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Abstract Introduction: This publication aims to show the clinical, endoscopic, and histological responses of two pediatric patients who received dupilumab as a management strategy for eosinophilic esophagitis. Dupilumab is a monoclonal antibody that inhibits the alpha chain of the interleukin (IL)-4 and IL-13 receptors involved in the Th2 inflammatory response. The potential therapeutic role of this biological drug has been demonstrated in pediatric clinical trials in other allergic pathologies, such as atopic dermatitis and asthma, with an adequate safety and effectiveness profile. Clinical cases: Two children with a personal history of atopy, allergic rhinitis, asthma, atopic dermatitis, and food allergy began with gastrointestinal symptoms that confirmed the diagnosis of eosinophilic esophagitis. Despite the different management strategies, adequate control of the disease was not achieved, and it is considered that they benefited from management with dupilumab due to the disease evolution and the coexistence of uncontrolled atopic dermatitis. Conclusions: In recent years, various management strategies in pediatrics have been published, particularly high-dose proton pump inhibitors, topical corticosteroids, and elimination diets. However, despite these strategies, at least one-third of patients may fail to achieve remission with initial treatment, making this entity a therapeutic challenge for the gastroenterologist and pediatric allergist. Our patients received the dose recommended for their weight and age and approved for asthma and atopic dermatitis, resulting in clinical and histological remission. The improvement in gastrointestinal symptoms was accompanied by better control of asthma, rhinitis, and dermatitis. None of the patients had adverse effects of the medication.
Resumen Introducción: El objetivo de esta publicación es mostrar la respuesta clínica, endoscópica e histológica de dos pacientes pediátricos que recibieron dupilumab como estrategia de manejo para esofagitis eosinofílica. El dupilumab es un anticuerpo monoclonal que inhibe la cadena alfa del receptor de las interleucinas 4 y 13, involucradas en la respuesta inflamatoria Th2. El potencial rol terapéutico de este medicamento biológico se ha demostrado en ensayos clínicos en pediatría en otras patologías alérgicas como la dermatitis atópica y el asma, y ha mostrado un adecuado perfil de seguridad y efectividad en pediatría. Casos clínicos: Se trata de dos niños con antecedentes personales de atopia, rinitis alérgica, asma, dermatitis atópica y alergia alimentaria, que inician con síntomas gastrointestinales que conducen a confirmar el diagnóstico de esofagitis eosinofílica, en quienes a pesar de las diferentes estrategias de manejo no se logra un adecuado control de la enfermedad, y se considera que se benefician del manejo con dupilumab por la evolución de la enfermedad, así como la coexistencia de dermatitis atópica no controlada. Conclusiones: En los últimos años se han publicado diferentes estrategias de manejo en pediatría, entre los que se destaca el uso de inhibidores de la bomba de protones a dosis altas, corticoides tópicos y las dietas de exclusión; sin embargo, a pesar de estas estrategias, al menos un tercio de los pacientes puede fallar en lograr la remisión con el manejo inicial, lo que convierte a esta entidad en un reto terapéutico para el gastroenterólogo y el alergólogo pediatra. Nuestros pacientes recibieron la dosis recomendada para su peso y edad aprobada en asma y dermatitis atópica, y se logró la remisión clínica e histológica. La mejoría de los síntomas gastrointestinales se acompañó de un mejor control del asma, la rinitis y la dermatitis. Ninguno de los pacientes tuvo efectos adversos al medicamento.
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Objective To analyze the short-term clinical efficacy and influencing factors of ustekinumab monoclonal antibody(UST)in the treatment of Crohn′s disease(CD).Methods Retrospective cohort study was used to collect the clinical data of CD patients treated with UST in the 10th People′s Hospital affiliated to Tongji University from December 2020 to October 2022.The main analysis is the short-term clinical efficacy and influencing factors of UST treatment for CD at weeks 8 and 16,And analyze the endoscopic response rate of some patients.Results A total of 91 CD patients who first used UST were included.The 8-week clinical response rate of UST treat-ment for CD was 61.5%,and the clinical response rate was 45%;The clinical response rate at 16 weeks was 71.4%,and the clinical response rate was 54.9%.56 cases underwent endoscopic re-examination in our hospital,and the endoscopic response rate at 16 weeks was 41.1%.Univariate analysis showed that fistula(including anal fistula,personal history of anal fistula,and intestinal skin fistula)is associated with clinical remission in Crohn′s disease patients at 8/16 weeks.Further multivariate COX regression analysis showed that the presence of a history of anal fistula surgery was an independent protective factor affecting clinical remission in CD patients treated with UST at 8 weeks(HR = 0.04,95%CI:0.00～0.38;P = 0.005)and 16 weeks(HR = 0.04,95%CI:0.01～0.34;P = 0.003)compared to those without fistula;Narrow lesions are an independent risk factor for 16 week clinical remission in CD patients compared to non-narrow and non-penetrating lesions(HR = 1.75,95%CI:1.08～2.84;P = 0.023).No patients were found to have stopped medication due to serious adverse reactions.Conclusions UST can improve the clinical remission and response of CD patients at 8/16 weeks,and has good short-term clinical efficacy.CD patients with a personal history of anal fistula are recommended to use UST monoclonal antibodies,while patients with stenotic lesions should be cautious in using UST monoclonal antibodies.Whether the patient has undergone surgical treatment in the past,as well as whether UST has been used on the first or non-first line,has no significant impact on clinical remission.
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Objective To analyze the global research status,hotspots,and frontiers of proprotein convertase subtilisin/Kexin type 9(PCSK9)monoclonal antibodies,and to provide a reference for related scientific research and the rational drug use in clinical practice in China.Methods The research literature related to PCSK9 monoclonal antibody included in the Web of Science database was searched for the period from January 2011 to February 2022,and the literature included in the study was visually analyzed by the CiteSpace software.Results A total of 723 articles were included,and the annual number of publica-tions showed an overall upward trend.The top three countries were the United States,France,and the United Kingdom.Sanofi was the organization with the largest number of articles,and the organization with the highest citation of articles was Brigham and Women's Hospital.The hotspots of research mainly included the use of PCSK9 monoclonal antibody in the treatment of patients with hypercholesterolemia,patients who do not tolerate statins,patients with high cardiovascular risk,and the efficacy and safety of PCSK9 monoclonal antibody in lipid-lowering therapy combined statins;The frontiers of research in recent two years is the appli-cation of PCSK9 monoclonal antibodies in patients with acute coronary syndrome and the clinical benefits after reducing the level of lipoprotein(a).Conclusion A large number of studies have confirmed the efficacy and safety of PCSK9 monoclonal anti-bodies in reducing blood lipids,but there is still a lack of research on its economics and application in special populations,which should be the focus of future research.
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Objective To explore the efficacy and safety of recombinant human anti-severe acute respiratory syn-drome coronavirus 2(anti-SARS-CoV-2)monoclonal antibody injection(F61 injection)in the treatment of patients with coronavirus disease 2019(COVID-19)combined with renal damage.Methods Patients with COVID-19 and renal damage who visited the PLA General Hospital from January to February 2023 were selected.Subjects were randomly divided into two groups.Control group was treated with conventional anti-COVID-19 therapy,while trial group was treated with conventional anti-COVID-19 therapy combined with F61 injection.A 15-day follow-up was conducted after drug administration.Clinical symptoms,laboratory tests,electrocardiogram,and chest CT of pa-tients were performed to analyze the efficacy and safety of F61 injection.Results Twelve subjects(7 in trial group and 5 in control group)were included in study.Neither group had any clinical progression or death cases.The ave-rage time for negative conversion of nucleic acid of SARS-CoV-2 in control group and trial group were 3.2 days and 1.57 days(P=0.046),respectively.The scores of COVID-19 related target symptom in the trial group on the 3rd and 5th day after medication were both lower than those of the control group(both P＜0.05).According to the clinical staging and World Health Organization 10-point graded disease progression scale,both groups of subjects improved but didn't show statistical differences(P＞0.05).For safety,trial group didn't present any infusion-re-lated adverse event.Subjects in both groups demonstrated varying degrees of elevated blood glucose,elevated urine glucose,elevated urobilinogen,positive urine casts,and cardiac arrhythmia,but the differences were not statistica-lly significant(all P＞0.05).Conclusion F61 injection has initially demonstrated safety and clinical benefit in trea-ting patients with COVID-19 combined with renal damage.As the domestically produced drug,it has good clinical accessibility and may provide more options for clinical practice.
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Objective:To preparation TREM2-specific monoclonal antibodies and to evaluation their properties and applica-tions lay a foundation for the development of druggable antibodies against TREM2 targets.Methods:The GST fusion protein containing the extracellular segment of TREM2 was expressed and purified,which was used as antigen to immunize mice.The mouse with high antiserum titer was used to generate specific monoclonal antibodies against TREM2 through cell fusion and monoclonal screening.The specificity and affinity of the monoclonal antibodies and their applications in different immunological experiments were detected.Results:A total of 29 strains of anti-TREM2 monoclonal antibodies were obtained,of which 24 strains could specifically bind to TREM2.The EC50 of antibodies were calculated above nanomolar.These monoclonal antibodies could be used for specific detection of TREM2 in Western blot,immunoprecipitation,flow cytometry and immunofluorescence experiments.Conclusion:Monoclonal anti-bodies against TREM2 with high affinity and specificity are successfully generated,which lay the foundation for the research and the development of antibody drugs targeting TREM2.
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@#Objective To select and optimize the process parameters of SARS-CoV-2 F61 affinity chromatography by the screening and optimization experiment of Design of Experiment(DoE),in order to obtain the optimal process conditions.Methods Eight process parameters that may affect the experimental response results in affinity chromatography were selected and their level ranges were determined.DoE screening test was used to perform 8 factor 2 level screening tests on the selected process parameters.The response values were detected and the mathematical model was fitted by statistical software.Three key process parameters significantly affecting the key quality attributes were obtained by Pareto diagram analysis(P < 0.05).Then DoE response surface method(RSM)was selected to optimize the key process parameters.First,the full factorial experiment design was completed,the response results were detected to fit the mathematical model,and the bending term P value was analyzed to judge the range of significant factors in the optimal range(bending P < 0.05),then according to the sequential complement of the central composite face-centered design(CCF)experiment,through the detection of the response results to fit the response surface model,the range of optimal conditions was obtained,and the stability of the optimal parameters was finally verified by repeated experiments.Results In the screening experiment,it was found that the significant factors affecting F61 in the affinity chromatography stage were elution buffer pH,elution buffer salt concentration,leaching buffer salt concentration and equilibrium buffer salt concentration.The optimal conditions of key process parameters in affinity chromatography were obtained by CCF.When the pH of elution buffer was 3.2,the elution buffer salt concentration was 0.07 mol/L NaCl,and the leaching buffer salt concentration was 0.31 mol/L NaCl,the yield of F61 reached 95.25%,the residual amount of host cell protein(HCP)was 97.33 ppm,and the monomer purity of the sample was98.51% at the affinity chromatography stage.Conclusion Different types of DoE methods were used to screen and optimize the process parameters of F61 affinity chromatography stage,and the optimal process conditions were obtained,which lays a foundation for the esta-blishment of F61 purification process.
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Myasthenia gravis (MG) is an autoimmune disease of the nervous system mediated by autoimmune antibodies, dependent on T cells and involved in multiple complement. Recent years, targeted biologics have shown advantages in a number of clinical studies of myasthenia gravis. This review focuses on targeted therapy on B cells, complement, neonatal fragment crystal receptor (FcRn) and cytokine monoclonal antibodies, as well as on the latest research progress of chimeric antigen receptor T cells (CAR-T) or chimeric autoantibody receptor T cells (CAAR-T) in MG therapy, in order to provide the latest drug information for clinicians.
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@#Objective To develop and verify a reporter gene assay for the determination of antibody dependent cellular phagocytosis(ADCP)potency of Ig G2 monoclonal antibody(m Ab)against epidermal growth factor receptor(EGFR)by combining Design of Experiment(DOE)and one factor at a time(OFAT).Methods The Jurkat/NFAT-Re/FcγRⅡa stably transformed cell line was used as effector cells,while the A431 cell line as the target cells.The JMP software was used to optimize the seven key factors in the experiment by combining DOE and OFAT analysis,while the ratio of upper and lower asymptotes(D/A)was used as the statistic,and the reporter gene method was developed to evaluate the ADCP potency of Ig G2 anti-EGFR m Ab.The method was verified according to the general chapter<9401>of Chinese Pharmaco-poeia（Ⅲ/Ⅳvolume,2020 edition)and used to determine the biological potency of Ig G2 anti-EGFR m Ab injection.Results After three rounds of experiments,the reporter gene method to evaluate the ADCP potency of Ig G2 anti-EGFR m Ab was developed.The method showed a dose-response relationship and was consistent with the four-parameter regression equa-tion y=(A-D）/[1+(x/C)~B]+D.The range of seven key conditions was determined:the density of effector cells was(1.25-3.75）×10~4 cells/well,the density ratio of effector cells to target cells was 1.0-2.0,the incubation time of target cells was 20-40 min,the incubation time of administration was 15-30 min,the total time was 5.5-6.5 h,and the color time was 5-30 min with luciferase detection system(Bright-Glo)as the color agent.The method had good specificity.Six independent tests were run for the five potency levels,with the correlation coefficient r of 0.994 5 and the linear regression equation slope of 1.02.The relative potency of five potency levels respectively was(62.15±1.38)%,(78.53±2.82)%,(99.12±3.95)%,(123.27±4.59)%and(155.22±7.04)%,the range of relative biases was-2.9%-0.2%,and the range of generalized cross-validation(GCV)was 2.2%-4.6%.The method had good linearity,relative accuracy and precision in the range of 64%-156%.The mean value of the potency of IgG2 anti-EGFR m Ab in three tests was(101.5±2.8)%.Conclusion The reporter gene assay developed in this study can be used to evaluate the ADCP potency of IgG2 anti-EGFR mAb
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【Objective】 To perform pre-transfusion examination and major crossmatch test using CD47 anti-idiotypic antibody (CD47 AID) (method 1) and reagent lack of anti-IgG4 anti-human globulin(method 2) in patients treated with CD47 monoclonal antibodies, and evaluate the feasibility of method 1 by comparing the transfusion efficacy of patients after cross matching with two methods. 【Methods】 Post-drug samples were collected from 18 clinical subjects treated with CD47 monoclonal antibody in our hospital. Antibody screening and major crossmatch test were performed using method 1 and method 2, and the difference of ΔHb (post-transfusion Hb minus pre-transfusion Hb) was compared after transfusion. The differences in ΔHb after transfusion were analyzed between the test group using method 1 and the control group without CD47 monoclonal antibody using ordinary microcolumn gel method. 【Results】 There was no significant difference in ΔHb between the test group using method 1 and test group using method 2 (8.40±0.71 vs 7.36±0.94, P>0.05). No significant difference was noticed in ΔHb between the test group using method 1 and the control group without CD47 monoclonal antibody (8.40±0.71 vs 6.59±0.77, P>0.05). 【Conclusion】 In the test group, major crossmatch test with method 1 has the same transfusion efficacy as the test with method 2. Method 1 is simple and easy to operate, and the results are objective and accurate. It is recommended to use method 1 for pre-transfusion antibody screening and major crossmatch tests for patients using CD47 monoclonal antibody.
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As a new treatment option after conventional corticosteroids and immunomodulatory drugs, biologics have been widely used in the clinical management of non-infectious uveitis in many countries due to their approved efficacy and safety. Anti-tumor necrosis factor-alpha monoclonal antibody is the most commonly used one. However, the guidance on its standardized application is lacking. The Ocular Immunology Group of Immunology and Rheumatology Academy in Cross-Straits Medicine Exchange Association compiled the Chinese expert consensus on treatment of non-infectious uveitis with anti-tumor necrosis factor-alpha monoclonal antibody. This evidence-based consensus is made according to the principle of consensus building and combines the clinical experience of the experts. Twelve recommendations are formatted on the application of Adalimumab and Infliximab. The interpretation of this consensus point will help improve the normative and effective application of anti-tumor necrosis factor-alpha monoclonal antibody in ophthalmologists, rheumatologists and immunologists.
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@#Abstract: Type I interferons play an important role in the pathogenesis of autoimmune diseases such as systemic lupus erythematosus (SLE). Monoclonal antibody shows therapeutic potential by blocking the signaling pathway. This study used recombinant human subunit 1 of the type I interferon receptor (IFNAR1) protein to immunize New Zealand white rabbits, and applied B cell cloning technology to screen and obtain rabbit parental antibodies. After humanization modification, QX006N was obtained. In vitro biological studies showed that QX006N could specifically bind to human IFNAR1 with an affinity of 108 pmol/L, and neutralize the type I interferon signaling pathway and this pathway mediated biological effects. This study provides a solid foundation for the development of antibody drugs targeting the type I interferon signaling pathway for the treatment of SLE.
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@#Objective To investigate the mechanism of anti-IL-17A monoclonal antibody(secukinumab) regulating autophagy and inflammation in gout.Methods The peripheral venous blood samples from 57 patients with acute gout(AG),57patients with intermittent gout(IG) and 82 healthy volunteers were collected and measured for the mRNA transcription levels of autophagy-related genes(ATGs) ATG4B,ATG7, A TG16L1,Beclin-1 and LC3B by RT-qPCR.The model of AG inflammation was established by adding monosodium urate(MSU) crystals into the peripheral venous blood samples of healthy volunteers,and the transcription and protein expression of IL-1β were detected by RT-qPCR and ELISA at 0,1,2,4,6 and8 h and different concentrations(0,100,200 and 400 μmol/L) of secukinumab.The peripheral blood samples of healthy volunteers were divided into control(without MSU treatment),MSU(100 μg/mL),MSU+colchicine(100 μg/mL+30 μg/mL) and MSU+secukinumab(100 μg/mL+400 μmol/L) groups,which were detected for the mRNA transcription and protein expression of IL-1 β and ATGs by RT-qPCR and Western blot,and for the expression of IL-1β,IL-12 and IL-35 by ELISA.Results The mRNA expression levels of ATG4B, Beclin-1 and LC3B in AG,IG and healthy control groups were significantly different(F=3.896,11.78 and 3.856,respectively,each P <0.05),among which the mRNA levels in AG were lower than those in IG and HC groups(t=2.692,3.234,2.231 and 2.085,4.795,2.748,respectively,each P <0.05);the expression levels of ATG16L1 mRNA were significantly different in the three groups(F=7.949,P <0.001),and was significantly lower in AG group than HC group(t=3.860,P <0.001).In AG inflammation model,the mRNA and protein expression of IL-1 β reached their peak in 2—4 h,and the anti-inflammation effect of secukinumab was the strongest at the concentration of 400 μmol/L.Compared with MSU group,the mRNA levels of ATG16L1 and LC3B(t=2.343 and 2.916,respectively,each P <0.05) as well as the expression levels of ATG4B,ATG7,Beclin-1,ATG16L1 and LC3B-Ⅱ proteins(t=28.84,11.6,8.402,4.124 and 2.458,respectively,each P <0.05) in MSU+secukinumab group decreased significantly.The expression levels of IL-12 and IL-35 in the control,MSU,MSU+colchicine and MSU+secukinumab groups showed significant difference(F=7.009 and 6.518,respectively,each P <0.01).Compared with MSU group,the expression level of IL-12 significantly decreased(t=2.604,P <0.05)in MSU+secukinumab group,and the expression level of IL-35 also decreased,while with no significant difference(t=1.928,P> 0.05).Conclusion Secukinumab can regulate the mRNA and protein expression of ATGs,reduce the levels of pro-inflammatory cytokines,and inhibit gout inflammation,which provides a reference for the treatment of gout.
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Human epidermal growth factor receptor 2 （HER2）-positive breast cancer is aggressive and prone to metastasis，and the applications of HER2 agents have improved the prognosis of patients with HER2-positive breast cancer. Among the marketed HER2 agents，macromolecular monoclonal antibodies that target the extracellular domain Ⅳ of HER2 were the cornerstone drugs of HER2-positive breast cancer，including trastuzumab，inetetamab，and margetuximab. Trastuzumab is available for the full-line treatment of breast cancer with sufficient proof of evidence-based medicine，sufficient practical experience and controllable safety. Inetetamab and trastuzumab have similar efficacy and controllable safety in HER2-positive metastatic breast cancer and neoadjuvant/ adjuvant therapy. Margetuximab focuses on patients carrying the CD16A-158F allele，and is an option of posterior line treatment for advanced breast cancer. It is necessary to select the most suitable drugs clinically according to the specific condition of the patient.
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@#Objective To investigate the mechanism of anti-IL-17A monoclonal antibody(secukinumab) regulating autophagy and inflammation in gout.Methods The peripheral venous blood samples from 57 patients with acute gout(AG),57patients with intermittent gout(IG) and 82 healthy volunteers were collected and measured for the mRNA transcription levels of autophagy-related genes(ATGs) ATG4B,ATG7, A TG16L1,Beclin-1 and LC3B by RT-qPCR.The model of AG inflammation was established by adding monosodium urate(MSU) crystals into the peripheral venous blood samples of healthy volunteers,and the transcription and protein expression of IL-1β were detected by RT-qPCR and ELISA at 0,1,2,4,6 and8 h and different concentrations(0,100,200 and 400 μmol/L) of secukinumab.The peripheral blood samples of healthy volunteers were divided into control(without MSU treatment),MSU(100 μg/mL),MSU+colchicine(100 μg/mL+30 μg/mL) and MSU+secukinumab(100 μg/mL+400 μmol/L) groups,which were detected for the mRNA transcription and protein expression of IL-1 β and ATGs by RT-qPCR and Western blot,and for the expression of IL-1β,IL-12 and IL-35 by ELISA.Results The mRNA expression levels of ATG4B, Beclin-1 and LC3B in AG,IG and healthy control groups were significantly different(F=3.896,11.78 and 3.856,respectively,each P <0.05),among which the mRNA levels in AG were lower than those in IG and HC groups(t=2.692,3.234,2.231 and 2.085,4.795,2.748,respectively,each P <0.05);the expression levels of ATG16L1 mRNA were significantly different in the three groups(F=7.949,P <0.001),and was significantly lower in AG group than HC group(t=3.860,P <0.001).In AG inflammation model,the mRNA and protein expression of IL-1 β reached their peak in 2—4 h,and the anti-inflammation effect of secukinumab was the strongest at the concentration of 400 μmol/L.Compared with MSU group,the mRNA levels of ATG16L1 and LC3B(t=2.343 and 2.916,respectively,each P <0.05) as well as the expression levels of ATG4B,ATG7,Beclin-1,ATG16L1 and LC3B-Ⅱ proteins(t=28.84,11.6,8.402,4.124 and 2.458,respectively,each P <0.05) in MSU+secukinumab group decreased significantly.The expression levels of IL-12 and IL-35 in the control,MSU,MSU+colchicine and MSU+secukinumab groups showed significant difference(F=7.009 and 6.518,respectively,each P <0.01).Compared with MSU group,the expression level of IL-12 significantly decreased(t=2.604,P <0.05)in MSU+secukinumab group,and the expression level of IL-35 also decreased,while with no significant difference(t=1.928,P> 0.05).Conclusion Secukinumab can regulate the mRNA and protein expression of ATGs,reduce the levels of pro-inflammatory cytokines,and inhibit gout inflammation,which provides a reference for the treatment of gout.
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Relato de caso de paciente com rinossinusite crônica com polipose nasal em tratamento com dupilumabe. São descritos os aspectos clínicos e o impacto na qualidade da vida do paciente. Imagens tomográficas evidenciam a melhora do processo inflamatório e a regressão dos pólipos nasais.
We report the case of a patient with chronic rhinosinusitis with nasal polyps treated with dupilumab. The clinical features and impact on the patient's quality of life are described. Computed tomography shows improvement of the inflammatory process and regression of the nasal polyps.
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Humans , Male , Middle Aged , Antibodies, Monoclonal , Anti-Inflammatory Agents, Non-SteroidalABSTRACT
Abstract Objectives: Despite the global impact of the Respiratory Syncytial Virus (RSV) infection in children, only one monoclonal antibody (Palivizumab) has been approved for clinical use. However, advances in the knowledge of RSV immunology may enable the development of safe and effective new vaccines and monoclonal antibodies in a few years. The purpose of this review is to summarize available data on approved and developing passive and active immunizations against RSV in childhood and pregnancy. Data source: A non-systematic review of RSV immunoprophylaxis in childhood and pregnancy was carried out in PubMed, path.org and clinical trial registries, without language restrictions, up to September 2022. Data synthesis: Three monoclonal antibodies and 17 active immunization candidates are under development in phase 1 to 3 clinical studies. Regarding the first group, Nirsevimab is a monoclonal antibody with a prolonged half-life whose approval for clinical use is expected in the next months. Among the vaccines under development, six techniques are being used: protein subunit, viral particles, live attenuated virus, recombinant viral vector, chimeric, and mRNA. The first two approaches are being tested primarily in pregnancy, while the others are being developed for the pediatric population. Conclusion: The approval of extended half-life monoclonal antibodies is the next expected advance in RSV prevention, although the costs may be a barrier to the implementation. Regarding active immunizations, maternal and infant vaccination are complementary strategies and there are many promising candidates in clinical studies using different platforms.
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Monoclonal antibodies (mAbs), which are commonly used to treat rheumatoid arthritis (RA), have been linked to a variety of adverse events (AEs). The objective of the study was to compare the safety profiles of six FDA approved mAbs (sarilumab, tocilizumab, adalimumab, golimumab, infliximab, and rituximab) marketed for the treatment of RA. A systematic review of the literature was conducted using the databases PubMed, Cochrane Library, and Science Direct. The manuscript comprised a total of 23 clinical studies. The percentage of patients who had AEs was calculated and presented using box-whisker and forest plots. Infections and infestations were found to be the most common AEs in RA patients treated with mAbs. Raised alanine aminotransferase (ALT), aspartate aminotransferase (AST), upper respiratory tract infection (URTI), and nasopharyngitis were frequently reported. The most common AEs were reported with adalimumab. The highest percentage of patients reporting AEs was associated with golimumab (52%), while rituximab had the fewest AEs (4.9%). In conclusion, rituximab appears to be a safer treatment option for RA as it is found to be associated with a lower risk of AEs, particularly respiratory infections.
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Zearalenone(ZEN) is a toxic metabolite produced by Fusarium culmorum, F. graminearum, F. tricinctum, and other fungi, with estrogenic characteristics. Exposure to or ingestion of ZEN during pregnancy can cause reproductive dysfunction, miscarriage, stillbirth, and malformation, and seriously endanger human life and health. The detection methods for ZEN in the Chinese Pharmacopoeia(2020 edition) are liquid chromatography(LC) and liquid chromatography-mass spectrometry(LC-MS), and it is stipulated that ZEN should not exceed 500 μg in 1 000 g of Coicis Semen. Although these detection methods by instruments can achieve the qualitative and quantitative analysis of ZEN in Coicis Semen, their high detection cost and long periods hinder the rapid screening of a large number of samples in the field. In this study, the synthesized ZEN hapten was conjugated with bovine serum albumin(BSA) and ovalbumin(OVA) to obtain the complete ZEN antigen. By virtue of antibody preparation techniques, ZEN monoclonal antibody 4F6 was prepared, which showed 177.5%, 137.1%, and 109.7% cross-reactivity with ZEN structural analogs zearalanol, zearalenone, and α-zearalenol, respectively, and no cross-reactivity with other fungal toxins such as aflatoxin. Direct competitive enzyme-linked immunosorbent assay(dcELISA) based on ZEN monoclonal antibody 4F6 was developed for the determination of ZEN in Coicis Semen with an IC_(50) of 1.3 μg·L~(-1) and a detection range of 0.22-21.92 μg·L~(-1). The recoveries were 83.91%-105.3% and the RSD was 4.4%-8.0%. The established dcELISA method was used to determine the ZEN residuals in nine batches of Coicis Semen samples, and the results were validated by LC-MS. The correlation between the two detection methods was found to be 0.993 9, indicating that the established dcELISA could be used for the rapid qualitative and quantitative detection of ZEN residuals in Coicis Semen.
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Humans , Female , Pregnancy , Zearalenone , Coix , Enzyme-Linked Immunosorbent Assay , Mycotoxins , Antibodies, MonoclonalABSTRACT
Morphine is a frequently used analgesic that activates the mu-opioid receptor(MOR),which has prominent side effects of tolerance.Although the inefficiency of morphine in inducing the endocytosis of MOR underlies the development of morphine tolerance,currently,there is no effective therapy to treat morphine tolerance.In the current study,we aimed to develop a monoclonal antibody(mAb)precisely targeting MOR and to determine its therapeutic efficacy on morphine tolerance and the underlying molecular mechanisms.We successfully prepared a mAb targeting MOR,named 3A5C7,by hybridoma technique using a strategy of deoxyribonucleic acid immunization combined with cell immunization,and identified it as an immunoglobulin G mAb with high specificity and affinity for MOR and binding ability to antigens with spatial conformation.Treatment of two cell lines,HEK293T and SH-SY5Y,with 3A5C7 enhanced morphine-induced MOR endocytosis via a G protein-coupled receptor kinase 2(GRK2)/β-arrestin2-dependent mechanism,as demonstrated by immunofluorescence staining,flow cytometry,Western blotting,coimmunoprecipitation,and small interfering ribonucleic acid(siRNA)-based knock-down.This mAb also allowed MOR recycling from cytoplasm to plasma membrane and attenuated morphine-induced phosphorylation of MOR.We established an in vitro morphine tolerance model using differentiated SH-SY5Y cells induced by retinoic acid.Western blot,enzyme-linked immunosorbent assays,and siRNA-based knockdown revealed that 3A5C7 mAb diminished hyperactivation of adenylate cyclase,the in vitro biomarker of morphine tolerance,via the GRK2/β-arrestin2 pathway.Furthermore,in vivo hotplate test demonstrated that chronic intrathecal administration of 3A5C7 significantly alle-viated morphine tolerance in mice,and withdrawal jumping test revealed that both chronic and acute 3A5C7 intrathecal administration attenuated morphine dependence.Finally,intrathecal electroporation of silencing short hairpin RNA illustrated that the in vivo anti-tolerance and anti-dependence efficacy of 3A5C7 was mediated by enhanced morphine-induced MOR endocytosis via GRK2/β-arrestin2 pathway.Collectively,our study provided a therapeutic mAb,3A5C7,targeting MOR to treat morphine tolerance,mediated by enhancing morphine-induced MOR endocytosis.The mAb 3A5C7 demonstrates promising translational value to treat clinical morphine tolerance.
ABSTRACT
Objective:To explore the effect of chemotherapy administration sequence combined with programmed cell death protein-1(PD-1)monoclonal antibody on the efficacy and immune-related adverse events(irAEs)in patients with advanced non-small cell lung cancer(NSCLC).Methods:The clinical data of 110 patients with advanced NSCLC treated at The First Affiliated Hospital of Zhengzhou University between November 2019 and January 2022 were retrospectively collected.The factors influencing irAEs were analyzed by univariate and multivariate Logistic regression analyses,while those influencing curative effect were analyzed by Kaplan-Meier curve analysis,Log-rank test,and univariate and multivariate Cox regression analyses.Results:Treatment with PD-1 monoclonal antibody after 2 days of chemotherapy(sequential treatment group,n=36)significantly prolonged progression-free survival(PFS)compared with PD-1 monoclonal antibody admin-istration on the same day of chemotherapy(simultaneous treatment group,n=74)(17.2 months vs.11.3 months,respectively;P＜0.05).The disease control rate(DCR)was better in the sequential treatment group than in the simultaneous treatment group(94.4％vs.79.7％,re-spectively;P=0.045),while the objective response rate(ORR)did not differ significantly(69.4％vs.51.4％,respectively;P=0.072).The Cox re-gression analysis showed that cytokerat in 19 fragment(Cyfra21-1)and d-dimer(D-dimer)affected the efficacy of combination therapy(P＜0.05).The Logistic regression analysis showed that age and lactic dehydrogenase(LDH)influenced the occurrence of irAEs(P＜0.05),while the administration sequence did not significantly affect the occurrence of irAEs(P=0.130).Conclusions:Administration sequence influences the efficacy of combination therapy,and patients with advanced NSCLC who receive sequential therapy may experience better efficacy.Age and LDH are negatively correlated with the occurrence of irAEs.