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: 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
• 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

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：肿瘤的逐步生长及其转移能力取决于足够的 肿瘤血液供应。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）的潜在治疗靶标，以及用于BCA检测的尿生物标志物。 趋化因子是通过调节募集的炎症反应的关键介体 来自先天性和适应性免疫系统的免疫细胞到解剖组织。另外，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 转移性疾病的血管生成和发育。以前，我们发现CXCL1在 BCA和CXCL1表达与疾病特异性较差的生存有关。我们还报道了CXCL1 使用A表达和分泌从人内皮细胞和CXCL1功能的干扰 中和抗体导致内皮细胞迁移和细胞增殖的减少。我们 以前开发了小鼠抗人CXCL1单克隆抗体（HL2401），并证明了这一点 HL2401对CXCL1的抑制会导致膀胱和前列腺畸形肿瘤生长的尺寸 通过抑制血管生成和增殖以及凋亡的诱导。最近，我们 开发了一种对CXCL1（NTC-001）的第一类人源中和中和的单克隆抗体，if 发现在动物中有效且安全，很容易进入1期临床试验。试点研究 证明NTC-001抑制了HUVEC和细胞增殖的毛细管形成和发芽 IC50值为60-165μg/ml的BCA细胞系。假设：人源化对CXCL1进行中和 单克隆抗体可能是BCA治疗的潜在策略。具体目的：1）评估我们的 人源化抗CXCL1抗体NTC-001，暴露于体内血管生成和肿瘤生长的抑制作用； 2）检查NTC-001对人源化BCA患者衍生型（PDX）中肿瘤生长的影响 模型。意义：从该项目获得的结果将为BCA提供新药 治疗及以后。方法论：使用包括Matrigel插头测定和人类BCA细胞在内的动物模型 线衍生的异种移植物，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患者衍生的Xenogroticon模型，我们将检查1）效率 NTC-001对肿瘤生长和生存的of 2）潜在影响，特别是中额减少症，3）对 肿瘤微环境。预期结果：根据我们以前的作品，我们期望反人类 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 区域：由于CXCL1在大多数癌症中都高度表达，因此发现将对 开发针对其他癌症的新疗法。