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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：
Hideki Furuya
金额：
$ 30.6万
依托单位：
CEDARS-SINAI MEDICAL CENTER
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：
https://reporter.nih.gov/project-details/10454422
关键词：
3-Dimensional Adaptive Immune System Address Affect Affinity Angiogenesis Inhibition Angiogenic Factor Animal Experiments Animal Model Animals Antibodies Apoptosis Area Automobile Driving Binding Biological Assay Biological Markers Bladder Bladder Neoplasm Blood Blood capillaries CD34 gene CXCL1 gene Cancer Detection Cancer Patient Cancer cell line Cell Line Cell Proliferation Cells Clinic Colon Carcinoma Complex Data Development Disease Dose Drug Controls Drug Kinetics Endothelial Cells Engraftment Epithelial Exhibits FDA approved Fc Receptor Goals Growth Hematopoietic stem cells Human IL6 gene IL8RB gene Immune Immune system Immunodeficient Mouse Immunofluorescence Immunologic In Vitro Induction of Apoptosis Inflammation Mediators Inflammatory Response Laboratories Ligands Longitudinal Studies Lymphocyte Malignant Neoplasms Malignant neoplasm of lung Malignant neoplasm of prostate Malignant neoplasm of urinary bladder Measures Methodology Modeling Monoclonal Antibodies Mouse Strains Mus Neoplasm Metastasis Neutropenia Neutrophil Infiltration Pharmaceutical Preparations Phase I Clinical Trials Pilot Projects Play Population Pre-Clinical Model Primary Neoplasm Process Prostate Reporting Research Role Specificity Stains T-Lymphocyte Testing Therapeutic Tissues Tube Tumor Angiogenesis Tumor Tissue Work Xenograft procedure angiogenesis anti-cancer therapeutic antibody test base bevacizumab cancer cell cancer therapy cancer type cell motility chemokine comparative efficacy evaluation humanized antibody humanized monoclonal antibodies in vitro Assay in vivo malignant breast neoplasm matrigel mouse model neonatal Fc receptor neutralizing antibody neutralizing monoclonal antibodies neutrophil novel therapeutics overexpression patient derived xenograft model pre-clinical preclinical efficacy preclinical study protein expression recruit success therapeutic target translational applications treatment response tumor growth tumor microenvironment tumor progression tumor vascular supply tumor xenograft tumor-immune system interactions tumorigenesis urinary

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。