PURPOSEAnti-CD45 antibody is predominantly used in the treatment of acute leukemia. CD45 is stably expressed on all leukocytes and their precursors, and therefore the liver and spleen constitute major antigen sinks. Thus, as the red marrow is the target organ, in radioimmunotherapy with anti-CD45 antibody, preloading with unlabeled antibody is a method to increase the absorbed dose to the target cells. In a previous study, a method to individually determine the optimal preload for five patients with acute leukemia was developed. Here, this method is examined and improved using two pretherapeutic measurement series and a refined pharmacokinetic model.METHODSTo obtain the biodistribution of 111In-labeled anti-CD45 antibody under different saturation conditions, two measurement series one with and one without preloading were conducted in five patients. For each patient, two physiologically based pharmacokinetic models were fitted to the data and the corrected Akaike information criterion was used to identify the model, which was empirically most supported. The resultant parameter values were compared to values reported in the literature. To individually determine the optimal amount of unlabeled antibody for therapy, computer simulations for preloads ranging from 0 to 60 mg were performed based on the estimated parameters of each patient. The prediction power of the model was assessed by comparing the simulated therapeutic serum curves to the actual 90Y measurements.RESULTSVisual inspection showed good fits and the adjusted R2 was >0.90 for all patients. All parameters were in a physiologically reasonable range. The relative deviation of the predicted area under the therapeutic serum curve and the measured curve was 15%-33%. The optimal preloading increased the marrow-over-liver selectivity up to 3.9 fold compared to the simulated biodistribution using a standard dose (0.5 mg/kg).CONCLUSIONSThe presented method can be used to individually determine the optimal preload and the corresponding residence times in radioimmunotherapy with anti-CD45 antibody.

2009-12-01·Best Practice & Research Clinical Haematology4区 · 医学

Optimising the conditioning regimen for acute myeloid leukaemia

4区 · 医学

Review

作者: Frederick R. Appelbaum

The conditioning regimen administered prior to allogeneic transplantation for acute myeloid leukaemia (AML) must be sufficiently immunosuppressive to ensure engraftment, and contributes to the anti-leukaemic impact of the procedure. A broad spectrum of regimens have been studied, varying in their intensity, whether high-dose or reduced intensity, and in the agents used, containing total body irradiation (TBI) plus cyclophosphamide, fludarabine, busulfan and/or anti-thymocyte globulin. Over the past 2 decades, research has influenced the way conditioning regimens are applied. Newer research shows that targeted radiotherapy using an anti-CD45 antibody should be able to reduce toxicity, improve tumour cell kill and thereby improve results.

2009-02-01·Journal of Nuclear Medicine1区 · 医学

Improving Anti-CD45 Antibody Radioimmunotherapy Using a Physiologically Based Pharmacokinetic Model

1区 · 医学

Article

作者: Reske, Sven N ; Glatting, Gerhard ; Kletting, Peter ; Bunjes, Donald

Radioimmunotherapy is a method to selectively deliver radioactivity to cancer cells via specific antibodies. A strategy to enhance the efficacy of radioimmunotherapy is the prior application of unlabeled antibody, resulting in an increase in the dose to the target tissue and a decrease in the burden to other organs. It was suggested that optimizing this approach might considerably improve radioimmunotherapy with anti-CD45 antibody. The present work develops a physiologically based pharmacokinetic model to individually determine the optimal preload for radioimmunotherapy with the YAML568 anti-CD45 antibody for each patient.METHODSA physiologically based pharmacokinetic model was developed to describe the biodistribution of anti-CD45 antibody. The transport of antibody to the organs of interest via blood flow, competitive binding of unlabeled and labeled antibody, degradation and excretion of antibody, and physical decay were included in the model. The model was fitted to the biokinetics data of 5 patients with acute myeloid leukemia. On the basis of the estimated parameters, simulations for a 0- to 534-nmol preload of unlabeled antibody were conducted and the organ residence times were calculated.RESULTSThe measured data could be adequately described by the constructed model. The estimated numbers of accessible antigens in the respective organ, in nanomoles, were 97+/-33 for red marrow, 49+/-24 for liver, 34+/-18 for spleen, 38+/-31 for lymph nodes, and 0.9+/-0.4 for blood. These ranges indicate high interpatient variability. The optimal amount of unlabeled antibody identified by simulations would improve the ratio of residence time in red marrow to residence time in liver by a factor of 1.6-2.4.CONCLUSIONThe efficacy of radioimmunotherapy using anti-CD45 antibody can be considerably increased with the presented model. A more selective delivery of radioactivity to the target organ and a reduction in the toxicity to normal tissue are achieved by determining the optimal preload. Furthermore, the adverse effects of radioimmunotherapy might be drastically reduced while saving antibody expenses. The validation of the model is ongoing. The model is easily extendible and therefore most probably applicable to radioimmunotherapy of other hematologic malignancies, such as antibodies targeted to CD20, CD33, or CD66.

项与 Anti-CD45 antibody-drug conjugate(Magenta Therapeutics) 相关的新闻（医药）

2023-02-06

·药时代

患者死亡，在研管线全凉，股价却大涨50%……？

前言风干两年的咸鱼，下了油锅居然还蹦跶一下，这种奇事还真就发生了。2023年1月25日，Magenta Therapeutics宣布，由于一名患者在服用药物后死亡，研究暂停，并重新评估药物安全性。2月2日，Magenta宣布要对战略替代方案进行全面审查。隔天，Magenta股票居然大涨51.66%。即便如此，现在它的市值也不到巅峰时的一个零头。01撞到头破血流才停下的临床试验Magenta这款可能导致了患者死亡的MGTA-117，是一款ADC药物，靶点为CD117，主要作用于骨髓中的造血干细胞和癌细胞。该药物正在急性髓系白血病和髓系综合性复发患者中进行剂量递增试验。MGTA-117的I/II期临床试验一波三折，过强的毒性已经早早为悲剧埋下伏笔。一开始，MGTA-117的IND申请就被FDA打回。FDA要求Magenta开发额外的生物测定方法，用于安全检测和剂量递增试验设计。2021年9月，临床暂停解除，但随着试验阶段进行，剂量不断提升，又出事了。2022年12月，MGTA-117连续出现两起4级呼吸系统严重不良反应事件。这一消息导致MGTA股价大跌50%。Magenta决定停止该队列（队列4）用药，但依旧根据队列3为新患者用药。尽管队列3的药物剂量少于队列4，但2022年1月25日，又有一名患者出现了呼吸衰竭与心脏骤停的5级严重不良反应，最终导致患者死亡。Magenta表示，该事件可能与MGTA-117有关，试验暂停。图片来源：雪球02墙外开花的亮眼产品Magenta这家公司诞生伊始，本和ADC没啥关系，他们的核心领域一度是干细胞疗法。Magenta推出的第一款干细胞治疗产品MGTA-456 ，是一种经过扩增的 cd34+ 细胞治疗产品，可用于快速诱导并维持造血干细胞的植入。根据Magenta在2020年公布的一项2期临床数据，该产品在神经和认知功能方面具有临床意义和持久的益处，并可解决脑肾上腺脑营养不良症(CALD)患儿的脑炎症。Magenta借助MGTA-456画了个大饼，让不少投资机构吃撑了。Magenta2018年上市时可谓是众星捧月，Atlas venture、Third Rock等知名投资公司领投。不幸的是，2020年6月，MGTA-456由于患者入组困难、新冠影响与临床试验设计等原因研究终止。另一款与MGTA-456相似的干细胞疗法MGTA-145接过MGTA-456的接力棒，成为了Magenta的主要管线。Magenta目前的管线布局如果只有这两款产品，Magenta恐怕只是一家平平无奇的小biotech，在医药行业群星中，只能当一个小小的背景板。但有野心的Magenta没有止步于此，“罪魁祸首”MGTA-117诞生了。干细胞移植需要对患者进行清髓，清除患者体内原有的干细胞。传统清髓手段主要依靠化疗，而Magenta另辟蹊径，希望通过ADC药物MGTA-117耗尽血液或骨髓中表达CD117的靶细胞，让患者无需化疗即可完成清髓。就这样，一家研究干细胞疗法的公司也搞起了ADC。在2019年12月9日的美国血液学会年会（ASH）上，美国国立卫生研究院分子和临床血液学部主任John Tisdale博士的口头报告专门强调了MGTA-117的研究进展，表明“这是一次非常成功的试验，人类首次在不使用放、化疗的情况下，通过ADC的手段，成功将基因修饰细胞移植到非人灵长类动物中。”03Magenta为什么这么头铁2021年3月，Magenta公布了2020年财报，一年亏损七千多万美元，现金流只能维持到2023年。这一消息让投资者望风而逃，一年时间，股价从最高值14.2美元跌到4.4美元左右。Magenta也成为了2022医药行业裁员大潮中的一朵小浪花。2022年4月，Magenta宣布裁员14%，并暂停MGTA-145计划在健康受试者中进行的临床试验。自此Magenta的核心管线停摆，ADC产品MGTA-117成为了Magenta最后的希望。MGTA-117的成败直接关系到整个公司的命运。也许这就是在出现了严重不良反应之后，MGTA-117的临床研究仍没有停止的原因。最终，患者死亡事件为这家公司的结局标上句点。最后的赌博全盘皆输，资本不相信眼泪，留给Magenta的时间不多了。Magenta的结局，很可能是被收购，或者与其他公司合并。即便是乐观估计，恐怕也得卖掉自己的管线。也可能是由于卖身传闻，投资者才纷纷涌入，致使股价大涨。投资者们希望会出现溢价收购的情况，此刻购入或许只是为了抄底，赌一把可以在Magenta后续战略调整中抢到点残羹冷炙罢了，并非真的看好这家公司。Magenta这次股价大涨，不过是从0.56美元的低价涨到0.85美元，勉强追回2022年12月患者发生4级严重不良反应事件后的股价而已。咸鱼没有翻身，只是被油锅煎得翘了起来。03小结有破釜沉舟般的勇气，不撞南墙不回头，是科学界成功的要素之一。近些年杀出重围的传奇biotech们，多少都有一些这样的特质。但他们是坚信自己的产品能成功，而不是拒绝接受已经失败的事实。像Magenta这样不能“力拔山兮”却“气盖世”，连壮烈自刎留个体面的机会都没有了。临死前最后的回光返照，只是投机客的引渡冥灯，悲兮悲兮。参考资料https://endpts.com/magenta-halts-stem-cell-work-and-may-sell-itself-following-patient-death-clinical-hold/https://endpts.com/patient-death-spurs-trial-halt-for-magenta-therapeutics/magenta官网消息其他网络公开资料封面图来源：pixabay推荐阅读正月十五猜灯谜！全是新药专题，您能猜中几道？～~ 附：十五家药企、机构之精美元宵节海报！~~专栏 | 知名投资专家柳达：化学药的开发有无范式？卖了8年的PD-1，还能保持20%的增长率，它是怎么做到的？这款药被2022版上海市新冠病毒感染诊疗规范推荐，临床价值在哪里？罗氏2022，营收近700亿美元！新增长抵消新冠影响诺和诺德2022财报公布：全年销售额大涨25%，GLP-1产品拉动整架马车点击这里，报名创新药BD高阶研讨会【上海站】！

抗体药物偶联物临床2期临床申请临床1期细胞疗法

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适应症	最高研发状态	国家/地区	公司	日期
急性髓性白血病	临床前	美国	Magenta Therapeutics, Inc.	-
动脉硬化	临床前	美国	Magenta Therapeutics, Inc.	-
自身免疫性疾病	临床前	美国	Magenta Therapeutics, Inc.	-
骨髓移植排斥反应	临床前	美国	Magenta Therapeutics, Inc.	-