Triple-negative breast cancer (TNBC) is a subset of breast cancers with poor prognosis and high mortality due to the lack of effective therapeutic regimens. This Phase I SBIR application is to develop E1-Rap, a novel immunoRNases, for treating TNBC. E1-Rap is a DOCK-AND-LOCKTM (DNLTM) complex, comprising four copies of ranpirnase (Rap) site-specifically tethered to the CH3-terminus of hRS7, a humanized monoclonal antibody targeting TROP-2, a transmembrane protein over-expressed in diverse epithelial cancers. We have shown that TROP-2 is present on the surface of TNBC cells, and targeted delivery of E1-Rap significantly enhances the binding, internalization, and cytotoxicity of Rap in TROP-2-positive cell lines. More importantly, E1-Rap has greatly improved the potency over the previously made fusion protein (Rap-hRS7), but maintained minimal toxicity to TROP-2-negative cell lines and human PBMC. In this Phase I application, we will scale up the production of E1-Rap and evaluate the in vivo properties of E1-Rap, including PK, stability, safety, bioavailability, and the therapeutic activity of E1-Rap in human TNBC xenograft models. Successful accomplishments of these Phase I goals will lead to a Phase II application aimed to complete the preclinical development of E1-Rap for clinical trials.
Public Health Relevance Statement: Public Health Relevance: This project will investigate the pharmacokinetics, safety, and bioavailability of E1-Rap, a DOCK-AND-LOCKTM complex of ranpirnase and hRS7 targeting TROP-2-positive epithelial cancers, in particular, triple-negative breast cancer (TNBC), and determine the therapeutic activity of E1-Rap in human TNBC xenograft models.
NIH Spending Category: Breast Cancer; Cancer
Project Terms: A kinase anchoring protein; Accounting; Affinity Chromatography; Aggressive behavior; Amino Acid Sequence; Amphibia; Animal Model; base; Binding (Molecular Function); Biological Availability; Blood; Body Weight decreased; Breast; Breast Cancer Cell; Buffers; Cancer cell line; Cell Culture Techniques; Cell Line; Cells; Chemistry; Chimeric Proteins; Clinical Trials; Complex; Cyclic AMP-Dependent Protein Kinases; cytotoxicity; Development; dimer; Dimerization; disulfide bond; Docking; Dose; Dose-Limiting; Drug Kinetics; Engineering; Enzyme-Linked Immunosorbent Assay; Epidermal Growth Factor Receptor; Epithelial; Escherichia coli; Estrogen Receptors; Fermentation; Goals; Hemorrhage; Human; Human Cell Line; human TACSTD2 protein; humanized monoclonal antibodies; Immunoglobulin G; improved; In Vitro; in vivo; Integral Membrane Protein; interest; Ions; Lead; malignant breast neoplasm; Malignant Neoplasms; Mammalian Cell; Measures; Metals; Monitor; Morphology; Mortality Vital Statistics; Mus; novel; Nude Mice; outcome forecast; Peripheral Blood Mononuclear Cell; Phase; pre-clinical; preclinical study; Preparation; Production; Progesterone Receptors; Property; Proteins; public health relevance; ranpirnase; Regimen; Ribonucleases; Safety; scale up; self assembly; Serum; Site; Small Business Innovation Research Grant; Solid; Surface; targeted delivery; Therapeutic; Tissues; Toxic effect; Treatment Efficacy; Treatment Protocols; triple-negative invasive breast carcinoma; tumor; tumor xenograft; Xenograft Model; Xenograft procedure
