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 gene 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.
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