RADIOLABELED ANTIBODY MEDIATED IMMUNOSUPPRESSION

放射性标记抗体介导的免疫抑制

• 批准号: 6173012
• 负责人: DANA C MATTHEWS
• 金额: $ 12.5万
• 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/6173012
• 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 造血组织的靶向放射治疗可改善骨转移的结果。 骨髓移植治疗急性白血病和遗传性疾病， 地中海贫血和镰状细胞性贫血， 移植，准备方案的毒性，以及 排斥T细胞耗尽HLA不匹配或无关的骨髓。 131 I-抗CD 45抗体已被证明提供更大的辐射 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 已经证明了使用131 I-抗CD 45的可行性和耐受性 抗体提供补充辐射造血组织时， 联合环磷酰胺和全身照射（TBI）。 然而，在这方面， 这种疗法的疗效应该提高，毒性应该降低， 通过抗体传递的辐射比例可以增加， 减少或消除作为TBI递送的辐射。 拟议 临床前研究将确定骨髓消融和免疫抑制 131 I-抗-CD 45抗体单独使用或与低剂量TBI联合使用的效果， 作为接受T细胞缺失骨髓移植的小鼠的准备方案 来自同源供体或在次要或主要器官上不匹配的供体 组织相容性位点 这些研究将包括评估 与这种低剂量率辐射相关的早期和晚期毒性 通过放射免疫缀合物递送。 进一步的研究将审查战略 与正常情况相比， 机关 这些将包括使用预定位方法的效果， 抗体-链霉亲和素偶联物，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 比131 I（8小时）半衰期短（如90 Y，64小时和186 Re，90小时 天），因为靶组织中的最高水平发生在 抗体给药后的前48至72小时。 的定义 放射性标记抗CD 45抗体免疫抑制和骨髓清除能力 抗体的造血特异性，以及这种抗体的造血特异性的优化， 在拟议的临床前研究中， 提高了治疗效果并降低了毒性， 骨髓移植治疗白血病和遗传疾病 它也可以 支持使用放射性标记的抗CD 45抗体， T细胞耗竭后的排斥和复发率HLA不匹配或无关 捐献骨髓移植