Abstract 4036: Integrating dendrimers and peptide-based biologics to co-target immune checkpoints and oncogenic pathways for HNSCC treatment

Abstract The utilization of peptides as cancer therapeutics has tremendous potential given their nature of mimicking protein functionalities while maintaining a high degree of modularity in their molecular design. However, their translation into the clinic remains a challenge due to their inferior binding kinetics, poor bioavailability, and short plasma half-life. To address these, we employed multivalent dendrimers that improve the binding and stability of the peptide-based biologis. We herein present a translatable, modular nanoparticle platform, utilizing generation 7 (G7) poly (amidoamine) (PAMAM) dendrimers conjugated with engineered peptides (dendrimer-peptide conjugates, DPCs). This approach capitalizes on the multivalent binding effect mediated by dendrimers. We found that DPCs functionalized with peptides targeting programmed death-ligand 1 (PD-L1, DPCPD-L1), a crucial immune checkpoint protein in HNSCC, exhibit significantly lower KD at 163 nM, which was three orders of magnitude stronger than free peptides. Furthermore, DPCPD-L1 prolonged the serum half-life to 10. 8 hours, approximately 14 times longer than that observed with PD-L1-binding peptide alone. The enhanced binding kinetics and plasma stability of DPCPD-L1 were translated into the in vivo efficacy, as evidenced by a significant 40% reduction in tumor volume after four injections of DPCPD-L1 at a dosage of 50 mg/kg in mice bearing oral carcinoma (MOC1) tumors. The transcriptomic analysis of DPCPD-L1-treated tumor tissues revealed an increased population of CD4- and CD8-positive lymphocytes while decreasing the regulatory T cells and tumor cell proliferation, which is likely related to the observed efficacy. Expanding on this study, we have employed peptides designed to bind to the epidermal growth factor receptor (EGFR), a key player in the oncogenic pathways of HNSCC. These peptides were conjugated to G7 PAMAM dendrimer, forming DPCEGFR. Similar to DPCPD-L1, DPCEGFR displayed improved binding affinity as proven by biophysical measurements and a series of in vitro assays. All these results highlight the versatility of our DPC platform, suggesting its potential applicability not only for targeting immune checkpoint proteins but also for intervening oncogenic pathways. With its simplicity, modularity, and versatility, this platform indicates the possibility of broadening its scope to incorporate multiple targeting and therapeutic factors, paving the way for its clinical translation, and providing new avenues in HNSCC treatment. Citation Format: DaWon Kim, Piper Rawding, Mari Iida, Kourtney Kostecki, Bridget Mehall, Deric Wheeler, Seungpyo Hong. Integrating dendrimers and peptide-based biologics to co-target immune checkpoints and oncogenic pathways for HNSCC treatment abstract. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts) ; 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84 (6Suppl): Abstract nr 4036.