Humanized anti-CXCL1 antibody for bladder cancer therapeutics
用于膀胱癌治疗的人源化抗 CXCL1 抗体
基本信息
- 批准号:10454422
- 负责人:
- 金额:$ 30.6万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-08-01 至 2024-07-31
- 项目状态:已结题
- 来源:
- 关键词:3-DimensionalAdaptive Immune SystemAddressAffectAffinityAngiogenesis InhibitionAngiogenic FactorAnimal ExperimentsAnimal ModelAnimalsAntibodiesApoptosisAreaAutomobile DrivingBindingBiological AssayBiological MarkersBladderBladder NeoplasmBloodBlood capillariesCD34 geneCXCL1 geneCancer DetectionCancer PatientCancer cell lineCell LineCell ProliferationCellsClinicColon CarcinomaComplexDataDevelopmentDiseaseDoseDrug ControlsDrug KineticsEndothelial CellsEngraftmentEpithelialExhibitsFDA approvedFc ReceptorGoalsGrowthHematopoietic stem cellsHumanIL6 geneIL8RB geneImmuneImmune systemImmunodeficient MouseImmunofluorescence ImmunologicIn VitroInduction of ApoptosisInflammation MediatorsInflammatory ResponseLaboratoriesLigandsLongitudinal StudiesLymphocyteMalignant NeoplasmsMalignant neoplasm of lungMalignant neoplasm of prostateMalignant neoplasm of urinary bladderMeasuresMethodologyModelingMonoclonal AntibodiesMouse StrainsMusNeoplasm MetastasisNeutropeniaNeutrophil InfiltrationPharmaceutical PreparationsPhase I Clinical TrialsPilot ProjectsPlayPopulationPre-Clinical ModelPrimary NeoplasmProcessProstateReportingResearchRoleSpecificityStainsT-LymphocyteTestingTherapeuticTissuesTubeTumor AngiogenesisTumor TissueWorkXenograft procedureangiogenesisanti-cancer therapeuticantibody testbasebevacizumabcancer cellcancer therapycancer typecell motilitychemokinecomparativeefficacy evaluationhumanized antibodyhumanized monoclonal antibodiesin vitro Assayin vivomalignant breast neoplasmmatrigelmouse modelneonatal Fc receptorneutralizing antibodyneutralizing monoclonal antibodiesneutrophilnovel therapeuticsoverexpressionpatient derived xenograft modelpre-clinicalpreclinical efficacypreclinical studyprotein expressionrecruitsuccesstherapeutic targettranslational applicationstreatment responsetumor growthtumor microenvironmenttumor progressiontumor vascular supplytumor xenografttumor-immune system interactionstumorigenesisurinary
项目摘要
SUMMARY
Background: The progressive growth of tumors and their ability to metastasize are dependent on an adequate
tumor blood supply. Chemokine (C-X-C motif) ligand 1 (CXCL1), a well-known chemokine, has been identified
as a potential therapeutic target for bladder cancers (BCa) as well as urinary biomarker for BCa detection.
Chemokines are known to be critical mediators of the inflammatory response by regulating recruitment of
immune cells from both the innate and adaptive immune systems to diseased tissues. Also, chemokines have
been known to regulate multiple processes during tumor progression including primary tumor growth, tumor
angiogenesis and development of metastatic disease. Previously, we found that CXCL1 is overexpressed in
BCa and CXCL1 expression is associated with a worse disease-specific survival. We also reported that CXCL1
is expressed and secreted from human endothelial cells and interference of CXCL1 function using a
neutralizing antibody resulted in a reduction in endothelial cell migration and cellular proliferation. We
previously developed mouse anti-human CXCL1 monoclonal antibody (HL2401) and demonstrated that
inhibition of CXCL1 by HL2401 results in the diminution of bladder and prostate xenograft tumoral growth
through the inhibition of angiogenesis and proliferation along with an induction of apoptosis. Recently, we
developed a first-in-class humanized neutralizing monoclonal antibody towards CXCL1 (NTC-001), that if
found to be effective and safe in animals, could readily move into phase 1 clinical trials. Pilot studies
demonstrated that NTC-001 inhibited capillary tube formation and sprouting in HUVEC and cell proliferation in
BCa cell lines with IC50 value of 60-165 μg/ml. Hypothesis: Neutralization of CXCL1 by humanized
monoclonal antibody can be a potent strategy for BCa therapy. Specific Aims: 1) To assess whether our
humanized anti-CXCL1 antibody, NTC-001, exhibit inhibitory effects on angiogenesis and tumor growth in vivo;
2) To examine the effect of NTC-001 on tumor growth in a humanized BCa patient-derived xenograft (PDX)
model. Significance: The results obtained from this project will provide a new drug into the clinic for BCa
therapy and beyond. Methodology: With animal models including Matrigel plug assay and human BCa cell
line derived xenografts, we will assess the effect of humanized antibody on angiogenesis and tumor growth.
Using BCa patient-derived xenograft model in humanized immune system mice, we will examine 1) the efficacy
of NTC-001 on tumor growth and survival, 2) potential effects, specifically neutropenia, and 3) the effects on
the tumor microenvironment. Expected Results: Based on our previous works, we expect that anti-human
CXCL1 humanized antibody is effective on bladder tumorigenesis. How results will affect other research
areas: Since CXCL1 is highly expressed in most cancers, the findings will have important implications on
developing new therapies against other cancers.
总结
背景:肿瘤的进行性生长及其转移能力依赖于足够的
肿瘤血供趋化因子(C-X-C基序)配体1(CXCL 1)是一种已知的趋化因子,
作为膀胱癌(BCa)的潜在治疗靶点以及用于BCa检测的尿生物标志物。
已知趋化因子是炎症反应的关键介质,其通过调节趋化因子的募集来调节炎症反应。
免疫细胞从先天和适应性免疫系统到患病组织。此外,趋化因子具有
已知在肿瘤进展过程中调节多个过程,包括原发性肿瘤生长、肿瘤生长抑制、肿瘤坏死因子受体、肿瘤坏死因子受体和肿瘤坏死因子受体。
血管生成和转移性疾病的发展。以前,我们发现CXCL 1在人乳腺癌细胞中过表达,
BCa和CXCL 1表达与较差的疾病特异性生存相关。我们还报道了CXCL 1
从人内皮细胞中表达和分泌,并使用免疫抑制剂干扰CXCL 1功能。
中和抗体导致内皮细胞迁移和细胞增殖减少。我们
先前开发的小鼠抗人CXCL 1单克隆抗体(HL 2401),并证明,
HL 2401抑制CXCL 1导致膀胱和前列腺异种移植肿瘤生长减少
通过抑制血管生成和增殖沿着诱导细胞凋亡。最近我们
开发了一种针对CXCL 1的一流人源化中和单克隆抗体(NTC-001),
在动物中发现是有效和安全的,可以很容易地进入1期临床试验。试点研究
表明NTC-001抑制HUVEC中毛细血管的形成和出芽以及HUVEC中的细胞增殖。
BCa细胞系,IC 50值为60-165 μg/ml。假设:CXCL 1被人源化细胞中和
单克隆抗体可能是BCa治疗有效策略。具体目标:1)评估我们的
人源化抗CXCL 1抗体NTC-001在体内表现出对血管生成和肿瘤生长抑制作用;
2)检查NTC-001对人源化BCa患者来源的异种移植物(PDX)中肿瘤生长的影响
模型意义:本项目的研究结果将为BCa的临床应用提供新的药物
治疗和超越。方法:采用Matrigel胶塞法和人BCa细胞培养法
系来源的异种移植物,我们将评估人源化抗体对血管生成和肿瘤生长的作用。
在人源化免疫系统小鼠中使用BCa患者来源的异种移植物模型,我们将检查1)BCa患者来源的异种移植物的功效,
NTC-001对肿瘤生长和存活的影响,2)潜在的作用,特别是中性粒细胞减少,和3)对
肿瘤微环境。预期结果:基于我们以前的工作,我们预计,
CXCL 1人源化抗体对膀胱肿瘤发生有效。结果如何影响其他研究
由于CXCL 1在大多数癌症中高度表达,这些发现将对癌症的治疗产生重要影响。
开发针对其他癌症的新疗法。
项目成果
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Hideki Furuya其他文献
Hideki Furuya的其他文献
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{{ truncateString('Hideki Furuya', 18)}}的其他基金
A Multiplex Protein Biomarker-Based Immunoassay for the Early Detection of Bladder Cancer and its Implications in Tumor Biology
用于膀胱癌早期检测的多重蛋白质生物标志物免疫测定及其在肿瘤生物学中的意义
- 批准号:
10591629 - 财政年份:2023
- 资助金额:
$ 30.6万 - 项目类别:
Humanized anti-CXCL1 antibody for bladder cancer therapeutics
用于膀胱癌治疗的人源化抗 CXCL1 抗体
- 批准号:
10290237 - 财政年份:2021
- 资助金额:
$ 30.6万 - 项目类别:
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