Novel Immunoregulatory Drugs for Systemic Lupus Erythematosus BioTherapeutics, Inc (BTI) is an emerging 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. Lead molecule, BT-11, is a new small molecule targeting the LANCL2 pathway in IBD with two open INDs, completed Phase I clinical testing and initiated a Phase II study in 2019. Systemic lupus erythematosus (SLE) is an autoimmune disease that afflicts 1.5 million Americans. Through our previous research on abscisic acid (ABA), we discovered the anti-inflammatory and pro-regulatory immunological effects of its receptor, lanthionine synthetase C-like 2 (LANCL2). Using a TLR7/8, resiquimod-induced model of SLE, we determined that the loss of LANCL2 increases susceptibility to severe disease and mortality. We have developed next-generation LANCL2-binding chemotypes, including the gut-restricted BT-11 and systemically distributed BT-96 that exert potent immune effects in vitro and in animal models of disease. This SBIR project will evaluate the therapeutic efficacy, pharmacokinetics (PK) profile and safety of novel LANCL2 agonists for the treatment of SLE. The Specific Aims for this SBIR Phase I application are to: (1) Evaluate the therapeutic efficacy and PK profile of BT-96 in the NZB/W F1 model of SLE. NZB/W F1 mice will be orally dosed with BT-96 at three dose levels therapeutically at 23 weeks of age. Survival, immunological signatures in blood and spleen, anti-nuclear antibodies, proteinuria, and kidney histopathology will be assessed as endpoints. Single and multiple dose pharmacokinetic profiles will be assessed in blood, spleen and kidney in NZB/W F1 mice. (2) Determine the immunomodulatory effects of BT-96 in primary human samples from SLE patients. We will test the efficacy of BT-96 in vitro to prevent inflammatory responses in primary human peripheral blood mononuclear cells (PBMCs) from SLE patients in response to general and nuclear antigen stimuli. Expected successful outcomes will include: i) a significant >35% difference in survival with oral dosing of BT-96 in NZB/W F1 mice, ii) > 50% in urine protein and serum anti-dsDNA at 36 weeks of age, and iii) > 30% reduction in IFNa, TNF and IL-6 in SLE PBMCs with BT-96 treatment. The SBIR Phase II will elucidate the cellular mechanisms of efficacy of BT-96 in SLE, determine synergism and comparative efficacy to current and experimental therapeutics (low-dose IL-2), characterize the role of LANCL2 in the pathogenesis of human SLE, and advance BT-96 through IND-enabling studies. The long-term goal of this project is to develop a novel immunomodulatory therapeutic capable of serving as a safer and more effective treatment for SLE and provide a path towards commercialization of an asset with an unmet need and a target population of over 5 million resulting in a market of over $3 billion by 2025.
Public Health Relevance Statement: Public Health Relevance Systemic lupus erythematosus (SLE) is a difficult to manage autoimmune disease that afflicts 1.5 million Americans and over 5 million worldwide that often results in an unrelenting progression to kidney failure, cardiovascular disease and other physical impairments that significantly reduce quality of life while causing a disproportionally high health care burden. Lanthionine synthetase C-like 2 (LANCL2) ligands have displayed efficacy and safety in other autoimmune indications including inflammatory bowel disease (IBD). This SBIR Phase I project will develop a new class of safer, more efficacious, orally active, systemically distributed LANCL2- based immunomodulatory therapeutics for SLE patients in preparation for advancement along the FDA regulatory pathway toward clinical development.
Project Terms: Abscisic Acid; Abscissic Acid; Abscissins; Adrenal Cortex Hormones; Corticoids; Corticosteroids; Age; ages; Interferon-alpha; (IFN) a; (IFN)-a; (IFN)a; Alferon; IFN Alpha; IFN a; IFN-a; IFNa; IFNa; Interferon Alfa-n3; Interferon-a; Leukocyte Interferon; Lymphoblast Interferon; Lymphoblastoid Interferon; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Antinuclear Antibodies; Antinuclear Factors; anti-DNA autoantibody; anti-Sm; antiDNA autoantibody; Autoimmune Diseases; autoimmune condition; autoimmune disorder; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Response Modifier Therapy; Biologic Therapy; Biological Therapy; biological therapeutic; biological treatment; biotherapeutics; biotherapy; Biotechnology; Biotech; Blood; Blood Reticuloendothelial System; Cardiovascular Diseases; cardiovascular disorder; Disease; Disorder; Animal Disease Models; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Genes; Goals; Half-Life; Human; Modern Man; Immunosuppression; Immunosuppression Effect; Immunosuppressive Effect; immune suppression; In Vitro; Inflammation; Inflammatory Bowel Diseases; Inflammatory Bowel Disorder; Interleukin-2; Co-Stimulator; Costimulator; Epidermal Thymocyte Activating Factor; IL-2; IL2 Protein; Interleukin 2; Interleukin 2 Precursor; Interleukin II; Interleukine 2; Interleukine 2 Precursor; Interleukine II; Lymphocyte Mitogenic Factor; Mitogenic Factor; T cell growth factor; T-Cell Growth Factor; T-Cell Stimulating Factor; Thymocyte Stimulating Factor; Interleukin-6; B cell differentiation factor; B cell stimulating factor 2; B-Cell Differentiation Factor; B-Cell Differentiation Factor-2; B-Cell Stimulatory Factor-2; BCDF; BSF-2; BSF2; HPGF; Hepatocyte-Stimulating Factor; Hybridoma Growth Factor; IFN-beta 2; IFNB2; IL-6; IL6 Protein; MGI-2; Myeloid Differentiation-Inducing Protein; Plasmacytoma Growth Factor; interferon beta 2; Kidney; Kidney Urinary System; renal; Kidney Transplantation; Kidney Grafting; Kidney Transplants; Renal Grafting; Renal Transplantation; Renal Transplants; kidney tx; Lead; Pb element; heavy metal Pb; heavy metal lead; Ligands; Ligase; Ligase Gene; Synthetases; Systemic Lupus Erythematosus; Lupus Erythematosus Disseminatus; SLE; Systemic Lupus Erythematous; Systemic Lupus Erythmatosus; disseminated lupus erythematosus; systemic lupus erythematosis; Lupus Nephritis; Lupus Glomerulonephritis; lymph nodes; Lymph Node Reticuloendothelial System; Lymph node proper; Lymphatic nodes; lymph gland; lymphnodes; macrophage; MÏ; mortality; Mus; Mice; Mice Mammals; Murine; Patients; Phagocytosis; Drug Kinetics; Pharmacokinetics; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Program Development; Proteins; Proteinuria; Quality of life; QOL; Kidney Failure; Kidney Insufficiency; Renal Failure; Renal Insufficiency; Research; Role; social role; Safety; Spleen; Spleen Reticuloendothelial System; Regulatory T-Lymphocyte; Treg; regulatory T-cells; Target Populations; Technology; Toxicology; Urine; Urine Urinary System; lanthionine; Nuclear Antigens; cytokine; Health Care Costs; Health Costs; Healthcare Costs; Healthcare; health care; chronic pain; base; Organ; Clinical; Phase; Predisposition; Susceptibility; Serum; Blood Serum; Stimulus; Agonist; Therapeutic; Double-Stranded DNA; dsDNA; ds-DNA; Knowledge; Immunes; Immune; Oral; Remission; Disease remission; American; Receptor Protein; receptor; synergism; PBMC; Peripheral Blood Mononuclear Cell; Histopathology; Immunomodulation; immune modulation; immune regulation; immunologic reactivity control; immunomodulatory; immunoregulatory; immunoregulation; novel; Memory B Cell; Memory B-Lymphocyte; Pathogenesis; Reporting; (TNF)-a; Cachectin; Macrophage-Derived TNF; Monocyte-Derived TNF; TNF; TNF A; TNF Alpha; TNF-a; TNFA; TNFa; Tumor Necrosis Factor; Tumor Necrosis Factor-alpha; TNF gene; Modeling; Sampling; response; drug development; Bioavailable; Experimental Therapies; Investigational Treatments; experimental therapeutic agents; experimental therapeutics; Investigational Therapies; resiquimod; MGF protein; MGSNF protein; STAT5; STAT5A; STAT5A gene; STAT5a Transcription Factor; Signal Transducer and Activator of Transcription 5A; Stat5a protein; Stat5alpha protein; mammary gland factor; mammary gland-specific nuclear factor; signal tranducer and activator of transcription 5; Stat5 protein; Inflammatory Response; Molecular Interaction; Binding; protein expression; preventing; prevent; small molecule; TLR7; Toll-Like Receptor 7; TLR7 gene; Address; Dose; Data; Regulatory Pathway; research clinical testing; Clinical Evaluation; Clinical Testing; clinical test; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Immunologics; Immunochemical Immunologic; Immunologic; Immunological; Immunologically; Preparation; Development; developmental; Immunomodulators; IMiD; Immune modulatory therapeutic; immune modulating agents; immune modulating drug; immune modulating therapeutics; immune modulators; immune modulatory agents; immune modulatory drugs; immunomodulating agents; immunomodulatory agents; immunomodulatory drugs; immunomodulatory therapeutics; Pathway interactions; pathway; Gene Expression Profile; Expression Signature; gene expression pattern; gene expression signature; transcriptional profile; transcriptional signature; care burden; next generation; anti-dsDNA antibodies; anti-dsDNA antibody; Treatment Efficacy; intervention efficacy; therapeutic efficacy; therapy efficacy; Outcome; Impairment; translational study; commercial application; commercialization; public health relevance; effective therapy; effective treatment; efficacy testing; comparative efficacy; compare efficacy; phase 2 study; phase II study; transcriptome sequencing; RNA Seq; RNA sequencing; RNAseq; precision medicine; precision-based medicine; clinical development; Precision Health; side effect; Computer Models; Computerized Models; computational modeling; computational models; computer based models; computerized modeling; therapeutically effective; Autoimmune
