Targeting leukocyte metabolism to treat human autoimmune disease

ImmuNext已经定义了一种抗MCT1的单抗(MAb)，该抗体将被开发用于治疗 人类自身免疫性疾病。膜单羧酸营养转运蛋白SLC16A1(MCT1)是一种 多通道跨膜蛋白负责促进关键代谢物的运输，包括 糖酵解产物：乳酸、丙酮酸和酮。我们强有力的初步数据支持单抗的宗旨 阻断活化淋巴细胞中单羧酸盐(包括乳酸)的MCT1转运将减弱 关键的炎症效应功能，从而抑制免疫功能，安全地治疗人类自身免疫 疾病。我们展示了单抗方法相对于有毒小分子方法的独特优势。 缺乏转运蛋白的特异性。MCT1抑制细胞增殖和细胞因子产生的机制 来自淋巴系而不是髓系细胞是一种独特的方法，数据表明它的调节最适合 对于SLE的治疗，缺乏针对T和B细胞的无毒药物。 拥有强大的专利地位、最先进的方法和熟练、经验丰富的药物开发 Team，一种一流的治疗性单抗，选择性地消融淋巴代谢用于治疗 将会发展出自身免疫性疾病。在第一阶段，我们将人源化大鼠抗MCT1抗体并选择 MAb领先于第二阶段。我们目前有一种人CD3/CD28激活的T细胞分析用于我们的初级 筛选和二次MCT1毒素转运试验用于铅抗体的选择。我们对主角的选择 治疗性抗体将通过以下方式确定：1)使用体外淋巴细胞分析的IC50测定；2) 通过量化异种移植物抗宿主病模型(人外周血单核细胞→和正常小鼠)的体内效力。在选择了 有了铅抗体和备份，我们将进入第二阶段，进行铅优化和临床前开发。 将对铅的免疫原性和制造性能进行评估。PK将被确定，我们将 扩展我们现有的酮PD生物标记物，以使用各种方法为未来的临床计划提供信息。 包括代谢组学、细胞因子分析和RNA序列分析。通过研究使用人类的行动机制 将SLE患者样本与健康对照组进行比较，并使用既定的运输和免疫学分析方法， 我们将在计划的临床试验中为患者分层确定更多的生物标记物。 有了合格的线索，我们将开始细胞系的开发和非GLP PK/PD/毒理学 食蟹类非人类灵长类动物的研究。我们已经召集了一个专家小组，帮助收集， 分析和处理这些研究产生的数据，以帮助勾勒出支持IND的GLP TOX 未来的研究和临床策略。 我们首屈一指的抗MCT1单抗将最终为患者提供独特的免疫代谢靶向 这种药物不仅可以治疗他们的症状，还可以消除正在发生的疾病，并与现有的 提供长期缓解和治愈的疗法。

ImmuNext has defined an anti-MCT1 monoclonal antibody (mAb) that will be developed for the treatment of human autoimmune disease. The membrane monocarboxylate nutrient transporter SLC16A1 (MCT1) is a multi-pass transmembrane protein responsible for the facilitated transport of critical metabolites, including products of glycolysis: lactate, pyruvate and ketones. Our strong preliminary data support the tenet that mAbs that block MCT1 transport of monocarboxylates (including lactate) from activated lymphocytes will attenuate key inflammatory effector functions, thereby suppressing immune function and safely treat human autoimmune diseases. We show the unique advantage of mab approaches over that of small molecules that are toxic and lack transporter specificity. The mechanism of MCT1 inhibition to reduce proliferation and cytokine production from lymphoid, but not myeloid cells is a unique approach and data suggest that its modulation is best suited for SLE treatment, where nontoxic drugs that target both T and B cells are lacking. With a strong patent position, state-of-the-art approaches and a skilled, experienced drug development team, a first-in-class, therapeutic mab that selectively ablates lymphoid metabolism for the treatment of autoimmune disease will be developed. In Phase 1, we will humanize the rat anti-MCT1 antibody and select mab leads for Phase 2. We currently have both a human CD3/CD28-activated T cell assay for our primary screen and a secondary MCT1 toxin transport assay for lead antibody selection. Our choice of the lead therapeutic antibody will be determined from: 1) IC50 determinations using in vitro lymphocyte assays and 2) by quantifying the in vivo potency in a xeno-GVHD model (human PBMC → NSG mice). After selection of the lead antibody and a backup, we will advance into Phase 2 with lead optimization and pre-clinical development. The lead will be assessed for immunogenicity and manufacturing properties. PK will be determined and we will expand upon our existing ketone PD biomarkers to inform future clinical plans using a variety of approaches, including metabolomics, cytokine analysis and RNA-seq. By examining the mechanism-of-action using human SLE patient samples compared to healthy controls and using established transport and immunological assays, we will identify additional biomarkers for patient stratification in the planned clinical trials. With a qualified lead in hand, we will commence cell line development and non-GLP PK/PD/toxicological studies in cynomolgus non-human primates. We have convened a panel of experts that will help collect, analyze and process the data generated from these studies to assist in outlining an IND-enabling GLP tox study and a clinical strategy going forward. Our first-in-class anti-MCT1 mAb will ultimately provide patients with a unique immunometabolic targeting drug that will not only treat their symptoms, but also abrogate ongoing disease and synergize with existing therapies to provide long term remission and cure.