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了需要更好的非成瘾性疼痛治疗方法。的 化疗诱导的周围神经病变（CIPN）施加在大约一半的患者接受 用于癌症的奥沙利铂治疗是显著的额外负担。虽然现在先进的分子工具 奥沙利铂化疗被引入攻击癌症，尽管有严重的副作用， 在许多研究中心作为主要治疗反应使用。其神经毒性的高流行率往往限制了 化疗剂量功效和最大治疗效果。患者可能会经历致残性感冒， 治疗后持续数年的机械性超敏反应。毒性作用会导致早产 终止治疗，影响生活质量和生存能力。CIPN可导致永久性症状， 高达40%的癌症幸存者随后残疾，因此以美元计的社会损失是不可估量的。那里 没有药物阻止CIPN的发展，并且CIPN对镇痛剂的治疗反应较差。我们 目前的合作重点是优化小分子单链可变抗体 本发明提供了逆转慢性神经性疼痛的单链抗体（scFv）疗法。较小的工程改造的scFv（25-28 kDa）具有类似的特征， 结合活性，但更强的组织和脑渗透性。这些小分子被认为是合适的药物 疼痛控制的候选物，因为它们满足关键参数如（1）对治疗靶点的高亲和力， (2)高热稳定性，（3）缺乏聚集，和（4）可从高表达细胞系获得。商业 生存力取决于目前正在申请专利的小分子脑渗透剂的人源化和亲和纯化 scFv疗法在鼠模型中有效。该提案的目的是将目前的小scFv人源化， 抗体，同时在鼠CIPN疼痛模型中保持超过50%的有效性。的方法 将用于确定人源化、亲和力成熟的最低要求，然后进行台架试验 所述抗体在CIPN模型体内和包括类人神经元的体外模型中有效， 表达系统和来自CIPN小鼠的初级感觉神经元，以验证继续使用 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 有效的和商业上可行的非阿片类药物治疗化疗诱导的神经性疼痛（CINP）。的 设计的单链可变片段（scFv）抗体疗法将预防CINP和/或减轻长时间的CINP。 站着，关闭CINP