Abstract 5740: Peptide-functionalized dendrimers for enhanced binding to immune checkpoint proteins

Abstract

Abstract The human immune system has complex and dynamic mechanisms to distinguish and eliminate malignant cells and defend the body against cancer. Various therapeutic approaches to stimulate the immune system have thus been investigated, demonstrating strong anti-tumor immune responses capable of controlling metastasis and preventing recurrence. Nevertheless, existing cancer immunotherapies suffer from several limitations, including inconsistent benefits across cancer types and patients. In recent years, the utilization of peptides for immunotherapy has attracted a great deal of interest due to their ability to mimic protein functionalities while maintaining a high degree of modularity and synthetic reproducibility in their molecular design. However, the clinical translation of otherwise promising peptide-based immunotherapeutics has been hindered due to their significantly weaker binding to target proteins and short half-life in plasma circulation in comparison to their monoclonal antibody counterparts. Nevertheless, these issues can potentially be addressed by conjugation to nanoparticles, which enhances cell binding/uptake and prolongs circulation. To this end, our group has extensively investigated the use of poly(amidoamine) (PAMAM) dendrimers to improve the therapeutic utility of peptides. These dendrimers can facilitate the simultaneous binding of conjugated peptides to multiple cell receptors, resulting in a significantly enhanced binding interaction through the multivalent binding effect. Here, we report an efficient de novo nanoparticle design strategy that combines organic synthesis, phage display, and molecular dynamics to identify a novel immuno-oncology therapeutic modality. We first employed phage display to identify several highly selective sequences that bind to the mouse ortholog of TIGIT—an inhibitory receptor expressed on lymphocytes that has been identified as a potential therapeutic target to enhance anti-tumor immune responses. Subsequent computational modeling (NAMD with CHARMM force field) revealed several conserved regions of interaction that we hypothesize drive favorable binding interactions and enhance the binding affinity of the peptide inhibitors. We next incorporated experimental kinetic measurements of the identified sequences with adaptive evolution computational modeling to identify optimized mutant analogs for dendrimer conjugation. It was found that the TIGIT targeting DPCs (dendrimer-peptide conjugates) demonstrated increased binding avidity in vitro and anti-tumor efficacy in vivo, most notably when administered in combination with PD-L1 targeting DPCs to a syngeneic mouse model bearing mouse oral carcinoma (MOC1) tumors. Overall, this work demonstrates the potential of rational peptide design and our multi-functional DPC platform for the development of both effective and novel immuno-oncology therapeutics. Citation Format: Piper Anne Rawding, Francesco Coppola, DaWon Kim, Michael Poellmann, Deric Wheeler, Petr Král, Seungpyo Hong. Peptide-functionalized dendrimers for enhanced binding to immune checkpoint proteins [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(6_Suppl):Abstract nr 5740.