Abstract: In this Direct to Phase II SBIR application, miRecule proposes to develop MC-30 an Antibody RNA Conjugate (ARC), composed of the anti-EGFR antibody cetuximab conjugated to a chemically modified mimic of the tumor suppressor microRNA miR-30-5p. Head and Neck Squamous Cell Carcinoma (HNSCC) is the 6th most common form of cancer worldwide. Greater than half of patients present with locoregionally advanced form of disease, with an average 5-year survival rate of ~40%. Cetuximab is currently approved to treat this subset of patients but only offers mild treatment benefit. This is partly due to EGFR targeted therapy often being compensated for by overexpression of other growth factor receptors (GFRs) such as MET and IGF1R. However, we have discovered that miR-30-5p simultaneously targets and repress all three of these GFRs. The rationale for miR- 30-5p replacement therapy is that it will be superior in its ability to treat heterogeneous late-stage HNSCC due to its ability to regulate not only EGFR, but also MET, IGF-1R, and over two dozen other mRNAs confirmed to be deregulated in tumor tissue and associated with proliferation, adhesion, migration, extracellular matrix remodeling, and differentiation. MC-30 has three independent mechanisms of action, inhibition of EGFR signaling and induction of ADCC by the cetuximab antibody component, and if the ARC is internalized the RNA payload can suppress several oncogenic mechanisms and kill the cancer cell. We have demonstrated in pre-clinical mouse models that MC-30 better than doubles tumor growth inhibition and survival compared to cetuximab. We have also demonstrated that in preliminary toxicology studies that MC- 30 has a similar safety profile in mice and NHPs to the parent antibody. In this direct to phase 2 application we will; 1) Validate MC-30 efficacy in diverse PDX and Syngeneic mouse models compared to standard of care. 2) Execute process development and scale up of our MC-30 ARC and create a panel of CMC release tests for GMP manufacturing. 3) PK Bioanalytical method tech transfer, and GLP validation for IND and Phase 1 studies. 4) Perform Non-GLP PK and maximum tolerated dose range finding studies in NHPs. Successful execution of this proposal will finish our data package for our Pre-IND meeting with FDA, and subsequent initiation of IND enabling studies.