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.

项目总结 干燥综合征(SjS)是一种高度致残的全身性自身免疫性疾病。症状包括粘膜 干燥(由于外分泌腺上皮的破坏，主要是唾液和泪液 腺体)、疼痛和疲劳。此外，30%-50%的患者有系统性和潜在致命性并发症的风险。 过去20年来治疗这种疾病的候选疗法都没有提供益处：没有批准的 SjS患者的免疫调节治疗。最近，针对CD40/CD40L相互作用，一个关键和良好的- 已知的T细胞介导的B细胞活化途径有望成为小鼠干燥综合征的治疗策略 这种疾病的模型。然而，抗CD40L抗体的预期临床应用极有可能显示出生命- 危险的不良事件：众所周知，这些候选药物会引发血栓栓子事件。此外，测试 目前CD40拮抗剂在几种自身免疫性疾病中的效果不佳，证实CD40是一种 非常难以捉摸的目标。 波士顿免疫技术和治疗公司(BITT)正在开发BITT-101，一种独特有效的优势 CD40的拮抗者。CD40L可以很容易地取代针对三聚体(活性)形式的CD40的拮抗剂；我们的 BITT-101结合并稳定CD40的非活性二聚体形式，主要阻断CD40-CD40L相互作用， 即使在配基存在的情况下。BITT已经完成了广泛的BITT-101验证，展示了其 在CD40L诱导的B细胞增殖实验和GvHD体内模型中具有明显的拮抗活性。 这个模型的结果也证实了Bitt-101通过选择性地击败了目前的CD40拮抗剂 消耗活性B细胞，前瞻性地允许更低的剂量和更高的疗效和安全性。 在拟议的快速通道项目中，BITT将完成BITT-101的临床前评估，以获得相关的 用于研究新药(IND)申请的数据。BITT将确认BITT-101在原代细胞中的活性 这将为BITT-101在这种临床未治疗的疾病中使用提供概念证明。 阳性的I期结果还将使IND毒理学和药代动力学研究取得进展，以 在第二阶段进行。在第二阶段，BITT还将测试BITT-101生产工艺是否适合GLP 标准合规性。 在SBIR项目结束时，BITT将准备将BITT-101推进到GMP生产和临床测试 预计将利用第三方投资者基金和SBIR第二阶段b相结合的方式。 这个项目的成功完成和初步的临床测试证据将有助于确保已经表达的 BITT将与其合作在SJS完成后期临床测试的制药公司的兴趣 并将BITT-101推向国际市场，首先是针对Sjs，然后是针对其他自身免疫性疾病。