Dendritic Nanoparticles for Enhanced Immune Checkpoint Blockade

Dendritic polymers have drawn considerable attention to be used as a nanoscale platform for various biomedical applications over the past few decades.  Primary advantages of dendrimers include their unique properties to serve as one of the ideal mediators for multivalent binding effect that often results in binding kinetics enhancement by orders of magnitude.  This presentation will focus on our recent efforts on poly(amidoamine) (PAMAM) dendrimers to be engineered as a versatile platform for various immune checkpoint inhibitors (ICIs) to improve their immunotherapy efficacy.  In particular, we have recently prepared dendrimer-based antagonists against programmed cell death protein 1 (PD-1)/programmed death-ligand 1 (PD-L1) interactions that are known as a common pathway of tumor cells evading from immune attack. Generation 7 (G7) PAMAM dendrimers were employed as a platform to accommodate multiple antibodies against PD-L1 (aPD-L1) or PD-L1-binding peptides, followed by characterization, binding kinetics measurements, in vitro cell assays, and in vivo tests.  The three independent binding measurements using surface plasmon resonance (SPR), bio-layer interferometry (BLI), and atomic force microscopy (AFM) all revealed that the dendrimer conjugates exhibited a significantly greater binding kinetics than their free counterparts (either aPD-L1 or PD-L1-binding peptides), by up to five orders of magnitude.  Such enhancement in binding strength was likely achieved through the multivalent binding effect mediated by dendrimers and surface stabilization of the peptide structure.  The enhanced binding was directly translated into significantly improved in vitro efficiency where a significant increase in IL-2 secretion and a reduction in chemoresistance of tumor cells were observed.  Finally, our in vivo studies using mouse models indicated that the dendrimer conjugates selectively accumulated to the tumor with much longer retention than free antibodies. The enhanced biodistribution, tumor selectivity, and effective PD-1/PD-L1 blockade of the dendrimer conjugates all contributed to a significantly improved therapeutic efficacy of the nanoparticles against 4T1-xenograft Balb/c syngeneic mice.  Our results collectively provide a strong proof-of-concept indicating that the dendrimer-based system would serve as a platform for various ICIs that effectively block the immune checkpoint pathways, thereby improving efficacy of cancer immunotherapy.

Seungpyo Hong, Milton J. Henrichs Endowed Chair Professor, University of Wisconsin-Madison