CXCL11

趋化因子系统参与调节细胞迁移、粘附、定位和细胞间相互作用，作用于肿瘤细胞和免疫细胞调节二者细胞活动，高度参与肿瘤的发展过程。根据肿瘤发生过程中所处的阶段、免疫细胞的活化状态、效应与调控反应间的平衡以及趋化因子受体在效应靶细胞和调节性靶细胞上的相对表达，趋化因子会表现出促肿瘤和抗肿瘤两种效应，甚至同一趋化因子作用于不同细胞，具有两种截然相反的效应。 一、促瘤趋化因子 1. CCL2：通过CCL2-CCR2轴募集肿瘤相关免疫抑制细胞；介导肿瘤与肿瘤相关巨噬细胞（TAM）相互作用，提高肿瘤干细胞特性、转移能力和治疗抵抗。 2. CXCL1/CXCL8：通过CXCL1/CXCL8-CXCR2轴募集肿瘤相关免疫抑制细胞。 3. CXCL12：通过CXCR4-CXCL12轴促进TAM分化为血管周围TAM细胞，提高血管通透性，使肿瘤细胞向血管内浸润；实体瘤增加骨髓基质细胞中CXCL12的表达，导致表达CXCR4的髓样细胞积聚，影响免疫细胞的发育成熟，CXCR4-CXCL12轴参与Treg向骨髓的迁移。 4. CCR4：在肿瘤微环境（TME）中募集调节性T细胞（Treg）。 5. CCR6：促进Treg细胞在TME原位增殖。 6. CCR8：在TME内DC细胞附近募集Treg，并通过抗原识别使Treg具有免疫抑制作用；通过CCR8-CCL1轴增加Foxp3表达维持Treg细胞的免疫抑制能力。 7. CCR4+Th2、CCR6+Th17、CXCR3+Th1、CXCR5+Tfh，以上4类趋化因子受体分别在不同细胞中的表达，与Treg抑制功能有一定相关性。 二、抗瘤趋化因子 1. XCL1：通过XCL1-XCR1轴介导cDC1细胞向肿瘤募集，促进cDC1与CD8+T细胞相互作用，促使T细胞扩增和获得效应器功能。 2. CXCL11：其表达与髓源性抑制细胞（MDSCs）的丰度和CD8+T细胞浸润程度成反比。 3. CCR7：介导cDC1和cDC2细胞从肿瘤向TDLN迁移，启动T细胞的效应功能。 4.  CCL21：介导T细胞和DC细胞向肿瘤引流淋巴结（TDLN）募集，其表达减少会影响免疫细胞群定位，最终可能导致T细胞活性降低。 5. CX3CR1：CD8+T细胞接收到CX3CR1信号才能发挥抗肿瘤作用。 三、双效趋化因子 1. CCR5：CCR5-CCL5轴介导cDC1向肿瘤募集，能同时募集Treg细胞和CD8+T细胞；调控TAM表型和功能，介导肿瘤与TAM相互作用，提高肿瘤肝细胞性、转移能力、治疗抵抗 2. CXCR3：CXCR3-CXCL9/CXCL10轴也能同时募集Treg和CD8+T细胞；使干细胞样TCF-1+细胞向cDC1细胞募集、在TME中重激活和通过接触IL-2获得效应器功能；调控免疫效应细胞在肿瘤附近的定位。 四、药物开发 一些趋化因子的研究进入了临床阶段，但总体而言疗效不显著。 1. CXCR3-CXCL9/10/11：IFN-γ是该趋化因子轴的主要驱动因素，联用可以增加效应细胞浸润；瘤内注射CXCL9/10/11等配体或者表达配体的溶瘤病毒，增加效应细胞浸润。 3. CXCR4：使用其拮抗剂 AMD3100， BL-8040可以促进肿瘤的T细胞浸润。 4. CCR4-CCL22/17：用于阻断该轴介导的Treg募集的策略，包括阻断抗体、siRNAs和拮抗剂： （1）CCR4抗体：mogamulizumab (KW-0761)是一种人源化、糖工程IgG1κ单克隆抗体，通过ADCC靶向表达CCR4的细胞。临床试验结果显示它可以消除淋巴瘤中Treg的积累。 （2）CCR4小分子抑制剂：FLX475和RPT193，FLX475联合派姆单抗治疗晚期或转移性癌症的1/2期临床试验(NCT03674567)最近已经完成，但尚未被报道；此外GSK 的(GSK2239633) 和AstraZeneca的(AZD-1678，AZD-2098) 也是CCR4的小分子抑制剂。 5. CCL2-CCR2：阻断CCL2-CCR2，可以抑制MDSCs的浸润： （1）抗CCR2抗体：MLN1202，治疗骨转移（NCT01015560）。 （2）CCR2小分子抑制剂：PF-04136309，联合白蛋白-紫杉醇/吉西他滨治疗中期静态PDA患者的1b期试验显示，外周血中炎症性单核细胞(IM)减少，而没有在骨髓中积累。但与标准化疗相比，CCR2抑制也会导致肺毒性增加。在另一项1b期试验中PF-04136309和叶酸，不同的标准化疗方案（边缘可切除和局部晚期胰腺癌），是安全的，减少单核细胞从骨髓，TAM浸润原发肿瘤，导致高于预期的客观反应率（49%）。 （3）CCR2拮抗剂：CCX872 ，用于治疗胰腺癌，总生存率提高（18个月时29%Vs18.6%）。 6. CCR5：CCR5拮抗剂Maraviroc，在体外模型中将巨噬细胞重新极化为免疫活性表型。目前还在招募的临床试验是卒中后认知障碍：NCT04966429 Safety and Efficacy of Maraviroc in Post-stroke Cognitive Impairment Phase2 7. CXCR1/CXCR2-CXCL8：阻断该轴，抑制肿瘤生长： （1）CXCR1/2抑制剂：Reparixin是一种临床级抑制剂，可在体外抑制乳腺癌的生长。 （2）CXCR1/2的小分子拮抗剂：包括SCH479833和SCH527123，在乳腺癌、CRC、自发性结肠癌肝转移和黑色素瘤的异种移植模型中具有抗肿瘤活性。 （3）CXCL8阻断抗体：ABX-CXCL8，在异种移植模型中抑制黑色素瘤的生长。 总体如麻省总医院Andrew D. Luster教授所言，趋化因子和趋化因子受体很难作为治疗靶点进行开发... Even if chemokines and chemokine receptors represent difficult therapeutic targets, they might help todissect cellular components critical for induction and maintenance of pro- and anti-tumorigenic immune cell states. 参考文献 Hanahan, D. et al. Hallmarks of cancer: the next generation. Cell. 2011; 144: 646-674. Hua, Y. et al. Tumors vs. chronic wounds: an immune cell’sperspective. Front. Immunol.    2019; 10: 2178.  Villablanca et al, Tumor-mediated liver X receptor-alpha activation inhibits CC chemokine receptor-7expression on dendritic cells and dampens antitumor responses. Nat. Med.  2010; 16: 98–105. Binnewies, M. et al, Unleashing type-2 dendritic cells to drive protective antitumor CD4(+)    T cell immunity. Cell. 2019; 177: 556–571.e16. Griffith, J.W. et al. Chemokines and chemokinereceptors: positioning cells for host defense    and immunity. Annu. Rev. 2014; 32: 659-702. Karan Kohli et al，Key chemokines direct migration of immune cells in solid tumors，Cancer Gene Ther . 2022;29(1):10-21. 本周好文推荐 如需转载请联系佰傲谷并在醒目位置注明出处 · · · · · · · ·

DONGTAN, KOREA, June 10, 2024 - iLeadBMS, a new drug R&D company under Ildong Pharmaceutical Group, announced on the 10th that it presented in vivo study results on its liver fibrosis treatment candidate 'IL1512' at the European Association for the Study of the Liver (EASL) 2024, held in Milan, Italy, from June 5th to the 8th. IL1512 is an oral CXCR7 agonist and is classified as a first-in-class drug, a type of drug that has never been developed for the same therapeutic indication previously. Last month, iLeadBMS presented the efficacy results of this drug for idiopathic pulmonary fibrosis (IPF) at the American Thoracic Society (ATS 2024), and this time around it announced the anti-fibrotic effects of the drug in the liver. CXCR7 is a G protein-coupled receptor that binds to chemokine ligands CXCL11 and CXCL12, targeting various pathways related to fibrosis such as fibroblast activation, inflammation, tissue repair, and angiogenesis. This makes it an ideal therapeutic target for treating fibrotic diseases. Given that CXCR7 agonists exerts their anti-fibrotic properties through a novel mechanism, iLeadBMS plans to develop anti-fibrotic drugs to treat fibrosis in various organs including but not limited to the lungs, liver, heart, kidneys, and skin, and is also considering utilizing the expedited review and Orphan Drug Designation (ODD) pathways offered by the FDA. Based on the presentation at the conference, iLeadBMS has confirmed the anti-fibrotic effects of IL1512 in the well-established CCl4 (carbon tetrachloride) liver fibrosis model with oral administration of the test article. Significant improvements in various anti-fibrotic indicators (col 1a1, hydroxyproline content, TGF-beta) were observed compared to the placebo. The presentation emphasized that IL1512, with its novel mechanism targeting CXCR7, demonstrated direct anti-inflammatory effects on the liver and improvement in fibrosis. Additionally, it highlighted that IL1512 showed either superior or at minimum, comparable efficacy and safety profiles compared to Elafibranor, the comparator drug. Based on these research results, iLeadBMS has identified preclinical candidate molecules with even greater improvements over IL1512 and, plans to start GLP (Good Laboratory Practice) toxicology studies in the second half of this year. About iLeadBMS Established in 2020, iLeadBMS specializes in the discovery and development of novel drugs, with an R&D pipeline targeting fibrotic diseases, protease inhibitors, solid tumors, and neurodegenerative diseases. For more information on iLeadBMS, please visit:

DONGTAN, KOREA, May 21, 2024 – iLeadBMS, a leading biotech company dedicated to the discovery and development of novel drugs for high unmet medical needs, has announced a positive outcome of IL1512, a first-in-class CXCR7 agonist, as a potential therapy for pulmonary fibrotic diseases at the American Thoracic Society (ATS 2024) conference held in San Diego from May 17th to 22nd. Idiopathic pulmonary fibrosis (IPF) is a rare lung disease characterized by progressive fibrosis of lung parenchyma, with a less than 40% survival rate five years after diagnosis. Research And Markets projects the IPF treatment market to reach approximately $6.1 billion (about 8 trillion KRW) by 2030, indicating significant unmet medical needs in this area. To address these high unmet needs, iLeadBMS has concentrated its research on CXCR7 (C-X-C chemokine receptor 7), a key mediator in signal transduction amplifying fibrosis and inflammation. CXCR7 selectively binds to chemokine ligands CXCL11 and CXCL12, targeting various pathways associated with fibrosis, inflammation, tissue repair, and angiogenesis. IL1512 has exhibited high selectivity for CXCR7 without binding to other chemokine receptors and demonstrated promising pharmacokinetics (DMPK) in mice and rats when orally administered. In a bleomycin-induced pulmonary fibrosis model, IL1512 showed dose-dependent improvements in the Ashcroft score, confirming its potentially superior anti-fibrotic efficacy compared to the standard therapy. Additionally, IL1512 displayed a favorable safety pro by the absence of weight loss associated with drug administration. Based on these results, it is anticipated that IL1512 will have a better safety and efficacy pro compared to currently available standard treatments. Preclinical studies for the selected CXCR7 agonist candidate have been initiated and GLP toxicity studies are planned for the second half of this year. The Company’s strategy aims to develop therapies with minimal side effects while providing broad anti-fibrotic effects, covering multiple organs beyond just the lungs. It is anticipated that expedited regulatory pathways such as Orphan Drug Designation (ODD) will be considered for the fibrosis program and concurrently, CXCR7 agonists with blood-brain barrier penetration potential, are also being explored for neurological disorders. About iLeadBMS Established in 2020, iLeadBMS specializes in the discovery and development of novel drugs, with an R&D pipeline targeting fibrotic diseases, protease inhibitors, solid tumors, and neurodegenerative diseases. For more information on iLeadBMS, please visit: