MONOCLONAL ANTI FCR ANTIBODY TREATMENT OF REFRACTORY ITP

抗FCR单克隆抗体治疗难治性ITP

• 批准号: 3354831
• 负责人: JAMES B BUSSEL
• 金额: $ 12.04万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 1990-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3354831
• 关键词: antiantibody; antibody formation; antibody receptor; antiidiotype antibody; antireceptor antibody; autoantibody; autoimmune disorder; blocking antibody; blood cell count; dosage; enzyme linked immunosorbent assay; gel electrophoresis; human subject; immunofluorescence technique; immunohematology; immunomodulators; immunoregulation; immunotherapy; monoclonal antibody; opsonin; plaque assay; platelets; radiotracer; reticuloendothelial system; splenectomy; therapy compliance; thrombocytopenia; thrombocytopenic purpura

3G8 is a mouse monoclonal anti Fc receptor antibody which recognizes and blocks the active site of FcRp52-70, an FcR found on granulocytes, tissue macrophages, and large granular lymphocytes. MPS FcR blockade with another mouse monoclonal anti FcR antibody (24G2) has been shown to decrease clearance of immune complexes in mice. Our studies in chimpanzees showed that infusion of 3G8 substantially slowed clearance of opsonized red cells. Clinical studies with intravenous gammaglobulin (IVGG) has suggested that MPS FcR blockade could underlie therapeutic responses in autoimmune thrombocytopenic purpura, a severe bleeding disorder in which profound thrombocytopenia is mediated by opsonization of platelets with antiplatelet antibody. After obtaining and IND, 3G8 was infused into 4 patients with refractory ITP all of whom had platelet counts consistently less than 10,000/ul and significant clinical bleeding. Three of 4 patients demonstrated substantial acute platelet increases to levels of 34,000/ul, 80,000/ul and 300,000/ul; one patient did not respond. Surprisingly, the 3 patients with acute responses also all had long-term benefits lasting months. Two patients continue to maintain adequate platelet counts without any therapy 3 and 10 months after 3G8, the 3rd patient regained responsiveness to IVGG and now requires IVGG treatment only every 5 weeks. Serial opsonized red cell clearances indicated that the acute effects were due to MPS FcR blockade. However the longterm effects could be caused by either prolonged MPS FcR blockade and/or by decreased levels of antiplatelet antibody. MPS FcR function will be studied by serial opsonized red cell clearances. The mechanism of this effect will be explored by studying antiidiotypic and antiantiidiotypic antibody levels. Antiidiotypes were detected in less than 2 weeks in patient #1 and persisted. Development of an antiantiidiotype could mimic the effect of 3G8 and create endogenous modulation of FcRp52-70 expression. Alternatively serial study of antiplatelet antibodies might reveal a decrease that could explain the longterm benefits. If seen , a decrease might occur as a result of the transient ablation of natural killer (NK) cells seen immediately following infusion of 3G8, since NK cells contribute to immunoregulation of immunoglobulin production. 3G8 is a promising new therapy of refractory ITP. Its use in these patients will allow study of FcR immunodulation in autoimmune disease.

3G 8是一种小鼠单克隆抗Fc受体抗体， 识别并阻断FcRp 52 -70的活性位点， 对粒细胞、组织巨噬细胞和大颗粒 淋巴细胞 用另一种小鼠单克隆抗体阻断MPS FcR 抗FcR抗体（24 G2）已被证明可以减少 小鼠的免疫复合物。 我们对黑猩猩的研究表明 3G 8的输注大大减缓了调理素的清除， 红细胞 静脉注射丙种球蛋白（IVGG）的临床研究 已经表明MPS FcR阻断可以作为治疗的基础， 自身免疫性血小板减少性紫癜，一种严重的 由严重血小板减少症介导的出血性疾病 通过用抗血小板抗体调理血小板。 后 获得IND，4例患者输注3G 8， 难治性ITP患者的血小板计数始终低于 超过10，000/ul和显著的临床出血。 四分之三 患者表现出显著的急性血小板增加， 水平为34，000/ul、80，000/ul和300，000/ul; 1名患者没有 回答。 令人惊讶的是，3名急性反应患者也都 有持续数月的长期益处。 两名患者继续 维持足够的血小板计数，无需任何治疗3和10 3G 8后3个月，第3例患者恢复了对 IVGG和现在需要IVGG治疗每5周。 系列调理作用红细胞清除表明，急性 效应是由于MPS FcR阻断。 然而，长期 延长MPS FcR阻断时间可能导致 和/或抗血小板抗体水平降低。 MPS FcR 将通过系列调理红细胞清除来研究功能。 通过研究，探讨了这一效应的机制 抗独特型和抗抗独特型抗体水平。 抗独特型 在患者#1中不到2周内检测到并持续存在。 抗抗独特型抗体的开发可以模拟3G 8的作用 并产生FcRp 52 -70表达的内源性调节。 另外，抗血小板抗体的系列研究可能揭示 这一下降可以解释长期收益。 如果看到， 减少可能是由于短暂消融的结果， 自然杀伤（NK）细胞输注后立即观察到 3G 8，因为NK细胞有助于免疫调节， 免疫球蛋白生产。 3G 8是一种有前途的新疗法， 难治性ITP 它在这些患者中的使用将允许研究FcR 自身免疫性疾病免疫调节。