A subset of high-titer anti-factor VIII A2 domain antibodies is responsive to treatment with factor VIII
A subset of high-titer anti-factor VIII A2 domain antibodies is responsive to treatment with factor VIII
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DOI：
10.1182/blood-2015-09-670034
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发表时间：
2016-04-21
期刊：
影响因子：
20.3
通讯作者：
Meeks, Shannon L.
中科院分区：
文献类型：
--
作者：
Eubanks, Joshua;Baldwin, W. Hunter;Meeks, Shannon L.
因子 VIII (fVIII) 的主要 B 细胞表位位于 A2 和 C2 结构域。在 C2 结构域内，在预测小鼠出血模型的致病性方面，抗体表位和动力学比抑制剂滴度更重要。为了研究 A2 结构域内的这一点，在小鼠模型中测试了多种抗人 fVIII A2 结构域单克隆抗体 (MAb) 的致病性。将单克隆抗体注射到 A 型血友病小鼠中，然后注射人 B 结构域缺失的 fVIII。测量 4 毫米尾巴剪断后的失血量。测试了以下抗 A2 单克隆抗体：高滴度 1 型抑制剂 4A4、2-76 和 1D4； 2-54，高滴度2型抑制剂； B94，2 型抑制剂；和非抑制性 MAb GMA-012、4C7 和 B25。所有高滴度 1 型 MAb 产生的失血量均显着高于对照小鼠，而所有非抑制性 MAb 产生的失血量与对照小鼠相似。尽管 2-54 的抑制剂滴度为 34 000 BU/mg 免疫球蛋白 G，但 2 型 MAb 并不具有致病性。此外，据报道，一名患有高滴度 2 型抗 A2 抑制剂且对 fVIII 有反应的患者。抑制剂滴度和出血表型之间的差异，加上 C2 结构域中的类似发现，强调了标准 Bethesda 测定中未检测到的抑制剂特性在预测 fVIII 治疗反应中的重要性。
The primary B-cell epitopes of factor VIII (fVIII) are in the A2 and C2 domains. Within the C2 domain, antibody epitope and kinetics are more important than inhibitor titer in predicting pathogenicity in a murine bleeding model. To investigate this within the A2 domain, the pathogenicity of a diverse panel of antihuman fVIII A2 domain monoclonal antibodies (MAbs) was tested in the murine model. MAbs were injected into hemophilia A mice, followed by injection of human B domain-deleted fVIII. Blood loss after a 4-mm tail snip was measured. The following anti-A2 MAbs were tested: high-titer type 1 inhibitors 4A4, 2-76, and 1D4; 2-54, a high-titer type 2 inhibitor; B94, a type 2 inhibitor; and noninhibitory MAbs GMA-012, 4C7, and B25. All high-titer type 1 MAbs produced blood loss that was significantly greater than control mice, whereas all non-inhibitory MAbs produced blood loss that was similar to control. The type 2 MAbs were not pathogenic despite 2-54 having an inhibitor titer of 34 000 BU/mg immunoglobulin G. In addition, a patient with a high-titer type 2 anti-A2 inhibitor who is responsive to fVIII is reported. The discrepancy between inhibitor titer and bleeding phenotype combined with similar findings in the C2 domain stress the importance of inhibitor properties not detected in the standard Bethesda assay in predicting response to fVIII therapy.