EFFICACY AND TOXICITY OF CD4 PEPTIDE 802-2 IN HUMAN UNRELATED DONOR BONE MARROW

CD4肽802-2在人类无关供体骨髓中的功效和毒性

• 批准号: 6446910
• 负责人: NEAL FLOMENBERG
• 金额: $ 19.62万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-04-11 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6446910
• 关键词: CD4 molecule; MHC class II antigen; bone marrow transplantation; clinical research; cyclic peptides; drug screening /evaluation; graft versus host disease; histocompatibility; homologous transplantation; human subject; human therapy evaluation; immunosuppressive; tissue /cell culture

DESCRIPTION: (Applicant's Description) Allogeneic bone marrow transplantation (BMT) 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 GvHD occurring 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. A variety of structural analogs of portions of the CD4 molecule have been developed which are efficacious, nontoxic, and (at least) additive in immunosuppressive activity to Cyclosporine. One cyclic heptapeptide, 802-2, is now ready for clinical investigation. This peptide requires only short term administration and is selectively active, in that T cells which encounter antigen in the presence of peptide are affected, while T cells which do not encounter antigen until after peptide has been cleared appear to remain functionally intact. This project builds on the previous observations through two specific aims. First, in collaboration with the National Marrow Donor Program, we will begin clinical testing of 802-2 peptide in prevention of GvHD in unrelated donor BMT through phase I and II clinical trials. Second, a variety of immunologic studies are proposed using cells from the donor-recipient pairs participating in the trial to further characterize the in vivo and in vitro effects of 802-2 peptide in man. The composite information gained should allow assessment of the efficacy of the present generation of CD4 analogs and facilitate the design and testing of next generation products. Ultimately this information should help improve outcome for recipients of unrelated donor BMT and reduce or eliminate the immunogenetic barrier which presently excludes at least a third of otherwise appropriate candidates from allogeneic transplantation.

描述：（申请人的描述）同种异体骨髓移植（BMT）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。 在无关供体BMT后发生GVHD频率和严重程度增加的因素中，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。已经开发了各种CD4分子部分的结构类似物，这些结构类似物是有效，无毒的，并且（至少）在对环孢素的免疫抑制活性中添加添加剂。 一个环状七肽802-2现在准备进行临床研究。 该肽仅需要短期给药并有选择性的活性，因为在存在肽存在下遇到抗原的T细胞受到影响，而直到清除肽后才会遇到抗原的T细胞似乎保持功能完好无损。 该项目通过两个特定目标建立在先前的观察基础上。 首先，通过与国家骨髓供体计划合作，我们将通过I和II阶段临床试验开始对802-2肽进行预防GVHD的临床测试。 其次，提出了各种免疫研究，使用参与试验的供体 - 征收对的细胞，以进一步表征人体体内和体外作用802-2肽在人中的体外作用。获得的综合信息应允许评估CD4类似物的现代有效性，并促进下一代产品的设计和测试。 最终，这些信息应有助于改善无关供体BMT的接受者的结果，并减少或消除免疫遗传障碍，目前将至少三分之一的其他适当候选者排除在同种异体移植中。