Application of TNFRSF25 agonists for prophylaxis and treatment of graft versus host disease

TNFRSF25激动剂在预防和治疗移植物抗宿主病中的应用

• 批准号: 9908366
• 负责人: Matthew Seavey
• 金额: $ 22.47万
• 依托单位: PELICAN THERAPEUTICS, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-01-07 至 2022-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9908366
• 关键词: ANXA5 gene; Adoptive Transfer; Agonist; Allogenic; Allografting; Animals; Antigens; Apoptosis; Biological Assay; Biological Markers; Blood; Bone Marrow; CASP3 gene; CD28 gene; CD3 Antigens; CD44 gene; CTLA4 gene; Cell Culture Techniques; Cell Death; Cell division; Cells; Chimeric Proteins; Clinic; Clinical; Collaborations; Complication; Custom; Development; Diagnosis; Disease; Dose; Drug Kinetics; Economics; Effectiveness; Ensure; Enzyme-Linked Immunosorbent Assay; FOXP3 gene; Family; Frequencies; Gastrointestinal tract structure; Genetic; Graft Tolerance; Granzyme; Growth; Haplotypes; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Hematopoietic stem cells; Histocompatibility Antigens; Human; Human Development; Immune; Immune signaling; Immunocompetence; In Vitro; Inflammatory; Interferon Type II; Interleukin-2; Kinetics; Life; Ligands; Liver; Lymphocyte; Maintenance; Mediating; Minor; Mixed Lymphocyte Culture Test; Modeling; Monitor; Monoclonal Antibodies; Morbidity - disease rate; Mus; Pathologic; Patients; Peripheral; Peripheral Blood Mononuclear Cell; Pharmacology; Phase; Phase I Clinical Trials; Phenotype; Plasma; Population; Pre-Clinical Model; Prevention; Procedures; Production; Prophylactic treatment; RIPK1 gene; Reagent; Regulatory T-Lymphocyte; Self Tolerance; Signal Transduction; Skin; Small Business Technology Transfer Research; Spleen; Surface; T-Lymphocyte; TNF gene; Therapeutic; Translating; Translations; Transplant Recipients; Transplantation; Universities; Work; base; cell type; clinical application; cytokine; cytotoxic; drug candidate; exhaustion; graft vs host disease; immune self tolerance; improved; in vivo; leukemia/lymphoma; lymph nodes; monocyte; mortality; mouse model; novel; novel therapeutic intervention; peripheral blood; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; post-transplant disease; pre-clinical; prevent; programmed cell death protein 1; programs; receptor; recruit; sex; success

PROJECT SUMMARY Graft-vs-Host-Disease (GVHD) is a frequent and life-threatening complication of hematopoietic stem cell transplantation (HSCT), a procedure that often represents the best treatment option for patients suffering from hematological malignancies. Even when HLA-matched family or unrelated donors are available, an unsatisfactorily high frequency (30-40%) of transplant recipients still develop GVHD. Thus, there remains an urgent need to develop strategies to treat and prevent GVHD for patients receiving either matched or unmatched donor-recipient HSCT. Recently, CD4+FoxP3+ regulatory T cells (Tregs), which provide non-redundant function to maintain peripheral immune self-tolerance, have demonstrated potential in pre-clinical models to promote allograft acceptance. However, translation of such an approach to the clinic remains hampered by the practical and economic hurdles associated with adoptive transfer of sufficient numbers of donor Tregs to patients. In this regard, Pelican Therapeutics has developed a novel reagent that takes advantage of the natural ligand of a key receptor, TNFRSF25, expressed on Tregs. Stimulation of TNFRSF25 using a fusion protein consisting of the ligand TL1A (TL1A-Ig), in combination with IL-2, induces a dramatic and selective expansion of Tregs that effectively reduces GVHD in mice following allogeneic HSCT. These initial studies utilized a model in which Tregs were expanded in vivo with TL1A-Ig/IL-2 and then adoptively transferred to murine recipients. In this Phase I STTR, Pelican will evaluate the potential for TL1A-Ig to be directly administered to recipients undergoing HSCT, obviating the need to expand Tregs in donors prior to transplant. To verify and corroborate efficacy, two independent murine models of aHSCT will be utilized, one involving complete MHC-mismatch and an MHC- matched minor antigen-mismatched donor/recipient pair reflecting genetic disparities in clinical HSCT. In vivo effectiveness of TL1A-Ig administration for GVHD amelioration will be evaluated using established quantitative metrics that include immune phenotyping, levels of Treg expansion, analyses of immune competence and reduction in clinical signs of GVHD. Pharmacokinetics and target engagement will be characterized as part of these studies to determine suitability of TL1A-Ig as a drug candidate. To begin to translate these findings to humans, a humanized TL1A-Ig (hTL1A-Ig) reagent will be characterized first, with regard to identification of expression and kinetics of endogenous TNFRSF25 presence in human primary peripheral blood mononuclear cell (PBMC) populations. Secondly, hTL1A-Ig target engagement and downstream signaling will be examined in human PBMCs to further establish and characterize translational potential. Completion of this Phase I proof-of- concept will establish rationale for advancing this molecule into further preclinical and IND-enabling development.

项目概要 移植物抗宿主病（GVHD）是造血干细胞常见且危及生命的并发症 移植（HSCT），这种手术通常代表患有以下疾病的患者的最佳治疗选择 血液系统恶性肿瘤。即使有 HLA 匹配的家庭或无关的捐赠者， 移植受者仍出现 GVHD 的频率（30-40%）令人不满意。因此，仍然存在一个 迫切需要为接受匹配或不匹配的患者制定治疗和预防 GVHD 的策略 供体-受体 HSCT。最近，CD4+FoxP3+调节性T细胞（Treg），提供非冗余功能 维持外周免疫自我耐受，已在临床前模型中证明了促进 同种异体移植接受。然而，这种方法向临床的转化仍然受到实际情况的阻碍。 以及将足够数量的供体 Tregs 过继转移给患者相关的经济障碍。在这个 就此而言，Pelican Therapeutics 开发了一种新型试剂，该试剂利用了关键的天然配体 受体 TNFRSF25，在 Tregs 上表达。使用由以下组成的融合蛋白刺激 TNFRSF25 配体 TL1A (TL1A-Ig) 与 IL-2 结合，诱导 Tregs 的显着且选择性扩增， 有效降低同种异体 HSCT 后小鼠的 GVHD。这些初步研究使用了一个模型，其中 使用 TL1A-Ig/IL-2 在体内扩增 Tregs，然后过继转移至小鼠受体中。在这个阶段 I STTR，Pelican 将评估 TL1A-Ig 直接给予接受 HSCT 的受者的可能性， 避免了移植前在供体中扩增 Tregs 的需要。为了验证和证实功效，两个 将使用独立的 aHSCT 小鼠模型，其中一个涉及完全 MHC 错配和一个 MHC-错配。 匹配的次要抗原不匹配的供体/受体对反映了临床 HSCT 中的遗传差异。体内 将使用既定的定量评估 TL1A-Ig 给药对 GVHD 改善的有效性 指标包括免疫表型、Treg 扩增水平、免疫能力分析和 GVHD 临床症状减少。药代动力学和靶点参与将被描述为 这些研究旨在确定 TL1A-Ig 作为候选药物的适用性。开始将这些发现转化为 对于人类，首先将表征人源化 TL1A-Ig (hTL1A-Ig) 试剂，以鉴定 人原代外周血单核细胞中内源性 TNFRSF25 的表达和动力学 细胞（PBMC）群体。其次，hTL1A-Ig 靶点参与和下游信号传导将在 人类 PBMC 进一步确定和表征转化潜力。完成第一阶段证明- 概念将为将该分子进一步推进临床前和 IND 奠定基础 发展。