MUC4

INB03 increases uptake of deruxtecan, the immunotoxin associated with trastuzumab deruxtecan (T-DXd, ENHERTU®), in models of resistant MUC4 expressing HER2 positive breast cancer and increases the tumor killing immunology of the tumor microenvironment. Boca Raton, Florida, Nov. 29, 2023 (GLOBE NEWSWIRE) -- INmune Bio, Inc. (NASDAQ: INMB) (the “Company”), a clinical-stage immunology company focused on developing treatments that harness the patient’s innate immune system to fight disease, is presenting data on the use of INB03, a dominant-negative TNF inhibitor of soluble TNF (sTNF) in the treatment of high-risk MUC4 expressing HER2. Roxana Schillaci, Ph.D., of Instituto de Biología y Medicina Experimental in Buenos Aries, Argentina, will present her work at the 46th annual San Antonio Breast Cancer Symposium, which runs from December 5 to 9. “This work demonstrates another way that MUC4 expression causes resistance to HER2-targeted immunotherapy in women with resistant breast cancer," said Dr. Schillaci, who is also associated with CONICET and is senior author of this work. “MUC4 expression decreases the uptake of the antibody-drug conjugate T-DXd. Decreased T-DXd uptake results in less tumor killing in this tumor model and we suspect it plays an important role in relapse of disease after treatment with T-DXd.” The poster, titled, “Blocking soluble TNF to improve potency of trastuzumab-deruxtecan by increasing internalization and antitumor innate immune response in a resistant HER2-positive breast cancer model,” shows that INB03 improves the potency of T-DXd in a model of immunotherapy resistant HER2+ breast cancer. INB03 decreases resistance to T-DXd therapy in three ways. INB03 decreases MUC4 expression on the surface of the breast cancer cells increasing the ability of the antibody to bind to the HER2 target on the cancer cell. The combination of low-dose (1.5mg/kg) T-DXd+INB03 decreases tumor growth as much as full dose (5mg/kg) T-DXd alone suggesting increased binding of the immunotoxin to the cancer cell improves anti-tumor effects. INB03 increases internalization of T-DXd and converts the immunosuppressive TME into one that is more tumor-sensitive by polarizing tumor associated macrophages (TAM) from M2-like to M1-like phenotype with increased expression of IFNg. The poster concludes that the combination of INB03 may allow for lower doses of T-DXd to be effective in women with MUC4 expressing HER2+ breast cancer and that addition of INB03 may improve the response to T-DXd in women with resistant HER2+ disease. “Response rates in women treated with T-DXd is high, but relapse is common after a period of time. Identifying and overcoming resistance mechanisms to trastuzumab-based antibody-drug conjugates (ADC) will be a key to improving outcomes,” said RJ Tesi M.D., CEO of INmune Bio. “The body of work performed by Roxana Schillaci is clinically relevant. Resistance to trastuzumab immunotherapy can be predicted prospectively based on simple immunohistochemistry stains detecting tumor expression of MUC4. We hope that this simple step will allow women to receive a treatment that subverts a resistance mechanism without waiting for treatment failure. We further believe that this precision medicine approach should improve the treatment of women with MUC4 expressing breast cancers.” ENHERTU® is a registered trademark of Daiichi Sankyo Company, Limited. About INB03 INB03 is a DN-TNF inhibitor that neutralizes soluble TNF (sTNF) without affecting trans membrane TNF (tmTNF) or TNF receptors. Compared to currently available non-selective TNF inhibitors, INB03 preserves the immune response to cancer by decreasing immunosuppressive cells in the TME including TAM and MDSC while promoting recruitment of anti-tumor immune cells including cytolytic CD8+ lymphocytes, NK cells and anti-tumor macrophages. INB03 has completed an open label dose-escalation Phase I trial in patients with advanced cancer. In that trial, INB03 was found to be safe and well tolerated - no dose limiting toxicity was found. INB03 decreased blood biomarkers of inflammation in patients with advanced cancer. INMB is planning a Phase II trial that uses INB03 as part of combination therapy. About INmune Bio, Inc. INmune Bio, Inc. is a publicly traded (NASDAQ: INMB), clinical-stage biotechnology company focused on developing treatments that target the innate immune system to fight disease. INmune Bio has two product platforms that are both in clinical trials: The Dominant-Negative Tumor Necrosis Factor (DN-TNF) product platform utilizes dominant-negative technology to selectively neutralize soluble TNF, a key driver of innate immune dysfunction and a mechanistic driver of many diseases. DN-TNF product candidates are in clinical trials to determine if they can treat cancer (INB03™), Mild Alzheimer’s disease, Mild Cognitive Impairment and treatment-resistant depression (XPro™). The Natural Killer Cell Priming Platform includes INKmune™ developed to prime a patient’s NK cells to eliminate minimal residual disease in patients with cancer. INmune Bio’s product platforms utilize a precision medicine approach for the treatment of a wide variety of hematologic and solid tumor malignancies, and chronic inflammation. To learn more, please visit . Forward Looking Statements Clinical trials are in early stages and there is no assurance that any specific outcome will be achieved. Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. Any forward-looking statements contained herein are based on current expectations but are subject to a number of risks and uncertainties. Actual results and the timing of certain events and circumstances may differ materially from those described by the forward-looking statements as a result of these risks and uncertainties. INB03™, XPro1595, and INKmune™ are still in clinical trials or preparing to start clinical trials and have not been approved by the US Food and Drug Administration (FDA) or any regulatory body and there cannot be any assurance that they will be approved by the FDA or any regulatory body or that any specific results will be achieved. The factors that could cause actual future results to differ materially from current expectations include, but are not limited to, risks and uncertainties relating to the Company’s ability to produce more drug for clinical trials; the availability of substantial additional funding for the Company to continue its operations and to conduct research and development, clinical studies and future product commercialization; and, the Company’s business, research, product development, regulatory approval, marketing and distribution plans and strategies. These and other factors are identified and described in more detail in the Company’s filings with the Securities and Exchange Commission, including the Company’s Annual Report on Form 10-K, the Company’s Quarterly Reports on Form 10-Q and the Company’s Current Reports on Form 8-K. The Company assumes no obligation to update any forward-looking statements in order to reflect any event or circumstance that may arise after the date of this release. INmune Bio Contact: David Moss, CFO (858) 964-3720 info@inmunenbio.com Investor Contact: Jason Nelson, Core IR (516) 842-9614 x-823

SIRP-CD47 is an innate immune checkpoint known as the “don’t eat me” signal. INB03 downregulates expression of SIRPα on macrophages promote increased cancer cell death by antibody dependent cellular phagocytosis (ADCP). Boca Raton, Florida, Oct. 30, 2023 (GLOBE NEWSWIRE) -- INmune Bio, Inc. (NASDAQ: INMB) (the “Company”), a clinical-stage immunology company focused on developing treatments that harness the patient’s innate immune system to fight disease, is presenting data on the use of INB03, a dominant-negative inhibitor of soluble TNF in the treatment of high-risk MUC4 expressing HER2+ breast cancer. Roxana Schillaci Ph.D. of Instituto de Biología y Medicina Experimental in Buenos Aries, Argentina, will present her work at the 38th annual Society of Immunotherapy in San Diego, California which runs from November 1-4. The poster entitled “INB03: a new immune checkpoint inhibitor that reprograms polarization and promotes ADCP in human macrophages,” shows that INB03 is an innate immune checkpoint inhibitor working through the SIRPα-CD47 pathway to promote ADCP. SIRPα is a surface protein expressed by macrophages that binds to CD47 expressed by tumor cells. SIRPα-CD47 is known as the “don’t eat me” signal that prevents phagocytosis of tumor cells and promotes resistance to immunotherapy. INB03 downregulates SIRPα expression to eliminate the “don’t eat me signal” and promote ADCP. Inhibition of the SIRPα-CD47 pathway has focused predominately on targeting CD47 with anti-CD47 therapeutics. Targeting SIRPα may provide differentiated pharmacokinetic, safety, and efficacy pro “Macrophages play an important role in the control of tumors, but cancer cells have developed very efficient ways to evade attack by the patient’s immune system,” said Roxana Schillaci, Ph.D. of CONECIT and senior author of this work. “TNF promotes expression of SIRPα on macrophages that bind to CD47 on tumor cells to prevent ADCP. Neutralization of sTNF with INB03 downregulates the expression of SIRPα to promote ADCP that should help control tumor growth and prevent resistance to immunotherapy.” The research presented in the poster examines animal models and human macrophages. INB03 neutralizes sTNF, repolarizing tumor protecting M2 macrophages to M1 anti-tumor macrophages, enhances ADCP with trastuzumab, and reduces SIRPα expression. In mice with trastuzumab resistant breast cancer, INB03 treatment polarizes splenic and tumor-infiltrating macrophages to M1 type macrophages that phagocytize tumor cells and decreased immune checkpoint expression (PD-L1, TIM3, LAG3) in tumor-infiltrating CD8+ T cells. RJ Tesi MD, CEO of INmune Bio, stated that, “a new therapeutic strategy for treating cancer is to improve the function of tumor-infiltrating macrophages. DN-TNF has been shown to improve macrophage phagocytosis in models of AD, MS, DMD, and cancer.” Microglia are tissue-based macrophages of the brain, while tumor macrophages are the phagocytic cells of the tumor microenvironment (TME). In disease, soluble TNF depresses macrophage phagocytic function, resulting in neurodegeneration, synaptic dysfunction, and demyelination in the brain or tumor growth and resistance to cancer immunotherapy. DN-TNF neutralizes sTNF and returns phagocytic function to normal. In neurodegenerative diseases, DN-TNF promotes microglial phagocytic function to promote remodeling and repair by decreasing neurodegeneration, improving synaptic plasticity, and promoting remyelination. In cancer, DN-TNF repolarizes immunosuppressive macrophages into tumor-killing macrophages and promotes ADCP. In both cases, normalizing phagocytic function should allow for therapeutic benefits. Acronyms: DN-TNF: Dominant-Negative Tumor Necrosis Factor sTNF: Soluble Tumor Necrosis Factor ADCP: Antibody Dependent Cellular Phagocytosis SIRPα: Signal-Regulatory Protein Alpha TME: Tumor Microenviornment AD: Alzheimer’s Disease MS: Multiple Scleroisis DMD: Duchenne Muscular Dystrophy CNS: Central Nervous System About INB03 INB03 is a DN-TNF inhibitor that neutralizes soluble TNF (sTNF) without affecting transmembrane TNF (tmTNF) or TNF receptors. Compared to currently available non-selective TNF inhibitors, INB03 preserves the immune response to cancer by decreasing immunosuppressive cells in the TME including TAM and MDSC while promoting recruitment of anti-tumor immune cells including cytolytic CD8+ lymphocytes, NK cells and anti-tumor macrophages. INB03 has completed an open label dose-escalation Phase I trial in patients with advanced cancer. In that trial, INB03 was found to be safe and well tolerated - no dose limiting toxicity was found. INB03 decreased blood biomarkers of inflammation in patients with advanced cancer. INMB is planning a Phase II trial that uses IN03 as part of combination therapy. About INmune Bio Inc. INmune Bio Inc. is a publicly traded (NASDAQ: INMB), clinical-stage biotechnology company focused on developing treatments that target the innate immune system to fight disease. INmune Bio has two product platforms that are both in clinical trials: The Dominant-Negative Tumor Necrosis Factor (DN-TNF) product platform utilizes dominant-negative technology to selectively neutralize soluble TNF, a key driver of innate immune dysfunction and a mechanistic driver of many diseases. DN-TNF product candidates are in clinical trials to determine if they can treat cancer (INB03™), Early Alzheimer’s disease, and treatment-resistant depression (XPro™). The Natural Killer Cell Priming Platform includes INKmune™ developed to prime a patient’s NK cells to eliminate minimal residual disease in patients with cancer. INmune Bio’s product platforms utilize a precision medicine approach for the treatment of a wide variety of hematologic and solid tumor malignancies, and chronic inflammation. To learn more, please visit . Forward Looking Statements Clinical trials are in the early stages and there is no assurance that any specific outcome will be achieved. Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. Any statements contained in this press release that do not describe historical facts may constitute forward-looking statements as that term is defined in the Private Securities Litigation Reform Act of 1995. Any forward-looking statements contained herein are based on current expectations but are subject to a number of risks and uncertainties. Actual results and the timing of certain events and circumstances may differ materially from those described by the forward-looking statements as a result of these risks and uncertainties. INB03™, XPro1595 (XPro™), and INKmune™ are still in clinical trials or preparing to start clinical trials and have not been approved by the US Food and Drug Administration (FDA) or any regulatory body and there cannot be any assurance that they will be approved by the FDA or any regulatory body or that any specific results will be achieved. The factors that could cause actual future results to differ materially from current expectations include, but are not limited to, risks and uncertainties relating to the Company’s ability to produce more drug for clinical trials; the availability of substantial additional funding for the Company to continue its operations and to conduct research and development, clinical studies and future product commercialization; and, the Company’s business, research, product development, regulatory approval, marketing and distribution plans and strategies. These and other factors are identified and described in more detail in the Company’s filings with the Securities and Exchange Commission, including the Company’s Annual Report on Form 10-K, the Company’s Quarterly Reports on Form 10-Q and the Company’s Current Reports on Form 8-K. The Company assumes no obligation to update any forward-looking statements in order to reflect any event or circumstance that may arise after the date of this release. INmune Bio Contact: David Moss, CFO (858) 964-3720 info@inmunenbio.com Investor Contact: Jason Nelson, Core IR (516) 842-9614 x-823

关键词MUC1；研究进展；肿瘤黏蛋白（Mucins）家族是一类由体内多种上皮细胞分泌的高分子量、高糖基化蛋白，广泛覆盖在管状器官如气管、支气管、胃肠道、生殖道等多种生殖上皮细胞表面，以及肝脏、胰腺、胆囊、肾、唾液腺和泪腺上皮细胞表面。根据结构的不同，Mucins可分为两个亚科，即分泌型和膜结合型。其中分泌型Mucins包括MUC2、MUC5AC、MUC5B、MUC6、MUC7、MUC8和MUC19，是黏液的主要成分，参与物理屏障、细胞粘附、免疫应答和细胞转导等多种生物学功能。膜结合型黏蛋白包括MUC1、MUC3A、MUC3B、MUC4、MUC12、MUC13、MUC15、MUC16、MUC17、MUC20和MUC21，可以作为上皮细胞的物理屏障防止病原体入侵，有助于维持黏膜屏障的完整性。关于MUC1MUC1是第一个被识别的Mucins，由MUC1基因编码，是一种I型单次跨膜蛋白。MUC1通常在乳腺、食道、胃、十二指肠、胰腺、子宫、前列腺和肺的腺或管腔上皮细胞中表达，在造血细胞中少量表达，但在皮肤上皮和间充质细胞中不表达。病理情况下，MUC1还在多种腺癌（如如96.7％的浸润性肺癌、90％的胰腺癌、前列腺癌、上皮性卵巢癌、77％的原发性肺癌、70％的乳腺癌等）细胞表面高表达，且其表达和肿瘤的转移、复发相关。不过，MUC1在正常细胞和肿瘤中的存在形式有所不同。在正常细胞中，MUC1以高度糖基化形式存在，而在肿瘤细胞表面，MUC1以糖基脱落的形式过表达。此外，MUC1还在肿瘤细胞细胞质中表达。研究发现，肿瘤相关MUC1主要通过阻断免疫细胞和癌细胞之间的相互作用、通过共刺激或共抑制分子调节免疫细胞信号和调节促炎细胞因子的产生等机制介导肿瘤免疫逃逸。而且，MUC1的表达强度与T细胞和NK细胞浸润呈负相关。肿瘤细胞上异常糖基化的MUC1直接与包括巨噬细胞在内的免疫细胞上表达的选择素或siglec家族蛋白结合，并抑制其功能。此外，MUC1通过与T细胞上的细胞间粘附分子1（ICAM-1）结合，抑制其功能。癌症相关的MUC1抑制树突状细胞（DC）成熟，促进IL-10（高）IL-12（低）调节性DC分化，从而使肿瘤能够逃脱免疫监视。MUC1也在可抑制免疫反应的树突状细胞上表达。此外MUC1可以激活PD-1在肿瘤细胞的表达。MUC1靶点进展鉴于在肿瘤发生、进展中发挥的作用，MUC1被认为是实体瘤药物研发的潜力靶点。目前全球药企围绕MUC1靶点研发出多款在研药物，其中最快处于2期临床。在研MUC1靶向药药物类型多样，涉及疫苗、单抗、双抗、抗体偶联药物（ADC）、嵌合抗原受体T细胞（CAR-T）疗法和嵌合抗原受体自然杀伤细胞（CAR-NK）疗法。全球部分在研MUC1靶向药资料来源：药渡数据库DS-3939DS-3939由第一三共和Glycotope合作开发，是利用Glycotope的抗TA-MUC1抗体和第一三共专有的DXd-ADC技术制成的ADC，DAR值为8。今年9月，该药治疗晚期实体瘤的1/2期临床试验完成首例患者给药。BLP25BLP25是由BLP25脂肽、三种脂质和免疫佐剂单磷酰脂质A构成的脂质体疫苗，通过靶向MUC1，诱导细胞免疫反应，导致表达MUC1的肿瘤组织产生免疫排斥反应。针对晚期NSCLC开展的1期临床试验结果显示：L-BLP25耐受性较好，且能诱导患者自身机体发生细胞免疫应答反应。不过由于后续研究中该疫苗疗效数据不佳，研究终止。MAb-AR20.5MAb-AR20.5是一款MUC1靶向的鼠单克隆抗体，今年8月被FDA授予孤儿药资格。已公布的1期临床试验结果显示：MAb-AR20.5在15名转移性癌症患者中表现良好，能诱导MUC1特异性免疫反应，且耐受性佳。此外，联合使用MAb-AR20.5、抗PD-L1和聚ICLC的临床前研究表明：该联合疗法能显着增加活化的CD8阳性T细胞。DXC-005DXC-005是多禧生物开发的一款MUC1靶向ADC，是国内首款获批临床的MUC1靶向ADC，治疗结直肠癌及胰腺癌。P-MUC1C-ALLO1P-MUC1C-ALLO1是一种同种异体CAR-T细胞疗法，被开发用于治疗多种实体瘤。在临床前模型中，该疗法被证明能消除三阴性乳腺癌和卵巢癌肿瘤细胞至检测不到的水平。已公布的1期临床研究数据显示：截至2022年11月14日，7例实体瘤患者完成给药，4例可进行评估，其中1例先前接受过4线治疗的HR+/HER2-的乳腺癌患者实现PR，2例此前接受过多线治疗的胃肠道肿瘤（结直肠癌和胰腺癌）患者达到SD。此外，该细胞疗法安全性和耐受性良好，没有剂量限制毒性、免疫效应细胞相关神经毒性综合征、移植物抗宿主病或细胞因子释放综合征。2023年8月，安斯泰来和Poseida Therapeutics达成一项战略投资合作。据悉投资总金额为5000万美元，其中2500万美元用于一次性支付后者P-MUC1C-ALLO1项目的独家谈判权和优先许可权。PAb001-ADCPAb001-ADC是一款靶向MUC1的ADC，体外研究显示其可降低乳腺癌细胞的增殖，并在异种移植小鼠模型中能有效靶向乳腺癌中的MUC1。2021年4月，齐鲁制药和Peptron达成合作协议，获得该疗法在全球的独家开发、制造、销售和商业化授权。ONKT-103ONKT-103是一款MUC1靶向的CAR-NK疗法，通过引入DR5-TRAIL变体死亡受体信号通路，最大限度地发挥抗肿瘤活性，目前处于临床前阶段。总结由于MUC1在肿瘤细胞中的异常糖基化和过表达，且其可以通过参与细胞内信号传导过程和相关生物分子的调节而参与癌症侵袭、转移、血管生成和细胞凋亡，MUC1被认为是肿瘤药物的潜力靶点，尤其是针对实体瘤。整体来看，部分MUC1靶向药已显现出抗肿瘤活性，但大多处于早期临床，未来MUC1靶向药的研发还是任重道远。不过MUC1靶点的潜力已引起药企的重视，齐鲁制药、安斯泰来等企业先后布局该领域。END👇关注药渡数据媒体矩阵