Fc folate Conjugate for the Treatment of Triple Negative Breast Cancer

Abstract According to the American Cancer Society in women in the U S will develop breast cancer at some point in their life and of these women will have triple negative breast cancer TNBC an aggressive subtype of breast cancer that lacks the three receptors ER PR HER that current drug treatment targets tamoxifen Herceptin Because of its aggressive nature and lack of effective treatment that specifically targets TNBC it is responsible for of all breast cancer deaths The only treatment options involve chemotherapeutics that destroy healthy tissue by targeting replicating cells Being able to target TNBC tumors directly would reduce toxicity associated with these drugs and decrease mortality from TNBC one of NeuLink s long term goals Recently folate receptor alpha FRA was found to be expressed on of TNBC tissue with high expression correlating with poor prognosis suggesting a target for treating TNBC Preliminary data generated at Wayne State University demonstrates the binding of a novel FRA binding molecule to FRA expressing TNBC cells Upon binding this molecule is able to recruit and activate neutrophils PMNs the major white blood cell in humans to destroy TNBC cells These findings suggest the use of a molecule of this type could effectively kill breast tumor cells and thus represents a promising effective targeted therapeutic treatment for TNBC The hypothesis for this Phase I STTR is that a novel FRA binding molecule NEU will stimulate PMNs by binding to its Fc R receptor to specifically destroy TNBC cells To test this hypothesis the following specific aims are proposed Determine which of NEU variants using of IgA Fc fragments will activate PMNs to kill andgt of human TNBC cell subtypes and Determine which NEU variants will decrease mean tumor volume by andgt in Fc R expressing xenograft models In Aim NEU variants will be synthesized and their ability to activate PMNs to kill basal like BL or mesenchymal like ML subtypes of human TNBC cells cell lines or clinical isolates by FRA binding and cross linking of Fc R on PMN s will be measured and compared PMN mediated ADCC will be tested in a Cr release assay and confirmed by myeloperoxidase MPO activity For Aim these NEU variants will be tested for ability to inhibit tumor growth in xenograft models using the highest NEU responding TNBC cells within both BL and ML subtype as well as clinical isolates from Aim Assessment of cancer cell viability apoptosis Ki active caspase and PMN activation MPO CD Ly G within tumors will be determined by IHC NEU stability in serum and Fc R specificity using isolated mouse PMNs will also be confirmed There is a clear need in the market for drugs specifically targeting TNBC for which no therapy is approved To successfully bring NEU to market as an orphan drug NeuLink together with their advisory board and small business consultants will guide NEU from pre clinical to clinical trials NeuLink s overall strategy after IND filing is to complete Phase I clinical trials and either establish a strategic alliance with a pharmaceutical partner or have NeuLink acquired Project Narrative Public Health Relevance Statement NeuLink Inc plans to develop a drug that will elicit the immune system in a novel way to target and kill triple negative breast cancer cells Since triple negative breast cancer is an aggressive subtype of breast cancer with a high mortality rate this drug would be beneficial in reducing mortality associated with this aggressive disease