Abstract
In recent years, the modalities in drug discovery are being diversified. The lipid nanoparticle (LNP) have attracted attention as the drug delivery vehicles for oligonucleotide therapeutics, which are not stable in the blood, to target organs. However, several LNPs are known to induce the complement activation-related pseudoallergy (CARPA). In order to reduce the risk of CARPA induction by LNP, animal models are used in non-clinical safety studies, but extrapolation to human safety evaluation is low due to species differences. On the other hand, it was assumed that the degree of complement activation by LNP using human samples could be greatly affected by the difference between donors. To address this issue, we attempted to establish in vitro complement activation assessment using multiple human plasmas in order to discover safer LNPs.
First, we investigated the LNP-induced complement activation by measuring the increase of two complement fragments, C3a and C5b-9, using human plasma from approximately 100 donors. As a result, it was observed a difference in the degree of increase in C3a and C5b-9 by LNP between donors. Therefore, we are investigating several factors that led to the donor difference, for example, involvement of anti-polyethylene glycol (PEG) antibody. PEG is one of the components of LNPs, and previous reports have shown that higher concentrations of anti-PEG IgM in the CARPA-symptomatic subjects group compared to the asymptomatic subjects after LNP administration, suggesting that the formation of LNP and anti-PEG IgM complexes is one of the factors related to the induction of CARPA (Kozma et al., Vaccines, 2023).
In this workshop, we will introduce the current status of LNP-mediated CARPA assessments using human plasma and will discuss the expected prospects and challenges for the future.
