Development of an extracellular matrix-targeted theranostic radiopharmaceutical for metastatic lung cancer

Cancer is the second leading cause of death in the United States with metastatic cancers accounting for 70-90% of all cancer fatalities. Lung cancer represents the most prevalent cancer type as well as the deadliest, accounting for approximately 20% of all cancer-related deaths. Despite recent advances in novel molecularly targeted therapeutic modalities, including antibody-drug conjugates, cell therapies, and immune checkpoint inhibitors, many lung cancer patients fail to benefit from these treatments and urgently require new therapeutic options, particularly for addressing disseminated metastatic disease. In contrast to targeting cell surface antigens on tumor cells or other cell types, Matrisome Bio is developing targeted therapeutics specific for disease-related components of the extracellular matrix (ECM), circumventing the need to reach tumor cells to facilitate drug delivery and internalization. Some ECM targets present advantages over cellular targets due to the ECM’s high abundance, its expression across various cancer types and stages of disease, including both early and advanced tumors, and its slow turnover, which enables extended retention of ECM-targeted therapeutics at disease sites. Research conducted prior to the founding of Matrisome Bio identified several proteins preferentially expressed in the ECM of lung tumors and metastases. Matrisome Bio is developing molecularly targeted drugs based on a suite of nanobodies that specifically target disease-associated ECM proteins that are highly expressed in lung cancer and other cancer indications and minimally expressed in normal healthy organs. Published research from Matrisome Bio’s founders demonstrates that ECM-specific nanobodies can effectively deliver various payloads in mouse models of solid tumors and metastatic disease. The efforts outlined in this grant aim to build upon these studies by developing a theranostic radiopharmaceutical targeted to an ECM component that we have identified, which is expressed in over 90% of lung tumors and metastases, and which we believe holds the potential to transform the treatment of advanced lung cancer. This Direct to Phase II SBIR application aims to (1) develop refined binder molecules facilitating optimized biodistribution and tumor uptake behavior, characterize target binding kinetics, and optimize preclinical-scale radiolabeling formulations; (2) characterize in vivo biodistribution and clearance kinetics of select binders and determine tolerability in a dose escalation study in preclinical models of lung cancer; and (3) evaluate preclinical efficacy, safety, and toxicity of lead binder molecules as well as conduct a pre-IND meeting with FDA. This project aims to demonstrate the feasibility of developing and optimizing ECM-targeting theranostic radiopharmaceuticals with characteristics suitable for effective use in the diagnosis and treatment of advanced lung cancer in humans. Project Number: 1R44CA298532-01A1 | Fiscal Year: 2025 | NIH Institute/Center: National Cancer Institute (NCI) | Principal Investigator: Dennis Zimmermann (+1 co-PI) | Institution: MATRISOME BIO, INC., Cambridge, MA | Award Amount: $1,233,778 | Activity Code: R44 | Study Section: Special Emphasis Panel[ZCA1 TCRB-5 (M2)] View on NIH RePORTER: https://reporter.nih.gov/project-details/11253387