HLA-DR Targeted Synthetic High Affinity Ligands

HLA-DR 靶向合成高亲和力配体

• 批准号: 6989497
• 负责人: GERALD L DENARDO
• 金额: $ 45.25万
• 依托单位: UNIVERSITY OF CALIFORNIA AT DAVIS
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-04-01 至 2007-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6989497
• 关键词: MHC class II antigen; antibody; athymic mouse; binding sites; biotechnology; cell line; chelating agents; chemical synthesis; computer simulation; immunologic receptors; immunologic substance development /preparation; ligands; model design /development; monoclonal antibody; neoplasm /cancer radioimmunotherapy; nonHodgkin' s lymphoma; nuclear magnetic resonance spectroscopy; pharmacokinetics; protein binding; protein structure; radiation dosage; radiochemistry; small molecule; surface plasmon resonance; therapy design /development

New therapeutic options are needed for NHL because more than two thirds of patients fail to achieve long-term disease free-survival. Despite a therapeutic index of only 10-30, conventional RIT has proven especially effective for NHL, when CD20, CD22 or Lym-1 MAbs have been used as the targeting molecule carrier for 131I, 67Cu, or 90Y in a nonmyeloablative strategy. Dose intensification incorporating BMT in a myeloablative strategy using 90Y-DOTA-peptide -Lym-1 having a biodegradable peptide linker modestly improved the therapeutic index and led us to appreciate the complexities involved in CMRIT. In preclinical studies, Taxol synergized RIT and CD22 MAb was found promising for immunotherapy. Both of these agents are under study by colleagues under other grants. We have shown that the HLA-DR epitope for Lym-1 MAb is a particularly attractive target because it is present on almost all malignant B cells and at much greater density than on normal B cells. Through interactions with colleagues at LLNL, unique opportunities have arisen to improve the therapeutic index 10-100 times using novel approaches to develop synthetic, small molecule high-affinity ligands (SHALs) that can better fulfill the potential of RIT by mimicking 131I-iodide in thyroid cancer, the prototype for RIT. The HLA-DR10 surface protein on malignant B cells has been chosen as a target because our wealth of information on it has convinced us of its attractiveness as a target in patients with NHL and CLL. Characterization of the Lym-1 epitope on HLA-DR identified binding sites especially attractive because of evidence for preferential binding to malignant lymphocytes when compared to normal lymphocytes. These binding sites will be used to model, design and generate synthetic molecules of high selectivity and binding to the HLA-DR of malignant lymphomas and leukemias. We have synthesized our first five bidentate SHALs and determined that at least one of these SHALs binds to isolated HLA-DR10 with a Kd of approximately 20nM. Preliminary experiments show this SHAL binds to human lymphoma cells and tissue, competes for binding to the same site as Lym-I and does not bind to other malignant cell lines. This natural extension of our ongoing translational activities, involving HLA-DR as a target for radioisotopic carrier molecules to deliver systemic radiotherapy, affords an opportunity to dose-intensify by dramatically improving the therapeutic index. This project has, and will continue to interact extensively with the Molecular Modeling group, the Pharmacy group and the Pharmacokinetics/Dosimetry group.

NHL需要新的治疗选择，因为超过三分之二的患者未能实现长期疾病的生存。尽管治疗指数仅为10-30，但当CD20，CD22或LYM-1 MAB被用作131i，67cu或90年代的靶向分子载体时，常规RIT已被证明对NHL特别有效。使用90Y-DOTA肽-Lym-1具有可生物降解肽接头的90y-DOTA肽-1，将BMT纳入髓能策略中，适度改善了治疗指数，并使我们欣赏了CMRIT涉及的复杂性。在临床前研究中，发现紫杉醇协同的RIT和CD22 MAB有望用于免疫疗法。这两种代理人都在其他赠款下的同事正在研究。我们已经表明，Lym-1 MAB的HLA-DR表位是一个特别有吸引力的靶标，因为它几乎存在于所有恶性B细胞上，并且密度比正常B细胞​​更大。通过与LLNL的同事的互动，独特 已经出现了使用新颖的方法来开发合成的，小分子高亲和力配体（SHALS）的新方法来改善治疗指数10-100倍，从而可以通过模仿甲状腺癌中的131i-iodide来更好地满足RIT的潜力。恶性B细胞上的HLA-DR10表面蛋白已被选为目标，因为我们的大量信息使我们相信了它作为NHL和CLL患者的目标的吸引力。与正常淋巴细胞相比，HLA-DR在HLA-DR上的表征鉴定出的结合位点在HLA-DR上鉴定出的结合位点的表征特别有吸引力。这些绑定位点将用于建模，设计和生成合成 高选择性分子并与恶性淋巴瘤和白血病的HLA-DR结合。我们已经合成了前五个Bentate Shals，并确定其中至少其中一种与孤立的HLA-DR10结合，KD约为20nm。初步实验表明，这种SHAL与人类淋巴瘤细胞和组织结合，竞争与Lym-I的位点结合，并且不与其他恶性细胞系结合。我们正在进行的翻译活动的这种自然扩展，涉及HLA-DR，作为放射性病载体分子提供全身放射疗法的靶标，可以通过显着改善治疗指数来剂量强化。 该项目已经并且将继续与分子建模组，药物组和药代动力学/剂量学组进行广泛相互作用。