A novel bispecific antihuman CD40/CD86 fusion protein with t-cell tolerizing potential.
Clinical trials designed to achieve tolerance in humans by selectively antagonizing one of the T-cell costimulatory pathways, CD40-CD40L or CD80/CD86-CD28, are pending. However, simultaneous blockade of both pathways synergistically prevented graft rejection and successfully induced donor-specific tolerance in animal models. Synergism is also supported in human T-cells in vitro following anti-CD86 mAb and anti-CD40 mAb blockade. Therefore, in our view the most promising clinical strategy would be to antagonize both CD40 and CD86. Fast clinical entrance of this anti-CD86 and anti-CD40 bidirectional concept is highly facilitated by a single molecule approach. In the present study, a single bispecific fusion protein was constructed that specifically binds human CD40 and CD86 and which combines the antagonistic activities of both anti-CD40 and anti-CD86 humanized mAb. The anti-CD40/86 fusion protein showed tolerance inducing potential as it prevented both allogeneic T-cell expansion and generation of cytotoxic effector T cells and induced anergic antigen specific regulatory T cells. These data provide proof of concept in successfully combining the antagonistic activity of two humanized mAb with great clinical potential in transplantation and autoimmunity, in one single molecule.
Koenen
Hans J P M
HJ
Department of Blood Transfusion and Transplantation Immunology (ABTI/OV603), University Medical Center Nijmegen, P-Box 9101, 6500 HB Nijmegen, The Netherlands. H.Koenen@abti.umcn.nl
den Hartog
Marcel T
MT
Heerkens
Sijmie
S
Fasse
Esther
E
Ortiz-Buijsse
Antonio
A
van Neerven
R J Joost
RJ
Simons
Peter J
PJ
Joosten
Irma
I
Boon
Louis
L
D018033:Antibodies, Bispecific / Q000276:immunology*; D015703:Antigens, CD / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D051940:B7-2 Antigen; D001665:Binding Sites; D019013:CD40 Antigens / Q000276:immunology*; D002478:Cells, Cultured; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D007140:Immunoglobulin Fab Fragments / Q000276:immunology; D008213:Lymphocyte Activation; D007959:Lymphocyte Culture Test, Mixed; D008214:Lymphocytes / Q000276:immunology; D008562:Membrane Glycoproteins / Q000276:immunology*; D011993:Recombinant Fusion Proteins / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*
D018033:Antibodies, Bispecific; D015703:Antigens, CD; D051940:B7-2 Antigen; D019013:CD40 Antigens; C497964:CD86 protein, human; D007140:Immunoglobulin Fab Fragments; D008562:Membrane Glycoproteins; D011993:Recombinant Fusion Proteins