ANTIBODY-DELIVERED LYMPHOHEMATOPOIETIC IRRADIATION

抗体递送的淋巴造血辐射

• 批准号: 3080117
• 负责人: DANA C MATTHEWS
• 金额: $ 7.72万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1992
• 资助国家: 美国
• 起止时间: 1992-09-01 至 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3080117
• 关键词: artificial immunosuppression; bone marrow transplantation; elements; immunoconjugates; iodine; laboratory mouse; monoclonal antibody; radiopharmacology; whole body irradiation effect

We have demonstrated that radiolabeled monoclonal antibodies reactive with the panhematopoietic CD45 antigen can deliver relatively specific irradiation to lymphohematopoietic tissues in preclinical studies in mice and macaques as well as in patients undergoing bone marrow transplantation for acute leukemia. The proposed studies examine strategies for improving the "therapeutic ratio" of radiation delivered to target lymphohematopoietic tissues, as compared to other normal organs, by 131I-labeled anti- CD45 antibody. These will include study of the effect of the use of an unlabeled preclearing dose" of antibody prior to administration of radiolabeled antibody, further definition of the relationship between antibody dose and relative lymphohematopoietic radiation, and the use of isotopes (186Re and 188Re) which have half lives which are shorter than that of 131I. Further studies will determine if radiolabeled anti-CD45 antibody can facilitate the engraftment of donor marrow, alone or with supplemental total body irradiation (TBI), by ablating host marrow and producing immunosuppression in mice undergoing marrow transplantation with T cell-depleted marrow from donors matched or mismatched for minor or major histocompatibility antigens. The ability to increase the dose of radiation to lymphohematopoietic tissues while minimizing the exposure of normal organs may decrease the high rate of relapse in patients undergoing marrow transplantation for advanced leukemia. It may also decrease the high rate of rejection of HLA- mismatched or unrelated donor marrow which has been depleted of T cells in an attempt to lower the incidence of Graft-vs.-Host Disease.

我们已经证明放射性标记的单克隆抗体 与泛造血 CD45 抗原反应可以传递 对淋巴造血组织进行相对特异性的照射 在小鼠、猕猴以及患者中进行的临床前研究 因急性白血病接受骨髓移植。 这 拟议的研究探讨了改善“治疗效果”的策略 照射到靶淋巴造血细胞的辐射比率” 与其他正常器官相比，通过 131I 标记的抗 CD45抗体。 这些将包括使用效果的研究 未标记的预清除剂量”的抗体之前 放射性标记抗体的施用，进一步定义 抗体剂量与相对淋巴造血功能的关系 辐射以及同位素（186Re 和 188Re）的使用 半衰期比 131I 短。 进一步深造 将确定放射性标记的抗 CD45 抗体是否可以促进 单独或补充总量的供体骨髓的植入 身体照射（TBI），通过消融宿主骨髓并产生 T 骨髓移植小鼠的免疫抑制 来自与轻微或不匹配的供体匹配或不匹配的细胞耗尽的骨髓 主要组织相容性抗原。 增加的能力 淋巴造血组织的辐射剂量，同时最大限度地减少 暴露正常器官可能会降低高复发率 接受骨髓移植的晚期患者 白血病。 它还可能降低 HLA- 的高排斥率 不匹配或不相关的供体骨髓已耗尽 T 细胞试图降低移植物抗宿主的发生率 疾病。