Factors Influencing Monoclonal Antibody Pharmacokinetics Across Varying Immune Perturbations

Abstract

The development of continuous-release devices or injectables for the long-term delivery of biologics is of great interest, especially monoclonal antibodies (mAbs) that require frequent, high-dose injections. Preclinical testing of these technologies in murine models is necessary for clinical translation; however, xenogeneic responses to the mAb and foreign body responses to the implants or injectables can confound results. Immune system knockout (KO) models that affect immune cells are often used in these experiments, but the effects of KO models on mAb pharmacokinetics (PK) are not well characterized. Here, we investigated the PK profile of the human mAb 3BNC117 after intravenous, subcutaneous, and intraperitoneal injections in four mouse strains: BL6, BCD, RAG2, and NSG mice. Noncompartmental analysis was used to quantify differences in PK between each mouse strain. Strikingly, both BL6 and NSG mice exhibited significantly higher mAb clearance compared to the other two strains. To better understand these differences, we developed a minimally physiological based PK model of mAb PK and estimated model parameters using nonlinear mixed effects modeling. The fitted model parameters illustrated how specific processes change in each strain, including the change in clearance rates over time in BL6 and differences in mAb lymphatic uptake in NSG mice. We then used simple allometric scaling relationships to assess which strains were reasonably predictive of human mAb PK. NSG and BL6 mice were found to be unpredictive of human PK, unlike RAG2 and BCD mice. Overall, these results highlight the importance of selecting an appropriate KO strain for preclinical mAb evaluation and demonstrate that RAG2 and BCD strains are suitable mouse models for investigation of mAb PK. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=64 SRC="FIGDIR/small/651349v1_ufig1.gif" ALT="Figure 1"> View larger version (16K): org.highwire.dtl.DTLVardef@138af32org.highwire.dtl.DTLVardef@763196org.highwire.dtl.DTLVardef@1b17331org.highwire.dtl.DTLVardef@10199e9_HPS_FORMAT_FIGEXP M_FIG C_FIG