Blinatumomab exposure and pharmacodynamic response in patients with non-Hodgkin lymphoma (NHL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 3051-3051 ◽  
Author(s):  
Youssef Hijazi ◽  
Matthias Klinger ◽  
Andrea Schub ◽  
Benjamin Wu ◽  
Min Zhu ◽  
...  
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Phase 1 ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Dose Requirement ◽  
Time Curve ◽  
Cell Counts ◽  
Dose Dependent

3051 Background: Blinatumomab (AMG 103) is an investigational, bispecific, T cell engaging (BiTE) antibody targeting CD19-expressing B cells. We describe the exposure-pharmacodynamic (PD) response of blinatumomab in patients with NHL, using a quantitative pharmacology approach. Methods: In a phase 1 study, 76 patients with NHL received blinatumomab by continuous intravenous infusion (cIV) at doses of 0.5 to 90 μg/m2/d in 4- or 8-week cycles. Pharmacokinetics (PK) was determined. PD responses evaluated included lymphocytes and cytokines measured during treatment, and sum of the products of the greatest diameters of tumor size in lymph nodes (SPD) at the end of treatment. Blinatumomab concentration at steady state (Css) and the cumulative area under the concentration (AUCcum)–time curve over the period before the evaluation of SPD were used to evaluate the exposure-SPD relationship. Results: Blinatumomab showed linear PK. Early PD responses were characterized by B cell depletion, T cell redistribution, and transient cytokine release. Following cIV at doses from 0.5 to 90 μg/m2/d, B cells declined at a first-order rate with a dose-dependent rate constant, ranging from 0.16 to 1.0 h-1. Complete B cell depletion was achieved within 48 hours at doses ≥5 μg/m2/d. A dose-independent decrease in T cell counts was observed within 24 hours after dosing, and T cells returned to baseline within 2 weeks of treatment. Cytokine elevation occurred in some patients and was dose-dependent. Blinatumomab exposure-SPD relationship was best described by an inhibitory Emax model (E = E0-(Imax*C)/(IC50+C)). According to the model estimation, a 50% reduction in SPD would be achieved when Css is 2141 pg/mL and AUCcum is 1381 h*μg/L, equivalent to a blinatumomab dose of 54 µg/m2/d given over 27 days. Conclusions: B lymphocytes were completely depleted from the circulation at blinatumomab doses ≥5 μg/m2/d. Depletion was faster at higher doses. Higher blinatumomab Css and AUCcum were associated with better tumor reduction. Tissue accessibility may explain the higher dose requirement for SPD reduction versus peripheral B cell depletion. The PK/PD model has utility for the design of future studies of blinatumomab in NHL. Clinical trial information: NCT00274742.

scholarly journals B cell depletion with anti-CD20 mAb exacerbates anti-donor CD4+ T cell responses in highly sensitized transplant recipients

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Asuka Tanaka ◽  
Kentaro Ide ◽  
Yuka Tanaka ◽  
Masahiro Ohira ◽  
Hiroyuki Tahara ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Responses ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Transplant Recipients ◽  
Cell Responses ◽  
Anti Cd20

AbstractPretransplant desensitization with rituximab has been applied to preformed donor-specific anti-human leukocyte antigen antibody (DSA)-positive recipients for elimination of preformed DSA. We investigated the impact of pretransplant desensitization with rituximab on anti-donor T cell responses in DSA-positive transplant recipients. To monitor the patients’ immune status, mixed lymphocyte reaction (MLR) assays were performed before and after desensitization with rituximab. Two weeks after rituximab administration, the stimulation index (SI) of anti-donor CD4+ T cells was significantly higher in the DSA-positive recipients than in the DSA-negative recipients. To investigate the mechanisms of anti-donor hyper responses of CD4+ T cells after B cell depletion, highly sensitized mice models were injected with anti-CD20 mAb to eliminate B cells. Consistent with clinical observations, the SI values of anti-donor CD4+ T cells were significantly increased after anti-CD20 mAb injection in the sensitized mice models. Adding B cells isolated from untreated sensitized mice to MLR significantly inhibited the enhancement of anti-donor CD4+ T cell response. The depletion of the CD5+ B cell subset, which exclusively included IL-10-positive cells, from the additive B cells abrogated such inhibitory effects. These findings demonstrate that IL-10+ CD5+ B cells suppress the excessive response of anti-donor CD4+ T cells responses in sensitized recipients.

scholarly journals Sustained B cell depletion by CD19-targeted CAR T cells is a highly effective treatment for murine lupus

2019 ◽  
Vol 11 (482) ◽  
pp. eaav1648 ◽  
Author(s):  
Rita Kansal ◽  
Noah Richardson ◽  
Indira Neeli ◽  
Saleem Khawaja ◽  
Damian Chamberlain ◽  
...  
Keyword(s):  
Clinical Trials ◽  
T Cells ◽  
T Cell ◽  
B Cells ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Murine Lupus ◽  
Car T Cells ◽  
Car T

The failure of anti-CD20 antibody (Rituximab) as therapy for lupus may be attributed to the transient and incomplete B cell depletion achieved in clinical trials. Here, using an alternative approach, we report that complete and sustained CD19+ B cell depletion is a highly effective therapy in lupus models. CD8+ T cells expressing CD19-targeted chimeric antigen receptors (CARs) persistently depleted CD19+ B cells, eliminated autoantibody production, reversed disease manifestations in target organs, and extended life spans well beyond normal in the (NZB × NZW) F1 and MRLfas/fas mouse models of lupus. CAR T cells were active for 1 year in vivo and were enriched in the CD44+CD62L+ T cell subset. Adoptively transferred splenic T cells from CAR T cell–treated mice depleted CD19+ B cells and reduced disease in naive autoimmune mice, indicating that disease control was cell-mediated. Sustained B cell depletion with CD19-targeted CAR T cell immunotherapy is a stable and effective strategy to treat murine lupus, and its effectiveness should be explored in clinical trials for lupus.

Sustained Depletion of B-Cells by a Humanized, Fc-Engineered Anti-CD20 Antibody, AME-133v, in Patients with Relapsed Follicular Lymphoma

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4977-4977
Author(s):  
Jennifer Wayne ◽  
Kristen N. Ganjoo ◽  
Andres Forero ◽  
Brad Pohlman ◽  
Sven de Vos ◽  
...  
Keyword(s):  
Clinical Trials ◽  
B Cells ◽  
Phase I ◽  
Follicular Lymphoma ◽  
B Cell ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Cell Counts ◽  
Evaluable Population ◽  
Anti Cd20

Abstract Abstract 4977 Sustained Depletion of B-Cells by a Humanized, Fc-Engineered Anti-CD20 Antibody, AME-133v, in Patients with Relapsed Follicular Lymphoma J Wayne,1 K Ganjoo,2 A Forero,3 B Pohlman,4 S de Vos,5 S Carpenter,6 J Wooldridge,6 S Marulappa,1 V Jain11Mentrik Biotech, LLC, Dallas, TX, 2Standford University Medical Center, Stanford, CA, 3Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL,4Cleveland Clinic Taussig Cancer Institute, Cleveland, OH, 5David Geffen School of Medicine at University of California, Los Angeles, CA, 6Eli Lilly and Company, Indianapolis, Indiana Introduction AME-133v is a humanized anti-CD20 monoclonal antibody that has a 13 to 20-fold increase in binding affinity and approximately 6-fold more potent effector function in antibody-dependent cell-mediated cytotoxicity (ADCC) compared to rituximab. Phase I/II clinical trials of AME-133v in patients with relapsed follicular lymphoma have demonstrated an overall response rate of greater than 30% with a complete response rate of 16%. The extent and duration of depletion of CD19+ B-cells in peripheral blood was used as a surrogate of therapeutic levels of AME-133v. Analysis from the Phase I/II clinical trials is presented in this report. Methods CD-19 positive B-cells in peripheral blood were measured in 77 patients with relapsed follicular lymphoma enrolled in two phase I/II clinical trials of AME-133v. These studies assessed five different doses of AME-133v (from 2 mg/m2 to 375 mg/m2). AME-133v was administered intravenously four times at weekly intervals in both trials. Blood samples were taken at multiple time points throughout the trial and a central lab measured levels of circulating CD19+ B-cells using fluorescence-activated cell sorting (FACS). Results Excluding the four patients enrolled in the 2 mg/m2 dose cohort, depletion of peripheral B-cells occurred in all patients and was sustained over time (Table 1). Baseline levels of B-cell counts ranged from 4 × 103 to 1,187 × 103 cells/μL, with an average of 102 × 103 cells/μL and a median of 60 × 103 cells/μL. Within 24 hours of the first infusion, all patients had depletion of circulating B-cells; ninety-six percent of patients had less than 10 × 103 cells/μL and two patients had less than 20 × 103 cells/μL. Interestingly, AME-133v was effective at depleting B-cells even at doses as low as 7.5 mg/m2. To assess sustainability of B-cell depletion after four doses of AME-133v, CD19+ cell counts were evaluated at nine weeks after the fourth infusion and every three months thereafter. Complete depletion of CD19+ lymphocytes was sustained for nine weeks. At five months after the last infusion of AME-133v, nearly two-thirds of patients had no detectable circulating B-cells. Sustained B-cell depletion lasted for at least eight months following the last infusion in 63% of patients. Table 1. B-cell counts for all patients in 7.5, 30, 100 and 375 mg/m2 cohorts. Percentages are cumulative Time Point Cell Count (x 103 cells/μL) 0 < 1 2 to 10 11 to 30 31 to 50 < 100 Day 1 (24 hours after last infusion) 62 % 66 % 96 % 100 % 100% 100% Day 7 (day of infusion 2) 75% 80% 95% 97% 97% 98% Day 28 (1 week after last infusion) 78 % 87% 95% 98% 98% 100% Day 84 (9 weeks after last infusion) 78% 87% 91% 96% 96% 98% Day 174 (5 months after last infusion) 60% 60% 70% 86% 93% 100% Day 264 (8 months after last infusion) 26% 26% 41% 63% 81% 89% Day 354 (11 months after last infusion) 0% 0% 15% 40% 55% 80% DEMOGRAPHIC CHARACTERISTICS (EVALUABLE POPULATION) “\f C \l 1 Demographic and Disease Characteristics on evaluable population (N=30) Conclusion The rapid and sustained effect of AME-133v on B-cell depletion, even in low-affinity FcγRIIIa patients, indicates a potentially relevant biological activity of the antibody in treating B-cell non-Hodgkin lymphoma. Notably, this depletion occurred even at very low doses of drug administration and persisted over time. This may be related to its higher affinity for CD20, increased ADCC, or both. The sustained B-cell depletion may result in prolonged clinical response and might mitigate the need for maintenance therapy. A randomized trial is being planned to compare efficacy of AME-133v vs. rituximab. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Monitoring B-cell repopulation after depletion therapy in neurologic patients

2018 ◽  
Vol 5 (4) ◽  
pp. e463 ◽  
Author(s):  
Erik Ellwardt ◽  
Lea Ellwardt ◽  
Stefan Bittner ◽  
Frauke Zipp
Keyword(s):  
B Cells ◽  
B Cell ◽  
Cell Depletion ◽  
Close Monitoring ◽  
B Cell Depletion ◽  
Cell Recovery ◽  
Cell Counts ◽  
White Blood Cell Counts ◽  
Anti Cd20 ◽  
Cell Repopulation

ObjectiveTo determine the factors that influence B-cell repopulation after B-cell depletion therapy in neurologic patients and derive recommendations for monitoring and dosing of patients.MethodsIn this study, we determined the association of body surface area (BSA; calculated by body weight and height with the Dubois formula), sex, pretreatment therapy, age, CSF data, and white blood cell counts with the risk and timing of B-cell repopulation, defined as 1% CD19+ cells (of total lymphocytes), following 87 B cell–depleting anti-CD20 treatment cycles of 45 neurologic patients (28 women; mean age ± SD, 44.5 ± 15.0 years).ResultsPatients with a larger BSA had a higher probability to reach 1% CD19+ cells than those with a smaller BSA (p < 0.05) following B-cell depletion therapy, although those patients had received BSA-adapted doses of rituximab (375 mg/m2). Sex, pretreatment, age, CSF data, or absolute lymphocyte and leukocyte counts during treatment did not significantly influence CD19+ B-cell recovery in the fully adjusted models. Intraindividual B-cell recovery in patients with several treatment cycles did not consistently change over time.ConclusionsB-cell repopulation after depletion therapy displays both high inter- and intra-individual variance. Our data indicate that a larger BSA is associated with faster repopulation of B cells, even when treatment is adapted to the BSA. A reason is the routinely used Dubois formula, underestimating a large BSA. In these patients, there is a need for a higher therapy dose. Because B-cell count–dependent therapy regimes are considered to reduce adverse events, B-cell monitoring will stay highly relevant. Patients' BSA should thus be determined using the Mosteller formula, and close monitoring should be done to avoid resurgent B cells and disease activity.

HuMax-CD20 Fully Human Monoclonal Antibody in Follicular Lymphoma. First Human Exposure: Early Results of an Ongoing Phase I/II Trial.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1400-1400 ◽  
Author(s):  
Anton Hagenbeek ◽  
Torben Plesner ◽  
Jan Walewski ◽  
Andrzej Hellmann ◽  
Brian K. Link ◽  
...  
Keyword(s):  
B Cells ◽  
Adverse Events ◽  
B Cell ◽  
Cell Count ◽  
Peripheral Blood ◽  
Tumor Response ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Cell Counts ◽  
Grade 3

Abstract HuMax-CD20 is a fully human monoclonal IgG1 antibody targeting a unique extracellular epitope of the CD20 molecule on B-cells. HuMax-CD20 stops growth of engrafted B-cell tumors in SCID mouse tumor models more efficiently than Rituximab®, and i.v. infusion of HuMax-CD20 in cynomolgus monkeys has led to profound, long lasting, dose-dependent B-cell depletion. A total of 40 patients with CD20+ relapsed or refractory follicular non-Hodgkin’s lymphoma grade I-II will be enrolled in this open-label, dose-escalating, international, multi-center clinical trial. Cohorts of 10 patients will receive i.v. infusions at doses of either 300, 500, 700 or 1000 mg once weekly for 4 weeks. The patients are followed for 12 months. Patients receive oral acetaminophen and i.v. antihistamin before infusion. In case of adverse events of CTC grade 3 or higher, i.v. glucocorticosteroids are given. The endpoints are CT scan verified tumor response according to the Cheson criteria, B-cell depletion in peripheral blood and lymph nodes, time to next anti-lymphoma treatment, duration of response, BCL2 conversion, pharmacokinetics, and adverse events. Tumor and bone marrow biopsies and CT scans are assessed centrally. The first 17 patients treated with HuMax-CD20 are the subject of this report. Mean age is 60 years. In the 300 mg group all 10 patients have received all 4 infusions. Seven patients have been enrolled in the 500 mg group; three of them have received 4 infusions, two have received 3 infusions, and two patients have received 2 infusions. Baseline B-cell count was in the range of 11-382 x 106 cells per L with a median of 114 x 106. One week after the first infusion the median B-cell count available in 16 patients was 8 x 106 cells per L with a range of 0–19 x 106. In six of the 16 patients no B-cells were detected. B-cell counts measured one week after the 4th infusion are available for 10 patients. Eight patients had no detectable B-cells, one patient had 11 x 106 and one had 34 x 106 cells per L. B-cell counts eight weeks after the 4th infusion are available for two patients. No B-cells were detectable in these two patients. No dose limiting toxicity has been reported with administration of 300 or 500 mg. One serious adverse event assessed as not related to HuMax-CD20 has been reported in the 300 mg group. Infusion related adverse events have primarily been seen during the first infusion of HuMax-CD20. The events have, as expected, predominantly been signs and symptoms of cytokine release, e.g. pruritus, dyspnoea, rigors/chills, nausea, hypotension, urticaria, fatigue, fever and rash. In 15 of the 17 patients, 51 adverse events have been reported. Nine adverse events were CTC grade 3, 16 were grade 2, and 26 events were grade 1. In conclusion, this analysis based on preliminary data for the first 17 patients treated with HuMax-CD20 demonstrated significant depletion of peripheral blood B-cells and a favorable safety profile. An updated report of results for all 40 patients including preliminary tumor response data will be presented.

scholarly journals Antibody-mediated B-cell depletion before adoptive immunotherapy with T cells expressing CD20-specific chimeric T-cell receptors facilitates eradication of leukemia in immunocompetent mice

Blood ◽  
2009 ◽  
Vol 114 (27) ◽  
pp. 5454-5463 ◽  
Author(s):  
Scott E. James ◽  
Nural N. Orgun ◽  
Thomas F. Tedder ◽  
Mark J. Shlomchik ◽  
Michael C. Jensen ◽  
...  
Keyword(s):  
T Cells ◽  
T Cell ◽  
B Cells ◽  
Transgenic Mice ◽  
B Cell ◽  
T Cell Receptors ◽  
Adoptive T Cell Therapy ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Cell Receptors

Abstract We have established a model of leukemia immunotherapy using T cells expressing chimeric T-cell receptors (cTCRs) targeting the CD20 molecule expressed on normal and neoplastic B cells. After transfer into human CD20 (hCD20) transgenic mice, cTCR+ T cells showed antigen-specific delayed egress from the lungs, concomitant with T-cell deletion. Few cTCR+ T cells reached the bone marrow (BM) in hCD20 transgenic mice, precluding effectiveness against leukemia. Anti-hCD20 antibody-mediated B-cell depletion before adoptive T-cell therapy permitted egress of mouse CD20-specific cTCR+ T cells from the lungs, enhanced T-cell survival, and promoted cTCR+ T cell–dependent elimination of established mouse CD20+ leukemia. Furthermore, CD20-specific cTCR+ T cells eliminated residual B cells refractory to depletion with monoclonal antibodies. These findings suggest that combination of antibody therapy that depletes antigen-expressing normal tissues with adoptive T-cell immunotherapy enhances the ability of cTCR+ T cells to survive and control tumors.

ZW38, a Novel Azymetric Bispecific CD19-Directed CD3 T Cell Engager Antibody Drug Conjugate with Controlled T Cell Activation and Improved B Cell Cytotoxicity

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1841-1841
Author(s):  
Gordon Ng ◽  
Thomas Spreter ◽  
Rupert Davies ◽  
Grant Wickman
Keyword(s):  
T Cell ◽  
B Cells ◽  
B Cell ◽  
T Cell Activation ◽  
Cell Activation ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Cell Cytotoxicity ◽  
Cytokine Release ◽  
Antibody Drug Conjugate

Abstract Although blinatumomab is an approved treatment for Philadelphia chromosome negative relapsed or refractory (r/r) precursor-B cell ALL and is under development for r/r B cell NHL, blinatumomab has several limitations impacting fuller therapeutic utility. For instance, blinatumomab therapy requires continuous infusion due to its rapid clearance owing to its size and lack of an antibody Fc and has been associated with potentially life-threatening CNS toxicities and cytokine release syndrome (Viardot A et al, Blood 2016; Goebeler ME et al, J Clin Oncol 2016; Topp et al, Lancet Oncol 2015). In addition, blinatumomab treatment is associated with higher incidence of relapse in patients with high disease burden, and its T cell redirected killing is limited by T cell immunosuppression (e.g. PD-1/PD-L1 up-regulation [Köhnke et al, J Hematol & Oncol 2015]; Treg suppression [Duell et al, ASH abstract 2014]). ZW38 is designed to address each of these limitations and represents a best in class CD19-directed CD3 T cell engager and a novel class of bispecific antibody drug conjugate (ADC). ZW38 contains an Azymetric IgG1-like Fc that carries mutations in the CH2 domain preventing FcgR dependent ADCC and ADCP and exhibits typical IgG1-like PK in rodent studies. Transient expression in mammalian CHO cells demonstrate ZW38 can be expressed at a titre of hundreds mg/L and can be purified using conventional IgG antibody methods and resins with typical IgG step purification yields and high heterodimer purity. Additionally, ZW38 has been conjugated to a microtubule inhibitor that lacks bystander killing. ZW38 antibody paratopes have been engineered to favor T cell-B cell functional engagement and selective target B cell cytotoxicity. In vitro studies demonstrated that ZW38 binds to human CD19+ B cells with >30-fold higher affinity than to human CD3+ T cells. Similar to blinatumomab, ZW38 can redirect the killing of target cancer B cells via T cell subtypes from human PBMC and its cytotoxicity is target B cell dependent. At concentrations that result in efficacious B cell depletion, ZW38 does not overly activate T cells. ZW38 is specifically engineered to induce more 'controlled' T cell activation than blinatumomab while still mediating sufficient T cell redirected target B cell depletion. ZW38 mediates T cell activation, cytokine release, and proliferation at nanomolar potency. By design, the sufficient, lower cytokine levels necessary for B cell killing may reduce the risk of cytokine release syndrome and T cell anergy. ZW38 exhibited potent growth inhibition in a panel of different B cell ALL and NHL cancer lines including but not limited to: G2, Nalm-6, RS4-11, Daudi, SUDHL-4 and SUDHL-6. In comparison to blinatumomab, ZW38 exhibits superior target B cell depletion in in vitro co-cultures of Raji lymphoma cells and human PBMC (ZW38 depletes > 90% B cells; blinatumomab depletes 20-90% B cells depending on the PBMC donor). In addition, ZW38 was effective in killing target B cells in PBMC cultures in which PD-1 has been up-regulated, which were resistant to blinatumomab killing in this assay. The dual mechanisms of action of ZW38, redirected T cell cytotoxicity and ADC cytotoxicity, may prolong and/or boost response rates, lower the incidence of relapse, and reduce the likelihood of acquired resistance while its 'controlled' T cell activation profile may reduce the risk of life-threatening and potentially fatal neurotoxicity and CRS. Disclosures Ng: Zymeworks: Employment, Patents & Royalties. Spreter:Zymeworks: Employment, Patents & Royalties. Davies:Zymeworks Biopharmaceuticals: Employment. Wickman:Zymeworks: Employment.

scholarly journals Immunological changes in diffuse large B-cell lymphomas after Rituximab-CHOP treatment: Own data and review of the literature

2012 ◽  
Vol 153 (42) ◽  
pp. 1658-1666 ◽  
Author(s):  
Zsófia Simon ◽  
Árpád Illés ◽  
Zsófia Miltényi ◽  
Ferenc Magyari ◽  
László Váróczy ◽  
...  
Keyword(s):  
T Cell ◽  
B Cell ◽  
B Cell Lymphoma ◽  
Infectious Complications ◽  
Cell Depletion ◽  
B Cell Depletion ◽  
Review Of The Literature ◽  
Cell Counts ◽  
Large B Cell

Introduction: Rituximab treatment may induce a long-term B-cell depletion, which can be accompanied with an increased infection risk. Aims: To examine the changes of the white blood cell, CD19+B-cell and CD4+T-cell counts and the levels of immunoglobulin G, A, M after rituximab containing chemotherapy and to explore the infectious complications in our patients and review of the literature. Patients and methods: Thirty-five diffuse large B-cell lymphoma patients were examined, who were treated with rituximab-cyclophosphamide-vincristine-doxoribicine-prednosolone (R-CHOP). The B- and T-cell populations were analyzed with flow-cytometry while the immunoglobulin levels were measured by nephelometry. Results: CD19+B-lymphocytes were undetectable after the treatment and their count only increased from the post-therapeutic 12th month. Infection did not occur in this group of patients. Conclusions: Rituximab induced B-cell depletion was appreciable also in this group of patients, while serious or unexpected infection did not occur. Increased infectious risk primarily can be observed after long-term, maintenance rituximab treatment. Orv. Hetil., 2012, 153, 1658–1666.

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