LL-37

本文为转化医学网原创，转载请注明出处 作者：Sophia 导读： 为了逃避免疫监视，肿瘤细胞在其膜表面表达外核苷酸焦磷酸酶磷酸二酯酶 1 （ENPP1），从而降解细胞外环状 GMP-AMP （cGAMP），从而抑制干扰素基因的环状 GMP-AMP 合酶 （cGAS） 刺激物 （STING） DNA 感应途径。为了充分了解这种肿瘤隐身机制，必须确定肿瘤微环境中是否也存在其他形式的具有水解cGAMP活性的ENPP1来调节这种先天免疫途径。 2024年3月18日，上海交通大学医学院季天海、杨朝勇、吴玲玲共同通讯在《Advanced Science》上发表题为“Tumor Exosomal ENPP1 Hydrolyzes cGAMP to Inhibit cGAS-STING Signaling”的研究论文，据报道， 多种肿瘤来源的外泌体携带ENPP1，能水解细胞产生的合成2′3′-cGAMP和内源性2′3′-cGAMP，抑制免疫细胞中的cGAS-STING通路。此外，肿瘤外泌体ENPP1还可以水解与LL-37（2′3′-cGAMP的有效转运蛋白）结合的2′3′-cGAMP，以抑制STING信号传导。此外，观察到从人乳腺癌和肺癌组织中分离出的外泌体中ENPP1的高表达，肿瘤外泌体ENPP1抑制CD8+ T细胞和CD4+ T细胞的免疫浸润。 研究结果阐明了肿瘤外泌体ENPP1在cGAS-STING通路中的基本功能，进一步加深了对肿瘤细胞和免疫系统之间串扰的理解。 https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/advs.202308131 研究背景 01 cGAS-STING通路是一种重要的先天免疫应答通路，在自身免疫性疾病和癌症中起着重要作用。从机理上讲，环状GMP-AMP合酶（cGAS）作为胞质DNA传感器，可以首先识别来自入侵微生物病原体或受损细胞的双链DNA（dsDNA），然后以三磷酸腺苷（ATP）和三磷酸鸟苷（GTP）为底物合成2′3′-环GMP-AMP（2′3′-cGAMP）。2′3′-cGAMP作为内源性第二信使，与干扰素基因刺激因子（STING）蛋白结合，募集坦克结合激酶1（TBK1）蛋白，激活干扰素调节因子IRF3。然后，磷酸化的 IRF3 进入细胞核并导致 I 型干扰素 （IFN） 的产生，从而启动抗癌和抗病毒的先天免疫反应。为了增强宿主的先天免疫反应，2′3′-cGAMP也可以输出到细胞外，以激活旁观者细胞中的cGAS-STING信号传导。事实上，2′3′-cGAMP 作为一种阴离子亲水分子，在依赖于病毒颗粒、细胞膜通道、SLC46A 溶质载体家族、工程跨膜 （TM） 缺陷 STING 蛋白或抗菌肽的细胞之间转移。 作为cGAS-STING通路的关键因素，了解细胞外cGAMP和转运蛋白-cGAMP复合物的命运是必要的。 截止目前，ENPP1是唯一可以水解免疫递质2′3′-cGAMP的可检测蛋白酶。然而， 除了分布在肿瘤细胞膜上的ENPP1蛋白外，肿瘤微环境中是否还存在其他形式的可以水解2′3′-cGAMP的ENPP1蛋白。 外泌体是由多种细胞类型分泌的脂质双层膜囊泡（直径 30-150 nm），携带母体细胞的各种生物活性分子（例如蛋白质和核酸）以促进细胞间通讯。事实上，研究表明，肿瘤来源的外泌体是肿瘤细胞与免疫细胞之间重要的通讯介质，也是肿瘤微环境中其他非肿瘤旁观者细胞之间的重要通讯介质，可以调节宿主的免疫反应。特别是，肿瘤来源的外泌体在调节先天免疫cGAS-STING信号转导中的作用逐渐被阐明。例如，经放射治疗的肿瘤细胞已被证明可以分泌携带dsDNA的外泌体，以激活免疫细胞中的STING。最近，信号转导接头分子 1 （STAM） 已被证明可以将活化的 STING 寡聚体转运到外泌体中并降解 STING 寡聚体以负调控 STING 信号转导。尽管这些研究表明外泌体在cGAS-STING通路的调控中起着重要作用，但 肿瘤来源的外泌体调节cGAMP的分子机制仍然未知，这限制了我们对肿瘤来源的外泌体在cGAS-STING信号通路和肿瘤免疫逃逸中的调控机制的充分认识。 研究结果 02 在此背景下，我们报道了各种肿瘤细胞衍生的外泌体携带 ENPP1 蛋白;事实上，ENPP1在这些外泌体中高度富集。我们发现肿瘤来源的外泌体可以帮助游离的 2′3′-cGAMP 激活 STING 信号传导。为了削弱外泌体介导的免疫增强，肿瘤外泌体ENPP1进一步水解细胞外2′3′-cGAMP，以抑制免疫细胞中的cGAS-STING通路。LL-37 作为一种由多种细胞类型表达的抗菌肽，已被证明是 2′3′-cGAMP 的有效转运蛋白，可以增强 cGAS-STING 信号转导的免疫反应。我们的研究还表明，肿瘤外泌体ENPP1可以有效地水解与LL-37结合的2′3′-cGAMP，从而抑制免疫细胞中的STING信号传导。事实上， 肿瘤外泌体 ENPP1 可能对任何形式的 2′3′-cGAMP 具有很强的降解活性，从而抑制 cGAS-STING 信号传导。 此外，我们的研究还表明，肿瘤外泌体ENPP1可以水解细胞产生的内源性2′3′-cGAMP，从而抑制旁观者细胞中的cGAS-STING通路。事实上， 我们观察到肿瘤外泌体在肺癌和乳腺癌患者的组织样本中表现出高 ENPP1 表达。重要的是，肿瘤外泌体ENPP1的表达水平分别与CD8+ T细胞和CD4+ T细胞浸润呈负相关。 肿瘤外泌体ENPP1介导的cGAS-STING信号通路在肿瘤微环境中水解2′3′-cGAMP和LL-37-2′3′-cGAMP的机制模型。 总体而言， 我们的研究揭示了肿瘤外泌体ENPP1通过水解2′3′-cGAMP抑制cGAS-STING信号传导的机制。 这突出了肿瘤来源的外泌体在先天免疫反应中的重要作用，并加深了我们对 ENPP1 介导的 cGAS-STING 通路的理解。 参考资料： https://onlinelibrary-wiley-com.libproxy1.nus.edu.sg/doi/full/10.1002/advs.202308131 注：本文旨在介绍医学研究进展，不能作为治疗方案参考。如需获得健康指导，请至正规医院就诊。 热门·直播/活动 🕓 上海｜06月14日-16日 ▶ 第六届上海国际癌症大会将于6月14-16日在上海举办，学科交叉，共同推进肿瘤研究与诊治多模态！ 🕓 北京｜09月20日-21日 ▶ 第五届单细胞技术应用研讨会暨空间组学前沿研讨会欢迎您的参与！ 点击对应文字 查看详情

STOCKHOLM, SE / ACCESSWIRE / November 29, 2023 / Promore Pharma (STO:PROMO)(FRA:8T0) Promore Pharma AB (publ) (the "Company" or "Promore") intends to acquire all the shares in PMD Device Solutions AB ("PMD") by making payment in the form of newly issued shares in the Company (the "Transaction"). The planned Transaction will constitute a so-called reverse acquisition. If completed, the voluntary liquidation that the Company entered following a resolution of the extraordinary general meeting on 5 October 2023 will be terminated and the Company will continue by assuming PMD's operations. The Company's current operations will be discontinued in connection with the Transaction. It is proposed to carry out the Transaction by way of a share issue directed to the shareholders of PMD with payment by way of non-cash contribution consisting of all shares in PMD. The termination of the voluntary liquidation and the Transaction is subject to a resolution at an extraordinary general meeting in the Company. Notice to the general meeting will be published through a separate press release. Prior to the Transaction, PMD plans to carry out a private placement of approximately SEK 26.5 million through an issue of shares to certain existing shareholders and new investors (the "Private Placement"). The Transaction in brief Promore intends to acquire all the shares in PMD for a purchase price of approximately SEK 125 million. The purchase price for all shares in PMD is intended to be paid with a total of 2,574,461,929 newly issued shares in the Company through a non-cash issue and the Transaction constitutes a so-called reverse acquisition. PMD have in connection with the Transaction resolved to carry out a Private Placement of approximately SEK 26.5 million at a subscription price of SEK 6.81 per share. The valuation of PMD determined through the Private Placement is the basis for the valuation of PMD in the proposed Transaction. Following the issue of the consideration shares at the extraordinary general meeting, Promore's existing shareholders will hold approximately 2.3 per cent of the shares in the Company and the shareholders of PMD will hold approximately 97.7 per cent in the Company. The Transaction is conditional on Nasdaq Stockholm approving the continued listing of the Company's shares on Nasdaq First North Growth Market and on the extraordinary general meeting of Promore resolving to carry out the Transaction. The two largest shareholders in the Company with a combined share of the votes of 49.7 per cent have agreed to enter into customary voting undertakings regarding the proposals to be put forward in connection with the Transaction. As part of the Transaction, Promore will undergo a name change to PMD Device Solutions AB and will continue to operate PMD's business. Changes will also be made to the board of directors and senior executives. In order to achieve an appropriate number of shares, it is proposed that Promore undertakes a reverse share split (1:128). Promore's current operations will be discontinued in connection with the Transaction. The extraordinary general meeting to resolve on the Transaction is expected to be held on 29 December 2023. Prior to the extraordinary general meeting, the preliminary approval from Nasdaq Stockholm is expected to be granted and a company description will be published. Certain shareholders of PMD and Promore have agreed to enter lock-up undertakings following completion of the Transaction. Information about PMD PMD develops and sells medical products for respiratory monitoring. Its primary product is RespiraSense™, a solution used for monitoring respiratory rate to detect deterioration of a patient's general condition early and to avoid preventable respiratory failure and adverse patient outcomes. RespiraSense™ is, to the PMD's knowledge, the world's only continuous, motion-tolerant respiratory rate monitor delivering class-leading reliability in measuring respiratory rate. PMD Device Solutions AB received FDA approval for RespiraSense™ in 2022. RespiraSense™ is a novel technology and today used in 25 hospitals across United Kingdom and Ireland. PMD seeks to continue increasing its market share in the United Kingdom, with Germany and the United States to follow with initial market access activities. PMD today generates over SEK 32 million of annual recurring revenue with gross margins of approximately 80 per cent and employs over 20 persons. Description of the Transaction Since spring 2023, Promore has faced a very challenging market situation with a low market value in relation to the Company's need for new investments. The company received the final results of the PHSU05 clinical trial, which showed that the treatment effect of Ensereptide was insufficient to justify further investments, which is why the board subsequently decided to discontinue this development project. This resulted in the Company's market value being greatly reduced. Furthermore, the financial markets have been unstable. In general, it has created a difficult climate for the Company to carry out public share issues, which would be needed to finance the continued development of the Company's main asset, the drug candidate Ropocamptide. Following a decision at an extraordinary general meeting held on 5 October 2023, Promore entered into voluntary liquidation with effect from 12 October 2023. In light of the proposed Transaction, the basis for the voluntary liquidation will no longer exist. Against this background, it will be proposed that the extraordinary general meeting in Promore to decide on the Transaction will also decide to terminate the voluntary liquidation process. PMD seeks to continue increasing its market share in the United Kingdom, with Germany and the United States to follow with initial market access activities. The board of PMD believes that a listing on the Nasdaq First North Growth Market will provide a quality stamp that contributes to confidence in discussions with potential customers and partners and an increased interest in PMD from the public, investors and other stakeholders. The Transaction will also enhance the conditions for creating shareholder value and gives PMD access to the capital market. The access to the stock market will also facilitate the implementation of the PMD's growth plans and ambition to expand the business into new markets globally. As part of the Transaction, Promore will undergo a name change to PMD Device Solutions AB and will continue to operate PMD's business. Changes will also be made to the board of directors and senior executives. To achieve an appropriate number of shares, it will be proposed for Promore to undertake a reverse share split of 1:128. Promore's current operations will be discontinued in connection with the Transaction. The background for this is that (i) the runway of the remaining patent family is limited, (ii) the competitive challenge has increased in recent years and (iii) the prior management, board and liquidator have exhausted all opportunities to monetize the remaining assets. The Transaction is proposed to be carried out as an issue of 2,574,461,929 new shares in Promore directed to the shareholders of PMD with payment by way of non-cash contribution of all shares in PMD. The subscription price in the share issue corresponds to a valuation of PMD of approximately SEK 153.5 million, which is the post-money valuation after the completion of the Private Placement in PMD. All current shareholders in PMD with a holding greater than 1.0 per cent have entered a lock-up agreement for 12 months following completion of the Transaction. All current shareholders in Promore with holdings of 10 per cent or more of the Promore shares have entered in a stepwise lock-up with 1/3 free from restriction after 6 months from the Transaction, another 1/3 free from restriction after 9 months of the Transaction and the balance free from restriction after 12 months from the Transaction. "I am pleased to present this opportunity of the reverse acquisition to the shareholders of Promore Pharma. During the last few weeks, we have done all in our power to be able to offer the current shareholders of Promore Pharma opportunities to realize remaining values in Promore Pharma," says Lars-Henrik Andersson, Liquidator. "The situation for the company has been extremely challenging since April 2023, and I believe that the intended transaction is the best feasible solution for all stakeholders of Promore Pharma," he continues. Myles Murray, founder and CEO of PMD says, "PMD's vision is to establish its innovations as the standard of care to reduce the incidence of adverse events a significant volume of people experience during exacerbations, acute episodes of pneumonia, and seasonal acute respiratory infections; both in hospital and the home. This transaction presents a unique opportunity to support our continued market expansion. We are grateful to the support received from the Team and Board of Promore Pharma during this transaction and we are grateful to continue serving an increasing number of both patients and shareholders by #MakingEveryBreathCount." Ownership structure following the Transaction and changes in the amount of shares and share capital The proposed Transaction constitutes a reverse acquisition whereby payment for all shares in PMD will be made through a non-cash issue of new shares in Promore to the sellers of PMD. Following the Transaction, the current shareholders of PMD, taking into account the Private Placement, will hold approximately 97.7 per cent of the shares and votes in the Company and the current shareholders of the Company will hold approximately 2.3 per cent of the shares and votes of the Company. The Transaction entails an increase in the amount of shares in the Company from 60,713,936 to 2,635,175,865 and an increase in the Company's share capital from SEK 2,428,557.44 to SEK 105,407,034.60. Following the proposed reverse split of shares, the number of shares will be 20,587,314. Through the Transaction, the majority shareholder in PMD, Myles Murray, will acquire an ownership stake in Promore equivalent to at least 30 percent of the total voting rights for the total number of shares in Promore. Myles Murray will be applying for conditional exemption from the obligation to submit a public takeover offer for all shares in Promore, which Myles Murray would otherwise be subject to, pursuant to applicable takeover rules for certain trading platforms. The exemption from the mandatory bid requirement will be conditional on the Transaction being approved by a shareholders' meeting in Promore with a two-thirds majority. Application for continued listing on Nasdaq First North Growth Market The Transaction will entail a significant change in the Company's operations and, due to this, a new listing process is required for Promore on Nasdaq First North Growth Market. Nasdaq Stockholm must first approve Promore for continued listing on Nasdaq First North Growth Market before the Transaction can be completed. Due to this and, provided that Nasdaq approves the listing, a company description will be published. Extraordinary general meeting The Company's acquisition of PMD will be subject to the approval of the extraordinary general meeting of Promore expected to be held on 29 December 2023. Due to the ongoing liquidation, the extraordinary general meeting will be convened by Promore's liquidator, at the request of Corespring New Technology AB, the largest shareholder in Promore. The extraordinary general meeting for decisions on matters relating to the Transaction is intended to be convened prior to receipt of preliminary approval for a continued listing from Nasdaq Stockholm. This includes terminating the voluntary liquidation, a change of company name, changes to the articles of association, election of a new board of directors, a reverse share split of shares and authorisation for the board of directors to issue new shares. The intention is that Nasdaq Stockholm's preliminary approval will be received and that a company description will be available before the extraordinary general meeting, which is expected to be held during December 2023. Private Placement in PMD and authorisation to issue additional shares in the Company For securing working capital to grow market share in the United Kingdom and to undertake market access activities in Germany and the United States, PMD plans to raise capital of approximately SEK 26.5 million through an issue of shares in PMD to certain existing shareholders and new investors prior to the completion of the Transaction. The investors include PMD's board member Christer Ahlberg (former CEO of Sedana Medical). PMD has engaged Redeye as financial adviser for the capital raise. In addition to what is needed to cover the Company's working capital for the next 12 months and due to end-of-year time constraints, it will be proposed for the Extraordinary General Meeting on 29 December 2023 to resolve on a specific authorisation. The specific authorisation will be aimed at enabling the new board of directors of Company to carry out an additional capital raise, on the same terms as in the Private Placement up to an amount not exceeding SEK 11.5 million in order to accommodate further interest in participation in the Private Placement. Change of Certified Adviser In connection with the Transaction, Promore will change certified Adviser from Erik Penser Bank AB to Redeye AB with effect from today's date. Advisors Eversheds Sutherland Advokatbyrå AB acts as legal advisor to PMD in connection with the Transaction and the Private Placement. Fóla Private Partners in Ireland acts as transaction advisor with the Transaction. Redeye AB acts as financial advisor in connection with PMD's Private Placement. For additional information, please contact Lars-Henrik Andersson, liquidator Phone: [+46] 8 527 91 600 E-mail: Lars-Henrik.Andersson@cirio.se Promore Pharma's Certified Adviser is Redeye Promore Pharma in brief Promore Pharma is a biopharmaceutical company specialized in the development of locally administered first-in-category pharmaceuticals for indications with high unmet medical needs, where very few efficacious prescription pharmaceuticals are available. The company is listed on Nasdaq First North Growth Market. This information is information that Promore Pharma is obliged to make public pursuant to the EU Market Abuse Regulation. The information was submitted for publication, through the agency of the contact persons set out above, at 2023-11-29 08:25 CET. Attachments Promore Pharma AB intends to carry out a reverse acquisition of PMD Device Solutions AB SOURCE: Promore Pharma View source version on accesswire.com: