Humanized anti-CXCL1 antibody for bladder cancer therapeutics

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SUMMARY Background: The progressive growth of tumors and their ability to metastasize are dependent on an adequate tumor blood supply. Chemokine (C-X-C motif) ligand 1 (CXCL1), a well-known chemokine, has been identified as a potential therapeutic target for bladder cancers (BCa) as well as urinary biomarker for BCa detection. Chemokines are known to be critical mediators of the inflammatory response by regulating recruitment of immune cells from both the innate and adaptive immune systems to diseased tissues. Also, chemokines have been known to regulate multiple processes during tumor progression including primary tumor growth, tumor angiogenesis and development of metastatic disease. Previously, we found that CXCL1 is overexpressed in BCa and CXCL1 expression is associated with a worse disease-specific survival. We also reported that CXCL1 is expressed and secreted from human endothelial cells and interference of CXCL1 function using a neutralizing antibody resulted in a reduction in endothelial cell migration and cellular proliferation. We previously developed mouse anti-human CXCL1 monoclonal antibody (HL2401) and demonstrated that inhibition of CXCL1 by HL2401 results in the diminution of bladder and prostate xenograft tumoral growth through the inhibition of angiogenesis and proliferation along with an induction of apoptosis. Recently, we developed a first-in-class humanized neutralizing monoclonal antibody towards CXCL1 (NTC-001), that if found to be effective and safe in animals, could readily move into phase 1 clinical trials. Pilot studies demonstrated that NTC-001 inhibited capillary tube formation and sprouting in HUVEC and cell proliferation in BCa cell lines with IC50 value of 60-165 μg/ml. Hypothesis: Neutralization of CXCL1 by humanized monoclonal antibody can be a potent strategy for BCa therapy. Specific Aims: 1) To assess whether our humanized anti-CXCL1 antibody, NTC-001, exhibit inhibitory effects on angiogenesis and tumor growth in vivo; 2) To examine the effect of NTC-001 on tumor growth in a humanized BCa patient-derived xenograft (PDX) model. Significance: The results obtained from this project will provide a new drug into the clinic for BCa therapy and beyond. Methodology: With animal models including Matrigel plug assay and human BCa cell line derived xenografts, we will assess the effect of humanized antibody on angiogenesis and tumor growth. Using BCa patient-derived xenograft model in humanized immune system mice, we will examine 1) the efficacy of NTC-001 on tumor growth and survival, 2) potential effects, specifically neutropenia, and 3) the effects on the tumor microenvironment. Expected Results: Based on our previous works, we expect that anti-human CXCL1 humanized antibody is effective on bladder tumorigenesis. How results will affect other research areas: Since CXCL1 is highly expressed in most cancers, the findings will have important implications on developing new therapies against other cancers.