Multiple system atrophy (MSA) is a rare, fatal neurodegenerative disease characterized by the accumulation of misfolded α-synuclein (αSyn) in glial cells, leading to the formation of glial cytoplasmic inclusions (GCI). We previous found that glial fatty acid-binding protein 7 (FABP7) played a crucial role in alpha-synuclein (αSyn) aggregation and toxicity in oligodendrocytes, inhibition of FABP7 by a specific inhibitor MF 6 reduced αSyn aggregation and enhanced cell viability in cultured cell lines and mouse oligodendrocyte progenitor cells. In this study we investigated whether MF 6 ameliorated αSyn-associated pathological processes in PLP-hαSyn transgenic mice (PLP-αSyn mice), a wildly used MSA mouse model with overexpressing αSyn in oligodendroglia under the proteolipid protein (PLP) promoter. PLP-αSyn mice were orally administered MF6 (0.1, 1 mg ·kg^-1 ·d^-1) for 32 days starting from the age of 6 months. We showed that oral administration of MF 6 significantly improved motor function assessed in a pole test, and reduced αSyn aggregation levels in both cerebellum and basal ganglia of PLP-αSyn mice. Moreover, MF 6 administration decreased oxidative stress and inflammation levels, and improved myelin levels and Purkinje neuron morphology in the cerebellum. By using mouse brain tissue slices and αSyn aggregates-treated KG-1C cells, we demonstrated that MF 6 reduced αSyn propagation to Purkinje neurons and oligodendrocytes through regulating endocytosis. Overall, these results suggest that MF 6 improves cerebellar functions in MSA by inhibiting αSyn aggregation and propagation. We conclude that MF 6 is a promising compound that warrants further development for the treatment of MSA.

2023-12-31·mAbs

A HER2-targeted antibody-novel DNA topoisomerase I inhibitor conjugate induces durable adaptive antitumor immunity by activating dendritic cells

Article

作者: Xu, Hui ; Wen, Haiying ; You, Meng ; Wang, Lu ; Shen, Hui ; Zhu, Xiaohong ; An, Maomao ; Cao, Yuxia ; Sun, Xiaowei ; Zhu, Huikai ; Zhou, Wei ; Shi, Lei ; Wang, Zhenzhen ; Fang, Peng ; Liu, Datao ; Li, Wendi ; Wei, Xin ; Li, Kaiying ; Tan, Xiaoding ; Yu, Dongan

We designed and developed a novel DNA topoisomerase I inhibitor MF-6, which was a more potent cytotoxin and a more potent inducer of immunogenic cell death compared with DXd. To utilize MF-6's ability to induce antitumor immunity, a human epidermal growth factor receptor 2 (HER2)-targeted antibody-drug conjugate (ADC) trastuzumab-L6 that included a cleavable linker and MF-6 was developed. Different from traditional cytotoxic ADC, the antitumor activity of trastuzumab-L6 was assessed by inducing tumor cell immunogenic cell death, activating dendritic cells and cytotoxic CD8+ T cells to acquire durable adaptive immune memory. Tumor cells treated with trastuzumab-L6 were committed to immunogenic cell death, with upregulation of damage-associated molecular patterns and antigen presentation molecules. In a syngeneic tumor model with a mouse cell line that expressed human HER2, immunocompetent mice showed greater antitumor efficacy compared with nude mice. The trastuzumab-L6-cured immunocompetent mice acquired adaptive antitumor memory and rejected subsequent tumor cell challenge. The trastuzumab-L6 efficacy was abrogated when cytotoxic CD8+ T cells were depleted and enhanced when regulatory CD4+ T cells were depleted. The combination of trastuzumab-L6 with immune checkpoint inhibitors significantly increased antitumor efficacy. Enhanced T cell infiltration, dendritic cell activation, and decreased type M2 macrophages in tumor post trastuzumab-L6 administration confirmed the immune-activating responses. In conclusion, trastuzumab-L6 was considered to be an immunostimulatory agent, rather than a traditional cytotoxic ADC, and its antitumor efficacy was enhanced when combined with an anti-PD-L1 and anti-CTLA-4 antibody, which suggested a potential therapeutic strategy.

2021-10-01·eBioMedicine1区 · 医学

A novel fatty acid-binding protein 5 and 7 inhibitor ameliorates oligodendrocyte injury in multiple sclerosis mouse models

1区 · 医学

ArticleOA

作者: Cheng, An ; Jia, Wenbin ; Kawahata, Ichiro ; Fukunaga, Kohji

BACKGROUNDMultiple sclerosis (MS) is an autoimmune disease characterised by the demyelination of mature oligodendrocytes in the central nervous system. Recently, several studies have indicated the vital roles of fatty acid-binding proteins (FABPs) 5 and 7 in regulating the immune response.METHODSWe assessed a novel FABP5/FABP7 inhibitor, FABP ligand 6 (MF 6), as a potential therapeutic for MS therapy. In vivo, we established MOG_35-55-administered experimental autoimmune encephalomyelitis (EAE) mice as an MS mouse model, followed by prophylactic and symptomatic treatment with MF 6. The therapeutic effect of MF 6 was determined using behavioural and biochemical analyses. In vitro, MF 6 effects on astrocytes and oligodendrocytes were examined using both astrocyte primary culture and KG-1C cell lines.FINDINGSProphylactic and symptomatic MF 6 therapy reduced myelin loss and clinical EAE symptoms. Furthermore, oxidative stress levels and GFAP-positive and ionised calcium-binding adaptor protein-1-positive cells were reduced in the spinal cord of MF 6-treated mice. In addition, MF 6 attenuated lipopolysaccharide-stimulated interleukin-1β and tumour necrosis factor-α accumulation in primary astrocyte culture. Moreover, MF 6 indicated a powerful protective function for the mitochondria in the oligodendrocytes of EAE mice via FABP5 inhibition.INTERPRETATIONSMF 6 is a potent inhibitor of FABP5 and FABP7; targeted inhibition of the two proteins may confer potential therapeutic effects in MS via immune inhibition and oligodendrocyte protection.FUNDINGThis work was supported by the Strategic Research Program for Brain Sciences from the Japan Agency for Medical Research and Development (JP17dm0107071, JP18dm0107071, JP19dm0107071, and JP20dm0107071).

项与 MF-6 相关的新闻（医药）

2024-07-16

·PRNewswire

FDA Grants Orphan Drug Designation to 7MW3711

SHANGHAI, July 16, 2024 /PRNewswire/ -- Mabwell (688062.SH), an innovation-driven biopharmaceutical company with entire industry chain, announced that its self-developed novel B7-H3-targeting ADC (R&D code: 7MW3711) has been granted Orphan Drug Designation (ODD) by the U.S. Food and Drug Administration (FDA), for the treatment of small cell lung cancer. The FDA grants Orphan Drug Designation to treatments for rare diseases in the United States that affect fewer than 200,000 patients. Orphan Drug Designation offers policy benefits to drug developers, including as aid with medication development, tax credits for a part of clinical trial expenditures, and seven years of market exclusivity upon approval. 7MW3711 is a novel B7-H3-targeting ADC developed by Mabwell's IDDC™ platform. It is composed of innovative antibody molecule, novel linker, and novel payload Mtoxin™ (TOP1i). When 7MW3711 enters human body, it specifically binds to antigens on the tumor cell membrane surface, be internalized and trafficked to the lysosome, release cytotoxic drug, and induce the apoptosis of tumor cells. 7MW3711 is pharmaceutical characterized as stable structure, homogeneous composition, high purity, and it is suitable for industrial scale-up. Compared with ADCs in the same class at home and abroad, 7MW3711 has shown better tumor killing effects in multiple animal tumor models. In the safety evaluation model of animals including cynomolgus monkeys, the on-target and off-target toxicities of 7MW3711 are effectively controlled, showing its good safety profile and pharmacokinetic properties. The above research results indicate that 7MW3711 has clinical differentiation characteristics and a promising future of clinical development. About the next generation ADC platform - IDDC™ IDDC™ is a next generation ADC site-specific conjugation technology platform independently developed by Mabwell, consisting of multiple systematic core patented technologies including the site-specific conjugation process DARfinity™, the site-specific linker IDconnect™, the novel payload Mtoxin™, and the conditional release structure LysOnly™. The next generation ADCs developed based on the above systematic patented technologies have better structural uniformity, quality stability, efficacy, and tolerability. The novel payload Mtoxin™ (MF6) demonstrates good pharmacodynamics, bystander killing efficacy, and anti-multidrug resistance. The IDDC™ platform has been validated in multiple drug candidates under development. Mabwell currently has several ADCs in clinical development stages. Among them, the novel Nectin-4-targeting ADC, 9MW2821, is in Phase III clinical trial for the indication of urothelial carcinoma. The novel B7-H3-targeting ADC, 7MW3711, and Trop-2-targeting ADC, 9MW2921, are both in clinical trial stages. About Mabwell Mabwell (688062.SH) is an innovation-driven biopharmaceutical company with the entire value chain of the pharmaceutical industry. We provide more effective and accessible therapy and innovative medicines to fulfill global medical needs. Since 2017, an advanced R&D system which covers target discovery, early discovery, druggability, preclinical, clinical research and manufacturing transformation was established. Mabwell has 14 pipeline products in different stages based on a world-class and state-of-the-art R&D engine, including 10 novel drug candidates and 4 biosimilars. We focus on the therapeutic areas of oncology, auto-immune diseases, metabolic disorders, ophthalmologic diseases and infectious diseases, etc. Of these, 3 products have been approved and commercialized, 1 product has been filed for MA approval, 3 products are in pivotal trials. We have also undertaken 1 national major scientific and technological special project for "Significant New Drugs Development", 2 projects for National Key R&D Programmes, and multiple provincial and municipal science and technological innovation projects. Mabwell's Taizhou factory possesses robust in-house manufacturing capability compliant with international GMP standards regulated by the NMPA, FDA and EMA, and has passed the EU QP Audit. The large-scale manufacturing base in Shanghai and the ADC commercialized manufacturing base in Taizhou are under construction. Our mission is "Explore Life, Benefit Health" and our vision is "Innovation, from ideas to reality". For more information, please visit . Forward-Looking Statements This press release contains forward-looking statements including, but not limited to, the potential safety, efficacy, regulatory review or approval and commercial success of our product candidates and those relating to the Company's product development, clinical studies, clinical and regulatory milestones and timelines, market opportunity, competitive position, possible or assumed future results of operations, business strategies, potential growth opportunities and other statements that are predictive in nature. "Forward-looking statements" are statements that are not historical facts and involve a number of risks and uncertainties, which may cause actual results to be materially different from any future results expressed or implied in the forward-looking statements. These statements may be identified by the use of forward-looking expressions, including, but not limited to, "expect," "anticipate," "intend," "plan," "believe," "estimate," "potential," "predict," "project," "should," "would", and similar expressions and the negatives of those terms. Forward-looking statements are based on the Company's current expectations and assumptions. Forward-looking statements are subject to a number of risks, uncertainties, and other factors, many of which are beyond the Company's control, including, but not limited to: environment; politic; economy; society; legislation; our dependence on our product candidates, most of which are still in preclinical or various stages of clinical development; our reliance on third-party vendors, such as contract research organizations and contract manufacturing organizations; the uncertainties inherent in clinical testing; our ability to complete required clinical trials for our product candidates and obtain approval from regulatory authorities for our product candidates; our ability to protect our intellectual property; the potential impact of COVID-19; the loss of any executive officers or key personnel. In case one or more of these risks or uncertainties deteriorate, or any assumptions are incorrect, the actual results may be seriously inconsistent with the stated results. The Company cautions all the persons not to place undue reliance on any such forward-looking statements, which speaks only as of the date of this press release. The Company disclaims any obligation, except as specifically required by law and the rules of the applicable Stock authority to publicly update or revise any such statements to reflect any change in expectations or in events, conditions, or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. All forward-looking descriptions, figures and assumptions in this press release are applicable to this statement. SOURCE Mabwell

临床3期孤儿药抗体药物偶联物免疫疗法

2024-07-16

·迈威生物

迈威生物靶向 B7-H3 ADC 创新药 7MW3711 获 FDA 孤儿药资格认定

重要新闻迈威生物 (688062.SH)，一家全产业链布局的创新型生物制药公司，宣布其自主研发的靶向 B7-H3 ADC 创新药（研发代号：7MW3711）获美国食品药品监督管理局（FDA）授予孤儿药资格认定（Orphan Drug Designation, ODD），用于治疗小细胞肺癌。 FDA 授予的孤儿药资格认定适用于在美国地区少于 20 万患者的罕见病的药物。孤儿药资格认定可为药物开发者带来政策优惠，包括在药物开发过程中提供帮助、临床费用部分税费减免，以及获批后享有七年的市场独占权。 7MW3711 基于迈威生物新一代 ADC 定点偶联技术平台 IDDC™ 开发，由创新抗体分子、新型连接子以及新型载荷 Mtoxin™（拓扑异构酶 I 抑制剂）构成，具有完全知识产权。7MW3711注射人体后，可与肿瘤细胞表面的抗原 B7-H3 结合内吞进入肿瘤细胞，通过特定酶解作用，定向释放小分子，从而实现对肿瘤的精准杀伤。 7MW3711 具有结构稳定，组分均一，纯度高，易于产业化放大等特点，相较国内外同类型药物，7MW3711 在多种动物肿瘤模型中均显示出更好的肿瘤杀伤作用。在食蟹猴等动物安全性评价模型中，7MW3711 显示具有良好的药物安全性及药代特性。上述研究结果表明 7MW3711 具有临床差异化特性以及广阔的临床开发前景。关于新一代 ADC 技术平台 IDDC™ IDDC™ 是迈威生物自主开发的新一代 ADC 定点偶联技术平台，由定点偶联工艺 DARfinity™，定点连接子接头 IDconnect™，新型载荷分子 Mtoxin™，以及条件释放结构 LysOnly™ 等多项系统化核心专利技术组成。基于 IDDC™ 平台构建的 ADC 具有良好的均一性、有效性以及安全性优势。新型载荷 Mtoxin™（MF6）具有良好的药效、旁观者杀伤效果，以及抗多药耐药等优势。目前 IDDC™ 平台已在多个在研品种中得到验证。公司已有多款 ADC 药物处于临床开发阶段。其中靶向 Nectin-4 ADC 创新药 9MW2821 在尿路上皮癌适应症已处于 III 期临床研究阶段。靶向 B7-H3 ADC 创新药 7MW3711 和靶向 Trop-2 ADC 创新药 9MW2921 均已处于临床试验阶段。关于迈威生物迈威生物 (688062.SH) 是一家全产业链布局的创新型生物制药公司，始终秉承“让创新从梦想变成现实”的愿景，践行“探索生命，惠及健康”的使命，通过源头创新，为患者提供疗效更好、可及性更强的生物创新药，满足全球未被满足的临床需求。2017 年成立以来，迈威生物构建了以抗体药物靶点发现与分子发现为起点，覆盖成药性研究、临床前研究、临床研究和生产转化等药品研发全周期的创新体系，实现集研发、生产、营销于一体的全产业链布局。我们专注于肿瘤和年龄相关疾病，涉及肿瘤、自身免疫、代谢、眼科、感染等治疗领域，凭借国际领先的特色技术平台和研发创新能力，建立了丰富且具有竞争力的管线。现有 14 个品种处于不同阶段，包括 10 个创新品种和 4 个生物类似药，其中 3 个品种上市，1 个品种药品上市许可申请已获受理，3 个品种处于关键注册临床试验阶段。并独立承担 1 项国家“重大新药创制”重大科技专项、2 项国家重点研发计划和多个省市级科技创新项目。迈威生物以创新为本，注重产业转化，符合中国 NMPA、美国 FDA、欧盟 EMA GMP标准的抗体和重组蛋白药物产业化基地已在江苏泰州投入使用，并已通过欧盟 QP 审计，位于上海金山和江苏泰州的大规模商业化生产基地正在建设中。欲了解更多信息，请访问：www.mabwell.com。前瞻性声明本新闻稿所发布的信息中可能会包含某些前瞻性表述。这些表述本质上具有相当风险和不确定性。在使用“预期”、“相信”、“预测”、“期望”、“打算”及其他类似词语进行表述时，凡与本公司有关的，目的均是要指明其属前瞻性表述。本公司并无义务不断地更新这些预测性陈述。这些前瞻性表述乃基于本公司管理层在做出表述时对未来事务的现有看法、假设、期望、估计、预测和理解。这些表述并非对未来发展的保证，会受到风险、不确性及其他因素的影响，有些乃超出本公司的控制范围，难以预计。因此，受我们的业务、竞争环境、政治、经济、法律和社会情况的未来变化及发展的影响，实际结果可能会与前瞻性表述所含资料有较大差别。本公司、本公司董事及雇员代理概不承担 (a) 更正或更新本网站所载前瞻性表述的任何义务;及 (b) 若因任何前瞻性表述不能实现或变成不正确而引致的任何责任。（滑动查看全部内容）

抗体药物偶联物孤儿药临床3期快速通道临床2期

2024-03-21

·BioSpace

Mabwell Presented IDDC™ Platform Technology and ADC Drug Development Achievements at the 14th World ADC London

SHANGHAI, March 21, 2024 /PRNewswire/ -- Mabwell (688062.SH), an innovation-driven biopharmaceutical company with entire industry chain, published "Mtoxin™ Payload Applied in IDDC™ ADC Platform Significant Increases Therapeutic Index and Overcome MultiDrug Resistance in Various Tumor" as poster presentation from March 12 to 15, 2024 at the 14th World ADC London. The development of several ADC drugs under the capabilities of IDDC™, a next generation ADC technology platform, was demonstrated. Overview of Poster Presentation Evolutions of conjugation technologies, new release structures, and multiple mechanism payloads have prompted the development of ADC field. However, further improving drug delivery and overcoming drug resistance are urgent problems for the next generation of ADC drugs. Mabwell has independently developed IDDC™ technology and novel payload Mtoxin™. The study results show: 1. DARfinity™ produces site-specific conjugated drugs with DAR 4 as the main component (DAR 4 ≥ 95%). 2. IDconnect™ enhances plasma stability and payload transfer efficiency of ADC drugs (40% increase from control group). 3. LysOnly™ technology enhances tumor-specific release capacity of ADC drugs and reduces off-target effects. 4. Mtoxin™ has good tumor penetration, bystander killing effect and anti-multidrug resistance. 5. ADC drugs developed based on IDDC™ and Mtoxin™ have good pharmacodynamic and safety characteristics, especially in the DXd-resistant multidrug resistance model. Summary IDDC™ is a clinically validated site-specific conjugation technology with good homogeneity, efficacy, and safety advantages. In addition, the novel payload Mtoxin™ (MF6) has good pharmacodynamics, bystander killing efficacy, and anti-multidrug resistance. Novel ADC Drugs Developed Based on IDDC™ Platform The IDDC™ platform has been validated in multiple drugs under study. 9MW2821 - novel Nectin-4-targeting ADC: For the indication of urothelial carcinoma, 9MW2821 is the first Nectin-4 ADC developed by a Chinese company to enter phase III clinical studies, making it the second globally in terms of progress. 9MW2821 is also the first therapeutic drug with the same target in the world to disclose clinical efficacy data for indications of cervical cancer and esophageal carcinoma. It has been granted Fast Track Designation by the U.S. Food and Drug Administration (FDA) for the treatment of advanced, recurrent, or metastatic esophageal squamous cell carcinoma. 7MW3711 - novel B7-H3-targeting ADC: Clinical trials have been conducted for 7MW3711 for the indication of advanced solid tumors in China, and it has received FDA approval to conduct clinical trials for patients with advanced malignant solid tumors. 9MW2921 - novel Trop-2-targeting ADC: Clinical trials have been conducted for 9MW2921 for the indication of advanced solid tumors in China. About Mabwell Mabwell (688062.SH) is an innovation-driven biopharmaceutical company with the entire value chain of the pharmaceutical industry. We provide more effective and accessible therapy and innovative medicines to fulfill global medical needs. Since 2017, an advanced R&D system which covers target discovery, early discovery, druggability, preclinical, clinical research and manufacturing transformation was established. Mabwell has 14 pipeline products in different stages based on a world-class and state-of-the-art R&D engine, including 10 novel drug candidates and 4 biosimilars. We focus on the therapeutic areas of oncology, auto-immune diseases, metabolic disorders, ophthalmologic diseases and infectious diseases, etc. Of these, 2 products have been approved and commercialized, 2 products have been filed for MA approval, 3 products are in pivotal trials. We have also undertaken 1 national major scientific and technological special project for "Significant New Drugs Development", 2 projects for National Key R&D Programmes, and multiple provincial and municipal science and technological innovation projects. Mabwell's Taizhou factory possesses robust in-house manufacturing capability compliant with international GMP standards regulated by the NMPA, FDA and EMA, and has passed the EU QP Audit. The large-scale manufacturing base located in Shanghai is under construction. Our mission is "Explore Life, Benefit Health" and our vision is "Innovation, from ideas to reality". For more information, please visit . Forward-Looking Statements This press release contains forward-looking statements including, but not limited to, the potential safety, efficacy, regulatory review or approval and commercial success of our product candidates and those relating to the Company's product development, clinical studies, clinical and regulatory milestones and timelines, market opportunity, competitive position, possible or assumed future results of operations, business strategies, potential growth opportunities and other statements that are predictive in nature. "Forward-looking statements" are statements that are not historical facts and involve a number of risks and uncertainties, which may cause actual results to be materially different from any future results expressed or implied in the forward-looking statements. These statements may be identified by the use of forward-looking expressions, including, but not limited to, "expect," "anticipate," "intend," "plan," "believe," "estimate," "potential," "predict," "project," "should," "would," and similar expressions and the negatives of those terms. Forward-looking statements are based on the Company's current expectations and assumptions. Forward-looking statements are subject to a number of risks, uncertainties, and other factors, many of which are beyond the Company's control, including, but not limited to: environment; politic; economy; society; legislation; our dependence on our product candidates, most of which are still in preclinical or various stages of clinical development; our reliance on third-party vendors, such as contract research organizations and contract manufacturing organizations; the uncertainties inherent in clinical testing; our ability to complete required clinical trials for our product candidates and obtain approval from regulatory authorities for our product candidates; our ability to protect our intellectual property; the potential impact of COVID-19; the loss of any executive officers or key personnel. In case one or more of these risks or uncertainties deteriorate, or any assumptions are incorrect, the actual results may be seriously inconsistent with the stated results. The Company cautions all the persons not to place undue reliance on any such forward-looking statements, which speaks only as of the date of this press release. The Company disclaims any obligation, except as specifically required by law and the rules of the applicable Stock authority to publicly update or revise any such statements to reflect any change in expectations or in events, conditions, or circumstances on which any such statements may be based, or that may affect the likelihood that actual results will differ from those set forth in the forward-looking statements. All forward-looking descriptions, figures and assumptions in this press release are applicable to this statement. View original content to download multimedia: SOURCE Mabwell Company Codes: Shanghai:688062

快速通道临床申请抗体药物偶联物临床3期

100 项与 MF-6 相关的药物交易

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