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Therapeutic antibodies for treating chemotherapy induced peripheral neuropathic pain

用于治疗化疗引起的周围神经性疼痛的治疗性抗体

基本信息

批准号：
10401479
负责人：
Andrea Grace Hohmann
金额：
$ 106.31万
依托单位：
ABALONE BIO, INC.
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-25 至 2024-04-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10401479
关键词：
Adverse reactions Agonist Animal Model Animals Anti Inflammatory Analgesics Antibodies Appearance Astrocytes Behavior Binding Biochemical Biological Assay Blood Blood - brain barrier anatomy Blood Cell Count Breast Cancer Patient CNR1 gene CNR2 gene Cancer Patient Cell Culture Techniques Cells Chemotherapy-induced peripheral neuropathy Clinical Clinical Trials Cognitive Color Cyclic AMP Data Development Dose Drug or chemical Tissue Distribution Engineering Enzymes Fc Receptor Fiber Freezing Funding Glial Fibrillary Acidic Protein Goals Half-Life Health Care Costs Histology Immune In Vitro Inflammation Inflammatory Interleukin-10 Interleukin-6 Kidney Lead Liver Measures Mediating Microglia Modeling Motor Skills Mus Neurologic Neuronal Injury Neurons Neuropathy Opioid Organ Organ Weight Paclitaxel Pain Patients Peripheral Pharmaceutical Preparations Phase Prevention Preventive Quality of life Reducing Agents Risk Rodent Model Safety Serum Serum Markers Shapes Skin Small Business Innovation Research Grant Spinal Cord Study models Symptoms TNF gene Technology Therapeutic Therapeutic antibodies Toxic effect Travel Variant Weight Yeasts abalone activating transcription factor 3 allodynia cell growth chemotherapeutic agent chemotherapy clinical candidate cytokine density design dimer dosage duloxetine falls first-in-human immunogenicity improved in vivo injured macrophage manufacturability meetings motor impairment mouse model nanobodies nerve damage off-label use pain behavior pain reduction painful neuropathy patient subsets pharmacokinetics and pharmacodynamics prevent prophylactic rational design receptor side effect small molecule taxane tumor

项目摘要

ABSTRACT Chemotherapy-induced peripheral neuropathy (CIPN) is an often long-lasting neurological condition that arises frequently in cancer patients who receive broadly used chemotherapies such as taxanes. CIPN causes abnormal pain and other symptoms that can limit chemotherapy dosage and significantly impact quality of life for years. There are no drugs that prevent CIPN or treat it well. Duloxetine is the only clinically proven efficacious pain- reducing agent, though it can cause significant side effects and its efficacy limited to a subset of patients. Opioids are used off-label, but also carry serious side effects. Thus, there is a critical unmet need for drugs that safely and effectively treat or prevent CIPN. Peripheral Cannabinoid 2 receptors (CB2) are a promising target for CIPN treatment. CB2 is constitutively expressed on inflammatory immune cells and induced in peripheral neurons in neuropathic conditions. Its activation has powerful neuroprotective, anti-inflammatory, and analgesic effects. Rodent models of CIPN show that small molecule CB2 agonists alleviate neuropathic pain behavior, and when administered prophylactically suppress CIPN both during dosing and for 100 days after. Several companies have developed small molecule CB2 agonists that, unfortunately, are rapidly cleared, penetrate the blood-brain barrier and/or have off-target effects (notably cognitive ones) mediated by the CB1 receptor. Abalone Bio used its proprietary Functional Antibody Selection Technology (FAST) to isolate a selective CB2-activating nanobody (VHH), which we converted into a VHH-Fc fusion lead antibody, ABt140, for in vivo studies. Phase I SBIR results show that ABt140 rapidly and durably reversed allodynia in mice with CIPN. In this Phase II SBIR project, Abalone Bio will first improve ABt140’s immunogenicity and manufacturability by rational engineering, and then the FAST platform will be used to increase its potency to select durable agonists from millions of computationally- designed variants. We will select 1 lead and at least 2 alternates using in vitro and in vivo assays. Using the paclitaxel CIPN mouse model, we will assess the lead’s ability to prevent CIPN development, reduce in nerve damage and inflammation, show no impairment of motor skills, and not affect chemotherapy’s anti-tumor efficacy. Finally, we will determine the lead antibody’s half-life and tissue distribution in mice, and using blood markers and organs appearance and weight, we will assess its toxicity at high doses. Successful completion of these aims will de-risk the project sufficiently to advance Abalone’s antibody drug to IND-enabling studies and eventually first in human trials for painful CIPN. Abalone’s drug may also have broad utility for other neuropathic pains and inflammatory conditions.

摘要