更新于：2024-11-01

CTSG

更新于：2024-11-01

基本信息

别名

组织蛋白酶G、Cathepsin G、Cathepsin G, C-terminal truncated form

+ [2]

简介

Serine protease with trypsin- and chymotrypsin-like specificity (PubMed:8194606, PubMed:29652924). Also displays antibacterial activity against Gram-negative and Gram-positive bacteria independent of its protease activity (PubMed:2116408, PubMed:2117044). Prefers Phe and Tyr residues in the P1 position of substrates but also cleaves efficiently after Trp and Leu (PubMed:29652924). Shows a preference for negatively charged amino acids in the P2' position and for aliphatic amino acids both upstream and downstream of the cleavage site (PubMed:29652924). Required for recruitment and activation of platelets which is mediated by the F2RL3/PAR4 platelet receptor (PubMed:3390156, PubMed:10702240). Binds reversibly to and stimulates B cells and CD4(+) and CD8(+) T cells (PubMed:7842483, PubMed:9000539). Also binds reversibly to natural killer (NK) cells and enhances NK cell cytotoxicity through its protease activity (PubMed:9000539, PubMed:9536127). Cleaves complement C3 (PubMed:1861080). Cleaves vimentin (By similarity). Cleaves thrombin receptor F2R/PAR1 and acts as either an agonist or an inhibitor, depending on the F2R cleavage site (PubMed:10702240, PubMed:7744748). Cleavage of F2R at '41-Arg-|-Ser-42' results in receptor activation while cleavage at '55-Phe-|-Trp-56' results in inhibition of receptor activation (PubMed:7744748). Cleaves the synovial mucin-type protein PRG4/lubricin (PubMed:32144329). Cleaves and activates IL36G which promotes expression of chemokines CXCL1 and CXLC8 in keratinocytes (PubMed:30804664). Cleaves IL33 into mature forms which have greater activity than the unprocessed form (PubMed:22307629). Cleaves coagulation factor F8 to produce a partially activated form (PubMed:18217133). Also cleaves and activates coagulation factor F10 (PubMed:8920993). Cleaves leukocyte cell surface protein SPN/CD43 to releases its extracellular domain and trigger its intramembrane proteolysis by gamma-secretase, releasing the CD43 cytoplasmic tail chain (CD43-ct) which translocates to the nucleus (PubMed:18586676). Cleaves CCL5/RANTES to produce RANTES(4-68) lacking the N-terminal three amino acids which exhibits reduced chemotactic and antiviral activities (PubMed:16963625). During apoptosis, cleaves SMARCA2/BRM to produce a 160 kDa cleavage product which localizes to the cytosol (PubMed:11259672). Cleaves myelin basic protein MBP in B cell lysosomes at '224-Phe-|-Lys-225' and '248-Phe-|-Ser-249', degrading the major immunogenic MBP epitope and preventing the activation of MBP-specific autoreactive T cells (PubMed:15100291). Cleaves annexin ANXA1 and antimicrobial peptide CAMP to produce peptides which act on neutrophil N-formyl peptide receptors to enhance the release of CXCL2 (PubMed:22879591). Acts as a ligand for the N-formyl peptide receptor FPR1, enhancing phagocyte chemotaxis (PubMed:15210802). Has antibacterial activity against the Gram-negative bacteria N.gonorrhoeae and P.aeruginosa (PubMed:2116408, PubMed:1937776). Likely to act against N.gonorrhoeae by interacting with N.gonorrhoeae penA/PBP2 (PubMed:2126324). Exhibits potent antimicrobial activity against the Gram-positive bacterium L.monocytogenes (PubMed:2117044). Has antibacterial activity against the Gram-positive bacterium S.aureus and degrades S.aureus biofilms, allowing polymorphonuclear leukocytes to penetrate the biofilm and phagocytose bacteria (PubMed:2117044, PubMed:32995850). Has antibacterial activity against M.tuberculosis (PubMed:15385470). Mediates CASP4 activation induced by the Td92 surface protein of the periodontal pathogen T.denticola, causing production and secretion of IL1A and leading to pyroptosis of gingival fibroblasts (PubMed:29077095).

关联

项与 CTSG 相关的药物

CBX-250

靶点

CTSG x HLA

作用机制

CTSG抑制剂 [+1]

在研机构

Crossbow Therapeutics, Inc.初创企业

原研机构

Crossbow Therapeutics, Inc.初创企业

在研适应症

髓系白血病

非在研适应症-

最高研发阶段临床前

首次获批国家/地区-

首次获批日期1800-01-20

LEX-032

靶点

CTSG x ELA2 x Serine protease

作用机制

CTSG抑制剂 [+3]

在研机构-

原研机构

Sparta Pharmaceuticals, Inc.

在研适应症-

非在研适应症

心肌梗塞 [+3]

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

LEX-028

靶点

CTSG

作用机制

CTSG抑制剂

在研机构-

原研机构

Lexin Pharmaceutical Corp

在研适应症-

非在研适应症

炎症

最高研发阶段终止

首次获批国家/地区-

首次获批日期1800-01-20

100 项与 CTSG 相关的临床结果

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100 项与 CTSG 相关的转化医学

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0 项与 CTSG 相关的专利（医药）

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2,926

项与 CTSG 相关的文献（医药）

2025-02-01·Food Chemistry

Investigating binding mechanism between coconut globulin and tannic acid mediated by atmospheric cold plasma: Protein structure and stability

Article

作者: Chen, Yile ; Jiang, Lianzhou ; Wang, Jiamei ; Zhang, Weimin ; Chen, Yang

Physical methods present promising avenues for inducing covalent modifications of proteins by polyphenols, circumventing the safety and sustainability issues associated with traditional approaches. This study sought to enhance the physicochemical properties of coconut globulin (CG) by facilitating covalent cross-linking with tannic acid (TA) through atmospheric cold plasma (ACP). The ACP treatment effectively transitioned the interaction between CG and TA from non-covalent to covalent in a voltage-dependent manner at pH 6.0, resulting in structural modifications of CG. The treatment with TA enhanced the spherical structure of CG, with a reduction in particle size from 474 to 384 nm. This size reduction was further amplified by the exposure of charged groups induced by ACP treatment. Consequently, the solubility, surface hydrophobicity, and viscosity of ACP-treated CG-TA increased, leading to an elevated denaturation temperature and enhanced physical stability. These results suggest a viable approach to improving the suboptimal physicochemical properties of plant proteins.

2024-12-01·Cellular and Molecular Life Sciences

Genome wide inherited modifications of the tomato epigenome by trans-activated bacterial CG methyltransferase

Article

作者: Beaubiat, Sébastien ; Kumar, Bapatla Kesava Pavan ; Yadav, Chandra Bhan ; Sherman, Amir ; Bouché, Nicolas ; Eshed, Ravit ; Arazi, Tzahi

AbstractBackgroundEpigenetic variation is mediated by epigenetic marks such as DNA methylation occurring in all cytosine contexts in plants. CG methylation plays a critical role in silencing transposable elements and regulating gene expression. The establishment of CG methylation occurs via the RNA-directed DNA methylation pathway and CG methylation maintenance relies on METHYLTRANSFERASE1, the homologue of the mammalian DNMT1.PurposeHere, we examined the capacity to stably alter the tomato genome methylome by a bacterial CG-specific M.SssI methyltransferase expressed through the LhG4/pOP transactivation system.ResultsMethylome analysis of M.SssI expressing plants revealed that their euchromatic genome regions are specifically hypermethylated in the CG context, and so are most of their genes. However, changes in gene expression were observed only with a set of genes exhibiting a greater susceptibility to CG hypermethylation near their transcription start site. Unlike gene rich genomic regions, our analysis revealed that heterochromatic regions are slightly hypomethylated at CGs only. Notably, some M.SssI-induced hypermethylation persisted even without the methylase or transgenes, indicating inheritable epigenetic modification.ConclusionCollectively our findings suggest that heterologous expression of M.SssI can create new inherited epigenetic variations and changes in the methylation profiles on a genome wide scale. This open avenues for the conception of epigenetic recombinant inbred line populations with the potential to unveil agriculturally valuable tomato epialleles.

2024-12-01·Medicinal Chemistry

Substituted 4H-3,1-benzoxazine-4-one Derivatives as Inhibitors of Cathepsin G

Article

作者: Aliter, Kholoud F. ; Al-Horani, Rami A.

Background:Cathepsin G (CatG) is a cationic serine protease with a wide substrate specificity. CatG has been reported to play a role in several pathologies, including rheumatoid arthritis, ischemic reperfusion injury, acute respiratory distress syndrome, and cystic fibrosis, among others.Objective:We aim to develop a new class of CatG inhibitors and evaluate their potency and selectivity against a series of serine proteases.Methods:In this communication, we report on a new class of CatG inhibitors of 4H-3,1-benzoxazin- 4-one derivatives. We constructed a small library of seven substituted 4H-3,1-benzoxazin-4-one derivatives and identified their inhibition potential against CatG. Five molecules were identified as CatG inhibitors with values of 0.84-5.5 μM. Inhibitor 2 was the most potent, with an IC50 of 0.84 ± 0.11 μM and significant selectivity over representative serine proteases of thrombin, factor XIa, factor XIIa, and kallikrein.Results:In this communication, we report on a new class of CatG inhibitors of 4H-3,1-benzoxazin- 4-one derivatives. We constructed a small library of seven substituted 4H-3,1-benzoxazin-4-one derivatives and identified their inhibition potential against CatG. Five molecules were identified as CatG inhibitors with values of 0.84-5.5 μM. Inhibitor 2 was the most potent, with an IC50 of 0.84 ± 0.11 μM and significant selectivity over representative serine proteases of thrombin, factor XIa, factor XIIa, and kallikrein.Conclusion:Thus, we propose this inhibitor as a lead molecule to guide subsequent efforts to develop clinically relevant potent and selective CatG inhibitors for use as anti-inflammatory agents.

项与 CTSG 相关的新闻（医药）

2024-09-25

·CPHI制药在线

国产DPP1抑制剂纳入突破性治疗品种，这一赛道生变，海思科强势崛起！

关注并星标CPHI制药在线近日，据CDE 官网，海思科公司的1类新药HSK31858片被纳入突破性治疗品种，用于非囊性纤维化支气管扩张。图片来源：CDE官网 HSK31858是由海思科开发的一款口服、强效和高选择性的DPP1抑制剂，主要用于治疗非囊性纤维化支气管扩张症(NCFBE)，可通过抑制嗜中性粒细胞NSP酶的活化，来抑制嗜中性粒细胞的活化和向循环系统的释放。目前已经完成在非囊性纤维化支气管扩张患者中的II期临床研究，研究达到预设终点，即将进入III期关键性临床研究阶段。在2024年欧洲呼吸学会（European Respiratory Society, ERS）上，海思科首次向全球呼吸医学界公布了HSK31858的II期临床研究结果。结果显示，与安慰剂组相比，20 mg HSK31858组和40 mg HSK31858组均显著降低急性加重发生频率。值得一提的是，今年年初，海思科又提交了HSK31858支气管哮喘适应症及慢性阻塞性肺疾病适应症的新药临床试验申请，展现了其在慢性呼吸系统疾病领域布局的巨大野心。 2023年11月，海思科与意大利Chiesi公司签署许可协议，将HSK31858在大中华区以外的全球开发、生产和商业化的独家权利授予Chiesi公司，交易总金额4.62亿美元，其中预付款1300万美元。 DPP1：中性粒细胞相关炎症疾病的潜在治疗靶点中性粒细胞释放的NSPs与多种炎症疾病相关。中性粒细胞在先天免疫和炎症中扮演着重要角色，其释放的中性粒细胞丝氨酸蛋白酶（NSPs，主要包括中性粒细胞弹性酶（NE）、蛋白酶3（PR3）和组织蛋白酶G（CatG））在此过程中起到重要作用。过度活化的NSPs与中性粒细胞相关炎症疾病导致的组织损伤相关，包括慢性阻塞性肺疾病（COPD）和非囊性纤维化支气管扩张（NCFBE）等疾病。 DPP1(dipeptidyl peptidase I，二肽基肽酶1)是一种存在于中性粒细胞中的酶，它可以激活中性粒细胞蛋白酶(NSPs)，是治疗中性粒细胞相关炎症疾病的潜在靶点。有研究表明，NCFBE患者痰中NE活性升高与肺部急性加重和肺功能下降相关，过量的PR3和CatG活性也可能在NCFBE疾病进展中发挥作用。因此DPP1是治疗中性粒细胞相关炎症疾病的潜在靶点。非囊性纤维化支气管扩张症是一种严重的慢性肺部疾病，其特征是痰液产生过多，并持续从呼吸道咳出，患者还会频繁出现呼吸道感染。目前，这种疾病还没有获得批准的治疗药物。 DPP1抑制剂：Insmed即将NDA，BI、海思科竞速目前，在全球范围内，DPP-1靶点的竞争并不激烈，针对DPP-1靶点的主要开发方向是支气管扩张症，历史上已经进入临床阶段的DPP-1抑制剂共有4款，其中Insmed手上的DPP-1抑制剂brensocatib近期临床3期试验取得成功，Insmed股价当天翻倍；BI的BI1291583和海思科的HSK31858均处于临床2期，其中海思科的海外权益已经授权给了Chiesi；葛兰素史克开发的GSK-2793660是最早进入临床的DPP1抑制剂，在2015年因长期用药的安全性和一些生物指标未到达已经终止开发。 Brensocatib最早由阿斯利康研发，2016年10月5日，阿斯利康以3000万美元首付款、1.2亿美元里程金的价格将其全球独家权益转让给了Insmed。今年5月，Insmed公布了ASPEN III期研究的数据，表明其DPP1抑制剂 brensocatib可以显著减轻非囊性纤维化支气管扩张患者的肺恶化。顶线数据显示，与安慰剂相比，brensocatib的10毫克剂量可使肺恶化的年化率降低21.1%，而25毫克剂量可使肺恶化的年化率降低19.4%。据该公司称，这两种效应均具有统计学意义，p值分别为0.0019和0.0046。 Brensocatib也达到了关键的次要终点。两种剂量都显着延长了第一次恶化事件的时间，并增加了患者在52周内没有此类事件的几率。高剂量组在52周后肺功能也有显著改善。 Insmed预计在今年第4季度向FDA提交NDA，Brensocatib将于2025年中期在美国上市。Brensocatib有望成为首个获批用于支气管扩张的DPP1抑制剂。此外，Brensocatib针对不伴鼻息肉的慢性鼻窦炎、囊性纤维化和化脓性汗腺炎等适应症正在或即将开展多项临床试验。 BI1291583是一款一种可逆性、高效和高选择性DPP-1抑制剂，在健康志愿者中开展的I期试验结果显示BI1291583具有良好的安全性和耐受性。临床前研究发现，BI 1291583 会优先分布到骨髓，骨髓分布最多可达到血浆分布的100 倍（同一模型中，brensocatib在骨髓和血浆之间的分布几乎相等）。BI 1291583 优先分布到骨髓能够最大限度地降低皮肤事件的风险，DPP-1抑制剂在临床中常见的皮肤相关的特别关注AE，BI 1291583的临床研究中患者的症状更轻，且与安慰剂组中报告的发生率相同。 HSK31858临床前数据优于Brensocatib，Ⅱ期临床试验结果良好。根据海思科的专利，HSK31858（推测为专利WO2022042591A1中的化合物1）在体外试验中表现出优于Brensocatib的DPP1抑制活性（非头对头研究），体内试验中也表现出更优的药代动力学特征、生物利用度和安全性。参考来源： 1. Chalmers J D, Kettritz R, Korkmaz B. Dipeptidyl peptidase 1 inhibition as a potential therapeutic approach in neutrophil-mediated inflammatory disease[J]. Frontiers in Immunology, 2023, 14. 2. Chalmers J D, Usansky H, Rubino C M, et al. Pharmacokinetic/pharmacodynamic evaluation of the dipeptidyl peptidase 1 inhibitor brensocatib for non-cystic fibrosis bronchiectasis[J]. Clinical Pharmacokinetics, 2022, 61(10): 1457-1469. END 【智药研习社直播预告】来源：CPHI制药在线声明：本文仅代表作者观点，并不代表制药在线立场。本网站内容仅出于传递更多信息之目的。如需转载，请务必注明文章来源和作者。投稿邮箱：Kelly.Xiao@imsinoexpo.com ▼更多制药资讯，请关注CPHI制药在线▼ 点击阅读原文，进入智药研习社~

突破性疗法引进/卖出临床2期

2024-05-10

·药渡

世界防治肥胖日特辑 | 肥胖炎症与中性粒细胞

在肥胖中，中性粒细胞是血液中最丰富的白细胞，是第一个浸润脂肪组织的免疫细胞，招募巨噬细胞和其他免疫细胞。因此它也是肥胖相关炎症的重要调节因子。最早的炎症浸润特征在脂肪细胞功能障碍的早期阶段，中性粒细胞渗入脂肪组织可以作为最初的炎症反应的特征。脂肪组织的慢性低度炎症则进一步导致中性粒细胞的活化。因此，肥胖炎症中的循环中性粒细胞数量增多，呈激活状态。炎症状态下的脂肪组织能够产生水平升高的炎症介质，如TNF-α、IL-1β、IL-6和IL-8，导致中性粒细胞从骨髓释放到外周循环，并且从内皮细胞壁脱边际，导致中性粒细胞增多。一旦进入脂肪组织，中性粒细胞可以通过释放CXCL2来募集更多的血液中性粒细胞。此外，人脂肪细胞中的脂质可以诱导中性粒细胞和巨噬细胞的迁移，以及其他细胞因子的分泌。肥胖个体的中性粒细胞受到NF-κB信号通路以及更高的ROS和促炎细胞因子生成水平的刺激，呈现激活表型。表现为血浆髓过氧化物酶(MPO)和中性粒细胞弹性蛋白酶(NE)浓度升高，CD66b表达增加。脂肪组织还产生瘦素。瘦素不仅促进造血，还可以刺激中性粒细胞的氧化爆发，诱导趋化作用，通过其受体激活NF-κB途径并抑制细胞凋亡。中性粒细胞与淋巴细胞比率(NLR)由于肥胖中的循环中性粒细胞生成、数量增加和激活，在患者中就体现为：代谢综合征患者的中性粒细胞计数显著高于消瘦患者。中性粒细胞在血管和浸润性脂肪组织以及动脉粥样硬化病变的内皮细胞中也呈升高水平。因此，中性粒细胞与淋巴细胞比率(NLR)这一简单的生物标志物可以将肥胖反应和全身性炎症联系起来。NLR反映了各种病理条件下先天(中性粒细胞)和获得性(淋巴细胞)免疫反应之间的关系。NLR也与较高的血浆CRP浓度相关。肥胖与高NLR之间存在显著关联。高NLR和高BMI的患者的无病生存率也最差。NLR值被发现与腹部肥胖的程度显著相关。超重人群中较高的NLR可能反映了这一人群中尚未造成明显症状、但已经存在的亚临床炎症。中性粒细胞加重炎症和并发症中性粒细胞通过中性粒细胞上的整合素CD11b与脂肪细胞上的ICAM-1结合而与脂肪细胞相互作用。（肥胖环境中的免疫细胞）这种相互作用激活中性粒细胞，并通过NF-κB和炎症小体NLRP3途径诱导其产生IL-1β，从而和TNF-α一起后续激活巨噬细胞。在高脂饮食小鼠的脂肪组织中，IL-1β和NLRP3mRNA水平与体重和肥胖呈正相关。脂肪细胞脂解产生的游离脂肪酸也可以吸引中性粒细胞，并刺激他们产生更多的IL-1β。中性粒细胞还分泌去甲肾上腺素，这会损害脂肪组织的能量消耗，并通过降解胰岛素受体底物1(IRS-1)来促进胰岛素抵抗。中性粒细胞还产生弹性蛋白酶(NE)，这会损害脂肪组织的能量消耗，并直接激活巨噬细胞。激活的中性粒细胞还可以通过释放天青素、IL-37、组织蛋白酶G、蛋白酶3(PR3)和人中性粒细胞多肽1-3等来招募单核细胞进入炎症脂肪组织中。Cells理论上，激活的中性粒细胞不仅能促进炎症加剧，应该也加强了更多的其他免疫功能。但实际上，在数量相似的情况下，肥胖患者的中性粒细胞的杀伤力似乎反而减弱，肥胖者的中性粒细胞的激活状态不能转化为更有效的抗菌功能。换句话说，肥胖者生理脆弱、感染和死亡的风险比正常体重的人更高。中性粒细胞在2类糖尿病中的表现1型糖尿病T1D患者的循环中性粒细胞数量减少，这也被认为是T1D的标志。相对地，T1D患者的胰腺中存在中性粒细胞，而T2D患者或非糖尿病对照组则不存在。循环中的中性粒细胞减少主要是由于中性粒细胞在疾病早期就显著渗入胰腺组织中。巨噬细胞和β细胞产生趋化因子CXCL1和CXCL2，进而将表达CXCR2的中性粒细胞招募到胰腺。因此，中性粒细胞是参与T1D发育早期的重要细胞。Cells某些中性粒细胞缺陷是T1D的特殊特征，而不是一般的糖依赖性缺陷。例如，在体外实验中显示，T1D患者的中性粒细胞的迁移能力受到损害，而T2D患者的中性粒细胞迁移没有受到影响。这种功能缺陷与CD62L的表达有关，但与高血糖浓度无关。2型糖尿病相对地，T2D与肥胖引起的慢性全身炎症有关。TNF-α是一种反复被认为与T2D有关的细胞因子。T2D患者的中性粒细胞在脂多糖刺激下分泌更多的IL-6和TNF-α，导致胰岛素抵抗，从而增加血糖浓度。与健康对照组的中性粒细胞相比，T2D患者的中性粒细胞表现出较低的吞噬活性、较低的ROS产生和较低的趋化能力。中性粒细胞还可以释放参与细胞间通讯的微泡。喂食高脂饮食的小鼠，中性粒细胞微泡浓度增加。这些微泡也聚集在动脉的某些区域，促进血管炎症和动脉粥样硬化。小结炎症与肥胖是密不可分的。中性粒细胞通过产生IL-1β进一步促进全身性的炎症，并通过和脂肪细胞的多种串扰以诱导巨噬细胞启动慢性炎症。也因此，中性粒细胞在肥胖环境和糖尿病等相关并发疾病中也是一个值得关注的指标。点击下方“药渡“，关注更多精彩内容免责声明“药渡”公众号所转载该篇文章来源于其他公众号平台，主要目的在于分享行业相关知识，传递当前最新资讯。图片、文章版权均属于原作者所有，如有侵权，请及时告知，我们会在24小时内删除相关信息。微信公众号的推送规则又双叒叕改啦，如果您不点个“在看”或者没设为"星标"，我们可能就消散在茫茫文海之中~点这里，千万不要错过药渡的最新消息哦！

临床研究基因疗法

2024-03-05

·GlobeNewswire-Health Care

Crossbow Therapeutics Selects First Development Candidate from its Portfolio of Next-Generation T-cell Engagers Directed at Intracellular Cancer Targets

CBX-250 is a first-in-class, potent, and specific T-cell engager for the treatment of myeloid leukemia Abstract summarizing preclinical characteristics of CBX-250 selected for an oral presentation at the American Association for Cancer Research (AACR) 2024 Annual Meeting Novel T-Bolt™ therapy being developed in strategic collaboration with MD Anderson CAMBRIDGE, Mass., March 05, 2024 (GLOBE NEWSWIRE) -- Crossbow Therapeutics, Inc., a biotechnology company focused on advancing T-Bolt™ therapies, a novel class of antibody therapeutics that mimic T-cell receptors (TCR-mimetics), today announced the nomination of its first development candidate, CBX-250, a first-in-class, potent, and specific T-cell engager (TCE) for the treatment of myeloid leukemia. Researchers from Crossbow and The University of Texas MD Anderson Cancer Center will present an abstract describing preclinical characteristics of CBX-250 at the American Association for Cancer Research (AACR) 2024 Annual Meeting in San Diego, Calif., which takes place April 5-10, 2024. The oral presentation will provide an overview of the preclinical characteristics of CBX-250, which targets a cathepsin G (CTSG) peptide-human leukocyte antigen (pHLA) complex. The complex is abundantly expressed on leukemic cells, but not on normal cells, allowing CBX-250 to target cancer cells efficiently while sparing normal myeloid cells. CBX-250 may offer an enhanced therapeutic window compared with TCEs that have shown limited clinical benefit in the treatment of myeloid malignancies, due to the lack of tumor-specific surface antigens. “Nominating CBX-250 as a development candidate validates our initial scientific hypothesis, and it brings us a step closer to entering the clinic and ultimately helping to cure cancer,” said Briggs Morrison, Chief Executive Officer of Crossbow. “We have selected a promising therapeutic that is highly accurate and potent in preclinical models. We’re pleased to collaborate with the team at MD Anderson and look forward to continuing to advance CBX-250 to the clinic.” The discovery and preclinical development of CBX-250 are the results of an ongoing strategic collaboration between Crossbow and MD Anderson. Gheath Alatrash, DO, PhD, and Jeffrey Molldrem, MD, led the discovery and validation of the CTSG-derived peptide, known as CG1, via functional studies with CG1-specific T cells and via mass spectrometry through interrogation of patient samples. Working with MD Anderson’s ORBIT platform, a core component of the institution’s Therapeutics Discovery division, Dr. Molldrem led the development of a TCR-mimetic binder to the CG1 pHLA complex, which Crossbow licensed for the development of off-the-shelf cancer immunotherapies. The team at Crossbow further enhanced the developability of the precursor molecule, incorporated it into an optimized TCE format, and carefully verified the construct’s potency, specificity, and manufacturability. “We are proud of our work with Crossbow on the CBX-250 development program, which represents a true collaboration between two innovative teams,” commented Jeffrey Molldrem, MD, Chair of Hematopoietic Biology and Malignancy and leader within Therapeutics Discovery at MD Anderson. “Through our strategic collaboration, we are working to advance CBX-250 rapidly into the clinic, and we hope to see these promising preclinical findings translated into a therapy that will positively impact the lives of patients.” CBX-250 is the first candidate in Crossbow’s portfolio of novel investigative therapies that target intracellular cancer antigens using TCR-mimetics. The upcoming AACR presentation will focus on the potency, specificity, and safety of CBX-250 in targeting leukemic myeloid cells versus normal tissues, as demonstrated preclinically both in vitro and in vivo. “The emergent field of TCR-mimetic antibody-based therapies is full of untapped therapeutic potential, with no approved drugs to date,” said Dmitri Wiederschain, PhD, Chief Scientific Officer of Crossbow. “Nominating CBX-250 as our first development candidate, based on our rigorous selection criteria, puts us at the forefront of an important opportunity to broaden the benefits of immunotherapy for those living with cancer and to target the entire universe of cancer antigens.” AACR 2024 Annual Meeting presentation details Title: Characterization of CBX-250, a first-in-class TCR-mimetic-based T-cell engager targeting a cathepsin G peptide-HLA complex for the treatment of myeloid leukemia (abstract #1236)Presenting Author: Geraldine Paulus, PhDSession Title: Tumor-Targeted Immune Cell EngagersSession Date/Time/Location: Sunday Apr. 7, 2024, 3:00PM-5:00PM PDT, San Diego Convention Center For more information on the abstract, the full text is available at https://www.abstractsonline.com/pp8/#!/20272/presentation/5708. About Crossbow Therapeutics, Inc. Crossbow Therapeutics, Inc., is a biotechnology company determined to improve the lives of people with cancer by unlocking the therapeutic potential of T-cell receptor (TCR)-mimetic antibodies. The company’s T-Bolt™ therapies are next-generation, easily assembled immunotherapies directed with high precision at previously unreachable cancer cell targets. Crossbow’s efficient and selective approach is designed to target the entire universe of cancer proteins, dramatically expanding the potential of antibody therapy to address many types of cancer. For more information about Crossbow Therapeutics, visit www.crossbowtx.com. Investor Contact:Crossbow Therapeutics, Inc.Geraldine Paulus, Co-Founder, Head of Corporate Development and OperationsGeraldine.paulus@crossbowtx.com Media Contact:SmithSolveCorey Carmichael(862) 260-7929Corey.carmichael@smithsolve.com

免疫疗法AACR会议