TRIGGERING CELL DEATH IN B CELL LYMPHOMA

触发 B 细胞淋巴瘤的细胞死亡

基本信息

批准号：
6236696
负责人：
Shoshana Levy
金额：
$ 25.1万
依托单位：
STANFORD UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
1997
资助国家：
美国
起止时间：
1997-06-27 至 1998-03-31
项目状态：
已结题

项目摘要

The long term goal of this project is to develop nw approaches to induce anti-proliferative effects in human B-cell lymphomas. Antibodies and synthetic peptide ligands will be used to target cell surface molecules. The hypothesis that different receptors transduce anti-proliferative signals through different signaling cascades will be tested by dissecting the pathways of cell death through two cell surface molecular complexes, (1) the antigen binding immunoglobulin receptor complex (IgR) and (2) the TAPA-1 complex with its associated molecules, CD1'9, CD21, MHC class II, and Leu-13. Cells will be triggered by antibodies to these targets to study events that precede cell death. Once cell death pathways are established for the two molecular complexes, we will test for the specific death pathways induced by human immunoglobulins that express the VH4.21 ene and by additional cell surface receptors such as CD20 and CD40. We will then test if alterations of intracellular thiols augment the anti- proliferative effects induced by antibodies against these molecular complexes. Knowledge of death pathways and physiological conditions that can affect them will be instrumental in attempting to augment the anti- proliferative effect. If indeed different pathways lead to cell death, it will be established if combined targeting of more than one receptor at a time is synergistic. In the same manner, synergy will be sought by altering physiologic conditions. To understand the physiologic role of the TAPA-1 molecule, we will attempt to clone its ligand, express it, and study the effect of the ligand on cell death. In addition to antibody targeted therapy we will evaluate if surrogate peptide ligands to cell surface receptors can be developed for targeted therapy. Recently we have demonstrated that synthetic peptide ligands can bind specifically to the IgR. Moreover, multimeric forms of these synthetic ligands were effective inducers of a signal transduction pathway that led to programmed cell death. Random peptide phage libraries will be used to test the feasibility of identifying peptide ligands to the antigen receptor of lymphoma patients. The efficacy of the surrogate peptide ligands will be tested and compared to that of antibodies in vitro in a B- lymphoma cell line. SCID mice will be used to test the effect of the anti-proliferative antibodies and peptide ligands and to t e st for synergy in vivo between the cell death pathways they induce. Optimal administration routes and schedules for synthetic peptides will be developed and pharmacokinetics, biodistribution and efficacy will be tested. Likewise, physiologic conditions that may augment the anti-proliferative effect of antibodies and synthetic peptides will be tested in the SCID mice.

该项目的长期目标是开发NW方法来诱导人B细胞淋巴瘤中的抗增殖作用。抗体和合成肽配体将用于靶向细胞表面分子。假设不同的受体转导抗增殖性通过不同信号级联的信号将通过解剖来测试细胞死亡通过两个细胞表面分子复合物的途径，（1）抗原结合免疫球蛋白受体复合物（IGR）和（2） TAPA-1复合物及其相关分子CD1'9，CD21，MHC II类，和Leu-13。细胞将由这些靶标的抗体触发研究细胞死亡之前的事件。一旦细胞死亡通路为两个分子复合物建立，我们将测试特定的由人类免疫球蛋白诱导的死亡途径表达VH4.21 ENE以及其他细胞表面受体，例如CD20和CD40。我们然后将测试细胞内硫醇的改变是否增加了抗抗体诱导的对这些分子引起的增殖作用复合物。对死亡途径和生理状况的了解可以影响他们将有助于尝试增加反抗增殖作用。如果确实会导致细胞死亡，那就如果将多个受体的一个以上受体的靶向组合成时间是协同作用的。以同样的方式，协同作用将由改变生理条件。了解 TAPA-1分子，我们将尝试克隆其配体，表达它，并研究配体对细胞死亡的影响。除抗体靶向疗法外，我们还将评估是否替代可以开发针对细胞表面受体的肽配体针对靶向受体治疗。最近，我们证明了合成肽配体可以专门与IGR结合。而且，这些形式的多聚体形式合成配体是信号转导途径的有效诱导剂这导致了编程的细胞死亡。随机肽噬菌体库将是用于测试将肽配体鉴定到抗原的可行性淋巴瘤患者的受体。替代肽的功效配体将进行测试，并将B-中的体外抗体进行比较淋巴瘤细胞系。 SCID小鼠将用于测试抗增殖的效果抗体和肽配体，并在体内进行协同作用他们诱导的细胞死亡途径。最佳管理路线和将开发合成肽的时间表和药代动力学，将测试生物分布和功效。同样，生理学可能增加抗体抗增殖作用的条件并将在SCID小鼠中测试合成肽。