A novel nanobody-based agonist-redirected checkpoint (ARC) molecule, aPD1-Fc-OX40L, for cancer immunotherapy

一种基于纳米抗体的新型激动剂重定向检查点 (ARC) 分子 aPD1-Fc-OX40L，用于癌症免疫治疗

基本信息

批准号：
10580259
负责人：
Maninder Sandey
金额：
$ 44.99万
依托单位：
AUBURN UNIVERSITY AT AUBURN
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：
2023-02-01 至 2026-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10580259
关键词：
Affinity Agonist Animal Model Automobile Driving Binding Biological Biological Models Blood Blood specimen CD8B1 gene Cancer Patient Canis familiaris Characteristics Clinical Clinical Trials Combined Modality Therapy Correlative Study Data Disease-Free Survival Drug Design Drug Kinetics Engineering Ensure Excision Extracellular Domain FDA approved Failure Fc Receptor Flow Cytometry Frequencies Genetically Engineered Mouse Goals Heterogeneity Human Immune Immune Targeting Immune checkpoint inhibitor Immunohistochemistry Immunooncology Immunotherapeutic agent Immunotherapy Individual Injections Inter-tumoral heterogeneity Intravenous infusion procedures Investigational New Drug Application Knowledge Libraries Lymphocyte Malignant Neoplasms Mediating Melanoma Cell Metastatic Neoplasm to the Lung Molecular Monoclonal Antibodies Neoadjuvant Therapy OX40 Oral Outcome PD-1 blockade PD-1/PD-L1 Pathologic Pathway interactions Patients Peripheral Blood Mononuclear Cell Persons Phase I/II Clinical Trial Phase II/III Clinical Trial Pre-Clinical Model Regulatory T-Lymphocyte Research Resistance Rodent Safety Signal Transduction Stable Disease Students T-Lymphocyte TNFSF4 gene Testing Therapeutic Toxic effect Tumor Necrosis Factor Receptor anti-PD-1 anti-tumor immune response antitumor effect cancer immunotherapy cancer therapy clinical efficacy crosslink design effector T cell flexibility human model immune checkpoint immune checkpoint blockade immunosuppressive checkpoint information gathering innovation insight melanoma member mucosal melanoma nanobodies novel novel therapeutics patient response peripheral blood programmed cell death ligand 1 programmed cell death protein 1 receptor response safety assessment student participation student training targeted treatment therapy design transcriptome treatment strategy tumor tumor microenvironment tumor necrosis factor ligand superfamily member 4

项目摘要

Immune checkpoint inhibitors (ICIs) have shown unprecedented clinical activity in a wide range of malignancies. However, their efficacy remains limited in many malignancies due to primary or acquired resistance. Targeted therapies that activate tumor necrosis factor receptor superfamily (TNFRSF) members, like OX40 & 4-1BB, are currently explored to augment the clinical efficacy of ICIs. In this study, we have constructed a novel-nanobody (Nb) based Agonist-Redirected Checkpoint (ARC) platform that consolidates immune checkpoint blockade (ICB) and TNFRSF agonism in a single biologic. Our long-term goal is to utilize this Nb-based ARC platform to develop novel immunotherapeutics to treat canine and human cancer patients. The objective of this R15 proposal is to investigate the impact of our first Nb-based ARC molecule, aPD1-Fc-OX40L, on local and systemic antitumor immune response in pet dogs with oral malignant melanoma (OM). aPD1-Fc-OX40L utilizes an anti-PD1 nanobody to disrupt the PD1/PD-L1 axis and the extracellular domain (ECD) of the OX40 ligand to activate the OX40 pathway. Our preliminary data show that aPD1-Fc-OX40L folds properly binds to cognate receptors with high affinity, activates the OX40 pathway, and blocks canine PD-L1 binding to PD1. Our specific aims will: (Aim 1) assess the safety and pharmacokinetic (PK) profile of aPD1-Fc-OX40L; (Aim 2) conduct a phase II/III clinical trial of aPD1-Fc-OX40L in canine patients with oral melanoma (OM); and (Aim 3) assess the functional activities of aPD1-Fc-OX40L over monotherapies. We will perform clinical correlative studies (using flow cytometry and immunohistochemistry (IHC)) on tumor and peripheral blood samples collected before and after administration of aPD1-Fc-OX40L to understand the cellular and molecular mechanisms that determine the antitumor immune response. Upon conclusion, we will gain valuable insights into the safety, PK profile, and clinical efficacy of aPD1-Fc-OX40L. This contribution is significant since this will be the first study to evaluate concomitant PD1 blockade and OX40 agonism in a highly relevant large animal model of human mucosal melanoma. The data gathered from this study will create a blueprint to employ a similar therapeutic strategy to treat human cancer patients. The proposed research is innovative because we have developed a highly flexible Nb-based ARC platform that can be easily adapted to engineer novel immunotherapeutic combinations targeting other immune checkpoints and TNFRSF receptors. The availability of these species-specific immunotherapeutics will allow the integration of canine patients with spontaneous tumors into immune-oncology research, which will benefit both humans and pet dogs. It will provide dogs with access to cutting-edge cancer treatments while ensuring that people are given treatments that are more likely to succeed.

免疫检查点抑制剂（ICIS）在广泛的恶性肿瘤中表现出了前所未有的临床活性。但是，由于原发性或获得的耐药性，它们的疗效在许多恶性肿瘤中仍然有限。目标激活肿瘤坏死因子受体超家族（TNFRSF）成员（例如OX40和4-1BB）的疗法是目前正在探索以增强ICIS的临床功效。在这项研究中，我们构建了一个新颖的纳米病（NB）基于激动剂划分的检查点（ARC）平台，该平台合并免疫检查点封锁（ICB）和单个生物学中的TNFRSF激动剂。我们的长期目标是利用这个基于NB的弧平台开发用于治疗犬和人类癌症患者的新型免疫治疗药。该R15提案的目的是研究我们第一个基于NB的弧分子APD1-FC-OX40L对局部和全身抗肿瘤的影响口腔恶性黑色素瘤（OM）的宠物犬的免疫反应。 APD1-FC-OX40L使用抗PD1 纳米机构破坏OX40配体的PD1/PD-L1轴和细胞外域（ECD）以激活 OX40途径。我们的初步数据表明，APD1-FC-OX40L折叠与同源受体正确结合高亲和力，激活OX40途径，并阻止犬PD-L1与PD1结合。我们的具体目标将：（目标 1）评估APD1-FC-OX40L的安全性和药代动力学（PK）曲线；（AIM 2）进行II/III期临床 APD1-FC-OX40L在口腔黑色素瘤患者中的试验（OM）；（目标3）评估功能活动单疗法上的APD1-FC-OX40L。我们将进行临床相关研究（使用流式细胞仪和在给药前后收集的肿瘤和外周血样本上的免疫组织化学（IHC）） APD1-FC-OX40L的细胞和分子机制，以确定抗肿瘤免疫回复。总结一下，我们将获得对安全性，PK概况和临床功效的宝贵见解 APD1-FC-OX40L。这项贡献很重要，因为这将是评估伴随PD1的第一项研究在人类粘膜黑色素瘤高度相关的大型动物模型中，封锁和OX40激动剂。数据从这项研究中收集的将创建蓝图，以采用类似的治疗策略来治疗人类癌症患者。拟议的研究具有创新性，因为我们开发了一个高度灵活的基于NB的弧线可以轻松适应针对其他免疫的新型免疫治疗组合的平台检查点和TNFRSF受体。这些物种特异性免疫疗法的可用性将允许将自发肿瘤的犬类患者整合到免疫肿瘤研究中，这将受益人类和宠物狗。它将为狗提供获得尖端癌症治疗的机会为人们提供更有可能成功的治疗方法。