Over the past decade, the administration of anti-CD20 monoclonal antibodies such as rituximab has demonstrated various degrees of effectiveness and has improved patients' outcomes during the treatment of autoimmun...Over the past decade, the administration of anti-CD20 monoclonal antibodies such as rituximab has demonstrated various degrees of effectiveness and has improved patients' outcomes during the treatment of autoimmune hematological disorders and hematological malignancies. However, the depletion of B-cells, the distribution of T-cell populations, and the reconstruction of host immunity resulting from the use of anti-CD20 monoclonal antibodies potentially lead to severe viral infections, such as hepatitis B virus(HBV), hepatitis C virus(HCV), parvovirus B19, and herpes viruses, in patients who are undergoing immune therapy or immunochemotherapy. Of these infections, HBV- and HCV-related hepatitis are a great concern in endemic areas because of the high morbidity and mortality rates in untreated patients. As a result, prophylaxis against HBV infection is becoming a standard of care in these areas. Parvovirus B19, a widespread pathogen that causes red blood cell aplasia in immunocompromised hosts, also causes hepatitis in healthy individuals. Recently, its association with hepatitis was recognized in a patient treated with rituximab. In addition, adenovirus, varicella-zoster virus hepatitis E virus, and rituximab itself have been linked to the occurrence of hepatitis during or after rituximab treatments. The epidemiologies and pathogeneses of these etiologies remain unknown. Because of the increasing use of anti-CD20 monoclonal antibodies for the treatment of hematological malignancies or autoimmune hematological disorders, it is imperative that physicians understand and balance the risks of hepatotropic virusassociated hepatitis against the benefits of using antiCD20 monoclonal antibodies.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.Conclusions:In this study,the PK,PD,immunogenicity,and safety profile of ripertamab(SCT400)were similar to rituximab(MabThera^(■))in Chinese patients with CD20-positive B-cell NHL.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 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
The increased incidence ofNHL （non-Hodgkin＇s lymphoma）, along with its high mortality rate and pronounced resistance to therapy pose an enormous challenge. Both traditional therapeutic strategies and recently devel...The increased incidence ofNHL （non-Hodgkin＇s lymphoma）, along with its high mortality rate and pronounced resistance to therapy pose an enormous challenge. Both traditional therapeutic strategies and recently developed therapeutic strategies against NHL such as chemoimmunotherapy and targeted therapy have drawbacks. Therefore, novel therapeutic approaches for NHL are urgently needed. Maytansine-loaded PLA-TPGS （polyethylene glycol 1000 succinate-polylactide） nanoparticles were synthesized. And then, rituximab targeting NHL was conjugated together by using EDC （1-ethyl-3-（3-dimethylaminopropyl） carbodiimide） as a coupling agent. The in vitro/vivo antitumor activity was evaluated by Raji cell proliferation inhibition and nude mice xenograft tumor models for NHL. Both the rituximab-conjugated and maytansine-loaded PLA-TPGS nanoparticles （maytansine-NPs （Nanoparticles）-rituximab） and maytansine-loaded PLA-TPGS nanoparticles （maytansine-NPs） presented significant inhibition effect on Raji cell proliferation in a concentration-dependent manner. Compared with conventional maytansine and maytansine-NPs, maytansine-NPs-rituximab showed significantly enhanced cytotoxicity and increased cell apoptosis in Raji cells. The maytansine-NPs-rituximab described in this paper might be a potential formulation for targeting chemotherapy and immunotherapy to CD20＋ B cell malignancies.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
The variable domain of heavy chain (VH) and light chain (VL) genes of anti-CD20 monoclonal antibody HL47 were cloned from anti-CD20 ScFv expression vector pCANBTEcd20 by PCR and ligated into vector pYZF to construct c...The variable domain of heavy chain (VH) and light chain (VL) genes of anti-CD20 monoclonal antibody HL47 were cloned from anti-CD20 ScFv expression vector pCANBTEcd20 by PCR and ligated into vector pYZF to construct chimeric anti-CD20 Fab’ fragment expression vector pTZFcd20. Chimeric anti-CD20 Fab’ fragment was expressed in E. coli 16C9 and purified by protein G affinity chromatography. Competitive inhibition assay showed that anti-CD20 Fab’ fragment inhibited binding of HI47 to CD20 on the surface of Daudi cells. Results from MTT assay indicated that chimeric anti-CD20 Fab’fragment inhibited the proliferation of Daudi cells, IC50=69 ug/mL. Affinity of chimeric anti-CD20 Fab’ fragment was determined, Ka was about 8.9×108 (mol/L)-1.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 patients with relapsed or refractory follicular lymphoma.展开更多
Post-transplant lymphoproliferative disorder(PTLD)is a rare but life-threatening complication of both allogeneic solid organ(SOT)and hematopoietic cell transplantation(HCT).The histology of PTLD ranges from benign pol...Post-transplant lymphoproliferative disorder(PTLD)is a rare but life-threatening complication of both allogeneic solid organ(SOT)and hematopoietic cell transplantation(HCT).The histology of PTLD ranges from benign polyclonal lymphoproliferation to a lesion indistinguishable from classic monoclonal lymphoma.Most commonly,PTLDs are Epstein-Barr virus(EBV)positive and result from loss of immune surveillance over EBV.Treatment for PTLD differs from the treatment for typical non-Hodgkin lymphoma because prognostic factors are different,resistance to treatment is unique,and there are specific concerns for organ toxicity.While recipients of HCT have a limited time during which they are at risk for this complication,recipients of SOT have a lifelong requirement for immunosuppression,so approaches that limit compromising or help restore immune surveillance are of high interest.Furthermore,while EBV-positive and EBV-negative PTLDs are not intrinsically resistant to chemotherapy,the poor tolerance of chemotherapy in the post-transplant setting makes it essential to minimize potential treatment-related toxicities and explore alternative treatment algorithms.Therefore,reduced-toxicity approaches such as single-agent CD20 monoclonal antibodies or bortezomib,reduced dosing of standard chemotherapeutic agents,and non-chemotherapy-based approaches such as cytotoxic T cells have all been explored.Here,we review the chemotherapy and non-chemotherapy treatment landscape for PTLD.展开更多
基金Supported by Research grants NSC 101-2321-B-002-032 and NSC 101-2314-B-002-157-MY3 from the National Science Council,TaiwanNHRI-EX102-10239BI,and NHRI-EX10210239BI from the National Health Research Institutes,TaiwanDOH100-TD-B-111-001 from the Department of Health,Taiwan
文摘Over the past decade, the administration of anti-CD20 monoclonal antibodies such as rituximab has demonstrated various degrees of effectiveness and has improved patients' outcomes during the treatment of autoimmune hematological disorders and hematological malignancies. However, the depletion of B-cells, the distribution of T-cell populations, and the reconstruction of host immunity resulting from the use of anti-CD20 monoclonal antibodies potentially lead to severe viral infections, such as hepatitis B virus(HBV), hepatitis C virus(HCV), parvovirus B19, and herpes viruses, in patients who are undergoing immune therapy or immunochemotherapy. Of these infections, HBV- and HCV-related hepatitis are a great concern in endemic areas because of the high morbidity and mortality rates in untreated patients. As a result, prophylaxis against HBV infection is becoming a standard of care in these areas. Parvovirus B19, a widespread pathogen that causes red blood cell aplasia in immunocompromised hosts, also causes hepatitis in healthy individuals. Recently, its association with hepatitis was recognized in a patient treated with rituximab. In addition, adenovirus, varicella-zoster virus hepatitis E virus, and rituximab itself have been linked to the occurrence of hepatitis during or after rituximab treatments. The epidemiologies and pathogeneses of these etiologies remain unknown. Because of the increasing use of anti-CD20 monoclonal antibodies for the treatment of hematological malignancies or autoimmune hematological disorders, it is imperative that physicians understand and balance the risks of hepatotropic virusassociated hepatitis against the benefits of using antiCD20 monoclonal antibodies.
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.Conclusions:In this study,the PK,PD,immunogenicity,and safety profile of ripertamab(SCT400)were similar to rituximab(MabThera^(■))in Chinese patients with CD20-positive B-cell NHL.
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.
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.
文摘The increased incidence ofNHL （non-Hodgkin＇s lymphoma）, along with its high mortality rate and pronounced resistance to therapy pose an enormous challenge. Both traditional therapeutic strategies and recently developed therapeutic strategies against NHL such as chemoimmunotherapy and targeted therapy have drawbacks. Therefore, novel therapeutic approaches for NHL are urgently needed. Maytansine-loaded PLA-TPGS （polyethylene glycol 1000 succinate-polylactide） nanoparticles were synthesized. And then, rituximab targeting NHL was conjugated together by using EDC （1-ethyl-3-（3-dimethylaminopropyl） carbodiimide） as a coupling agent. The in vitro/vivo antitumor activity was evaluated by Raji cell proliferation inhibition and nude mice xenograft tumor models for NHL. Both the rituximab-conjugated and maytansine-loaded PLA-TPGS nanoparticles （maytansine-NPs （Nanoparticles）-rituximab） and maytansine-loaded PLA-TPGS nanoparticles （maytansine-NPs） presented significant inhibition effect on Raji cell proliferation in a concentration-dependent manner. Compared with conventional maytansine and maytansine-NPs, maytansine-NPs-rituximab showed significantly enhanced cytotoxicity and increased cell apoptosis in Raji cells. The maytansine-NPs-rituximab described in this paper might be a potential formulation for targeting chemotherapy and immunotherapy to CD20＋ B cell malignancies.
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.
基金This work was supported by the State "863" High-Tech Project (Grant No. 102-09-03-03).
文摘The variable domain of heavy chain (VH) and light chain (VL) genes of anti-CD20 monoclonal antibody HL47 were cloned from anti-CD20 ScFv expression vector pCANBTEcd20 by PCR and ligated into vector pYZF to construct chimeric anti-CD20 Fab’ fragment expression vector pTZFcd20. Chimeric anti-CD20 Fab’ fragment was expressed in E. coli 16C9 and purified by protein G affinity chromatography. Competitive inhibition assay showed that anti-CD20 Fab’ fragment inhibited binding of HI47 to CD20 on the surface of Daudi cells. Results from MTT assay indicated that chimeric anti-CD20 Fab’fragment inhibited the proliferation of Daudi cells, IC50=69 ug/mL. Affinity of chimeric anti-CD20 Fab’ fragment was determined, Ka was about 8.9×108 (mol/L)-1.
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 patients with relapsed or refractory follicular lymphoma.
基金We acknowledge support of the NCI Cancer Center Support Grant P30 CA008748.
文摘Post-transplant lymphoproliferative disorder(PTLD)is a rare but life-threatening complication of both allogeneic solid organ(SOT)and hematopoietic cell transplantation(HCT).The histology of PTLD ranges from benign polyclonal lymphoproliferation to a lesion indistinguishable from classic monoclonal lymphoma.Most commonly,PTLDs are Epstein-Barr virus(EBV)positive and result from loss of immune surveillance over EBV.Treatment for PTLD differs from the treatment for typical non-Hodgkin lymphoma because prognostic factors are different,resistance to treatment is unique,and there are specific concerns for organ toxicity.While recipients of HCT have a limited time during which they are at risk for this complication,recipients of SOT have a lifelong requirement for immunosuppression,so approaches that limit compromising or help restore immune surveillance are of high interest.Furthermore,while EBV-positive and EBV-negative PTLDs are not intrinsically resistant to chemotherapy,the poor tolerance of chemotherapy in the post-transplant setting makes it essential to minimize potential treatment-related toxicities and explore alternative treatment algorithms.Therefore,reduced-toxicity approaches such as single-agent CD20 monoclonal antibodies or bortezomib,reduced dosing of standard chemotherapeutic agents,and non-chemotherapy-based approaches such as cytotoxic T cells have all been explored.Here,we review the chemotherapy and non-chemotherapy treatment landscape for PTLD.
