Anti-tumor necrosis factor(TNF) biologics are currentlyamongst the most widely used and efficacious therapies for inflammatory bowel disease(IBD). The development of therapeutic drug monitoring for infliximab and ada-...Anti-tumor necrosis factor(TNF) biologics are currentlyamongst the most widely used and efficacious therapies for inflammatory bowel disease(IBD). The development of therapeutic drug monitoring for infliximab and ada-limumab has allowed for measurement of drug levels and antidrug antibodies. This information can allow for manipulation of drug therapy and prediction of response. It has been shown that therapeutic anti-TNF drug levels are associated with maintenance of remission, and development of antidrug antibodies is predictive of loss of response. Studies suggest that a low level of drug antibodies, however, can at times be overcome by dose escalation of anti-TNF therapy or addition of an immunomodulator. We describe a retrospective case series of twelve IBD patients treated at the University of California-Irvine, who were on infliximab or adalimumab therapy and were found to have detectable but low-level antidrug antibodies. These patients underwent dose escalation of the drug or addition of an immunomodulator, with subsequent follow-up drug levels obtained. Eight of the twelve patients(75%) demonstrated resolution of antidrug antibodies, and were noted to have improvement in disease activity. Though data regarding overcoming low-level anti-TNF drug antibodies remains somewhat limited, cases described in the literature as well as our own experience suggest that this may be a viable strategy for preserving the use of an anti-TNF drug. Low-level anti-TNF drug antibodies may be overcome by dose escalation and/or addition of an immunomodulator, and can allow for clinical improvement in disease status. Therapeutic drug monitoring is an important tool to guide this strategy.展开更多
Colorectal cancer(CRC) ranked third in cancer related death and its incidence has been increasing worldwide. In recent decades important therapeutic advances have been developed in treatment of metastatic CRC(mCRC), s...Colorectal cancer(CRC) ranked third in cancer related death and its incidence has been increasing worldwide. In recent decades important therapeutic advances have been developed in treatment of metastatic CRC(mCRC), such as monoclonal antibodies against epidermal growth factor receptor(anti-EGFR), which provided additional clinical benefits in mCRC. However, anti-EGFR therapies have limited usage due to approximately 95% of patients with KRAS mutated mCRC do not response to anti-EGFR treatment. Thus, KRAS mutation is predictive of nonresponse to anti-EGFR therapies but it alone is not a sufficient basis to decide who should not be received such therapies because; approximately fifty percent(40%-60%) of CRC patients with wild-type KRAS mutation also have poor response to anti-EGFR based treatment. This fact leads us to suspect that there must be other molecular determinants of response to anti-EGFR therapies which have not been identified yet. Current article summarizes the clinical efficacy of anti-EGFR therapies and also evaluates its resistance mechanisms.展开更多
Antibodies against the toxin portion of recombinant immunotoxins （RIT） reduce their efficacy and pose a potential safety risk. To overcome this problem we mutated the very immunogenic immunotoxin SSIP to produce LMB...Antibodies against the toxin portion of recombinant immunotoxins （RIT） reduce their efficacy and pose a potential safety risk. To overcome this problem we mutated the very immunogenic immunotoxin SSIP to produce LMB-T20, a de-immunized RIT that has the eight human T-cell epitopes in SSIP modified or removed. To determine the effect of T-cell epitope removal in vivo we mapped the T-cell epitopes in immune-competent BALB/c mice and found that these mice recognize two epitopes. One corresponds to the human immunodominant T-cell epitope and the other to a human subdominant epitope; both were eliminated in LMB-T20. We found that mice immunized with LMB-T20 did not have T-cell activation and did not develop anti-drug antibodies （ADA）, whereas mice immunized with SSIP, showed T-cell activation, and developed ADA detected by both ELISA and drug neutralizing assays. The ability of the mice treated with LMB-T20 to respond to other antigens was not compromised. We conclude that elimination of T-cell epitopes is sufficient to prevent formation of antibodies to an immunogenic foreign protein.展开更多
This paper investigated the porcine surfactant protein A (pSP-A) immunogenicity in murine model. Many elegant stu-dies about SP-A therapeutic applications are available however specific studies about its exogenous imm...This paper investigated the porcine surfactant protein A (pSP-A) immunogenicity in murine model. Many elegant stu-dies about SP-A therapeutic applications are available however specific studies about its exogenous immunogenicity were not easily assumed. Therefore, we investigated the immunogenicity of this porcine protein in mice. The mice re-ceived pSP-A subcutaneously on days 0 and 7. The animals were observed during 90 days and the blood was collected on days 30, 60 and 90 for assessment the immunogenic potential of pSP-A. Some animals showed circulating antibodies above the screening cut point, which was calculated based on control mice sera signals. However, those antibodies were considered false positive read-outs by the performed competitive inhibition assay. Also no neutralizing antibodies were detected able to avoid the porcine protein ability to promote lipid aggregation. So far in this model, porcine surfactant protein-A could be considered not immunogenic.展开更多
目的分析缺血性视网膜静脉阻塞继发黄斑水肿(RVO-ME)患者基线血清己糖激酶1抗体滴度与抗血管内皮生长因子(VEGF)治疗后视力改善的相关性。方法招募2017年6月至2020年2月在首都医科大学宣武医院确诊为缺血性RVO-ME并接受初始抗VEGF治疗...目的分析缺血性视网膜静脉阻塞继发黄斑水肿(RVO-ME)患者基线血清己糖激酶1抗体滴度与抗血管内皮生长因子(VEGF)治疗后视力改善的相关性。方法招募2017年6月至2020年2月在首都医科大学宣武医院确诊为缺血性RVO-ME并接受初始抗VEGF治疗的53例患者,其中缺血性视网膜中央静脉阻塞(CRVO)23例(CRVO组),缺血性视网膜分支静脉阻塞(BRVO)30例(BRVO组)。另选取该院同期30例行超声乳化的白内障患者作为对照组。研究对象行基线血清己糖激酶1抗体滴度检测、眼科常规检查和光学相干断层成像(OCT)检查。所有RVO-ME患者按照“3+按需治疗方案(pro re nata,PRN)”向玻璃体内注射抗VEGF药物治疗。随访12个月,采用多元线性回归分析缺血性RVO-ME患者抗VEGF治疗后视力改善的影响因素。结果CRVO组基线logMAR BCVA高于对照组和BRVO组,CRVO组和BRVO组基线CRT、基线血清己糖激酶1抗体滴度高于对照组,且CRVO组基线CRT、基线血清己糖激酶1抗体滴度高于BRVO组,差异有统计学意义(P<0.05)。RVO-ME患者基线血清己糖激酶1抗体滴度与随访6个月(r=0.377,P=0.005)、9个月(r=0.362,P=0.008)和12个月(r=0.465,P<0.001)时BCVA改善呈正相关,与随访12个月时中断EZ横向长度减少值(r=0.401,P=0.001)呈正相关。多元线性回归分析结果显示,基线logMAR BCVA、基线血清己糖激酶1抗体滴度是缺血性RVO-ME患者抗VEGF治疗随访12个月时BCVA改善的影响因素(P<0.05)。结论己糖激酶1抗体作为一种新的血清生物标志物,与缺血性RVO-ME患者抗VEGF治疗后的视力改善相关。展开更多
There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction ca...There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic anti. bodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation, Glycosyla- tion of a mAb or Fc.fusion protein can have a significant impact on the PK of these molecules, mAb charge can be important and variants with pl values of 1-2 unit difference are likely to impact PK with lower pl values being favorable for a longer half.life. Most mAbs display target mediated drug disposition （TMOO）, which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody （ADA） response and off.target binding, which require careful consideration during the discovery stage, mAbs are primarily absor- bed through the lymphatics via convection and can be conveniently administered by the subcutaneous （sc） route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be rea- sonably estimated using cynomolgus monkey data and allometric scaling methods.展开更多
AIM:To characterize the prevalence of hepatitis C virus(HCV)infection among Chinese intravenous drug users(IDUs).METHODS:A total of 432 adult IDUs(95 women and337 men)in Shanghai were included in the study.The third-g...AIM:To characterize the prevalence of hepatitis C virus(HCV)infection among Chinese intravenous drug users(IDUs).METHODS:A total of 432 adult IDUs(95 women and337 men)in Shanghai were included in the study.The third-generation Elecsys Anti-HCV assay(Roche Diagnostics GmbH,Sandhofer Strasse 116,D-68305,Mannheim,Germany)was used to screen for antibodies against HCV.The RIBA strip,a supplemental antiHCV test with high specificity,was performed on all of the samples that tested positive during the initial screening.All of the anti-HCV positive samples were analyzed with a Cobas TaqMan 48 Analyzer(Roche Diagnostics)for direct detection of HCV RNA.All of the HCV RNA-positive samples were sequenced for genotype determination.RESULTS:The preliminary screening identified 262(60.6%)subjects who were seropositive for HCV.Of the 62 females and 200 males seropositive subjects,16(16.7%)and 65(19.3%),respectively,were confirmed by RIBA,yielding an overall HCV seropositive rate of18.8%.Four female(6.5%)and 14 male(7.0%)subjects tested positive for HCV RNA,indicating an active infection rate of 4.2%for the entire study population.The 18 HCV RNA-positive serum samples were genotyped.Seven individuals were genotype 1b,and four were genotype 1a.One individual each was infected with genotypes 2a,2b and 3a.Four subjects were coinfected with multiple strains:two with genotypes 1a and 2a,and two with genotypes 1b and 2a.The active infection rate among HCV-seropositive individuals was22.2%,which was significantly lower than most estimates.CONCLUSION:The prevalence of HCV is relatively low among IDUs in Shanghai,with a spontaneous recovery rate much higher than previous estimates.展开更多
Thiopurine analogs and anti-tumor necrosis factor(TNF)agents have dramatically changed the therapeutics of inflammatory bowel diseases(IBD),improving short and long-term outcomes.Unfortunately some patients do not res...Thiopurine analogs and anti-tumor necrosis factor(TNF)agents have dramatically changed the therapeutics of inflammatory bowel diseases(IBD),improving short and long-term outcomes.Unfortunately some patients do not respond to therapy and others lose response over time.The pharmacokinetic properties of these drugs are complex,with high inter-patient variability.Thiopurine analogs are metabolized through a series of pathways,which vary according to the patients’pharmacogenetic profile.This profile largely determines the ratios of metabolites,which are in turn associated with likelihoods of clinical efficacy and/or toxicity.Understanding these mechanisms allows for manipulation of drug dose,aiming to reduce the development of toxicity while improving the efficacy of treatment.The efficacy of anti-TNF drugs is influenced by many pharmacodynamic variables.Several factors may alter drug clearance,including the concomitant use of immunomodulators(thiopurine analogs and methotrexate),systemic inflammation,the presence of anti-drug antibodies,and body mass.The treatment of IBD has evolved with the understanding of the pharmacologic profiles of immunomodulating and TNF-inhibiting medications,with good evidence for improvement in patient outcomesobserved when measuring metabolic pathway indices.The role of routine measurement of metabolite/drug levels and antibodies warrants further prospective studies as we enter the era of personalized IBD care.展开更多
Purpose: Detailed analysis of a patient with epithelial Lewis Y (LeY) positive cancer who received twice 50 mg of the humanized Lewis Y carbohydrate specific mAb IGN311 and developed a clinically significant human ant...Purpose: Detailed analysis of a patient with epithelial Lewis Y (LeY) positive cancer who received twice 50 mg of the humanized Lewis Y carbohydrate specific mAb IGN311 and developed a clinically significant human anti-human antibody (HAHA) response (Ab2). Results: Clinical stabilization of the disease was assigned to in this patient. The HAHA response consisted mainly of IgG1 and was found to be directed against the IGN311 binding site. Consistent with the induction of the HAHA response, CDC activity against Lewis Y positive target cells was completely abolished at day 8 and could not be restored by the second 50 mg infusion indicating complete neutralization of applied IGN311. The ADCC reactivity was also significantly reduced and anti-anti idiotype-specific antibodies (Ab3) were detectable at day 65. Conclusions: Induction of Ab3 antibodies should be considered as an additional factor influencing the efficacy of humanized antibodies. In this context, the potential threat of induced HAHA responses against therapeutic mAbs might have to be reconsidered because they might actually have also beneficial immunological long-term effects leading to an active immunization component induced by therapeutic antibodies.展开更多
文摘Anti-tumor necrosis factor(TNF) biologics are currentlyamongst the most widely used and efficacious therapies for inflammatory bowel disease(IBD). The development of therapeutic drug monitoring for infliximab and ada-limumab has allowed for measurement of drug levels and antidrug antibodies. This information can allow for manipulation of drug therapy and prediction of response. It has been shown that therapeutic anti-TNF drug levels are associated with maintenance of remission, and development of antidrug antibodies is predictive of loss of response. Studies suggest that a low level of drug antibodies, however, can at times be overcome by dose escalation of anti-TNF therapy or addition of an immunomodulator. We describe a retrospective case series of twelve IBD patients treated at the University of California-Irvine, who were on infliximab or adalimumab therapy and were found to have detectable but low-level antidrug antibodies. These patients underwent dose escalation of the drug or addition of an immunomodulator, with subsequent follow-up drug levels obtained. Eight of the twelve patients(75%) demonstrated resolution of antidrug antibodies, and were noted to have improvement in disease activity. Though data regarding overcoming low-level anti-TNF drug antibodies remains somewhat limited, cases described in the literature as well as our own experience suggest that this may be a viable strategy for preserving the use of an anti-TNF drug. Low-level anti-TNF drug antibodies may be overcome by dose escalation and/or addition of an immunomodulator, and can allow for clinical improvement in disease status. Therapeutic drug monitoring is an important tool to guide this strategy.
文摘Colorectal cancer(CRC) ranked third in cancer related death and its incidence has been increasing worldwide. In recent decades important therapeutic advances have been developed in treatment of metastatic CRC(mCRC), such as monoclonal antibodies against epidermal growth factor receptor(anti-EGFR), which provided additional clinical benefits in mCRC. However, anti-EGFR therapies have limited usage due to approximately 95% of patients with KRAS mutated mCRC do not response to anti-EGFR treatment. Thus, KRAS mutation is predictive of nonresponse to anti-EGFR therapies but it alone is not a sufficient basis to decide who should not be received such therapies because; approximately fifty percent(40%-60%) of CRC patients with wild-type KRAS mutation also have poor response to anti-EGFR based treatment. This fact leads us to suspect that there must be other molecular determinants of response to anti-EGFR therapies which have not been identified yet. Current article summarizes the clinical efficacy of anti-EGFR therapies and also evaluates its resistance mechanisms.
文摘Antibodies against the toxin portion of recombinant immunotoxins （RIT） reduce their efficacy and pose a potential safety risk. To overcome this problem we mutated the very immunogenic immunotoxin SSIP to produce LMB-T20, a de-immunized RIT that has the eight human T-cell epitopes in SSIP modified or removed. To determine the effect of T-cell epitope removal in vivo we mapped the T-cell epitopes in immune-competent BALB/c mice and found that these mice recognize two epitopes. One corresponds to the human immunodominant T-cell epitope and the other to a human subdominant epitope; both were eliminated in LMB-T20. We found that mice immunized with LMB-T20 did not have T-cell activation and did not develop anti-drug antibodies （ADA）, whereas mice immunized with SSIP, showed T-cell activation, and developed ADA detected by both ELISA and drug neutralizing assays. The ability of the mice treated with LMB-T20 to respond to other antigens was not compromised. We conclude that elimination of T-cell epitopes is sufficient to prevent formation of antibodies to an immunogenic foreign protein.
文摘This paper investigated the porcine surfactant protein A (pSP-A) immunogenicity in murine model. Many elegant stu-dies about SP-A therapeutic applications are available however specific studies about its exogenous immunogenicity were not easily assumed. Therefore, we investigated the immunogenicity of this porcine protein in mice. The mice re-ceived pSP-A subcutaneously on days 0 and 7. The animals were observed during 90 days and the blood was collected on days 30, 60 and 90 for assessment the immunogenic potential of pSP-A. Some animals showed circulating antibodies above the screening cut point, which was calculated based on control mice sera signals. However, those antibodies were considered false positive read-outs by the performed competitive inhibition assay. Also no neutralizing antibodies were detected able to avoid the porcine protein ability to promote lipid aggregation. So far in this model, porcine surfactant protein-A could be considered not immunogenic.
文摘目的分析缺血性视网膜静脉阻塞继发黄斑水肿(RVO-ME)患者基线血清己糖激酶1抗体滴度与抗血管内皮生长因子(VEGF)治疗后视力改善的相关性。方法招募2017年6月至2020年2月在首都医科大学宣武医院确诊为缺血性RVO-ME并接受初始抗VEGF治疗的53例患者,其中缺血性视网膜中央静脉阻塞(CRVO)23例(CRVO组),缺血性视网膜分支静脉阻塞(BRVO)30例(BRVO组)。另选取该院同期30例行超声乳化的白内障患者作为对照组。研究对象行基线血清己糖激酶1抗体滴度检测、眼科常规检查和光学相干断层成像(OCT)检查。所有RVO-ME患者按照“3+按需治疗方案(pro re nata,PRN)”向玻璃体内注射抗VEGF药物治疗。随访12个月,采用多元线性回归分析缺血性RVO-ME患者抗VEGF治疗后视力改善的影响因素。结果CRVO组基线logMAR BCVA高于对照组和BRVO组,CRVO组和BRVO组基线CRT、基线血清己糖激酶1抗体滴度高于对照组,且CRVO组基线CRT、基线血清己糖激酶1抗体滴度高于BRVO组,差异有统计学意义(P<0.05)。RVO-ME患者基线血清己糖激酶1抗体滴度与随访6个月(r=0.377,P=0.005)、9个月(r=0.362,P=0.008)和12个月(r=0.465,P<0.001)时BCVA改善呈正相关,与随访12个月时中断EZ横向长度减少值(r=0.401,P=0.001)呈正相关。多元线性回归分析结果显示,基线logMAR BCVA、基线血清己糖激酶1抗体滴度是缺血性RVO-ME患者抗VEGF治疗随访12个月时BCVA改善的影响因素(P<0.05)。结论己糖激酶1抗体作为一种新的血清生物标志物,与缺血性RVO-ME患者抗VEGF治疗后的视力改善相关。
文摘There are many factors that can influence the pharma- cokinetics （PK） of a mAb or Fc-fusion molecule with the primary determinant being FcRn-mediatad recycling. Through Fab or Fc engineering, IgG-FcRn interaction can be used to generate a variety of therapeutic anti. bodies with significantly enhanced half-life or ability to remove unwanted antigen from circulation, Glycosyla- tion of a mAb or Fc.fusion protein can have a significant impact on the PK of these molecules, mAb charge can be important and variants with pl values of 1-2 unit difference are likely to impact PK with lower pl values being favorable for a longer half.life. Most mAbs display target mediated drug disposition （TMOO）, which can have significant consequences on the study designs of preclinical and clinical studies. The PK of mAb can also be influenced by anti-drug antibody （ADA） response and off.target binding, which require careful consideration during the discovery stage, mAbs are primarily absor- bed through the lymphatics via convection and can be conveniently administered by the subcutaneous （sc） route in large doses/volumes with co-formulation of hyaluronidase. The human PK of a mAb can be rea- sonably estimated using cynomolgus monkey data and allometric scaling methods.
基金Supported by Science and Technology Commission Xuhui District and Xuhui Health Bureau of ShanghaiNo.SHXH201226
文摘AIM:To characterize the prevalence of hepatitis C virus(HCV)infection among Chinese intravenous drug users(IDUs).METHODS:A total of 432 adult IDUs(95 women and337 men)in Shanghai were included in the study.The third-generation Elecsys Anti-HCV assay(Roche Diagnostics GmbH,Sandhofer Strasse 116,D-68305,Mannheim,Germany)was used to screen for antibodies against HCV.The RIBA strip,a supplemental antiHCV test with high specificity,was performed on all of the samples that tested positive during the initial screening.All of the anti-HCV positive samples were analyzed with a Cobas TaqMan 48 Analyzer(Roche Diagnostics)for direct detection of HCV RNA.All of the HCV RNA-positive samples were sequenced for genotype determination.RESULTS:The preliminary screening identified 262(60.6%)subjects who were seropositive for HCV.Of the 62 females and 200 males seropositive subjects,16(16.7%)and 65(19.3%),respectively,were confirmed by RIBA,yielding an overall HCV seropositive rate of18.8%.Four female(6.5%)and 14 male(7.0%)subjects tested positive for HCV RNA,indicating an active infection rate of 4.2%for the entire study population.The 18 HCV RNA-positive serum samples were genotyped.Seven individuals were genotype 1b,and four were genotype 1a.One individual each was infected with genotypes 2a,2b and 3a.Four subjects were coinfected with multiple strains:two with genotypes 1a and 2a,and two with genotypes 1b and 2a.The active infection rate among HCV-seropositive individuals was22.2%,which was significantly lower than most estimates.CONCLUSION:The prevalence of HCV is relatively low among IDUs in Shanghai,with a spontaneous recovery rate much higher than previous estimates.
文摘Thiopurine analogs and anti-tumor necrosis factor(TNF)agents have dramatically changed the therapeutics of inflammatory bowel diseases(IBD),improving short and long-term outcomes.Unfortunately some patients do not respond to therapy and others lose response over time.The pharmacokinetic properties of these drugs are complex,with high inter-patient variability.Thiopurine analogs are metabolized through a series of pathways,which vary according to the patients’pharmacogenetic profile.This profile largely determines the ratios of metabolites,which are in turn associated with likelihoods of clinical efficacy and/or toxicity.Understanding these mechanisms allows for manipulation of drug dose,aiming to reduce the development of toxicity while improving the efficacy of treatment.The efficacy of anti-TNF drugs is influenced by many pharmacodynamic variables.Several factors may alter drug clearance,including the concomitant use of immunomodulators(thiopurine analogs and methotrexate),systemic inflammation,the presence of anti-drug antibodies,and body mass.The treatment of IBD has evolved with the understanding of the pharmacologic profiles of immunomodulating and TNF-inhibiting medications,with good evidence for improvement in patient outcomesobserved when measuring metabolic pathway indices.The role of routine measurement of metabolite/drug levels and antibodies warrants further prospective studies as we enter the era of personalized IBD care.
文摘Purpose: Detailed analysis of a patient with epithelial Lewis Y (LeY) positive cancer who received twice 50 mg of the humanized Lewis Y carbohydrate specific mAb IGN311 and developed a clinically significant human anti-human antibody (HAHA) response (Ab2). Results: Clinical stabilization of the disease was assigned to in this patient. The HAHA response consisted mainly of IgG1 and was found to be directed against the IGN311 binding site. Consistent with the induction of the HAHA response, CDC activity against Lewis Y positive target cells was completely abolished at day 8 and could not be restored by the second 50 mg infusion indicating complete neutralization of applied IGN311. The ADCC reactivity was also significantly reduced and anti-anti idiotype-specific antibodies (Ab3) were detectable at day 65. Conclusions: Induction of Ab3 antibodies should be considered as an additional factor influencing the efficacy of humanized antibodies. In this context, the potential threat of induced HAHA responses against therapeutic mAbs might have to be reconsidered because they might actually have also beneficial immunological long-term effects leading to an active immunization component induced by therapeutic antibodies.
