Developing Novel NLRX1-Based Immuno-Oncology Therapeutics

开发基于 NLRX1 的新型免疫肿瘤疗法

• 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
• 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

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NLRX 1的新型免疫肿瘤治疗药物 Biotherapeutics Inc（BTI）是一家临床阶段的生物技术公司，协同结合了 先进的计算建模与平移实验，以加速开发新的 精准医疗和健康产品。这种SBIR应用来自于核苷酸方面有希望的数据- 结合寡聚化结构域，富含亮氨酸重复序列的X1（NLRX 1）作为新的癌症治疗靶点。 我们的产品：BTI已经确定了第一个小分子化合物家族， 调节分子NLRX 1。该项目的目标是验证NLRX 1作为免疫肿瘤学靶点， 开发基于NLRX 1的新型口服一流免疫肿瘤学疗法。 背景：癌症的发病率持续增长，而癌症是人类死亡的第二大原因。 美国的特别是免疫原性癌症，那些最有可能用免疫- 基于药物的治疗方法每年导致超过50万新病例和超过23万死亡。因此，有一个未满足的 临床上需要更安全、更有效的癌症治疗方法。虽然NLRX 1的激活已经显示出在以下方面的功效： 自身免疫性疾病，抑制NLRX 1可以增加效应器反应，促进溶瘤反应， 使免疫细胞对检查点受体敏感并减少自噬。NX-43是我们的顶级NLRX 1抑制剂， 在两种结直肠癌（CRC）模型中具有较强的治疗效果。第一阶段申请将描述 NX-43介导的对存活的影响，并验证其对NLRX 1的安全性和特异性。其目的是： AIM 1.通过测量细胞活力评估NX-43对CT-26细胞的直接和间接细胞毒性 以及在存在和不存在淋巴结淋巴细胞的情况下的体外细胞凋亡。 AIM 2.确定NX-43在CRC的CT-26和AOM/DSS模型中的体内治疗功效， 促进存活并诱导瘤内免疫活化。 AIM 3.在脱靶结合试验中评价NX-43的ADME-Tox和药代动力学，药代动力学 分析、大鼠7天剂量范围毒性研究和ADME-Tox测定。 预期结果：验证NX-43作为靶向和抑制NLRX 1的主要拮抗分子 通过：i）≤ 100 µM时癌细胞活力降低50%; ii）口服NX显著改善生存期- 43治疗的CRC小鼠模型;和iii）大鼠口服NOAEL ≥ 500 mg/kg的良性安全性特征。 SBIR II期将评估NX-43联合治疗的疗效， 在其他癌症模型中，将NX-43推进到IND使能的大鼠GLP毒理学研究。 商业应用：该项目的成功将启动一个以 NLRX 1抑制性免疫肿瘤学治疗剂。BTI的新NLRX靶向口服免疫肿瘤学 治疗可能会扰乱超过85亿美元的结直肠癌市场，并在全球范围内增加123亿美元。 黑色素瘤，肾细胞癌和非小细胞肺癌，预计到2026年市场将达到1730亿美元。