ITGB7

在自免病狼疮中，自身核酸通过内体或溶酶体中的TLR7和TLR9触发免疫激活，分别介导对RNA和DNA耐受的丧失，激活自反应性B细胞和一些髓源抗原呈递细胞。尽管拥有共同信号通路MyD88，但使用单个TLR7和TLR9敲除(KO)狼疮易发MRL/lpr小鼠后显示，它们具有相反的作用：TLR7促进SLE，TLR9则抑制SLE。这一所谓“TLR悖论”提示二者存在信号传递机制的差异。TLR7促进SLE的机制越来越多的证据表明，SLE患者的表型与外周血中IgD- CD27-双阴性B细胞的CXCR5- CD11c+亚群TLR7信号升高相关。TLR7过表达导致自免疾病的矛盾表现：小鼠模型显示，由于TLR7编码Yaa位点的复制或转基因TLR7表达而增加的TLR7信号会加剧自身免疫；而在其他狼疮模型中，TLR7的缺失可预防或改善疾病。从机制而言，TLR7驱动的自发生发中心(GCs)与TLR7驱动的双阴性B细胞具有相对作用。目前认为，TLR7可以依赖于MyD88信号通路，独立于GCs造成疾病进展。Nature上的一项研究发现了一例与TLR7的功能获得突变有关的人类SLE病例，首次验证了人体内TLR7与SLE的因果关系，同时确定了TLR7中一个致病突变Y264H。小鼠模型显示该变体：可增强TLR7信号通路和下游NF-κB激活；可增加对鸟苷的亲和力，从而使其对通常不会刺激TLR7信号的单链RNA敏感；增强活化BCR细胞的生存能力；增强GCs、abc和浆细胞内抗体的扩增；临床表现包括：血小板减少、增值性肾小球肾炎加重、肝脏淋巴样浸润、局灶性心肌纤维化、血清中促炎细胞因子水平升高等等。TLR9保护和促进SLE发展的复杂调节此前有三种假说用于解释TLR9对疾病的调控：信号通路：TLR9-MyD88信号通路可诱导拮抗调控因子；DNA抗体：产生依赖于TLR9的DNA抗体可通过非炎症性方式清除自身抗原而具有保护作用；相互作用：TLR9蛋白可抑制TLR7的表达和功能，但其信号通路功能除外。但是这三种各自独立的理论无法解释为什么在实际实验中MyD88信号通路驱动的差异性结果。因此，研究人员通过小鼠模型来探索缺少配体或缺少结合MyD88信号通路的TLR9突变能够造成的影响：其小鼠模型选择了红斑狼疮易发的MRL/lpr株，引入内源性TLR9位点以分别阻断TLR9配体结合和阻断MyD88信号通路。TLR9配体结合和信号通路两种变量的控制Nat Immunol 23, 1457–1469 (2022).（1）整体可见，TLR9在狼疮中具有支架保护作用(scaffold protective role)。同时阻断了TLR9蛋白表达、配体结合与MyD88通路的TLR9-/-（TLR9K51E）小鼠显示：生存期增长，并改善了肾小球肾炎(GN)和间质性肾炎(IN)评分。原始CD4+细胞百分比增加，总B细胞和边缘区(MZ) B细胞频率增加，年龄相关B细胞(ABC)和浆母细胞(PB)频率减少。TLR9依赖性抗核小体自身抗体明显减少。这些数据表明：在没有TLR9配体结合的情况下，升高TLR9表达可以预防狼疮。生存曲线差异Nat Immunol 23, 1457–1469 (2022).（2）阻断配体结合情况下，TLR9-MyD88信号通路有促病表现。尽管已知TLR9的表达本身呈现保护作用，但是在表达TLR9水平的前提下，有配体结合也有MyD88通路的Tlr9+/−小鼠呈临床表现加重，存活率显著降低。在不依赖MyD88信号通路时，缺少抗核小体自身抗体并不会导致疾病进一步进展。因此，认为疾病加重与DNA抗体及其比例的变化无关。Nat Immunol 23, 1457–1469 (2022).因此这一致病性应该来自于单独的TLR9-MyD88信号通路。（3）由上述三种TLR9蛋白水平、配体结合能力阻断、信号通路阻断控制变量实验的不同小鼠模型结果，可以假设，TLR9保护疾病免于进展的机制中存在一种依赖配体结合但独立于MyD88的调节信号网络。Nat Immunol 23, 1457–1469 (2022).（4）Tlr9P915H小鼠中，TLR9的保护能力更明显。这表明TLR9具有独立于MyD88的配体依赖、调节信号和myd88介导的促炎信号。这种通路是B细胞中所独有的，会使其更容易分化为ABCs、CD80+PDL2+记忆样B细胞、PBs和PC，倾向于抑制B细胞激活。Tlr9−/−和Tlr9P915H不同的基因型可产生不同的PBs亚群。Nat Immunol 23, 1457–1469 (2022).二者也诱导不同的ABC和PB细胞状态。与Tlr9P915H相比，TLR9-/-模型能上调ABC中的共刺激(CD80, CD86和ITGB7)和PB标记(CD44, CD138和IRF4)。Tlr9P915H ABC则上调T-BET、BCL6和CD300a。TLR9和TLR7的相互作用（1）TLR9对TLR7分布的影响：在B细胞中，TLR9的分布较为均匀。相对地，TLR7的分布呈异质性。B细胞固有的应变差异或与IFN依赖性TLR7上调有关。Nat Immunol 23, 1457–1469 (2022).TLR9和TLR7在内质网退出和转运到晚期核内体的过程中存在对UNC93b伴侣的竞争。其中，UNC03bD34A突变可导致其优先与TLR7结合，从而增加TLR7内体转运和信号转导。换个角度来说，TLR7的转运和信号传递增加，那么TLR9的缺失也会导致更为严重的临床表现。不过，TLR9的缺失对TLR7在正常静息B细胞中的数量或定位的影响很小。（2）TLR9表达不影响TLR7信号传导：TLR7激动剂剂量反应实验和细胞RNA测序结果显示：在一定剂量范围内，TLR7诱导的NF-κB信号没有可检测到的差异。在TLR9存在或不存在的情况下，TLR7诱导的转录并不受到TLR9那种独立于MyD88、配体依赖的保护作用的影响。Nat Immunol 23, 1457–1469 (2022).整体而言，TLR7促进SLE疾病的作用大于TLR9的保护作用和/或TLR9和TLR7之间的直接相互作用。参考资料：1. Brown, G.J., Cañete, P.F., Wang, H. et al. TLR7 gain-of-function genetic variation causes human lupus. Nature 605, 349–356 (2022). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41586-022-04642-z2. Leibler, C., John, S., Elsner, R.A. et al. Genetic dissection of TLR9 reveals complex regulatory and cryptic proinflammatory roles in mouse lupus. Nat Immunol 23, 1457–1469 (2022). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41590-022-01310-23.Bernard, N.J. TLR7 drives human lupus. Nat Immunol 23, 817 (2022). https://doi-org.libproxy1.nus.edu.sg/10.1038/s41590-022-01235-w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﹀‍‍ ·········点亮在看，传递信息♥

Presentation will include summary safety, pharmacokinetic and pharmacodynamic data from single ascending dose (SAD), food effect and multiple ascending dose (MAD) studies All dosing regimens well-tolerated across Phase 1 High receptor occupancy (RO) in Phase 1 SAD study confirmed by MAD results with increasing RO over time: receptor saturation at 100 mg BID dose WALTHAM, Mass., May 28, 2021 (GLOBE NEWSWIRE) -- Morphic Therapeutic (Nasdaq: MORF), a biopharmaceutical company developing a new generation of oral integrin therapies for the treatment of serious chronic diseases, today announced that new Phase 1 data for MORF-057 will be presented in an ePoster at the Congress of European Crohn’s and Colitis Organisation (ECCO) 2021 Virtual Congress on July 9, 2021. The abstract for this e-presentation is now available on the ECCO website and contains data that provide additional support for the tolerability, pharmacokinetic and pharmacodynamic profile of MORF-057 as a twice-daily oral treatment candidate for inflammatory bowel disease (IBD). The complete ePoster is anticipated to report the full Phase 1 results, including data from an additional dose cohort from the MAD study and further pharmacokinetic (PK) endpoint data from a food effect study that were ongoing at the time of abstract submission. “These data confirm the tolerability and pharmacodynamic profile that was reported with the initial MORF-057 SAD data. In these results, we observed α4β7 RO levels that exceeded our expectations across a range of doses, each of which was well tolerated,” said Peter Linde, M.D., chief medical officer at Morphic Therapeutic. “We are incredibly excited about the results from this Phase 1 study that strongly support our upcoming Phase 2 ulcerative colitis program.” Data contained in the abstract demonstrate that single and multiple ascending doses of MORF-057 were well tolerated, with only mild, non-serious adverse events observed. MORF-057 also demonstrated a favorable PK profile with systemic exposure that was predictable and generally proportional to dose. In addition, these MORF-057 clinical data are consistent with non-clinical drug metabolism and PK (DMPK) profiling which will also be presented in a separate poster at the ECCO’21 Virtual Congress. High levels of target engagement of the α4β7 integrin receptor were observed in the Phase 1 MORF-057 SAD study. As previously reported, the mean α4β7 RO’s for the 100 mg, 150 mg and 400 mg SAD cohorts were greater than 95%. These observations were confirmed in the MAD study, with increasing RO levels at steady state in all doses tested. Increased duration of dosing demonstrated increasing mean RO and decreasing inter-subject RO variability. In these new data, results from two of the three MAD cohorts were available at the time of abstract publication. The mean α4β7 RO for the 50 mg cohort receiving twice-daily (BID) administration of MORF-057 for 14 days was greater than 90% at steady state. The mean α4β7 RO in the 100 mg BID cohort at steady state was greater than 99%, or complete receptor saturation. MORF-057 Abstracts at ECCO’21 Virtual Congress The full title of the MORF-057 Phase 1 ePoster (P306) is: MORF-057, an oral selective α4β7 integrin inhibitor for Inflammatory Bowel Disease, leads to specific target engagement in a single and multiple ascending dose study in healthy subjects The full title of the MORF-057 non-clinical DMPK ePoster (P037) is: Nonclinical pharmacokinetics and absorption, distribution, metabolism, and excretion properties of MORF-057 support its clinical development as an oral selective α4β7 integrin inhibitor About MORF-057 Morphic is developing MORF-057 as a selective, oral small molecule inhibitor of the α4β7 integrin for patients with inflammatory bowel disease (IBD). α4β7 has been clinically validated as a target for the treatment of IBD by the success of the approved injectable antibody therapeutic vedolizumab. MORF-057 is designed to block the interactions between α4β7 on the surface of lymphocytes and the mucosal endothelial cell ligand MAdCAM-1, substantially reducing lymphocyte migration from the bloodstream into intestinal mucosal tissues and causing inflammation that is associated with IBD. About Morphic TherapeuticMorphic Therapeutic is a biopharmaceutical company developing a new generation of oral integrin therapies for the treatment of serious chronic diseases, including autoimmune, cardiovascular, and metabolic diseases, fibrosis and cancer. In collaboration with AbbVie, Janssen, and Schrödinger, Morphic is advancing its pipeline and discovery activities using its proprietary Morphic Integrin Technology (MInT) Platform which leverages the Company’s unique understanding of integrin structure and biology. For more information, visit . Forward-Looking Statements This press release contains “forward-looking statements” within the meaning of the Securities Act of 1933, as amended, the Securities Exchange Act of 1934, as amended, and of the “safe harbor” provisions of the Private Securities Litigation Reform Act of 1995, including, but not limited to: the MInT Platform’s ability to discover drug candidates, Morphic’s plans to develop and commercialize oral small-molecule integrin therapeutics, the execution and completion of the MORF-057 Phase 1 clinical trial as designed, any expectations about safety, efficacy, timing and ability to commence or complete clinical studies and to obtain regulatory approvals for MORF-057 and other candidates in development, the timing of further data presentation and the ability of MORF-057 to treat inflammatory bowel disease or related indications. Statements including words such as “believe,” “plan,” “continue,” “expect,” “will,” “develop,” “signal,” “potential,” “anticipated,” or “ongoing” and statements in the future tense are forward-looking statements. These forward-looking statements involve risks and uncertainties, as well as assumptions, which, if they do not fully materialize or prove incorrect, could cause our results to differ materially from those expressed or implied by such forward-looking statements. Forward-looking statements are subject to risks and uncertainties that may cause Morphic’s actual activities or results to differ significantly from those expressed in any forward-looking statement, including risks and uncertainties in this press release and other risks set forth in our filings with the Securities and Exchange Commission, including Morphic’s or a partner’s ability to complete a current or future clinical trial of any of our current or future product candidates, develop or obtain regulatory approval for or commercialize any product candidate, Morphic’s ability to protect intellectual property, the potential impact of the COVID-19 pandemic and the sufficiency of our cash, cash equivalents and investments to fund our operations. These forward-looking statements speak only as of the date hereof and Morphic specifically disclaims any obligation to update these forward-looking statements or reasons why actual results might differ, whether as a result of new information, future events or otherwise, except as required by law. ContactsMorphic TherapeuticChris Erdmanchris.erdman@morphictx.com617.686.1718 Media ContactTom Donovan, Ten Bridge Communicationstom@tenbridgecommunications.com857.559.3397