Pre-targeting immunotherapy for light chain (AL) amyloidosis
轻链 (AL) 淀粉样变性的预靶向免疫治疗
基本信息
- 批准号:9292835
- 负责人:
- 金额:$ 35万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-04-01 至 2020-03-31
- 项目状态:已结题
- 来源:
- 关键词:AddressAffinityAmyloidAmyloid FibrilsAmyloidosisAntibodiesAutologous Stem Cell TransplantationBindingBiodistributionBiological AssayCardiacCessation of lifeClinicalClinical ManagementClinical TrialsClone CellsComplementComplexDepositionDiagnosisDiseaseDisease modelDisease remissionEpitopesEtiologyExcisionFunctional disorderGoalsHeparin BindingHumanImmunologicsImmunotherapeutic agentImmunotherapyIn VitroLibrariesLightLight-Chain ImmunoglobulinsLinear Sequence EpitopesMeasurementMediatingMetadataMethodsMonoclonal AntibodiesMorbidity - disease rateMultiple MyelomaMusOrganPathogenesisPathologicPathologyPatientsPeptidesPhase I Clinical TrialsPlasma CellsPrealbuminProteinsProtocols documentationRadiolabeledReagentResearchResourcesSecureSeriesSystemTestingTherapeutic UsesTherapeutic antibodiesTissuesVisceralWorkbasechemotherapyexperienceextracellularimaging agentin vitro Assayin vivoloss of functionmortalitymouse modelnoveloutcome forecastprimary amyloidosis of light chain typeprogramssingle photon emission computed tomographysynthetic peptidetreatment response
项目摘要
Light chain amyloidosis (AL) is the most common form of systemic amyloid disease, with an estimated 4,500
new cases each year in the US. AL is a complex plasma cell-related disease characterized by the formation of
insoluble, immunologically-inert protein fibrils composed of misfolded monoclonal immunoglobulin light chain
components Extracellular amyloid fibrils can deposit in any organ or tissue causing loss of function, morbidity,
and, ultimately, death. Despite decades of active research and increased understanding of pathological
mechanisms, AL remains incurable, and the prognosis for patients is poor with a median survival of less than 3
years.
Effective clinical management of patients with AL requires, in addition to chemotherapy, removal of
destructive tissue amyloid so that organ function can be allowed to recover. A proven method of amyloid
removal is opsonization of the deposits by using amyloid-reactive antibodies. Although promising, preliminary
results from two ongoing clinical trials of anti-AL amyloid antibodies indicate that they may be effective in
only approximately 50% of patients. To address this deficiency we have developed a strategy that uses a novel
bifunctional “peptope” – that combines a pan-amyloid-reactive peptide and a linear epitope sequence – to
enhance the efficacy and extend the utility of current immunotherapeutic antibodies, such as the chimeric
reagent, 11-1F4.
In this proposal, we will evaluate and characterize a peptope comprised of the amyloid-reactive peptide
p5+14 and a high affinity epitope (0.3 nM) recognized by 11-1F4. Using a battery of quantitative in vitro
binding assays as well as in vivo dual-energy SPECT imaging and tissue biodistribution studies, we will
quantify the efficacy of peptope-mediated amyloid targeting of the 11-1F4 antibody. Finally, we will
investigate, using mouse models of systemic and localized amyloidosis, the ability of peptope-antibody
immunotherapy to induce amyloid removal in vivo. We anticipate that this novel, two-stage opsonizing
immunotherapy will enhance the efficacy of 11-1F4-based therapy in patients with AL and potentially extend
the utility of this antibody to other forms of systemic amyloid disease.
AL amyloidosis remains a devastating and incurable disease. The goal of this application is to develop
bifunctional peptides that simultaneously bind amyloid and the 11-1F4 monoclonal antibody to generate a novel
immunotherapy for AL amyloidosis. This approach will complement and extend current antibody-based
therapies for amyloid removal, thereby restoring organ function and securing long term survival and remission
for patients with AL.
轻链淀粉样变性 (AL) 是系统性淀粉样蛋白疾病最常见的形式,估计有 4,500
美国每年都有新病例。 AL 是一种复杂的浆细胞相关疾病,其特征是形成
由错误折叠的单克隆免疫球蛋白轻链组成的不溶性免疫惰性蛋白原纤维
细胞外淀粉样原纤维可以沉积在任何器官或组织中,导致功能丧失、发病、
以及最终的死亡。尽管数十年的积极研究和对病理学的了解不断增加
AL 仍无法治愈,患者预后较差,中位生存期低于 3
年。
AL 患者的有效临床管理除了化疗外还需要去除
破坏组织的淀粉样蛋白,从而使器官功能得以恢复。一种经过验证的淀粉样蛋白方法
去除是通过使用淀粉样反应性抗体对沉积物进行调理。尽管前景广阔,但初步
两项正在进行的抗 AL 淀粉样蛋白抗体临床试验的结果表明,它们可能有效
仅约50%的患者。为了解决这个缺陷,我们开发了一种策略,使用一种新颖的方法
双功能“肽”——结合了泛淀粉样蛋白反应肽和线性表位序列——
增强现有免疫治疗抗体的功效并扩展其用途,例如嵌合抗体
试剂,11-1F4。
在本提案中,我们将评估和表征由淀粉样反应肽组成的肽
p5+14 和 11-1F4 识别的高亲和力表位 (0.3 nM)。使用一组体外定量
结合测定以及体内双能 SPECT 成像和组织生物分布研究,我们将
量化肽介导的 11-1F4 抗体淀粉样蛋白靶向的功效。最后,我们将
使用全身性和局部淀粉样变性小鼠模型研究肽抗体的能力
免疫疗法诱导体内淀粉样蛋白去除。我们预计这种新颖的两阶段调理作用
免疫疗法将增强基于 11-1F4 的治疗对 AL 患者的疗效,并可能延长治疗时间
该抗体对其他形式的系统性淀粉样蛋白疾病的效用。
AL 淀粉样变性仍然是一种毁灭性且无法治愈的疾病。该应用程序的目标是开发
双功能肽同时结合淀粉样蛋白和 11-1F4 单克隆抗体,产生新型
AL 淀粉样变性的免疫疗法。这种方法将补充和扩展当前基于抗体的方法
去除淀粉样蛋白的疗法,从而恢复器官功能并确保长期生存和缓解
对于 AL 患者。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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JONATHAN S WALL其他文献
JONATHAN S WALL的其他文献
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{{ truncateString('JONATHAN S WALL', 18)}}的其他基金
Development of a Theranostic Immunotherapy for Systemic Amyloidosis
系统性淀粉样变性治疗诊断免疫疗法的开发
- 批准号:
10209131 - 财政年份:2021
- 资助金额:
$ 35万 - 项目类别:
Development of a Theranostic Immunotherapy for Systemic Amyloidosis
系统性淀粉样变性治疗诊断免疫疗法的开发
- 批准号:
10353419 - 财政年份:2021
- 资助金额:
$ 35万 - 项目类别:
Development of a Theranostic Immunotherapy for Systemic Amyloidosis
系统性淀粉样变性治疗诊断免疫疗法的开发
- 批准号:
10579884 - 财政年份:2021
- 资助金额:
$ 35万 - 项目类别:
Development of chimeric antigen receptor-expressing macrophages for enhanced phagocytosis of systemic amyloid
开发表达嵌合抗原受体的巨噬细胞以增强系统性淀粉样蛋白的吞噬作用
- 批准号:
10263880 - 财政年份:2020
- 资助金额:
$ 35万 - 项目类别:
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