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 需要新的治疗方案，因为超过三分之二的患者无法实现长期无病生存。尽管治疗指数仅为 10-30，但当 CD20、CD22 或 Lym-1 MAb 在非清髓策略中用作 131I、67Cu 或 90Y 的靶向分子载体时，传统 RIT 已被证明对 NHL 特别有效。使用具有可生物降解肽接头的 90Y-DOTA-肽 -Lym-1 将 BMT 纳入清髓策略中的剂量强化适度改善了治疗指数，并使我们认识到 CMRIT 所涉及的复杂性。在临床前研究中，紫杉醇协同 RIT 和 CD22 MAb 被发现有望用于免疫治疗。同事们正在其他资助下研究这两种药物。我们已经证明，Lym-1 MAb 的 HLA-DR 表位是一个特别有吸引力的靶标，因为它存在于几乎所有恶性 B 细胞上，并且密度比正常 B 细胞高得多。通过与 LLNL 同事的互动，独特的 使用开发合成小分子高亲和力配体 (SHAL) 的新方法将治疗指数提高 10-100 倍的机会已经出现，这些配体可以通过模仿甲状腺癌中的 131I-碘化物（RIT 的原型）来更好地发挥 RIT 的潜力。恶性 B 细胞上的 HLA-DR10 表面蛋白已被选为靶点，因为我们对它的大量信息使我们确信它作为 NHL 和 CLL 患者靶点的吸引力。 HLA-DR 上 Lym-1 表位的表征确定了特别有吸引力的结合位点，因为有证据表明与正常淋巴细胞相比，优先结合恶性淋巴细胞。这些结合位点将用于建模、设计和生成合成的 高选择性并与恶性淋巴瘤和白血病的 HLA-DR 结合的分子。我们已经合成了前 5 个双齿 SHAL，并确定这些 SHAL 中至少有一个以大约 20nM 的 Kd 与分离的 HLA-DR10 结合。初步实验表明，该 SHAL 与人淋巴瘤细胞和组织结合，与 Lym-I 竞争与相同位点的结合，并且不与其他恶性细胞系结合。我们正在进行的转化活动的自然延伸，涉及 HLA-DR 作为放射性同位素载体分子的靶标来提供全身放射治疗，提供了通过显着提高治疗指数来加强剂量的机会。 该项目已经并将继续与分子建模小组、药学小组和药代动力学/剂量测定小组进行广泛的互动。