PDX Pharmaceuticals has been curating a mesoporous silica-based nanoparticle platform (Pdx-NP) to deliver a range of therapeutic cargoes, including antisense oligonucleotides, small molecules, peptides, and antibodies. Worapol Ngamcherdtrakul, Head of Research & COO, PDX Pharmaceuticals, proposed that this platform is more effective than other lipid-based systems at targeting tissues beyond the liver.
The platform uses a mesoporous silica core nanoparticle of roughly 50 nanometres that is benign, soluble over time, and biodegradable. The nanoparticle is combined with polyethylene amine, which is bioreducible and cross-linked to enhance efficacy and lower toxicity. This facilitates effective endosomal escape of cargo like siRNA or oligonucleotides. The particle is then stabilised and ready to be loaded with cargo. Ngamcherdtrakul added that he has made efforts to optimise loading onto their particle.
The crux of the talk focused on the company’s lead candidate, ARAC-02, which they want to bring to the clinic. ARAC-02 is a particle that co-delivers three compounds: PLK1 siRNA, CpG, and PDL-1.
Preclinical data showed that ARAC-02 achieved significant gene knockdown and tumour reduction in mouse models. For example, the knockdown data of PLK1 in tumours residing in the lungs showed an 84% gene knockdown and a 90% tumour reduction. Not only did Ngamcherdtrakul achieve tumour reduction, but also success in immune checkpoint inhibitor-resistant tumours. By manipulating the tumour microenvironment, one could enhance T-cell-mediated immune responses to overcome resistance to checkpoint inhibitors.
Further data showed that in vitro, ARAC-02 effectively kills non-small cell lung cancer (NSCLC) cells across mutation types while sparing healthy cells. Additionally, the studies showed that efficacy is T-cell dependent, as shown by CD8+ T-cell depletion experiments. The platform also demonstrated versatility by effectively delivering various therapeutic agents, including antisense oligonucleotides and cytokines.
Regarding ARAC-02’s suitability in a clinical setting, Ngamcherdtrakul explained that it is manufacturable, scalable, and has been tech-transferred to a GMP-compliant manufacturer. PDX Pharmaceuticals is also keen to partner and collaborate with other companies to push their lead candidate into the clinic.
