The proposed developmental activity will result in a humanized monoclonal antibody, Tiptuhumab, which acts as a radiomodulator/immunotherapeutic. This antibody targets the cancer neoantigen, Tax Interacting Protein-1 (TIP-1), and is cytotoxic to non-small-cell lung cancer cells, NSCLC. For patients with NSCLC, the 5-year overall survival rate is 14.9% with a median survival time of 4 months. The challenge in treatment outcomes is partly due to tumor genetic heterogeneity, patient heterogeneity, tumor-induced immunosuppression, and limited drug bioavailability to cancer cells. The impact of current cytotoxic chemotherapies on NSCLC is limited by resistance to therapy and disease recurrence. In addition to the limited survival rates, some of the major problems with the current treatment modalities of NSCLC include their lack of specificity and the attendant cytotoxicity to normal cells. The proposed research is the development of our lead antibody, towards IND enabling studies. We identified TIP-1 through the use of bacteriophage displayed peptide libraries and subsequent affinity purification of surface proteins from lung cancer. TIP-1 is a scaffold protein that binds to cellular proteins that regulate cancer cell viability and invasiveness. TIP-1 expression is elevated in cancer cells including NSCLC and localizes to the cell surface. TIP-1 overexpression correlates with the poor outcomes in terms of both overall survival and progression-free survival. Our anti-TIP-1 antibody binds to and sensitizes NSCLC cells to radiation. Anti-TIP-1 mAbs are internalized and trigger apoptosis. In addition, we have demonstrated the specificity of this antibody to implanted NSCLC cells in animal tumor models. We will humanize our lead mouse monoclonal antibody and measure the efficacy of Tiptuhumab as an effective immunotherapeutic agent in preclinical / PDX / humanized model systems of NSCLC. Furthermore, we will study the pharmacokinetics and pharmacodynamics using established methods in rats and monkey, and determine the human dosage for planned first in human clinical trials. The goal of this research is to develop and demonstrate the efficacy of Tiptuhumab and prepare for a pre-IND meeting with FDA.