The effect of the neonatal Fc receptor on human IgG biodistribution in mice

Chen, Nancy; Wang, Weirong; Fauty, Scott E.; Fang, Yulin; Hamuro, Lora; Hussain, Azher; Prueksaritanont, Thomayant

doi:10.4161/mabs.27765

Cited by 43 publications

(48 citation statements)

References 32 publications

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“…While few reports suggest FcRn may not contribute significantly toward tissue distribution of mAbs, 14 a recent report proposes that FcRn may play a significant role in mAb biodistribution. 15 Our data (Fig. 5) shows that the relationship between protein size and tissue uptake holds true for both FcRn binding and nonFcRn binding antibody fragments, suggesting an insignificant contribution of FcRn in transcytosis-mediated tissue uptake.…”

Section: Discussionmentioning

confidence: 59%

Influence of molecular size on tissue distribution of antibody fragments

Krippendorff

Sharma

et al. 2015

mAbs

133

104

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Biodistribution coefficients (BC) allow estimation of the tissue concentrations of proteins based on the plasma pharmacokinetics. We have previously established the BC values for monoclonal antibodies. Here, this concept is extended by development of a relationship between protein size and BC values. The relationship was built by deriving the BC values for various antibody fragments of known molecular weight from published biodistribution studies. We found that there exists a simple exponential relationship between molecular weight and BC values that allows the prediction of tissue distribution of proteins based on molecular weight alone. The relationship was validated by a priori predicting BC values of 4 antibody fragments that were not used in building the relationship. The relationship was also used to derive BC50 values for all the tissues, which is the molecular weight increase that would result in 50% reduction in tissue uptake of a protein. The BC50 values for most tissues were found to be~35 kDa. An ability to estimate tissue distribution of antibody fragments based on the BC vs. molecular size relationship established here may allow better understanding of the biologics concentrations in tissues responsible for efficacy or toxicity. This relationship can also be applied for rational development of new biotherapeutic modalities with optimal biodistribution properties to target (or avoid) specific tissues.

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Section: Discussionmentioning

confidence: 59%

Influence of molecular size on tissue distribution of antibody fragments

Krippendorff

Sharma

et al. 2015

mAbs

133

104

View full text Add to dashboard Cite

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“…Studies from blood and brain tissue analysis of 125 I-labeled IgG intravenously administered into WT and FcRn KO mice showed no significant differences in the AUC (area under the curve of IgG concentration) ratio between brain and blood. [24][25][26] Interestingly, studies using methods to localize dosed antibodies via immunohistochemistry and confocal microscopy of antibody against rat FcRn a-chain in rat brain seemed to suggest that FcRn enabled the transport of monoclonal antibodies across the blood-brain barrier. The likely mechanism is reverse transcytosis in brain microvascular endothelial cells that form the blood brain barrier, enabling the efflux of IgG from the brain.…”

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confidence: 99%

Tissue expression profile of human neonatal Fc receptor (FcRn) in Tg32 transgenic mice

Fan

Avery

Wang

et al. 2016

mAbs

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“…26 It has been previously documented from mAb biodistribution studies in mice using a radiolabeled mAb that the liver and spleen are the primary sites for IgG catabolism. 27,28 Measuring the concentration of FcRn protein in liver and spleen relative to other organs will help elucidate the role of FcRn in the distribution and catabolism of mAbs.…”

Section: Introductionmentioning

confidence: 99%

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

Avery

Wang

Kavosi

et al. 2016

mAbs

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(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.

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The effect of the neonatal Fc receptor on human IgG biodistribution in mice

Abstract: (2014) The effect of the neonatal Fc receptor on human IgG biodistribution in mice, mAbs, 6:2, 502-508,

Cited by 43 publications

References 32 publications

Influence of molecular size on tissue distribution of antibody fragments

Influence of molecular size on tissue distribution of antibody fragments

Tissue expression profile of human neonatal Fc receptor (FcRn) in Tg32 transgenic mice

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

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