In vitro potency, pharmacokinetic profiles, and pharmacological activity of optimized anti-IL-21R antibodies in a mouse model of lupus.
Using phage display, we generated a panel of optimized neutralizing antibodies against the human and mouse receptors for interleukin 21 (IL-21), a cytokine that is implicated in the pathogenesis of many types of autoimmune disease. Two antibodies, Ab-01 and Ab-02, which differed by only four amino acids in V(L) CDR3, showed potent inhibition of human and mouse IL-21R in cell-based assays and were evaluated for their pharmacological and pharmacodynamic properties. Ab-01, but not Ab-02, significantly reduced a biomarker of disease (anti-dsDNA antibodies) and IgG deposits in the kidney in the MRL-Fas(lpr) mouse model of lupus, suggesting that anti-IL-21R antibodies may prove useful in the treatment of lupus. Ab-01 also had a consistently higher exposure (AUC(0-infinity)) than Ab-02 following a single dose in rodents or cynomolgus monkeys (2-3-fold or 4-7-fold, respectively). Our data demonstrate that small differences in CDR3 sequences of optimized antibodies can lead to profound differences in in vitro and in vivo properties, including differences in pharmacological activity and pharmacokinetic profiles. The lack of persistent activity of Ab-02 in the MRL-Fas(lpr) mouse lupus model may have been a consequence of faster elimination, reduced potency in blocking the effects of mouse IL-21R, and more potent/earlier onset of the anti-product response relative to Ab-01.
Vugmeyster
Yulia
Y
Department of Pharmacokinetics, Pfizer, Inc., Andover, MA, USA.
Guay
Heath
H
Szklut
Pamela
P
Qian
Ming D
MD
Jin
Macy
M
Widom
Angela
A
Spaulding
Vikki
V
Bennett
Frann
F
Lowe
Leslie
L
Andreyeva
Tatyana
T
Lowe
David
D
Lane
Steven
S
Thom
George
G
Valge-Archer
Viia
V
Gill
Davinder
D
Young
Deborah
D
Bloom
Laird
L
D000818:Animals; D000888:Antibodies, Anti-Idiotypic / Q000008:administration & dosage* / Q000276:immunology; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000276:immunology / Q000493:pharmacokinetics; D057134:Antibodies, Neutralizing / Q000008:administration & dosage* / Q000276:immunology; D002478:Cells, Cultured; D022801:Complementarity Determining Regions / Q000235:genetics; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D007274:Injections, Intraperitoneal; D007275:Injections, Intravenous; D007279:Injections, Subcutaneous; D007378:Interleukins / Q000276:immunology; D008180:Lupus Erythematosus, Systemic / Q000276:immunology / Q000628:therapy*; D008252:Macaca fascicularis; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D008815:Mice, Inbred Strains; D051381:Rats; D017207:Rats, Sprague-Dawley; D053655:Receptors, Interleukin-21 / Q000037:antagonists & inhibitors* / Q000276:immunology; D000098546:Interleukin-21
D000888:Antibodies, Anti-Idiotypic; D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D022801:Complementarity Determining Regions; D007378:Interleukins; D053655:Receptors, Interleukin-21; D000098546:Interleukin-21