SBIR-STTR Award

Neuropathic pain can be difficult to treat with only 30-40% of patients achieving meaningful (>40-50%) pain relief. Current therapies (e.g. gabapentin) mainly address symptoms by focusing on blocking neurotransmission in the pain pathway with limited efficacy, potentially severe side effects and narrow therapeutic index. Thus, novel therapies are needed to safely manage symptoms and also target the underlying pathophysiological mech- anisms that will improve the functional status and life quality of affected patients. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of Treg by direct binding to its high affinity receptor that attenuates neuropathic pain. However, several drawbacks exist for current low-dose rIL2 therapy, including a short half life, propensity to in vitro aggregation causing adverse local reaction at injec- tion sites, and potentially narrow therapeutic window. We have designed a proprietary IL2-based therapy that will enable selective stimulation of Tregs with an extended half life, minimal in vitro aggregation, and broad ther- apeutic window. In the proposed Phase I SBIR study, we will evaluate the dose-response of the drug candidate in the rat model of CCI neuropathy. We also will determine the potential side effects and toxicity using the func- tional observational battery assays in healthy rats. Specific Aim. To determine whether rat IL2 analog will abrogate neuropathic pain in the CCI model in rats without behavioral side effects or toxicity. The long-term goal is to develop the drug candidate as a safe and disease-modifying analgesic therapy. Weekly dosing will provide sustained pain relief for neuropathic pain patients without significant side effects, tolerance or addiction.

Public Health Relevance Statement:
Principal Investigator/Program Director (Last, First, Middle: Ridong Chen Narrative We will determine whether induction of regulatory T cells with an optimized IL2 analog will abrogate neuropathic pain without behavioral side effects in the well-established animal model.

Project Terms:
Affect; Analgesics; painkiller; pain reliever; pain medication; pain killer; Antinociceptive Drugs; Antinociceptive Agents; Anodynes; Analgesic Preparation; Analgesic Drugs; Analgesic Agents; Opioid Analgesics; opioid painkiller; opioid pain reliever; opioid pain medication; opioid anesthetic; opioid analgesia; opiate pain reliever; opiate pain medication; opiate analgesic; opiate analgesia; inhibitor/antagonist; inhibitor; Anticonvulsants; Anticonvulsive Drugs; Anticonvulsive Agents; Anticonvulsant Drugs; Anticonvulsant Agent; Antidepressive Agents; anti-depressive agents; anti-depressants; anti-depressant drugs; anti-depressant agent; Antidepressants; Antidepressant Drugs; Antidepressant Agent; Binding Sites; Reactive Site; Combining Site; Biological Assay; Biologic Assays; Bioassay; Assay; Blood Vessels; vascular; Cell Count; Cell Number; Cell physiology; Subcellular Process; Cellular Process; Cellular Physiology; Cellular Function; Cell Process; Cell Function; Cells; Cell Body; Diabetic Neuropathies; diabetes-associated neuropathy; Disease; Disorder; Pharmaceutical Preparations; drug/agent; Pharmaceutic Preparations; Medication; Drugs; eosinophil; eosinocyte; Marrow Eosinophil; Eosinophilic Leukocyte; Eosinophilic Granulocyte; Blood Eosinophil; Acidophilic Leukocyte; Escherichia coli; E. coli; E coli; Goals; Half-Life; Homeostasis; Physiological Homeostasis; Autoregulation; Human; Modern Man; In Vitro; Inflammation; Interleukin-2; Thymocyte Stimulating Factor; T-Cell Stimulating Factor; T-Cell Growth Factor; T cell growth factor; Mitogenic Factor; Lymphocyte Mitogenic Factor; Interleukine II; Interleukine 2 Precursor; Interleukine 2; Interleukin II; Interleukin 2 Precursor; Interleukin 2; IL2 Protein; IL-2; Epidermal Thymocyte Activating Factor; Costimulator; Co-Stimulator; Kidney; renal; Kidney Urinary System; Natural Killer Cells; NK Cells; K lymphocyte; Cytotoxic cell; Lidocaine; Lignocaine; Maintenance; melanoma; Malignant Melanoma; Memory; Mutation; genome mutation; Genetic defect; Genetic Change; Genetic Alteration; Norepinephrine; Noradrenaline; Levonorepinephrine; Levarterenol; Pain; Painful; Patients; Phenotype; Plasma; Reticuloendothelial System, Serum, Plasma; Plasma Serum; Blood Plasma; Quality of life; QOL; Rattus; Rats Mammals; Rat; Common Rat Strains; Recombinant Proteins; Serotonin; Hippophaine; Enteramine; 5HT; 5-Hydroxytryptamine; 5-HT; Serum Albumin; Streptozocin; Zanosar; Streptozotocin; STZ; Syndrome; Regulatory T-Lymphocyte; regulatory T-cells; Treg; Thymus Gland; Thymus Reticuloendothelial System; Thymus Proper; Thymus; Toxicology; Tramadol; United States; Work; gabapentin; Neurontin; cytokine; Generations; neural injury; nerve injury; Fusion Protein; Chimera Protein; Chimeric Proteins; base; improved; Site; Phase; Self Tolerance; Recombinant Human Interleukin-2; Recombinant Human IL-2; Proleukin; Aldesleukin; diabetic; T8 Lymphocytes; T8 Cells; CD8-Positive Lymphocytes; CD8+ T-Lymphocyte; CD8+ T cell; CD8 lymphocyte; CD8 T cells; CD8 Cell; CD8-Positive T-Lymphocytes; analog; Peripheral nerve injury; Therapeutic; Attenuated; programs; Mechanics; mechanical; Immune; Immunes; Severities; Neuropathy; neuropathic; Autoimmune Process; Autoimmune; Reaction; restoration; allodynia; body system; Organ System; molecular size; receptor; Receptor Protein; functional status; reuptake; Animal Model; model organism; model of animal; Animal Models and Related Studies; Toxic effect; Toxicities; pregabalin; 3-isobutyl GABA; Therapeutic Index; neurotransmission; neuronal signaling; neural signaling; nerve signaling; glial signaling; glia signaling; axonal signaling; axon-glial signaling; axon signaling; Neuronal Transmission; Nerve Transmission; Nerve Impulse Transmission; Modeling; response; immunogenic; IL2 gene; TCGF Gene; T-Cell Growth Factor Gene; Interleukin-2 Gene; Interleukin 2 Precursor Gene; IL2; IL-2 Gene; Aldesleukin Gene; Adverse effects; treatment adverse effect; therapy adverse effect; side effect; Treatment Side Effects; Eragrostis; Teff; NK Cell Activation; Natural Killer Cell Activation; Binding; Molecular Interaction; prevent; preventing; IL2RA gene; TCGFR; IL2RA; IL2R; CD25; Renal carcinoma; Renal Cancer; Kidney Carcinoma; Kidney Cancer; Address; Dose; Symptoms; Affinity; Data; Mammalian Cell; Small Business Innovation Research; SBIR; Small Business Innovation Research Grant; Principal Investigator; manage symptom; symptom management; Behavioral; pathway; Pathway interactions; neuropathic pain; painful neuropathy; cost; neurobehavioral; designing; design; chronic constriction injury; innovative; innovate; innovation; novel therapy; novel drugs; novel drug treatments; next generation therapeutics; new therapy; new therapeutics; new drugs; new drug treatments; novel therapeutics; addictive disorder; addiction; type 1 diabetic; type I diabetic; mechanical allodynia; pre-clinical safety; preclinical safety; drug candidate; targeted therapy; targeted therapeutic agents; targeted therapeutic; targeted drug treatments; targeted drug therapy; targeted treatment; SCURFIN; JM2; Forkhead Box P3; FOXP3; FOXP3 gene; common symptom; immune modulatory therapies; immune modulating therapies; immunomodulatory therapies; Injections; pain patient; relieve pain; pain relief

More than 25 million Americans suffer from chronic pain. Due to the lack of other treatments, there has been an overreliance on opioids, contributing to an alarming epidemic of opioid overdose addictions and deaths. Neu- ropathic pain is difficult to treat, with only 30-40% of patients achieving meaningful (>40-50%) pain relief. Current therapies (e.g., duloxeline and gabapentin) mainly address symptoms by focusing on blocking neurotransmis- sion in the pain pathway with limited efficacy, severe side effects, and narrow therapeutic indices. Hence, novel non-opioid therapies are urgently needed to safely manage symptoms and also target the underlying pathophys- iological mechanisms that will improve the functional status and quality of life of affected patients. It has been recently shown that CD4+ Th1 is a major player for neuropathic pain development. Interleukin-2 (IL-2) is the key cytokine for the generation, survival, and function of regulatory T cells by direct binding to its high affinity receptor. Treatment with low-dose rIL-2 increased anti-inflammatory regulatory T cells and M2 type macrophages and inhibited pathogenic interferon- secreting T helper type 1 cells. This rIL-2 treatment was efficacious in human clinical studies for autoimmune diseases without complications or infections. Hence, resto- ration or enhancement of regulatory T cells with low-dose IL2 may offer a novel strategy for prevention and treatment of neuropathic pain. However, several drawbacks exist for current low-dose rIL2 therapy, including a short half-life, propensity for in vitro aggregation causing adverse local reaction at injection sites, and a potential narrow therapeutic window. We have designed proprietary IL2-based variants that will enable selective stimu- lation of Tregs with an extended half-life and a broad therapeutic window. In the Phase I study, we successfully identified the variant, designated APT603, which selectively stimulates regulatory T cells and provides robust analgesic efficacy in the chronic constriction injury model of mononeuropathy in rats with an excellent safety profile. With an experienced drug development team, we propose to determine dose responses in two well es- tablished models of neuropathic pain with distinct pathophysiology and to conduct critical activities necessary to enable IND filing for APT603.  Specific Aim 1: Determine the therapeutic index of APT603 for abrogating neuropathic pain in STE- induced (T1D) diabetic rats and in a rat model of sciatic nerve chronic constriction injury (CCI).  Specific Aim 2: Manufacture cGMP (Current Good Manufacturing Practice) grade APT603.  Specific Aim 3: Evaluate the nonclinical safety of APT603. The long-term goal is to develop the drug candidate as a safe and disease-modifying analgesic therapy. Weekly or bi-weekly dosing will provide sustained neuropathic pain relief for patients without inducing significant side effects, tolerance, or addiction.

Public Health Relevance Statement:
Principal Investigator/Program Director (Last, First, Middle: Ridong Chen Narrative We will determine whether induction of regulatory T cells with an optimized IL2 analog robustly abrogates neuropathic pain with excellent safety in two well-established animal models. With a strong interdisciplinary drug development team, we propose to initiate critical activities necessary to enable IND filing for this novel drug candidate.

Project Terms:
Affect; Analgesics; Analgesic Agents; Analgesic Drugs; Analgesic Preparation; Anodynes; Antinociceptive Agents; Antinociceptive Drugs; pain killer; pain medication; pain reliever; painkiller; inhibitor/antagonist; inhibitor; Anti-Inflammatory Agents; Anti-Inflammatories; Anti-inflammatory; Antiinflammatories; Antiinflammatory Agents; antiinflammatory; Anticonvulsants; Anticonvulsant Agent; Anticonvulsant Drugs; Anticonvulsive Agents; Anticonvulsive Drugs; Antidepressive Agents; Antidepressant Agent; Antidepressant Drugs; Antidepressants; anti-depressant agent; anti-depressant drugs; anti-depressants; anti-depressive agents; Autoimmune Diseases; autoimmune condition; autoimmune disorder; Binding Sites; Combining Site; Reactive Site; Blood Glucose; Blood Sugar; Blood Vessels; vascular; Malignant Neoplasms; Cancers; Malignant Tumor; malignancy; neoplasm/cancer; Cell Count; Cell Number; Cell physiology; Cell Function; Cell Process; Cellular Function; Cellular Physiology; Cellular Process; Subcellular Process; Cells; Cell Body; Clinical Research; Clinical Study; Cessation of life; Death; Insulin-Dependent Diabetes Mellitus; Brittle Diabetes Mellitus; IDDM; Juvenile-Onset Diabetes Mellitus; Ketosis-Prone Diabetes Mellitus; Sudden-Onset Diabetes Mellitus; T1 DM; T1 diabetes; T1D; T1DM; Type 1 Diabetes Mellitus; Type 1 diabetes; Type I Diabetes Mellitus; insulin dependent diabetes; juvenile diabetes; juvenile diabetes mellitus; ketosis prone diabetes; type I diabetes; type one diabetes; Diabetic Neuropathies; diabetes-associated neuropathy; Disease; Disorder; Pharmaceutical Preparations; Drugs; Medication; Pharmaceutic Preparations; drug/agent; eosinophil; Blood Eosinophil; Eosinophilic Granulocyte; Eosinophilic Leukocyte; Marrow Eosinophil; Escherichia coli; E coli; E. coli; Goals; Cyclic GMP; Guanosine Cyclic Monophosphate; cGMP; Half-Life; Homeostasis; Autoregulation; Physiological Homeostasis; Human; Modern Man; In Vitro; Infection; Interferons; IFN; 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; Kidney; Kidney Urinary System; renal; Natural Killer Cells; Cytotoxic cell; K lymphocyte; NK Cells; Lidocaine; Lignocaine; macrophage; Mφ; Maintenance; melanoma; Malignant Melanoma; Memory; Mutation; Genetic Alteration; Genetic Change; Genetic defect; genome mutation; Nervous system structure; Nervous System; Neurologic Body System; Neurologic Organ System; Neurons; Nerve Cells; Nerve Unit; Neural Cell; Neurocyte; neuronal; Norepinephrine; Levarterenol; Levonorepinephrine; Noradrenaline; Pain; Painful; Patients; Pharmacology; Phenotype; Plasma; Blood Plasma; Plasma Serum; Reticuloendothelial System, Serum, Plasma; Postherpetic neuralgia; post herpetic neuralgia; Quality of life; QOL; Rattus; Common Rat Strains; Rat; Rats Mammals; Recombinant Proteins; Safety; sciatic nerve; Serotonin; 5-HT; 5-Hydroxytryptamine; 5HT; Enteramine; Hippophaine; Serum Albumin; Streptozocin; STZ; Streptozotocin; Zanosar; Syndrome; Regulatory T-Lymphocyte; Treg; regulatory T-cells; Thymus Gland; Thymus; Thymus Proper; Thymus Reticuloendothelial System; Trigeminal Neuralgia; Epileptiform Neuralgia; Fothergill Disease; Fothergill's neuralgia; Tic Douloureux; Trifacial Neuralgia; trifocal neuralgia; United States; Work; gabapentin; Neurontin; cytokine; Generations; GTP-Binding Proteins; G-Proteins; GTP-Regulatory Proteins; Guanine Nucleotide Coupling Protein; Guanine Nucleotide Regulatory Proteins; Mediating; chronic pain; Polyneuropathy; Chimeric Proteins; Chimera Protein; Fusion Protein; base; improved; Site; Phase; Variant; Variation; Self Tolerance; Sensory Ganglia; Aldesleukin; Proleukin; Recombinant Human IL-2; Recombinant Human Interleukin-2; Lesion; diabetic; Opioid; Opiates; CD8-Positive T-Lymphocytes; CD8 Cell; CD8 T cells; CD8 lymphocyte; CD8+ T cell; CD8+ T-Lymphocyte; CD8-Positive Lymphocytes; T8 Cells; T8 Lymphocytes; Th1 Cells; Th-1 Cell; Type 1 Helper Cell; non-opioid analgesic; non-narcotic analgesic; non-opiate analgesic; non-opioid; non-opioid therapeutics; nonnarcotic analgesics; nonopiate analgesic; nonopioid; nonopioid analgesics; analog; duloxetine; Peripheral nerve injury; peripheral nerve crush injuries; Functional disorder; Dysfunction; Physiopathology; pathophysiology; Therapeutic; Attenuated; programs; mechanical; Mechanics; Immunes; Immune; Severities; Reaction; restoration; allodynia; Mononeuropathies; American; experience; molecular size; Receptor Protein; receptor; functional status; reuptake; Animal Models and Related Studies; model of animal; model organism; Animal Model; Toxicities; Toxic effect; 3-isobutyl GABA; pregabalin; Therapeutic Index; Nerve Impulse Transmission; Nerve Transmission; Neuronal Transmission; axon signaling; axon-glial signaling; axonal signaling; glia signaling; glial signaling; nerve signaling; neural signaling; neuronal signaling; neurotransmission; novel; Preventative strategy; Preventive strategy; Prevention strategy; Benefits and Risks; Reporting; Modeling; response; drug development; Aldesleukin Gene; IL-2 Gene; IL2; Interleukin 2 Precursor Gene; Interleukin-2 Gene; T-Cell Growth Factor Gene; TCGF Gene; IL2 gene; Pathogenicity; Natural Killer Cell Activation; NK Cell Activation; Molecular Interaction; Binding; preventing; prevent; CD25; IL2R; IL2RA; TCGFR; IL2RA gene; Kidney Cancer; Kidney Carcinoma; Renal Cancer; Renal carcinoma; Address; Dose; Symptoms; Affinity; Data; Mammalian Cell; Principal Investigator; Development; developmental; symptom management; manage symptom; Pathway interactions; pathway; painful neuropathy; neuropathic pain; post stroke pain; poststroke pain; neuroinflammation; neuroinflammatory; design; designing; novel strategies; new approaches; novel approaches; novel strategy; chronic constriction injury; manufacturing process; diabetic rat; Rat model of diabetes; diabetic rat model; innovation; innovate; innovative; somatosensory; novel therapeutics; new drug treatments; new drugs; new therapeutics; new therapy; next generation therapeutics; novel drug treatments; novel drugs; novel therapy; addiction; addictive disorder; type I diabetic; type 1 diabetic; mechanical allodynia; drug candidate; phase 1 study; Phase I Study; FOXP3 gene; FOXP3; Forkhead Box P3; JM2; SCURFIN; symptom treatment; symptomatic treatment; treat symptom; opioid epidemic; opiate crisis; opioid crisis; opioid overdose; opiate overdose; opiate related overdose; opioid drug overdose; opioid induced overdose; opioid intoxication; opioid medication overdose; opioid poisoning; opioid related overdose; opioid toxicity; immunomodulatory therapies; Immune Modulation Therapy; immune modulating therapies; immune modulatory therapies; immune-modulation treatment; immunomodulation therapy; immunomodulation treatment; immunomodulatory therapy; immunomodulatory treatment; Injections; pain relief; relieve pain; side effect; effector T cell; Teff cell; Autoimmune