Targeting leukocyte metabolism to treat human autoimmune disease

靶向白细胞代谢治疗人类自身免疫性疾病

• 批准号: 9763441
• 负责人: JAY L ROTHSTEIN
• 金额: $ 99.61万
• 依托单位: IMMUNEXT, INC.
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-03-01 至 2021-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9763441
• 关键词: Activated Lymphocyte; Affinity; Antibodies; Attenuated; Autoimmune Diseases; B-Lymphocytes; Biological Assay; Biological Markers; Blocking Antibodies; Burn injury; CD28 gene; CD3 Antigens; Cell Culture Techniques; Cell Line; Cells; Cellular Assay; Charge; Clinic; Clinical; Clinical Trials; Data; Development; Disease; Disease Progression; Disease model; Disease remission; Dose; Drug Targeting; Ensure; Foundations; Future; Glycolysis; Hand; Human; Immune; Immune response; Immunization; Immunology procedure; In Vitro; Individual; Inflammatory; Integral Membrane Protein; Interferons; Interleukin-2; Ketones; Laboratories; Lead; Legal patent; Leukocytes; Lupus; Lymphocyte; Lymphocyte Activation; Lymphoid; Macaca fascicularis; Maintenance; Measures; Mediating; Membrane; Metabolic; Metabolism; Modeling; Monoclonal Antibodies; Mus; Natural Immunity; Nutrient; Pathway interactions; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; Phase; Phenotype; Positioning Attribute; Process; Production; Property; Pyruvate; Rattus; Regulatory T-Lymphocyte; Research Design; Research Personnel; Rivers; Sampling; Solubility; Specificity; Stress Tests; Symptoms; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Therapeutic Monoclonal Antibodies; Therapeutic antibodies; Tissues; Toxic effect; Toxicology; Toxin; Urine; Variant; Work; base; biomarker discovery; cross reactivity; cytokine; design; drug development; effector T cell; experience; healthy volunteer; human disease; human tissue; immune function; immunogenicity; immunoregulation; in vivo; inhibitor/antagonist; lead optimization; mRNA Expression; metabolomics; nonhuman primate; novel; novel therapeutics; off-patent; patient biomarkers; patient stratification; pharmacodynamic biomarker; pharmacokinetics and pharmacodynamics; pre-clinical; preclinical development; prevent; programs; protein expression; small molecule; stability testing; subcutaneous; success; synergism; therapy outcome; transcriptome; transcriptome sequencing

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.

ImmuNext已经确定了一种抗MCT 1单克隆抗体（mAb），将开发用于治疗 人类自身免疫性疾病膜单羧酸营养转运蛋白SLC 16 A1（MCT 1）是一种具有生物学活性的蛋白质。 一种多通道跨膜蛋白，负责促进关键代谢物的转运，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这样的原则， 阻断MCT 1从活化的淋巴细胞转运单羧酸盐（包括乳酸盐）的药物将减弱 关键的炎症效应子功能，从而抑制免疫功能并安全地治疗人类自身免疫性疾病 疾病我们展示了mAb方法相对于毒性小分子方法的独特优势， 缺乏转运蛋白特异性。MCT 1抑制减少增殖和细胞因子产生的机制 从淋巴细胞，而不是骨髓细胞是一种独特的方法，数据表明，它的调制是最适合的 用于SLE治疗，其中缺乏靶向T和B细胞的无毒药物。 凭借强大的专利地位，最先进的方法和熟练，经验丰富的药物开发 团队，一流的，治疗性单克隆抗体，选择性消融淋巴代谢的治疗， 会发展成自身免疫性疾病。在第1阶段，我们将人源化大鼠抗MCT 1抗体， mAb在II期研究中处于领先地位。我们目前有一个人CD 3/CD 28激活的T细胞检测，用于我们的主要研究。 筛选和用于先导抗体选择的二次MCT 1毒素转运测定。我们对主角的选择 治疗性抗体将通过以下方式确定：1）使用体外淋巴细胞测定法测定IC 50，和2） 通过定量异种-GVHD模型（人PBMC → NSG小鼠）中的体内效力。的选择之后 先导抗体和备用抗体，我们将进入第二阶段，进行先导优化和临床前开发。 将评估电极导线的免疫原性和制造特性。PK将确定，我们将 扩展我们现有的酮PD生物标志物，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-seq。通过使用人体试验研究其作用机制， SLE患者样品与健康对照相比，并使用已建立的转运和免疫学测定， 我们将在计划的临床试验中确定用于患者分层的其他生物标志物。 有了合格的领导者，我们将开始细胞系开发和非GLP PK/PD/毒理学 在食蟹猴非人灵长类动物中的研究。我们召集了一个专家小组， 分析和处理这些研究生成的数据，以帮助概述IND使能GLP毒性 研究和临床策略。 我们的一流抗MCT 1 mAb最终将为患者提供独特的免疫代谢靶向 药物，不仅将治疗他们的症状，但也消除正在进行的疾病，并协同与现有的 提供长期缓解和治愈的治疗。