximab antibodies at month-6 with response to treatment: remission, relapse and the need for another rituximab course; (ii) confirmed if anti-rituximab antibodies could neutralize rituximab B-cells depletion; and (iii) tested whether anti-rituximab antibodies could cross-inhibit new humanized anti-CD20 therapies. Anti-rituximab antibodies were detected in 10 patients (23%). Seventeen patients received a second rituximab course after a median time of 12 months (7–12), following nine cases of resistance and eight relapses. Anti-rituximab antibodies were significantly associated with faster B-cell reconstitution at month-6 (75 [57–89] vs. 2 [0–41] cells/μl, p = 0.006), higher proteinuria 12 months after rituximab infusion (1.7 [0.7; 5.8] vs. 0.6 [0.2; 3.4], p = 0.03) and before treatment modification (3.5 [1.6; 7.1] vs. 1.7 [0.2; 1.7] p = 0.0004). Remission rate 6 months after rituximab was not different according to anti-rituximab status (p > 0.99) but the rate of relapse was significantly higher for patients with anti-rituximab antibodies (p < 0.001). These patients required more frequently a second course of rituximab infusions (7/10 vs. 10/34, p = 0.03). Anti-rituximab antibodies neutralized rituximab activity in 8/10 patients and cross-reacted with other humanized monoclonal antibodies in only two patients. Three patients with anti-rituximab antibodies were successfully treated with ofatumumab. Anti-rituximab antibodies could neutralize rituximab B cells cytotoxicity and impact clinical outcome of MN patients. Humanized anti-CD20 seems to be a satisfying therapeutic alternative for patients with anti-rituximab antibodies and resistant or relapsing MN.

P152 Improved access to transplant via neutralization of rituximab by anti-rituximab antibodies

P152 Improved access to transplant via neutralization of rituximab by anti-rituximab antibodies

A Randomized, Multiple-Dose, Multicenter, Comparative Parallel Study to Evaluate the Safety and Efficacy of Intravenous Infusion of Rituximab (Hetero) and Reference Medicinal Product (Rituximab, Roche) in Indian Patients of Non-Hodgkin's Lymphoma (HERILY)

Abstract Objective: To compare the antitumor efficacy, safety, and pharmacodynamic (PD) characteristics of Hetero-rituximab (test) with reference medicinal product (rituximab, Roche) in non-Hodgkin's lymphoma. Patients and Methods: One hundred and thirty-five patients with diffuse large B-cell lymphoma (DLBCL) were randomized to receive intravenous infusion of either test or reference product. Efficacy (best overall response [BOR] rate [primary end point]), safety, PD (CD19), and immunological assessments (secondary end points) were done at the end of cycle 3 and cycle 6. Results:: At the end of 6 cycles, BOR rate was 73.47% in Hetero-rituximab test arm compared to the 69.09% in reference arm. Anti-rituximab antibodies were found to be negative at cycle 3 and cycle 6 for all patients. Patients treated with Hetero-rituximab show a significant depletion in CD19+ cell which was comparable with reference drug. Safety and immunogenic potential of the test drug was comparable to the reference drug in the patients of DLBCL. Conclusion: BOR rate at cycle 3, cycle 6, and end of the study lies within the prespecified limit for noninferiority which concludes that test product is therapeutically noninferior to reference medicinal product.

Anti-Rituximab antibody in patients with NMOSDs treated with low dose Rituximab

BackgroundRituximab is a mouse-human chimeric anti-CD20 monoclonal antibody and has been increasingly used for preventing relapses in NMOSDs. The clinical relevance of Anti-Rituximab antibodies (ARA) against Rituximab in NMOSDs is unknown. MethodsNineteen NMOSDs patients receiving repeated 100mg Rituximab treatment were recruited. The ARA was quantitatively analyzed by enzyme linked immunoassay. Annualized relapse rate (ARR) and Expanded Disability Status Scale (EDSS) were analyzed concurrently. ResultsARR was reduced markedly since starting Rituximab therapy in the majority (78.9%) of NMOSDs patients. 36.9% (7/19) patients were ARA positive. There was no significant difference in the improvement of ARR and EDSS after treatment with Rituximab in either ARA positive or negative groups. The frequency of Rituximab reinfusion was higher in patients with ARA, suggesting that the presence of ARA led to an increased frequency of Rituximab reinfusion to maintain B cell depletion. ConclusionThe majority of (78.9%) patients with NMOSDs were responsive to low dose Rituximab. The presence of ARA is associated with the requirement for increased frequency of Rituximab reinfusion to maintain treatment response in NMOSDs. In patients with ARA it might be necessary to detect ARA levels and monitor B cell depletion closely, or even attempt other treatments.

Rituximab in clinical practice: dosage, drug adherence, Ig levels, infections, and drug antibodies

The objective of this study is to explore the following: (1) the impact of two different initial doses and cumulative 2-year dose of rituximab (RTX) on drug adherence and predictors of adherence to treatment in rheumatoid arthritis (RA) patients in an observational clinical setting, (2) immunoglobulin levels (IgG/IgM/IgA) during repeated treatment and their relation to infections, and (3) development of anti-rituximab antibodies (ADA). All RA patients receiving RTX from January 2003 to April 2012 at the department were included. The initiating doses were 500 or 1000 mg intravenously days 1 and 15. Drug adherence was estimated using life-table. Baseline predictors of adherence to treatment were analyzed using Cox regression model. Levels of immunoglobulins were measured at treatment initiation and before retreatment. Serum levels of RTX and ADA were measured in 96 patients at 6 months using ELISA. One hundred fifty-three patients were included. Seventy-four (48%) started treatment with 500 and 79 (52%) with 1000 mg. No difference in drug adherence was seen between the different initial or cumulative RTX doses. Methotrexate (MTX) use and low DAS28 at baseline predicted better drug adherence. Ig levels decreased with repeated treatments but low levels were not associated with infections. 11/96 patients had developed ADA at 6 months. Long-term adherence to RTX in RA patient was not influenced by starting- or cumulative 2-year doses. MTX use and low DAS28 at baseline was positively associated with drug adherence. Decreasing Ig levels during treatment were not associated with risk of infections. Development of ADA may influence treatment efficacy and tolerability.

Predicting and managing primary and secondary non-response to rituximab using B-cell biomarkers in systemic lupus erythematosus

ObjectiveTo assess factors associated with primary and secondary non-response to rituximab in systemic lupus erythematosus (SLE) and evaluate management of secondary non-depletion non-response (2NDNR).Methods125 patients with SLE treated with rituximab...

Development of antirituximab antibodies in children with nephrotic syndrome

Rituximab is actively used as a rescue therapy for nephrotic syndrome (NS). The development of antidrug antibodies, including antirituximab antibodies (ARA) and human antichimeric antibodies (HACA), is reported with rituximab treatment in various diseases. Here we report two pediatric patients with NS who developed ARA. Rituximab was given as a rescue therapy for two patients with steroid-dependent NS. Both patients had been treated orally with glucocorticosteroid, methylprednisolone, and calcineurin inhibitors but experienced frequent relapses. With rituximab treatment, the patients remained in remission for several months. After the B-cell count recovered, the patients received a second course of rituximab administration and experienced a hypersensitivity reaction during drug infusion. CD19 cell counts rose despite treatment with rituximab. ARA titers were monitored before and after rituximab treatment, and the development of ARA after the second course of rituximab administration was confirmed. We report the development of HACA in two patients with NS who did not achieve B-cell depletion after repeated administration of rituximab. This report suggests that additional studies are needed to determine the incidence of ARA in patients with NS, and its clinical significance.

SAT0125 Association of Rituximab Levels to Clinical Response and B Cell Recovery in Rheumatoid Arthritis Patients

BackgroundRituximab effects in rheumatoid arthritis patients have been extensively described in the literature. However, kinetics of rituximab levels in serum and their association with the clinical and immunological changes in...

Development of Antirituximab Antibodies May Portend Therapy Failure in Patients with Pemphigus

Rituximab is a chimeric antibody that appears to be useful in the management of pemphigus. However, antichimeric antibodies might develop in treated

Immunogenicity of rituximab in patients with severe pemphigus

Pemphigus is a life-threatening autoimmune bullous disease associated with autoantibodies to desmoglein 1 and/or 3. The anti-CD20 chimeric mouse monoclonal antibody rituximab has previously been successfully applied in more than 130 reported pemphigus patients with severe and/or refractory disease. Since antibodies against other therapeutics such as IFNalpha and beta, erythropoietin, and TNFalpha antagonists had led to decreased efficacy of these drugs, we determined anti-rituximab antibodies in 11 patients with pemphigus before rituximab administration as well as 3, 9, and 15 months thereafter. For this purpose, a novel, affinity capture elution assay was established using rabbit IgG against the F(ab)2 fragment of rituximab. In addition, serum levels of rituximab were determined by a competition ELISA. In 2 of 11 pemphigus patients, antibodies to rituximab were detected. In both patients, only a partial remission was observed under treatment. In addition, when followed over a longer period of time, the occurrence of anti-rituximab antibodies paralleled an increase in disease activity. Of the 9 patients without development of antiantibodies to rituximab, in 5, all lesions healed and in 4, partial remissions were seen. These observations show that antibodies to rituximab are generated in some patients during rituximab treatment and may be associated with a less favourable response to treatment.

Comparison of Pharmacokinetics and Pharmacodynamics of two different dosing regimens of Proleukin® (IL-2) in Combination with rituximab: The effect of NK cell expansion.

Background: Published results from studies testing two different dosing regimens of IL-2 in combination with rituximab have shown that thrice-weekly dosing of IL-2 resulted in greater expression of NK cell as compared to a daily dosing (Gluck, et al. Clin Cancer Res 2004). Expanded NK cells are desired to drive effective rituximab induced ADCC. Here we report on the observed pharmacokinetic (PK) differences associated with the differences in pharmcodynamics (PD) observed with the two regimens.Methods: Two different subcutaneous (SC) IL-2 dosing regimens in combination with rituximab (375 mg/m² weekly IV infusions weeks 1 through 4) were studied: daily IL-2 (6 MIU daily weeks 2–5) versus thrice-weekly IL-2 (14 MIU weeks 2–5) resulting in a total of 42 MIU weekly for each regimen. Serum samples for IL-2, rituximab, and soluble IL-2 receptor (sIL-2r) were analyzed using an ELISA assay. Anti-IL-2 and anti-rituximab antibodies (Ab) were also determined. IL-2 and rituximab serum concentration-time data were analyzed by model-independent methods using WinNolin.Results: Daily dosing of IL-2 exhibited time-dependent pharmacokinetics characterized by lower concentrations of IL-2 upon repeat SC dosing. An increase in IL-2 clearance coincided with an increase in sIL-2r concentrations in the systemic circulation. By the fifth dose, sIL-2r concentrations reached steady state at approximately 2–3 times higher concentrations than the baseline value. In contrast, the thrice-weekly dosing of IL-2 demonstrates no time-dependent kinetics; there were no observed differences in IL-2 plasma concentrations after the first dose or after repeated dosing. Surprisingly, a similar increase in sIL-2r levels from baseline was observed after multiple thrice-weekly dosing of IL-2. The pharmacokinetics of rituximab was similar after daily or thrice-weekly regimens of IL-2 and were comparable to values reported in the literature. The incidences of Ab against IL-2 and rituximab were low (<7%).Conclusion: Concomitant administration of IL-2 with rituximab is well tolerated, with no evidence of pharmacokinetic interaction. Thrice-weekly dosing regimen results in more sustained plasma IL-2 levels with repeated dosing than daily IL-2 dosing. Hence the sustained plasma levels and AUC associated with the thrice-weekly dosing potentially explains why this regimen results in greater NK cell expansion that does the daily dosing.