A novel bispecific antihuman CD40/CD86 fusion protein with t-cell tolerizing potential |
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Authors: | Koenen Hans J P M den Hartog Marcel T Heerkens Sijmie Fasse Esther Ortiz-Buijsse Antonio van Neerven R J Joost Simons Peter J Joosten Irma Boon Louis |
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Affiliation: | 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 |
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Abstract: | 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. |
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