Small-molecule agonists of the RIG-I-like receptor pathway as cancer immunotherapeutics

RIG-I 样受体途径的小分子激动剂作为癌症免疫治疗药物

基本信息

批准号：
9555530
负责人：
Peter Probst
金额：
$ 22.5万
依托单位：
KINETA, INC.
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-04-01 至 2019-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9555530
关键词：
Adjuvant Adoptive Transfer Agonist Anthracyclines Antigen Presentation Antigens Apoptosis Apoptotic Binding Proteins Biological Assay Blocking Antibodies CD8-Positive T-Lymphocytes CT26 Cancer Model Cancer Vaccines Cell Death Cell membrane Cell surface Cells Chemical Structure Chemicals Cytotoxic agent DNA Data Dendritic Cells Dendritic cell activation Endoplasmic Reticulum Evaluation Exhibits Formulation Genetic Goals Human IRF3 gene Immune Immune Tolerance Immune checkpoint inhibitor Immune response Immune system Immunotherapeutic agent Immunotherapy In Vitro Infiltration Injections Injury Innate Immune Response Kinetics Lead Ligands Liposomes Malignant Neoplasms Measures Mediating Metabolic Methods Modeling Molecular Monoclonal Antibodies Mus Natural Immunity Nucleic Acids Oral Ovarian Pancreas Pathway interactions Patients Pattern Pattern recognition receptor Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Plasma Proteins Population Pre-Clinical Model Production Property RNA Radiation therapy Receptor Signaling Safety Series Signal Transduction Solubility Stress Structure-Activity Relationship T cell response T-Lymphocyte Therapeutic Therapeutic Effect Therapeutic Uses Tissues Treatment Failure Viral Virus analog antitumor effect aqueous base calreticulin cancer cell cancer immunotherapy cancer type cell killing chemokine cytokine design drug development high throughput screening immune activation immune checkpoint immune checkpoint blockers immunogenic cell death implantation improved in vitro Assay in vivo in vivo evaluation intravenous administration lead candidate lead optimization melanoma neoantigens neoplastic cell novel oxaliplatin pathogen preclinical development prevent receptor recruit research clinical testing response scaffold small molecule tripolyphosphate tumor tumor growth tumor microenvironment uptake

Adjuvant Adoptive Transfer Agonist Anthracyclines Antigen Presentation Antigens Apoptosis Apoptotic Binding Proteins Biological Assay Blocking Antibodies CD8-Positive T-Lymphocytes CT26 Cancer Model Cancer Vaccines Cell Death Cell membrane Cell surface Cells Chemical Structure Chemicals Cytotoxic agent DNA Data Dendritic Cells Dendritic cell activation Endoplasmic Reticulum Evaluation Exhibits Formulation Genetic Goals Human IRF3 gene Immune Immune Tolerance Immune checkpoint inhibitor Immune response Immune system Immunotherapeutic agent Immunotherapy In Vitro Infiltration Injections Injury Innate Immune Response Kinetics Lead Ligands Liposomes Malignant Neoplasms Measures Mediating Metabolic Methods Modeling Molecular Monoclonal Antibodies Mus Natural Immunity Nucleic Acids Oral Ovarian Pancreas Pathway interactions Patients Pattern Pattern recognition receptor Permeability Pharmaceutical Chemistry Pharmaceutical Preparations Phase Plasma Proteins Population Pre-Clinical Model Production Property RNA Radiation therapy Receptor Signaling Safety Series Signal Transduction Solubility Stress Structure-Activity Relationship T cell response T-Lymphocyte Therapeutic Therapeutic Effect Therapeutic Uses Tissues Treatment Failure Viral Virus analog antitumor effect aqueous base calreticulin cancer cell cancer immunotherapy cancer type cell killing chemokine cytokine design drug development high throughput screening immune activation immune checkpoint immune checkpoint blockers immunogenic cell death implantation improved in vitro Assay in vivo in vivo evaluation intravenous administration lead candidate lead optimization melanoma neoantigens neoplastic cell novel oxaliplatin pathogen preclinical development prevent receptor recruit research clinical testing response scaffold small molecule tripolyphosphate tumor tumor growth tumor microenvironment uptake

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项目摘要

PROJECT SUMMARY Cancer immunotherapy is predicated on overcoming immune tolerance to tumors and facilitating immune- mediated tumor cell killing. Current approaches include the use of therapeutic cancer vaccines, adoptive transfer of immune effectors, and the use of immunostimulatory monoclonal antibodies that block immune checkpoints. Although these therapies have shown promise in treating many types of cancer, they are not effective in all patients. A frequent basis for treatment failure appears to be a tumor microenvironment that does not support the recruitment or infiltration of tumor-reactive T cells. At Kineta, we are developing small- molecule compounds that target RIG-I-like receptor pathways, and other IRF3-inducing pathways, to stimulate innate immunity. Because of the unique immune-stimulating properties of these IRF3 agonists, we have begun to evaluate their potential as cancer immunotherapeutics. Our proof-of-concept compound, KIN1312, induces immunogenic cell death, a cell death pathway that elicits an innate immune activation cascade within the tumor microenvironment that primes a T cell response against tumor neoantigens and that recruits activated T cells into the tumor. KIN1312 inhibits tumor growth in mice, and mice exhibiting tumor regression in response to KIN1312 are immune to re-challenge with live tumor cells of the same type. In this Phase I application, we will evaluate a panel of structure-activity relationship (SAR)-derived KIN1312 analogs, and a small number of compounds representing alternative chemical scaffolds, with the goal of improving overall potency and drug- like properties. In Aim 1, we will screen compounds for their ability to induce cytokine production in mouse and human cancer cells and to induce apoptotic cell death. In addition, we will measure the ability of compounds to induce translocation of calreticulin to the outer cell membrane, the release of damage-associated molecular patterns, and dendritic cell activation. In parallel, we will rank compounds for desirable drug-like properties including aqueous solubility, metabolic stability, and formulation compatibility. At least four unique chemical series will be chosen for advancement to Aim 2. In Aim 2, we will determine the effects of these compounds on tumor growth in mice. We evaluate the therapeutic effects of the compounds by injection of compound into tumors induced by implantation of CT26 cancer cells. In parallel, we will assess the antitumor effects of systemic (intravenous) administration of KIN1312 that has been formulated in liposomes. We will also use liposome formulated KIN1312 to perform an initial evaluation of in vivo safety. From these studies, we will select a lead and backup chemical series for advancement to Phase II, which will include second-stage medicinal chemistry optimization and preclinical development as a novel immunotherapy aimed at modifying the tumor microenvironment to facilitate immune-mediated tumor cell killing.

项目摘要癌症免疫疗法是基于克服对肿瘤的免疫耐受性的介导的肿瘤细胞杀死。当前的方法包括使用治疗性癌症疫苗，收养免疫效应子的转移以及使用免疫抗体的免疫刺激单克隆抗体的使用检查点。尽管这些疗法在治疗多种类型的癌症方面表现出了希望，但它们不是对所有患者有效。经常进行治疗失败的基础似乎是一种肿瘤微环境不支持肿瘤反应性T细胞的募集或浸润。在Kineta，我们正在开发小型分子化合物靶向类似RIG-I的受体途径和其他诱导IRF3的途径，以刺激先天免疫。由于这些IRF3激动剂具有独特的免疫刺激特性，我们已经开始评估它们作为癌症免疫治疗药的潜力。我们的概念验证化合物KIN1312诱导免疫原性细胞死亡，这是一种细胞死亡途径，引起肿瘤内的先天免疫激活级联对肿瘤新抗原的T细胞反应的微环境，并募集了激活的T细胞进入肿瘤。 KIN1312抑制小鼠的肿瘤生长，并且表现出肿瘤消退的小鼠响应 KIN1312免疫可与同类类型的活肿瘤细胞重新挑战。在此I阶段应用程序中，我们将评估一个结构 - 活性关系（SAR）衍生的KIN1312类似物和少数数量的结构活动关系（SAR）代表替代化学支架的化合物，目的是提高整体效力和药物喜欢属性。在AIM 1中，我们将筛选化合物，以诱导鼠标和人类癌细胞并诱导凋亡细胞死亡。此外，我们将测量化合物的能力诱导钙网蛋白易位到外细胞膜，损伤相关分子的释放模式和树突状细胞激活。同时，我们将对所需的类似药物的特性进行排名包括水溶性，代谢稳定性和配方兼容性。至少四种独特的化学物质系列将被选为AIM 2的进步。在AIM 2中，我们将确定这些化合物对小鼠的肿瘤生长。我们通过将化合物注射到植入CT26癌细胞引起的肿瘤。同时，我们将评估在脂质体中制定的KIN1312的全身性（静脉内）给药。我们还将使用脂质体配制了KIN1312，以对体内安全性进行初步评估。从这些研究中，我们将选择一个铅和备份化学系列以促进第二阶段，其中包括第二阶段药物化学优化和临床前开发作为一种新型免疫疗法，旨在改变肿瘤微环境促进免疫介导的肿瘤细胞杀死。