Objective： This study was designed to determine the safety, pharmacokinetics and biologic effects of a humanmouse chimeric anti-CD20 monoclonal antibody （SCT400） in Chinese padents with CD20-positive B-cell non- Ho...Objective： This study was designed to determine the safety, pharmacokinetics and biologic effects of a humanmouse chimeric anti-CD20 monoclonal antibody （SCT400） in Chinese padents with CD20-positive B-cell non- Hodgkin＇s lymphoma （CD20 B-cell NHL）. SCT400 has an identical amino acid sequence as rituximab, with the exception of one amino acid in the CH1 domain of the heavy chain, which is common in Asians. Methods： Fifteen patients with CD20＋ B-cell NHL received dose-escalating SCT400 infusions （250 mg/m2： n=3; 375 mg/m2： n=9; 500 mg/m2： n=3） once weekly for 4 consecutive weeks with a 24-week follow-up period. The data of all patients were collected for pharmacoklnetics and pharmacodynamics analyses. Results： No dose-limiting toxicities were observed. Most drug-related adverse events were grade 1 or 2. Two patients had grade 3 or 4 ncutropenia. Under premedication, the drug-related infusion reaction was mild. A rapid, profound and durable depletion of circulating B cells was observed in all dose groups without significant effects on T cell count, natural killer （NK） cell count or immunoglobulin levels. No patient developed anti- SCT400 antibodies during the course of the study. SCT400 serum half-life （Tin）, maximum concentration （Cmax and area under the curve （AUC） generally increased between the first and fourth infusions （P〈0.05）. At the 375 mg/m2 dose, the T1/2 was 122.5±46.7 h vs. 197.0,75.0 11, respectively, and the Cmax was 200.6±20.2 pg/mL vs. 339.1±71.0 ng/mL, respectively. From 250 mg/m2 to 500 mg/m2, the Cmax and AUC increased significantly in a dose-dependent manner （P〈0.05）. Patients with a high tumor burden had markedly lower serum SCT400 concenmations compared with those without or with a low tumor burden. Of the 9 assessable patients, 1 achieved complete response and 2 achieved partial responses. Conclusions; SCT400 is well-tolerated and has encouraging preliminary efficacy in Chinese patients with CD20＋ B-cell NHL.展开更多
Immunoglobulin A nephropathy(IgAN)is the most common primary glomerular disease,and the“four-hit”theory represents its currently accepted pathogenic mechanism.Mucosal immunity triggered by infections in the respirat...Immunoglobulin A nephropathy(IgAN)is the most common primary glomerular disease,and the“four-hit”theory represents its currently accepted pathogenic mechanism.Mucosal immunity triggered by infections in the respiratory tract,intestines,or other areas leads to antigen presentation,T cell stimulation,B cell maturation,and the production of IgA-producing plasma cells.The proteins B-lymphocyte stimulator(BLyS)and a proliferation-inducing ligand(APRIL)are involved in this process,and alternative complement and lectin pathway activation are also part of the pathogenic mechanism.Kidney Disease Improving Global Outcomes guidelines indicate that a specific effective treatment for IgAN is lacking,with renin-angiotensin-aldosterone system inhibitors being the primary therapy.Recent research shows that biological agents can significantly reduce proteinuria,stabilize the estimated glomerular filtration rate,and reverse some pathological changes,such as endocapillary proliferation and crescent formation.There are four main categories of biological agents used to treat IgA nephropathy,specifically anti-CD20 monoclonal antibodies,anti-BLyS or APRIL monoclonal antibodies,monoclonal antibodies targeting both BLyS and APRIL(telitacicept and atacicept),and monoclonal antibodies inhibiting complement system activation(narsoplimab and eculizumab).However,further research on the dosages,treatment duration,long-term efficacy,and safety of these biological agents is required.展开更多
Hepatitis B virus (HBV) infection remains an endemic disease in most parts of the world despite available prophylactic vaccines.Non-Hodgkin's lymphoma is the most common hematological malignancy,and certain patien...Hepatitis B virus (HBV) infection remains an endemic disease in most parts of the world despite available prophylactic vaccines.Non-Hodgkin's lymphoma is the most common hematological malignancy,and certain patients undergoing therapy are at increased risk of HBV reactivation.Rituximab,a monoclonal antibody,is well studied in HBV reactivation,but newer agents have been implicated as well.Here,we review novel agents suspected in HBV reactivation and effective strategies to prevent HBV reactivation.Fifteen years of literature were reviewed in order to better understand the reactivation rates of hepatitis B in patients with non-Hodgkin's lymphoma.Anti-CD20 antibodies continue to be the main medications that can lead to HBV reactivation,and HBV reactivation rates have decreased with increased awareness.HBV reactivation is uncommon when using other novel agents.Entecavir and lamivudine remain the agents of choice to prevent HBV reactivation in high risk patients.In conclusion,the immunosuppressive effect of NHL and its therapy provide a pathway for HBV reactivation,especially in patients treated with anti-CD20 antibody.Since many HBV positive patients are often excluded from clinical trials of novel agents in NHL,more aggressive post-market surveillance of new agents,welldesigned best practice advisories,and timely case reports are needed to reduce the incidence of HBV reactivation.Lastly,large prospective investigations coupled with well-utilized best practice advisories need to be conducted to understand the impact of more potent novel NHL therapy on HBV reactivation.(C) 2016 The Second Affiliated Hospital of Chongqing Medical University.Published by XIA & HE Publishing Inc.All rights reserved.展开更多
Type 1 diabetes （T1D） is an insulin-dependent diabetes because of insufficient insulin production by the pancreatic islet 15 cells. Although the patnogemc mechanism of T1D is not yet completely clear, the current vi...Type 1 diabetes （T1D） is an insulin-dependent diabetes because of insufficient insulin production by the pancreatic islet 15 cells. Although the patnogemc mechanism of T1D is not yet completely clear, the current view of T1D pathogenesis is that under certain genetic background, exogenous or endogenous factors trigger autoimmunity against islet β cells in the pancreas causing β cell damage and subsequent insufficiency of insulin production. About two decades ago, it was first demonstrated that T cells specific ~o 15 cell antigens were activated and participated in the pathogenesis of T I D.3＇4 A great deal of work following these reports in both animal models and humans has provided convincing data further supporting T1D is a T cell-mediated autoimmune disease.展开更多
In recent years,therapies for follicular lymphoma (FL) have steadily improved.A series of phase Ⅲ trials comparing the effect of rituximab with chemotherapy vs chemotherapy alone in treating FL have indicated signifi...In recent years,therapies for follicular lymphoma (FL) have steadily improved.A series of phase Ⅲ trials comparing the effect of rituximab with chemotherapy vs chemotherapy alone in treating FL have indicated significant improvements in progression-free survival (PFS) and overall survival.Recent studies have found that prolonged response durations and PFS were obtained with maintenance therapy using rituximab or interferon after completion of first line therapy.For patients with relapsed or refractory FL,phase Ⅱ studies have assessed the effectiveness of combination therapies using a Toll-like receptor-9 agonist (1018ISS),oblimersen sodium (a Bcl-2 antisense oligonucleotide),bendamustine,and rituximab,as well as veltuzumab,a new humanized anti-CD20 antibody,and epratuzumab.In addition,the effectiveness of yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab as radioimmunotherapies has been reported.Furthermore,three phase Ⅲ studies on an idiotype vaccine are near completion.Unfortunately,these vaccines,which appeared highly effective in phase Ⅰ and Ⅱ trials,do not appear to result in prolonged PFS.This report will summarize the current knowledge on therapies for treatment of FL,and will conclude with a brief discussion of feasiblefuture options for effective treatments.Lastly,we added descriptions of the management of gastrointestinal FL,which is considered to be controversial because it is rare.展开更多
Objective:This multi-center,open-label,randomized,parallel-controlled phaseⅡstudy aimed to compare the pharmacokinetics(PK),pharmacodynamics(PD)and safety profile of ripertamab(SCT400),a recombinant antiCD20 monoclon...Objective:This multi-center,open-label,randomized,parallel-controlled phaseⅡstudy aimed to compare the pharmacokinetics(PK),pharmacodynamics(PD)and safety profile of ripertamab(SCT400),a recombinant antiCD20 monoclonal antibody,to rituximab(MabThera^(■))in patients with CD20-positive B-cell non-Hodgkin lymphoma(NHL).Methods:Patients with CD20-positive B-cell NHL who achieved complete remission or unconfirmed complete remission after standard treatment were randomly assigned at a 1:1 ratio to receive a single dose of ripertamab(375mg/m^(2))or rituximab(MabThera^(■),375 mg/m^(2)).PK was evaluated using area under the concentration-time curve(AUC)from time 0 to d 85(AUC_(0-85d)),AUC from time 0 to week 1(AUC0-1 w),AUC from time 0 to week 2(AUC_(0-2 w)),AUC from time 0 to week 3(AUC_(0-3 w)),AUC from time 0 to week 8(AUC_(0-8 w)),maximum serum concentration(C_(max)),terminal half-life(T_(1/2)),time to maximum serum concentration(T_(max))and clearance(CL).Bioequivalence was confirmed if the 90%confidence interval(90%CI)of the geometric mean ratio of ripertamab/rituximab was within the pre-defined bioequivalence range of 80.0%-125.0%.PD,immunogenicity,and safety were also evaluated.Results:From December 30,2014 to November 24,2015,a total of 84 patients were randomized(ripertamab,n=42;rituximab,n=42)and the PK analysis was performed on 76 patients(ripertamab,n=38;rituximab,n=38).The geometric mean ratios of ripertamab/rituximab for AUC_(0-85d),ATC_(0-inf),and Cmaxwere 96.1%(90%CI:87.6%-105.5%),95.9%(90%CI:86.5%-106.4%)and 97.4%(90%CI:91.6%-103.6%),respectively.All PK parameters met the pre-defined bioequivalence range of 80.0%-125.0%.For PD and safety evaluation,there was no statistical difference in peripheral CD 19-positive B-cell counts and CD20-positive B-cell counts at each visit,and no difference in the incidence of anti-drug antibodies was observed between the two groups.The incidences of treatment-emergent adverse events and treatment-related adverse events were also comparable between the two groups.Conc展开更多
The coronavirus disease 2019(COVID-19)pandemic poses a great threat to public health.Individuals who are immunocompromised because of the progression of the primary disease or receiving immunosuppressive medications a...The coronavirus disease 2019(COVID-19)pandemic poses a great threat to public health.Individuals who are immunocompromised because of the progression of the primary disease or receiving immunosuppressive medications are prone to severe COVID-19 complications and poor outcomes.Abundant data have shown that many COVID-19 vaccines are safe and effective in large-scale populations;however,these clinical trials have excluded immunocompromised populations.Available evidence indicates that immunocompromised populations have a blunted immune response to other vaccines,raising concerns regarding the efficacy of COVID-19 vaccination in these populations.Thus,there is an urgent need to delineate the efficacy of COVID-19 vaccines in these vulnerable populations.Here,we review the characteristics of specific humoral and cellular responses to COVID-19 vaccination in immunocompromised populations,including HIV-infected patients and those receiving immunosuppressive treatment,especially solid organ transplant recipients and those undergoing anti-CD20 treatment.We also addressed the challenges that immunocompromised populations will face in the future pandemic and the need for basic and clinical translational studies to highlight the best vaccination strategies for these populations.展开更多
AIM: To evaluate pretreatment hepatitis B virus (HBV) testing, vaccination, and antiviral treatment rates in Veterans Affairs patients receiving anti-CD20 Ab for quality improvement.METHODS: We performed a retrospecti...AIM: To evaluate pretreatment hepatitis B virus (HBV) testing, vaccination, and antiviral treatment rates in Veterans Affairs patients receiving anti-CD20 Ab for quality improvement.METHODS: We performed a retrospective cohort study using a national repository of Veterans Health Administration (VHA) electronic health record data. We identified all patients receiving anti-CD20 Ab treatment (2002-2014). We ascertained patient demographics, laboratory results, HBV vaccination status (from vaccination records), pharmacy data, and vital status. The high risk period for HBV reactivation is during anti-CD20 Ab treatment and 12 mo follow up. Therefore, we analyzed those who were followed to death or for at least 12 mo after completing anti-CD20 Ab. Pretreatment serologic tests were used to categorize chronic HBV (hepatitis B surface antigen positive or HBsAg+), past HBV (HBsAg-, hepatitis B core antibody positive or HBcAb+), resolved HBV (HBsAg-, HBcAb+, hepatitis B surface antibody positive or HBsAb+), likely prior vaccination (isolated HBsAb+), HBV negative (HBsAg-, HBcAb-), or unknown. Acute hepatitis B was defined by the appearance of HBsAg+ in the high risk period in patients who were pretreatment HBV negative. We assessed HBV antiviral treatment and the incidence of hepatitis, liver failure, and death during the high risk period. Cumulative hepatitis, liver failure, and death after anti-CD20 Ab initiation were compared by HBV disease categories and differences compared using the χ<sup>2</sup> test. Mean time to hepatitis peak alanine aminotransferase, liver failure, and death relative to anti-CD20 Ab administration and follow-up were also compared by HBV disease group.RESULTS: Among 19304 VHA patients who received anti-CD20 Ab, 10224 (53%) had pretreatment HBsAg testing during the study period, with 49% and 43% tested for HBsAg and HBcAb, respectively within 6 mo pretreatment in 2014. Of those tested, 2% (167/10224) had chronic HBV, 4% (326/7903) past HBV, 5% (427/8110) resolved HBV, 8% (628/8110) likely pr展开更多
Aim:Anti-CD20 monoclonal antibody is a cornerstone therapy for follicular lymphoma.Following anti-CD20 therapy,a potential decrease in CD20 antigen,and therefore a loss of the tumor target might be expected.However,th...Aim:Anti-CD20 monoclonal antibody is a cornerstone therapy for follicular lymphoma.Following anti-CD20 therapy,a potential decrease in CD20 antigen,and therefore a loss of the tumor target might be expected.However,the incidence and clinical significance of CD20 loss on tumor cells in patients with relapsed or refractory follicular lymphoma are unknown.This study aims to investigate the incidence and outcome of patients with relapsed or refractory follicular lymphoma patients harboring the loss of the tumor target,CD20.Methods:All consecutive adult patients with relapsed or refractory follicular lymphoma referred to the Early Drug Department at Gustave Roussy were included.The main objectives were to assess the incidence and prognosis of the loss in expression of CD20 antigen on the surface of tumor cells on patient outcome.Results:Over the study period 2013-2018,131 patients were screened for clinical trials with B-cell malignancies in the early drug department of Gustave Roussy in France.Forty-four patients presented with relapsed or refractory follicular lymphoma and 32 had tumor biopsies at the time of relapse that were retained for analysis.The median(range)age was 67.5 years(55.3-75.3)and the median number of prior anti-cancer systemic therapies was 3(2-4).At the time of relapse,CD20 expression was positive in 84%of tumors(n=27)and negative in 16%of tumors(n=5).At a median follow-up of 18.3(0.6-83.3)months,CD20 negativity was associated with a poorer prognosis with a median overall survival of 8.9 months(95%CI:2.4-19.1)in comparison to CD20 positive patients(28.3 months,95%CI:25.1-75.3 months,P=0.019).Conclusion:The loss of the tumor target antigen,CD20,occurred in 16%of patients with relapse or refractory follicular lymphoma.Due to confounding factors in patients who received anti-CD20 immunotherapy,it was not possible to formally establish the prognostic significance of CD20 negativity.However,we suggest that a check for CD20 antigen positivity nevertheless be performed to adapt subsequent therapies for p展开更多
OBJECTIVE To explore the biodistribution and anti-tumoractivity of ^(131)I labeled rituximab injected intratumorally orintraperitoneally in vivo in nude mice bearing Raji human Burkitt's lymphoma xenografts.METHOD...OBJECTIVE To explore the biodistribution and anti-tumoractivity of ^(131)I labeled rituximab injected intratumorally orintraperitoneally in vivo in nude mice bearing Raji human Burkitt's lymphoma xenografts.METHODS The rituximab and the mouse IgG were labeled withNa^(131)I using the IODO-GEN method.BALB/C nude mice werexenografted with ^(131)I-Rituximab or ^(131)I-IgG and killed on the 1st,3rd,7th,and 15th day after injection.The tumor/non-tumor ratio(T/NT)and the dose injected in each gram of the tissue(%ID/g)from12 organs or tissues of interest,e.g.tumor,blood,were calculated.The long and short axes of each tumor were measured by calipersat 2-3-day intervals after treatment,and the growth inhibition ofthe tumor was calculated using the MIRD formula.RESULTS When comparing intraperitoneal injection(IP)andintratumoral injection(IT)of ^(131)I-IgG,intratumoral injection of^(131)I-rituximab produced a significantly higher tumor/non-tumorratio in all tissues and organs of interest on the 1st,3rd,and 7thday,respectively(P<0.05).The %ID/g of tumor was 1.4-1.7-foldand 1.5-3.7-fold in the IP and IgG IT groups,respectively,but the%ID/g of non-tumors was significantly lower in the IP group andIgG IT group.Similarly,the tumor growth was greatly inhibitedby intratumoral injection of the ^(131)I-rituximab,whereas it wasless inhibited by other forms of the treatment(P<0.05).However^(131)I-rituximab injected intratumorally inhibited tumor growth ina dose-dependent manner.The inhibition rate was less with alow dose(75μCi)and greater with a high dose(150μCi),yet thedifference was not significant(P>0.05).CONCLUSION Tumors can absorb the highest amount of theradiolabelled antibodies,and the tumor/non-tumor ratios in thegroup with intratumoral injection of the ^(131)I-rituximab resulted inthe optimal anti-tumor activity.展开更多
基金supported in part by Chinese National Major Project for New Drug Innovation (2008ZX09312-020,2009ZX09503-014,2012ZX09303012 and 2013ZX09402301)National Key Technology Support Program (2014BAI09B12)+1 种基金Beijing Municipal Science and Technology Commission Major Project for New Drug Innovation (Z111102071011001)Beijing Municipal Science and Technology Commission Project for Beijing Key Laboratory (Z121102009212055)
文摘Objective： This study was designed to determine the safety, pharmacokinetics and biologic effects of a humanmouse chimeric anti-CD20 monoclonal antibody （SCT400） in Chinese padents with CD20-positive B-cell non- Hodgkin＇s lymphoma （CD20 B-cell NHL）. SCT400 has an identical amino acid sequence as rituximab, with the exception of one amino acid in the CH1 domain of the heavy chain, which is common in Asians. Methods： Fifteen patients with CD20＋ B-cell NHL received dose-escalating SCT400 infusions （250 mg/m2： n=3; 375 mg/m2： n=9; 500 mg/m2： n=3） once weekly for 4 consecutive weeks with a 24-week follow-up period. The data of all patients were collected for pharmacoklnetics and pharmacodynamics analyses. Results： No dose-limiting toxicities were observed. Most drug-related adverse events were grade 1 or 2. Two patients had grade 3 or 4 ncutropenia. Under premedication, the drug-related infusion reaction was mild. A rapid, profound and durable depletion of circulating B cells was observed in all dose groups without significant effects on T cell count, natural killer （NK） cell count or immunoglobulin levels. No patient developed anti- SCT400 antibodies during the course of the study. SCT400 serum half-life （Tin）, maximum concentration （Cmax and area under the curve （AUC） generally increased between the first and fourth infusions （P〈0.05）. At the 375 mg/m2 dose, the T1/2 was 122.5±46.7 h vs. 197.0,75.0 11, respectively, and the Cmax was 200.6±20.2 pg/mL vs. 339.1±71.0 ng/mL, respectively. From 250 mg/m2 to 500 mg/m2, the Cmax and AUC increased significantly in a dose-dependent manner （P〈0.05）. Patients with a high tumor burden had markedly lower serum SCT400 concenmations compared with those without or with a low tumor burden. Of the 9 assessable patients, 1 achieved complete response and 2 achieved partial responses. Conclusions; SCT400 is well-tolerated and has encouraging preliminary efficacy in Chinese patients with CD20＋ B-cell NHL.
基金This study was supported by grants from the Key Clinical Specialty Discipline Construction Program of Fujian,Grant/Award Number:2017ZDZKSBFujian Clinical Medical ResearchCenter for Immune Kidney Disease,Grant/Award Number:2021Y2016。
文摘Immunoglobulin A nephropathy(IgAN)is the most common primary glomerular disease,and the“four-hit”theory represents its currently accepted pathogenic mechanism.Mucosal immunity triggered by infections in the respiratory tract,intestines,or other areas leads to antigen presentation,T cell stimulation,B cell maturation,and the production of IgA-producing plasma cells.The proteins B-lymphocyte stimulator(BLyS)and a proliferation-inducing ligand(APRIL)are involved in this process,and alternative complement and lectin pathway activation are also part of the pathogenic mechanism.Kidney Disease Improving Global Outcomes guidelines indicate that a specific effective treatment for IgAN is lacking,with renin-angiotensin-aldosterone system inhibitors being the primary therapy.Recent research shows that biological agents can significantly reduce proteinuria,stabilize the estimated glomerular filtration rate,and reverse some pathological changes,such as endocapillary proliferation and crescent formation.There are four main categories of biological agents used to treat IgA nephropathy,specifically anti-CD20 monoclonal antibodies,anti-BLyS or APRIL monoclonal antibodies,monoclonal antibodies targeting both BLyS and APRIL(telitacicept and atacicept),and monoclonal antibodies inhibiting complement system activation(narsoplimab and eculizumab).However,further research on the dosages,treatment duration,long-term efficacy,and safety of these biological agents is required.
文摘Hepatitis B virus (HBV) infection remains an endemic disease in most parts of the world despite available prophylactic vaccines.Non-Hodgkin's lymphoma is the most common hematological malignancy,and certain patients undergoing therapy are at increased risk of HBV reactivation.Rituximab,a monoclonal antibody,is well studied in HBV reactivation,but newer agents have been implicated as well.Here,we review novel agents suspected in HBV reactivation and effective strategies to prevent HBV reactivation.Fifteen years of literature were reviewed in order to better understand the reactivation rates of hepatitis B in patients with non-Hodgkin's lymphoma.Anti-CD20 antibodies continue to be the main medications that can lead to HBV reactivation,and HBV reactivation rates have decreased with increased awareness.HBV reactivation is uncommon when using other novel agents.Entecavir and lamivudine remain the agents of choice to prevent HBV reactivation in high risk patients.In conclusion,the immunosuppressive effect of NHL and its therapy provide a pathway for HBV reactivation,especially in patients treated with anti-CD20 antibody.Since many HBV positive patients are often excluded from clinical trials of novel agents in NHL,more aggressive post-market surveillance of new agents,welldesigned best practice advisories,and timely case reports are needed to reduce the incidence of HBV reactivation.Lastly,large prospective investigations coupled with well-utilized best practice advisories need to be conducted to understand the impact of more potent novel NHL therapy on HBV reactivation.(C) 2016 The Second Affiliated Hospital of Chongqing Medical University.Published by XIA & HE Publishing Inc.All rights reserved.
基金This Work was supported by grants from the National Natural Science Foundation of China （No. 81172854）, and NIH 1R21DK080216-01A2.
文摘Type 1 diabetes （T1D） is an insulin-dependent diabetes because of insufficient insulin production by the pancreatic islet 15 cells. Although the patnogemc mechanism of T1D is not yet completely clear, the current view of T1D pathogenesis is that under certain genetic background, exogenous or endogenous factors trigger autoimmunity against islet β cells in the pancreas causing β cell damage and subsequent insufficiency of insulin production. About two decades ago, it was first demonstrated that T cells specific ~o 15 cell antigens were activated and participated in the pathogenesis of T I D.3＇4 A great deal of work following these reports in both animal models and humans has provided convincing data further supporting T1D is a T cell-mediated autoimmune disease.
文摘In recent years,therapies for follicular lymphoma (FL) have steadily improved.A series of phase Ⅲ trials comparing the effect of rituximab with chemotherapy vs chemotherapy alone in treating FL have indicated significant improvements in progression-free survival (PFS) and overall survival.Recent studies have found that prolonged response durations and PFS were obtained with maintenance therapy using rituximab or interferon after completion of first line therapy.For patients with relapsed or refractory FL,phase Ⅱ studies have assessed the effectiveness of combination therapies using a Toll-like receptor-9 agonist (1018ISS),oblimersen sodium (a Bcl-2 antisense oligonucleotide),bendamustine,and rituximab,as well as veltuzumab,a new humanized anti-CD20 antibody,and epratuzumab.In addition,the effectiveness of yttrium-90 ibritumomab tiuxetan and iodine-131 tositumomab as radioimmunotherapies has been reported.Furthermore,three phase Ⅲ studies on an idiotype vaccine are near completion.Unfortunately,these vaccines,which appeared highly effective in phase Ⅰ and Ⅱ trials,do not appear to result in prolonged PFS.This report will summarize the current knowledge on therapies for treatment of FL,and will conclude with a brief discussion of feasiblefuture options for effective treatments.Lastly,we added descriptions of the management of gastrointestinal FL,which is considered to be controversial because it is rare.
基金funded by Sinocelltech Ltd, Beijing Chinapartly supported by China National Major Project for New Drug Innovation (No. 2012ZX09303012 and No. 2017ZX09304015)
文摘Objective:This multi-center,open-label,randomized,parallel-controlled phaseⅡstudy aimed to compare the pharmacokinetics(PK),pharmacodynamics(PD)and safety profile of ripertamab(SCT400),a recombinant antiCD20 monoclonal antibody,to rituximab(MabThera^(■))in patients with CD20-positive B-cell non-Hodgkin lymphoma(NHL).Methods:Patients with CD20-positive B-cell NHL who achieved complete remission or unconfirmed complete remission after standard treatment were randomly assigned at a 1:1 ratio to receive a single dose of ripertamab(375mg/m^(2))or rituximab(MabThera^(■),375 mg/m^(2)).PK was evaluated using area under the concentration-time curve(AUC)from time 0 to d 85(AUC_(0-85d)),AUC from time 0 to week 1(AUC0-1 w),AUC from time 0 to week 2(AUC_(0-2 w)),AUC from time 0 to week 3(AUC_(0-3 w)),AUC from time 0 to week 8(AUC_(0-8 w)),maximum serum concentration(C_(max)),terminal half-life(T_(1/2)),time to maximum serum concentration(T_(max))and clearance(CL).Bioequivalence was confirmed if the 90%confidence interval(90%CI)of the geometric mean ratio of ripertamab/rituximab was within the pre-defined bioequivalence range of 80.0%-125.0%.PD,immunogenicity,and safety were also evaluated.Results:From December 30,2014 to November 24,2015,a total of 84 patients were randomized(ripertamab,n=42;rituximab,n=42)and the PK analysis was performed on 76 patients(ripertamab,n=38;rituximab,n=38).The geometric mean ratios of ripertamab/rituximab for AUC_(0-85d),ATC_(0-inf),and Cmaxwere 96.1%(90%CI:87.6%-105.5%),95.9%(90%CI:86.5%-106.4%)and 97.4%(90%CI:91.6%-103.6%),respectively.All PK parameters met the pre-defined bioequivalence range of 80.0%-125.0%.For PD and safety evaluation,there was no statistical difference in peripheral CD 19-positive B-cell counts and CD20-positive B-cell counts at each visit,and no difference in the incidence of anti-drug antibodies was observed between the two groups.The incidences of treatment-emergent adverse events and treatment-related adverse events were also comparable between the two groups.Conc
基金National Natural Science Foundation of China (No.82101837)Beijing Natural Science Foundation(No.7222171)Emergency Key Program of Guangzhou Laboratory (No.EKPG21-30-4)。
文摘The coronavirus disease 2019(COVID-19)pandemic poses a great threat to public health.Individuals who are immunocompromised because of the progression of the primary disease or receiving immunosuppressive medications are prone to severe COVID-19 complications and poor outcomes.Abundant data have shown that many COVID-19 vaccines are safe and effective in large-scale populations;however,these clinical trials have excluded immunocompromised populations.Available evidence indicates that immunocompromised populations have a blunted immune response to other vaccines,raising concerns regarding the efficacy of COVID-19 vaccination in these populations.Thus,there is an urgent need to delineate the efficacy of COVID-19 vaccines in these vulnerable populations.Here,we review the characteristics of specific humoral and cellular responses to COVID-19 vaccination in immunocompromised populations,including HIV-infected patients and those receiving immunosuppressive treatment,especially solid organ transplant recipients and those undergoing anti-CD20 treatment.We also addressed the challenges that immunocompromised populations will face in the future pandemic and the need for basic and clinical translational studies to highlight the best vaccination strategies for these populations.
基金Supported by(in part)by resources from the Veterans Affairs(VA) Cooperative Studies Program Epidemiology Center-Durham,the Puget Sound VA Health Care System,and the VA Office of Public Health and Human Health Pathogens
文摘AIM: To evaluate pretreatment hepatitis B virus (HBV) testing, vaccination, and antiviral treatment rates in Veterans Affairs patients receiving anti-CD20 Ab for quality improvement.METHODS: We performed a retrospective cohort study using a national repository of Veterans Health Administration (VHA) electronic health record data. We identified all patients receiving anti-CD20 Ab treatment (2002-2014). We ascertained patient demographics, laboratory results, HBV vaccination status (from vaccination records), pharmacy data, and vital status. The high risk period for HBV reactivation is during anti-CD20 Ab treatment and 12 mo follow up. Therefore, we analyzed those who were followed to death or for at least 12 mo after completing anti-CD20 Ab. Pretreatment serologic tests were used to categorize chronic HBV (hepatitis B surface antigen positive or HBsAg+), past HBV (HBsAg-, hepatitis B core antibody positive or HBcAb+), resolved HBV (HBsAg-, HBcAb+, hepatitis B surface antibody positive or HBsAb+), likely prior vaccination (isolated HBsAb+), HBV negative (HBsAg-, HBcAb-), or unknown. Acute hepatitis B was defined by the appearance of HBsAg+ in the high risk period in patients who were pretreatment HBV negative. We assessed HBV antiviral treatment and the incidence of hepatitis, liver failure, and death during the high risk period. Cumulative hepatitis, liver failure, and death after anti-CD20 Ab initiation were compared by HBV disease categories and differences compared using the χ<sup>2</sup> test. Mean time to hepatitis peak alanine aminotransferase, liver failure, and death relative to anti-CD20 Ab administration and follow-up were also compared by HBV disease group.RESULTS: Among 19304 VHA patients who received anti-CD20 Ab, 10224 (53%) had pretreatment HBsAg testing during the study period, with 49% and 43% tested for HBsAg and HBcAb, respectively within 6 mo pretreatment in 2014. Of those tested, 2% (167/10224) had chronic HBV, 4% (326/7903) past HBV, 5% (427/8110) resolved HBV, 8% (628/8110) likely pr
文摘Aim:Anti-CD20 monoclonal antibody is a cornerstone therapy for follicular lymphoma.Following anti-CD20 therapy,a potential decrease in CD20 antigen,and therefore a loss of the tumor target might be expected.However,the incidence and clinical significance of CD20 loss on tumor cells in patients with relapsed or refractory follicular lymphoma are unknown.This study aims to investigate the incidence and outcome of patients with relapsed or refractory follicular lymphoma patients harboring the loss of the tumor target,CD20.Methods:All consecutive adult patients with relapsed or refractory follicular lymphoma referred to the Early Drug Department at Gustave Roussy were included.The main objectives were to assess the incidence and prognosis of the loss in expression of CD20 antigen on the surface of tumor cells on patient outcome.Results:Over the study period 2013-2018,131 patients were screened for clinical trials with B-cell malignancies in the early drug department of Gustave Roussy in France.Forty-four patients presented with relapsed or refractory follicular lymphoma and 32 had tumor biopsies at the time of relapse that were retained for analysis.The median(range)age was 67.5 years(55.3-75.3)and the median number of prior anti-cancer systemic therapies was 3(2-4).At the time of relapse,CD20 expression was positive in 84%of tumors(n=27)and negative in 16%of tumors(n=5).At a median follow-up of 18.3(0.6-83.3)months,CD20 negativity was associated with a poorer prognosis with a median overall survival of 8.9 months(95%CI:2.4-19.1)in comparison to CD20 positive patients(28.3 months,95%CI:25.1-75.3 months,P=0.019).Conclusion:The loss of the tumor target antigen,CD20,occurred in 16%of patients with relapse or refractory follicular lymphoma.Due to confounding factors in patients who received anti-CD20 immunotherapy,it was not possible to formally establish the prognostic significance of CD20 negativity.However,we suggest that a check for CD20 antigen positivity nevertheless be performed to adapt subsequent therapies for p
文摘OBJECTIVE To explore the biodistribution and anti-tumoractivity of ^(131)I labeled rituximab injected intratumorally orintraperitoneally in vivo in nude mice bearing Raji human Burkitt's lymphoma xenografts.METHODS The rituximab and the mouse IgG were labeled withNa^(131)I using the IODO-GEN method.BALB/C nude mice werexenografted with ^(131)I-Rituximab or ^(131)I-IgG and killed on the 1st,3rd,7th,and 15th day after injection.The tumor/non-tumor ratio(T/NT)and the dose injected in each gram of the tissue(%ID/g)from12 organs or tissues of interest,e.g.tumor,blood,were calculated.The long and short axes of each tumor were measured by calipersat 2-3-day intervals after treatment,and the growth inhibition ofthe tumor was calculated using the MIRD formula.RESULTS When comparing intraperitoneal injection(IP)andintratumoral injection(IT)of ^(131)I-IgG,intratumoral injection of^(131)I-rituximab produced a significantly higher tumor/non-tumorratio in all tissues and organs of interest on the 1st,3rd,and 7thday,respectively(P<0.05).The %ID/g of tumor was 1.4-1.7-foldand 1.5-3.7-fold in the IP and IgG IT groups,respectively,but the%ID/g of non-tumors was significantly lower in the IP group andIgG IT group.Similarly,the tumor growth was greatly inhibitedby intratumoral injection of the ^(131)I-rituximab,whereas it wasless inhibited by other forms of the treatment(P<0.05).However^(131)I-rituximab injected intratumorally inhibited tumor growth ina dose-dependent manner.The inhibition rate was less with alow dose(75μCi)and greater with a high dose(150μCi),yet thedifference was not significant(P>0.05).CONCLUSION Tumors can absorb the highest amount of theradiolabelled antibodies,and the tumor/non-tumor ratios in thegroup with intratumoral injection of the ^(131)I-rituximab resulted inthe optimal anti-tumor activity.
