Advancing Development of Novel Immunotherapy for Chemotherapy-induced Peripheral Neuropathy (CIPN)

推进化疗引起的周围神经病变 (CIPN) 的新型免疫疗法的发展

• 批准号: 10588384
• 负责人: KARIN N. WESTLUND-HIGH
• 金额: --
• 依托单位: ALBUQUERQUE VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-04-01 至 2027-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10588384
• 关键词: Acute; Advanced Development; Adverse effects; Affect; Afferent Neurons; Affinity; Affinity Chromatography; Aftercare; Amino Acids; Analgesics; Antibodies; Antibody Affinity; Antibody Therapy; Anxiety; Behavior; Binding; Biological Products; Brain; Cancer Patient; Cancer Survivor; Cell Line; Cells; Central Nervous System; Chemotherapy-induced peripheral neuropathy; Chinese Hamster Ovary Cell; Chronic; Chronic Phase; Clinical Trials; Complementarity Determining Regions; Data; Deglutition; Development; Dose; Effectiveness; Engineering; Ensure; Exhibits; Goals; High Prevalence; Hour; Human; Hypersensitivity; Immune response; Immunotherapy; In Vitro; Intellectual Property; Intranasal Administration; Lead; Legal patent; Malignant Neoplasms; Mechanics; Methodology; Modeling; Molecular; Monoclonal Antibodies; Mus; Muscle Cramp; Nerve Pain; Nervous System; Neurons; Pain; Pain management; Parents; Pathologic; Patients; Peptides; Peripheral Nerves; Pharmaceutical Preparations; Pharyngeal structure; Phase; Platinum; Production; Proteins; Publishing; Purinoceptor; Quality of life; Rattus; Reporting; Response Latencies; Rodent; Role; Safety; Sequential Treatment; Single Parent; Site; Specific qualifier value; Specificity; Symptoms; System; Testing; Therapeutic; Therapeutic Effect; Tissues; Touch sensation; Toxic effect; Toxicology; Translating; Treatment Efficacy; Validation; antagonist; antibody test; cGMP production; cancer therapy; cell bank; chemotherapy; chronic neuropathic pain; chronic pain; design; disability; drug candidate; efficacy evaluation; efficacy study; efficacy validation; experience; humanized antibody; immunogenicity; in vitro Model; in vivo; lead optimization; manufacture; mouse model; nanomolar; nerve injury; neurotoxicity; non-opioid analgesic; novel; opioid epidemic; oxaliplatin; pain model; pain score; painful neuropathy; pharmacokinetics and pharmacodynamics; phase III trial; premature; prevent; receptor; research clinical testing; single molecule; small molecule; therapeutic protein; therapeutic target; therapy design; thermostability; tool; treatment response; validation studies

The opioid crisis has emphasized the need for better non-addictive therapeutics for pain management. The chemotherapy-induced peripheral neuropathy (CIPN) imposed on approximately half of patients receiving oxaliplatin treatment for cancer is a significant additional burden. While sophisticated molecular tools are now being introduced to attack cancer and despite severe adverse effects, oxaliplatin chemotherapy remains in wide usage as a primary treatment response at many sites. Its high prevalence of neurotoxicity often limits chemotherapeutic dosing efficacy and maximum therapeutic effect. Patients can experience disabling cold and mechanical hypersensitivity that persist for years after treatment. The toxic effects can cause premature termination of treatment, impacting quality of life and survivability. CIPN can lead to permanent symptoms and disability in up to 40% of cancer survivors subsequently, thus the societal loss in dollars is inestimable. There are no drugs preventing development of CIPN, and CIPN has a poor therapeutic response to analgesics. Our current collaborative effort focuses on optimizing a small molecule single chain Fragment variable antibody (scFv) therapy that reverses chronic neuropathic pain. Smaller engineered scFvs (25-28 kDa) feature similar binding activity but stronger tissue and brain penetrability. These small molecules are considered suitable drug candidates for pain control since they satisfy key parameters such as (1) high affinity for the therapeutic target, (2) high thermostability, (3) lack of aggregation, and (4) availability from high expression cell lines. Commercial viability is dependent on humanization and affinity purification of the current patent pending small brain penetrant scFv therapy effective in murine models. The objective of this proposal is to humanize the current small scFv antibody and while maintaining more than 50% effectiveness in the murine CIPN pain model. The methodology used will be to ascertain the minimum requirements for humanization, affinity maturation, and then to bench test the antibody for effectiveness in the CIPN model vivo and in in vitro models including human-like neurons, expression systems, and primary sensory neurons from CIPN mice to validate feasibility for continuing with human clinical trials. Finally, we will seek independent commercial confirmation to demonstrate safety with PK/PD, distribution, and toxicology validation studies. The ultimate objective of this project is realization of an effective and commercially viable non-opioid treatment for chemotherapy induced neuropathic pain (CINP). The single chain Fragment variable (scFv) antibody therapy designed would prevent CINP and/or mitigate long standing, disabling CINP.

阿片类药物危机强调需要更好的非成瘾性治疗方法来管理疼痛。的