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疗法来治疗疼痛。这 大约一半接受化疗的患者会出现化疗引起的周围神经病变（CIPN） 奥沙利铂治疗癌症是一个重大的额外负担。虽然现在已经有了先进的分子工具 奥沙利铂被用于治疗癌症，尽管有严重的副作用，但奥沙利铂化疗仍然广泛使用 在许多地点用作主要治疗反应。其神经毒性的高患病率通常限制了 化疗剂量功效和最大治疗效果。患者可能会经历致残的感冒和 治疗后持续数年的机械过敏。毒性作用可能导致早产 终止治疗，影响生活质量和生存能力。 CIPN 可导致永久性症状 随后高达 40% 的癌症幸存者残疾，因此社会损失无法估量。那里 没有药物可以预防 CIPN 的发生，并且 CIPN 对镇痛药的治疗反应较差。我们的 目前的合作重点是优化小分子单链片段可变抗体 （scFv）疗法可逆转慢性神经性疼痛。较小的工程化 scFv (25-28 kDa) 具有相似的特性 结合活性强，但组织和脑的穿透性更强。这些小分子被认为是合适的药物 疼痛控制的候选者，因为它们满足关键参数，例如（1）对治疗靶点的高亲和力， (2) 高热稳定性，(3) 缺乏聚集，以及 (4) 来自高表达细胞系的可用性。商业的 可行性取决于当前正在申请专利的小脑渗透剂的人源化和亲和纯化 scFv 疗法在小鼠模型中有效。该提案的目的是使当前的小型 scFv 人性化 抗体，同时在小鼠 CIPN 疼痛模型中保持 50% 以上的有效性。方法论 用于确定人源化、亲和力成熟的最低要求，然后进行基准测试 抗体在CIPN体内模型和体外模型（包括类人神经元）中的有效性， 表达系统和 CIPN 小鼠的初级感觉神经元，以验证继续进行的可行性 人体临床试验。最后，我们将寻求独立的商业确认以证明安全性 PK/PD、分布和毒理学验证研究。该项目的最终目标是实现 有效且商业上可行的非阿片类药物治疗化疗引起的神经性疼痛（CINP）。这 单链片段可变 (scFv) 抗体疗法旨在预防 CINP 和/或减轻长期 站立，禁用 CINP。