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

基本信息

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
项目类别：
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

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

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项目摘要

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地进行疼痛管理的非添加性治疗。这化学疗法诱导的周围神经病（CIPN）对大约一半的患者施加奥沙利铂治疗癌症是一个重大的额外负担。而复杂的分子工具现在是被引入攻击癌症，尽管有严重的不良影响，奥沙利铂化学疗法仍处于广泛状态在许多地点，用途是主要治疗响应。其神经毒性的高流行率通常限制化学治疗剂量功效和最大治疗作用。患者可以经历致命的寒冷和治疗后多年的机械性超敏反应。有毒作用会导致过早终止治疗，影响生活质量和生存能力。 CIPN会导致永久症状，并随后，多达40％的癌症幸存者的残疾，因此美元的社会损失是不可估量的。那里没有阻止CIPN发展的药物，并且CIPN对镇痛药的治疗反应差。我们的当前的协作工作重点是优化小分子单链片段变量抗体（SCFV）逆转慢性神经性疼痛的治疗。较小的工程SCFV（25-28 kDa）具有类似的功能结合活性，但组织和大脑的渗透性更强。这些小分子被认为是合适的药物疼痛控制的候选者由于满足关键参数，例如（1）对治疗目标的高亲和力，（2）高温稳定性，（3）缺乏聚集，（4）高表达细胞系的可用性。商业的生存能力取决于人性化和当前专利的亲和力净化，尚待小脑渗透物 SCFV治疗在鼠模型中有效。该提议的目的是使当前的小型SCFV人性化抗体并在鼠CIPN疼痛模型中保持超过50％的效率。方法使用的将是确定人性化，亲和力成熟的最低要求，然后进行基准测试 CIPN模型体内和包括人类神经元的体外模型中有效性的抗体，表达系统以及来自CIPN小鼠的主要感觉神经元，以验证可行性继续人类临床试验。最后，我们将寻求独立的商业确认，以证明安全 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和商业上可行的非阿片类药物治疗化学疗法诱导的神经性疼痛（SINP）。这设计的单链片段变量（SCFV）抗体疗法设计将防止稀释和/或减轻长时间站立，禁用辛普。