Bench to Bedside Modeling of mRNA Encoding IgG Using a Multiscale Mechanistic Pharmacokinetic-Toxicokinetic (PK-TK) Model: A Case Study With Anti-Claudin 18.2.

ABSTRACT: In vivo expression of mRNA-encoded antibodies offers a novel platform for targeted therapies. However, translating preclinical findings to clinical applications remains challenging due to complex processes, including nanoparticle delivery, cellular uptake, mRNA translation, and target binding. This study developed a multiscale mechanistic pharmacokinetic-toxicokinetic (PK-TK) model to characterize and predict the in vivo behavior of an mRNA therapeutic encoding an anti-claudin 18.2 IgG, scaling from preclinical models to human predictions. The model integrates key processes: (i) lipid nanoparticle (LNP)-mediated delivery and endocytosis via low-density lipoprotein receptors (LDLR), (ii) endosomal escape and mRNA release, (iii) cytoplasmic mRNA translation into IgG, (iv) IgG systemic distri

SUBMITTER: Desai DA 

PROVIDER: S-EPMC12451478 | biostudies-literature | 2025 Sep

REPOSITORIES: biostudies-literature