(59a) Controlling the Immune Response through Controlling the Aggregation Kinetics of Engineered Peptides

Regardless of the organism in which it occurs, the immunogenic cell death process follows a similar trend: aggregation of proteins (or peptides) at a cell membrane causes damage to the cell membrane, and this damage subsequently releases natural adjuvants called damage-associated molecular patterns (DAMPs) which are natural adjuvants for the immune system. For example, Alzheimer’s Disease is a multifactorial disease of unknown etiology, but the central hypothesis is that it is triggered by an accumulation of the pathogenic peptide amyloid beta Aβ_1-42 in the brain. Aβ_1-42 spontaneously aggregates into soluble fibrils and oligomers, which are the primary toxic forms of Aβ_1-42, and create immunogenic cell death and DAMPs release. We recently designed peptides inspired by the intermolecular interactions as in Aβ_1-42 peptides and aggregate in the cellular environment, inducing a local and transient immunogenic cell death. The results of the process akin to Aβ_1-42 oligomers in terms of inducing the immune response through cell membrane rupture, which we called “peptide-aggregation induced immunogenic rupture (PAIIR)”.¹

In this study, we showed the control over peptide assembly, as in Aβ_1-42 oligomerization, to control the immune response effect of PAIIR, as vaccine adjuvants.² In this study, we created aggregates of the PAIIR that can assemble in different kinetics (shown as 0.002% fastest and 0.2% slowest). The aggregation kinetics affected their cell membrane rupture kinetics, thus their immunogenicity. We showed detailed characterization of the peptide aggregation, membrane damage, and cell death profiles of these aggregates on several cell lines. We used ovalbumin (OVA) as the antigen and prepared cocktails of different aggregation PAIIRs. Antibody formation in mice followed the same aggregation kinetics profile (Fig.1); the slowest aggregation provided the highest number of antibodies. In this study, we showed controlling the effects of biomaterials on the cells and overall organism, through molecular engineering principles.

[1] Hamsici, S. et al. Peptide framework for screening the effects of amino acids on assembly. Science Advances (2022)

[2] Gunay, G. et al. Peptide Aggregation Induced Immunogenic Rupture (PAIIR). BioRxiv (2022)