Advancing the commercialization readiness of nanoparticle-based immunotherapy for cancer treatment

Treatment of non-small cell lung cancer (NSCLC) requires a combination of many highly toxic drugs and radiation therapy, yet the 5-year survival rate remains about 18%. Immune checkpoint inhibitors (ICIs) targeting PD-L1/PD-1 has caused a paradigm shift in NSCLC treatment, but the response rate is still only 15-20%. PDX Pharmaceuticals in partnership with Oregon Health and Science University is developing a next generation immunotherapy called ARAC-02 that may lead to curative outcomes in a large number of NSCLC patients. ARAC-02 (Antigen Release Agent and Checkpoint Inhibitor) is built upon our core patented nanoparticle platform (Pdx-NPTM) capable of co-delivering multiple therapeutic agents, while keeping a small size in saline, suitable for systemic administration and tumor accumulation. ARAC-02 co-delivers a polo-like kinase 1 (PLK1) siRNA to kill cancer and release antigens as well as modulate immunosuppression in the tumor microenvironment, a PD-L1 antibody to home to cancer cells and serve as immune checkpoint blockade, and immune-stimulant CpG to enhance antigen presentation, leading to strong anti-tumor immune response. The parent fast-track SBIR application was deemed highly impactful and novel that it received a rare perfect score from the NIH scientific review panel. The data was published in Nature Communications and a US patent of ARAC-02 compositions and uses was issued in 2022. We have met the Phase I milestones (formulation optimization) and progressed to Phase II project (efficacy and safety evaluation in multiple animal models). To increase commercialization readiness of ARAC-02, we request the CRP fund to support two activities. Aim 1: To protect intellectual properties (IPs) of the ARAC pipeline. PDX Pharma has been developing next-generation nanoparticle delivery platform (Pdx-NP) and first-in-class combination immunotherapies utilizing our expertise in nanotechnology along with cancer systems biology to select synergistic drug combinations that maximize efficacy and minimize toxicity. Our effort and strong data have led to five US patents issued in the past 2 years. Specific to ARAC-02, we request CRP funds to (1) pursue IP protection of Pdx-NPTM and ARAC-02 abroad (in 10 countries and the EU) and (2) expand the IP coverage to other therapeutic classes beyond PLK1 inhibitors through continuation patent applications. Aim 2: To initiate GMP-compliant manufacturing of ARAC-02. A key ARAC-02’s component is PD-L1 antibody conjugated nanoparticle (A-NP), which will be mixed with PLK1 siRNA and CpG in the clinic. The core nanoparticle (NP) has already been manufactured at large-scale by the CRO. In this Aim, we will perform tech- transfer the synthesis and characterization of A-NP to the same CRO for process familiarization. This aim will be followed by a full GMP-compliant synthesis campaign, which will be funded through private investment. Strong IP portfolio and GMP readiness will enhance our success rate in the upcoming private fund raising and the follow-on Phase IIB SBIR application toward complete IND-enabling studies and clinical trials of ARAC-02.