Anti-CXCL13 mAb to mitigate prostate cancer health disparities

抗 CXCL13 mAb 可减轻前列腺癌健康差异

• 批准号: 8998175
• 负责人: Shailesh Singh
• 金额: $ 31.53万
• 依托单位: JYANT, INC.
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-01 至 2018-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8998175
• 关键词: Address; Adjuvant; Affect; African American; American; Antibodies; Antibody Response; Apoptosis; B-Lymphocyte Epitopes; BLR1 gene; Benign; Biological; Blood; Blood Chemical Analysis; Bone Marrow; Bone neoplasms; CD4 Positive T Lymphocytes; CXCL13 gene; Cancer Patient; Caspase; Caucasians; Cell Line; Clinical; Critical Pathways; Data; Disease; Disease Outcome; Dose; Endothelial Cells; Endothelium; Engineering; Enzyme-Linked Immunosorbent Assay; Ethnic group; European; Femur; Flow Cytometry; Frequencies; Growth; Helper-Inducer T-Lymphocyte; Hormones; Hour; Human; Immune; Immunofluorescence Immunologic; Implant; In Situ Nick-End Labeling; Inflammation; Injection of therapeutic agent; Intervention; Lead; Leukocytes; Ligands; Luciferases; Malignant neoplasm of prostate; Measures; Mediating; Metastatic Neoplasm to the Bone; Methodology; Monitor; Monoclonal Antibodies; Morehouse School of Medicine; Mus; Neoplasm Metastasis; Organ; Osteolytic; Outcome; PC3 cell line; Patients; Pharmaceutical Preparations; Phase; Phenotype; Photons; Physicians; Play; Process; Production; Prostate; Prostatic Neoplasms; Race; Refractory; Reporting; Research; Research Personnel; Resected; Resistance; Role; SCID Mice; Saline; Sampling; Serum; Site; Small Business Technology Transfer Research; Staging; Staining method; Stains; T-Lymphocyte; T-Lymphocyte Epitopes; Technology; Testing; Therapeutic; Time; Tissues; Toxic effect; Translating; Tumor Biology; Uncertainty; Validation; Whole Blood; Xenograft procedure; base; bone; bone invasion; cancer health disparity; cell growth; chemokine; chemotherapy; clinically relevant; docetaxel; dosage; experience; health disparity; hormone refractory prostate cancer; imaging system; immunogenicity; improved; luminescence; migration; mortality; mouse model; novel; prevent; prostate cancer model; public health relevance; racial and ethnic; receptor; response; therapy resistant; tumor; tumor growth; tumor progression

 DESCRIPTION (provided by applicant): The most common metastatic site for hormone refractory prostate cancer (HRPC; PCa) is bone. While docetaxel can prolong the overall survival in patients with metastatic HRPC, current treatments do not provide a cure. Further complicating the matter, HRPC is a disease that affects a variety of patients differently, which can be problematic for physicians to provide standardized treatments with similar outcomes. African Americans (AAs) with HRPC can experience significantly lower rates of overall survival, faster rates of tumor progression and poor responses to chemotherapy than compared to European Americans (EAs) with this disease. Unfortunately, the mechanisms behind these PCa health disparities have not been well studied. To address these issues, investigators at Morehouse School of Medicine and JYANT Technologies, Inc. have identified a critical pathway that controls PCa cell growth, metastasis (to bone), and docetaxel response rates - the CXCL13:CXCR5 axis. We previously reported the functional expression of CXCR5 by PCa cell lines and that CXCL13 (the only ligand for CXCR5) can mediate PCa cell growth, migration, invasion, and docetaxel resistance. In addition, we reported significantly higher CXCR5 expression by prostate tumors from patients with advance PCa, than compared to normal matched or benign disease tissues. Our exciting preliminary data show CXCR5 expression by prostate tumors resected from AA patients are significantly (as much as two-fold) higher than EAs with the same disease stage. Previously, we demonstrated serum CXCL13 levels are significantly higher in PCa patients and this ligand is secreted by bone marrow endothelium under conditions found during this disease. Finally, we show that our murine anti-human CXCL13 antibody both prevented and shrunk HRPC xenografts established in femurs of SCID mice. In consideration of these findings, JYANT Technologies seeks to develop a novel humanized anti-human CXCL13 monoclonal antibody (CXCL13 HuMAB) for the treatment of HRPC and to address the disparities in clinical and therapeutic outcomes with this disease. To complete these objectives, we will use clinically relevant mouse models of osteolytic and osteoblastic HRPC as well as docetaxel-resistant xenografts to carry out the following aims: Aim One will ascertain the immunogenicity, using naïve B6 mice, and the PK/PD profile of CXCL13 HuMAB, in SCID mice bearing luciferase-expressing osteolytic (PC3-luc) and osteoblastic (C4-2b-luc) xenografts in femurs. Aim Two will determine the systemic and immune toxicity as well as the efficacy of CXCL13 HuMAB to inhibit prostate tumor growth and docetaxel-resistance in bone, using SCID mice challenged in femurs with hormone refractory (PC3-luc and C4-2b-luc) and/or docetaxel-resistant (PC3R-luc and C4-2bR-luc) PCa cell lines.

 描述（由申请人提供）：激素难治性前列腺癌（HRPC；PCa）最常见的转移部位是骨。虽然多西他赛可以延长转移性 HRPC 患者的总生存期，但目前的治疗方法无法治愈。使问题进一步复杂化的是，HRPC 是一种对不同患者产生不同影响的疾病，这对于医生提供具有相似结果的标准化治疗可能存在问题。与患有 HRPC 的欧洲裔美国人 (EA) 相比，患有 HRPC 的非洲裔美国人 (AA) 的总体生存率明显较低，肿瘤进展速度较快，化疗反应较差。不幸的是，这些 PCa 健康差异背后的机制尚未得到充分研究。为了解决这些问题，莫尔豪斯医学院和 JYANT Technologies, Inc. 的研究人员确定了控制 PCa 细胞生长、转移（骨）和多西他赛反应率的关键途径 - CXCL13:CXCR5 轴。我们之前报道了PCa细胞系CXCR5的功能表达，并且CXCL13（CXCR5的唯一配体）可以介导PCa细胞生长、迁移、侵袭和多西他赛耐药。此外，我们报告称，与正常匹配或良性疾病组织相比，晚期 PCa 患者的前列腺肿瘤中 CXCR5 的表达显着更高。我们令人兴奋的初步数据显示，从 AA 患者身上切除的前列腺肿瘤的 CXCR5 表达显着（高达两倍）高于具有相同疾病阶段的 EA。此前，我们证明 PCa 患者的血清 CXCL13 水平显着较高，并且这种配体是在这种疾病期间发现的条件下由骨髓内皮分泌的。最后，我们表明，我们的鼠抗人 CXCL13 抗体既可以预防 SCID 小鼠股骨中建立的 HRPC 异种移植物，又可以使 HRPC 异种移植物缩小。考虑到这些发现，JYANT Technologies 寻求开发一种新型人源化抗人 CXCL13 单克隆抗体 (CXCL13 HuMAB)，用于治疗 HRPC 并解决该疾病临床和治疗结果的差异。为了完成这些目标，我们将使用临床相关的溶骨性和成骨性 HRPC 小鼠模型以及多西紫杉醇抗性异种移植物来实现以下目标：目标一将使用幼稚 B6 小鼠确定免疫原性，以及 CXCL13 HuMAB 在携带荧光素酶表达溶骨细胞的 SCID 小鼠中的免疫原性和 CXCL13 HuMAB 的 PK/PD 谱。 股骨中的 (PC3-luc) 和成骨细胞 (C4-2b-luc) 异种移植物。目标二将使用在股骨中接受激素难治性（PC3-luc 和 C4-2b-luc）和/或多西他赛抗性（PC3R-luc 和 C4-2bR-luc）PCa 细胞系的 SCID 小鼠，确定 CXCL13 HuMAB 的全身和免疫毒性以及抑制前列腺肿瘤生长和骨中多西他赛耐药性的功效。