RADIOLABELED ANTIBODY MEDIATED IMMUNOSUPPRESSION

放射性标记抗体介导的免疫抑制

• 批准号: 2895561
• 负责人: DANA C MATTHEWS
• 金额: $ 12.07万
• 依托单位: FRED HUTCHINSON CANCER RESEARCH CENTER
• 依托单位国家: 美国
• 财政年份: 1997
• 资助国家: 美国
• 起止时间: 1997-04-09 至 2002-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2895561
• 关键词: CD antigens; bone marrow transplantation; chemical conjugate; disease /disorder model; hematopoietic tissue; histocompatibility typing; immunoconjugates; immunosuppression; iodine; laboratory mouse; monoclonal antibody; radiobiology; radionuclides; radiotracer; whole body irradiation dosage; yttrium

DESCRIPTION: (Adapted from the applicant's abstract): The ability to target radiation to hematopoietic tissues may improve the outcome of bone marrow transplantation for acute leukemia and for genetic disorders such as thalassemia and sickle cell anemia by decreasing the relapse rates after transplant, the toxicity of the preparative regimens, and the risk of rejection of T cell depleted HLA-mismatched or unrelated marrow. 131I-anti-CD45 antibody has been demonstrated to deliver greater radiation doses to the marrow, spleen and lymph nodes than to non-target organs in preclinical studies in mice and macaques. Preliminary clinical studies in patients with advanced AML, ALL, or MDS undergoing marrow transplantation have demonstrated the feasibility and tolerability of using 131I-anti-CD45 antibody to deliver supplemental radiation to hematopoietic tissues when combined with cyclophosphamide and total body irradiation (TBI). However, the efficacy of this therapy should improve and toxicity should decrease if the proportion of radiation delivered via antibody could be increased, while decreasing or eliminating the radiation delivered as TBI. The proposed preclinical studies will determine the marrow ablative and immunosuppressive effects of 131I-anti-CD45 antibody by using it, alone or with low dose TBI, as a preparative regimen for mice receiving T-depleted marrow transplants from congenic donors or donors mismatched at minor or major histocompatibility loci. These studies will include the assessment of both early and late toxicities associated with this low-dose-rate radiation delivered by radioimmunoconjugates. Further studies will examine strategies to improve the ratio of radiation delivered to target as compared to normal organs. These will include the effect of a pretargeting method using an antibody-streptavidin conjugate followed at a later time point by an isotope-biotin moiety. The effect of the use of alternative isotopes with a shorter half-life (such as 90Y, 64 hours and 186Re, 90 hours) than 131I (8 days) will be tested, as the highest levels in target tissues occur within the first 48 to 72 hours after antibody administration. The definition of the immunosuppressive and marrow ablative capacity of radiolabeled anti-CD45 antibody, and the optimization of the hematopoietic specificity of such radiation in the proposed preclinical studies, should ultimately allow improved efficacy and decreased toxicity of preparative regimens used in marrow transplantation for leukemia and genetic disorders. It may also support the use of radiolabeled anti-CD45 antibody to decrease both the rejection and relapse rates after T-depleted HLA-mismatched or unrelated donor marrow transplants.

描述：（改编自申请人的摘要）：能够 对造血组织进行靶向放疗可能会改善骨的预后 骨髓移植治疗急性白血病和遗传性疾病，例如 通过降低地中海贫血和镰状细胞性贫血的复发率 移植、准备方案的毒性以及风险 排斥 T 细胞耗尽的 HLA 不匹配或不相关的骨髓。 131I-抗 CD45 抗体已被证明可以提供更大的辐射 骨髓、脾脏和淋巴结的剂量高于非靶器官的剂量 小鼠和猕猴的临床前研究。 初步临床研究 接受骨髓移植的晚期 AML、ALL 或 MDS 患者 已证明使用 131I-anti-CD45 的可行性和耐受性 抗体向造血组织提供补充辐射 与环磷酰胺和全身照射（TBI）相结合。 然而， 如果出现以下情况，这种疗法的功效应该会提高并且毒性应该会降低 通过抗体传递的辐射比例可以增加，同时 减少或消除 TBI 带来的辐射。 拟议的 临床前研究将确定骨髓消融和免疫抑制 单独使用或与低剂量 TBI 一起使用 131I-抗 CD45 抗体的效果， 作为接受 T 耗尽骨髓移植的小鼠的准备方案 来自同类捐献者或次要或主要不匹配的捐献者 组织相容性位点。 这些研究将包括对两者的评估 与这种低剂量率辐射相关的早期和晚期毒性 由放射免疫结合物递送。 进一步的研究将检验策略 与正常情况相比，提高到达目标的辐射比率 器官。 这些将包括使用预定位方法的效果 抗体-链霉亲和素缀合物，随后在稍后的时间点 同位素-生物素部分。 使用替代同位素的效果 半衰期（如 90Y，64 小时和 186Re，90 小时）比 131I 更短（8 天）将进行测试，因为目标组织中的最高水平发生在 抗体施用后的前 48 至 72 小时。 的定义 放射性标记抗 CD45 的免疫抑制和骨髓消融能力 抗体，以及此类抗体的造血特异性的优化 拟议的临床前研究中的辐射，最终应允许 提高了制备方案的疗效并降低了毒性 骨髓移植治疗白血病和遗传性疾病。 也可能是 支持使用放射性标记的抗 CD45 抗体来降低 T 耗尽后 HLA 不匹配或不相关的排斥和复发率 供体骨髓移植。