Lupus nephritis (LN) remains the strongest predictor of morbidity and mortality for people with Systemic Lupus Erythematosus (SLE), an autoimmune disease disproportionately affecting women and minorities. The current standard of care for LN, glucocorticoids and immunosuppressive agents, has many side effects and long-term toxicity. Therefore, there is an urgent and unmet need for targeted therapies. SLE is characterized by an aberrant activation of toll-like receptor (TLR) signaling in immune cells that drives inflammatory leukocyte activation and influx into major organs, with approx. 40% of lupus patients showing glomerular injury and renal disease, LN. The integrin CD11b, expressed primarily on myeloid cells, is an immune receptor that modulates functions of these cells. Among its many roles, it mediates leukocyte influx in tissues and has recently been shown to also control overactive TLR signaling in these cells. Recent GWAS studies showed high correlation between patients with SNPs in ITGAM, which codes for CD11b, and incidence of SLE and LN. Studies also showed that the three most common coding ITGAM SNPs primarily reduce CD11b's role as a rheostat of TLR- signaling, without affecting its surface expression, suggesting reduced CD11b function as a contributor to SLE and LN. It also suggested that CD11b activation could serve as a potential therapeutic strategy for LN. Towards that, our co-founder (Vineet Gupta) discovered that allosteric activation of integrin CD11b is a novel therapeutic strategy and is an effective method to target this integrin for reducing leukocyte activation and tissue influx. He and his team developed a first-generation CD11b small molecule allosteric agonist, called LA1, that selectively engages CD11b in vivo, is orally bioavailable, non-toxic, reduces autoimmune disease and significantly reduces influx of inflammatory myeloid cells into tissues. Drs Gupta, Barbosa and the team also developed an LA1 analog, called GB1275, that has been translated as an oral therapeutic that is currently under Phase 1/2 clinical trials in cancer patients. The primary goal of this proposal is to find and develop a new series of allosteric agonists of CD11b with tractable SAR, drug-like properties and with enhanced potency over the first-generation compounds that can be administered chronically for treating autoimmune diseases, like LN. We have developed an assay platform and a focused integrin targeting library of ~800 compounds that can be used to rapidly identify and develop novel, highly potent CD11b agonist candidates with high confidence. Here, we propose two specific aims to design, screen and identify novel CD11b agonists with improved potency over LA1 and to characterize them in vitro and in vivo for their readiness for drug development. Our long-term goal is to develop the new compounds into a next generation of therapeutics to treat lupus nephritis in humans.
Public Health Relevance Statement: The studies proposed will use medicinal chemistry approaches to design, test and develop novel small molecule compounds as future therapeutics for lupus nephritis. The company is pioneering a novel therapeutic approach and has developed a suite of assays and unique library of compounds that show drug-like properties with high potential for clinical development.
Project Terms: Receptor Activation; Receptor Signaling; in vivo; Cancer Patient; Small Business Innovation Research Grant; SBIR; Small Business Innovation Research; Characteristics; follow-up; Active Follow-up; active followup; follow up; followed up; followup; Development; developmental; GWA study; GWAS; genome wide association; genome wide association scan; genome wide association studies; genomewide association scan; genomewide association studies; genomewide association study; whole genome association analysis; whole genome association studies; whole genome association study; genome wide association study; designing; design; next generation; Minority; Lupus; lupus like nephritis; migration; protective effect; Impairment; new drug treatments; new drugs; new pharmacological therapeutic; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel pharmaco-therapeutic; novel pharmacological therapeutic; novel therapy; novel therapeutics; tumor; new therapeutic approach; new therapeutic intervention; new therapeutic strategies; new therapy approaches; new treatment approach; new treatment strategy; novel therapeutic approach; novel therapeutic strategies; novel therapy approach; novel therapeutic intervention; standard of care; Immune Cell Activation; immune activation; targeted drug therapy; targeted drug treatments; targeted therapeutic; targeted therapeutic agents; targeted therapy; targeted treatment; Formulation; co-morbid symptom; co-occuring symptom; comorbid symptom; concurrent symptom; cooccuring symptom; symptom association; symptom comorbidity; associated symptom; clinical candidate; experiment; experimental research; experiments; experimental study; clinical development; immunosuppressive myeloid cells; myeloid suppressor cells; myeloid-derived suppressive cells; suppressive myeloid cells; Myeloid-derived suppressor cells; side effect; damage to kidney; kidney damage; renal damage; in silico; virtual screenings; virtual screening; Phase 1/2 Clinical Trial; Phase I/II Clinical Trial; pharmacologic; Circulation; immune modulating agents; IMiD; Immune modulatory therapeutic; immune modulating drug; immune modulating therapeutics; immune modulatory agents; immune modulatory drugs; immunomodulating agents; immunomodulating drugs; immunomodulator agent; immunomodulator drug; immunomodulator medication; immunomodulator prodrug; immunomodulator therapeutic; immunomodulatory agents; immunomodulatory drugs; immunomodulatory therapeutics; Affect; Autoimmune Diseases; autoimmune condition; autoimmune disorder; autoimmunity disease; Autoimmunity; Autoimmune Status; B-Lymphocytes; B blood cells; B cell; B cells; B-Cells; B-cell; Biological Assay; Assay; Bioassay; Biologic Assays; Biological Availability; Bioavailability; Physiologic Availability; Cell physiology; Cell Function; Cell Process; Cellular Function; Cellular Physiology; Cellular Process; Subcellular Process; Cells; Cell Body; Pharmaceutical Chemistry; Medicinal Chemistry; Pharmaceutic Chemistry; Clinical Trials; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; Future; Glucocorticoids; Goals; Government; Half-Life; Human; Modern Man; Immunosuppressive Agents; Immunosuppressants; Immunosuppressive drug; Immunosuppressive treatment; immune suppressive agent; immune suppressor; immunosuppressive substance; immunosuppressor; In Vitro; Incidence; Integrins; Integrins Extracellular Matrix; Interferon Type I; Interferons; IFN; Kidney; Kidney Urinary System; renal; Kidney Diseases; Nephropathy; Renal Disease; kidney disorder; renal disorder; Laboratories; Lead; Pb element; heavy metal Pb; heavy metal lead; Leukocytes; Blood leukocyte; Leukocytes Reticuloendothelial System; Marrow leukocyte; White Blood Cells; White Cell; white blood cell; white blood corpuscle; Libraries; Systemic Lupus Erythematosus; Lupus Erythematosus Disseminatus; SLE; Systemic Lupus Erythematous; Systemic Lupus Erythmatosus; disseminated lupus erythematosus; systemic lupus erythematosis; Lupus Nephritis; Lupus Glomerulonephritis; Methods; Morbidity - disease rate; Morbidity; mortality; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Persons; Patients; Drug Kinetics; Pharmacokinetics; Plasminogen; EC 3.4.21.7; Profibrinolysin; Production; Proteins; Immunologic Receptors; Immunological Receptors; immune receptor; Risk; Role; social role; Solubility; Structure-Activity Relationship; chemical structure function; structure function relationship; Testing; Tissues; Body Tissues; Translating; Urokinase; U-PA; U-Plasminogen Activator; Urinary Plasminogen Activator; Urokinase Plasminogen Activator; Urokinase-Type Plasminogen Activator; Woman; Generations; Macrophage-1 Antigen; CR3; CR3 Receptor; Complement 3 Receptor; Integrin alpha-M beta-2; Integrin alphaMbeta2; Mac 1; Mac-1 Adhesive Receptor; Mac-1 Antigen; Mac-1 Receptor; Mo1 Antigen Receptor; Mo1 Glycoprotein Receptor; aMß2; Mediating; kidney injury; renal injury; Injury to Kidney; injuries; Injury; Organ; improved; Surface; Chronic; Clinical; Phase; Series; Chemicals; Evaluation; analog; Agonist; Oncology Cancer; Oncology; Therapeutic; Inflammatory; Immune; Immunes; Oral; drug efficacy; Toxic effect; Toxicities; Toll-like receptors; TLR protein; Toll-Like Receptor Family Gene; novel; Single Nucleotide Polymorphism; Single Base Polymorphism; single nucleotide variant; Code; Coding System; Property; drug development; Myeloid Cells; leukocyte activation; Pathogenicity; Integrin alpha Subunits; Integrin a Subunits; alpha Integrins; a-Integrins; Integrin alpha Chains; Preparedness; Readiness; small molecule; ITGB2 gene; CD18; ITGB2; LCAMB; MF17; ITGAM gene; CD11b; CR3A; ITGAM; MAC1A; MO1A; Dose; Dose Limiting; Myeloid Cell Activation
