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
Department of Blood Transfusion and Transplantation Immunology (ABTI/OV603), University Medical Center Nijmegen, P-Box 9101, 6500 HB Nijmegen, The Netherlands.
Transplantation. 2004 Nov 27;78(10):1429-38. doi: 10.1097/01.tp.0000140481.41441.63.
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.
旨在通过选择性拮抗T细胞共刺激途径之一（CD40 - CD40L或CD80/CD86 - CD28）来实现人体耐受性的临床试验正在进行中。然而，在动物模型中，同时阻断这两条途径可协同预防移植排斥反应并成功诱导供体特异性耐受性。在体外，抗CD86单克隆抗体和抗CD40单克隆抗体阻断后，人T细胞也支持协同作用。因此，我们认为最有前景的临床策略是拮抗CD40和CD86两者。单一分子方法极大地促进了这种抗CD86和抗CD40双向概念的快速临床应用。在本研究中，构建了一种单一的双特异性融合蛋白，它能特异性结合人CD40和CD86，并结合了抗CD40和抗CD86人源化单克隆抗体的拮抗活性。抗CD40/86融合蛋白显示出诱导耐受性的潜力，因为它既能阻止同种异体T细胞扩增和细胞毒性效应T细胞的产生，又能诱导无反应性抗原特异性调节性T细胞。这些数据证明了将两种在移植和自身免疫方面具有巨大临床潜力的人源化单克隆抗体的拮抗活性成功结合在一个单一分子中的概念。
