Anti-CXCL13 mAb to mitigate prostate cancer health disparities

 描述(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。虽然多西紫杉醇可以延长转移性HRPC患者的总体生存时间，但目前的治疗方法并不能提供治愈的方法。更复杂的是，HRPC是一种对各种患者产生不同影响的疾病，这可能会给医生提供类似结果的标准化治疗带来问题。与患有这种疾病的欧洲美国人(EAs)相比，患有HRPC的非裔美国人(AA)的总存活率显著降低，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还没有得到很好的研究。为了解决这些问题，莫尔豪斯医学院和JYANT Technologies，Inc.的研究人员已经确定了控制PCa细胞生长、转移(到骨骼)和多西紫杉醇反应率的关键途径-CXCL13：CXCR5轴。我们先前报道了CXCR5在PCa细胞系中的功能表达，CXCL13(CXCR5的唯一配体)可以介导PCa细胞的生长、迁移、侵袭和多西紫杉醇耐药。此外，我们报告了进展期前列腺癌患者的前列腺癌组织中CXCR5的表达显著高于正常匹配组织或良性疾病组织。我们令人兴奋的初步数据显示，从AA患者切除的前列腺癌组织中CXCR5的表达显著高于相同疾病分期的EAS患者(高达两倍)。在此之前，我们证明了PCa患者的血清CXCL13水平显著升高，这种配体是在疾病期间发现的条件下由骨髓内皮细胞分泌的。最后，我们证明了我们的鼠抗人CXCL13抗体可以预防和缩小在SCID小鼠股骨中建立的HRPC异种移植。考虑到这些发现，JYANT Technologies寻求开发一种新的人源化抗人CXCL13单抗(CXCL13 HuMAB)，用于治疗HRPC，并解决这种疾病在临床和治疗结果方面的差异。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小鼠模型以及对多西紫杉醇耐药的异种移植模型来实现以下目的：目的：目的利用朴素的B6小鼠，以及CXCL13HuMAb在SCID小鼠的股骨中表达荧光素酶表达的溶骨性(PC3-LUC)和成骨细胞(C4-2b-LUC)异种移植的免疫原性，以及CXCL13HuMAb的PK/PD谱。目的研究CXCL13HuMAb对激素耐药(PC3-LUC和C4-2b-LUC)和/或多西紫杉醇耐药(PC3R-LUC和C4-2BR-LUC)PCa细胞的全身毒性和免疫毒性，以及CXCL13HuMAB抑制前列腺癌生长和骨中多西紫杉醇耐药的效果。

 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.