Defining dose-response relationships in the therapeutic blockade of B7RP-1-dependent immune responses.
The ICOS (Inducible T cell Co-Stimulator)/B7RP-1 (B7-related protein 1) interaction is critical for the proper activation of a T lymphocyte. In this manuscript we describe a systematic in vivo approach to determine the level of blockade required to impair the generation of a T cell-dependent antibody response. We have developed an overall strategy for correlating drug exposure, target saturation, and efficacy in a biological response that can be generalized for most protein therapeutics. Using this strategy, we determined that low levels of B7RP-1 blockade are still sufficient to inhibit the immune response. These data suggest that contact between the T cell and the antigen-presenting cell during antigen presentation is much more sensitive to inhibition than previously believed and that ICOS/B7RP-1 blockade may be efficacious in the treatment of autoimmune diseases.
Metz
Daniela P
DP
Department of Inflammation Research, Amgen, Inc, One Amgen Center Drive, Thousand Oaks, CA 91320, USA. dmetz@amgen.com
Mohn
Deanna
D
Zhang
Ming
M
Horan
Tom
T
Kim
Helen
H
Deshpande
Rohini
R
Jacobsen
Frederick
F
Shen
Wenyan D
WD
Zhang
Liana
L
Doellgast
George
G
Narayanan
Adimoolam
A
Dalphin
Mark
M
Kuchimanchi
Kameswara Rao V
KR
Horner
Michelle
M
Chung
James
J
Siu
Gerald
G
D000536:Aluminum Hydroxide / Q000276:immunology; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D000938:Antigen-Presenting Cells / Q000276:immunology; D018941:Antigens, CD19 / Q000378:metabolism; D001402:B-Lymphocytes / Q000378:metabolism; D018122:B7-1 Antigen / Q000235:genetics / Q000494:pharmacology*; D001665:Binding Sites; D017252:CD3 Complex / Q000378:metabolism; D016207:Cytokines / Q000097:blood; D004305:Dose-Response Relationship, Drug; D005260:Female; D016650:Fluorescein-5-isothiocyanate / Q000378:metabolism; D005456:Fluorescent Dyes / Q000378:metabolism; D006433:Hemocyanins / Q000276:immunology; D055633:Immune System Phenomena / Q000187:drug effects*; D060945:Inducible T-Cell Co-Stimulator Ligand; D051379:Mice; D008807:Mice, Inbred BALB C; D018448:Models, Immunological; D011485:Protein Binding; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D013601:T-Lymphocytes / Q000378:metabolism; D013696:Temperature; D013997:Time Factors
D000911:Antibodies, Monoclonal; D018941:Antigens, CD19; D018122:B7-1 Antigen; D017252:CD3 Complex; D016207:Cytokines; D005456:Fluorescent Dyes; D060945:Inducible T-Cell Co-Stimulator Ligand; D011993:Recombinant Fusion Proteins; D000536:Aluminum Hydroxide; D006433:Hemocyanins; C032808:keyhole-limpet hemocyanin; D016650:Fluorescein-5-isothiocyanate