Imperial College London
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ProfessorFrederickTam

Faculty of Medicine, Department of Immunology and Inflammation

Ken and Mary Minton Chair of Renal Medicine
 
 
 
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Contact

 

+44 (0)20 3313 2354f.tam

 
 
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Location

 

9N, 15C, Commonwealth BuildingHammersmith HospitalHammersmith Campus

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Summary

 

Publications

Citation

BibTex format

@article{Tam:2017:10.1016/j.ejphar.2017.12.040,
author = {Tam, FWK and Höllriegl, W and Bauer, A and Baumgartner, B and Dietrich, B and Douillard, P and Kerschbaumer, R and Höbarth, G and McKee, J and Schinagl, A and Thiele, M and Weber, A and Wolfsegger, M and Turecek, M and Muchitsch, E-M and Scheiflinger, F and Glantschnig, H},
doi = {10.1016/j.ejphar.2017.12.040},
journal = {European Journal of Pharmacology},
pages = {206--216},
title = {Pharmacokinetics, disease-modifying activity, and safety of an experimental therapeutic targeting an immunological isoform of macrophage migration inhibitory factor, in rat glomerulonephritis},
url = {http://dx.doi.org/10.1016/j.ejphar.2017.12.040},
volume = {820},
year = {2017}
}
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RIS format (EndNote, RefMan)

TY  - JOUR
AB  - New therapeutic agents are needed to overcome the toxicity and suboptimal efficacy observed in current treatment of glomerulonephritis (GN). BaxB01 is a fully human monoclonal antibody targeting a disease-related immunologically distinct isoform of Macrophage migration Inhibitory Factor (MIF), designated oxidized MIF (oxMIF) and locally expressed in inflammatory conditions. We report the pharmacokinetic profile of BaxB01, and its dose and exposure-related disease-modifying activity in experimentally induced rat GN.BaxB01 bound to rat oxMIF with high affinity and reduced rat macrophage migration in vitro. After intravenous administration in rats, BaxB01 demonstrated favorable pharmacokinetics, with a half-life of up to nine days. Disease modification was dose-related (≥10 mg/kg) as demonstrated by significantly reduced proteinuria and diminished histopathological glomerular crescent formation. Importantly, a single dose was sufficient to establish an exposure-related, anti-inflammatory milieu via amelioration of glomerular cellular inflammation. Pharmacodynamic modeling corroborated these findings, consistently predicting plasma exposures that were effective in attenuating both anti-inflammatory activity and reducing loss of kidney function. This pharmacologic benefit on glomerular function and structure was sustained during established disease, while correlation analyses confirmed a link between the antibody's anti-inflammatory activity and reduced crescent formation in individual rats. Finally, safety assessment in rats showed that the experimental therapeutic was well tolerated without signs of systemic toxicity or negative impact on kidney function.These data define therapeutically relevant exposures correlated with mechanism-based activity in GN, while toxicological evaluation suggests a large therapeutic index and provides evidence for achieving safe and effective exposure to a MIF isoform-directed therapeutic in nephritis-associated disease.
AU  - Tam,FWK
AU  - Höllriegl,W
AU  - Bauer,A
AU  - Baumgartner,B
AU  - Dietrich,B
AU  - Douillard,P
AU  - Kerschbaumer,R
AU  - Höbarth,G
AU  - McKee,J
AU  - Schinagl,A
AU  - Thiele,M
AU  - Weber,A
AU  - Wolfsegger,M
AU  - Turecek,M
AU  - Muchitsch,E-M
AU  - Scheiflinger,F
AU  - Glantschnig,H
DO  - 10.1016/j.ejphar.2017.12.040
EP  - 216
PY  - 2017///
SN  - 0014-2999
SP  - 206
TI  - Pharmacokinetics, disease-modifying activity, and safety of an experimental therapeutic targeting an immunological isoform of macrophage migration inhibitory factor, in rat glomerulonephritis
T2  - European Journal of Pharmacology
UR  - http://dx.doi.org/10.1016/j.ejphar.2017.12.040
UR  - http://hdl.handle.net/10044/1/55523
VL  - 820
ER  -
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