CTLA4-IG-ANTICD40 FUSION PROTEIN FOR IMMUNOTHERAPY

阻断两种主要的T细胞共刺激通路B7- CD 28或CD 40-CD 40 L，单独不足以允许无限期 高免疫原性同种异体移植物的植入。 然而，Larsen et al. 最近的研究表明，阻断B7-CD 28和CD 40-CD 40 L 途径同时有效地中止T细胞克隆扩增， 促进完全同种异体皮肤的长期存活 移植物，并抑制慢性血管排斥反应的发展， 主要是血管化的同种异体心脏移植 这些发现是伟大的 重要性固体器官移植在人类，因为尽管 在临床免疫抑制、慢性血管性疾病、 排斥反应仍然是移植失败的主要原因， 仍然没有有效的治疗方法。 因此，我们建议设立一个 基于CTLA 4-Ig的B7结合能力和CTLA 4-Ig的B7结合能力的融合蛋白， 人源化抗CD 40 Mab 5D 12的CD 40阻断活性。 在 阶段I将产生将CTLA 4-Ig连接到scFv形式的融合蛋白 5D 12的 该融合蛋白将被表达和纯化， 体外免疫调节活性。 在第二阶段，蛋白质 将在恒河猴肾移植模型中进行研究。 这种融合蛋白将提供一种新的，专有的治疗方法， 同种异体移植。

Blocking either of the two major T-cell costimulatory pathways, B7- CD28 or CD40-CD40L, alone is not sufficient to permit indefinite engraftment of highly immunogenic allografts. However, Larsen et al. Have recently shown that blocking the B7-CD28 and CD40-CD40L pathways simultaneously effectively aborts T-cell clonal expansion in vitro and in vivo, promotes long-term survival of fully allogeneic skin grafts, and inhibits the development of chronic vascular rejection of primarily vascularized cardiac allografts. These findings are of great importance for solid organtransplantation in humans, since despite the many advances in clinical immunosuppression, chronic vascular rejection remains the major source of transplant failure for which there remains no effective therapy. We therefore propose to generate a fusion protein based on the B7-binding capacity of CTLA4-lg and the CD40-blocking activity of the humanized anti-CD40 Mab 5D12. In phase I will create a fusion protein linking CTLA4-lg to the scFv form of 5D12. This fusion protein will be expressed and purified and in vitro immunomodulatory activity demonstrated. In phase II the protein will be studied in a rhesus monkey model of kidney transplantation. This fusion protein will provide a novel, proprietary therapy for allograft transplantation.