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，以加速新颖的开发该 SBIR 应用源于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该项目的目标是验证 NLRX1 作为免疫肿瘤学靶点的调节分子。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。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。基于治疗的药物每年会导致超过 500,000 例新病例和超过 230,000 例死亡，因此，存在未得到满足的情况。临床需要更安全、更有效的癌症治疗方法，而 NLRX1 的激活已显示出疗效。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，我们的顶级 NLRX1 抑制剂 NX-43 发挥作用。该 I 期应用将在两种结直肠癌 (CRC) 模型中表现出强大的治疗效果。 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 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- 显着提高生存率； 43 CRC 小鼠模型的治疗；以及 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 BTI 的新型 NLRX1 靶向口服免疫肿瘤疗法。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。