Developing Novel NLRX1-Based Immuno-Oncology Therapeutics

开发基于 NLRX1 的新型免疫肿瘤疗法

基本信息

批准号：
10080198
负责人：
Andrew Leber
金额：
$ 23.07万
依托单位：
BIOTHERAPEUTICS, INC.
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-01 至 2021-12-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10080198
关键词：
Apoptosis Autoimmune Diseases Autophagocytosis Awareness Benign Binding Biological Assay Biological Availability Biological Response Modifier Therapy Biotechnology CD4 Positive T Lymphocytes CT26 Cancer Model Cause of Death Cell Survival Cells Cessation of life Chronic Clinical Clinical Trials Colitis Colorectal Cancer Combined Modality Therapy Computer Models Cytokine Receptors Data Dependence Development Dose Drug Kinetics Drug or chemical Tissue Distribution Exhibits Family Functional disorder Goals Granzyme Immune Immune response Immunization Immunohistochemistry Immunologic Surveillance Immunooncology Immunotherapeutic agent In Vitro Incidence Infiltration Inflammation Inflammatory Inflammatory Response Investigation Knock-out Knowledge Lead Legal patent Leucine-Rich Repeat Life Cycle Stages Ligands Lung diseases Lymphocyte Malignant Neoplasms Measurement Mediating Medical Metabolism Methods Mitochondria Modeling Mus Myeloid Cell Activation No-Observed-Adverse-Effect Level Non-Small-Cell Lung Carcinoma Nucleotides Oncolytic Oral Outcome Pathway interactions Pharmaceutical Preparations Phase Phenotype Plasma Polyps Positioning Attribute Precision Health Process Production Program Development Rattus Reaction Renal Cell Carcinoma Safety Small Business Innovation Research Grant Specificity TNF gene Testing Therapeutic Therapeutic Effect Toxic effect Toxicology Treatment Efficacy Tumor Immunity United States Validation Viral adaptive immunity anti-cancer base cancer cell cancer subtypes cancer therapy checkpoint receptors commercial application comparative cytokine cytotoxicity draining lymph node drug development immune activation immune checkpoint immunogenic in vivo inflammatory marker inhibitor/antagonist innovation lymph nodes melanoma mortality mouse model novel novel therapeutics precision medicine public health relevance receptor research clinical testing response safety study small molecule small molecule therapeutics success therapeutic target transcriptomics tumor

项目摘要

Developing Novel NLRX1-Based Immuno-Oncology Therapeutics Biotherapeutics Inc (BTI) is a clinical-stage biotech company that synergistically combines the power of advanced computational modeling with translational experimentation to accelerate the development of novel products for precision medicine and health. This SBIR application results from promising data on nucleotide- binding oligomerization domain, leucine rich repeat containing X1 (NLRX1) as a new cancer therapeutic target. Our Product: BTI has identified the first family of small-molecule compounds that bind and inhibit the novel regulatory molecule, NLRX1. The goal of this project is to validate NLRX1 as an immuno-oncology target and develop novel NLRX1-based, oral first-in-class immuno-oncology therapeutics. Background: The incidence of cancer continues to grow while cancer is the second leading cause of death in the United States. In particular, immunogenic cancers, those with the highest potential to be treated with immune- based therapeutics, result in over 500,000 new cases per year and over 230,000 deaths. Thus, there is an unmet clinical need for safer, more efficacious cancer therapeutics. While activation of NLRX1 has shown efficacy in autoimmune disease, inhibition of NLRX1 can increase effector responses to promote oncolytic reactions, de- sensitize immune cells to checkpoint receptors and reduce autophagy. NX-43, our top NLRX1 inhibitor, exerts strong therapeutic efficacy in two models of colorectal cancer (CRC). This Phase I application will characterize the NX-43-mediated effects on survival and validate its safety and specificity to NLRX1. The Aims are to: AIM 1. Assess the direct and indirect cytotoxicity of NX-43 on CT-26 cells by measurement of cell viability and apoptosis in vitro in the presence and absence of lymph node lymphocytes. AIM 2. Determine the therapeutic efficacy of NX-43 in vivo in the CT-26 and AOM/DSS models of CRC to promote survival and induce intratumoral immune activation. AIM 3. Evaluate the ADME-Tox and pharmacokinetics of NX-43 in off-target binding assays, pharmacokinetic analysis, 7-d dose ranging toxicity studies in rats and ADME-Tox assays. Expected Outcomes: Validation of NX-43 as a lead antagonistic molecule for targeting and inhibiting NLRX1 through: i) 50% reduction in cancer cell viability at ≤ 100 µM; ii) significant improvement of survival by oral NX- 43 treatment in mouse models of CRC; and iii) a benign safety profile with NOAEL ≥ 500 mg/kg oral in rats. SBIR Phase II will assess the efficacy of combination therapies with NX-43, evaluate therapeutic effects in additional models of cancer and advance NX-43 to IND-enabling GLP toxicology studies in rats. Commercial Application: Success in this project will launch a new drug development pipeline centered on NLRX1-inhibiting immuno-oncology therapeutics. BTI’s new NLRX1-targeting oral immune-oncology therapeutics could disrupt a market of over $8.5B in colorectal cancer and an additional $12.3B across melanoma, renal cell carcinoma, and non-small cell lung cancer, a market projected to reach $173B by 2026.

开发基于NLRX1的新型免疫肿瘤治疗药 Biotherapeutics Inc（BTI）是一家临床阶段生物技术公司，协同结合了通过翻译实验的高级计算建模，以加速新型精确医学和健康的产品。该SBIR应用是由核苷酸 - 有望的数据引起的结合寡聚结构域，含有X1（NLRX1）作为新的癌症治疗靶标的亮氨酸富集重复。我们的产品：BTI确定了第一个结合和抑制新颖的小分子化合物的第一家族调节分子，NLRX1。该项目的目的是验证NLRX1为免疫肿瘤的目标和开发基于NLRX1的新型口服一流的免疫肿瘤疗法。背景：癌症的事件继续增长，而癌症是死亡的第二大原因美国。特别是免疫原性的癌症，那些用免疫治疗的潜力最高的癌症基于理论，每年导致超过500,000例新病例和230,000多人死亡。那是一个未满足的对更安全，更高效的癌症治疗的临床需求。虽然NLRX1的激活显示出有效性自身免疫性疾病，抑制NLRX1可以增加效应子的反应以促进溶瘤反应，从而对检查点受体的敏感免疫小球并减少自噬。 NX-43，我们的顶级NLRX1抑制剂，执行在两个模型的结直肠癌（CRC）模型中，强大的理论效率。该阶段I应用程序将表征 NX-43介导的对生存的影响并验证其对NLRX1的安全性和特异性。目的是： AIM 1。通过测量细胞活力来评估CT-26细胞上NX-43的直接和间接细胞毒性在存在和不存在淋巴结淋巴细胞的情况下，体外凋亡。 AIM 2。确定CT-26中NX-43在体内的治疗效率和CRC的AOM/DSS模型至促进生存并诱导肿瘤内免疫激活。 AIM 3。评估脱靶结合测定中NX-43的ADME-TOX和药代动力学，药代动力学分析，在大鼠和ADME-TOX分析中的毒性研究的7-D剂量。预期结果：NX-43作为靶向和抑制NLRX1的铅拮抗分子的验证通过：i）在≤100µm时癌细胞活力降低50％； ii）口服NX-的生存率显着提高 43 CRC小鼠模型中的处理； iii）良性安全性，大鼠的Noael≥500mg/kg口服。 SBIR II期将评估组合疗法与NX-43的有效性，评估治疗作用癌症的其他模型和将NX-43推进到大鼠中的GLP毒理学研究。商业应用：该项目的成功将启动以焦点为中心的新药开发管道 NLRX1抑制免疫肿瘤疗法。 BTI的新NLRX1靶向口服免疫肿瘤学治疗可能会破坏大肠癌超过$ 8.5B的市场，额外的$ 12.3B 黑色素瘤，肾细胞癌和非小细胞肺癌预计到2026年将达到173B美元。