Efficacy and Safety of Cytotect®CP, Hyperimmune Anti-CMV IVIg as CMV Prophylaxis in Patients Developing Acute Grade II-IV GVHD After Allogeneic Hematopoietic Cell Transplantation: A Prospective, Open-label, Phase II Study

Many risk factors are known to be associated with high risk of developing CMV infection in positive CMV-serostatus patients: negative CMV-serostatus donor, unrelated or mismatched donor, use of antithymocyte globulin (ATG), and development of GVHD. Acute GVHD occurs during the first hundred days after transplantation. In spite of systematic GVHD prophylactic using immunosuppressive agents, approximately 50% of transplantation recipients develop GVHD. The first-line treatment of acute GVHD is methylprednisolone 2 mg/kg/day. Probably because of the use corticosteroids but also due to the GVHD itself, approximately 46% of CMV seropositive patients develop CMV infection (report from the national database of the SFGM-TC, data unpublished yet).
CMV infection leads to longer duration of hospitalization and increases the risk of mortality, particularly in cases of CMV disease. Available antiviral agents used to prevent CMV infections are generally reputed to cause significant side effects. These agents can prevent full immunological post-transplant reconstitution and cause profound cytopenia. Some agents may be responsible for renal impairment, which prevents continuation of immunosuppressive treatment; this is especially the case with calcineurin inhibitors in allo-HCT patients. Indeed, compared to placebo, intravenous ganciclovir has been shown to reduce the risk of CMV infection and disease, although it did not appear to improve overall survival. However, it was responsible for 30% of cases of severe neutropenia in allo-HCT patients, increasing the risk of bacterial and fungal coinfections. CMV infection treatment is commonly based on ganciclovir and foscavir and, to a lesser extent, on other drugs, including cidofovir. However, these drugs cause high levels of toxicity, resulting in myelotoxicity in the case of ganciclovir, or, in the case of foscavir and cidofovir, potential renal failure, incurring treatment discontinuation.
CMV prophylaxis using drugs with fewer side-effects is necessary in patients at high risk of CMV infection.
With its safety profile, Cytotect®CP offers an alternative option for CMV prophylaxis with avoidance of renal and bone marrow impairment.
Considering the high risk of developing CMV infection, we decided to investigate the efficacy and safety of Cytotect®CP in patients requiring systematic corticosteroids (≥ 1 mg/kg/day) for an initial episode of grade II-IV acute GVHD following a first allo-HCT.

开始日期2022-09-13

申办/合作机构

Centre Hospitalier Universitaire de Lille

[+1]

NCT04934527

/ Completed临床2期

Evaluating a Therapeutic Association Between CMV-specific Immunoglobulin Infusion and Pre-transplant CD16-expressing Gamma Delta Vdelta 2 Negative T-cells in CMV-positive Patients for Preventive Treatment of CMV Infection in Renal Transplantation

CMV infection in transplantation remains the most frequent infectious complication causing increased morbidity and mortality. International recommendations advocate prevention of this infection by instituting direct antiviral treatment or monitoring viral replication by PCR with the start of curative antiviral treatment when the DNAemia is positive.
The risk of CMV infection varies according to the serostatus of the donor (D) and recipient (R) at the time of transplantation. In the absence of prophylaxis, CMV infection occurs in 60-80% of D+R-, 50-60% of D+R+ and 25-50% of D-R+.
The humoral anti-CMV response is represented by the production of antibodies to envelope proteins (gB and gH) and to molecules involved in viral attachment and entry into target cells. However, the majority of CMV-specific antibodies do not have antiviral neutralising activity. The investigators have identified a new player in the specific anti-CMV response expressing the Fc RIIIa receptor (CD16), that interacts with anti-CMV immunoglobulins (Ig): the Tgamma-delta V delta 2-negative lymphocyte (LTgdVd2neg). This lymphocyte subpopulation shows persistent expansion in the peripheral blood of kidney transplant patients with CMV infection. These cells express an effector-memory phenotype (CD45RA+/CD27-). This expansion is associated with resolution of infection in patients. The investigators have shown that CD16 is specifically and constitutively expressed on the surface of CMV-induced LTgdVd2neg in healthy volunteers and kidney transplant patients. The investigators have observed that one of the antiviral activities of anti-CMV IgG lies in its binding to the Fc RIIIa receptor (CD16) on the surface of LTgdVd2neg. The anti-CMV IgGs capturing virions thus activate CD16+ LTgdVd2neg with production of IFN interferon which in turn is responsible for inhibition of CMV viral multiplication.
Anti-CMV IgG is a recommended therapeutic option, with a marketing authorisation for the prevention of CMV infection in kidney transplantation in Europe and a Temporary Authorisation for Use in France.
Thus, R+ patients expressing a significant level of LTgdVd2neg CD16+ at D0 of transplantation could be protected against CMV, in the absence of direct antiviral treatment by the addition of anti-CMV Ig.

开始日期2021-11-17

申办/合作机构

Biotest AG

NCT05170269

/ Terminated临床3期

Prevention of Maternal-fetal Cytomegalovirus Transmission After Primary Maternal Infection With Gestational Age ≤ 14 Weeks - an Open-label, Single-arm, Prospective Trial Investigating Efficacy and Safety of Cytotect CP Biotest

A phase 3, open-label, single-arm, prospective, multi-center trial of Cytotect CP Biotest (BT097) for prevention of maternal-fetal CMV transmission after primary maternal CMV infection. The main purpose of the trial is to demonstrate efficacy and safety of Cytotect CP Biotest in preventing maternal-fetal transmission of cytomegalovirus (CMV).

开始日期2021-11-17

申办/合作机构

Biotest AG

100 项与 Cytomegalovirus immune globulin (Biotest) 相关的临床结果

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项与 Cytomegalovirus immune globulin (Biotest) 相关的文献（医药）

2023-08-01·Antiviral research

New therapeutic perspective in the prevention of congenital cytomegalovirus infection

Article

作者: Hantz, Sébastien ; Berto, Laurie ; Coste Mazeau, Perrine ; Andouard, Déborah ; Alain, Sophie ; Chianea, Thierry ; El Hamel, Chahrazed

INTRODUCTION:

Hyperimmune globulin Cytotect CP® is a candidate for cytomegalovirus congenital infection prevention. We previously demonstrated its efficacy to prevent villi infection in our first-trimester placenta explants up to day 7, but with an inefficiency at day 14 (Coste-Mazeau et al., Microorganisms, 2021). As this could impact clinical efficacy, we now study the effect of weekly administration of Cytotect CP® on the prevention of villi infection.

METHODS:

Human embryonic lung fibroblast cells were infected at confluence with the endothelial strain TB40/E. Placentae were collected from voluntary pregnancy terminations (8-14 weeks of gestation) from cytomegalovirus-seronegative women. After 5 days of infection of the cells, villi explants were simultaneously added on sponges with Cytotect CP® at various concentrations. After 7 days, Cytotect CP® was renewed in only half of the plates. Villi were collected at days 7 and 14 with or without medium renewal. We compared the viral load by duplex quantitative PCR cytomegalovirus/albumin and the toxicity by measuring β-hCG concentrations in the supernatants with and without medium renewal.

RESULTS:

We did not find any efficacy of Cytotect CP® at day 14 when Cytotect CP® is not renewed, but a regular decrease of the viral load when the immunoglobulins were renewed at day 7, with an EC50 = 0.52 U/mL. We did not observed toxicity of Cytotect CP® with or without renewal of the molecule.

CONCLUSION:

Cytotect CP® is more effective when renewed at day 7. The prevention of congenital cytomegalovirus infection could be enhanced by reducing the spacing of doses.

2021-01-01·Fetal diagnosis and therapy3区 · 医学

Serial Monitoring and Hyperimmunoglobulin versus Standard of Care to Prevent Congenital Cytomegalovirus Infection: A Phase III Randomized Trial

3区 · 医学

Article

作者: Devlieger, Roland ; Jückstock, Julia ; Rippel, Natascha ; Wartenberg-Demand, Andrea ; Enders, Martin ; Herbold, Marlis ; Friese, Klaus ; Schütze, Joachim ; Buxmann, Horst ; Siklós, Pal ; Nigro, Giovanni ; Niemann, Gabriele ; Schüttrumpf, Jörg

Introduction: Nonrandomized studies support the potential of cytomegalovirus hyperimmunoglobulin (CMV-HyperIg) in preventing maternofetal CMV transmission, but prospective interventional studies show equivocal results. We present a prospective phase-III international randomized open-label trial on the potential effect of CMV-HyperIg following serial monitoring of CMV serostatus. Methods: CMV-seronegative pregnant women (gestational age [GA] <14 weeks) were 1:1 randomized to monthly CMV-serostatus monitoring and CMV-HyperIg upon seroconversion (treatment), or routine prenatal care with CMV-serostatus testing at end of pregnancy (control). Ethical considerations required that control subjects with confirmed seroconversion be offered Cytotect®. The primary endpoint was the proportion of fetuses/newborns with congenital CMV infection. Secondary endpoints included neonatal CMV disease and safety during the 24-month follow-up. Results: The treatment arm counted 4,800 randomized subjects: 52 seroconverted (median GA 24 [11–35] weeks), of which 45 completed follow-up. The control arm counted 4,735 randomized subjects: 42 seroconverted, of which 34 completed follow-up (evaluable data for 28 newborns) and 8 subjects chose off-label Cytotect®. Congenital CMV rates were 13/28 newborns (46.4% [CI 27.51; 66.13]) vs. 16/45 newborns (35.6% [CI 21.87; 51.22]) in control and treated arms, respectively (p = 0.46). Newborn CMV disease was mostly mild and spontaneously resolving. There were no major safety concerns. The target sample was not reached within an acceptable time frame. Conclusions: Serial monitoring of CMV serostatus with CMV-HyperIg treatment was associated with a mild nonsignificant reduction in the vertical CMV transmission rate. Studies on the optimal preventive strategy are hampered by epidemiological and ethical challenges and should focus on GA-dependent transmission rates and accurate dating of infection.

2020-04-01·JOURNAL OF HEART AND LUNG TRANSPLANTATION

Utilization of PHS Increased Risk for Transmission of Infectious Disease Donor Organs in Lung Transplantation: One Center's 7-year Experience

Article

作者: Villavicencio, M ; Irwin, L ; Basler, D ; Palafox, J ; Astor, T ; McEnery, C ; Delgado, O

PURPOSE:

Over the past several years 37 to 41% of all deceased donor organs in Region 1 were designated as Public Health Service increased risk for infectious disease transmission compared to 25-27% nationally. Limited by the number of standard donors our Center sought to develop guidelines for utilizing these donors and implement a system for follow-up testing for disease transmission. We reviewed our single-center 7-year experience utilizing PHS donor organs in our lung transplant program.

METHODS:

Our Center developed a protocol based on the PHS Guidelines to guide the lung transplant program in the management of recipients. Transplant recipients of PHS donor organs had blood testing (serology and viral load) for HIV, HBV and HCV performed on the day of transplant; 1-3 months and 6-12 months after transplant. A QAPI project was implemented to ensure medical record documentation and follow-up testing was conducted.

RESULTS:

From 2013 to October 2019 there were 66 lung transplants performed from PHS donor organs. A retrospective analysis revealed one false positive HIV antibody test; and 15 recipients (23%) converted their HBV core antibody from negative to positive at the 1-3 month time frame after surgery. Of the 15, 11 converted back to HBV core antibody negative within a year after transplant; 2 patients did not have testing performed/expired; and 2 patients were still within the first year after surgery and remained HBV core antibody positive. Although the etiology of the conversion remains unclear it was attributed to the administration of cytomegalovirus immune globulin in the recipients. Of note, 8 of the 66 PHS organs (12%) were also HCV positive and were transplanted under an IRB protocol. The recipients of HCV NAT positive donor organs were started on direct acting anti-viral agents. All of these patients remained HCV viral load negative after transplant. In addition to these donors, there was one HCV antibody/NAT positive donor organ that did not meet PHS criteria that was tracked and the recipient was HCV viral load negative after transplant.

CONCLUSION:

Our Center experience suggests that there is limited risk to using PHS donor organs in lung transplantation. Special considerations may be warranted in tracking recipients of HCV positive donor organs that may not meet PHS donor organ criteria.

项与 Cytomegalovirus immune globulin (Biotest) 相关的新闻（医药）

2023-05-20

·生物制品圈

静注巨细胞病毒人免疫球蛋白（pH4）体外药效学研究

中文摘要目的实验室确认静注巨细胞病毒人免疫球蛋白（pH4）（human cytomegalovirus immunoglobulin for intravenous injection，CMV-IVIG）抑制巨细胞病毒（cytomegalovirus，CMV）感染的有效性。方法分别通过免疫荧光染色和细胞病变实验测定CMV-IVIG抑制CMV的即早基因1表达和致细胞病变能力，确认CMV-IVIG有效性。结果即早基因1表达量与病变细胞数量随着制品稀释倍数的增加而增加；27倍稀释的CMV-IVIG可抑制90.77%~95.85%的CMV感染力；103倍稀释的CMV-IVIG可抑制＞90%的细胞病变。结论 CMV-IVIG中的中和抗体能特异性中和CMV，阻止CMV感染细胞，且具有良好的量效关系。正文巨细胞病毒（cytomegalovirus，CMV）是疱疹病毒科β属的DNA病毒[1]，在发展中国家成年人中感染率可达100%[2]。虽然通常呈隐性感染，但当机体免疫功能低下时，病毒可被激活而发生显性感染[3]。孕妇初次或复发CMV感染引起新生儿宫内感染或围产期感染侵袭胎儿，是导致先天畸形的重要原因之一[4]。目前尚无治疗CMV感染疾病的特效药物，由于抗CMV抗体可以保护特定人群抵抗CMV感染疾病[5-9]，因此，目前使用抗病毒药物或联合抗病毒药物和静注巨细胞病毒人免疫球蛋白（human CMV immunoglobulin for intravenous injection，CMV-IVIG）（pH4）预防和治疗 CMV感染疾病[10]。成都蓉生药业有限责任公司（成都蓉生）研制的CMV-IVIG（pH4）系从健康人血浆中筛选含高效价CMV中和抗体（CMV neutralizing antibody，CMV-NA）的血浆，采用成都蓉生分离工艺和成品配方，经两步病毒灭活（低pH孵放和纳米膜过滤）制备的特异性CMV-IVIG冻干制剂，供静脉输注。输注后可迅速提高患者血浆中CMV-NA水平，理论上可通过CMV-NA与CMV中的抗原结合，阻止病毒侵入健康细胞并清除CMV，起到预防和治疗CMV感染及相关性疾病的作用。由于人CMV种属特异性高，难以建立动物模型，因此本品未能做动物实验以验证其药效，只能选择体外药效实验，而离体人源组织和器官珍贵难觅，且涉及伦理规范，我们选择用正规商业来源的敏感人源细胞进行了药效学实验研究。CMV基因组复制缓慢，基因表达具有严格的时相性。即早基因（immediate early gene，IE）1在感染后3 h开始在细胞核中表达，6 h后即可被检出；而CMV晚期基因的转录和翻译发生在感染后的36~48 h[11]。因此，采用免疫组织化学法可使感染CMV的细胞核特异性着色。1材料与方法1.1材料1.1.1 实验样品成都蓉生研制的6批CMV-IVIG（pH4）：V002、V003、V004、V005、V006、V007为2种规格，浓度相同，装量不同，其中V002、V004、V006 为20 000 U（25 ml）/瓶，V003、V005、V007为40 000 U（50 ml）/瓶，制品的纯度分别为98.3%、98.1%、98.3%、98.4%、98.2%、98.4%；分子大小分布分别为99.2%、99.2%、99.1%、99.2%、99.1%、99.1%。复溶后用维持液（含2%胎牛血清的MEM培养基）根据不同实验特点稀释成不同稀释倍数（IE1表达量抑制实验样品：128、256、512······4 096倍；细胞病变实验样品：1 000、1 050、1 100······1 350倍）溶液待用。1.1.2 细胞和病毒株 MRC-5人胚肺成纤维细胞、CMV均购自美国典型培养物保藏中心。1.1.3 主要试剂 MEM基础培养基购自美国Life Technologies公司，胎牛血清购自浙江天杭生物科技股份有限公司，生物素化抗鼠IgG购自美国Jackson ImmunoResearch公司，亲和素化链霉抗生物素蛋白和TrueBlue显色剂购自美国KPL公司，抗CMV IE1单克隆抗体购自美国Merck Millipore公司。1.1.4 主要设备 BSC-1500Ⅱ A2-X生物安全柜购自济南鑫贝西生物技术有限公司，XDS-1B倒置显微镜购自重庆光电仪器有限公司，GL-99T Ⅰ型体视显微镜购自桂林桂光仪器有限公司。1.2方法1.2.1 IE1表达量抑制实验 CMV-IVIG与中和用CMV等量混和，每个浓度样品2个复孔，37 °C、5%CO2中和1 h。然后加入MRC-5细胞于37 ℃、5%CO2培养16~18 h。同时设阳性对照（维持液代替CMV-IVIG）和阴性对照（维持液代替CMV-IVIG和病毒）。经过细胞固定、封闭及加抗CMV IE1单克隆抗体、生物素化抗鼠IgG、亲和素化链霉抗生物素蛋白，最后显色。显色后在体视显微镜下采集各孔图像，用克隆计数软件计数每孔的特异性着色细胞核。降低感染力程度（％）=100－样品孔平均核着色个数÷病毒孔平均核着色个数×1001.2.2 细胞病变实验 CMV-IVIG与同体积的CMV于37 ℃、5%CO2中和1 h后，加入 MRC-5细胞于37 ℃、5%CO2培养48 h，设阳性对照（维持液代替CMV-IVIG）和阴性对照（维持液代替CMV-IVIG和病毒），在倒置生物显微镜下观察MRC-5细胞的致细胞病变程度，记录观察结果。2结果2.1IE1表达量抑制实验结果同体积的不同稀释倍数CMV-IVIG在加入相同量的CMV后，残留病毒数不同，残留病毒感染细胞后在细胞核内表达的IE1数量也不同，经染色后计数结果也不同。稀释倍数越高，特异性着色的细胞核越多，即IE1表达越多，见图1。随着CMV-IVIG稀释倍数的增加，降低病毒感染力的程度减小，病毒感染力增强（IE1表达越多）。在128倍稀释度时，能降低约93%的病毒感染力，而在4 096倍稀释度时50%样品降低病毒感染力的能力已降到0，见表1。2.2细胞病变实验结果同体积的不同稀释倍数的CMV-IVIG能中和的同体积病毒液中的病毒数不同，残存的病毒导致的MRC-5细胞病变的范围程度也不同。随着CMV-IVIG稀释程度的增加，相同体积样品内含有的CMV-NA量也减少，而致细胞病变的程度增加，说明CMV-NA能特异性有效阻止CMV感染细胞，避免细胞发生病变（图2、3）。3讨论目前全球仅有CytoGam®和Cytotect®品牌的CMV-IVIG应用于欧美市场，且已上市多年，国内至今仍无同类产品上市。为了在实验室确认成都蓉生研制的CMV-IVIG产品对CMV的有效性，我们用CMV敏感的MRC-5细胞开展了本研究。从两方面进行试验设计：（1）CMV感染MRC-5细胞数小时后会在细胞核内大量表达IE1，通过组织化学染色使病毒感染的细胞核出现特异性着色现象，且1个着色细胞核代表1个感染并表达IE1细胞[12]。将系列稀释的CMV-IVIG分别与CMV悬液混和，再感染MRC-5细胞。感染细胞培养后，通过对感染细胞中的染色颗粒的计数测定中和后的残留病毒IE1的表达能力。（2）CMV感染MRC-5细胞，在细胞内的繁殖过程引起细胞肿胀变形，由细长梭形变为球形（巨细胞），即细胞病变。将系列稀释的CMV-IVIG分别与CMV悬液混和，然后感染MRC-5细胞。感染后的细胞经过培养，在倒置显微镜下观察残余病毒引起的致细胞病变程度。IE1表达量抑制实验结果中，随着CMV-IVIG稀释倍数的增加，相同体积样品内含有的CMV-NA量也减少，IE1表达越多，即病毒感染力越强，CMV-IVIG 能降低病毒感染力的程度越小，在128倍稀释时，杀灭了绝大部分病毒（平均93%），而在4 096倍稀释时50%样品已无降低病毒感染力能力（IE1表达与阳性对照一致）。细胞病变实验结果显示，随着制品稀释程度的增加，致细胞病变的程度也在增加，说明CMV-NA能特异性有效阻止CMV感染细胞，避免细胞发生病变。成都蓉生研制的CMV-IVIG标示效价单位为可以直接有效中和活病毒的中和抗体效价单位，而非对应病毒抗原片段的抗体总量。我们的体外药效学研究结果显示：产品所含有的特异性中和抗体能有效中和病毒，阻止CMV感染细胞；中和病毒的能力与CMV-IVIG中的中和抗体含量呈正相关，具有良好的量效关系。基于上述结果，该产品应具有相应的临床药效。作者刘波1 吴强2 张航3 李小姣3 李伟4 杨春4 吴佳君5 秦婷婷51成都蓉生药业有限责任公司质量检定部，成都 610219；2成都蓉生药业有限责任公司生产管理部，成都 610219；3北京天坛生物制品股份有限公司科研管理部，北京 100024；4成都蓉生药业有限责任公司血液制品研发部，成都 610219；5成都蓉生药业有限责任公司科研质量部，成都 610219通信作者：秦婷婷，Email：1590825@qq.com引用本文：刘波, 吴强, 张航, 等. 静注巨细胞病毒人免疫球蛋白（pH4）体外药效学研究 [J]. 国际生物制品学杂志, 2023, 46(2): 61-64. DOI: 10.3760/cma.j.cn311962-20220628-00036

临床结果

100 项与 Cytomegalovirus immune globulin (Biotest) 相关的药物交易

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适应症	最高研发状态	国家/地区	公司	日期
妊娠期感染性疾病	临床3期	德国	Biotest AG	2021-11-17
巨细胞病毒感染	临床3期	奥地利	Biotest AG	2008-07-09
巨细胞病毒感染	临床3期	比利时	Biotest AG	2008-07-09
巨细胞病毒感染	临床3期	匈牙利	Biotest AG	2008-07-09
急性移植物抗宿主病	临床2期	法国	Biotest AG	2022-09-13

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研究	分期	人群特征	评价人数	分组	结果	评价	发布日期


P405 (EBMT2023)	N/A	巨细胞病毒感染	61	Cytotect	獵醖遞獵遞獵齋獵衊衊(繭糧醖鬱襯簾簾淵膚醖) = Cytotect was safe and well tolerated - no significant adverse events were recorded 憲簾憲觸衊齋製窪獵膚 (獵窪範夢壓範獵遞選膚 )	积极	2023-04-23
P531 (EBMT2018)	N/A	血液肿瘤 CMV copies	294	Megalotect	選選艱窪鑰窪齋繭鑰糧(繭膚襯鹽願膚選衊鹽顧) = 壓簾蓋觸齋顧蓋憲觸醖襯鬱齋餘糧衊襯築網積 (醖齋醖鹽艱構觸鏇憲積 ) 更多	积极	2018-11-19
P531 (EBMT2018)	N/A	血液肿瘤 CMV copies	294	Foscarnet	壓繭廠積簾觸構觸遞觸(顧獵憲鹽範鏇廠範構衊) = 衊築築繭夢廠選膚窪鑰襯鏇鹽遞網淵齋積衊積 (膚願壓窪範艱遞糧顧遞 )	积极	2018-11-19