BIOLOGIC & CLINICAL PROPERTIES OF CD4 STRUCTURAL ANALOGS

生物制剂

• 批准号: 6173445
• 负责人: NEAL FLOMENBERG
• 金额: $ 112.7万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6173445
• 关键词: CD4 molecule; cyclic peptides; graft versus host disease; histocompatibility; immunosuppressive; synthetic peptide

OVERALL DESCRIPTION (Applicant's Description) Allogeneic bone marrow transplantation has emerged as the preferred therapy for a variety of disorders. Unfortunately, outcome is limited by development of graft-versus-host disease (GvHD) and by opportunistic infection. Of the factors that contribute to the increased frequency and severity of GvHDoccurring after unrelated donor BMT, genotypic matching for HLA-DRB1 and HLA-DQB1 appear to be particularly important. While the present modalities used to prevent GvHD are of benefit, they are not selective in their effects on the immune system, in that responses to opportunistic pathogens are blunted along with the GVH response. Given the importance of HLA class II allodisparities in initiating GVH responses, one of the logical targets for the development of new immune suppressive agents is the CD4 molecule, which plays a critical role in the activation of CD4+ T cells in response to HLA-class II allodisparities. Portions of the CD4 molecule which were predicted to interact with other cell surface molecules were targeted for the design of synthetic peptide analogs with the rationale that through competition, they would interfere with T-cell activation. These molecules have demonstrated immunosuppressive activity in GvHD models which is additive to that of Cyclosporine. The peptides require only short term administration and are selectively active, in that only those T-cells which encounter antigen in the presence of peptide are affected, while other T cells remainfunctionally intact. No toxicity has been observed to date. One cyclic heptapeptide, 802-2, is now ready for clinical investigation. Three scientific projects are proposed. Based on further structural and functional studies, derivatives of our current lead compounds will be developed. The 802-2 peptide will be further characterized in in vitro and animal models, as will new compounds that are developed. In conjunction with the National Marrow Donor Program, a multicenter trial will be conducted to test the clinical efficacy of 802-2 peptide in unrelated donor BMT. The effects of 802-2 peptide on human lymphocytes after in vivo or in vitro exposure will also be determined. The ultimate goals of these investigations are: (1) to improve clinical outcome for our present patient populations, and (2) to reduce or eliminate the risk of GvHD arising from donor-host HLA class II disparities which presently excludes at least a third of otherwise appropriate candidates from allogeneic transplantation. The composite information gained should allow assessment of the efficacy of the present generation of CD4 analogs as well as the design and preclinical testing of next generation products.

总体描述（申请人的描述）同种异体骨髓移植已成为各种疾病的首选疗法。 不幸的是，结果受到移植抗宿主病（GVHD）的发展和机会性感染的限制。 在无关的供体BMT之后，导致GVHDoccurring的频率和严重程度增加的因素，HLA-DRB1和HLA-DQB1的基因型匹配似乎尤其重要。 尽管用于预防GVHD的当前方式有益，但它们对免疫系统的影响没有选择性，因为对机会性病原体的反应与GVH响应一起被削弱。 鉴于HLA II类同种疗法在启动GVH响应中的重要性，因此开发新的免疫抑制剂的逻辑靶标之一是CD4分子，它在CD4+ T细胞激活中起着对HLA级II同行的响应而起着至关重要的作用。 预计将与其他细胞表面分子相互作用的CD4分子的一部分是针对合成肽类似物的设计，其理由是通过竞争，它们会干扰T细胞激活。 这些分子在GVHD模型中表现出了免疫抑制活性，这是环孢素的添加剂。 肽仅需要短期给药并有选择性的活性，因为只有在存在肽存在下遇到抗原的那些T细胞受到影响，而其他T细胞在肽存在下仍保持完整。 迄今为止尚未观察到毒性。一个环状七肽802-2现在准备进行临床研究。提出了三个科学项目。 基于进一步的结构和功能研究，将开发我们当前铅化合物的衍生物。 802-2肽将在体外和动物模型中进一步表征，而开发的新化合物也将进一步。 与国家骨髓供体计划一起，将进行多中心试验，以测试在无关的供体BMT中802-2肽的临床疗效。 还将确定802-2肽对体内或体外暴露后人淋巴细胞的影响。这些调查的最终目标是：（1）改善目前的患者人群的临床结果，（2）降低或消除由供体 - 宿主HLA II类差异引起的GVHD风险，目前将至少三分之一的其他适当候选者因同种异性移植而排除。 获得的复合信息应允许评估现代CD4类似物以及下一代产品的设计和临床前测试的功效。