Immunomodulatory properties of FK734, a humanized anti-CD28 monoclonal antibody with agonistic and antagonistic activities.
BACKGROUND
We describe immunomodulatory effects of FK734, a humanized version of a mouse anti-human CD28 mAb (clone TN228), in vitro and in a chimeric human-mouse model of allograft rejection.


METHODS
Cytokine production and proliferation were assessed in a mixed lymphocyte reaction containing FK734, human T cells, and endothelial cells or monocytes. FK734 was also administered to SCID mice engrafted with human skin and adoptively transferred with human peripheral blood mononuclear cells allogeneic to the skin graft.


RESULTS
In vitro, FK734 enhanced secretion of interleukin-2 and interferon-gamma as well as proliferation of CD4+ and CD8+ T cells stimulated by allogeneic human leukocyte antigen (HLA)-DR+ human umbilical vein endothelial cells (which lack B7 molecules and FcgammaRs) or by blood monocytes (which express low levels of B7 molecules and FcgammaRs) compared with control mAb, but these effects were significantly smaller than those provided by mAb 28.2, a stimulatory mouse anti-human CD28 mAb, at comparable concentrations. However, FK734 generally inhibited cytokine secretion and T cell proliferation in cocultures with human umbilical vein endothelial cells transduced to express CD86. In vivo using SCID/beige mice bearing human skin with adoptively transferred peripheral blood mononuclear cells, administration of FK734 protected human endothelial cell-lined microvessels, significantly but incompletely reducing endothelial cell injury and T cell infiltration into the graft one or two weeks later.


CONCLUSIONS
FK734 is a partial agonist of CD28 signaling that can reduce human T cell alloresponses in the presence of strong costimulation by B7 molecules in vitro and can reduce T cell-mediated skin allograft rejection in vivo.
Shiao
Stephen L
SL
Section of Immunobiology, Yale University School of Medicine, New Haven, Connecticut 06520, USA.
McNiff
Jennifer M
JM
Masunaga
Taro
T
Tamura
Kouichi
K
Kubo
Kaori
K
Pober
Jordan S
JS
D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology*; D061067:Antibodies, Monoclonal, Humanized; D051940:B7-2 Antigen / Q000378:metabolism; D018106:CD28 Antigens / Q000187:drug effects* / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000187:drug effects* / Q000276:immunology; D049109:Cell Proliferation / Q000187:drug effects; D018920:Coculture Techniques; D016207:Cytokines / Q000378:metabolism; D042783:Endothelial Cells / Q000276:immunology; D005260:Female; D006084:Graft Rejection / Q000517:prevention & control*; D006801:Humans; D007371:Interferon-gamma / Q000378:metabolism; D007376:Interleukin-2 / Q000378:metabolism; D008213:Lymphocyte Activation; D051379:Mice; D016513:Mice, SCID; D016038:Skin Transplantation
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D051940:B7-2 Antigen; D018106:CD28 Antigens; D016207:Cytokines; C518265:FK734 monoclonal antibody; D007376:Interleukin-2; D007371:Interferon-gamma