IL27RA

IL-27是IL-6家族的成员，在结构上与 IL-12 和 IL-6家族相关。其受体IL-27R通过JAK/STAT信号通路传导。IL-6家族6个促癌成员IL-27R由IL-27Rα和gp130链构成，其中gp130还是IL-35、IL-6、IL-11等细胞因子受体的重要组成部分。此外，gp130和IL-27Rα可以在包括NIH3T3细胞、B细胞、T细胞、NK细胞、DC、单核细胞、肥大细胞、内皮细胞和脂肪细胞等细胞中表达。健康人体中，IL-27可由DC、巨噬细胞和单核细胞等APC通过TLR和IFN-γ依赖的方式产生。IL-27在肿瘤、自免和肥胖炎症作用中均表现出多效性。抗肿瘤已报道的作用机制包括：抑制肿瘤作用促进肿瘤作用诱导产生IFN-γ，提高肿瘤特异性CD8+ T细胞的存活率和分化能力激活NFIL3和T-bet来诱导TIM-3表达激活T细胞和NK细胞介导的肿瘤免疫反应激活STAT1，驱动Treg表达CD39，从而发挥Treg促瘤作用促进造血干细胞扩增和分化为M1表型髓系祖细胞激活STAT1，介导PD-L1表达介导CD8+ T细胞免疫反应诱导癌变B细胞凋亡激活NK细胞，通过Fas/FasL依赖诱导肿瘤细胞凋亡与多肌胞嘧啶结合，通过增强TLR3表达诱导肿瘤细胞凋亡通过诱导产生CXCL10和IFN-γ诱导的单核因子，抑制肿瘤组织新生血管形成。通过下调促血管生成相关基因(如VEGFR1、PTGS1、COx-1和FGFR3)和上调抗血管生成相关基因(如IP-10和TIP3)，阻碍肿瘤新血管生成。IL-27被用来预测乳腺癌生存、免疫检查点表达、免疫细胞浸润。联合PD-1/PD-L1、IDO阻断剂可能是更好的策略。J Immunother Cancer. 2023;11(11):e007530. 抑肥胖理论上，IL-27/IL-27Rα信号能够抵御肥胖和胰岛素抵抗的发展，促进产热和能量消耗。但实际上，IL-27在调节脂肪细胞内炎症反应方面具有双重作用。在体外细胞实验中检测到，在TNF-α或LPS刺激下，前脂肪细胞和脂肪细胞均可分泌IL-27。Acta Physiologica Sinica已知机制包括：抑制肥胖发展促进肥胖发展通过WSX-1信号特异性调控小鼠内脏脂肪组织内Treg数量，进而抑制肥胖的发展。在没有炎症因子干预的情况下，IL-27 刺 激 前 脂 肪 细 胞 后， 可 通 过 激 活ERK和JNK/STAT3途径降低MCP-1、IL-6、TNF-α和COX-2经典炎症基因mRNA的表达，抑制炎症反应。当肥胖已诱发炎症时，IL-27会加重脂肪组织内炎症的进展。在HFD喂养的 IL-27Rα敲除小鼠模型中，脂肪组织中IL-6、TNF-α增加，巨噬细胞浸润增加。直接作用于脂肪细胞，通过p38MAPK/PGC-1α 信号通路诱导产热效应子 UCP1 的表达，促进产热，进而调节肥胖。在体外细胞实验中检测到，在 TNF-α或LPS刺激下，前脂肪细胞和脂肪细胞均可分泌 IL-27。体外实验中，在培养基中加入TNF-α后，IL-27能与TNF-α协同作用，显著增加MCP-1、IL-6、COX-2和TNF-α的表达。同时，成人和儿童的IL-27作用也有差异。有研究显示，成人血清IL-27水平会随着肥胖程度的加重而降低，且在减肥成功后 IL-27 的水平恢复正常。但肥胖儿童血浆中则观察到IL-27水平升高。抗自免以类风湿关节炎(RA)为例：抑制促炎因子分泌致病作用在RA发病早期，IL-27可能通过抑制IL-17和IL-6的分泌，延缓RA的进程。可通过诱导FLS表达粘附分子及释放炎症趋化因子加重RA。可通过与IL-6竞争二者共同的受体亚基gp130而自然拮抗IL-6激活mTOR信号通路，导致外周血中B细胞的失调及功能异常。在RA滑膜中， IL-27能抑制TNF-α或者IL-17A刺激下的FLS产生IL-6。能抑制初始CD4+ T细胞分化为Th17细胞，并通过STAT1依赖性途径抑制Th17细胞的发育，进而减少IL-17的产生。抑制TNF-α诱导产生CCL20，间接阻碍包括Th17细胞在内的CCR6+细胞群的募集，从而减少IL-17分泌。肠道驻留的Treg细胞还会在肠道炎症期间产生IL-27，以限制潜在Th17的分化，从而抑制对肠道细菌的促炎作用，并减轻了自身免疫和自体炎症条件下的肠道损伤。值得注意的是，IL-27和IL-10由不同的Treg细胞组产生。IL-27作为Treg细胞来源的肠道Th17反应抑制因子的具体机制尚不明确，可能是通过STAT1和STAT3受体发出信号。Nat Immunol抗病毒IL-27 可以在PBMC、CD4+ T细胞、MDM及DC等不同免疫细胞中阻碍HIV病毒的复制，其作用机制可能包括：通过激活 CD4+ T细胞中的抗病毒蛋白基因；调节Th1/Th2比率；诱导MDM中 IFIG表达；上调巨噬细胞中的免疫限制因子APOBEC3G及BST-2；下调宿主因子 SPTBN1 及抑制 YB-1 的乙酰化发挥其抑制作用，等等。小结目前进展最快的IL-27单抗应该是Surface的SRF388Coherus的casdozokitug，均已进入2期临床。2024年1月，Coherus在公布了casdozokitug联合疗法治疗局部晚期或转移性肝细胞癌的2期数据，ORR为38%(n=29)，其中3例患者实现完全缓解。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·····

近日（11月2日），Surface Oncology在其发布的第三季度财报中提及将放弃靶向CD39单抗SRF617的内部临床开发。而由于管线被砍，连带着Surface将实施组织结构调整（裁员），这将导致其员工数量减少约20%。虽然管线被砍，但Surface的CEO却强调暂停SRF617开发的决定是“一项战略商业决定”，他们仍然认为SRF617在各种肿瘤类型中具有治疗潜力。目前Surface Oncology会将精力集中在IL-27单抗SRF388和CCR8单抗SRF114上，砍去SRF617的管线后，公司的现金流将维持至2024年第二季度。如果不砍去SRF617的管线的话，根据2021年该公司全年财报的预估，仅够维持到将要到来的2023年。押注IL27对于Surface Oncology来说，也并非没有好消息，十月FDA批准了CCR8单抗SRF114的新药临床申请（IND）。总体来说，Surface Oncology押注的是IL-27单抗SRF388的临床进展。此外，IL-27单抗SRF388作为非小细胞肺癌患者的单一疗法的研究中，观察到两个确认的部分缓解。此外，患有腺癌的患者经历了持续的疾病稳定，持续超过56周。这三名患者之前都接受过化疗和抗PD-(1)1药物治疗。基于这些结果，Surface已经开始了Simon的II期试验的第二阶段，评估SRF388联合pembrolizumab（K药）在NSCLC患者中的应用，这些患者在1-3次既往治疗(包括化疗和抗PD-1药物)后的进展，预计总共招募40名非小细胞肺癌患者。此外，由于基于在这些适应症中看到的令人鼓舞的数据，Surface已经停止在肾细胞癌(RCC)研究中的招募，以专注于非小细胞肺癌和HCC。为何押注IL27？IL-27由活化的抗原呈递细胞产生，如树突细胞和活化的巨噬细胞，由p28和EB13亚单位组成，它们独特地组织成异二聚体装配体。同时IL-27是各种肿瘤免疫抑制环境中的关键调节因子，具有如下所述的功能：①IL-27诱导几种免疫调节受体(如PD-L1、TIM-3、LAG-3和TIGIT)的表达，并减少炎性细胞因子的产生②IFN刺激的基因信号在多种人类肿瘤中表达，并与对包括化疗、放疗和免疫检查点抑制在内的癌症治疗的抗性相关。这些IFN刺激的基因也被IL-27上调。③IL-27和1型干扰素(IFNα2，IFNβ1)可以抵消人类PBMCs中PD-(L)1途径抑制后的“从衰竭状态中恢复”的T细胞，从而防止T细胞攻击癌细胞。而IFNγ则没有这种功能。而SRF388是一种完全人类抗IL-27抗体，能够和IL-27R竞争IL-27上的相同结合表位。SRF388竞争性抑制IL-27受体活性，为SRF388的有效拮抗特性提供了结构证据。图：SRF388的作用机制 来源DOI:https://doi-org.libproxy1.nus.edu.sg/10.1016/j.celrep.2022.111490小编总结IL27和CD39作为近年来出现的新兴靶点，Surface Oncology的一用一砍凸显了目前仅有1.464亿美元现金跑道的窘境。不过正如该公司的NZV-930和GSK4381562那样，CD39抗体SRF617或许能找到一个好买家。参考来源：https://investors.surfaceoncology.com/news-releases/news-release-details/surface-oncology-announces-promising-srf388-monotherapy-data-non

CAMBRIDGE, Mass., Nov. 02, 2022 (GLOBE NEWSWIRE) -- Surface Oncology (Nasdaq: SURF), a clinical-stage immuno-oncology company developing next-generation immunotherapies that target the tumor microenvironment, today provided a corporate update and reported financial results for the third quarter of 2022. “We are excited by the monotherapy activity seen with SRF388 in relapsed non-small cell lung cancer (NSCLC), an area of high unmet need globally,” said Rob Ross, M.D., chief executive officer. “Two patients with squamous NSCLC have had confirmed partial responses to monotherapy treatment. Both patients had progressed on multiple prior systemic treatments, including anti-PD-(L)1 antibodies and chemotherapy. In addition, a third patient with highly pretreated NSCLC experienced durable disease stabilization and has remained on study for over a year without progression. Based on these promising results in relapsed NSCLC, we have opened the second stage of our trial investigating SRF388 as a monotherapy, and we have treated our first patients in a new cohort to investigate SRF388 in combination with pembrolizumab in second to fourth line NSCLC. We look forward to sharing additional data from those trials in the first half of 2023.” Dr. Ross added, “While we continue to believe SRF617 holds therapeutic potential in a variety of tumor types, we have made the strategic decision to pause internal development of that program and focus our efforts on SRF388 and SRF114. As a result, we are implementing a corresponding reduction in our workforce. The work done by our impressive team of scientists and clinicians was outstanding, but we believe it is in the best interest of patients and our shareholders to invest our resources where they can have the greatest potential impact in the near term. We are actively pursuing partnership opportunities to advance SRF617 outside of Surface.” Clinical Program Updates SRF388, first-in-class antibody targeting IL-27 In the ongoing study evaluating SRF388 as a monotherapy in NSCLC, two confirmed partial responses have been observed as of the data cut-off of August 24, 2022, in patients treated at or above the recommended Phase 2 dose (22% ORR (2/9)), which includes 100% (2/2) of patients with squamous NSCLC. Additionally, a patient with adenocarcinoma has experienced durable disease stabilization, ongoing for more than 56 weeks. All three of these patients had previous treatment with chemotherapy and with anti-PD-(L)1 agents. Based on these results, Surface has opened the second stage of the Simon’s 2-stage trial which is expected to enroll 40 patients with NSCLC in total. Surface has initiated a single-arm Phase 2 study evaluating SRF388 in combination with pembrolizumab in patients with NSCLC who have progressed after 1-3 prior lines of therapy, including chemotherapy and anti-PD-1 agents. The study is anticipated to enroll up to 40 patients with NSCLC. Surface anticipates sharing clinical results from the ongoing SRF388 studies in the first half of 2023. Surface has stopped enrollment in the renal cell carcinoma (RCC) study to focus efforts on NSCLC and HCC based on encouraging data seen in those indications. SRF617, novel antibody targeting CD39 Following a portfolio review, Surface made the strategic decision to pause the internal clinical development of SRF617, a novel antibody targeting CD39. In conjunction with this change, Surface is implementing an organizational restructuring that will result in a reduction of approximately 20% of its workforce. This change will enable the company to focus its resources on the advancement of SRF388 and SRF114, which Surface believes hold the greatest near-term potential to provide benefit to patients and drive value for shareholders. Management now projects that current cash and cash equivalents are sufficient to fund Surface into the second quarter of 2024. Surface is actively pursuing potential business development opportunities for SRF617. SRF114, potential best-in-class antibody targeting CCR8 In October, the U.S. Food and Drug Administration (FDA) cleared the Investigational New Drug (IND) application for SRF114, a potential best-in-class CCR8 inhibitor. Surface expects to enroll the first patient soon. Third Quarter and Subsequent Corporate Highlights In October, Surface announced the publication of a study entitled, “Structural basis of activation and antagonism of receptor signaling mediated by Interleukin-27” in Cell Reports. The study was a collaborative research effort between the Unit for Structural Biology at the VIB-University of Ghent Center for Inflammation Research and Surface Oncology. The research provides important structural evidence that the SRF388 antibody directly competes with the IL-27 receptor to prevent downstream signaling of the cytokine. In September, Surface presented new preclinical data demonstrating IL-27 induces a gene expression signature that has been associated with resistance to chemotherapy, radiotherapy, and checkpoint inhibition at the 10th Annual Cytokines Meeting of the International Cytokine and Interferon Society (ICIS). The findings support the continued clinical investigation of SRF388 in multiple tumor types. Corporate Update Conference Call and Webcast Surface management will host a conference call and live webcast today, November 2, 2022, at 8:30 a.m. ET to discuss the SRF388 data and other corporate updates. Individuals interested in viewing the webcast may do so by registering via this webcast link or by visiting the Investor Relations section of the company's website at: www.surfaceoncology.com. To access the conference call by phone, please use this registration link, and you will be provided with dial-in details. A webcast re-play will be available in the investor relations section on the company's website shortly following the completion of the call. Financial Results As of September 30, 2022, cash, cash equivalents and marketable securities were $146.4 million, compared to $154.1 million on December 31, 2021. General and administrative (G&A) expenses were $6.0 million for the third quarter ended September 30, 2022, compared to $5.8 million for the same period in 2021. The increase primarily relates to personnel related costs from increased headcount. G&A expenses included $1.1 million in stock-based compensation expense for the third quarter ended September 30, 2022. Research and development (R&D) expenses were $16.9 million for the third quarter ended September 30, 2022, compared to $14.0 million for the same period in 2021. The increase was primarily driven by expenses incurred for the SRF388 and SRF617 Phase 1 and Phase 2 clinical trials as well as manufacturing expenses incurred for the SRF114 program. R&D expenses included $0.7 million in stock-based compensation expense for the third quarter ended September 30, 2022. For the third quarter ended September 30, 2022, net loss was $23.2 million, or basic and diluted net loss per share of $0.39. Net loss was $19.9 million for the same period in 2021, or basic and diluted net loss per share of $0.44. About Surface Oncology Surface Oncology is an immuno-oncology company developing next-generation antibody therapies focused on the tumor microenvironment. Its pipeline includes two wholly-owned programs; SRF388, a Phase 2 program which targets IL-27, and SRF114 which selectively depletes regulatory T cells in the tumor microenvironment via targeting CCR8. In addition, Surface has two partnerships with major pharmaceutical companies: a collaboration with Novartis targeting CD73 (NZV930; Phase 1) and a collaboration with GlaxoSmithKline targeting PVRIG (GSK4381562, formerly SRF813; Phase 1). Surface’s novel, investigational cancer immunotherapies are designed to achieve a clinically meaningful and sustained anti-tumor response and may be used alone or in combination with other therapies. For more information, please visit www.surfaceoncology.com.