Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies

Abstract

(2016) Utility of a human FcRn transgenic mouse model in drug discovery for early assessment and prediction of human pharmacokinetics of monoclonal antibodies, mAbs, 8:6, 1064-1078, DOI: 10.1080/19420862.2016 To link to this article: https://doi.org/10. 1080/19420862.2016 ABSTRACTTherapeutic antibodies continue to develop as an emerging drug class, with a need for preclinical tools to better predict in vivo characteristics. Transgenic mice expressing human neonatal Fc receptor (hFcRn) have potential as a preclinical pharmacokinetic (PK) model to project human PK of monoclonal antibodies (mAbs). Using a panel of 27 mAbs with a broad PK range, we sought to characterize and establish utility of this preclinical animal model and provide guidance for its application in drug development of mAbs. This set of mAbs was administered to both hemizygous and homozygous hFcRn transgenic mice (Tg32) at a single intravenous dose, and PK parameters were derived. Higher hFcRn protein tissue expression was confirmed by liquid chromatography-high resolution tandem mass spectrometry in Tg32 homozygous versus hemizygous mice. Clearance (CL) was calculated using non-compartmental analysis and correlations were assessed to historical data in wild-type mouse, non-human primate (NHP), and human. Results show that mAb CL in hFcRn Tg32 homozygous mouse correlate with human (r 2 D 0.83, r D 0.91, p < 0.01) better than NHP (r 2 D 0.67, r D 0.82, p < 0.01) for this dataset. Applying simple allometric scaling using an empirically derived best-fit exponent of 0.93 enabled the prediction of human CL from the Tg32 homozygous mouse within 2-fold error for 100% of mAbs tested. Implementing the Tg32 homozygous mouse model in discovery and preclinical drug development to predict human CL may result in an overall decreased usage of monkeys for PK studies, enhancement of the early selection of lead molecules, and ultimately a decrease in the time for a drug candidate to reach the clinic.

Linear pharmacokinetic parameters for monoclonal antibodies are similar within a species and across different pharmacological targets: A comparison between human, cynomolgus monkey and hFcRn Tg32 transgenic mouse using a population-modeling approach

“…The exponents required to predict cynomolgus monkey data to human were in agreement with the literature examples. The hFcRn Tg32 mouse data were encouraging as it predicted well to human, and provides a potential species to replace cynomolgus monkey for human PK predictions of mAbs 23 . Volumes of distribution from central and peripheral compartments in general scaled with an allometric exponent of 1, similar to literature analyses.…”

“…In addition, for a subset of mAbs, PK data were available in transgenic mice expressing the human neonatal Fc receptor (Tg32 homozygous hFcRn mice). The hFcRn Tg32 mouse model was chosen over wild type (WT) mouse because mAb PK is often variable in WT mouse with poor predictability to human, which may be due to species differences in binding of human mAbs to mouse FcRn 22 , 23 . Following cellular uptake of mAbs exhibiting linear CL, FcRn functions as a salvage receptor to protect IgG from rapid intracellular catabolism.…”

“…In cynomolgus monkey, single dose IV PK data were available for 23/ 27 mAbs, administered at 1–3 dose levels with n=2 monkeys/ dose. In hFcRn Tg32 transgenic mice, 11 /27 mAbs were administered as previously described 23 at a single IV dose of 3.5 mg/kg (1 mAb) or 5 mg/kg (10 mAbs) with n=5–6 mice per mAb. For the marketed mAbs, popPK estimates were obtained from the literature 19 …”

Utility of immunodeficient mouse models for characterizing the preclinical pharmacokinetics of immunogenic antibody therapeutics

“…However, other studies have shown that hFcRn transgenic mice provided numerically superior human clearance predictions compared to wild-type mice. 3,12 A recent publication using a larger cohort of antibodies showed the Tg32 hFcRn strain predicted human clearance within 2-fold for 100% of the molecules evaluated, whereas wild-type mice predicted human clearance within 2-fold for 73% of the molecules evaluated. 12 A YTE engineered mutation in the Fc region of mAbX-YTE was also evaluated in the SCID mouse model and PK properties were compared to mAbX, which is the same molecule without any mutations.…”

“…3,12 A recent publication using a larger cohort of antibodies showed the Tg32 hFcRn strain predicted human clearance within 2-fold for 100% of the molecules evaluated, whereas wild-type mice predicted human clearance within 2-fold for 73% of the molecules evaluated. 12 A YTE engineered mutation in the Fc region of mAbX-YTE was also evaluated in the SCID mouse model and PK properties were compared to mAbX, which is the same molecule without any mutations. This mutation increases affinity to the human FcRn receptor and can promote recycling of the antibody instead of subsequent degradation, therefore prolonging exposure and half-life.…”