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.
Public Health Relevance Statement: MCT1 is an important metabolite transporter expressed on the white blood cells, these cells being one of the main components in autoimmune disease development. ImmuNext has developed a novel antibody that binds and blocks the function of MCT1, leading to the suppression of the overactive immune system and potential disease regression. Through a series of engineering, screening and optimization steps, we plan to develop this antibody into a novel drug that can provide lupus patients with a therapy that will reset their diseased immune system, restoring them to a healthy, balanced state.
Project Terms: Activated Lymphocyte; Affinity; Antibodies; Attenuated; Autoimmune Diseases; B-Lymphocytes; base; Binding; Biological Assay; Biological Markers; biomarker discovery; Blocking Antibodies; Burn injury; CD28 gene; CD3 Antigens; Cell Culture Techniques; Cell Line; Cells; Cellular Assay; Charge; Clinic; Clinical; Clinical Trials; cross reactivity; cytokine; Data; design; Development; Disease; Disease model; Disease Progression; Disease regression; Disease remission; Dose; drug development; Drug Targeting; Engineering; Ensure; experience; Foundations; Future; Glycolysis; Graft-vs-Host Disease; Hand; healthy volunteer; Human; human disease; human tissue; Immune; immune function; Immune response; Immune system; Immune System Diseases; Immunization; immunogenicity; Immunology procedure; immunoregulation; In Vitro; in vivo; Individual; Inflammatory; inhibitor/antagonist; 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; metabolomics; Modeling; Monoclonal Antibodies; mRNA Expression; Mus; Natural Immunity; nonhuman primate; novel; novel therapeutics; Nutrient; Pathway interactions; patient biomarkers; patient stratification; Patients; Peripheral Blood Mononuclear Cell; Pharmaceutical Preparations; pharmacodynamic biomarker; Phase; Phenotype; Positioning Attribute; pre-clinical; preclinical development; prevent; Process; Production; programs; Property; protein expression; Pyruvate; Rattus; Regulatory T-Lymphocyte; Research Design; Research Personnel; Rivers; Sampling; screening; Series; small molecule; Solubility; Specificity; stability testing; Stress Tests; subcutaneous; success; Symptoms; synergism; Systemic Lupus Erythematosus; T-Lymphocyte; Testing; Therapeutic; Therapeutic antibodies; Therapeutic Monoclonal Antibodies; therapy outcome; Tissues; Toxic effect; Toxicology; Toxin; transcriptome; transcriptome sequencing; Urine; Variant; Work
