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:
- 金额:--
- 依托单位:
- 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:
- 关键词:AcuteAdvanced DevelopmentAdverse effectsAffectAfferent NeuronsAffinityAffinity ChromatographyAftercareAmino AcidsAnalgesicsAntibodiesAntibody AffinityAntibody TherapyAnxietyBehaviorBindingBiological ProductsBrainCancer PatientCancer SurvivorCell LineCellsCentral Nervous SystemChemotherapy-induced peripheral neuropathyChinese Hamster Ovary CellChronicChronic PhaseClinical TrialsComplementarity Determining RegionsDataDeglutitionDevelopmentDoseEffectivenessEngineeringEnsureExhibitsGoalsHigh PrevalenceHourHumanHypersensitivityImmune responseImmunotherapyIn VitroIntellectual PropertyIntranasal AdministrationLeadLegal patentMalignant NeoplasmsMechanicsMethodologyModelingMolecularMonoclonal AntibodiesMusMuscle CrampNerve PainNervous SystemNeuronsPainPain managementParentsPathologicPatientsPeptidesPeripheral NervesPharmaceutical PreparationsPharyngeal structurePhasePlatinumProductionProteinsPublishingPurinoceptorQuality of lifeRattusReportingResponse LatenciesRodentRoleSafetySequential TreatmentSingle ParentSiteSpecific qualifier valueSpecificitySymptomsSystemTestingTherapeuticTherapeutic EffectTissuesTouch sensationToxic effectToxicologyTranslatingTreatment EfficacyValidationantagonistantibody testcGMP productioncancer therapycell bankchemotherapychronic neuropathic painchronic paindesigndisabilitydrug candidateefficacy evaluationefficacy studyefficacy validationexperiencehumanized antibodyimmunogenicityin vitro Modelin vivolead optimizationmanufacturemouse modelnanomolarnerve injuryneurotoxicitynon-opioid analgesicnovelopioid epidemicoxaliplatinpain modelpain scorepainful neuropathypharmacokinetics and pharmacodynamicsphase III trialprematurepreventreceptorresearch clinical testingsingle moleculesmall moleculetherapeutic proteintherapeutic targettherapy designthermostabilitytooltreatment responsevalidation studies
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
项目成果
期刊论文数量(0)
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科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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KARIN N. WESTLUND-HIGH其他文献
KARIN N. WESTLUND-HIGH的其他文献
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{{ truncateString('KARIN N. WESTLUND-HIGH', 18)}}的其他基金
ShEEP Request for Biotek Cytation 5 Imaging System
ShEEP 请求 Biotek Cytation 5 成像系统
- 批准号:
10175798 - 财政年份:2020
- 资助金额:
-- - 项目类别:
Modulating Pain Generators of Chronic Trigeminal Neuropathic Pain
调节慢性三叉神经病理性疼痛的疼痛发生器
- 批准号:
10513813 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Peripheral and Central Pain Generators of Chronic Trigeminal Neuropathic Pain
慢性三叉神经病理性疼痛的周围和中枢疼痛发生器
- 批准号:
9031396 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Modulating Pain Generators of Chronic Trigeminal Neuropathic Pain
调节慢性三叉神经病理性疼痛的疼痛发生器
- 批准号:
10293538 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Modulating Pain Generators of Chronic Trigeminal Neuropathic Pain
调节慢性三叉神经病理性疼痛的疼痛发生器
- 批准号:
10012520 - 财政年份:2016
- 资助金额:
-- - 项目类别:
Physiological and Emotional Reactivity to Pain after Physical and Sexual Abuse
身体和性虐待后对疼痛的生理和情感反应
- 批准号:
8214456 - 财政年份:2011
- 资助金额:
-- - 项目类别:
Glutamate Induced Molecular Events Contributing to Chro*
谷氨酸诱导的分子事件有助于 Chro*
- 批准号:
6533040 - 财政年份:2001
- 资助金额:
-- - 项目类别:
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