Research progress of biological agents in thyroid-associated ophthalmopathy / 国际眼科杂志(Guoji Yanke Zazhi)

Thyroid-associated ophthalmopathy(TAO)is a rare organ-specific autoimmune disease with an unclear pathogenesis. At present, the treatment still relies mainly on glucocorticoids and traditional immunosuppressants. However, some patients respond poorly to these drugs and experience treatment-related adverse reactions, highlighting the urgent need for novel drugs for TAO treatment. In recent years, with the deepening of research on the pathogenesis of TAO, a multitude of biologics targeting specific targets have emerged. Among them, teprotumumab, which targets the insulin-like growth factor-I receptor(IGF-IR), has been approved by the Food and Drug Administration for the treatment of TAO, and several other biologics are currently in clinical trials. This review provides the latest reference for the clinical prevention, treatment, and research of TAO by summarizing the current clinical research status of biologics targeting IGF-IR, neonatal Fc receptor(FcRn), thyroid-stimulating hormone receptor(TSHR), B cells, cytokines, and other biological agents in TAO and analyzing their impact on clinical treatment and future research trends.

Application of immunotherapy in relapsed/refractory B-cell acute lymphoblastic leukemia / 中国药房

Immunotherapy， as an emerging treatment method， has been proven to improve the prognosis of patients with relapsed/refractory B-cell acute lymphoblastic leukemia （B-ALL） and has good application prospects. Immunotherapy， including chimeric antigen receptor T cell immunotherapy （CAR-T） and monoclonal antibodies， has shown great potential for application， and has been approved for marketing. This article summarizes the application of the above two therapies in the treatment of relapsed/ refractory B-ALL， and concludes that CAR-T is a kind of personalized immunotherapy， and the selection of ideal targets is an important part of its action. Currently， the ideal targets in clinical studies include CD19， CD22 and CD19/CD22. Monoclonal antibodies， including blinatumomab and inotuzumab ozogamicin， have shown superior therapeutic efficacy for relapsed/refractory B- ALL. Immunotherapy has shown superior therapeutic effects compared to conventional chemotherapy， expanding the selection of treatment options for relapsed/refractory B-ALL.

Research advances in monoclonal antibodies for treatment of drug resistance in inflammatory bowel disease / 中国生物制品学杂志

@#Inflammatory bowel disease(IBD)is a complex inflammatory disease mediated by immunity that is treated with the goal of maintaining disease remission and preventing recurrence. With the deep study of the molecular mechanism of the occurrence and development of IBD,many related target molecules have been found,and the monoclonal antibodies of corresponding targets have been used to treat the disease,while the drug resistance phenomenon generated during treatment has seriously affected the treatment effect. In this paper,monoclonal antibodies such as infliximab were reviewed for the treatment of IBD resistance,with a view to understanding its possible mechanisms and exploring effective treatments and preventive measures

Perfil de pacientes com urticária crônica espontânea submetidos ao tratamento com omalizumabe em Chapecó, SC / Profile of patients with chronic spontaneous urticaria treated with omalizumab in Chapecó, south of Brazil

Introdução: A urticária crônica espontânea é caracterizada por lesões máculo-papulares eritematosas, associadas a prurido e angioedema, que não possui estímulo externo reconhecido e de difícil controle. A primeira e a segunda linha terapêutica, disponibilizadas pelo Sistema Único de Saúde, não apresentam resultados significativos, os quais se tornam refratários. O omalizumabe, considerado terceira linha terapêutica e que não é amplamente disponibilizado pelo Sistema Único de Saúde, pode apresentar resultado significativo na interrupção dos sintomas da doença. Objetivo: O presente estudo tem como objetivo avaliar pacientes com urticária crônica espontânea que usaram ou estão em uso de omalizumabe. Métodos: Trata-se de um estudo observacional transversal do tipo série de casos, cuja análise foi feita através dos prontuários, com população de 34 pacientes com urticária crônica espontânea submetidos ao tratamento com omalizumabe no Instituto de Olhos de Santa Catarina (IOSC). Resultados: Constatou-se no estudo que a maioria dos pacientes com urticária crônica espontânea em uso de omalizumabe é constituída do sexo feminino (76,5%) e idade média de 41 anos. A doença mais associada à urticária crônica espontânea foi depressão (38,2%). O sucesso do tratamento com omalizumabe é medido pelo questionário UAS7 (Urticaria Activity Score), o qual, segundo os dados dos prontuários, todos os pacientes apresentavam resultado maior que 35 pontos antes do uso da medicação, e 32 conseguiram alcançar um índice de 0 após o uso do omalizumabe, variando apenas no tempo de tratamento. Conclusão: A urticária crônica espontânea é uma doença que não tem cura e possui alta refratariedade, mas pode ter seus sintomas reduzidos, principalmente com o uso do omalizumabe, que se mostrou eficiente nos casos analisados.

Introduction: Chronic spontaneous urticaria is a disease characterized by erythematous maculopapular eruption, associated with itching and angioedema, that has no recognized external stimulus and is difficult to control. First- and second-line treatments, available through the Brazilian Unified Health System, do not yield meaningful results, and patients become refractory. Omalizumab, considered a third-line treatment and not widely available through the Brazilian Unified Health System, may yield meaningful results in halting disease symptoms. Objective: To evaluate patients with chronic spontaneous urticaria who have used or are using omalizumab. Methods: We conducted a cross-sectional case series observational study with a review of the medical records of 34 patients with chronic spontaneous urticaria treated with omalizumab at the Eye Institute of Santa Catarina, south of Brazil. Results: Most patients with chronic spontaneous urticaria receiving omalizumab were female (76.5%) with a mean age of 41 years. The disease most commonly associated with chronic spontaneous urticaria was depression (38.2%). Omalizumab treatment success was measured with the Urticaria Activity Score (UAS7). Based on data extracted from the medical records, all 34 patients had a score greater than 35 before treatment. After receiving omalizumab, 32 patients managed to reach a score of 0, differing only in the duration of treatment. Conclusion: Chronic spontaneous urticaria is an incurable, highly refractory disease, but its symptoms can be reduced mainly with the use of omalizumab, which proved to be effective in the cases analyzed here.

Use of monoclonal antibodies in cancer immunotherapy: types and mechanisms of action / Uso de anticuerpos monoclonales en la inmunoterapia del cáncer: tipos y mecanismos de acción

Abstract Immunotherapy is one of the most innovative treatments in the current field of oncology and consists of stimulating the immune system to eliminate tumoral cells. Monoclonal antibodies (mAbs) are glycoproteins secreted by B-cells capable of recognizing and neutralizing foreign organisms or antigens. Structurally, they are composed of two heavy and two light chains. The generation of therapeutic mAbs is one of the most developed and fastest-growing areas of the biotechnological and pharmaceutical industries and is an important adjunct to cancer therapy. Several antibodies have been approved for human administration and can be mouse-derived, chimeric, humanized, or fully human. mAbs main mechanism of action includes the lysis of the tumoral cells through inducing apoptosis, phagocytosis, complement activation, or signaling inhibition.

Resumen La inmunoterapia es un tratamiento innovador para la oncología actual, que consiste en la estimulación del sistema inmunitario para la eliminación de las células tumorales. Los anticuerpos monoclonales (mAbs) son glicoproteínas secretadas por los linfocitos B, capaces de reconocer y neutralizar organismos extraños o antígenos. Estructuralmente se componen de dos cadenas pesadas y dos cadenas ligeras. La generación de mAbs terapéuticos es una de las áreas de mayor crecimiento en la industria biotecnológica y farmacéutica y representa un complemento importante en la terapia del cáncer. Existen diversos mAbs que han sido aprobados para su administración en humanos, y pueden ser derivados de ratón, quiméricos, humanizados o completamente humanos. Los mecanismos de acción consisten principalmente en la lisis de las células tumorales a través de la inducción de la apoptosis, fagocitosis, activación del complemento o inhibición de la señalización celular.

Evaluation of the use of CGRP monoclonal antibodies (mAbs) in migraine prophylaxis in a private clinic / Avaliação do uso de anticorpos monoclonais (mAbs) CGRP na profilaxia de enxaqueca em clínica privada

Introduction: Migraine is considered the second most prevalent neurological disorder in the population and highly disabling. Objective: The aim of this study is to evaluate the use of calcitonin gene-related peptide (CGRP) monoclonal antibodies in migraine prophylaxis, with emphasis on therapeutic response, adverse effects, and impacts on quality of life. Method; A quantitative, retrospective, and descriptive study was carried out, through the analysis of medical records and telephone interviews with patients seen at the Serviço de Neurologia e Neurocirurgia, in the city of Passo Fundo, RGS, Brazil, currently or previously having used at least one dose of the medication. Conclusion: Thus, it is understood that CGRP monoclonal antibodies are able to reduce monthly headache days, reduce pain intensity and promote improvement in work capacity. Therefore, they can be considered effective, safe and well-adhered medications for migraine prophylaxis.

Introdução: A enxaqueca é considerada o segundo distúrbio neurológico mais prevalente na população e altamente incapacitante. Objetivo: O objetivo deste estudo é avaliar o uso de anticorpos monoclonais do peptídeo relacionado ao gene da calcitonina (CGRP) na profilaxia da enxaqueca, com ênfase na resposta terapêutica, efeitos adversos e impactos na qualidade de vida. Método; Foi realizado um estudo quantitativo, retrospectivo e descritivo, por meio de análise de prontuários e entrevistas telefônicas com pacientes atendidos no Serviço de Neurologia e Neurocirurgia, na cidade de Passo Fundo, RGS, Brasil, que já usaram ou usaram pelo menos uma dose do medicamento. Conclusão: Assim, entende-se que os anticorpos monoclonais CGRP são capazes de reduzir os dias mensais de cefaleia, reduzir a intensidade da dor e promover melhora na capacidade de trabalho. Portanto, podem ser considerados medicamentos eficazes, seguros e de boa adesão para a profilaxia da enxaqueca.

Ebola outbreak in Guinea, 2021: Clinical care of patients with Ebola virus disease

Background: Experience from the Zaire Ebolavirus epidemic in the eastern Democratic Republic of the Congo (2018­2020) demonstrates that early initiation of essential critical care and administration of Zaire Ebolavirus specific monoclonal antibodies may be associated with improved outcomes among patients with Ebola virus disease (EVD). Objectives: This series describes 13 EVD patients and 276 patients with suspected EVD treated during a Zaire Ebolavirus outbreak in Guinea in 2021. Method: Patients with confirmed or suspected EVD were treated in two Ebola treatment centres (ETC) in the region of N'zérékoré. Data were reviewed from all patients with suspected or confirmed EVD hospitalised in these two ETCs during the outbreak (14 February 2021 ­ 19 June 2021). Ebola-specific monoclonal antibodies, were available 2 weeks after onset of the outbreak. Results: Nine of the 13 EVD patients (age range: 22­70 years) survived. The four EVD patients who died, including one pregnant woman, presented with multi-organ dysfunction and died within 48 h of admission. All eight patients who received Ebola-specific monoclonal antibodies survived. Four of the 13 EVD patients were health workers. Improvement of ETC design facilitated implementation of WHO-recommended 'optimized supportive care for EVD'. In this context, pragmatic clinical training was integrated in routine ETC activities. Initial clinical manifestations of 13 confirmed EVD patients were similar to those of 276 patients with suspected, but subsequently non confirmed EVD. These patients suffered from other acute infections (e.g. malaria in 183 of 276 patients; 66%). Five of the 276 patients with suspected EVD died. One of these five patients had Lassa virus disease and a coronavirus disease 2019 (COVID-19) co-infection. Conclusion: Multidisciplinary outbreak response teams can rapidly optimise ETC design. Trained clinical teams can provide WHO-recommended optimised supportive care, including safe administration of Ebola-specific monoclonal antibodies. Pragmatic training in essential critical care can be integrated in routine ETC activities. Contribution: This article describes clinical realities associated with implementation of WHO-recommended standards of 'optimized supportive care' and administration of Ebola virus specific treatments. In this context, the importance of essential design principles of ETCs is underlined, which allow continuous visual contact and verbal interaction of health workers and families with their patients. Elements that may contribute to further quality of care improvements for patients with confirmed or suspected EVD are discussed.

Establishment and verification of double antibody sandwich ELISA for detection of content of varicella-zoster virus glycoprotein E / 中国生物制品学杂志

@#ObjectiveTo develop and verify a double antibody sandwich ELISA for the quantitative detection of varicellazoster virus(VZV)glycoprotein E(gE).MethodsHybridoma cell lines secreting antibody against VZV-gE stably were screened by mouse hybridoma fusion technology,using VZV whole virus antigen as immunogen.The antibody titer in mouse ascites was detected by indirect ELISA.After purified by Hi Trap2=0.995 6,P=0.000 1)。结论 建立的双抗体夹心ELISA法具有良好的准确性、精密性和特异性，可用于VZV疫苗中g E抗原含量的快速检测。 ObjectiveTo develop and verify a double antibody sandwich ELISA for the quantitative detection of varicellazoster virus(VZV)glycoprotein E(gE).MethodsHybridoma cell lines secreting antibody against VZV-gE stably were screened by mouse hybridoma fusion technology,using VZV whole virus antigen as immunogen.The antibody titer in mouse ascites was detected by indirect ELISA.After purified by Hi Trap(TM)Mabselect(TM)Mabselect(TM)Su Re and Hi Trap(TM)Su Re and Hi Trap(TM)Desalting,monoclonal antibodies(m Abs)were analyzed for the purity by 12%SDS-PAGE,detected for the specificity by Western blot,and identified for the subtype by mouse monoclonal antibody typing kit.Capture antibody and enzyme-labeled antibody were screened by epitope superposition test,which were determined for the working concentrations by chessboard titration(capture antibody concentrations were 0.25,0.5,1,2,5 and 10μg/m L,enzyme-labeled antibody dilutions were 1∶500,1∶1 000,1∶2 000,1∶5 000 and 1∶10 000),and then a double antibody sandwich ELISA(DAS-ELISA)was developed for the detection of VZV-gE content.In addition,the linear range,accuracy,precision and specificity of the method were verified.The gE content in the supernatant of 3 batches of CHO-VZV-gE cells cultured in 7 L bioreactor for 1～14 d were detected by the developed method.ResultsFour positive hybridoma cell lines secreting specific antibodies against VZV-gE stably were obtained and named as m Ab-B2,m Ab-11,K9C7 and K9F4.The antibodies in mouse ascites showed titers of10(TM)Desalting,monoclonal antibodies(m Abs)were analyzed for the purity by 12%SDS-PAGE,detected for the specificity by Western blot,and identified for the subtype by mouse monoclonal antibody typing kit.Capture antibody and enzyme-labeled antibody were screened by epitope superposition test,which were determined for the working concentrations by chessboard titration(capture antibody concentrations were 0.25,0.5,1,2,5 and 10μg/m L,enzyme-labeled antibody dilutions were 1∶500,1∶1 000,1∶2 000,1∶5 000 and 1∶10 000),and then a double antibody sandwich ELISA(DAS-ELISA)was developed for the detection of VZV-gE content.In addition,the linear range,accuracy,precision and specificity of the method were verified.The gE content in the supernatant of 3 batches of CHO-VZV-gE cells cultured in 7 L bioreactor for 1～14 d were detected by the developed method.ResultsFour positive hybridoma cell lines secreting specific antibodies against VZV-gE stably were obtained and named as m Ab-B2,m Ab-11,K9C7 and K9F4.The antibodies in mouse ascites showed titers of106～106～107with purities of about 97%after purification,which all specifically bound to VZV whole virus protein with light chains ofκchain and heavy chains of Ig G_(2b),Ig G_1,Ig G_(2b)and Ig G_(2a)respectively.m Ab-B2 was determined as capture antibody and HPR-labeled m Ab-11 as enzyme-labeled antibody with the optimum working concentrations of 1.5μg/m L and 1∶5 000respectively.The internal reference concentration of gE antigen was in the range of 1.95～1 000 ng/m L,which showed a good linear relationship with A_(450).The four-parameter equation was Y=(0.15-3.99)/[1+(X/67.4)7with purities of about 97%after purification,which all specifically bound to VZV whole virus protein with light chains ofκchain and heavy chains of Ig G_(2b),Ig G_1,Ig G_(2b)and Ig G_(2a)respectively.m Ab-B2 was determined as capture antibody and HPR-labeled m Ab-11 as enzyme-labeled antibody with the optimum working concentrations of 1.5μg/m L and 1∶5 000respectively.The internal reference concentration of gE antigen was in the range of 1.95～1 000 ng/m L,which showed a good linear relationship with A_(450).The four-parameter equation was Y=(0.15-3.99)/[1+(X/67.4)(1.49)]+3.99,and R(1.49)]+3.99,and R2value was 0.999.The recoveries of accuracy verification were 94.9%～114.0%;The coefficients of variation(CVs)of precision verification were all less than 15%.Except CHO-VZV-gE cell culture supernatant,attenuated live varicella vaccine and attenuated live herpes zoster vaccine,the A_(450)of other samples were all less than 0.15 with no cross reaction.The content of gE in the supernatant of three batches CHO-VZV-gE cells increased gradually with the culture time,and was positively related with culture time within 14 days(R2value was 0.999.The recoveries of accuracy verification were 94.9%～114.0%;The coefficients of variation(CVs)of precision verification were all less than 15%.Except CHO-VZV-gE cell culture supernatant,attenuated live varicella vaccine and attenuated live herpes zoster vaccine,the A_(450)of other samples were all less than 0.15 with no cross reaction.The content of gE in the supernatant of three batches CHO-VZV-gE cells increased gradually with the culture time,and was positively related with culture time within 14 days(R2=0.995 6,P=0.000 1).ConclusionThe developed double antibody sandwich ELISA had good accuracy,precision and specificity,which might be used for rapid detection of gE antigen content in VZV vaccine.

Advances in Emerging Therapies for Multiple Myeloma / 肿瘤防治研究

Multiple myeloma (MM) is an incurable plasma cell malignancy with a typical course characterized by response to initial treatment and eventual resistance. Despite major advances in the clinical treatment of multiple myeloma driven by the introduction of new drugs (e.g., proteasome inhibitors and immunomodulators), MM remains incurable. Nevertheless, subsequent cycles of remission and relapse continue as long as new treatments are available to patients. With the development of many new treatments, the approval of 12 new drugs over the past 15 years, and the promising trend of clinical trials, the treatment landscape has dramatically changed and patient survival has improved. This article reviews the progress of new treatments for MM.

Progress on application of PD⁃1／PD⁃L1 monoclonal antibodies in oncotherapy / 中国生物制品学杂志

@#Abstract：Programmed death receptor⁃ 1（PD⁃1）belongs to the family of immunoglobulin B7⁃CD28，which plays an important role in regulating immune response in human body. Since the first PD⁃1／PD⁃ligand 1（PD⁃L1）monoclonal antibody was approved for marketing in China in 2018，the value of PD⁃1／PD⁃L1 immunotherapy in oncotherapy has attracted wide attention. Based on the introduction of the action mechanism of PD⁃1／PD⁃L1 mAbs，this paper reviews the application progress of 8 on ⁃ market PD ⁃ 1／PD ⁃ L1 mAbs in China in oncotherapy from the perspectives of approved indications，clinical trials，usage and dosage，and adverse reactions，in order to provide reference for the rational appli⁃ cation of PD⁃1／PD⁃L1 monoclonal antibodies in clinic.

Role of lactadherin anti-idiotypic monoclonal antibodies Ab2β in the treatment of human rotavirus-induced diarrhea in a neonatal mouse model / 中国热带医学

@#Abstract: Objective To investigate the preventive and therapeutic effects of anti-idiotypic monoclonal antibodies (Ab2β) of lactadherin on neonatal mice infected with human rotavirus (HRV), and to analyze the underlying mechanism. Methods Hybridoma technology was used to prepare Ab2β of lactadherin. One hundred and twenty 7-day-old Kunming mice were randomly divided into groups A, B, C and control, each consisting of 30 mice. Groups A, B, and C were all infected with HRV via oral gavage. Group A received no treatment, group B was orally administered lactadherin for 7 days prior to infection, and group C was orally administered lactadherin for 7 days after infection, the control group was orally administered cell culture medium that did not contain the virus. The clinical manifestations (diarrhea, body weight) at different time points after infection of the neonatal mice in each group were observed, and the content of rotavirus antigen in the feces of neonatal mice was detected by enzyme-linked immunosorbent assay (ELISA). After HRV infection for 7 days, immunohistochemical staining was used to examine the expression level of intercellular adhesion molecule-1 (ICAM-1) in mouse small intestinal tissues in each group. Results No diarrhea occurred in the control group at any time point. Groups A, B, and C showed diarrhea symptoms after HRV challenge for 1 day. The degree of diarrhea in groups B and C was lower than that in group A at 2-4 days after HRV challenge, and the difference was statistically significant (P<0.05). The HRV antigen content in the feces of the neonatal mice in groups B and C was lower than that in group A at 1-5 days after HRV challenge, and the difference was statistically significant (P<0.05). There was no significant difference in the degree of diarrhea and HRV antigen content between groups B and C at each time point (P>0.05). There was no significant difference in the body weight of the neonatal mice in each group before infection and 1 day after infection (P>0.05); the weight of neonatal mice in groups B and C was higher than that in group A at 3, 5 and 7 days after HRV challenge, and the difference was statistically significant (P<0.05), and there was no significant difference in body weight between groups B and C at each time point after HRV challenge (P>0.05). The number of ICAM-1 expressing cells in the small intestine of the three groups A, B, and C was higher than that of the control group after HRV challenge for 7 days, and the difference was statistically significant (P<0.05). The cell number and gray value of ICAM-1 expressing cells in groups B and C were lower than those in group A, and the difference was statistically significant (P<0.05). Conclusions Anti-idiotypic monoclonal antibodies (Ab2β) of lactadherin has a good preventive and therapeutic effects on human rotavirus infection in neonatal mice, and can significantly improve diarrhea symptoms and reduce HRV viral load. Its specific mechanism may be related to the inhibition of ICAM-1.

Role of lactadherin anti-idiotypic monoclonal antibodies Ab2β in the treatment of human rotavirus-induced diarrhea in a neonatal mouse model / 中国热带医学

@#Abstract: Objective To investigate the preventive and therapeutic effects of anti-idiotypic monoclonal antibodies (Ab2β) of lactadherin on neonatal mice infected with human rotavirus (HRV), and to analyze the underlying mechanism. Methods Hybridoma technology was used to prepare Ab2β of lactadherin. One hundred and twenty 7-day-old Kunming mice were randomly divided into groups A, B, C and control, each consisting of 30 mice. Groups A, B, and C were all infected with HRV via oral gavage. Group A received no treatment, group B was orally administered lactadherin for 7 days prior to infection, and group C was orally administered lactadherin for 7 days after infection, the control group was orally administered cell culture medium that did not contain the virus. The clinical manifestations (diarrhea, body weight) at different time points after infection of the neonatal mice in each group were observed, and the content of rotavirus antigen in the feces of neonatal mice was detected by enzyme-linked immunosorbent assay (ELISA). After HRV infection for 7 days, immunohistochemical staining was used to examine the expression level of intercellular adhesion molecule-1 (ICAM-1) in mouse small intestinal tissues in each group. Results No diarrhea occurred in the control group at any time point. Groups A, B, and C showed diarrhea symptoms after HRV challenge for 1 day. The degree of diarrhea in groups B and C was lower than that in group A at 2-4 days after HRV challenge, and the difference was statistically significant (P<0.05). The HRV antigen content in the feces of the neonatal mice in groups B and C was lower than that in group A at 1-5 days after HRV challenge, and the difference was statistically significant (P<0.05). There was no significant difference in the degree of diarrhea and HRV antigen content between groups B and C at each time point (P>0.05). There was no significant difference in the body weight of the neonatal mice in each group before infection and 1 day after infection (P>0.05); the weight of neonatal mice in groups B and C was higher than that in group A at 3, 5 and 7 days after HRV challenge, and the difference was statistically significant (P<0.05), and there was no significant difference in body weight between groups B and C at each time point after HRV challenge (P>0.05). The number of ICAM-1 expressing cells in the small intestine of the three groups A, B, and C was higher than that of the control group after HRV challenge for 7 days, and the difference was statistically significant (P<0.05). The cell number and gray value of ICAM-1 expressing cells in groups B and C were lower than those in group A, and the difference was statistically significant (P<0.05). Conclusions Anti-idiotypic monoclonal antibodies (Ab2β) of lactadherin has a good preventive and therapeutic effects on human rotavirus infection in neonatal mice, and can significantly improve diarrhea symptoms and reduce HRV viral load. Its specific mechanism may be related to the inhibition of ICAM-1.

Passive antibody therapy in emerging infectious diseases / 医学前沿

The epidemic of corona virus disease 2019 (COVID-19) caused by severe acute respiratory syndrome Coronavirus 2 and its variants of concern (VOCs) has been ongoing for over 3 years. Antibody therapies encompassing convalescent plasma, hyperimmunoglobulin, and neutralizing monoclonal antibodies (mAbs) applied in passive immunotherapy have yielded positive outcomes and played a crucial role in the early COVID-19 treatment. In this review, the development path, action mechanism, clinical research results, challenges, and safety profile associated with the use of COVID-19 convalescent plasma, hyperimmunoglobulin, and mAbs were summarized. In addition, the prospects of applying antibody therapy against VOCs was assessed, offering insights into the coping strategies for facing new infectious disease outbreaks.

Migraine treatment with biological therapies. The state of the art / Tratamento da enxaqueca com terapias biológicas. O Estado da arte

Migraine is a highly prevalent and debilitating neurological disorder. Most patients do not receive a correct diagnosis and effective treatments. Apart of the few specialists and tertiary centers worldwide, the treatment of migraine is usually symptomatic and prevention, as well as treatments of the underlying mechanisms, are not aimed. It results in frustration and substantial burden. The last few years witnessed the releasing of specific biological therapies, mostly addressing one of the peptides involved in migraine pathophysiology, the calcitonin gene-related peptide (CGRP). Either the small molecules as well as the monoclonal antibodies against CGRP or its canonical receptor have been launched in markets across the globe and represent interesting options for the treatment of migraine. Onabotulinumtoxin A has also been proposed for chronic migraine as well, but not for episodic migraine, based on its unique ability to inhibit the SNARE complex formation and the release of numerous potential mediators of migraine. However, despite the favorable figures on efficacy and tolerability of these compounds, the regulations, and particulars of different countries, regarding the structures and reimbursement of medical care, demonstrated different adhesion profiles of chosen populations to receive these emerging weapons against migraine-imposed suffering. This review addresses the use and characteristics of biological therapies used in migraine treatment.

A enxaqueca é um distúrbio neurológico altamente prevalente e debilitante. A maioria dos pacientes não recebe um diagnóstico correto e tratamentos eficazes. Com exceção dos poucos especialistas e centros terciários em todo o mundo, o tratamento da enxaqueca é geralmente sintomático e a prevenção, bem como o tratamento dos mecanismos subjacentes, não são direcionados. Isso resulta em frustração e fardo substancial. Os últimos anos testemunharam o lançamento de terapias biológicas específicas, abordando principalmente um dos peptídeos envolvidos na fisiopatologia da enxaqueca, o peptídeo relacionado ao gene da calcitonina (CGRP). Tanto as pequenas moléculas como os anticorpos monoclonais contra CGRP ou o seu receptor canônico foram lançados em mercados em todo o mundo e representam opções interessantes para o tratamento da enxaqueca. A onabotulinumtoxina A também foi proposta para enxaqueca crônica, mas não para enxaqueca episódica, com base em sua capacidade única de inibir a formação do complexo SNARE e a liberação de numerosos mediadores potenciais da enxaqueca. No entanto, apesar dos números favoráveis ​​sobre a eficácia e tolerabilidade destes compostos, os regulamentos e particularidades de diferentes países, no que diz respeito às estruturas e reembolso dos cuidados médicos, demonstraram diferentes perfis de adesão das populações escolhidas para receber estas armas emergentes contra o sofrimento imposto pela enxaqueca. Esta revisão aborda o uso e as características das terapias biológicas utilizadas no tratamento da enxaqueca.

Uso de belimumabe em paciente com lúpus eritematoso sistêmico refratário ao tratamento convencional: relato de caso / Use of belimumab in a patient with systemic lupus erythematosus refractory to conventional treatment: case report

O lúpus eritematoso sistêmico (LES) é uma doença de caráter imunomediado, ocasionada por fatores hormonais, ambientais e genéticos. Caracteriza-se pela presença de autoanticorpos reativos para diferentes células e tecidos, apresentando manifestações clínicas diversificadas, períodos de exacerbação e remissão, o que dificulta o tratamento desses pacientes. Este relato de caso destaca o progresso do uso de anticorpo monoclonal humano em uma paciente do gênero feminino, diagnosticada com LES em maio de 2019, aos 30 anos, e, por ser refratária ao tratamento medicamentoso convencional, utilizou o tratamento com anticorpo monoclonal humano belimumabe, com início em setembro de 2019. O belimumabe é um anticorpo monoclonal humano que se liga à proteína estimuladora de linfócito B (BLyS) solúvel, inclusive dos autorreativos, e desta maneira, reduz a diferenciação de linfócitos B em plasmócitos, diminuindo os níveis de IgG sérica e dos anticorpos anti-dsDNA, além de melhorar o quadro clínico dos pacientes. Apesar de ser um medicamento biológico de alto custo, diminui drasticamente os sintomas clínicos do LES, possibilitando a redução do uso do corticoide e os efeitos consequentes de seu uso, além de reestabelecer os parâmetros laboratoriais alterados pela doença, sem alteração de indicadores hepáticos e renais. O LES não tem cura, logo, o objetivo do tratamento é diminuir os sintomas e conter as fases ativas da doença.

Systemic lupus erythematosus is an immune-mediated disease caused by hormonal, environmental and genetic factors. It is characterized by the presence of reactive autoantibodies to different cells and tissues, with diverse clinical manifestations and periods of exacerbation and remission, which complicates treatment. This case report highlights progress with the use of a human monoclonal antibody in a woman diagnosed with systemic lupus erythematosus in May 2019 (at age 30). Since she was refractory to conventional drugs, belimumab treatment was begun in September 2019. Belimumab is a human monoclonal antibody that binds to soluble B lymphocyte-stimulating proteins, including self-reactive ones, and reduces the differentiation of B lymphocytes into plasma cells, decreasing the serum IgG and anti-dsDNA antibody levels, in addition to improving patient clinical status. Despite being a high-cost biological drug, it drastically reduces the clinical symptoms of systemic lupus erythematosus, enabling reduced used of corticosteroids and their effects, in addition to reestablishing laboratory parameters altered by the disease, without changing liver and kidney indicators. Since systemic lupus erythematosus has no cure, the goal of treatment is to reduce symptoms and the active phases of the disease.

Reações adversas aos anticorpos monoclonais para doenças alérgicas / Adverse reactions to monoclonal antibodies in allergic diseases

A utilização de agentes imunobiológicos em alergia e imunologia tem sido cada vez mais frequente nos últimos anos, emergindo como potencialmente eficazes para o tratamento de doenças alérgicas e de hipersensibilidade. O uso de imunobiológicos em doenças alérgicas está recomendado nas formas graves onde a eficácia, segurança e custo-efetividade estão comprovados. O objetivo deste artigo é sintetizar os efeitos adversos mais comuns ou significativos, incluindo as reações de hipersensibilidade aos principais anticorpos monoclonais aprovados para o tratamento de doenças alérgicas licenciados e comercializados no Brasil até o momento.

The use of immunobiological agents in allergy and immunology has increased in recent years, emerging as potentially effective strategies to treat allergic and hypersensitivity diseases. The use of immunobiological agents is recommended in the severe forms of allergic diseases, for which their efficacy, safety, and cost-effectiveness have been established. The purpose of this study was to summarize the most common or significant adverse effects, including hypersensitivity reactions to the main monoclonal antibodies approved for the treatment of allergic diseases that are currently licensed and marketed in Brazil.

Development of monoclonal antibodies against prM of Dengue virus 4 / Desenvolvimento de anticorpos monoclonais para prM de Dengue vírus 4

Introduction: dengue is a most common mosquito-borne viral disease in the Americas and tropical countries. Objective: in this work, mice were hyperimmunized with DENV 4 antigen to produce monoclonal antibodies (mAbs). Methodology: DENV 4 (GenBank KC806069) was inoculated in C6/36 cell monolayers cultivated in Leibovitz's 15 medium supplemented with 5% fetal bovine serum and incubated at 28 oC. The virus stock was submitted to concentration and ultracentrifugation and stored at -80 oC until use (VC DENV 4). Balb/c mice were injected intraperitoneally with 50µg of DENV-4 and successive intraperitoneal injections of 25 µg of VCDENV 4 with Freund's incomplete adjuvant were performed. The spleen cells were fused to SP2/0 myeloma cells with PEG 1540 and distributed in 96-well microplates with Iscove's modified medium with Hipoxantina­Aminopterina­Timidina. Hybridoma screening by indirect ELISA showed positive results for six mAbs, and their characterization was performed by Western blotting and Indirect Immunofluorescence (IFI) techniques. Results: the six mAbs showed strong recognition of prM (24/29 kDa), and minor reaction to E protein (66 kDa), E/E protein dimer (105 kDa), and NS1 (49 kDa) protein in two mAbs. The use of mAbs anti-prM as a diagnostic tool using IFI has been demonstrated to detect DENV-4 antigen in infected cells or tissues. Conclusion: DENV 4 generate mAbs with strong reactivity to prM with potential use to confirm the presence of DENV 4 antigen in tissues or infected cells.

Introdução: a dengue é uma doença viral transmitida por mosquitos comumente das Américas e países tropicais. Objetivo: neste trabalho, camundongos foram hiperimunizados com antígeno DENV 4 para produzir anticorpos monoclonais (mAbs). Metodologia: DENV 4 (GenBank KC806069) foi inoculado em monocamadas de células C6 / 36 cultivadas em meio Leibovitz 15 suplementado com 5% de soro fetal bovino e incubadas a 28oC. O estoque viral foi submetido à concentração, ultracentrifugação e armazenado a -80 oC (VC DENV 4). Camundongos Balb / c foram injetados intraperitonealmente com 50 µg de VC DENV-4 e injeções intraperitoneais sucessivas de 25 µg de antigeno com adjuvante incompleto de Freund. As células do baço foram misturadas a células SP2/0 com PEG 1540 e distribuídas em microplacas de 96 poços com meio Iscove Modificado em presença de Hipoxantina ­ Aminopterina ­ Timidina. A triagem de hibridomas por ELISA indireto apresentou resultados positivos para seis mAbs, e sua caracterização foi realizada por técnicas de Western blotting e Imunofluorescência Indireta (IFI). Resultados: os seis mAbs mostraram forte reconhecimento de prM (24/29 kDa) e reação menor à proteína E (66 kDa), dímero de proteína E / E (105 kDa) e proteína NS1 (49 kDa) em dois mAbs. O uso de mAbs anti-prM como uma ferramenta de diagnóstico utilizando IFI demonstrou eficacia em detectar o antígeno DENV-4 em células ou tecidos infectados. Conclusão: o mAbs produzidos para DENV 4 demonstraram uma forte reatividade contra prM, e poderiam ser uma ferramenta de uso potencial no diagnóstico de DENV 4 .

César Milstein / César Milstein

Resumen El presente comentario, escrito en virtud del decreto del gobierno nacional que designó a 2021 como año de homenaje al Dr. César Milstein, es una visión personal sobre el significado del desarrollo de los anticuerpos monoclonales, del aporte que brindó y brinda a la ciencia y tecnología actual y del contexto del correspondiente Premio Nobel en el ámbito de la Inmunología y las Ciencias Médicas. El objetivo de este artículo es transmitir, a modo de homenaje, algunas de mis experiencias en la especialidad y la relación profesional y personal con el creador de la producción de anticuerpos monoclonales por fusión de células somáticas, tecnología que continúa realizando grandes aportes al conocimiento.

Abstract The present commentary, which was written by virtue of the national government decree that designated 2021 as the year of the tribute to Dr. César Milstein, is a personal vision of the meaning of the development of monoclonal antibodies, of the contribution that he has always made to the current science and technology, and of the context of the corresponding Nobel Prize within the sphere of Immunology and the Medical Sciences. The aim of this article is to share, as a tribute, some of my experiences in the specialty and my professional and personal relationship with the creator of the immense breakthrough still being delivered by his development.

Resumo O presente comentário, escrito em virtude do decreto do governo nacional que nomeou o ano 2021 como ano de homenagem ao Dr. César Milstein, é uma visão pessoal sobre o significado do desenvolvimento dos anticorpos monoclonais, da contribuição que ofereceu e oferece à ciência e tecnologia atual e do contexto do correspondente Prêmio Nobel no âmbito da Imunologia e das Ciências Médicas. O objetivo deste artigo é transmitir, à maneira de homenagem, algumas das minhas experiências na especialidade e na relação profissional e pessoal com o criador do imenso avanço que continua nos oferecendo seu descobrimento.

Infecções graves por SARS-CoV-2 com uso de tocilizumabe / Severe infections by SARS-CoV-2 with the use of tocilizumab

O SARS-CoV-2 é causador da doença infecciosa COVID-19. A infecção estimula o sistema imunológico a produzir citocinas próinflamatórias. A principal citocina envolvida é a IL-6, e está ligada à gravidade da doença. Devido à associação dos altos níveis de IL-6 com a mortalidade na COVID-19, investiga-se sobre o uso de tocilizumabe (TCZ), um anticorpo monoclonal humanizado antirreceptor de IL-6 humana. O objetivo desta revisão sistemática é avaliar a eficácia do uso do TCZ em pacientes com COVID-19 grave. As buscas foram feitas através das bases de dados Science Direct e PubMed em setembro de 2021. Foram incluídos os ensaios clínicos randomizados com pacientes em um único estágio de COVID-19, casos graves e sem restrição de idade, os quais receberam o TCZ como medicação de intervenção combinado a tratamentos protocolados por cada hospital e associado a corticosteroides. A análise desses estudos demonstrou resultados significantes sobre o uso de TCZ em casos severos de COVID-19. O uso de TCZ associado a glicocorticoides levou a uma redução no índice de mortalidade e de submissão a ventilações mecânicas e a uma melhora expressiva em relação à escala "WHO-endorsed 7-point ordinal scale". Entretanto, não houve melhora relevante quanto ao uso do TCZ de maneira isolada.

SARS-CoV-2 causes the COVID-19 infectious disease that affects the respiratory tract. From the beginning of the infection, the immune system starts to produce pro-inflammatory cytokines and chemokines. The main cytokine involved is IL-6 and is linked to the severity and prognosis of the disease, as it provokes a storm of cytokines and severe inflammatory responses. Due to the association of high levels of IL-6 with severity and mortality in COVID-19, the use of Tocilizumab (TCZ), a humanized anti-human IL-6 receptor monoclonal antibody, which binds to IL receptors, is being investigated. -6 and blocks intracellular signaling reducing cytokine storm and hyperinflammatory state. The aim of this review is to assess the effectiveness of using TCZ in the treatment of patients with severe COVID-19. Searches were performed using the Science Direct and PubMed databases in May 2021. Randomized clinical trials with patients in a single stage of COVID­19, severe cases and without age restriction, who received TCZ as medication for treatment, were included. Intervention was combined with treatments protocoled by each hospital and associated with corticosteroids. The analysis of these studies showed significant results regarding the use of TCZ in severe cases of COVID-19. The use of TCZ associated with glucocorticoids led to a reduction in the rate of mortality and compliance with mechanical ventilation and a significant improvement in relation to the "WHO-endorsed 7-point ordinal scale". However, there was no evidence of relevant improvement when using TCZ alone.

Anemia hemolítica autoimune na doença de Castleman multicêntrica: relato de caso / Autoimmune hemolytic anemia in multicentric Castleman's disease: case report

A doença de Castleman é um distúrbio linfoproliferativo raro, podendo se manifestar sob a forma de massas localizadas ou como doença multicêntrica. A doença de Castleman multicêntrica é caracterizada por adenopatias generalizadas, visceromegalias, manifestações autoimunes e infecções recorrentes. Este artigo apresenta o relato de caso de anemia hemolítica autoimune por anticorpos quentes em paciente com doença de Castleman multicêntrica. Resposta eficaz foi obtida com uso de corticoterapia sistêmica e tocilizumabe.

Castleman disease is a rare lymphoproliferative disorder that can manifest as localized masses or as multicentric disease. Multicentric Castleman disease is characterized by generalized adenopathies, visceromegaly, autoimmune manifestations, and recurrent infections. This article presents the case report of a patient with multicentric Castleman's disease and autoimmune hemolytic anemia by warm antibodies. Effective response was obtained with systemic corticotherapy and tocilizumab.