MONOCLONAL ANTI FCR ANTIBODY TREATMENT OF REFRACTORY ITP

抗FCR单克隆抗体治疗难治性ITP

• 批准号: 3354830
• 负责人: JAMES B BUSSEL
• 金额: $ 14.28万
• 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/3354830
• 关键词: antiantibody; antibody formation; antiidiotype antibody; antireceptor antibody; autoantibody; autoimmune disorder; blocking antibody; blood cell count; cell mediated cytotoxicity; 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.

3G8是一种小鼠单克隆抗FC受体抗体 识别并阻止了FCRP52-70的活动位置，发现了一个FCR 在粒细胞，组织巨噬细胞和大颗粒上 淋巴细胞。 MPS FCR与另一种小鼠单克隆 抗FCR抗体（24G2）已显示可降低清除率 小鼠的免疫复合物。 我们在黑猩猩的研究表明 注入3G8的重量大大减慢了调子的清除率 红细胞。 静脉注射γ球蛋白（IVGG）的临床研究 已建议MPS FCR封锁可能是治疗的基础 自身免疫性血小板减少紫红色的反应，严重 介导深度血小板减少症的出血障碍 通过用抗血小板抗体的血小板调理。 后 获得并IND，将3G8注入4例患者 难治性iTP所有的血小板数量始终减少 超过10,000/UL和大量临床出血。 4中的三个 患者表现出大量急性血小板增加到 34,000/UL，80,000/UL和300,000/UL的水平；一个患者没有 回应。 令人惊讶的是，3例急性反应的患者也 长期福利持续了几个月。 两个患者继续 保持足够的血小板计数，没有任何疗法3和10 3G8后几个月，第三名患者恢复了对 IVGG和现在只需要每5周一次IVGG治疗。 串行打折的红细胞间隙表明急性 效果是由于MPS FCR封锁所致。 但是长期 效果可能是由长时间的MPS FCR封锁引起的 和/或抗血小板抗体的水平降低。 MPS FCR 功能将通过连续的红细胞间隙来研究。 通过研究将探索这种效果的机制 抗替代型和抗体型型抗体水平。 抗iDiotypes 在不到2周的患者中检测到，并持续存在。 抗替代型的开发可以模仿3G8的效果 并创建FCRP52-70表达的内源性调制。 替代地对抗血小板抗体的系列研究可能揭示 可以解释长期收益的减少。 如果看见，一个 减少可能是由于瞬时消融而发生的 自然杀手（NK）细胞在输注后立即看到 3G8，因为NK细胞有助于免疫调节 免疫球蛋白产生。 3G8是一种有希望的新疗法 难治性ITP。 它在这些患者中的使用将允许研究FCR 自身免疫性疾病的免疫调节。