Anti-CXCL13 mAb to mitigate prostate cancer health disparities

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 CXCL CXCR axis We previously reported the functional expression of CXCR by PCa cell lines and that CXCL the only ligand for CXCR can mediate PCa cell growth migration invasion and docetaxel resistance In addition we reported significantly higher CXCR expression by prostate tumors from patients with advance PCa than compared to normal matched or benign disease tissues Our exciting preliminary data show CXCR 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 CXCL 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 CXCL 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 CXCL monoclonal antibody CXCL 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 na ve B mice and the PK PD profile of CXCL HuMAB in SCID mice bearing luciferase expressing osteolytic PC luc and osteoblastic C b luc xenografts in femurs Aim Two will determine the systemic and immune toxicity as well as the efficacy of CXCL HuMAB to inhibit prostate tumor growth and docetaxel resistance in bone using SCID mice challenged in femurs with hormone refractory PC luc and C b luc and or docetaxel resistant PC R luc and C bR luc PCa cell lines PUBLIC HEALTH RELEVANCE To date there is no cure for metastatic HRPC chemoresistance toxicities and variable response rates hinder the use of many drugs e g docetaxel to treat PCa Using clinically relevant HRPC models this study tests the utility of targeting the CXCL CXCR axis which is highly elevated in AAs than compared to EAs with HRPC