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
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:To evaluate the immunosuppressive effect of monoclonal antibodies (McAb) against cell surface adhesion molecules on transplant rejection. Methods: C57BL/6 (H-2b) mouse cardiac grafts were transplanted into B...Objective:To evaluate the immunosuppressive effect of monoclonal antibodies (McAb) against cell surface adhesion molecules on transplant rejection. Methods: C57BL/6 (H-2b) mouse cardiac grafts were transplanted into BALB/c(H- 2d) mice. This model was used to investigate the possibility of immunosuppressive induction with CD44 McAb, leukocyte function associated antigen (LFA-1) and intercellular adhesion molecule (ICAM-1). Results: Treatment of the allograft recipients with CD44 McAb alone, or both LFA-1 and ICAM-1 or combination of these 3 McAb significantly prolonged the cardiac allografts survival as compared with PBS controls (P<0.01). The combination of anti-CD44 and ICAM-1 and LFA-1 McAb was shown to produce more significant prolongation of grafts survival than anti-CD44 McAb alone or both anti-ICAM- 1 and LFA-1 McAb (P < 0.01). Histological examination of the grafts treated with the McAb displayed greatly reduced mononuclear cell infiltration. The proliferation of spleen cells from recipient BALB/c with McAb treatment was significantly inhibited in response to the stimulators of C57BL/6 spleen cells, but increased upon the stimulation of C3H/He (H-2k) spleen cells, as demonstrated by mixed lymphocyte reaction. Similarly, the cytotoxic activity against donor H-2-compatible (H-2b) target cells, EL-4 cells, was significantly suppressed. The spleen cells from allografted recipient BALB/c mice with McAb treatment induced specific tolerance for C57BL/6 cardiac grafts in allografted recipients, whereas those from allografted BALB/c mice without McAb treatment induced acute rejection. Conclusion: These results indicate that antiadhesion therapy using a combination of McAb to adhesion molecules can induce specific immunosuppression of transplant rejection.展开更多
From the mouse hybridoma cell line secreting an anti-CD4 monoclonal antibody (McAb), total RNA was prepared. The VH and VL genes were amplified by RT-PCR with family specific primer pairs. The PCR products were cloned...From the mouse hybridoma cell line secreting an anti-CD4 monoclonal antibody (McAb), total RNA was prepared. The VH and VL genes were amplified by RT-PCR with family specific primer pairs. The PCR products were cloned into pGEM-T vectors, then tranfected into JM109. The VH and VL genes were snalyzed by automatic DNA sequencer. According to Kabat classification, the VH and VL genes belong to the mouse ig heavy subgroup Ⅱ(A) and x chain subgroupⅢ, respectively. The VH and VL genes were subcloned into pr1-Expr and Pk Expr respectively, then transfected into XL2-Blue. The VH- Pr1 and VL- pk were trans feeted by electroporation into mouse myeloma cell X63Ag8. 653. The transfectoma cells were selected by G418 screening, and then supernatant of cultured transfectoma were analyzed by ELISA and immunofluorescence techniques.We have acquired transfectoma cells secreting anti-CD4 chimeric antibodies.These chimeric antibodies are able to kill tumor cells specifically in vitro.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
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
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
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
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
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.
文摘Objective:To evaluate the immunosuppressive effect of monoclonal antibodies (McAb) against cell surface adhesion molecules on transplant rejection. Methods: C57BL/6 (H-2b) mouse cardiac grafts were transplanted into BALB/c(H- 2d) mice. This model was used to investigate the possibility of immunosuppressive induction with CD44 McAb, leukocyte function associated antigen (LFA-1) and intercellular adhesion molecule (ICAM-1). Results: Treatment of the allograft recipients with CD44 McAb alone, or both LFA-1 and ICAM-1 or combination of these 3 McAb significantly prolonged the cardiac allografts survival as compared with PBS controls (P<0.01). The combination of anti-CD44 and ICAM-1 and LFA-1 McAb was shown to produce more significant prolongation of grafts survival than anti-CD44 McAb alone or both anti-ICAM- 1 and LFA-1 McAb (P < 0.01). Histological examination of the grafts treated with the McAb displayed greatly reduced mononuclear cell infiltration. The proliferation of spleen cells from recipient BALB/c with McAb treatment was significantly inhibited in response to the stimulators of C57BL/6 spleen cells, but increased upon the stimulation of C3H/He (H-2k) spleen cells, as demonstrated by mixed lymphocyte reaction. Similarly, the cytotoxic activity against donor H-2-compatible (H-2b) target cells, EL-4 cells, was significantly suppressed. The spleen cells from allografted recipient BALB/c mice with McAb treatment induced specific tolerance for C57BL/6 cardiac grafts in allografted recipients, whereas those from allografted BALB/c mice without McAb treatment induced acute rejection. Conclusion: These results indicate that antiadhesion therapy using a combination of McAb to adhesion molecules can induce specific immunosuppression of transplant rejection.
文摘From the mouse hybridoma cell line secreting an anti-CD4 monoclonal antibody (McAb), total RNA was prepared. The VH and VL genes were amplified by RT-PCR with family specific primer pairs. The PCR products were cloned into pGEM-T vectors, then tranfected into JM109. The VH and VL genes were snalyzed by automatic DNA sequencer. According to Kabat classification, the VH and VL genes belong to the mouse ig heavy subgroup Ⅱ(A) and x chain subgroupⅢ, respectively. The VH and VL genes were subcloned into pr1-Expr and Pk Expr respectively, then transfected into XL2-Blue. The VH- Pr1 and VL- pk were trans feeted by electroporation into mouse myeloma cell X63Ag8. 653. The transfectoma cells were selected by G418 screening, and then supernatant of cultured transfectoma were analyzed by ELISA and immunofluorescence techniques.We have acquired transfectoma cells secreting anti-CD4 chimeric antibodies.These chimeric antibodies are able to kill tumor cells specifically in vitro.
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.
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.
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.
