Bench to Bedside Modeling of mRNA Encoding IgG Using a Multiscale Mechanistic Pharmacokinetic-Toxicokinetic (PK-TK)...

Area of Science:

• Pharmacology and Toxicology
• Biotechnology
• Immunology

Background:

• In vivo expression of mRNA-encoded antibodies is a promising therapeutic strategy.
• Translating preclinical findings to clinical applications for mRNA therapeutics faces challenges in delivery, uptake, translation, and binding.

Purpose of the Study:

• To develop a multiscale mechanistic pharmacokinetic-toxicokinetic (PK-TK) model for mRNA-encoded antibody therapeutics.
• To characterize and predict the in vivo behavior of an mRNA therapeutic encoding an anti-claudin 18.2 IgG, from preclinical models to human predictions.

Main Methods:

• Integrated key processes: lipid nanoparticle (LNP) delivery, endocytosis via LDLR, endosomal escape, mRNA translation, IgG distribution, target binding, and cytokine elevation.
• Leveraged in vitro and in vivo data from mice, rats, and non-human primates (NHPs).
• Employed allometric scaling and considered inter-species differences in LDLR expression for human translation.

Main Results:

• The model successfully recapitulated mRNA, expressed IgG, and cytokine/chemokine levels in mice.
• Sensitivity analysis identified critical translational bottlenecks.
• Human predictions informed the selection of a 0.01 mg/kg starting dose for first-in-human trials.

Conclusions:

• The multiscale PK-TK model provides a rational basis for dose selection by highlighting species-specific differences in nanoparticle processing and mRNA translation.
• This framework enhances translational predictability for mRNA-based protein therapeutics, streamlining clinical development.