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（由适用提供）：激素难治性前列腺癌（HRPC; PCA）最常见的转移部位是骨骼。虽然多西他赛可以延长转移性HRPC患者的总体存活率，但目前的治疗方法无法治愈。进一步使此事复杂化的是，HRPC是一种对各种患者的影响，对医生提供具有相似预后的标准化治疗可能是有问题的。与患有这种疾病相比，具有HRPC的非裔美国人（AAS）的总生存率，肿瘤进展的速度更快，对化学疗法的反应速度更快，对这种疾病的反应率明显较低。不幸的是，这些PCA健康分布背后的机制尚未很好地研究。为了解决这些问题，Morehouse医学院和Jyant Technologies，Inc。的研究人员已经确定了控制PCA细胞生长，转移（骨骼）和多西他赛响应率的关键途径-CXCL13：CXCR5轴。我们先前报道了PCA细胞系CXCR5的功能表达，并且CXCL13（CXCR5的唯一配体）可以介导PCA细胞的生长，迁移，侵袭和多西他赛抗性。此外，与正常匹配或良性疾病组织相比，我们报告的前列腺肿瘤的CXCR5表达明显更高。我们令人兴奋的初步数据表明，从AA患者切除的前列腺肿瘤表达CXCR5的表达明显高于相同疾病阶段的EA。以前，我们证明了PCA患者的血清CXCL13水平明显更高，并且在这种疾病期间发现的情况下，该配体被骨髓内皮分泌。最后，我们表明我们的鼠抗抗人CXCL13抗体均预防和缩小在SCID小鼠股骨中建立的HRPC Xenographictics。考虑到这些发现，Jyant Technologies试图开发一种新型的人源化抗人类CXCL13单克隆抗体（CXCL13 Humab）来治疗HRPC，并解决这种疾病的临床和治疗结果中的分布。 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）和成骨细胞（C4-2B-LUC）异种移植物中的异种移植物。 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 horsetone refractory (PC3-luc and C4-2b-luc) and/or docetaxel-resistant (PC3R-luc and C4-2bR-luc) PCa cell lines.