Anti-CXCL13 mAb to mitigate prostate cancer health disparities

 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是一种对各种患者影响不同的疾病，这对于医生提供具有类似结果的标准化治疗可能存在问题。患有HRPC的非洲裔美国人（AAs）的总生存率显著低于患有这种疾病的欧洲裔美国人（EAs），肿瘤进展速度更快，对化疗的反应也更差。不幸的是，这些PCa健康差异背后的机制尚未得到很好的研究。为了解决这些问题，Morehouse医学院和JYANT技术公司的研究人员。已经确定了控制PCa细胞生长、转移（至骨）和多西他赛反应率的关键途径-CXCL 13：CXCR 5轴。我们先前报道了CXCR 5在PCa细胞系中的功能性表达，CXCL 13（CXCR 5的唯一配体）可以介导PCa细胞的生长、迁移、侵袭和多西他赛耐药。此外，我们报道了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CXCR 5表达显著更高。我们令人兴奋的初步数据显示，从AA患者切除的前列腺肿瘤的CXCR 5表达显著（高达两倍）高于具有相同疾病阶段的EA。以前，我们证明了PCa患者的血清CXCL 13水平显着较高，这种配体在这种疾病期间发现的条件下由骨髓内皮分泌。最后，我们表明，我们的鼠抗人CXCL 13抗体预防和缩小了在SCID小鼠股骨中建立的HRPC异种移植物。考虑到这些发现，JYANT Technologies寻求开发一种新型人源化抗人CXCL 13单克隆抗体（CXCL 13 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，我们将使用溶骨性和成骨性HRPC以及紫杉醇耐药异种移植物的临床相关小鼠模型来实现以下目标：目标一将使用未处理B6小鼠确定免疫原性，以及在股骨中携带表达磷酸酶的溶骨性（PC 3-luc）和成骨性（C4-2b-luc）异种移植物的SCID小鼠中确定CXCL 13 HuMAB的PK/PD特征。目的二将使用在股骨中用激素难治性（PC 3-luc和C4-2b-luc）和/或紫杉醇耐药（PC 3R-luc和C4 - 2bR-luc）PCa细胞系攻击的SCID小鼠来确定CXCL 13 HuMAB抑制前列腺肿瘤生长和骨中紫杉醇耐药的全身和免疫毒性以及功效。

 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.