Advancing BITT-101 a novel dominant CD40 antagonist for use in treatment of Sjogren Syndrome.

推进 BITT-101 成为一种新型 CD40 拮抗剂，用于治疗干燥综合征。

• 批准号: 10760568
• 负责人: Kenneth Olivier
• 金额: $ 29.8万
• 依托单位: BOSTON IMMUNE TECHNOLOGIES AND THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-21 至 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10760568
• 关键词: Adverse event; Affinity; Anti-CD40; Antibodies; Autoimmune; Autoimmune Diseases; B Cell Proliferation; B-Cell Activation; B-Lymphocytes; Benchmarking; Binding; Biological Assay; Biological Products; Blood; Blood Platelets; Boston; Cells; Clinic; Clinical; Clinical Trials; Coculture Techniques; Cyclic GMP; Data; Development; Disease; Disease model; Dose; Drug Kinetics; Dryness; Epithelium; Event; Exocrine Glands; Fatigue; Formulation; Frequencies; Funding; Future; Health; Human; Immune; Immune System Diseases; Immunoglobulin M; Immunology; In Vitro; International; Investigational Drugs; Investigational New Drug Application; Lacrimal gland structure; Life; Ligands; Macaca fascicularis; Marketing; Mediating; Modeling; Mucous Membrane; New Drug Approvals; Pain; Pathway interactions; Patient risk; Patients; Performance; Pharmacologic Substance; Phase; Primates; Process; Production; Reaction; Regulatory Affairs; Running; Safety; Salivary Glands; Schedule; Secure; Signal Transduction; Sjogren' s Syndrome; Small Business Innovation Research Grant; Specificity; Spleen; Symptoms; T-Lymphocyte; TNFRSF5 gene; TNFSF5 gene; Technology; Testing; Therapeutic; Therapeutic Agents; Toxic effect; Toxicology; Validation; antagonist; design; dimer; dosage; graft vs host disease; immune modulating agents; immunomodulatory therapies; in vitro activity; in vivo; in vivo Model; interest; large scale production; mouse model; novel; novel strategies; novel therapeutic intervention; novel therapeutics; pharmacologic; pre-clinical assessment; prevent; programs; prospective; receptor; research clinical testing; systemic autoimmune disease; targeted treatment; therapeutic candidate; validation studies

PROJECT SUMMARY Sjögren’s syndrome (SjS) is a highly disabling systemic autoimmune disease. Symptoms include mucosal dryness (as a result of the destruction of the epithelium of exocrine glands, mainly the salivary and lacrimal glands), pain, and fatigue. Moreover, 30-50% of patients risk systemic and potentially lethal complications. Candidate therapeutics for the disease over the past 20 years all failed to provide benefit: there is no approved immunomodulatory treatment for SjS patients. Recently, targeting the CD40/CD40L interaction, a key and well- known pathway in T-cell-mediated B-cell activation emerged as a promising therapeutic strategy for SjS in mouse models of the disease. However, prospective clinical use of anti-CD40L antibodies is highly likely to display life- threatening adverse events: these candidates are known to trigger thromboembolic events. Also, testing of current CD40 antagonists in several autoimmune diseases displayed poor results, confirming that CD40 is an extremely elusive target. Boston Immune Technologies and Therapeutics (BITT) is developing BITT-101, a uniquely efficient dominant antagonist to CD40. CD40L can easily displace antagonists raised against trimeric (active) forms of CD40; our BITT-101 binds and stabilizes the inactive dimeric form of CD40, dominantly blocking CD40-CD40L interaction, even in the presence of ligand. BITT has already completed extensive BITT-101 validation, demonstrating its dominant antagonist activity in vitro in CD40L-induced B-cell proliferation assays, and in in vivo models of GvHD. Results in this model also confirmed that BITT-101 outcompetes current CD40 antagonists, by selectively depleting active B cells, prospectively allowing for lower dosage and higher efficacy and safety. In the proposed Fast-Track project, BITT will complete pre-clinical assessment of BITT-101 to obtain relevant data for an Investigational New Drug (IND) application. BITT will confirm BITT-101 activity in primary cells from SjS patients during Phase I, which will provide proof of concept for BITT-101 use in this clinically unmet disease. Positive Phase I results will also allow advancement to IND-enabling toxicology and pharmacokinetic studies, to be conducted in Phase II. During the Phase II, BITT will also test BITT-101 production process suitability for GLP standard compliance. At the end of the SBIR project, BITT will be ready to advance BITT-101 to GMP production and clinical testing for which a combination of third-party investor funds and SBIR Phase IIb are expected to be leveraged. Successful completion of this project and initial clinical testing evidence will help to secure the already expressed interest of pharmaceutical companies with whom BITT will engage to complete late-stage clinical testing in SjS and launch BITT-101 into international markets, first for SjS and then for other auto-immune diseases.

项目摘要 Sjögren's综合征（SJS）是一种高度残疾的系统性自身免疫性疾病。症状包括粘膜 干燥（由于外分泌网格上皮的破坏，主要是唾液和泪 腺体），疼痛和疲劳。此外，30-50％的患者风险全身性和潜在的致命并发症。 在过去20年中，该疾病的候选疗法未能提供好处：没有批准 SJS患者的免疫调节治疗。最近，针对CD40/CD40L相互作用，键和良好 T细胞介导的B细胞激活中已知的途径是小鼠中SJS的有前途的疗法 疾病的模型。但是，抗CD40L抗体的前瞻性临床使用极有可能表现出寿命 - 威胁性不利事件：已知这些候选人会触发血栓栓塞事件。另外，测试 当前的几种自身免疫性疾病中的CD40拮抗剂表现出较差的结果，证实CD40是一种 极其弹性的目标。 波士顿免疫技术和治疗学（BITT）正在开发Bitt-101，这是一种独特的效率优势 CD40的对手。 CD40L可以轻松地置换针对CD40的三聚体（活跃）形式的拮抗剂；我们的 BITT-101结合并稳定CD40的非活性二聚体形式，主要阻止CD40-CD40L相互作用， 即使是配体的存在。比特已经完成了广泛的Bitt-101验证，证明了其 CD40L诱导的B细胞增殖测定法和GVHD的体内模型中的体外拮抗剂活性。 该模型中的结果还证实，Bitt-101通过有选择性地胜过电流CD40拮抗剂 耗尽活性B细胞，前瞻性允许较低的剂量以及更高的效率和安全性。 在拟议的快速轨道项目中，BITT将完成Bitt-101的临床前评估，以获得相关 研究新药（IND）应用的数据。 BITT将确认BITT-101的活性 SJS患者在第一阶段将提供BITT-101在该临床未经疾病中使用的概念证明。 积极的I期结果还将允许进步促进毒理学和药代动力学研究，从而发展到 在第二阶段进行。在第二阶段，BITT还将测试BITT-101生产过程的适用性GLP 标准合规性。 在SBIR项目的结尾，BITT将准备将Bitt-101推向GMP生产和临床测试 预计将利用第三方投资者基金和SBIR IIB的组合。 成功完成该项目和初始临床测试证据将有助于确保已经表达的 Bitt将与之互动的制药公司的兴趣，以完成SJS的晚期临床测试 并将Bitt-101推出国际市场，首先是SJS，然后是其他自动免疫疾病。