更新于：2024-05-01

GEF-H1

Rho鸟嘌呤核苷酸交换因子2

更新于：2024-05-01

基本信息

别名

ARHGEF2、GEF-H1、GEFH1

+ [10]

简介

Activates Rho-GTPases by promoting the exchange of GDP for GTP. May be involved in epithelial barrier permeability, cell motility and polarization, dendritic spine morphology, antigen presentation, leukemic cell differentiation, cell cycle regulation, innate immune response, and cancer. Binds Rac-GTPases, but does not seem to promote nucleotide exchange activity toward Rac-GTPases, which was uniquely reported in PubMed:9857026. May stimulate instead the cortical activity of Rac. Inactive toward CDC42, TC10, or Ras-GTPases. Forms an intracellular sensing system along with NOD1 for the detection of microbial effectors during cell invasion by pathogens. Required for RHOA and RIP2 dependent NF-kappaB signaling pathways activation upon S.flexneri cell invasion. Involved not only in sensing peptidoglycan (PGN)-derived muropeptides through NOD1 that is independent of its GEF activity, but also in the activation of NF-kappaB by Shigella effector proteins (IpgB2 and OspB) which requires its GEF activity and the activation of RhoA. Involved in innate immune signaling transduction pathway promoting cytokine IL6/interleukin-6 and TNF-alpha secretion in macrophage upon stimulation by bacterial peptidoglycans; acts as a signaling intermediate between NOD2 receptor and RIPK2 kinase. Contributes to the tyrosine phosphorylation of RIPK2 through Src tyrosine kinase leading to NF-kappaB activation by NOD2. Overexpression activates Rho-, but not Rac-GTPases, and increases paracellular permeability (By similarity). Involved in neuronal progenitor cell division and differentiation (PubMed:28453519). Involved in the migration of precerebellar neurons (By similarity).

关联

项与 GEF-H1 相关的药物

Plinabulin

普那布林

靶点

GEF-H1

作用机制

GEF-H1激动剂

在研机构

The University of Texas MD Anderson Cancer Center [+6]

原研机构

BeyondSpring Pharmaceuticals, Inc.

在研适应症

化疗引起的发热性中性粒细胞减少症 [+16]

非在研适应症

晚期非小细胞肺癌

最高研发阶段临床3期

首次获批国家/地区-

首次获批日期1800-01-20

项与 GEF-H1 相关的临床试验

NCT05745350 / Not yet recruiting临床2期IIT

An Open-Label, Single-Arm, Phase II Study of Pembrolizumab, Plinabulin Plus Etoposide and Platinum as First-Line Therapy for Extensive-Stage Small-Cell Lung Cancer

Monoclonal antibodies against programmed death 1 (PD-1) and its ligand PD-L1 have shown efficacy in patients with ES-SCLC in the monotherapy and combination therapy settings. Up to now, Atezolizumab and Durvalumab has been approved for first line treatment for ES-SCLC in China combined with EP or EC. Besides, KEYNOTE-604 study revealed that adding pembrolizumab to standard first-line EP significantly improves PFS in patients with ES-SCLC and is associated with durable responses in a subset of patients. 12-m PFS rate were 13.6% with pembrolizumab plus EP and 3.1% with placebo plus EP. The statistical threshold for declaring significant prolongation of OS was narrowly missed. Considering sicker pts was enrolled and the interim analysis was quite often, even though the investigators narrowly missed the OS endpoint, longer numerical OS data was observed. The latest version of NCCN SCLC guidelines still recommended pembrolizumab as an option for ES-SCLC patients.
Plinabulin received breakthrough designation from both US and China FDA for CIN (Chemotherapy Induced Neutropenia) prevention indication. As a "pipeline in a drug," plinabulin is being broadly studied in combination with various immuno-oncology agents that could boost the effects of the PD-1/PD-L1 antibodies and re-sensitize PD-1/PD-L1 antibody resistant patients. In a poster released at 2021 ASCO conference, a phase I trial of Plinabulin in combination with nivolumab and ipilimumab in patients with relapsed small cell lung cancer: Big Ten Center Research Consortium (BTCRC-LUN17-127) study. Plinabulin in combination with nivolumab and ipilimumab was safe and well tolerated with promising efficacy signal of 46% ORR.
From above, Pembrolizumab, Plinabulin plus Etoposide and Platinum as First-Line Therapy for ES-SCLC should be a promising combination therapy, as the investigators expect increased efficacy and reduced toxicity with the addition of Plinabulin. In this proof of concept phase II study, the investigators will investigate that the efficacy and safety of Pembrolizumab, Plinabulin plus Etoposide and Platinum as First-Line Therapy for ES-SCLC.

开始日期2023-11-01

申办/合作机构

武汉协和医院

NCT05599789 / Recruiting临床2期IIT

A Phase 2 Study of Pembrolizumab in Combination With Plinabulin and Docetaxel in Previously Treated Patients With Metastatic Non-Small Cell Lung Cancer and Progressive Disease (PD) After Immunotherapy (Anti-PD-1/PD-L1 Inhibitor) Alone or in Combination With Platinum-doublet Chemotherapy (KeyPemls-004)

A Phase 2 Study of Pembrolizumab in Combination with Plinabulin and Docetaxel in previously treated Patients with Metastatic Non-Small Cell Lung Cancer and progressive disease (PD) after immunotherapy (Anti-PD-1/PD-L1 inhibitor) alone or in combination with Platinum-doublet Chemotherapy.

开始日期2023-02-01

申办/合作机构

北京协和医院

[+2]

NCT05130827 / Active, not recruiting临床2期IIT

Pilot Trial of Plinabulin and Pegfilgrastim to Reduce the Duration of Absolute Neutropenia After Autologous Hematopoietic Cell Transplantation for Patients With Multiple Myeloma

This study will see how long it takes for white blood cell counts to return to normal in people with multiple myeloma (MM) who receive plinabulin and pegfilgrastim after undergoing an autologous hematopoietic stem cell transplant (AHCT).

开始日期2021-12-21

申办/合作机构

Memorial Sloan Kettering Cancer Center

[+1]

100 项与 GEF-H1 相关的临床结果

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100 项与 GEF-H1 相关的转化医学

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0 项与 GEF-H1 相关的专利（医药）

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654

项与 GEF-H1 相关的文献（医药）

2024-02-12·Journal of cell science

TIAM-1 regulates polarized protrusions during dorsal intercalation in the C. elegans embryo through both its GEF and N-terminal domains.

Article

作者: Yuyun Zhu ; Zoe Tesone ; Minyi Tan ; Jeff Hardin

Mediolateral cell intercalation is a morphogenetic strategy used throughout animal development to reshape tissues. Dorsal intercalation in the C. elegans embryo involves the mediolateral intercalation of two rows of dorsal epidermal cells to create a single row that straddles the dorsal midline, and so is a simple model to study cell intercalation. Polarized protrusive activity during dorsal intercalation requires the C. elegans Rac and RhoG orthologs CED-10 and MIG-2, but how these GTPases are regulated during intercalation has not been thoroughly investigated. In this study, we characterize the role of the Rac-specific guanine nucleotide exchange factor (GEF), TIAM-1, in regulating actin-based protrusive dynamics during dorsal intercalation. We find that TIAM-1 can promote formation of the main medial lamellipodial protrusion extended by intercalating cells through its canonical GEF function, while its N-terminal domains function to negatively regulate the generation of ectopic filiform protrusions around the periphery of intercalating cells. We also show that the guidance receptor UNC-5 inhibits these ectopic filiform protrusions in dorsal epidermal cells, and that this effect is in part mediated via TIAM-1. These results expand the network of proteins that regulate basolateral protrusive activity during directed rearrangement of epithelial cells in animal embryos.

2024-02-08·JCI insight

PREX1 improves homeostatic proliferation to maintain a naïve CD4 T cell compartment in older age.

Article

作者: Huimin Zhang ; Hirohisa Okuyama ; Abhinav Jain ; Rohit R Jadhav ; Bowen Wu ; Ines Sturmlechner ; Jose Morales ; Shozo Ohtsuki ; Cornelia M Weyand ; Jörg J Goronzy

The human adult immune system maintains normal T-cell counts and compensates for T-cell loss over lifetime mainly through peripheral homeostatic proliferation after the ability of the thymus to generate new T cells has rapidly declined at adolescence. This process is mainly driven by STAT5-activating cytokines, most importantly IL-7, and is very effective in maintaining a large naïve CD4 T cell compartment into older age. Here, we describe that naïve CD4 T cells undergo adaptations to optimize IL-7 responses by upregulating the guanine-nucleotide exchange factor PREX1 at older age. PREX1 promotes nuclear translocation of phosphorylated STAT5, thereby supporting homeostatic proliferation in response to IL-7. Through the same mechanism, increased expression of PREX1 also biases naïve cells to differentiate into effector T cells. These findings are consistent with the concept that primarily beneficial adaptations during aging, i.e., improved homeostasis, account for unfavorable functions of the aged immune system, in this case biased differentiation.

2024-02-01·Neuropathology and applied neurobiology

Comparative interactome mapping of Tau-protein in classical and rapidly progressive Alzheimer's disease identifies subtype-specific pathways.

Article

作者: Abrar Younas ; Neelam Younas ; Muhammad Javed Iqbal ; Isidre Ferrer ; Inga Zerr

AIMS:

Tau is a key player in Alzheimer's disease (AD) and other Tauopathies. Tau pathology in the brain directly correlates with neurodegeneration in AD. The recent identification of a rapid variant of AD demands an urgent need to uncover underlying mechanisms leading to differential progression in AD. Accordingly, we aimed to dissect the underlying differential mechanisms of toxicity associated with the Tau protein in AD subtypes and to find out subtype-dependent biomarkers and therapeutic targets.

METHODS:

To identify and characterise subtype-specific Tau-associated mechanisms of pathology, we performed comparative interactome mapping of Tau protein in classical AD (cAD) and rapidly progressive AD (rpAD) cases using co-immunoprecipitation coupled with quantitative mass spectrometry. The mass spectrometry data were extensively analysed using several bioinformatics approaches.

RESULTS:

The comparative interactome mapping of Tau protein revealed distinct and unique interactors (DPYSL4, ARHGEF2, TUBA4A and UQCRC2) in subtypes of AD. Interestingly, an analysis of the Tau-interacting proteins indicated enrichment of mitochondrial organisation processes, including negative regulation of mitochondrion organisation, mitochondrial outer membrane permeabilisation involved in programmed cell death, regulation of autophagy of mitochondrion and necroptotic processes, specifically in the rpAD interactome. While, in cAD, the top enriched processes were related to oxidation-reduction process, transport and monocarboxylic acid metabolism.

CONCLUSIONS:

Overall, our results provide a comprehensive map of Tau-interacting protein networks in a subtype-dependent manner and shed light on differential functions/pathways in AD subtypes. This comprehensive map of the Tau-interactome has provided subsets of disease-related proteins that can serve as novel biomarkers/biomarker panels and new drug targets.

项与 GEF-H1 相关的新闻（医药）

2024-01-26

·蒲公英Ouryao

恒瑞医药诉讼请求被驳回

转自：蒲公英Ouryao 综合：蒿山君2024年1月26日，恒瑞医药与万春医药的纠纷迎来后续。万春医药公告称恒瑞医药相关诉讼请求被仲裁庭驳回。这或许意味着恒瑞医药付给大连万春的2亿元首付款将要打了水漂。一场争议BD始末近日，万春医药发布公告称，公司在中国的58%控股子公司万春布林参与了恒瑞发起的仲裁程序。2024年1月10日，中国国际经济贸易仲裁委员会的仲裁庭作出了最终裁决，驳回了恒瑞提出的所有诉讼请求。至此，普那布林BD纠纷案告一段落，恒瑞医药付出去的2亿元首付款可能将“打水漂”。大连万春、万春生物均属美股上市企业万春医药集团体系。主公司万春生物2017年纳斯达克上市。2021年4月份，万春向国家药监局和美国FDA递交了普那布林新药上市申请，获得受理并纳入优先审评。4个月后的2021年8月，恒瑞医药与万春达成合作。恒瑞医药与万春方面合作时约定，就GEF-H1激活剂普那布林在大中华地区的联合开发权益以及独家商业化权益，恒瑞医药支付首付款加里程碑款总额不超过13亿元。此外，恒瑞医药拟以自筹资金1亿元认购大连万春的股份，后者在完成本轮融资后，公司对其持股占比不低于2.5%。普那布林同时具有抗肿瘤和缓解化疗副作用前景，一度被寄望成为新的利润增长点。业界普遍认为普那布林有望成为30年来CIN领域中的突破性治疗品种。 2021年9月，万春医药公布了普那布林用于NSCLC的III期临床数据，却被质疑入组患者不标准。合作4个月后的2021年12月1日，万春医药宣布普那布林CIN的上市申请被FDA拒绝批准，理由是仅一个三期注册临床不能充分证明治疗获益，FDA要求进行第二项注册临床。2023年3月10日，恒瑞医药公告披露，普那布林的新药上市申请未获NMPA批准。但公司已向万春支付2亿元首付款，并且后续没有研发计划。双否之后，恒瑞医药选择与万春医药对簿公堂。2023年9月，恒瑞医药申请冻结大连万春2亿元的法律裁定被公开。2024年1月26日，恒瑞医药与万春医药的纠纷迎来后续。万春医药公告称恒瑞医药相关诉讼请求被仲裁庭驳回。但单一品类药品的研发失败并不代表恒瑞整体BD战略的失败。恒瑞BD，按下加速键公开资料显示，截至2023年，恒瑞创新转型取得了丰硕成果：15款创新药已成功上市，其中13款是自主研发的1类创新药；270多项临床试验正在国内外开展，每年产生10个FIC/BIC临床前候选化合物，产品管线丰富度、数量及研发效率居于业内领先位置。2018年-2022年，恒瑞共与十大药企达成了战略合作。到2023年，恒瑞的BD动作更是按下了加速键。从创新药EZH2抑制剂SHR2554开启2023年对外授权的首章，到与默克达成最高可达14亿欧元的交易，一年时间共达成5起海外BD授权，出现了1个月内连续产生3笔License-out授权交易的情况，并首次与MNC牵手。2023年全年，恒瑞BD交易额超40亿美元。当前全球BD交易不断，身在其中的本土药企，练好研发能力和创新产品之外，尽快补上BD市场这一课。欢迎留言，更多观点。2023年精彩文章推荐:推荐阅读：蒲公英Ouryao视频号投稿、广告、商务合作： Qinrenlvcha

临床3期引进/卖出优先审批突破性疗法

2023-11-22

·药渡Daily

第3代长效升白药中美上市启示：老牌药企也需创新药焕新春

细说起来，亿帆医药也算得上千禧年那波成立的中流砥柱企业。一路发展至今，彼此之间的行为轨迹也大抵相似——流通代理，仿制引进、自研造血。它的前身是合肥亿帆医药，成立于2003年，以药品配送和代理起家。而从两票制政策出台的2017年回望过去，如果停留在经销商阶段，那么亿帆医药也只是死伤惨重的someone。但正如每一个存活至今的老牌药企一样，转型是必经的道路。但相比仿制药企猝不及防所遭受的集采痛击，亿帆医药相对走得没有那么阵痛。2014年，亿帆医药找上鑫富药业，重组上市获得一大笔资金。此后开始一路大量并购制药企业/管线：从国药一心买了7个血液瘤产品，收购创新药公司DHY半数股权，境外并购NovoTek、SciGen等等，花钱妥妥“暴发户”做派。但医药的特性在于，一款“爆品”跑出，就有可能收回全部成本。当初DHY旗下的子公司上海健能隆，现更名为亿一生物，就贡献了一款重磅升白药——艾贝格司亭α注射液（F-627）——继上半年成功国内上市后，11月又成功闯关FDA，以Ryzneuta为名成功在美上市。只需要一个杠杆，亿帆药业就可以撬动某个细分市场。那么，F-627会成为升白药的黑马吗？升白药突然杀出一匹黑马去年以来，靶向化疗ADC的热度节节攀高，但目前获批的一线疗法中，ADC也多是以和免疫检查点抑制剂联用出现，作为不适用化疗的替补选手。换言之，肿瘤治疗手段中，化疗的地位仍然无可撼动。这也意味着，化疗所带来的常见副作用，仍然有解决价值。骨髓抑制是化疗的常见副作用，其中生存时间最短的粒细胞数量率先降低。粒细胞水平变化的U型曲线，常常开始于药物治疗的第1周期；而后2周左右下降到最低点，至自然恢复往往需要等待3-4周时间。但重度的粒细胞减少，“轻”则导致化疗剂量降低/延迟给药，甚至终止给药，致使癌症患者的临床疗效降低；重则引起细菌感染等并发症，致使患者死亡率显著升高。临床上，粒细胞集落刺激因子（G-CSF）是预防和治疗中性粒细胞减少症的主要手段之一——有数据表明，自第1化疗周期起使用G-CSF进行一级预防，可使得中性粒细胞缺乏伴发热（FN）风险降低50%。目前市场上，既有短效也有长效G-CSF，既有原研也有仿制药。全球首款短效G-CSF非格司亭（Neupogen）由安进于1991年推出市场；而后在2002年，安进复又推出它的长效剂型培非格司亭（Neulasta）。从时间上也可看出，培非格司亭的专利期已过。在2018年，美国市场上开始涌现出一大批它的仿制药，其中销售额尚可一提的是山德士推出的Ziextenzo，2022年卖出4.33亿美元，但相比原研药培非格司亭的20.51亿美元，仍有很远差距。墙外竞争火葬场，墙内也不好过。在F-627获批之前，国内已经有6款长效G-CSF获批，形成了由石药集团的津优力，齐鲁制药的新瑞白和恒瑞医药的艾多三足鼎立的场面，后来者山东新时代的申力达、双鹭药业的久立、复星医药的佩金，尚未成一方气候。那么，F-627能从其中突围而出吗？这个问题也叩问着亿帆药业。F-627的结构F-627有它的特别之处，首先它是全球首个双分子G-CSF Fc融合蛋白，获得了疗效增加、半衰期延长的双重buff：不光是化疗周期只需给药1次，在疗效方面也拔高为培非格司亭的2-3倍。其次在安全性方面，F-627造成肌肉疼痛、骨骼疼痛和脱离率更低，解决了二代长效G-CSF药物因采用PEG化修饰而造成部分患者出现过敏的副反应。上述提到的国内3个G-CSF 长效头部选手都是采取了PEG化修饰，这是亿帆药业为之自信可超越前辈们的一点。撬起临床的杠杆如IQVIA数据统计，2022年全球G-CSF 全球市场份额为60.2亿美元；回观国内，中国的G-CSF规模大约为150亿元，其中有90%的市场规模都由长效G-CSF贡献。考虑到化疗所铺开的摊子，升白药的市场还会进一步扩大。在G-CSF之外，新型升白药GEF-H1激活剂普纳布林曾被寄予厚望。恒瑞以总计不超过13亿元价格从万春医药中license-in该药物，用于治疗由化疗引起的中性粒细胞减少症。恒瑞打了一个算盘，普纳布林和自己旗下的长效G-CSF艾多协同使用，会成为中性粒细胞减少症这一适应症中的重磅拳头搭档。然后事态后续发展却出乎所有人意料。当万春医药向FDA提交普纳布林的上市申请被猝不及防打回之后，恒瑞医药陷入了有关普纳布林的临床试验争议泥潭。今年9月，北京第二中级人民法院公布民事裁定书，批准恒瑞医药对于冻结大连万春名下2亿元资产的财产保全申请。普纳布林没有打开美国市场，但是F-627打开了。对于一款药物的未来销售的预期insight，就在临床试验中。那么，回过头来看亿帆药业，F-627的临床试验又是表现如何？中国进行的III期研究SP11631中，在至少接受过4个疗程的乳腺癌化疗的入组患者中，F-627分别达到了主要和次要指标，即与协和麒麟的升白药惠尔血并无统计学差异。具体来说，第1化疗周期内3级或4级中性粒细胞减少症的平均持续时间，F-627组非劣于对照组惠尔血组，分别为0.68天和0.71天，中性粒细胞减少症的发生率分别为34.2%和42.9%，以及第1化疗周期内FN的发生率，分别为0.8% 和1.7%。境外进行的两项III期研究GC-627-04和GC-627-05也选择了乳腺癌患者，也均达到了主要和次要目标，其中GC-627-05的对照组选择了安进的培非格司亭，且效果不劣于后者。国内方面，亿帆药业将F-627的相关权益于2021年12月授予正大天晴南京顺欣，并获得最高可达2.1亿元的首付款与里程碑付款，及分级的净销售额提成费。今年5月上市后，F-627的正式定价为5998元/支，坦白来说，相比恒瑞的艾多之类已被纳入医保，总疗程用下来的价格要比F-627少一半。不过我们也能看到，亿帆药业也正在积极推进医保谈判。根据方正证券估算，如果F-627参与国谈，降价为3000元/支，以及此后每两年定价略有下调，按照市场规模估算出F-627在国内的销售峰值将有望超过30亿元。海外的搏斗更为激烈，和国内一样，亿帆药业在国外当地寻找代理商。将F-627的美国权益授权给ACROTECH公司；将德国、瑞士的商业化权益许可授权给APOGEPHA公司；将希腊及塞浦路斯的商业化权益许可给KALTEQ公司。另一款生物药管线2023年上半年，亿帆医药总创收达到19.4亿元，同期增长9.87%。而进一步看营收来源，发现中成药和化药占了近两壁江山。相比之下，生物药的营收收入相差了一个量级。但是伴随F-627为代表的管线的逐步实现商业化，生物药将成为亿帆医药第二增长曲线。在亿帆医药的生物药版图中，还有一个值得关注的候选药物是F-652。作为全球首个进入临床研究的重组IL-22融合蛋白药物，F-652目前在研适应症包括酒精性肝炎、慢性肝衰竭急性、移植物抗宿主病、坏死性小肠结肠炎（常见于新生儿）。除了最后一项，前3项适应症都在中美两地开展了临床研究，并已经进展到II期阶段。以慢性肝衰竭急性来说，这是一种在慢性肝病基础上出现的急性肝损伤症候群，具有高病死率。我国作为“乙肝大国”，慢性乙肝的患病人数已经达到3000万左右。临床前数据显示，F-652可通过逆转肝内STAT1/STAT3激活失衡，促进肝脏再生和减少细菌感染从而改善慢性肝衰竭急性小鼠的存活率。此外，F-652在移植物抗宿主病和酒精性肝炎适应症上均通过了美国FDA IIa期临床试验，并获得移植物抗宿主病孤儿药资格。酒精性肝炎也正面临着治疗方法短缺的困境，常用的激素疗法主要疗效指标的达成反应率仅为6-12%，而F-652却能达到82%。简而言之，“万金油”的F-652，瞄准了近50亿美元的潜在市场。如果F-652能成功上市，哪怕只取一瓢，对亿帆医药来说，也是动辄十亿美元的营收增长。小结亿帆医药是国内老牌药企，但在很多人的印象中，这家药企还是以原料药和中成药为主，而忽视了其向创新药转型的魄力。第三代长效G-CSF的F-627先后在国内外同年获批中性粒细胞减少症，打开国际化窗口。而后瞄准4项适应症，更“万金油”的F-652也在中美两地进入II期临床试验。当大家习惯盯着创新药企的动态时，传统药企借助其殷实的资金以及销售渠道等历史积淀，通过引进或自研创新药管线，在新型生物药的开发方面，同样占据了不可小觑的一方。参考资料亿帆医药股份有限公司2023年半年度报告摘要艾贝格司亭 α 注射液（CXSS2200018）申请上市技术审评报告，2023.07方正证券：亿帆医药F627获批FDA上市，国产创新药出海不断拓展

抗体药物偶联物并购专利到期

2023-11-07

·GlobeNewswire-Health Care

BeyondSpring Presents Poster Highlighting Preclinical and Clinical POC Immunomodulating Activity of Plinabulin Inducing Dendritic Cell Maturation and Re-sensitization in Immunotherapy Refractory Tumors when Combined with Radiation and PD-1/PD-L1 Inhibitors

New Clinical Data from MD Anderson Presented at the Society for Immunotherapy of Cancer’s 38th Annual Meeting80% DCR (disease control rate) in non-radiated tumor with Durable Responses in Heavily Pretreated Patients in 6 different cancersFull data was presented at SITC’s 38th Annual Meeting; The Company will host a call at 8:30 a.m. ET today. Dial in: 877-407-0792, conference title: Clinical Significance of Plinabulin SITC Presentation with PI Dr. Steven Lin from MD Anderson NEW YORK, Nov. 07, 2023 (GLOBE NEWSWIRE) -- BeyondSpring Inc. (NASDAQ: BYSI) (“BeyondSpring” or the “Company”), a global clinical-stage biopharmaceutical company focused on using a groundbreaking technology platform for drug discovery and developing innovative therapies to improve clinical outcomes for patients with high unmet medical needs, today announced new data that translates preclinical proof-of-concept to clinical evidence of plinabulin’s immunomodulating activity. BeyondSpring and MD Anderson presented the data at the Society for Immunotherapy of Cancer's (SITC) 38th Annual Meeting on Nov 4th in San Diego, CA on an open-label, Phase 1 basket study at The University of Texas MD Anderson Cancer Center in cancer patients after progressing on PD-1, PD-L1 and/or CTLA-4 antibodies (NCT04902040) in six cancer types. Based on preclinical models, where plinabulin plus radiation and anti-PD-1 antibody enhances dendritic cell (DC) activation, T-cell proliferation, and abscopal effect, a clinical study was initiated to test these findings. At the Phase 1 data cut-off (August 31, 2023), 19 heavily pretreated patients with 6 different cancers were exposed to plinabulin (30 mg/m2) after radiation initiation to an amendable lesion (3-6 hours apart) plus anti-PD-1 antibody, including pembrolizumab or nivolumab. 11 out of 14 patients eligible for efficacy assessment per RECIST criteria and had measurable target lesion responses in the non-irradiated tumor lesion. Disease control rate evaluates the tumor reduction in non-irradiated tumor to assess abscopal effect from immune agents. 80% DCR (disease control rate) in non-irradiated tumor: In 10 immunotherapy-refractory patients of 6 different cancers (Hodgkin Lymphoma, NSCLC, SCCHN, Merkel Cell Carcinoma, RCC, Fibrolamellar HCC), plinabulin triple combination is safe and yields encouraging response with 80% disease control rate (3 PR, 5 SD, 2 PD).Durable Response in heavily pre-treated patients: 2 Hodgkin’s lymphoma patients who progressed after 12 or 16 prior lines of therapy respectively, had durable responses with one PR and one SD. These patients continued treatment after data cutoff.DC maturation in responding patients: Plinabulin administered after radiation initiation induces an early systemic immune response (detectable 3 days later) in subsets of peripheral blood DC and monocytes in patients with clinical benefits (PR+SD).Plinabulin mediates GEF-H1-dependent immune activation in responding patients: In patients with PR+SD, tumor scRNAseq analysis indicates GEF-H1-dependent immune activation in subsets of DC and monocyte-derived macrophages. Such activation was not seen in patients with PD.Additional biomarker analyses at baseline and post-treatment are underway. “There are severe unmet medical needs for cancer patients who progress on immunotherapies. We have been studying Plinabulin for 6 years, starting from preclinical proof-of-concept work in showing its DC maturation, abscopal effect and selective sequencing benefit with radiation, presented at the 2020 AACR meeting, and now the successful clinical translation in the triple IO regimen and its notable high disease control rate in these hard-to-treat and multiple refractory cancers,” Dr. Steven H. Lin, MD/PhD, professor of radiation oncology at MD Anderson commented. “These results are encouraging but preliminary. Based on the consistent mechanism in DC maturation in responding patients, this sets the stage for additional clinical studies of plinabulin/IO combinations in IO-refractory settings in a number of indications, including NSCLC and Hogkins Lymphoma.” SITC Conference Abstract Number: 732Title: Immune Activation with Plinabulin Enhances Anti-tumor response Combining Radiation with Immune Checkpoint BlockadePresenter: Steven H. Lin, MD/PhDSession: Poster Hall Phase 1 Study RegimenAll subjects received a triple combo treatment of Radiation Therapy (RT) + Plinabulin + Pembrolizumab or Nivolumab in Cycle 1, followed by the same anti-PD-1 antibody and plinabulin combo regimen in Cycle 2 and beyond until disease progression or development of unacceptable toxicity, withdrawal from study treatment, or discontinuation of this study. A short course of local consolidative RT was administered in Cycle 1 starting from Day 1. Optional sequential RT may have been administered to target other untreated lesions at discretion of the treating doctor in Cycle 2 of any regimens.Plinabulin was dosed on Day 1 and Day 4 of Cycle 1 of any anti-PD-1 regimen, and if optional RT was given in Cycle 2, Plinabulin was also given on Day 4 of Cycle 2. Plinabulin was given on Day 1 of Cycle 3 and thereafter. Anti-PD-1 antibody was dosed on Day 1 of every treatment cycle (also on Day 15 [Q4W] in case of regimen containing Nivolumab as Anti-PD-1 mAb).Subjects received the same anti-PD-1/PD-L1 mAb they failed in the prior treatment. Conference Call and Webcast InformationBeyondSpring will host a conference call and webcast today at 8:30 a.m. Eastern Time. The dial in numbers for the conference call are 1-877-407-0792 (U.S.) or 1-201-689-8263 (international). Please reference conference title: Clinical Significance of Plinabulin SITC Presentation with PI Dr. Steven Lin from MD Anderson. A live webcast will be available on BeyondSpring’s website at www.beyondspringpharma.com under “Events & Presentations” in the Investors section. An archived replay of the webcast will be available for 30 days. About BeyondSpringBeyondSpring (NASDAQ: BYSI) is a global clinical-stage biopharmaceutical company focused on developing innovative therapies to improve clinical outcomes for patients with high unmet medical needs. The Company is advancing its first-in-class lead asset, Plinabulin, as a direct anti-cancer agent in various cancer indications and to prevent chemotherapy-induced neutropenia. Its pipeline also includes three preclinical immuno-oncology assets. Additionally, BeyondSpring’s subsidiary, SEED Therapeutics, leverages a proprietary targeted protein degradation (TPD) drug discovery platform and has an initial R&D collaboration with Eli Lilly. Learn more by visiting https://beyondspringpharma.com. Investor Contact:IR@beyondspringpharma.com Media Contact:PR@beyondspringpharma.com

临床结果免疫疗法AACR会议放射疗法