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 定义了一种抗 MCT1 单克隆抗体 (mAb)，该抗体将被开发用于治疗 人类自身免疫性疾病。膜单羧酸盐营养转运蛋白 SLC16A1 (MCT1) 是一种 多次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这样的原则：单克隆抗体 阻断 MCT1 从激活的淋巴细胞中转运单羧酸盐（包括乳酸）的药物将会减弱 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 方法相对于有毒且小分子方法的独特优势。 缺乏转运蛋白特异性。 The mechanism of MCT1 inhibition to reduce proliferation and cytokine production 来自淋巴细胞而不是骨髓细胞是一种独特的方法，数据表明它的调节最适合 用于 SLE 治疗，缺乏针对 T 和 B 细胞的无毒药物。 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 将会发展为自身免疫性疾病。在第一阶段，我们将大鼠抗MCT1抗体人源化并选择 mab 处于第 2 阶段的领先地位。我们目前对我们的主要研究进行了人类 CD3/CD28 激活 T 细胞测定 screen and a secondary MCT1 toxin transport assay for lead antibody selection.我们对领导者的选择 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).选定后 先导抗体和备用抗体，我们将通过先导抗体优化和临床前开发进入第二阶段。 将评估先导物的免疫原性和制造特性。 PK将确定，我们将 expand upon our existing ketone PD biomarkers to inform future clinical plans using a variety of approaches, including metabolomics, cytokine analysis and RNA-seq.通过使用人体检查作用机制 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 对食蟹猴非人类灵长类动物的研究。我们召集了一个专家小组来帮助收集、 分析和处理这些研究生成的数据，以协助概述支持 IND 的 GLP 毒理学 研究和未来的临床策略。 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.