Development of a LRP6 Monoclonal Antibody for Triple Negative Breast Cancer

DESCRIPTION provided by applicant Triple negative breast cancer TNBC represents an aggressive tumor type with a distinct lack of effective treatment options Standard of care chemotherapy regimens typically produce a partial response followed by regression months to years later This Phase I application tests the hypothesis that in subtypes of TNBC activation of the WNT pathway represents the underlying mechanism of resistance to chemotherapy Subsets of TNBC patients demonstrate high levels of LRP which correlates with activated WNT signaling and poor prognosis Over the past years a clear link has been established between breast cancer stem cells and activated WNT signaling Cells that are not affected by chemotherapy often exhibit activated WNT signaling However the distinct lack of effective WNT inhibitors has slowed the translation of these discoveries into patients No WNT inhibitors are available in the clinic We have developed a monoclonal antibody that targets LRP a co receptor in the canonical WNT pathway The initial mouse IgG antibody SST mAb demonstrates significant in vitro and in vivo activity to inhibit the WNT pathway Based on these studies in order to facilitate clinical development we have developed a human chimeric version SST mAb that potently inhibits WNT signaling in a TNBC cell line SST mAb targets the hinge region of the extracellular domain of LRP which is unique from other approaches by pharma biotech to target LRP Additionally SST mAb specifically targets canonical WNT activation unlike other pan WNT inhibitors currently in early clinical trials This SBIR Phase I application proposal is designed to initially evaluate SST mAbandapos s in vitro potency in inhibiting the growth of TNBC cell lines with elevated LRP as well assess SST mAbandapos s efficacy in established cancer stem cell assays We will perform subsequent studies to evaluate SST mAbandapos s in vivo efficacy as monotherapy and in combination with standard of care drugs currently used for treating TNBC Targeted biologics have the distinct advantage of exhibiting specificity for the target while minimizing off target toxicities Our overall goal and development approach uses an established model for a streamlined progression through to clinical trials Successful completion of these Phase I aims represents critical steps toward those goals PUBLIC HEALTH RELEVANCE The discovery of a therapeutic to effectively treat triple negative breast cancer TNBC would represent a major breakthrough in cancer research This application outlines the next steps in the evaluation a unique monoclonal antibody that targets subsets of TNBC patients that have high levels of WNT signaling Successful completion of these aims will allow us to progress this technology closer to proof of concept in the clinic