CEACAM1

REHOVOT, Israel, Feb. 01, 2024 (GLOBE NEWSWIRE) -- Purple Biotech Ltd. ("Purple Biotech" or "the Company") (NASDAQ/TASE: PPBT), a clinical-stage company developing first-in-class therapies that harness the power of the tumor microenvironment to overcome tumor immune evasion and drug resistance, today announced it has determined 100mg/kg is the recommended Phase 2 dose (RP2D) for NT219 in combination with cetuximab in the treatment of head and neck cancer based on its Phase 1/2 dose escalation study (NCT04474470). NT219 is a first-in-class small molecule dual inhibitor of IRS1/2 and STAT3. The RP2D was determined based on data from the open-label dose escalation study designed to assess the safety, pharmacokinetics, pharmacodynamics and efficacy of NT219 in combination with Erbitux® (cetuximab), in previously treated recurrent and/or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) patients. The Company recently reported that NT219, in combination with cetuximab, demonstrated a dose dependent anti-tumor activity with confirmed partial responses. No dose-limiting toxicities were reported. The additional supporting data used for this determination was pharmacokinetics of NT219 across all dose levels. Further dose optimization is planned for future studies. The Phase 1 dose escalation study is being concluded and the remaining patients' data are expected to be reported during the first half of 2024. The Company is now advancing its upcoming Phase 2 Proof of Concept study of NT219 for the treatment of R/M SCCHN. Detailed clinical results from the dose escalation portion of the study are intended to be presented at the European Society of Medical Oncology Targeted Anticancer Therapies (ESMO TAT) Congress 2024 in Paris on February 26, 2024, in an Oral Presentation titled “Interim results of a Phase 1/2 trial of NT219 in combination with cetuximab in patients with advanced/metastatic Squamous Cell Carcinoma of the Head and Neck (SCCHN).” “This is a major milestone for the development of NT219 for an indication in need of more effective therapies. As we progress into a Phase 2 study, our goal is to establish NT219 as standard of care for squamous cell carcinoma of the head and neck for patients who have not responded to first line treatments,” stated Gil Efron, Chief Executive Officer of Purple Biotech. “We look forward to treating more patients with NT219 in a Phase 2 study.” About NT219 NT219 is a first-in-class, small molecule that promotes Insulin Receptor Substrates 1/2 (IRS) degradation and inhibits Signal Transducer and Activator of Transcription 3 (STAT3) phosphorylation, two major complementary signalling pathways that play a key role in the tumor and its microenvironment. IRS1/2 acts as scaffolds, organizing signalling complexes that mediate mitogenic, metastatic, angiogenic, and anti-apoptotic signals from IGF1R and other oncogenes, consisting of an important driver in multiple cancers and is highly involved in triggering drug resistance. STAT3 is a transcription factor that is broadly hyperactivated in many cancers, promoting proliferation, survival, angiogenesis, metastasis, and tumor immune evasion. Feedback activation of STAT3 plays a prominent role in mediating drug resistance to various anti-cancer therapies. As an inhibitor of both IRS1/2 and STAT3, NT219 has the potential to prevent the development of resistance to multiple approved therapies. About Purple Biotech Purple Biotech Ltd. (NASDAQ/TASE: PPBT) is a clinical-stage company developing first-in-class therapies that seek to overcome tumor immune evasion and drug resistance. The Company's oncology pipeline includes NT219, CM24 and IM1240. NT219 is a dual inhibitor, novel small molecule that simultaneously targets IRS1/2 and STAT3. A phase 2 study of NT219 at its recommended Phase 2 level in combination with cetuximab in patients with recurrent and/or metastatic SCCHN is planned. CM24 is a humanized monoclonal antibody that blocks CEACAM1, an immune checkpoint protein that supports tumor immune evasion and survival through multiple pathways. The Company is advancing CM24 as a combination therapy with anti-PD-1 checkpoint inhibitors in a Phase 2 study for the treatment of pancreatic ductal adenocarcinoma (PDAC). The Company has entered into a clinical collaboration agreement with Bristol Myers Squibb for the Phase 2 clinical trials to evaluate the combination of CM24 with the PD-1 inhibitor nivolumab in addition to chemotherapy. The Company is advancing a preclinical platform of conditionally-activated tri-specific antibody that engages both T cells and NK cells to mount a strong, localized immune response within the tumor microenvironment. The cleavable capping technology confines the compound's therapeutic activity to the local tumor microenvironment, and thereby potentially increases the anticipated therapeutic window in patients. The third arm specifically targets the Tumor Associated Antigen (TAA). The technology presents a novel mechanism of action by unleashing both Innate and adaptive immune systems to mount an optimal anti-tumoral immune response. IM1240 is the first tri-specific antibody in development that targets 5T4 expressed in a variety of solid tumors and is correlated with advanced disease, increased invasiveness and poor clinical outcomes. The Company's corporate headquarters are located in Rehovot, Israel. For more information, please visit . Forward-Looking Statements and Safe Harbor Statement Certain statements in this press release that are forward-looking and not statements of historical fact are forward-looking statements within the meaning of the safe harbor provisions of the Private Securities Litigation Reform Act of 1995. Such forward-looking statements include, but are not limited to, statements that are not statements of historical fact, and may be identified by words such as "believe", "expect", "intend", "plan", "may", "should", "could", "might", "seek", "target", "will", "project", "forecast", "continue" or "anticipate" or their negatives or variations of these words or other comparable words or by the fact that these statements do not relate strictly to historical matters. You should not place undue reliance on these forward-looking statements, which are not guarantees of future performance. Forward-looking statements reflect our current views, expectations, beliefs or intentions with respect to future events, and are subject to a number of assumptions, involve known and unknown risks, many of which are beyond our control, as well as uncertainties and other factors that may cause our actual results, performance or achievements to be significantly different from any future results, performance or achievements expressed or implied by the forward-looking statements. Important factors that could cause or contribute to such differences include, among others, risks relating to: the plans, strategies and objectives of management for future operations; product development for NT219, CM24 and IM1240; the process by which such early stage therapeutic candidates could potentially lead to an approved drug product is long and subject to highly significant risks, particularly with respect to a joint development collaboration; the fact that drug development and commercialization involves a lengthy and expensive process with uncertain outcomes; our ability to successfully develop and commercialize our pharmaceutical products; the expense, length, progress and results of any clinical trials; the impact of any changes in regulation and legislation that could affect the pharmaceutical industry; the difficulty in receiving the regulatory approvals necessary in order to commercialize our products; the difficulty of predicting actions of the U.S. Food and Drug Administration or any other applicable regulator of pharmaceutical products; the regulatory environment and changes in the health policies and regimes in the countries in which we operate; the uncertainty surrounding the actual market reception to our pharmaceutical products once cleared for marketing in a particular market; the introduction of competing products; patents obtained by competitors; dependence on the effectiveness of our patents and other protections for innovative products; our ability to obtain, maintain and defend issued patents; the commencement of any patent interference or infringement action against our patents, and our ability to prevail, obtain a favorable decision or recover damages in any such action; and the exposure to litigation, including patent litigation, and/or regulatory actions, and other factors that are discussed in our Annual Report on Form 20-F for the year ended December 31, 2022 and in our other filings with the U.S. Securities and Exchange Commission ("SEC"), including our cautionary discussion of risks and uncertainties under "Risk Factors" in our Registration Statements and Annual Reports. These are factors that we believe could cause our actual results to differ materially from expected results. Other factors besides those we have listed could also adversely affect us. Any forward-looking statement in this press release speaks only as of the date which it is made. We disclaim any intention or obligation to publicly update or revise any forward-looking statement or other information contained herein, whether as a result of new information, future events or otherwise, except as required by applicable law. You are advised, however, to consult any additional disclosures we make in our reports to the SEC, which are available on the SEC's website, . CONTACTS: Company Contact: Lior Fhima Chief Financial Officer IR@purple-biotech.com

前言肿瘤免疫治疗的疗效在很大程度上取决于肿瘤微环境，尤其是肿瘤免疫微环境。新的研究表明，微生物存在于肿瘤细胞和免疫细胞内，表明这些微生物可以影响肿瘤免疫微环境的状态。肿瘤微生物微环境在肿瘤免疫微环境中的作用是多方面的：可能作为免疫激活剂、抑制剂或旁观者。潜在的机制包括：（I）癌细胞和免疫细胞呈递微生物抗原，（II）微生物抗原模拟肿瘤抗原，（III）微生物诱导的免疫原性细胞死亡，（IV）由模式识别受体介导的微生物辅助性，（V）微生物衍生的代谢物，以及（VI）微生物对抑制性检查点的刺激。总的来说，肿瘤微生物微环境调节肿瘤免疫微环境，使其成为改善免疫治疗的潜在靶点。这是一个面临重大挑战的新领域，值得进一步探索。肿瘤微生物微环境人体容纳着数万亿的微生物，其中一些微生物有助于致癌或抗癌反应。微生物，如细菌、真菌、病毒和支原体，存在于肿瘤组织内。在癌细胞和肿瘤浸润性免疫细胞内可以观察到微生物的残留物，如DNA、RNA、肽和细胞壁成分。一些微生物代谢物，包括脂肪酸和肌苷，可以在肿瘤内积聚，并与癌细胞和免疫细胞上的受体结合。这些成分在肿瘤的发生、发展、转移和免疫反应中都发挥作用，由它们形成的微环境不同于通常提到的肿瘤微环境，因此可作为一个新的类型，称为“肿瘤微生物微环境”。    肿瘤微生物微环境具有临床意义。首先，肿瘤内微生物组具有肿瘤类型特异性和亚型特异性，有可能被用作诊断工具。例如，胰腺癌微生物组主要为变形菌门；而结直肠癌微生物组主要为厚壁菌门和变形菌门。其次，肿瘤组织的微生物组与正常组织的微生物组明显不同，使其成为强大的治疗靶点。某些微生物在肿瘤组织中特异性聚集，微生物被肿瘤吸引这一事实使这些微生物能够被用作精确的抗癌药物载体。第三，肿瘤微生物组在不同生存率的患者中是不同的，这使其成为一种潜在的预后工具。在胰腺癌中，与生存期短的患者相比，长期存活患者的肿瘤微生物组具有更高的α多样性和假黄单胞菌-链霉菌-糖多胞菌-克劳斯芽孢杆菌的特征。肿瘤微生物微环境的作用机制多项研究已经观察到肿瘤内微生物与肿瘤微环境之间的相关性。最近的研究表明肿瘤微生物微环境作用于肿瘤微环境存在多种机制，包括：（I）癌细胞和免疫细胞呈递细菌肽，（II）细菌抗原模拟肿瘤抗原（III）微生物诱导的免疫原性细胞死亡（IV）辅助模式识别受体介导的信号通路（V）微生物衍生代谢物（VI）刺激抑制性检查点。 微生物抗原可能激活抗肿瘤T细胞成功诱导适应性抗肿瘤反应需要两个关键步骤。第一步是由人类白细胞抗原（HLA）呈递肿瘤抗原以激活CD8+T细胞。第二步是激活的CD8+T细胞识别和杀死抗原特异性的癌细胞。然而，癌细胞可以通过多种机制向免疫细胞隐藏其抗原。细菌肽在黑色素瘤转移中普遍存在，它们可以通过黑色素瘤细胞和肿瘤浸润性免疫细胞上的HLA分子呈现，证明其作为肿瘤特异性抗原的潜力。携带细菌肽HLA复合物的B细胞在体内可激活肿瘤浸润性T细胞分泌IFN-γ，其他细菌肽也在多种黑色素瘤患者中普遍存在，此外，鉴于细菌肽是外源性的，与肿瘤抗原相比，它们更有可能触发免疫反应。然而，细菌肽作为肿瘤特异性抗原仍然存在一些问题。首先，正常组织中是否存在细菌肽尚不清楚，如果细菌肽也出现在正常组织中，那么这些组织将不可避免地受到攻击。其次，癌细胞呈现的细菌肽在体内没有触发有效的抗癌免疫，其根本原因尚不清楚。细菌肽、癌细胞和体内免疫细胞之间的相互作用需要进一步研究。微生物抗原模拟激活抗肿瘤T细胞抗原模拟是一种微生物与肿瘤抗原共享相似抗原表位的现象, 微生物特异性T细胞可以识别并杀死表达类似抗原表位的癌细胞。Alexandra Snyder及其同事分析了不同预后的黑色素瘤患者的肿瘤新抗原表位。他们发现一些肿瘤新抗原表位与微生物表位同源，而且同源性越高，临床预后越好。这一发现表明，抗原模拟存在于肿瘤中，并有可能影响免疫反应。Shin Heng Chiou及其同事分析了178例肺癌患者的77万条T细胞受体序列。他们发现，与正常组织相比，肿瘤组织过表达了一种与EB病毒和大肠杆菌发生交叉反应的蛋白质，这种而且交叉反应存在于多个肺癌样本中。未来有必要探索在各种类型的肿瘤中存在的微生物抗原模拟，这些“模拟抗原”可能为癌症治疗提供新的前景。微生物诱导的免疫原性细胞死亡免疫原性细胞死亡（ICD）是一种细胞死亡形式，死亡细胞释放抗原和佐剂以增强免疫反应。它可以由微生物触发，一些研究人员将细菌的空包膜和oxaliplatin结合起来治疗晚期结直肠癌小鼠模型，联合策略通过强化ICD强烈抑制肿瘤生长并延长小鼠的生存期。溶瘤病毒或细菌特异性地定向于肿瘤微环境并溶解肿瘤细胞，从而释放肿瘤抗原、损伤相关分子模式和病原体相关分子模式，以招募外周免疫细胞或重新启动已有的抗肿瘤免疫细胞。同时，微生物本身可以作为一种很有前途的免疫佐剂来促进炎性TME，从而进一步增强抗肿瘤免疫。辅助模式识别受体调节TME微生物辅助性是指来源于微生物的病原体相关分子模式的免疫调节作用。病原体相关的分子模式可以通过模式识别受体（PRR）来感知，Toll样受体（TLR）是研究最多的PRR亚型，TLRs的微生物激活在肿瘤免疫微环境中扮演着双刃剑的角色。首先，肿瘤内微生物通过TLR驱动免疫抑制肿瘤微环境的形成。在患有胰腺癌的小鼠模型中，肿瘤内微生物选择性激活单核细胞中的TLR，以诱导M2样TAM分化。TLR4识别的细菌脂多糖诱导肝细胞表达CXCL1，CXCL1是一种趋化因子，可招募CXCR2+多形核MDSC形成免疫抑制环境，促进小鼠胆管癌。类似地，TLR4识别的梭杆菌上调IL-6/p-STAT3/c-MYC信号通路，导致M2样TAM极化和结直肠癌进展。另一方面，肿瘤内微生物通过TLR维持免疫刺激性肿瘤微环境，因此充当抗癌剂。在肺癌小鼠模型中，细菌脂蛋白激活TLR2，MDSCs被重新编程以分化为炎症M1表型。此外，TLR激动剂与IFN-γ协同作用，增加促炎细胞因子TNF-α、IL-12p40和IL-12p70，降低IL-10，形成炎症微环境，激活抗肿瘤免疫反应。总的来说，微生物通过PRR调节肿瘤免疫微环境，一种特定的微生物可以同时与各种PRR相互作用，因此，微生物的免疫调节作用是许多不同PRRs介导的信号通路的总和。微生物的衍生代谢物微生物代谢产物如短链脂肪酸（SCFA）、胆汁酸和肌苷可进入血液。一些微生物源性代谢产物的受体在癌细胞和肿瘤浸润的免疫细胞上表达，表明微生物源性代谢产物在肿瘤微环境中的潜在作用。SCFA是由肠道厌氧菌发酵的膳食纤维的产物，SCFA包括乙酸、丙酸和丁酸。对于正常的肠上皮细胞，SCFAs起到抑制促肿瘤炎症的作用。例如，丁酸可以增加了肠道微环境中IL-10和维甲酸的水平，从而促进了幼稚T细胞向调节性T细胞的分化。此外，它还促进调节性T细胞的增殖，从而抑制促肿瘤炎症。次级胆汁酸，如ω-murocholic酸，下调肝窦内皮细胞趋化因子CXCL16的分泌。因此，CXCR6-CXCL16相互作用招募的自然杀伤T细胞减少。抗生素可以消除微生物，逆转上述效应。目前的研究表明胆汁酸通过CXCL16-CXCR6调节自然杀伤细胞在肝癌的发生和发展中起着重要作用。刺激抑制性检查点有核梭杆菌通过Fap2和TIGIT之间的相互作用或Fap2和CEACAM1之间的相互作用抑制自然杀伤细胞和细胞毒性T细胞的活性。幽门螺杆菌通过其外膜蛋白HopQ作用于CEACAM1，抑制免疫细胞。除了幽门螺杆菌和核梭杆菌外，其他细菌，如致病性奈瑟菌，也能与CEACAM1结合。另一个检查点CD47在肿瘤细胞表面表达。SIRPα是CD47的配体，在树突状细胞和巨噬细胞上表达。瘤内注射抗生素清除了双歧杆菌，降低了CD47阻断的效果，表明双歧杆菌可能是CD47阻断的潜在佐剂。肿瘤微生物微环境的临床应用成功诱导抗肿瘤适应性免疫应答需要三个要素：抗原、佐剂和合适的免疫微环境。肿瘤微生物环境同时影响这三种元素，使其成为ICIs治疗的一个有希望的组合。内源性微生物调节的临床策略包括抗生素和益生菌。外源性微生物调控利用合成生物学方法产生的微生物，如工程菌和溶瘤病毒。使用卡介苗（BCG）治疗非肌肉浸润性膀胱癌以及使用溶瘤病毒talimogenelaherparepvec（T-VEC）治疗晚期黑色素瘤是成功的肿瘤微生物微环境调节的两个例子。 合成生物学长期以来，微生物一直被用作可编程的药物输送平台。最近，微生物被设计用来加强免疫治疗。研究设计了一株非致病性大肠杆菌，以负载CD47纳米抗体阻断剂。该菌株在肿瘤内定植并释放CD47纳米抗体阻断剂，然后激活肿瘤浸润性T细胞以消除肿瘤。另一种名为SYNB1891的工程化大肠杆菌菌株也采用了类似的策略。该菌株激活抗原呈递细胞中的STING通路，从而增强癌细胞的吞噬作用。除了向肿瘤中添加免疫刺激微生物外，合成生物学还可以将免疫抑制微生物从肿瘤中移除。例如，有核梭杆菌特异性噬菌体和纳米银颗粒的复合物清除了肿瘤内的有核梭杆菌，减少了肿瘤内髓源性抑制细胞，增强了ICIs的功效。抗生素和免疫检查点抑制剂临床上，抗生素使用与ICIs治疗的临床结果呈负相关。抗生素对免疫治疗的影响可以用抗生素介导的微生物调节来解释。一方面，抗生素可引起微生物干扰，损害ICIs的疗效。另一方面，抗生素可以清除化疗诱导的有害微生物，从而提高ICIs的疗效。因此，在临床前实验和临床试验中都需要监测微生物的变化，以确认微生物在抗生素和ICIs相互作用中的影响。益生菌和免疫检查点抑制剂目前，正在进行几项将益生菌和ICIs相结合的临床试验。已发现口服益生菌通过多效性机制恢复抗癌免疫和ICIs功效。然而，口服益生菌引起的肿瘤微生物微环境的变化尚不明确，因此需要在未来的临床试验中检测。小结总的来说，微生物，包括细菌、真菌、病毒及其成分和代谢物，存在于各种肿瘤组织中，形成肿瘤微生物微环境。目前的研究已经揭示了一些微生物作为免疫激活剂、抑制剂或旁观者的作用。考虑到肿瘤微生物微环境的多方面作用，其调节策略包括合成生物学、抗生素和益生菌可作为免疫治疗的潜在组合。肿瘤微生物微环境是一个面临重大挑战和机遇的新领域。全面了解肿瘤内微生物及其在肿瘤免疫微环境中的作用将为研究肿瘤-免疫-微生物关系提供一个概念性转变。肿瘤微生物组可能被用作一种预后或预测工具，这也可能有助于开发新的抗癌药物。重要的是，它可能开启下一波精准医学和免疫治疗的组合策略。参考文献：1.The role of the tumor microbemicroenvironment in the tumor immune microenvironment: bystander, activator, orinhibitor? J Exp Clin Cancer Res. 2021; 40: 327.封面图来源：123rf为什么一定要出海？刚开年，美国就有「超过500种」药品宣布涨价……超10亿美元！罗氏首次入手ADC，为什么选择这家中国药企？点击阅读原文，查看更多精彩内容！

WUXI, China, Dec. 20, 2023 /PRNewswire/ -- BioCity Biopharma today announced dosing of the first patient in a Phase Ib/II clinical trial of its anti-TIM-3 monoclonal antibody (mAb) BC3402 in combination with IMFINZI (durvalumab) for the treatment of advanced hepatocellular carcinoma (HCC) in China. The study is being conducted at Zhongshan Hospital with Prof. Jia Fan as the principal investigator. Dr. Fan is a world-renowned liver cancer surgeon, member of the Chinese Academy of Sciences, and president of Zhongshan Hospital. Liver cancers are highly prevalent in China, with 410,000 newly diagnosed patients (appx. 50% of all new cases worldwide) and responsible for 390,000 deaths annually. Among liver cancers, 90% are HCC. The unmet medical need for impactful novel treatments are significant for HCC treatments in China in which the 5-year survival rate for subjects with advanced disease is about 7%. Based on previous research, TIM-3 is highly expressed by HCC, lung, and other cancers that are resistant to monoclonal antibodies targeting immune checkpoints, particularly PD-1 and PD-L1. Simultaneous inhibition of PD-1/PD-L1 and TIM-3 prevents T cell exhaustion and promotes tumor killing. Synergy has been observed with the combination of BC3402 and anti-PD-1/CTLA-4 treatment in pre-clinical and translational studies. In addition, encouraging clinical outcomes have been reported in clinical trials with other anti-TIM-3 antibodies in combination with anti-PD1/L-1 antibodies. BioCity and AstraZeneca will work closely with the investigators to advance this clinical study. It is hoped that this trial will help demonstrate the potential clinical benefit of BC3402 in combination with durvalumab for the management of advanced HCC. About BC3402 BC3402 is a potential best-in-class anti-TIM-3 mAb that binds to multiple TIM-3 epitopes and has a higher binding affinity than other anti-TIM-3 mAbs in development. BC3402 has been demonstrated to efficiently block the binding of CEACAM1, PtdSer and Gal-9 to TIM-3, alleviating the inhibitory effects of Tregs, and restoring IL-2 production by T cells. Moreover, BC3402 has shown synergistic anti-cancer activity with mAbs targeting PD-1 and CTLA-4, which are important clinical targets for liver cancer. BC3402 has completed a phase I clinical study in advanced solid tumors showing a favorable safety profile and antitumor activity. Multiple phase Ib/II clinical studies are on-going with BC3402 in combination with other agents in solid tumors as well as hematological malignances. About BioCity Founded in December 2017, BioCity is a clinical-stage biopharmaceutical company committed to developing novel and highly differentiated, modality-independent therapeutics for cancer and autoimmune disorders including chronic kidney diseases (CKD). The company has established a pipeline of more than 10 innovative drug candidates including small molecules, monoclonal and bispecific antibodies, and antibody-drug conjugates (ADCs). Currently, BioCity Biopharma has 6 oncology assets in Phase 1 development, including the first-in-Class CDH3-targeting ADC, WEE1 and ATR inhibitors targeting the DNA damage response (DDR) pathway, and agents targeting the immune system including a T cell engager (CD3/EGFR BsAb), an immune checkpoint inhibitor (TIM-3 mAb), and a T cell activator (4-1BB mAb). In addition, an endothelin A (ETA)-receptor selective antagonist for CKD is in phase 2 clinical development. For more information, please visit: SOURCE BioCity Biopharma