Developing Novel NLRX1-Based Immuno-Oncology Therapeutics

开发基于NLRX1的新型免疫肿瘤治疗药物 生物治疗公司(BTI)是一家临床阶段的生物技术公司，它协同结合了 先进的计算建模和平移实验加速了小说的发展 精准医疗和健康产品。这种SBIR的应用来自于关于核苷酸的有前景的数据- 结合低聚结构域，富含亮氨酸重复序列的X1(NLRX1)作为新的肿瘤治疗靶点。 我们的产品：BTI已经确定了第一个小分子化合物家族，可以结合和抑制这种新的 调控分子NLRX1。该项目的目标是验证NLRX1作为免疫肿瘤学靶点和 开发基于NLRX1的新型口服一流免疫肿瘤疗法。 背景：癌症发病率持续增长，癌症是#年的第二大死因。 美国。尤其是免疫原性癌症，那些最有潜力接受免疫- 以疗法为基础，每年导致500,000多个新病例和230,000多人死亡。因此，有一个未得到满足的 临床上需要更安全、更有效的癌症治疗方法。而NLRX1的激活已经显示出在 自身免疫性疾病，抑制NLRX1可增加效应反应，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。我们最大的NLRX1抑制剂NX-43 在两种结直肠癌(CRC)模型中有很强的治疗效果。此第一阶段应用程序的特点是 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。我们的目标是： 目的1.通过测定细胞活力来评价NX-43对CT-26细胞的直接和间接细胞毒作用 并在体外有无淋巴结淋巴细胞的情况下进行细胞凋亡。 目的：观察NX-43对结直肠癌CT-26和AOM/DSS模型的体内治疗作用。 促进生存，诱导瘤内免疫激活。 目的3.在靶外结合试验中评价NX-43的ADME-Tox和药代动力学。 分析、大鼠7天剂量范围毒性试验和ADME-TOX试验。 预期结果：确认NX-43为靶向和抑制NLRX1的先导拮抗分子 通过：i)在≤100um时癌细胞活力降低50%；ii)口服NX显著提高存活率- 43对小鼠结直肠癌模型的治疗；以及iii)对大鼠口服NOAEL≥500 mg/kg的良性安全性。 SBIR第二阶段将评估与NX-43联合治疗的疗效，评估 其他癌症模型和推进NX-43到IND-Enabling GLP大鼠毒理学研究。 商业应用：该项目的成功将启动以以下为中心的新药开发流水线 NLRX1-抑制免疫肿瘤疗法。BTI的新NLRX1靶向口腔免疫肿瘤学 治疗公司可能扰乱超过85亿美元的结直肠癌市场，并在全球范围内再增加123亿美元 黑色素瘤、肾细胞癌和非小细胞肺癌，这一市场预计到2026年将达到1730亿美元。

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.