An antibody to IP-10 is a potent antagonist of cell migration in vitro and in vivo and does not affect disease in several animal models of inflammation.
IP-10 secretion is induced by pro-inflammatory cytokines and mediates the migration of CXCR3+ cells. Its elevation in clinical samples has been associated with multiple inflammatory diseases and its antagonism has been reported to be effective in several animal models of inflammatory disease. We generated a mouse anti-mouse IP-10 monoclonal antibody (mAb; Clone 20A9) that specifically bound murine IP-10 with high affinity and inhibited in vitro IP-10 induced BaF3/mCXCR3 cell migration with an IC(50) of approximately 4 nM. The 20A9 mAb was completely absorbed in vivo and had dose proportional pharmacokinetic exposure with a serum half life of 2.4-6 days. The 20A9 mAb inhibited IP-10 mediated T-cell recruitment to the airways, indicating that it is effective in vivo. However, administration of the 20A9 mAb had no significant effect on disease in mouse models of delayed type hypersensitivity, collagen induced arthritis, cardiac allograft transplantation tolerance, EAE or CD4+ CD45RBHi T-cell transfer-induced IBD. These data suggest that the 20A9 mAb can antagonize IP-10 mediated chemotaxis in vitro and in vivo and that this is insufficient to cause a therapeutic benefit in multiple mouse models of inflammatory disease.
Byrne
Fergus R
FR
Amgen Inc., Thousand Oaks, CA, USA. fbyrne@amgen.com
Winters
Aaron
A
Brankow
David
D
Hu
Sylvia
S
Juan
Todd
T
Steavenson
Shirley
S
Doellgast
George
G
Kuchimanchi
Kamesh
K
Brown
Heather
H
Anderson
Sharon
S
Smelt
Sara
S
Sullivan
Tim
T
Alcorn
Dina
D
Tocker
Joel
J
Dean
Charley
C
Macmaster
John
J
Kirchner
Jacqueline
J
Buys
Janet
J
Manoukian
Raffi
R
Jiao
Eric
E
Zou
Xiaoming
X
Campanella
Gabriele S
GS
Siu
Gerald
G
D000818:Animals; D000911:Antibodies, Monoclonal / Q000493:pharmacokinetics / Q000494:pharmacology* / Q000627:therapeutic use*; D001169:Arthritis, Experimental / Q000473:pathology / Q000628:therapy; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology; D018414:CD8-Positive T-Lymphocytes / Q000166:cytology / Q000187:drug effects; D002465:Cell Movement / Q000187:drug effects* / Q000276:immunology; D054357:Chemokine CXCL10 / Q000037:antagonists & inhibitors* / Q000276:immunology*; D004195:Disease Models, Animal; D004681:Encephalomyelitis, Autoimmune, Experimental / Q000473:pathology / Q000628:therapy; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control; D016027:Heart Transplantation / Q000276:immunology; D007249:Inflammation / Q000473:pathology / Q000628:therapy; D015212:Inflammatory Bowel Diseases / Q000473:pathology / Q000628:therapy; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008811:Mice, Inbred DBA; D008815:Mice, Inbred Strains; D016513:Mice, SCID; D054448:Precursor Cells, B-Lymphoid / Q000166:cytology / Q000187:drug effects; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D054357:Chemokine CXCL10