A Phase III, Multicenter, Open-Label Study to Evaluate the Efficacy, Safety, Pharmacokinetics, and Pharmacodynamics of Emicizumab Prophylaxis in Patients With Type 3 Von Willebrand Disease

This is a Phase III, multicenter, open-label clinical study designed to evaluate the efficacy, safety, pharmacokinetics, and pharmacodynamics of emicizumab prophylaxis in participants aged 2 years and above, who have been diagnosed with Type 3 von Willebrand disease (VWD). Participants on prior standard of care (SOC) on-demand therapy will be assessed via a randomized comparison (Arm A - emicizumab prophylaxis and Arm B - continuation of SOC on-demand therapy), while participants on prior SOC prophylactic therapy (Arm C - emicizumab prophylaxis) will be assessed via intra-participant analysis with data obtained from the preceding non-interventional study (NIS), WP45335 (NCT06883240).

开始日期2025-06-15

申办/合作机构

Hoffmann-La Roche Ltd.

CTRI/2024/08/071826

/ Recruiting临床4期IIT

Outcome of Emicizumab Prophylaxis in Patients of Haemophilia A with or without Inhibitor An Early Experience from A Tertiary Care Hospital From Eastern India - NIL

开始日期2024-08-15

申办/合作机构-

NCT05248594

/ RecruitingN/AIIT

Real World Use of Emicizumab in Infants and Children Ages 0-3 Years With Hemophilia A

We have developed a questionnaire to elucidate the dosing, frequency and indication for the use of emicizumab in patients with Hemophilia A (mild, moderate or severe) ages 0-3 years. We are also collecting data on any pre-, peri and post surgical practices while on emicizumab. More importantly, we are asking if pediatricians are planning to introduce factor 8 to children who are already on emicizumab for primary prophylaxis as well as how and when they are planning to do so. We hope that this data will help inform understanding of current use of emicizumab in infants and young children as a form of primary prophylaxis, especially when venous access has historically been a limiting factor.

开始日期2024-08-01

申办/合作机构

Montefiore Medical Center

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100 项与艾美赛珠单抗相关的临床结果

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100 项与艾美赛珠单抗相关的转化医学

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100 项与艾美赛珠单抗相关的专利（医药）

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678

项与艾美赛珠单抗相关的文献（医药）

2025-12-31·JOURNAL OF MEDICAL ECONOMICS

Systematic review of cost-effectiveness modelling studies for haemophilia

Review

作者: Meier, Niklaus ; Ammann, Daniel ; Schwenkglenks, Matthias ; Probst, Jano ; Pletscher, Mark

AIMS:

Haemophilia is a rare genetic disease that hinders blood clotting. We aimed to review model-based cost-effectiveness analyses (CEAs) of haemophilia treatments, describe the sources of clinical evidence used by these CEAs, summarize the reported cost-effectiveness of different treatment strategies, and assess the quality and risk of bias.

METHODS:

We conducted a systematic literature review of model-based CEAs of haemophilia treatments by searching databases, the Tufts Medical Center CEA registry, and grey literature. We summarized and qualitatively synthesized the approaches and results of the included CEAs, without a meta-analysis due the diversity of the studies.

RESULTS:

32 eligible studies were performed in 12 countries and reported 53 pairwise comparisons. Most studies analysed patients with haemophilia A rather than haemophilia B. Comparisons of prophylactic versus on-demand treatment indicated that prophylaxis may not be cost-effective, but there was no clear consensus. Emicizumab was generally cost-effective compared with clotting factor treatments and was always dominant for patients with inhibitors. Immune tolerance induction following a Malmö protocol was found to be cost-effective compared to bypassing agents, while there was no consensus for the other protocols. Gene therapies as well as treatment with extended half-life coagulation factors were always cost-effective over their comparators. Studies were highly heterogenous regarding their time horizons, model structures, the inclusion of bleeding-related mortality and quality-of-life impacts. This heterogeneity limited the comparability of the studies. 19 of the 32 included studies received industry funding, which may have biased their results.

LIMITATIONS:

It was not possible to perform a quantitative synthesis of the results due to the heterogeneity of the underlying studies.

CONCLUSION:

Differences in results between previous CEAs may have been driven by heterogeneity in modelling approaches, clinical input data, and potential funding biases. A more consistent evidence base and modelling approach would enhance the comparability between CEAs.

2025-07-01·THROMBOSIS RESEARCH

In vitro effects of Mim8 and combined Mim8-bypassing therapy on thrombin generation, thromboelastography and fibrin clot ultrastructure

Article

作者: Dargaud, G Yesim ; Nougier, Christophe ; Lund, Jacob ; Josset, Laurie ; Rezigue, Hamdi

INTRODUCTION:

Mim8, a fully human bispecific IgG4 antibody, FVIIIa mimetic, which emerges as a promising prophylactic treatment option for patients with hemophilia A (HA).

AIM:

This study investigates the in vitro hemostatic activity of Mim8 in blood samples from six patients with severe hemophilia A using a thrombin generation assay (TGA) and thromboelastography. The results were compared to those obtained with emicizumab.

MATERIALS AND METHODS:

TG was assessed in both platelet-poor (PPP) and platelet-rich plasma (PRP). Fibrin clots formed during TG were collected, and clot ultrastructure was examined using scanning electron microscopy (SEM). Whole blood samples were analyzed using ROTEM-NATEM.

RESULTS:

Mim8 significantly improved the TG capacity of severe HA plasma samples. Mim8 6 μg/mL demonstrated higher TG capacity compared to emicizumab 50 μg/mL. In PRP samples fortified with Mim8 6 μg/mL and rFVIIa 90 μg/kg together, ETP levels were fully normalized. No synergistic effect was observed when FVIII concentrate was combined with Mim8 at therapeutic doses due to the higher affinity of FVIII for FIXa and FX compared to Mim8. ROTEM-NATEM in whole blood confirmed the TGA results. SEM showed a more robust fibrin clot structure with thinner fibrin fibers in the presence of Mim8 compared to emicizumab.

CONCLUSIONS:

Mim8 significantly improves TG in vitro in both PPP and PRP from patients with severe HA, with ETP levels comparable to those of FVIII at 100 IU/dL. The TGA can effectively monitor the combined treatment with Mim8 and either rFVIIa or APCC, which is not possible with currently available routine laboratory tests.

2025-06-01·JOURNAL OF PHARMACOKINETICS AND PHARMACODYNAMICS

Diffusion dimensionality modeling of subcutaneous/intramuscular absorption of antibodies and long-acting injectables

Article

作者: Ramanathan, Murali ; Krzyzanski, Wojciech

To evaluate the role of diffusion process dimensionality in drug absorption following subcutaneous or intramuscular administration. The diffusion dimensionality model is based on analytical solutions of the 1-, 2- or 3-dimensional diffusion equations for a bolus input linked to a central compartment with first-order elimination. The model equations were reparameterized to contain three parameters for the time needed for the drug diffusion from the administration site, drug absorption into the central compartment, and the elimination rate constant. The diffusion dimensionality models were challenged with previously published subcutaneous absorption data for 13 antibody drugs and insulin lispro, and the long-acting injectable antipsychotic drugs: subcutaneous Perseris™, intramuscular Invega Sustenna®, Risperdal Consta®, and olanzapine. The Bayesian information criterion was used for model selection. The solution to the diffusion equation for a bolus dose administration is strongly dependent on the number of dimensions. The maximal concentration is lowest for the 3-dimensional diffusion equation. The pharmacokinetic profiles of all 13 antibodies were satisfactorily approximated by a diffusion dimensionality model. Three antibodies (CNTO5825, ACE910 and ustekinumab) were best described by the 2-dimensional diffusion equation. The 2- and 3-dimensional diffusion equations were equivalent for ABT981, guselkumab, adalimumab, nemolizumab, omalizumab, and secukinumab. Golimumab, DX2930, AMG139, and mepolizumab were best described by the 3-dimensional diffusion equation. All the long-acting antipsychotic dosage forms except Risperdal Consta were modeled satisfactorily. Diffusion dimensionality models are a parsimonious and effective approach for modeling drug absorption profiles of subcutaneously and intramuscularly administered small molecule and protein drugs and their dosage forms.

428

项与艾美赛珠单抗相关的新闻（医药）

2025-06-12

·同写意

连环画：双特异性抗体

同写意年度巨献！！7月25-26日，邀您相聚金鸡湖畔，与5000人一起为中国医药创新“同写意”！1、双特异性或双靶点药物的崛起应和了如今药物研发的最大困境：小分子药和蛋白药的药物靶点不够用了。2006年时统计的已获批药物共针对324个药靶。2017年，已获批药物的药靶数量扩展到893个，其中667个是人蛋白。假设传统药物（不包括核酸药和细胞治疗）可开发的药靶共有1000个，所有生物技术和制药公司的共同竞争空间则受到极大的禁锢。但如果考虑双靶点药物的话，药靶空间（双药靶的随机组合数）增长了500倍。图片来源：参考资料132、双特异性抗体（这里简称双抗或bsAb）是最重要的一类双靶点药物，也是近些年来最热门的药物研发领域之一。它的研发历史已有几十年: 图中黄色的立柱代表和双抗有关的论文每年发表篇数（左轴），紫色的立柱代表每年进入临床试验的双抗数。到目前为止，已有三个双抗药获批，其中两个还在市场上（Amgen的Blincyto / Blinatumomab和Chugai的Hemlibra / Emicizumab），但有上百个双抗药分子正在临床试验中被评估。未来几年将是双抗药全面爆发的时代。3、双特异性抗体不等同于两种单克隆抗体的联合用药。和联合用药相比，双抗的优势包括单一的药代动力学特性（PK profile）和相对简单的申报流程：如果两种单抗在体内有不同的半衰期，在联合用药中需要平衡两者的给药时间表；联合用药在申报时需要准备两套CMC、毒理数据等。但双抗药最重要的优势是obligate effects，或全新功能。图片来源：参考资料144、如果一个双抗药的效果仅仅等同于（additive effects）或超过（synergistic effects）两种母单抗的联合用药产生的效果，它还不是最理想的双抗药。一个理想的双抗药可以产生全新的功能、全新的效果。如果这种新功能是两种母抗体不管如何联用也无法获得的，它就是obligate effects 。图片来源：参考资料185、双抗产生新功能主要有两个机理。第一个机理是通过空间重排产生新的药效（spatial obligate mechanisms）。在这种情况下，双抗同时结合两个药靶，把它们拉近，进而启动下一步行为。最常见的双抗——细胞桥接双抗——就是利用这个机理(a)。比如，T细胞导向双抗同时结合T细胞上的CD3和肿瘤细胞表面上的某种抗原（tumor associated antigen, TAA），桥接两种细胞，并激活T细胞，以杀死肿瘤细胞。还有的双抗，如b和c所示，同时结合同一细胞表面上的两种受体，或者导致细胞凋亡，或者促进细胞生长。这种效果只有在两种受体被交联时才会发生。Hemlibra则是d图描绘的双抗类型的一个例子：Hemlibra模仿FVIIIa因子，把FIXa和FX拉到一起，激活FX，引起血凝反应。图片来源：参考资料186、双抗产生新功能的第二个主要机理是在时间维度上完成的（temporal obligate mechanisms）。双抗分子先通过一个结合臂结合一个靶点，再因此被置换到新的空间（比如通过血脑屏障（图e），或被内吞入细胞（图f）），最后通过另一个结合臂结合第二个靶点，触发下游反应。如果第一个结合事件不发生，该双抗接触不到第二个靶点。从这个角度看，该双抗的第一个结合臂是第二个的递送装置。图片来源：参考资料147、图1中的499,500种双靶点组合只是可能的成药空间（双抗的成药空间比这要小的多）。理性设计只能找到寥寥不多的几种双抗。要从中找到更多的能产生新功能的组合需要一个高通量的筛选手段。对于双抗药来说，第一个难题是如何构建足够大的双抗分子库以供筛选。假设针对每个靶点有10种结合片段（binders）可供选择（覆盖不同的表位和亲和力），那么针对两个靶点就至少需要10 x 10 = 100种双抗分子。即使对大公司来说，制备、提纯100种蛋白分子也不是一件容易的事。这还只是在双靶点的成药空间中筛选。如果要从多靶点空间中寻找合适的双抗，制备的蛋白数量急剧增加。可以说，构建大规模的双抗分子库是双抗药研发的一个主要门槛。这里，我们以UCB的技术平台为代表来探讨一下制药公司是如何攻克这一难关的。在筛选阶段，UCB的所有结合片段都是以单臂Fab形式存在，这些Fab又分两种格式：Fab-Y和Fab-X。Fab-Y的C端带着一段多肽Y，而Fab-X的C端则带有可结合Y的scFv，两者混合后会形成一个临时的、可供筛选的Fab-KD-Fab双抗。Fab-KD-Fab技术的最大优势是节省了蛋白制备、纯化的成本。针对两种抗原A和B，UCB团队只需制备10种针对A的Fab-Y和10种针对B的Fab-X，一共20个蛋白，而不是100个蛋白。所有100种双抗都可以通过Fab-Y和Fab-X混合而生成。图片来源：参考资料148、UCB有一个项目是筛选抑制纤维化的双抗药物。人的肺（或肾）成纤维细胞与气管（或近端肾小管）上皮细胞混合培养，在培养液中加入不同的双抗分子，最后用免疫荧光方法比较各类蛋白纤维和细胞外基质的沉积程度。抑制纤维化可能的靶点有22个，双靶点的组合数就达到228种（理论上应该是231种可能：22 x 21 / 2）, 再考虑针对同一靶点有多种Fab，一共有2000个双抗需要被制备、筛选。而UCB采用Fab-KD-Fab技术，只需制备130种Fab分子作为起始原料就可以覆盖所有可能的双抗。图片来源：参考资料149、结果显示，一种双抗组合可以成功抑制细胞外基质的沉积或纤维化，而这种效果是两种单抗或其联合用药无法达到的。至此，UCB通过高通量筛选成功地找到一个抑制纤维化的候选双抗药物。其它公司也有自己的独特技术来构建大规模的双抗分子库，比如Genmab的DuoBody技术平台。10、一旦双靶点和双binder组合选定，下一步就要决定该双抗采取何种格式。双抗主要有三种格式：片段格式（左图），非对称的IgG类抗体格式（中图），和对称的IgG类抗体格式（右图）。每种格式里还有多种不同版本，图中给出的只是有代表性的例子。图片来源：Harpoontx.com/science/11、和IgG类双抗药相比，片段双抗主要有两个优势：由于其分子量小，它们可以更容易地渗透到肿瘤或靶向组织内，还可以结合到全长抗体不易接触的表位。但片段双抗的主要缺点是由于缺乏Fc，它们不能结合FcRn受体，因此体内半衰期短。比如Blincyto采取的是BiTE格式（左图），在体内的半衰期只有4个小时，其每个治疗周期需要连续28天静脉输液，给患者带来极大的不便，也增加了治疗费用。片段双抗可以通过改造而克服这一缺点。比如，Harpoon Therapeutics的TriTAC技术在片段双抗之间再加上能结合白蛋白（HSA）的抗体片段（右图）。片段双抗也可以和Fc融合而延长半衰期。图片来源：参考资料1812. 截至2019年6月份的数据表明，已进入或即将进入临床阶段的双抗药物中，非对称的IgG类双抗药占大部分——约60%。非对称IgG类双抗药的最大局限性是其生产过程中的效率问题。13、一个单克隆抗体是由两个相同的重链和两个相同的轻链构成。轻链与重链之间、重链与重链之间通过二硫键联结。在生产单抗蛋白时，先需要将两种质粒转染进同一个细胞（CHO或HEK293）里。一个质粒携带重链基因，另一个携带轻链基因。细胞同时表达重链蛋白和轻链蛋白，两种蛋白再自动组装成一个抗体分子，被细胞分泌到培养液里，不会有相似的副产物。但用细胞表达双抗分子时，事情就变得复杂一些。一个非对称IgG类双抗分子包含4个不同的蛋白链。宿主细胞需要被转染4种质粒，分泌出的抗体蛋白并不是100%想要的双抗。14、在细胞内，轻链与重链之间，重链与重链之间会随机配对。最后组装出的抗体分子会出现16种可能，10种蛋白分子。假设每种配对的概率都相同（实际上概率有些差异），我们所需要的双抗蛋白分子（红圈标出的）只占所有产物的1/8或12.5%。这不但导致了低效率的生产流程，而且还使提纯过程变得异常复杂：双抗很难从其它相似的抗体产物中分离出来。15、为了解决错配问题，工业界已经开发出很多创新技术。解决重链错配的常见技术有Genentech发明的Knobs-into-holes（KiH），Novimmune发明的Common Heavy Chain策略，和Regeneron发明的Fc双突变技术。KiH技术是在两种重链上引入不同的突变，使得同种重链无法配对，而异种重链则榫卯相扣。Common Heavy Chain策略则是使用同一个重链，对不同抗原的特异性主要由不同的轻链决定。Fc双突变技术与前两个技术不同。它不会导致单一配对，但便于选择性地提纯。一个重链还是野生型，另一个重链则引入两个突变（H435R和Y436F）。杂合重链双聚体与蛋白A的结合力比纯和突变重链双聚体高，但比纯和野生重链双聚体低。这样在蛋白提纯的过程中可以选择性地把含有杂合重链双聚体的双抗分子纯化出来。图片来源：参考资料1716、解决重轻链错配的常见技术有Common Light Chain策略，罗氏开发的CrossMab技术，Merck KGaA开发的CH1: CL界面改造技术，和药明生物、Invenra等公司开发的CH1: CL置换技术。Common Light Chain策略是使用同一个轻链，对不同抗原的特异性主要由不同的重链可变区决定。CrossMab技术（之一）是将一侧的轻重链的CH1和CL互相调换，这样野生的重链只能和野生的轻链配对，而含CL域的重链只能和含CH1的轻链配对。在CH1: CL界面改造技术中，一侧的CH1和CL各引入一系列突变，使得改造后的重、轻链依然能结合，但和野生型的轻、重链相排斥。药明生物的WuXiBody技术是通过将其中一对轻、重链的CH1/CL结构域置换为TCR Cα / Cβ而实现；与此相似，Invenra的B-body技术是将其中一对轻、重链的CH1/CL结构域置换为一对儿其它抗体结构域（未披露具体信息）。图片来源：参考资料13和1817、现在处于临床阶段的双抗候选药的85%是用来治疗肿瘤的，而抗肿瘤双抗药的大部分是T细胞导向双抗（T-cell redirecting bispecific antibodies, 简称TRBA），即有CD3结合臂的双抗。在剩下的篇幅中，让我们来重点讨论一下TRBA。图片来源：参考资料1118、T细胞表面的CD3和TCR组成CD3-TCR复合体，用来结合抗原呈递细胞（APC）表面的MHC-抗原片段。TRBA则绕开了MHC的限制，激活T细胞，把T细胞的火力引向了肿瘤细胞。TRBA的一个结合臂靶向肿瘤细胞表面的抗原（TAA），另一个结合臂结合T细胞表面的CD3ε，起到CD3ε激动剂的作用。TAA-TRBA-CD3-TCR形成了类似于MHC-peptide-TCR-CD3的免疫突触（IS），T细胞被激活，释放颗粒酶、穿孔素等蛋白，从而引起肿瘤细胞的裂解。图片来源：参考资料2419、正如前文所言，处于临床阶段的TRBA候选药物有很多种。Genentech的Mosunetuzumab就是其中之一。Mosunetuzumab是一个靶向B细胞表面的CD20的非对称全长双抗。它的Fc部分引进了一个突变（N297G）, 去除了ADCC作用，以避免误伤T细胞。图片来源：www.biooncology.com/pipeline-molecules/cd20-tcb.html; 参考资料920、罗氏正在开发的Glofitamab（CD20-TCB或RG6026）是另一个TRBA例子。Glofitamab的独特之处在于它与CD20的结合是二价的，与CD3是单价的。这种格式增强了它杀死肿瘤细胞的能力。另外，它的Fc部分只保留了FcRn结合位点，但不会引起免疫效应，从而既保留了长的生物半衰期又不会误伤T细胞。从Glofitamab的结构示意图（右上角）可以看出，为了避免错配，这个分子的设计至少采用了三个技术：KiH，CrossMab和CH1:CL电荷界面。图片来源：参考资料2421、 T细胞导向双抗经常被拿来和另一种合成免疫（synthetic immunity）治疗手段——CAR-T作比较。作为第二代TRBA的代表，Mosunetuzumab、CD20TCB和Regeneron的REGN1979在一期临床试验中显示了对B淋巴瘤的良好疗效，不亚于已上市的CAR-T疗法。有两点需要说明的是，Kymriah（Tisagenlecleucel）和Yescarta （Axicabtagene Ciloleucel）的靶向抗原是CD19，而这三个TRBA靶向CD20。另外，TRBA和CAR-T之间还从没做有过头对头的临床试验比较。根据表中的数据作横向比较还需谨慎。ORR为客观应答率，CR为完全缓解率。图片来源：参考资料2422、CAR-T最常见的副作用是细胞因子风暴（CRS）和神经毒性。和已上市的CAR-T疗法相比，三个TRBA的这两项副作用的发生频率和严重程度都有降低。图片来源：参考资料1223、尽管如此，TRBA在药效和安全性上还有很大的提高空间。提高药效大致可以从7个方面下手：（A）T细胞结合臂靶向的受体不仅仅局限于CD3（由黄色的椭圆代表），还可以从CD28，CD2和αβTCR中选择；（B）T细胞结合臂可以靶向CD3的不同表位；（C）TRBA可以采取多种格式，包括片段双抗和类IgG双抗；（D）癌细胞表面上的TAA密度也影响TRBA的效果；（E）形成的TAA-TRBA-CD3-TCR的空间尺度对癌细胞的杀伤力也有影响，而这是由TRBA的格式、TAA的大小、TAA上的结合表位与癌细胞膜之间的距离等因素决定的；（F）增加TRBA与TAA的亲和力会增加对癌细胞的杀伤力；（G）调整TRBA与CD3的亲和力可改变TRBA的药效和毒性。（G）比较复杂。一般来说，TRBA与CD3的亲和力（affinity）或总亲和力（avidity）不能太高，否则将导致TRBA和循环中的T细胞率先结合，不能有效渗入肿瘤，也产生很多副作用。图片来源：参考资料624、让我们先看一个通过（A）来提高对肿瘤细胞杀伤力的例子。激活T细胞并使之持续增殖、保持对肿瘤细胞的杀伤力需要两个信号：第一个信号是由CD3-TCR复合体介导的，引起细胞因子的分泌；第二个信号是由CD28介导的，抑制T细胞凋亡。设计TRBA时一般只考虑了第一个信号，因此TRBA经常引起T细胞无能化（anergy）而限制了T细胞的持久杀伤作用。但双信号这个概念已经被应用在第二代、第三代CAR-T的设计中：CAR的膜内部分既包括CD3ζ（信号1），又包括CD28的膜内激活域（信号2）。图片来源：参考资料2025、Sanofi设计的三特异性抗体就同时靶向这两个信号通路。这个三抗的一个结合臂靶向骨髓瘤细胞表面上的CD38，另一个结合臂同时靶向CD3和CD28。为了降低引起CRS的风险，这个分子被设计成与CD3ε的亲和力相对不高（KD ~ 20 nM，而anti-CD28和anti-CD38与各自靶点的KD分别为2 nM和4 nM）。在细胞和动物实验中，CD38 / CD3 x CD28三抗显示了对肿瘤细胞的持久杀伤力。图片来源：参考资料2426、TRBA的主要副作用是CRS。有没有可能只保留TRBA对肿瘤细胞的裂解能力，但又剔除其引起CRS的风险？研究表明，细胞杀伤力和CRS都依赖于TCR刺激，但是它们需要不同强度的CD3结合水平。细胞毒性T细胞（CTL）有两种不同的激活阈值，引起细胞因子释放的CD3结合率阈值要比细胞裂解阈值高得多，至少相差百倍。因此，可以通过减弱其对T细胞的亲和力或增加其TAA / CD3结合价比例来设计更安全的TRBA。IGM Biosceinces设计的IGM2323就是这样一个例子。它由靶向CD20的IgM五聚体和一个靶向CD3的scFv构成。也就是说，IGM-2323对CD20和CD3的结合价之比为10：1。图片来源：参考资料2327、在细胞实验中，IgM版本的双抗比IgG版本显示了对肿瘤细胞的更强的杀伤力。图片来源：参考资料2328. 而同时在细胞和动物（包括猴子）实验中，和IgG版本双抗相比，IGM-2323几乎不引起细胞因子的释放。IGM-2323正在一期临床试验中被评估。图片来源：参考资料1729、增加TRBA安全性的另一个办法是，让它只在肿瘤微环境（TME）中才被激活，才能招募T细胞。Maverick Therapeutics的COBRA技术平台就是建立在这一机理上。MVC-101是通过COBRA推出的一个三抗候选药。它可以结合EGFR和HSA（延长生物半衰期），但只能有条件地结合CD3。在其它组织中，它结合CD3的VH和VL分别被VLi和VHi所屏蔽，不能结合CD3。肿瘤及其周边中富含MMP2和MMP9等基质金属蛋白酶。在MMP的作用下，分子内的衔接链被剪断，含VLi、VHi和anti-HSA的一半蛋白分子被释放。剩下的半个分子两两配对，形成了可四价结合EGFR、两价结合CD3的双聚体双抗。在取得了良好的细胞和动物数据后，MVC-101即将进入临床试验。图片来源：www.affimed.com/rock-platform/innate-cell-engagers/; 参考资料2630、招募T细胞不是桥接双抗的唯一策略。Affimed公司通过ROCK技术推出了一系列招募NK细胞的候选双抗药。ROCK双抗既可以结合肿瘤细胞表面的TAA，又可结合NK细胞表面的CD16A（即FcγRIIIa），通过激活先天免疫系统和ADCC来裂解肿瘤细胞。这种双抗既保留了杀伤肿瘤的药效，又降低了TRBA的CRS风险。Affimed的管线领头项目AFM13靶向CD30和T细胞淋巴瘤，目前正在二期临床试验中被评估。31、未来10年将是多特异性抗体药的爆发期。双抗药发展到今天，是几十年来学术界和工业界在概念上、技术上不断产生突破日积月累的结果。几十家生物技术和制药公司都做出了重要贡献。我在这里仅列出文中涉及的公司。在不久的未来，双抗药将被广泛用来治愈顽疾，拯救生命。到那时，我们不应忘记，它们的背后是一系列的创新和众多的开拓者。参考资料：（上下滑动查看更多）1. Overington, J. P., Al-Lazikani, B. & Hopkins, A. L. (2006) How many drug targets are there?, Nature reviews Drug discovery. 5, 993-6.2. Krah, S., Kolmar, H., Becker, S. & Zielonka, S. (2018) Engineering IgG-Like Bispecific Antibodies-An Overview, Antibodies (Basel). 7.3. Santos, R., Ursu, O., Gaulton, A., Bento, A. P., Donadi, R. S., Bologa, C. G., Karlsson, A., Al-Lazikani, B., Hersey, A., Oprea, T. I. & Overington, J. P. (2017) A comprehensive map of molecular drug targets, Nature reviews Drug discovery. 16, 19-34.4. Tustian, A. D., Endicott, C., Adams, B., Mattila, J. & Bak, H. (2016) Development of purification processes for fully human bispecific antibodies based upon modification of protein A binding avidity, MAbs. 8, 828-38.5. Klein, C., Schaefer, W., Regula, J. T., Dumontet, C., Brinkmann, U., Bacac, M. & Umana, P. (2019) Engineering therapeutic bispecific antibodies using CrossMab technology, Methods. 154, 21-31.6. Weinkove, R., George, P., Dasyam, N. & McLellan, A. D. (2019) Selecting costimulatory domains for chimeric antigen receptors: functional and clinical considerations, Clin Transl Immunology. 8, e1049.7. De Nardis, C., Hendriks, L. J. A., Poirier, E., Arvinte, T., Gros, P., Bakker, A. B. H. & de Kruif, J. (2017) A new approach for generating bispecific antibodies based on a common light chain format and the stable architecture of human immunoglobulin G1, J Biol Chem. 292, 14706-14717.8. Fischer, N., Elson, G., Magistrelli, G., Dheilly, E., Fouque, N., Laurendon, A., Gueneau, F., Ravn, U., Depoisier, J. F., Moine, V., Raimondi, S., Malinge, P., Di Grazia, L., Rousseau, F., Poitevin, Y., Calloud, S., Cayatte, P. A., Alcoz, M., Pontini, G., Fagete, S., Broyer, L., Corbier, M., Schrag, D., Didelot, G., Bosson, N., Costes, N., Cons, L., Buatois, V., Johnson, Z., Ferlin, W., Masternak, K. & Kosco-Vilbois, M. (2015) Exploiting light chains for the scalable generation and platform purification of native human bispecific IgG, Nat Commun. 6, 6113.9. Bacac, M., Colombetti, S., Herter, S., Sam, J., Perro, M., Chen, S., Bianchi, R., Richard, M., Schoenle, A., Nicolini, V., Diggelmann, S., Limani, F., Schlenker, R., Husser, T., Richter, W., Bray-French, K., Hinton, H., Giusti, A. M., Freimoser-Grundschober, A., Lariviere, L., Neumann, C., Klein, C. & Umana, P. (2018) CD20-TCB with Obinutuzumab Pretreatment as Next-Generation Treatment of Hematologic Malignancies, Clin Cancer Res. 24, 4785-4797.10. Strohl, W. R. & Naso, M. (2019) Bispecific T-Cell Redirection versus Chimeric Antigen Receptor (CAR)-T Cells as Approaches to Kill Cancer Cells, Antibodies (Basel). 8.11. Zhukovsky, E. A., Morse, R. J. & Maus, M. V. (2016) Bispecific antibodies and CARs: generalized immunotherapeutics harnessing T cell redirection, Curr Opin Immunol. 40, 24-35.12. Ellerman, D. (2019) Bispecific T-cell engagers: Towards understanding variables influencing the in vitro potency and tumor selectivity and their modulation to enhance their efficacy and safety, Methods. 154, 102-117.13. Labrijn, A. F. (2019) Bispecific Antibodies: New Strategies and Case Studies in Antibody Engineering & Therapeutics 2019 San Diego, CA.14. Finney, H. M. (2019) Bispecific Target Discovery by Screenign a Large "Select, Mix & Assay" Combinatorial Library in Antibody Engineering & Therapeutics 2019 San Diego, CA.15. Joshi, K. (2019) Toward a Deeper Understanding of Bispecific Antibodies in Antibody Engineering & Therapeutics 2019 San Diego, CA.16. Wang, Q., Chen, Y., Park, J., Liu, X., Hu, Y., Wang, T., McFarland, K. & Betenbaugh, M. J. (2019) Design and Production of Bispecific Antibodies, Antibodies (Basel). 8.17. Zhu, Y., Shen, R., Hao, R., Wang, S. & Ho, M. (2020) Highlights of Antibody Engineering & Therapeutics 2019 in San Diego, USA: Bispecific Antibody Design and Clinical Applications, Antibody Therapeutics.18. Labrijn, A. F., Janmaat, M. L., Reichert, J. M. & Parren, P. (2019) Bispecific antibodies: a mechanistic review of the pipeline, Nature reviews Drug discovery. 18, 585-608.19. Bonisch, M., Sellmann, C., Maresch, D., Halbig, C., Becker, S., Toleikis, L., Hock, B. & Ruker, F. (2017) Novel CH1:CL interfaces that enhance correct light chain pairing in heterodimeric bispecific antibodies, Protein Eng Des Sel. 30, 685-696.20. Garfall, A. L. & June, C. H. (2019) Trispecific antibodies offer a third way forward for anticancer immunotherapy, Nature. 575, 450-451.21. Wu, L., Seung, E., Xu, L., Rao, E., Lord, D. M., Wei, R. R., Cortez-Retamozo, V., Ospina, B., Posternak, V., Ulinski, G., Piepenhagen, P., Francesconi, E., El-Murr, N., Beil, C., Kirby, P., Li, A., Fretland, J., Vicente, R., Deng, G., Dabdoubi, T., Cameron, B., Bertrand, T., Ferrari, P., Pouzieux, S., Lemoine, C., Prades, C., Park, A., Qiu, H., Song, Z., Zhang, B., Sun, F., Chiron, M., Rao, S., Radošević, K., Yang, Z.-y. & Nabel, G. J. (2020) Trispecific antibodies enhance the therapeutic efficacy of tumor-directed T cells through T cell receptor co-stimulation, Nature Cancer. 1, 86-98.22. Nabel, G. (2019) Trispecific Antibodies for Treating Cancer and AIDS in Antibody Engineering & Therapeutics 2019 San Diego, CA.23. Chen, D. S. (2019) Defining the Light at the End of the Tunnel: Biologic Problems and Engineering Solutions in Cancer Immunotherapy in Antibody Engineering & Therapeutics 2019 San Diego, CA.24. Budde, E. (2019) Clinical Use of Bispecific Antibodies in Treating B Cell Lymphoma in Antibody Engineering & Therapeutics 2019 San Diego, CA.25. Tesar, M. (2019) CD16A, NK Cell Targeting in Antibody Engineering & Therapeutics 2019 San Diego, CA.26. Haneke, T., Rajkovic, E., Treder, M., Tesar, M. & Koch, J. (2019) Redirected Optimized Cell Killing (ROCK®): A novel multispecific antibody platform for innate immune cell engagement to fight cancer in NK2019 Luxembourg.

细胞疗法

2025-06-09

·药时代

从三期临床到百亿美元交易：PD-(L)1/VEGF双抗引爆产业新风暴

一个三期临床数据，一笔百亿美元交易，让PD-（L）1/VEGF双抗再度成为业内焦点。先说，一个三期临床数据。2025年5月30日，Summit公布了PD-1/VEGF双抗（依沃西单抗，AK112）首个全球性三期HARMONi研究数据。由于AK112是全球首个且唯一在三期单药头对头研究中打败K药的“明星产品”，其首个全球3期临床结果备受业界瞩目。结果显示，在HARMONi研究中，AK112达到了无进展生存期（PFS）的主要终点，风险比为0.52（95%CI：0.41–0.66；p<0.00001）；可惜的是，总生存期（OS）终点则尚未达到统计学意义，风险比为0.79（95% CI：0.62 – 1.01；p=0.057）。OS数据作为评估药物的有效性的金标准，是否具备统计学显著性获益，是FDA支持上市许可的关键证据。特别是在FDA监管收紧的趋势下，上述不确定性无疑给两位研发者康方与Summit带来打击。事实也确实如此，受此消息影响，两家药企股价大跌。再谈一笔百亿美元交易。2025年6月2日，BioNTech与BMS就PD-L1/VEGF双抗（BNT327）达成111亿美元的交易，交易本身没有问题，只是其令人咂舌的估值金额，让不少业内人士意难平。据悉，交易标的BNT327由普米斯原研，曾用代号为PM8002。2023年11月，BioNTech以5500万美元的首付款+超10亿美元的里程碑付款，获得了该药在全球（大中华区除外）的开发、生产和商业化权利。前后不足两年时间，产品价值就翻了超7倍。巨大落差下，“中国资产被贱卖”、“BioNTech是倒爷”等言论在社交媒体上持续发酵。毋庸置疑，前后两则重磅消息将PD-（L）1/VEGF双抗再次带到了“风暴中心”。那么PD-（L）1/VEGF双抗为何如此火爆？主要原因有两个。一是业内相信，PD-(L)1/VEGF 双抗有望迭代 PD-(L)1单抗市场，成为下一代IO基石药物。各大药企顺着迭代PD-1单抗的思路，将PD-(L)1/VEGF双抗打造成超级大药，AK112大败K药给了他们希望。据开源证券预测，预计至2028年PD-(L)1/VEGF双抗全球市场规模近 700 亿美金，市场潜力巨大。二是PD-(L)1/VEGF双抗在兼具增效与减副潜力的同时，还具有更高的商业价值。PD-(L)1-VEGF双抗不仅能用于非小细胞肺癌，在乳腺癌、肾癌、黑色素瘤等领域也表现出潜力。得益于此，截至目前已有BMS、辉瑞和默沙东三家MNC买入了PD-(L)1/VEGF双抗。交易是火热的，赛道是拥挤的。据不完全统计，全球已有超35款相关产品在研，其中13款产品已经入临床阶段。不难发现，PD-（L）1/VEGF双抗离不开“确定性”，资本寒冬下，没有什么比实打实的临床数据更值得让人投资。那么，PD-（L）1/VEGF双抗能否带动双抗市场整体的狂欢？答案是肯定的。回归双抗药物本质，就是能够同时靶向两个抗原或者一个抗原的两个不同表位，能在靶细胞和功能分子或细胞之间架起桥梁，激发具有导向性的免疫反应。那么，你可能会想：如果只是需结合两个抗原，直接用两个单抗联用就可以，为什么还要去做双抗？那是因为把两个抗原的识别域绑定在一个分子上，会创造出单抗联用所不可能拥有的新功能，如“关联桥接”，通过桥接来创造新的免疫突触，或通过桥接模拟酶的功能、促进反应复合物的形成（艾美赛珠单抗等）；“双重富集”，通过靶向同一靶点的不同表位，来强化对该靶点的亲和识别，或通过靶向在同一局部富集的两个分子来实现双重富集。简而言之，双抗相比单抗特异性更强、更能准确靶向肿瘤细胞并降低脱靶毒性，真正意义上的实现了1+1>2。从市场角度出发，据不完全统计，目前全球已有19款双抗上市，涉及的靶点包括CD3、CD19、CD20、EGFR、cMET、PD-1等等。其中，早在2023年就有2款产品全球销售额超过10亿美元，罗氏的艾美赛珠单抗的销售额更是高达46.2亿美元。商业化的成功，不仅验证了双抗药物的可及性，更激发了投资者热情。特别是后PD-1时代，单抗在迭代，放化疗在迭代，别人都是双抗+ADC，你还在单抗联用，不谈实际药效如何，融资都可能举步维艰。小结：回到文章开头，当AK112与PM8002点燃了舆论热情的同时，无法忽视的是，双抗药物市场已经迈入了第二轮高速增长的拐点。可以想象当首款PD-（L）1/VEGF双抗上市之际，或将有更多百亿美元交易达成。参考资料：1.111亿美元！BioNTech与百时美施贵宝达成全球战略合作，携手推进来自普米斯的PD-L1/VEGF双抗（创新药时代）2.已上市19款双抗药物，我们整理了它们的序列！需要自取（小药说药）3.风暴中心的PD-(L)1/VEGF双抗，还是被低估了（医药魔方）4.PD-(L)1/VEGF双抗“通货膨胀”（氨基观察）5.其他公开资料图片来源：pixabay真香定律！美国药企豪掷百亿美元，与中国药企之间双向奔赴，外媒纷纷报道2025-06-08【ASCO热点】婚姻状况影响生死？研究揭示癌症患者生存率差异2025-06-07吴一龙教授：我的ASCO 20252025-06-06版权声明/免责声明本文为原创文章。本文仅作信息交流之目的，不提供任何商用、医用、投资用建议。文中图片、视频、字体、音乐等素材或为药时代购买的授权正版作品，或来自微信公共图片库，或取自公司官网/网络，部分素材根据CC0协议使用，版权归拥有者，药时代尽力注明来源。如有任何问题，请与我们联系。衷心感谢!药时代官方网站:www.drugtimes.cn联系方式:电话:13651980212微信:27674131邮箱:contact@drugtimes.cn点击这里，查看更多精彩！

临床3期引进/卖出医药出海

2025-06-06

·PipelineReview

Novo Nordisk to present phase 3 trials across hemophilia portfolio, reinforcing commitment to research in rare blood disorders, at ISTH 2025

PLAINSBORO, NJ, USA I June 6, 2025 I Novo Nordisk today announced that new hemophilia data will be presented at the upcoming International Society on Thrombosis and Haemostasis (ISTH) Congress, June 21-25. Key data presentations across both hemophilia A and B (HA and HB), with and without inhibitors, will share insights on clotting, thrombin generation, bleeding episodes and medication impact, patient administration preferences, physician treatment satisfaction, and global real-world diagnosis and treatment data for joint bleeds. “At Novo Nordisk, we believe understanding the whole person and their journey is essential to addressing the unmet needs in people with hemophilia. Our research is rooted in a deep understanding of the hemophilia community, aiming to drive critical advancements across rare blood disorders in order to help address these unmet needs,” said Stephanie Seremetis, Chief Medical Officer and CVP for Rare Disease at Novo Nordisk. “Through this latest research, we are honored to build on our long-standing legacy in rare blood disorders to support patients who face the challenges of this complex condition.” New phase 3 data will be presented on Mim8, an investigational mimetic therapy designed to replicate the function of missing clotting factors. 1 Analysis from the phase 3 FRONTIER5 trial will assess the safety and preferences of people with HA, with and without inhibitors, who switch from emicizumab to Mim8. In addition, new data from two prospective, multicenter, open label, phase 3 trials (explorer7 and explorer8) will investigate joint bleeds, non-joint bleeds, and annualized bleeding rate with preventive concizumab being investigated versus on-demand treatment across both HA and HB, with and without inhibitors. Summary of presentations Accepted data at the 33 rd ISTH Congress includes the following poster and oral presentations. Additional information can be found on the ISTH website . Full details of Novo Nordisk abstracts to be presented: About hemophilia Hemophilia is a rare inherited bleeding disorder that impairs the body’s ability to make blood clots, a process needed to stop bleeding. 2 It is estimated to affect approximately 1,125,000 people worldwide. 3 There are different types of hemophilia, which are characterized by the type of clotting factor protein that is defective or missing. Hemophilia A is caused by a missing or defective clotting Factor VIII (FVIII), and hemophilia B is caused by a missing or defective clotting Factor IX (FIX). 2 Hemophilia is often treated by replacing the missing clotting factor via intravenous infusions, also known as replacement therapy. However, sometimes the body can produce inhibitors as an immune response to the clotting factor replacement therapy. When this happens, the therapy may not work and can limit treatment options. 5 About Novo Nordisk Novo Nordisk is a leading global healthcare company that’s been making innovative medicines to help people with diabetes lead longer, healthier lives for more than 100 years. This heritage has given us experience and capabilities that also enable us to drive change to help people defeat other serious chronic diseases such as obesity, rare blood, and endocrine disorders. We remain steadfast in our conviction that the formula for lasting success is to stay focused, think long-term, and do business in a financially, socially, and environmentally responsible way. With a U.S. presence spanning 40 years, Novo Nordisk U.S. is headquartered in New Jersey and employs over 10,000 people throughout the country across 12 manufacturing, R&D, and corporate locations in eight states plus Washington DC. For more information, visit novonordisk-us.com , Facebook , Instagram , and X . References SOURCE: Novo Nordisk

临床3期

100 项与艾美赛珠单抗相关的药物交易

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外链

KEGG	Wiki	ATC	Drug Bank
D10821	艾美赛珠单抗	B02BX06	DB13923

研发状态

批准上市

10 条最早获批的记录,

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适应症	国家/地区	公司	日期
凝血因子缺乏症	日本	Chugai Pharmaceutical Co., Ltd.	2018-03-23
血友病A	美国	Genentech, Inc.	2017-11-16

未上市

10 条进展最快的记录,

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适应症	最高研发状态	国家/地区	公司	日期
血管性血友病3型	临床3期	比利时	Hoffmann-La Roche Ltd.	2025-06-15
获得性因子 VIII缺乏症	临床2期	奥地利	Hoffmann-La Roche, Inc.	2021-03-23
获得性因子 VIII缺乏症	临床2期	德国	Hoffmann-La Roche, Inc.	2021-03-23
血友病	临床1期	中国	罗氏（中国）投资有限公司	2018-03-12
血友病	临床1期	中国	F. Hoffmann-La Roche Ltd.	2018-03-12

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临床结果

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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


ASH2024	N/A	血友病A	-	Emicizumab	鬱遞遞鹹衊糧鬱網顧夢(膚獵窪鹹觸繭鬱鏇醖鑰) = 獵鬱糧鬱鹽淵遞構繭壓鬱築餘窪憲顧淵餘夢壓 (鏇衊糧選衊糧鹹鑰獵觸, 1.1) 更多	-	2024-12-09
ASH2024	N/A	-	-	Emicizumab	壓築醖製醖鏇糧艱淵餘(鹹壓簾衊築遞鹹蓋願鬱) = 憲選願網淵構夢願鬱鬱遞蓋鑰糧顧範膚觸觸範 (鑰糧網觸衊壓淵壓齋選 ) 更多	-	2024-12-08
NCT04431726 (HAVEN 7, ASH2024)	临床3期	血友病A FVIII inhibitors	55	Emicizumab	構窪積衊壓築齋築顧膚(醖襯顧蓋構憲餘鑰簾築) = 蓋淵築鏇顧廠艱鏇淵鏇顧顧蓋艱鏇簾觸醖積夢 (構選齋壓夢餘網鏇鏇顧 )	积极	2024-12-08
				Factor VIII	構窪積衊壓築齋築顧膚(醖襯顧蓋構憲餘鑰簾築) = 鏇繭廠鹹壓艱願鹽膚鹽顧顧蓋艱鏇簾觸醖積夢 (構選齋壓夢餘網鏇鏇顧 )
ASH2024	N/A	血友病A	-	Emicizumab	襯鏇顧衊廠積膚獵觸築(鑰夢壓窪壓鏇餘鬱蓋廠) = 範簾願鹽膚鏇繭繭壓鹹鏇衊願糧築觸餘鹽餘顧 (鹹淵繭壓糧範鏇範製遞 )	-	2024-12-07
				Comparators	襯鏇顧衊廠積膚獵觸築(鑰夢壓窪壓鏇餘鬱蓋廠) = 觸鑰衊壓夢夢夢遞繭簾鏇衊願糧築觸餘鹽餘顧 (鹹淵繭壓糧範鏇範製遞 )
EHA2024	N/A	血友病A	16	Emicizumab	觸製遞淵膚膚積鏇餘憲(簾餘壓憲壓鏇築築獵鏇) = 餘壓壓繭襯構衊築鬱繭願廠淵壓醖網夢選淵簾 (遞積選構顧壓築積憲夢 )	不佳	2024-05-14
				FVIII replacement	觸製遞淵膚膚積鏇餘憲(簾餘壓憲壓鏇築築獵鏇) = 蓋廠艱簾繭簾築廠製遞願廠淵壓醖網夢選淵簾 (遞積選構顧壓築積憲夢 )
EHA2024	N/A	-	25	octocog alfa	壓獵蓋鹽窪鏇網選選壓(積鏇製顧衊選鏇築鑰齋) = 鹹淵簾觸糧夢齋鬱願築襯觸壓觸夢鏇餘齋淵襯 (鹽鏇蓋觸齋餘築製獵鑰, 38)	-	2024-05-14
				emicizumab	壓獵蓋鹽窪鏇網選選壓(積鏇製顧衊選鏇築鑰齋) = 憲衊糧獵膚鑰選顧範齋襯觸壓觸夢鏇餘齋淵襯 (鹽鏇蓋觸齋餘築製獵鑰, 9)
P11-5.023 (AAN2024)	N/A	获得性因子 VIII缺乏症 Factor VIII level \| Factor VIII inhibitor level	-	Emicizumab	遞淵網壓鑰糧衊繭鑰鬱(壓鹹遞鑰遞鏇遞廠鬱憲) = Apixaban was initiated for secondary prevention with no ischemic or hemorrhagic events at 3 and 6 month follow ups 餘選繭夢鹽範廠製網鹽 (糧淵顧築夢齋簾齋願糧 ) 更多	不佳	2024-04-09
NCT03191799 (STASEY, Pubmed \| TH Open) 人工标引	临床3期	血友病A	56	Emicizumab prophylaxis with additional hemostatic medication	願艱壓積糧壓艱構繭鹹(窪淵鬱鹽鹹鏇窪窪膚願) = 鏇憲顧鬱膚繭選淵鹽憲鏇蓋積憲鏇製夢廠鬱顧 (蓋廠簾繭膚鑰鹹鏇糧襯 ) 更多	积极	2024-01-12
				Emicizumab prophylaxis without additional hemostatic medication	願艱壓積糧壓艱構繭鹹(窪淵鬱鹽鹹鏇窪窪膚願) = 齋憲獵衊獵壓膚餘襯遞鏇蓋積憲鏇製夢廠鬱顧 (蓋廠簾繭膚鑰鹹鏇糧襯 )
ASH2023	N/A	血友病A	-	Emicizumab	夢廠夢選繭築壓齋選淵(鏇製窪積糧廠選鹽壓襯) = 膚觸窪顧願製鹽繭壓構顧繭鬱糧齋繭鹹糧積構 (壓糧鬱構範窪願糧蓋衊 )	-	2023-12-11
				Efanesoctocog alfa	夢廠夢選繭築壓齋選淵(鏇製窪積糧廠選鹽壓襯) = 壓觸製窪膚憲鹹憲網膚顧繭鬱糧齋繭鹹糧積構 (壓糧鬱構範窪願糧蓋衊 )
ASH2023	N/A	血友病A	127	Emicizumab prophylaxis	鏇製鬱遞鑰衊襯網構網(構餘鹽醖簾壓齋壓衊築) = 襯製鑰網醖積醖遞網淵夢壓衊蓋鹹鬱夢夢積鹹 (淵築鏇觸願鑰廠願夢鬱 ) 更多	-	2023-12-10