Abatacept does not induce direct gene expression changes in antigen-presenting cells.
BACKGROUND
It has been proposed that ligation of CD80 and CD86 induces reverse signaling into antigen-presenting cells. In this study, we tested the ability of abatacept, a soluble human fusion protein comprising the extracellular domain of cytotoxic T lymphocyte antigen 4 and a fragment of the Fc domain of IgG(1), to activate antigen-presenting cells by measuring changes in global transcriptional responses.


METHODS
Affymetrix chips were used to measure gene expression levels using mRNA isolated from immature and mature human dendritic cells and a B cell line following 6 h of treatment with abatacept.


RESULTS
In contrast to robust transcriptional responses induced by the control treatment phorbol-12-myristate-13-acetate, abatacept induced minimal gene changes in three different populations of antigen-presenting cells. Furthermore, no gene changes were observed in response to belatacept, a modified version of abatacept that binds with higher avidity to CD80 and CD86.


CONCLUSIONS
We conclude that reverse signaling in antigen-presenting cells is unlikely to occur in response to either abatacept or belatacept, thereby supporting the modulation of CD28 signaling on T cells as the main mechanism of action for these therapeutics.
Carman
Julie A
JA
Discovery Biology, Bristol-Myers Squibb, Princeton, NJ, USA. julie.carman@bms.com
Davis
Patricia M
PM
Yang
Wen-Pin
WP
Zhu
Jun
J
Chang
Han
H
He
Aiqing
A
Truong
Amy
A
Suchard
Suzanne J
SJ
Nadler
Steven G
SG
D000069594:Abatacept; D017951:Antigen Presentation / Q000187:drug effects*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology; D018122:B7-1 Antigen / Q000276:immunology / Q000378:metabolism*; D051940:B7-2 Antigen / Q000276:immunology / Q000378:metabolism*; D045744:Cell Line, Tumor; D016207:Cytokines / Q000096:biosynthesis / Q000276:immunology; D003713:Dendritic Cells / Q000187:drug effects* / Q000276:immunology; D015870:Gene Expression / Q000187:drug effects; D006801:Humans; D018796:Immunoconjugates / Q000494:pharmacology*; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D010703:Phorbol Esters / Q000494:pharmacology
D018122:B7-1 Antigen; D051940:B7-2 Antigen; D016207:Cytokines; D018796:Immunoconjugates; D007166:Immunosuppressive Agents; D010703:Phorbol Esters; C119222:phorbol-12-myristate; D000069594:Abatacept