Epitope masking reagents in transfusion medicine

描述（由申请人提供）：需要长期输血的患者可能会产生许多不同的红细胞抗原同种抗体，即使在全国范围内搜索，也无法确定交叉匹配的红细胞单位。当这种情况发生时，患者被迫放弃治疗，在某些情况下，红细胞输血可以挽救生命。因此，长期输血的患者，如镰状细胞病和其他慢性贫血患者，因对多种血型抗原进行同种异体免疫而发病和死亡。目前，没有任何治疗干预措施可以避免多种同种异体抗体的情况，并允许输血交叉配型不相容的血液。然而，抗红细胞抗体可以被修饰以维持其抗原结合活性，但失去溶血所需的活性，例如固定补体或与吞噬细胞上的Fc受体结合的能力。我们假设这些修饰的抗体会掩盖起作用的抗原表位，从而通过完整的IgG阻断红细胞溶血。因此，我们建议通过设计这种抗体来开发一种新的治疗方法，我们称之为表位掩蔽试剂（EMRs）。我们的中心假设是，emr的使用将通过掩盖负责溶血的抗体识别的表位，允许输入交叉配型不相容的红细胞。为了对这种方法进行详细的机制发展，我们创建了一种新的小鼠模型来研究交叉配伍不相容输血。利用该模型，我们可以1)获得供体小鼠和受体小鼠之间具有单一抗原差异的红细胞，2)使小鼠免疫供体红细胞上的血型抗原，3)通过静脉途径输注填充的、白细胞诱导的供体红细胞，4)检测输注红细胞的体内抗体结合，5)监测输注红细胞的溶血和循环寿命。我们建议使用这种交叉配型不相容输血模型作为开发和测试电子病历疗效的平台。需要多次输血的患者会接触到许多献血者。因此，最终可能很难找到适合他们的血液。在这种情况下，如果他们输了不相容的血液，他们有输血反应的风险，但如果他们不输也有风险。我们建议开发新的治疗方法，允许在这种情况下向患者输注不相容的血液。

DESCRIPTION (provided by applicant): Patients whose illness requires chronic transfusions can develop so many different alloantibodies to RBC antigens that no crossmatch-compatible RBC units can be identified despite nationwide searches. When this occurs, patients are forced to forgo the therapeutic, and, in some cases, lifesaving benefits of RBC transfusion. Thus, chronically transfused patients, such as those with sickle cell disease and other chronic anemias, suffer morbidity and mortality from alloimmunization against multiple blood group antigens. Currently, no therapeutic interventions can circumvent the situation of multiple alloantibodies and allow for transfusion of crossmatch-incompatible blood. However, anti-RBC antibodies can be modified to maintain their antigen binding activity but lose activities required for hemolysis, such as the ability to fix complement or bind to Fc Receptors on phagocytes. We hypothesize that these modified antibodies will mask the offending epitopes, thereby blocking RBC hemolysis by intact IgG. Thus, we propose to develop a novel therapeutic approach by engineering such antibodies, which we refer to as epitope masking reagents (EMRs). Our central hypothesis is that the use of EMRs will allow transfusion of crossmatch- incompatible RBC by masking epitopes recognized by antibodies responsible for hemolysis. To allow for a detailed mechanistic development of this approach, we created a novel murine model for studying crossmatch-incompatible transfusions. Using this model, we can 1) obtain RBC with a single antigenic difference between donor and recipient mice, 2) immunize mice to the blood group antigen on the donor RBC, 3) transfuse packed, leukoreduced, donor RBC by an intravenous route, 4) detect in vivo antibody binding to transfused RBC, and 5) monitor hemolysis and circulatory lifespan of transfused RBC. We propose to use this model of crossmatch-incompatible transfusion as a platform to develop and test the efficacy of EMRs. Patients requiring many blood transfusions are exposed to many blood donors. Therefore, it may eventually become difficult to find compatible blood for them. In this case, they are at risk for a transfusion reaction if they are transfused with incompatible blood, but are also at risk if they are not transfused. We propose to develop novel therapies that would allow transfusions of incompatible blood to patients in this setting.