Abatacept binds to the Fc receptor CD64 but does not mediate complement-dependent cytotoxicity or antibody-dependent cellular cytotoxicity.
OBJECTIVE
To assess the ability of abatacept to mediate complement-dependent cytotoxicity (CDC) or antibody-dependent cellular cytotoxicity (ADCC) of antigen-presenting cells, and to characterize the binding of abatacept to the 3 Fc receptor classes.


METHODS
CDC was measured in vitro using rabbit, baby rabbit, guinea pig, or human complement with human B cell line PM-LCL as the target. ADCC was also measured with PM-LCL target cells, but with human peripheral blood mononuclear cells from 12 healthy blood donors as effectors. Fc receptor binding was analyzed in vitro by flow cytometry and surface plasmon resonance (SPR).


RESULTS
In contrast to unmodified CTLA4-Ig, abatacept did not mediate CDC or ADCC of target B cells. While abatacept was found to bind its target receptor, CD80/86, it did not appreciably bind the low-affinity Fc receptors CD16 and CD32 as measured by flow cytometry and SPR. Abatacept was found to minimally bind the high-affinity Fc receptor CD69 as measured by flow cytometry and SPR with a Kd of 3 X 10-7 M as measured by SPR.


CONCLUSIONS
Abatacept does not mediate CDC or ADCC of target B cells in vitro and has limited Fc receptor binding. These data support the concept that abatacept therapeutic activity is primarily due to the binding to CD80/86 through the CTLA4 extracellular domain and not through activities mediated by the modified Fc domain.
Davis
Patricia M
PM
Discovery Biology, Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543, USA.
Abraham
Ralph
R
Xu
Linda
L
Nadler
Steven G
SG
Suchard
Suzanne J
SJ
D000069594:Abatacept; D000595:Amino Acid Sequence; D000818:Animals; D000920:Antibody-Dependent Cell Cytotoxicity / Q000187:drug effects; D002460:Cell Line; D003165:Complement System Proteins / Q000378:metabolism; D003602:Cytotoxicity, Immunologic / Q000187:drug effects*; D006168:Guinea Pigs; D006801:Humans; D018796:Immunoconjugates / Q000235:genetics / Q000378:metabolism* / Q000494:pharmacology*; D007074:Immunoglobulin G / Q000235:genetics; D066298:In Vitro Techniques; D008969:Molecular Sequence Data; D011817:Rabbits; D017452:Receptors, IgG / Q000378:metabolism*; D017386:Sequence Homology, Amino Acid