Abstract
In recent years, there have been significant advances in the treatment of breast cancer resulting in remarkably high survival rates. However, treatment options for metastatic triple negative breast cancer (TNBC) are quite limited due to a lack of identifiable, unique markers. Using a phage display-based whole cell biopanning procedure, we developed two human antibodies that bind to tumor cells with a metastatic TNBC phenotype. Our studies further identified domain 1 of HSPG2 (perlecan) protein as the cognate cell surface antigen bound by the antibody. Immunohistochemistry studies utilizing patient tissue samples revealed significant cell surface expression of HSPG2 in both primary tumors and metastatic lesions. Further, higher HSPG2 expression correlated with poor survival in TNBC. The affinity-matured antibody inhibited the growth of triple negative MDA-MB-231 tumors to a greater extent in nude mice than in NSG mice, pointing to the potential role of natural killer cell-mediated antibody-dependent cell cytotoxicity. This mechanism of action was confirmed through in vitro assays using mouse splenocytes and human peripheral blood mononuclear cells (PBMCs). These results suggest that HSPG2 is a promising target in metastatic TNBC and HSPG2-targeted antibodies could represent a potentially novel class of targeted therapeutics for TNBC.
Highlights
Phage display is an effective method for generating target-specific antibody or peptide fragments and for potentially identifying new targets[6]
Our studies further identified heparan sulfate proteoglycan 2 (HSPG2) as the cognate cell surface antigen bound by the antibody
Our results suggest that HSPG2 is a promising therapeutic target in triple negative breast cancer (TNBC)
Summary
Phage display is an effective method for generating target-specific antibody or peptide fragments and for potentially identifying new targets[6]. This method utilizes large, diverse libraries of bacteriophage, displaying antibody fragments on their surface, for in vitro high-throughput screening against a desired peptide/antigen. One key advantage of phage display is its potential to identify new targets in their native, physiological form. This can be useful in cases where targets are not known or have been difficult to identify. We utilized a whole cell, competition-based phage display procedure to identify high affinity binders to metastatic TNBC cells. Our results suggest that HSPG2 is a promising therapeutic target in TNBC
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