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 NLRX1 的新型免疫肿瘤疗法 Biotherapeutics Inc (BTI) 是一家临床阶段的生物技术公司，协同结合了 先进的计算模型与转化实验，以加速新颖的开发 精准医疗和健康产品。该 SBIR 应用源自有关核苷酸的有希望的数据 结合寡聚结构域、富含亮氨酸重复序列的 X1 (NLRX1) 作为新的癌症治疗靶点。 我们的产品：BTI 已鉴定出第一个小分子化合物家族，可结合并抑制新型药物 调节分子，NLRX1。该项目的目标是验证 NLRX1 作为免疫肿瘤学靶点并 开发新型基于 NLRX1 的口服一流免疫肿瘤疗法。 背景：癌症发病率持续上升，癌症已成为人类第二大死因。 美国。特别是免疫原性癌症，那些最有可能通过免疫治疗进行治疗的癌症 基于治疗的疾病每年导致超过 500,000 例新病例和超过 230,000 例死亡。因此，有一个未满足的 临床需要更安全、更有效的癌症治疗方法。虽然 NLRX1 的激活已显示出在 自身免疫性疾病，抑制 NLRX1 可以增加效应反应，促进溶瘤反应，去 使免疫细胞对检查点受体敏感并减少自噬。 NX-43，我们的顶级 NLRX1 抑制剂，发挥 对两种结直肠癌（CRC）模型具有很强的治疗效果。该第一阶段应用的特点是 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。目标是： 目的 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。 目的 2. 确定 NX-43 在 CRC CT-26 和 AOM/DSS 模型中的体内治疗效果，以 促进存活并诱导瘤内免疫激活。 目标 3. 在脱靶结合测定、药代动力学中评估 NX-43 的 ADME-Tox 和药代动力学 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 NLRX1 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- 显着改善生存 43 结直肠癌小鼠模型的治疗； iii) 大鼠口服 NOAEL ≥ 500 mg/kg 的良性安全性。 SBIR II 期将评估 NX-43 联合疗法的疗效，评估治疗效果 其他癌症模型，并将 NX-43 推进到支持 IND 的大鼠 GLP 毒理学研究。 商业应用：该项目的成功将推出一条以 NLRX1 抑制免疫肿瘤疗法。 BTI 的新 NLRX1 靶向口服免疫肿瘤学 治疗方法可能会扰乱结直肠癌领域超过 $8.5B 的市场，以及其他领域的额外 $12.3B 市场 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 $173B。