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：
10290237
负责人：
Hideki Furuya
金额：
$ 11.71万
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 2023-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10290237
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 response success therapeutic target 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.

概括背景：肿瘤的进行性生长及其转移能力依赖于足够的趋化因子（C-X-C 基序）配体 1 (CXCL1) 是一种众所周知的趋化因子，已被鉴定。作为膀胱癌 (BCa) 的潜在治疗靶点以及用于 BCa 检测的尿液生物标志物。已知趋化因子通过调节炎症反应的募集而成为炎症反应的关键介质。来自先天性和适应性免疫系统的免疫细胞对患病组织也有作用。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、肿瘤此前，我们发现CXCL1在血管生成和转移性疾病的发展中过度表达。 BCa 和 CXCL1 表达与较差的疾病特异性生存相关。我们还报道了 CXCL1。由人内皮细胞表达和分泌，并使用 a 干扰 CXCL1 功能中和抗体导致内皮细胞迁移和细胞增殖减少。先前开发了小鼠抗人CXCL1单克隆抗体（HL2401）并证明 HL2401 抑制 CXCL1 导致膀胱和前列腺异种移植肿瘤生长减少最近，我们通过抑制血管生成和增殖以及诱导细胞凋亡。开发了针对 CXCL1 (NTC-001) 的一流人源化中和单克隆抗体，如果发现在动物中有效且安全，可以轻松进入第一阶段临床试验。证明 NTC-001 抑制 HUVEC 中毛细管的形成和萌芽以及细胞增殖 BCa 细胞系的 IC50 值为 60-165 μg/ml 假设：人源化 CXCL1 的中和作用。单克隆抗体可以成为 BCa 治疗的有效策略具体目标： 1) 评估我们的治疗是否有效。人源化抗CXCL1抗体NTC-001在体内表现出对血管生成和肿瘤生长的抑制作用； 2) 检查 NTC-001 对人源化 BCa 患者异种移植物 (PDX) 中肿瘤生长的影响模型意义：该项目获得的结果将为BCa提供进入临床的新药。治疗及其他方法：使用动物模型，包括基质胶塞测定和人类 BCa 细胞。细胞系衍生的异种移植物，我们将评估人源化抗体对血管生成和肿瘤生长的影响。在人源化免疫系统小鼠中使用 BCa 患者来源的异种移植模型，我们将检查 1) 的功效 NTC-001 对肿瘤生长和存活的影响，2) 潜在影响，特别是中性粒细胞减少症，以及 3) 对预期结果：根据我们之前的工作，我们预计抗人类。 CXCL1 人源化抗体对膀胱肿瘤发生有效，结果将如何影响其他研究。领域：由于 CXCL1 在大多数癌症中高度表达，因此这些发现将对以下领域产生重要影响：开发针对其他癌症的新疗法。