JTA-009, a fully human antibody against human AILIM/ICOS, ameliorates graft-vs-host reaction in SCID mice grafted with human PBMCs.
OBJECTIVE
Activation-inducible lymphocyte immunomediatory molecule (AILIM; also referred to as inducible costimulator [ICOS]) is the third molecule identified in the CD28 family participating in T-cell activation. AILIM/ICOS has been implicated in both effector and pathogenic T-cell functions, as evidenced by the beneficial effects of AILIM/ICOS blockade in several murine disease models. In the present study, the role of human AILIM/ICOS in T-cell function was investigated using a fully human monoclonal antibody specific to human AILIM/ICOS (JTA-009).


METHODS
The effect of JTA-009 on allogenic T-cell proliferation was examined using human mixed lymphocyte reaction (MLR). To investigate the efficacy of AILIM/ICOS blockade in vivo, a graft-vs-host disease (GVHD) model, in which severe combined immunodeficient (SCID) mice were grafted with human peripheral blood mononuclear cells (PBMCs), was used.


RESULTS
In MLR, suppressive effect of JTA-009 on allogenic T-cell proliferation was detected with comparable potency to CD28 blockade by cytotoxic T-lymphocyte antigen 4 (CTLA4)-Ig at an intermediate culture phase. JTA-009 acts as a blocking antibody in vivo and inhibited binding of human AILIM/ICOS to mouse AILIM/ICOS ligand (B7h). Treatment with JTA-009 significantly prolonged survival of mice, with reductions of human interferon-gamma levels in blood and number of human cells in spleens.


CONCLUSIONS
These results demonstrate that human AILIM/ICOS plays a role in the GVHD pathogenesis mediated by human T cells, and its blockade is attractive for abrogating undesired T-cell responses as is well-documented in mice.
Tajima
Nobuyuki
N
Biological and Pharmacological Laboratories Central Pharmaceutical Research Institute, Takatsuki, Japan. nobuyuki.tajima@ims.jti.co.jp
Tezuka
Katsunari
K
Tanimoto
Atsuo
A
Miyai
Atsuko
A
Tanimoto
Minako
M
Maruhashi
Junji
J
Watanabe
Yoshihiro
Y
D000069594:Abatacept; D000818:Animals; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D000945:Antigens, Differentiation, T-Lymphocyte / Q000276:immunology* / Q000502:physiology; D004195:Disease Models, Animal; D006086:Graft vs Host Disease / Q000209:etiology / Q000628:therapy*; D006801:Humans; D018796:Immunoconjugates / Q000627:therapeutic use; D060889:Inducible T-Cell Co-Stimulator Protein; D007371:Interferon-gamma / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000637:transplantation*; D051379:Mice; D016513:Mice, SCID; D014183:Transplantation, Heterologous
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D000945:Antigens, Differentiation, T-Lymphocyte; C556692:ICOS protein, human; C556694:Icos protein, mouse; D018796:Immunoconjugates; D060889:Inducible T-Cell Co-Stimulator Protein; C533330:JTA-009; D000069594:Abatacept; D007371:Interferon-gamma