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。

基本信息

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
项目类别：
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&apos 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

项目摘要

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.

项目概要干燥综合征 (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（由于外分泌腺的上皮细胞，主要是唾液腺和泪腺的破坏）此外，30-50% 的患者还面临全身性和潜在致命并发症的风险。过去20年针对该疾病的候选疗法均未能带来益处：尚无批准的药物最近，针对 SjS 患者的免疫调节治疗，针对 CD40/CD40L 相互作用，这是一个关键且良好的治疗。 T 细胞介导的 B 细胞激活的已知途径成为小鼠 SjS 的一种有前景的治疗策略然而，抗CD40L抗体的前瞻性临床使用很可能显示出生命- 有害的不良事件：已知这些候选药物会引发血栓栓塞事件。目前的 CD40 拮抗剂在多种自身免疫性疾病中表现不佳，这证实了 CD40 是一种极其难以捉摸的目标。波士顿免疫技术和治疗公司 (BITT) 正在开发 BITT-101，这是一种独特高效的主导药物 CD40L 的拮抗剂可以轻松取代针对我们的三聚体（活性）形式的 CD40 的拮抗剂； BITT-101 结合并稳定 CD40 的无活性二聚体形式，主要阻断 CD40-CD40L 相互作用，即使在配体存在的情况下，BITT 也已经完成了广泛的 BITT-101 验证，证明了它的有效性。 CD40L 诱导的 B 细胞增殖测定中的体外拮抗剂活性以及 GvHD 的体内模型。该模型的结果还证实，BITT-101 通过选择性地胜过当前的 CD40 拮抗剂消耗活性 B 细胞，前瞻性地允许剂量降低或提高疗效和安全性。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研究性新药 (IND) 申请的数据将确认 BITT-101 在原代细胞中的活性。 I 期 SjS 患者，这将为 BITT-101 在这种临床未满足的疾病中的使用提供概念证明。第一阶段的积极结果也将有助于推进 IND 毒理学和药代动力学研究，在第二阶段期间，BITT还将测试BITT-101生产工艺是否适合GLP。标准合规性。 SBIR项目结束后，BITT将准备好将BITT-101推进GMP生产和临床测试预计将利用第三方投资者基金和 SBIR IIb 期的组合。该项目的成功完成和初步临床测试证据将有助于确保已经表达的 BITT 将与其合作完成 SjS 后期临床测试的制药公司的兴趣并将 BITT-101 推向国际市场，首先用于 SjS，然后用于其他自身免疫性疾病。