Development of a radiation-activatable nanoparticle for lung cancer therapy

Abstract Lung cancer is the second most common cancer and the leading cause of cancer-related deaths. In the U.S., it is estimated that 234,580 people will be diagnosed with lung cancer in 2024. Non-small cell lung cancer (NSCLC) is the most common type of lung cancer, accounting for 80-85% of all cases. Despite advances in radiation therapy (RT), the prognosis for patients with unresectable stage III NSCLC remains poor. To improve efficacy, chemotherapy, most commonly platinum-based doublets, is often administered to patients during RT, known as chemoradiotherapy (CRT). However, toxicity often leads to treatment delays or discontinuation. Therefore, there is an urgent need for new CRT strategies that provide comparable or superior efficacy to conventional CRT but are better tolerated by patients. Athna Biotech, Inc. is developing a novel CRT approach that utilizes radiation to locally activate systemically delivered therapeutics. The company has synthesized a radiation-responsive prodrug, DM1-NO, which is nitrosylated DM1, a maytansinoid. This prodrug can be loaded into PEG-PLGA polymeric nanoparticles and delivered to tumors. To enhance delivery efficiency, the nanoparticles are conjugated with NTSmut, a ligand with high affinity towards NTSR1, which is upregulated in 59.7% of lung tumors. During RT, irradiation increases oxidative stress in tumors, resulting in the dissociation of DM1-NO and the release of DM1 and nitric oxide (NO). Both DM1 and NO are potent radiosensitizers, working synergistically to enhance RT. During the STTR Phase I period, we have demonstrated the selective accumulation and sustained retention of AB-001 within tumors, enhanced tumor penetration, and superior efficacy in combination with radiotherapy compared to conventional treatments while minimizing toxic exposure to vital organs. Successful completion of Phase I studies validated the feasibility and efficacy of AB-001. In this Phase II application, Athna Biotech will work with our academic collaborators and industry partners to further develop AB-001. Specifically, we will scale up and optimize the manufacturing processes of AB-001, produce a GLP batch for stability study and analytical method validation, and assess the efficacy and toxicity of AB-001 in additional murine lung tumor models. Following our Pre-IND meeting with the FDA, we will conduct IND-enabling toxicity evaluations and comprehensive pharmacokinetic studies with AB-001. Successful completion of Phase II will pave the way for IND filing and subsequent human clinical trials. This will ultimately advance AB-001 towards regulatory approval and commercialization, addressing an unmet medical need in the treatment of NSCLC.