A Phase III, Multicenter, Randomized, Placebo Controlled, Double-blind Study to Assess Efficacy and Safety of Crizanlizumab (5 mg/kg) Versus Placebo, With or Without Hydroxyurea/Hydroxycarbamide Therapy, in Adolescent and Adult Sickle Cell Disease Patients With Frequent Vaso-Occlusive Crises

A phase III, multi-center, randomized, placebo-controlled, double-blind study to assess efficacy and safety of crizanlizumab (5 mg/kg) versus placebo, with or without hydroxyurea/hydroxycarbamide therapy, in adolescent and adult Sickle Cell Disease patients with frequent vaso-occlusive crises.

开始日期2024-10-01

申办/合作机构

Novartis Pharmaceuticals Corp.

NCT05469828 / Not yet recruiting临床1/2期IIT

Crizanlizumab Improves Tissue Oxygen Supply Demand Matching in Patients With Sickle Cell Anemia

Hypothesis
Efficient unloading of oxygen to regions of high metabolic demand requires a healthy microvasculature to sense local oxygen tension and regulate flow, accordingly. In sickle cell disease patients, the investigators have demonstrated oxygen supply-demand mismatch, or SDM, in proportion to anemia severity. SDM occurs in both the peripheral circulation and the brain, and four characteristics: 1) Hyperemia beyond expected for the level of anemia, 2) Corresponding loss of vascular dilatory reserve, 3) Impaired oxygen unloading to the tissues, and 4) Tissue hypoxia. In sickle cell disease, red blood cell (RBC) and white blood cell (WBC) adhere to vascular endothelium triggering transient or irreversible microvascular damage as well as releasing vasoactive substances that contribute to microvascular dysregulation. The investigators postulate that ongoing microvascular damage/dysregulation in the setting of increased total blood flow contributes to SDM. The investigators believe SEG101, by lowering RBC and WBC adhesion to the microvasculature, will improve SDM and tissue oxygenation.
Objectives
Primary - The investigators will test whether SEG101 improves SDM in patients with sickle cell anemia by measuring the change in tissue oxygenation measured by near infrared spectroscopy (NIRS).
Secondary/Exploratory - The investigators will identify end-organ disease and whether improvement of SDM by SEG101 occurs in patients with sickle cell anemia.

开始日期2024-07-01

申办/合作机构

Children's Hospital Los Angeles

[+1]

NCT05146739 / Active, not recruiting临床1期IIT

A Phase 1 and Pharmacokinetic Study of Uproleselan (GMI-1271, NSC #801708) in Combination With Fludarabine and Cytarabine for Patients With Acute Myeloid Leukemia, Myelodysplastic Syndrome or Mixed Phenotype Acute Leukemia That Expresses E-selectin Ligand on the Cell Membrane and is in Second or Greater Relapse or That is Refractory to Relapse Therapy

This phase I trial tests the safety, side effects, and best dose of uproleselan in combination with fludarabine and cytarabine in treating patients with acute myeloid leukemia, myelodysplastic syndrome or mixed phenotype acute leukemia that has come back (relapsed) or does not respond to treatment (refractory) and that expresses E-selectin ligand on the cell membrane. Uproleselan binds to E-selectin expressed on endothelial cells of the bone marrow and prevents their interaction with selectin-E ligand-expressing cancer cells. This may prevent leukemia cells from being sequestered in the bone marrow niche and escaping the effect of chemotherapy. Chemotherapy drugs, such as fludarabine and cytarabine, work in different ways to stop the growth of cancer cells, either by killing the cells, by stopping them from dividing, or by stopping them from spreading. Giving uproleselan in combination with fludarabine and cytarabine may enhance their activity.

开始日期2023-10-10

申办/合作机构

National Cancer Institute

[+1]

100 项与 Selectins 相关的临床结果

登录后查看更多信息

100 项与 Selectins 相关的转化医学

登录后查看更多信息

0 项与 Selectins 相关的专利（医药）

登录后查看更多信息

28,086

项与 Selectins 相关的文献（医药）

2025-01-01·Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease

Monocyte and macrophage profiles in patients with inherited long-chain fatty acid oxidation disorders

Article

作者: Hahn, Nico ; Haverkamp, Jorien ; Verberk, Sanne G S ; Sjouke, Barbara ; Hendriks, Jerome J.A. ; Hendriks, Jerome J A ; Langeveld, Mirjam ; Visser, Gepke ; Gorki, Friederieke S. ; Van den Bossche, Jan ; de Goede, Kyra E. ; Gorki, Friederieke S ; Heister, Daan ; Snelder, Khya S ; de Goede, Kyra E ; Snelder, Khya S. ; Houtkooper, Riekelt H ; Houtkooper, Riekelt H. ; Verberk, Sanne G.S.

Patients with inherited disorders of the long-chain fatty acid oxidation (lcFAO) machinery present with a heterogeneous profile of disease manifestations and aggravation of symptoms is often triggered by inflammatory activation. Monocytes and macrophages are innate immune cells that play a major role in the onset and resolution of inflammation. These cells undergo metabolic rewiring upon activation including the regulation of the FAO rate. The rewiring of FAO and the effect of lcFAO disorders (lcFAOD) on human monocyte and macrophage phenotype and function remain largely unknown. Here, we performed extensive phenotyping of circulating monocytes and analyzed plasma cytokine levels in 11 lcFAOD patients and 11 matched control subjects. In patients with lcFAOD, we observed induced plasma levels of the inflammatory cytokines IL-1β and IL-6, and enhanced CD206 and CD62L surface marker expression in circulating monocyte subsets. To mimic the most common lcFAOD very-long-chain acyl-CoA dehydrogenase disorder (VLCADD), we used siRNA-mediated knockdown of the ACADVL gene (encoding VLCAD) in macrophages derived from healthy volunteers. Hereby, we found that siVLCAD affected IL-4-induced alternative macrophage activation while leaving LPS responses and cellular metabolism intact. In the same line, monocyte-derived macrophages from lcFAOD patients had elevated levels of the IL-4-induced alternative macrophage markers CD206 and CD200R. Still, they did not show major metabolic defects or changes in the LPS-induced inflammatory response. Our results indicate that monocytes and macrophages from lcFAOD patients present no major inflammatory or metabolic differences and show that IL-4-induced surface markers are intertwined with lcFAO in human macrophages.

2025-01-01·Gene

Integration of bioinformatics and multi-layered experimental validation reveals novel functions of acetylation-related genes in intervertebral disc degeneration

Article

作者: Tang, Jinlong ; Feng, Shuo ; Li, Hao ; Wang, Song ; Zheng, Wei ; Liu, Yong ; Li, Zheng ; Lu, Xiaoqing ; Song, Tongqu ; Zhu, Zhengya ; Wang, Lei ; Zhu, Jun ; Yuan, Feng

BACKGROUNDThe molecular mechanisms underlying intervertebral disc degeneration (IDD) remain poorly understood. The purpose of this work is to elucidate key molecules and investigate the roles of acetylation-related RNAs and their associated pathways in IDD.METHODDatasets GSE70362 and GSE124272 were obtained from the Gene Expression Omnibus (GEO) and combined to investigate differentially expressed genes (DEGs) associated with acetylation in IDD patients compared to healthy controls. Critical genes were pinpointed by integrating GO, KEGG and PPI networks. Furthermore, CIBERSORTx analysis was used to investigate the differences in immune cell infiltration between different groups and the biological processes (BP), cellular components (CC) and molecular functions (MF) were calculated by GSEA and GSVA. In addition, The single-cell database GSE165722 was incorporated to validate the specific expression patterns of hub genes in cells and identify distinct cell subtypes. This provides a theoretical basis for a more in-depth understanding of the roles played by critical cell subtypes in the process of IDD. Subsequently, tissues from IVD with varying degrees of degeneration were collected to corroborate the key DEGs using western blot, RT-qPCR, and immunofluorescence staining.RESULTSBy integrating various datasets and references, we identified a total of 1620 acetylation-related genes. These genes were subjected to a combined analysis with the DEGs from the databases included in this study, resulting in the discovery of 358 acetylation-related differentially expressed genes (ARDEGs). A comparative analysis with differentially expressed genes obtained from three databases yielded 19 ARDEGs. The PPI network highlighted the top 10 genes (IL1B, LAMP1, PPIA, SOD2, LAMP2, FBL, MBP, SELL, IRF1 and KHDRBS1) based on their protein interaction relationships. CIBERSORTx immune infiltration analysis revealed a moderate positive correlation between the gene IL1β and Mast.cells.activated, as well as a similar correlation between the gene IRF1 and Mast.cells.activated. Single-cell dataset was used to identify cell types and illustrate the distribution of hub genes in different cell types. The two cell types with the highest AUCell scores (Neutrophils and Monocytes) were further explored, leading to the subdivision of Neutrophils into two new cell subtypes: S100A9-type Neutrophils and MARCKS-type Neutrophils. Monocytes were labeled as HLA-DRA9-type Monocytes and IGHG3-type Monocytes. Finally, molecular biology techniques were employed to validate the expression of the top 10 hub genes. Among them, four genes (IL1β, SOD2, LAMP2, and IRF1) were confirmed at the gene level, while two (IL1β and SOD2) were validated at the protein level.CONCLUSIONIn this study, we carried out a thorough analysis across three databases to identify and compare ARDEGs between IDD patients and healthy individuals. Furthermore, we validated a subset of these genes using molecular biology techniques on clinical samples. The identification of these differently expressed genes has the potential to offer new insights for diagnosing and treating IDD.

2025-01-01·Synthetic and Systems Biotechnology

Establishment of the CRISPR-Cpf1 gene editing system in Bacillus licheniformis and multiplexed gene knockout

Article

作者: Li, Youran ; Shi, Guiyang ; Liu, Suxin ; Wang, Yanling ; Xiao, Fengxu ; Zhang, Yupeng

Bacillus licheniformis is a significant industrial microorganism. Traditional gene editing techniques relying on homologous recombination often exhibit low efficiency due to their reliance on resistance genes. Additionally, the established CRISPR gene editing technology, utilizing Cas9 endonuclease, faces challenges in achieving simultaneous knockout of multiple genes. To address this limitation, the CRISPR-Cpf1 system has been developed, enabling multiplexed gene editing across various microorganisms. Key to the efficient gene editing capability of this system is the rigorous screening of highly effective expression elements to achieve conditional expression of protein Cpf1. In this study, we employed mCherry as a reporter gene and harnessed P _mal for regulating the expression of Cpf1 to establish the CRISPR-Cpf1 gene editing system in Bacillus licheniformis. Our system achieved a 100 % knockout efficiency for the single gene vpr and up to 80 % for simultaneous knockout of the double genes epr and mpr. Furthermore, the culture of a series of protease-deficient strains revealed that the protease encoded by aprE contributed significantly to extracellular enzyme activity (approximately 80 %), whereas proteases encoded by vpr, epr, and mpr genes contributed to a smaller proportion of extracellular enzyme activity. These findings provide support for effective molecular modification and metabolic regulation in industrial organisms.

191

项与 Selectins 相关的新闻（医药）

2024-10-30

·Schrodinger Inc.

基于物理理论的血脑屏障穿透预测方法

人体天生具有对抗外来入侵者的能力。皮肤作为一道物理屏障，可以防止病毒和细菌进入血液循环,我们的免疫系统也会生成抗体来抵抗特定的病原体。血脑屏障（Blood-Brain Barrier, BBB）是另一种重要的防御机制——它是由细胞构成的膜，可以过滤血液并保护大脑免受毒素的侵害。这层膜中的转运蛋白能够识别外来物质并将它们阻挡在大脑之外。血脑屏障对保护大脑至关重要，但也给中枢神经系统（CNS）疾病如阿尔茨海默病、多发性硬化症和帕金森病等的治疗药物开发带来了极大的挑。虽然血脑屏障具有一定的通透性，但要设计出能够成功穿透大脑的分子并非易事。根据最近的一项分析，与非中枢神经系统药物相比，中枢神经系统药物的开发时间要长20％，部分原因就是药物穿过血脑屏障面临的挑战。在开发针对中枢神经系统的小分子药物时，药物化学家必须考虑的一个重要属性：未结合脑-血浆分配系数，简称Kp,uu。这个指标是指药物在血浆和大脑之间的分布比率，能够直接量化血脑屏障的穿透能力，也是中枢神经系统药物研发团队决策的重要参数。薛定谔的内部治疗团队一直积极开发多个中枢神经系统药物的临床前研发专案。在启动这些工作时，我们评估了现有的计算工具，发现它们在预测脑Kp,uu方面的准确性不足，因此我们决定开发一款更为精准的工具。通过持续的研发积累，我们将获得的知识不断反馈到平台中，不断提升其功能，以更好地服务于我们的团队和所有客户。在早期的一个中枢神经系统药物研发专案中，我们获得了大量的脑PK数据，并观察到脑Kp,uu与E-sol（溶解能量）之间存在的强相关性。E-sol 是通过量子力学计算得出的一种基本分子特性，用于测量化合物从气相转化为水相所需的能量。Kp,uu与E-sol之间的这种相关联促使我们在不同项目中用更多分子来进一步验证这种方法。很快，我们意识到 E-sol 可以预测血脑屏障的穿透性。随后，我们将这种物理理论的计算方法应用于多个分子库，包括公共数据集。结果表明，E-sol预测Kp,uu的准确率达到了79％，显著高于现有的任何计算工具。我们开发的这种物理理论方法还可以与机器学习方法结合起来，用于筛选大型化学库中具有良好脑穿透性的潜在化合物。薛定谔治疗团队在中枢神经系统项目中应用E-sol方法，成功加速并提高了脑穿透分子发现的效率。这不仅是薛定谔计算平台强大功能的一个典型案例，也体现了内部团队在研发过程中积累的知识如何不断反馈到平台中，进一步提升平台的能力，为团队自身及所有客户带来更大的价值。最近，我们已在薛定谔LiveDesign平台中成功实施Kp,uu预测，并在多个内部项目中得到了有效应用。我们还在创建一个正确的工作流程，以便外部团队也能在他们的药物研发研究中使用E-sol。相信这种基于物理学的高精度Kp,uu预测方法，将帮助药物化学家和药物发现团队更快速地设计出更好的中枢神经系统治疗药物。作者 Eric Therrien Eric Therrien 是薛定谔治疗团队的主管。自2016年以来，Eric 一直担任计算化学和药物化学家，领导多个合作和内部药物发现项目，重点应用自由能微扰（FEP）方法。他于2005年在蒙特利尔大学获得有机化学博士学位，并在麦吉尔大学进行博士后研究，专攻计算化学领域。埃里克参与了多个药物发现项目，包括肿瘤学、免疫学和神经学领域，并共同撰写了30多篇论文和专利。销售｜china_sales@schrodinger.com 技术｜help@schrodinger.com 培训｜education@schrodinger.com

2024-10-29

·生物探索

Nat Immunol | 淋巴结兼具效应和干性SIV特异性TOX+TCF1+CD39+CD8+T细胞与SIV限制相关

引言在人类免疫缺陷病毒（human immunodeficiency virus，HIV）感染中，CD8+T细胞对于病毒的清除至关重要【1】。因此，CD8+T细胞生物学动态与HIV感染患者息息相关。在慢性感染和肿瘤中，持续的抗原刺激诱导耗竭性T细胞（exhausted T cell，Tx）的产生【2】。TX的典型特征是由TOX等转录因子驱动的转录组和表观组重塑介导的效应功能减弱和抑制性受体的高表达【2】。值得注意的是，TOX不仅表达于Tx，也会表达于部分多功能效应记忆性T细胞，有时甚至与TCF-1共表达【3,4】，呈现干细胞样特性。研究表明，在大多数HIV感染患者中，HIV-特异性CD8+T细胞耗竭分子表达增加与高病毒载量和疾病进展相关【3,5】。在HIV感染患者外周血中，部分HIV-特异性CD8+T细胞中检测到TCF-1和TOX共表达【4】。作为HIV病毒存在和复制的主要位点，淋巴结内CD8+T细胞的表型和功能状态对于治疗策略的改善和设计至关重要。近日，美国埃默里大学国家灵长动物研究中心微生物与免疫学部Mirko Paiardini研究团队在Nature Immunology杂志发表了题为Distinct SIV-specific CD8+ T cells in the lymph node exhibit simultaneous effector and stem-like profiles and are associated with limited SIV persistence的研究文章。这项研究通过流式、质谱、scRNA-seq和TCR-seq等分析在淋巴结内鉴定一群具有干细胞特性中间效应功能的SIV-特异性TOXhiTCF1+CD39+CD8+T细胞，该细胞倾向于淋巴滤泡定居并与靶细胞靠近，且能分化为终末效应细胞参与SIV病毒控制，为SIV/HIV感染提供新的免疫治疗靶点。作者首先在恒河猴中建立猴免疫缺陷病毒（simian immunodefciency virus，SIVmac239）早期（42天）和晚期（17个月）感染模型。流式分析表明淋巴结CD8+T细胞内TOX表达随SIV感染时间延长而显著增加，尤其在CD95+记忆性CD8T细胞（memory CD8+T，TM）。与此同时，流式分析进一步发现淋巴结内 TOX+CD8+TM呈现GzmB+TCF-1-CD39+PD-1+TIGIT+TIM3+CD101+（传统效应T细胞，effector T, TEFF）和GzmK+GzmBlowTCF-1highCD39+PD-1+TIGIT+TIM3+CD101+两种。在未感染恒河猴中，淋巴结CD8+TM主要是TCF1+CD39-（占87%），而TCF1+CD39+只占6%；而在SIV早期感染淋巴结CD8+TM中，TCF1+CD39-占60%，TCF1+CD39+增加至27%；在晚期感染中，TCF1+CD39-降低至30%，而TCF1-CD39+TEFF占30%，TCF1+CD39+增加至40%。尽管TCF1+CD39+细胞群低表达细胞毒GzmB分子，但其与传统TCF1-CD39+TEFF细胞群有相似地活化脱颗粒能力。总之，这些数据表明SIV感染促进淋巴结CD8+T细胞TCF1-CD39+和TCF1+CD39+两种细胞群中TOX表达，虽然TCF1+CD39+细胞低表达细胞毒分子，但表现中间效应功能。为了深入探究TCF1+CD39+CD8+TM功能，作者分离SIV感染恒河猴淋巴结内TCF1+CD39-、TCF1+CD39+和TCF1-CD39+CD8+TM并行质谱分析。结果证实TCF1+CD39+低表达细胞毒分子，包括perforin、GzmB和GzmA。此外，TCF1+CD39+细胞群高表达CD62L（T细胞迁移和淋巴结驻留相关）、CRTAM（淋巴结驻留）、DAP10、EOMES和IFNAR2（抗病毒相关）、NKG2C、NKG2D、CD94、CD160和GzmM（NK细胞毒相关以及T细胞增殖、扩增和功能相关）、CCL5（限制HIV感染）、ZHX3和PLK1（促增殖）和Bcl6（维持CD8细胞干性）。随后，作者分离早期SIV感染淋巴结中SIV特异性CD8+TM并行scRNA-seq分析，发现细胞分为C1（效应）、C2（干细胞样）、C3（增殖）、C4（IFN）和C5（其他）群。值得注意的是，TCF1+CD39+主要富集在C2群，表明干细胞样特性。TCR-seq分析指出TCF1+CD39+细胞群TCR克隆扩增，且主要克隆型与C1群重叠，表明TCF1+CD39+细胞群与TEFF存在线性关系。研究报道PD-1阻断促进干细胞样CD8+T细胞增殖和向TEFF分化【6】。作者发现PD-1抑制剂确实显著增加TCF1+CD39+CD8+TM和TCF1-CD39+TEFF比例，但Ki-67的增加仅在TCF1+CD39+CD8+TM细胞。这些结果表明TCF1+CD39+CD8+TM是一种有干细胞特性的中间效应细胞群，且具有向TEFF分化的能力。随后，作者在SIV感染恒河猴中发现TCF1+CD39+CD8+TM的比例与血浆病毒载量以及淋巴结SIV DNA库呈负相关，表明其可以控制病毒和疾病进展。考虑到CD8+T细胞归巢至淋巴结滤泡与低病毒载量有关【7-9】，作者检测TCF+CD39+CD8+T细胞向淋巴结滤泡的迁移能力。首先，相比于TCF-CD8+T细胞，TCF-CD39+和TCF+CD39+CD8+T细胞CXCR5（滤泡归巢受体）表达显著增加，且TCF1+CD39+CD8+TM中CXCR5的表达同样与血浆病毒载量以及淋巴结SIV DNA库呈负相关，表明CXCR5对于TCF1+CD39+CD8+TM抗SIV的重要作用。其次，免疫荧光证实相比于TCF-CD8+T细胞，更多的TCF1+CD39+CD8+TM定位于B淋巴滤泡区，且与病毒RNA+CD4+靶细胞距离更近，表明TCF1+CD39+CD8+TM细胞具有更好的能力与感染CD4+靶细胞相遇以控制病毒。最后，作者在人HIV淋巴结样本中同样检测到TCF1+CD39+CD8+T细胞的存在。虽然低表达GzmB，但抗原刺激同样诱导脱颗粒和IFNγ表达，表明人HIV感染中TCF1+CD39+CD8+TM细胞可能具有类似的抗病毒能力。综上所述，这项研究在猴和人缺陷免疫病毒感染淋巴结中鉴定一群具有干细胞样中间效应功能的TCF1+CD39+CD8+T细胞群，该细胞尽管缺乏经典细胞毒分子表达，但可以通过CXCR5定位于淋巴结滤泡区并与病毒感染CD4+T细胞作用，并继续分化为终末效应T细胞控制病毒载量，为促进TCF1+CD39+CD8+T扩增介导的病毒控制免疫治疗提供理论基础。参考文献 1. David R, Collins., Gaurav D, Gaiha., Bruce D, Walker.(2020). CD8+ T cells in HIV control, cure and prevention. Nat Rev Immunol, 20(8), 0. doi:10.1038/s41577-020-0274-9 2. Christian U, Blank., W Nicholas, Haining., Werner, Held., Patrick G, Hogan., Axel, Kallies., Enrico, Lugli., et al. (2019). Defining 'T cell exhaustion'. Nat Rev Immunol, 19(11), 0. doi:10.1038/s41577-019-0221-9 3. Jean-Christophe, Beltra., Sasikanth, Manne., Mohamed S, Abdel-Hakeem., Makoto, Kurachi., et al. (2020). Developmental Relationships of Four Exhausted CD8+ T Cell Subsets Reveals Underlying Transcriptional and Epigenetic Landscape Control Mechanisms. Immunity, 52(5), 0. doi:10.1016/j.immuni.2020.04.014 4. Takuya, Sekine., André, Perez-Potti., Son, Nguyen., Jean-Baptiste, Gorin., Vincent H, Wu., Emma, et al. (2020). TOX is expressed by exhausted and polyfunctional human effector memory CD8+ T cells. Sci Immunol, 5(49), 0. doi:10.1126/sciimmunol.aba7918 5. David R, Collins., Jonathan M, Urbach., Zachary J, Racenet., Umar, Arshad., Karen A, Power., et al. (2021). Functional impairment of HIV-specific CD8+ T cells precedes aborted spontaneous control of viremia. Immunity, 54(10), 0. doi:10.1016/j.immuni.2021.08.007 6. Se Jin, Im., Masao, Hashimoto., Michael Y, Gerner., Junghwa, Lee., Haydn T, Kissick., Matheus C, et al. (2016). Defining CD8+ T cells that provide the proliferative burst after PD-1 therapy. Nature, 537(7620), 0. doi:10.1038/nature19330 7. Morgan A, Reuter., Perla M, Del Rio Estrada., Marcus, Buggert., Constantinos, Petrovas., Sara, et al. (2017). HIV-Specific CD8(+) T Cells Exhibit Reduced and Differentially Regulated Cytolytic Activity in Lymphoid Tissue. Cell Rep, 21(12), 0. doi:10.1016/j.celrep.2017.11.075 8. Son, Nguyen., Claire, Deleage., Samuel, Darko., Amy, Ransier., Duc P, Truong., Divyansh, Agarwal., et al. (2019). Elite control of HIV is associated with distinct functional and transcriptional signatures in lymphoid tissue CD8(+) T cells. Sci Transl Med, 11(523), 0. doi:10.1126/scitranslmed.aax4077 9. Constantinos, Petrovas., Sara, Ferrando-Martinez., Michael Y, Gerner., Joseph P, Casazza., Amarendra, et al. (2017). Follicular CD8 T cells accumulate in HIV infection and can kill infected cells in vitro via bispecific antibodies. Sci Transl Med, 9(373), 0. doi:10.1126/scitranslmed.aag2285 https://doi.org/10.1038/s41590-024-01875-0 责编|探索君排版|探索君来源|BioArt End 往期精选围观一文读透细胞死亡(Cell Death) | 24年Cell重磅综述（长文收藏版）热文 Cell | 是什么决定了细胞的大小？热文 Nature | 2024年值得关注的七项技术热文 Nature | 自身免疫性疾病能被治愈吗？科学家们终于看到了希望热文 CRISPR技术进化史 | 24年Cell综述

免疫疗法细胞疗法

2024-10-29

·GlobeNewswire-Health Care

Lyell Immunopharma to Acquire ImmPACT Bio and Prioritizes its Pipeline to Focus on Next-Generation CAR T-cell Therapies

Strengthens Lyell’s clinical pipeline with the addition of IMPT-314, a dual-targeting CD19/CD20 CAR T-cell product candidate Data from ImmPACT’s multi-center Phase 1-2 clinical trial of IMPT-314 in patients with large B-cell lymphoma treated in the 3rd line CAR-naïve setting to be presented at a major medical conference later this year; initiation of a pivotal trial for IMPT-314 expected in 2025 Lyell has prioritized its pipeline to focus on next-generation CAR T-cell therapies, including IMPT-314 and LYL119, and is discontinuing development of LYL797, LYL845 and earlier-stage TIL programs Cash runway following the close of the transaction is expected to fund operations into 2027, through important clinical milestones for each pipeline program Lyell will host an investor webcast at 4:30 PM ET today Oct. 24, 2024 -- Lyell Immunopharma, Inc. (Nasdaq: LYEL) announced today that it has entered into a definitive agreement to acquire ImmPACT Bio USA Inc. (“ImmPACT”), a privately-owned clinical-stage biotechnology company. ImmPACT’s lead program, IMPT-314, is a CD19/20-targeting chimeric antigen receptor (CAR) T-cell product candidate that Lyell will continue to develop for hematologic malignancies, including large B-cell lymphoma. IMPT-314 was designed to outperform the efficacy of approved CD19 CAR T-cell therapies via a dual-targeting CAR T-cell design and to improve CAR T-cell persistence by enriching for naïve and central memory T cells during manufacturing. The acquisition of ImmPACT is expected to significantly strengthen Lyell’s clinical-stage pipeline of next- generation CAR T-cell therapies and complement its suite of proprietary technologies designed to generate longer-lasting, functional T cells to achieve more durable outcomes for patients with solid tumors and hematologic malignancies. “Lyell’s vision is to bring meaningful and durable clinical benefit to patients suffering from cancer with our next-generation cell therapies,” stated Lynn Seely, M.D., Lyell’s President and Chief Executive Officer. “The emerging data from ImmPACT’s ongoing Phase 1-2 trial and the Phase 1 clinical data from a published UCLA-sponsored trial suggest the potential of IMPT-314 to have improved complete response rates and duration of response compared to the approved CD19 CAR T-cell therapies in CAR-naïve patients with aggressive B-cell lymphoma. Since licensing this product candidate from UCLA, the team at ImmPACT has made impressive progress in the multi-center IMPT-314 Phase 1-2 clinical program. We look forward to presenting initial data from this program at a major medical conference later this year and initiating a pivotal trial for IMPT-314 in 2025.” “I am incredibly proud of the ImmPACT team and all of their accomplishments in developing next-generation CAR T-cell therapies,” stated Sumant Ramachandra, M.D., Ph.D., Chief Executive Officer of ImmPACT. “This transaction validates our novel science and enhances the potential for this therapy to make a meaningful impact on patients' lives. I am confident that in Lyell, we have found a team that shares our passion for advancing novel science to benefit patients.” ImmPACT licensed its dual-targeting CD19/CD20 CAR T-cell product candidate from the University of California, Los Angeles (UCLA). Phase 1 data in 13 patients with relapsed/refractory (R/R) aggressive non-Hodgkin lymphoma treated in a UCLA-sponsored clinical trial were presented at the 2024 AACR Special Conference in Cancer Research: Tumor Immunology and Immunotherapy. CAR T-cell naïve patients with R/R diffuse large B-cell lymphoma or primary mediastinal B-cell lymphoma after at least two lines of therapy or mantle cell lymphoma, follicular lymphoma or chronic lymphocytic leukemia/small lymphocytic lymphoma after at least three lines of therapy were evaluated. Autologous T cells were obtained and enriched for CD14-/CD25-/CD62L+ naïve or memory T cells. Twelve out of 13 patients achieved a complete or partial response (92% objective response rate), with ten achieving a confirmed complete response (CR) (77% CR rate). The median progression-free survival was 50.1 months, and median overall survival was not reached with a median follow up of 32 months (range: 5.7 – not estimable). A favorable safety profile was observed. The ongoing Phase 1-2 clinical trial initiated by ImmPACT is a multi-center, open-label clinical trial designed to evaluate the tolerability and clinical benefit of IMPT-314 in patients with R/R aggressive B-cell lymphoma and determine a recommended Phase 2 dose. Initial Phase 1-2 clinical data evaluating IMPT-314 primarily in patients who have received at least two prior lines of therapy for large B-cell lymphoma will be presented at a major medical conference this year. IMPT-314 has received Fast Track Designation from the U.S. Food and Drug Administration for the treatment of R/R aggressive B-cell lymphoma. Lyell expects to initiate a pivotal trial in 2025 for IMPT-314 in patients in the 3rd line setting who have not yet been exposed to CAR T-cell therapy. In connection with the acquisition, Lyell has prioritized its pipeline to focus resources on its most differentiated CAR T-cell clinical programs, including IMPT-314 following the close of the acquisition and LYL119. The enhanced anti-exhaustion technology incorporated into LYL119, including c-Jun overexpression, NR4A3 knockout, Epi-R and Stim R, has the potential to achieve improved efficacy at lower cell doses with an acceptable safety profile. In a validated in vivo preclinical model of non-small cell lung cancer, LYL119 achieved tumor control at a 10-fold lower cell dose than LYL797 with more gradual cell expansion to peak, and a substantial increase in the duration of cell killing demonstrated by a repetitive tumor cell killing assay in vitro. Lyell is discontinuing development of LYL797, its ROR1-targeted CAR T-cell product candidate to focus on the Phase 1 clinical trial of its next-generation ROR1-targeted CAR T-cell product candidate LYL119, which is expected to initiate enrollment of patients with platinum-resistant ovarian cancer or relapsed/refractory endometrial cancer this year or early next year. The LYL845 tumor-infiltrating lymphocyte (TIL) program is also being discontinued as the clinical data in patients with advanced melanoma did not meet our rigorous pre-determined criteria for continued development. Its next-generation TIL and rejuvenation programs that are in preclinical development will also be discontinued. Following the close of the transaction, Lyell expects its cash balance will fund operations into 2027, through important clinical milestones for each pipeline program, including initiation of a pivotal trial for IMPT-314, which is expected to start in 2025. Upon closing, Lyell will acquire worldwide rights to ImmPACT’s pipeline, including the next- generation bispecific CD19/CD20 autologous CAR T-cell therapy, currently in clinical development for B-cell lymphoma and autoimmune diseases, and an activating TGF-beta Claudin 18.2 CAR T-cell candidate, which is in preclinical development. Lyell will prioritize the development of IMPT-314 for patients with B-cell lymphoma. Deal terms include upfront consideration payable upon closing the potential transaction of $30 million in cash, subject to certain adjustments, and 37.5 million shares of Lyell common stock. ImmPACT shareholders will also be eligible to receive contingent consideration consisting of 12.5 million shares of Lyell common stock that may be earned upon the achievement of a value-enhancing clinical milestone and a low single-digit royalty on future net sales of the dual-targeting CD19/20 CAR T-cell product in the United States. The proposed transaction, which has been unanimously approved by the Boards of Directors of both companies, is expected to close in the fourth quarter of 2024. The closing of the proposed transaction is subject to expiration of the Hart-Scott-Rodino antitrust waiting period and the satisfaction of other customary closing conditions. Goldman Sachs & Co LLC is acting as sole financial advisor to Lyell in this transaction and Skadden, Arps, Slate, Meagher & Flom LLP is acting as its legal advisor. Cooley LLP is acting as ImmPACT’s legal advisor. Lyell’s management will host an investor conference call and Webcast beginning at 4:30 pm ET today. The Webcast can be accessed here. A replay of the event and presentation materials will be archived on the Investor page of the Lyell Website following the end of the event. Lyell is a clinical-stage company advancing a pipeline of next-generation CAR T-cell therapies for patients with solid tumors or hematologic malignancies. Lyell’s product candidates are enhanced with novel technology designed to generate T cells that resist exhaustion and have qualities of durable stemness in order to drive durable tumor cytotoxicity and achieve consistent and long-lasting clinical response. Lyell is based in South San Francisco, California with facilities in Seattle and Bothell, Washington. To learn more, please visit www.lyell.com. The content above comes from the network. if any infringement, please contact us to modify.