Combination therapy for inhibitor reversal in haemophilia A using monoclonal anti-CD20 and rapamycin.
Combination therapy for inhibitor reversal in haemophilia A using monoclonal anti-CD20 and rapamycin.
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使用单克隆抗CD20和雷帕霉素的血友病A抑制剂逆转的组合疗法。
DOI：
10.1160/th16-05-0404
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发表时间：
2017-01-05
影响因子：
6.7
通讯作者：
Herzog RW
中科院分区：
文献类型：
--
作者：
Biswas M;Rogers GL;Sherman A;Byrne BJ;Markusic DM;Jiang H;Herzog RW
凝血因子VIII（FVIII）抗体（抑制剂）的产生是血友病A（HA）静脉替代治疗的主要并发症。目前的免疫耐受诱导（ITI）方案并不普遍有效。利妥昔单抗是一种针对CD 20的B细胞耗竭抗体，在患者中显示出抑制剂逆转的混合结果。本研究的目的是开发一种联合治疗HA中的抑制剂逆转，使用抗鼠CD 20（抗mCD 20）抗体和雷帕霉素，其靶向B和T细胞反应。此外，它还广泛表征了IgG骨架在抗CD 20抗体耗竭B细胞中的作用。为此，通过每周IV注射FVIII在BALB/c-HA小鼠中产生抑制剂。随后，间隔3周分2次IV注射抗mCD 20（18 B12）（含IgG 2a或IgG 1骨架），并表征B细胞消除和恢复情况。雷帕霉素口服给药3次/周（持续1个月），同时继续FVIII注射。将抗mCD 20的IgG骨架从IgG 2a改变为IgG 1可减少B细胞（包括记忆B细胞）的总体消耗，边缘区、B-10和B-1 B细胞未受到特别影响。虽然两种抗体单独使用均无效，但与雷帕霉素联合使用时，抗mCD 20 IgG 2a而非IgG 1能够逆转HA小鼠中的抑制剂。该方案对于起始滴度约10 BU特别有效。尽管IgG 1抗mCD 20保留了潜在的致耐受性B细胞亚群，但IgG 2a与雷帕霉素联合给药时可指导持续的低反应性。该方案代表了HA中抑制剂逆转的有前景的治疗，因为这两种化合物已广泛用于人类患者。
Development of antibodies (inhibitors) against coagulation factor VIII (FVIII) is a major complication of intravenous replacement therapy in haemophilia A (HA). Current immune tolerance induction (ITI) regimens are not universally effective. Rituximab, a B cell-depleting antibody against CD20, has shown mixed results for inhibitor reversal in patients. This study aims to develop a combinatorial therapy for inhibitor reversal in HA, using anti-murine CD20 (anti-mCD20) antibody and rapamycin, which targets both B and T cell responses. Additionally, it extensively characterizes the role of the IgG backbone in B cell depletion by anti-CD20 antibodies. For this, inhibitors were generated in BALB/c-HA mice by weekly IV injection of FVIII. Subsequently, anti-mCD20 (18B12) with IgG2a or IgG1 backbone was injected IV in 2 doses 3 weeks apart and B cell depletion and recovery was characterized. Rapamycin was administered orally 3x/week (for 1 month) while continuing FVIII injections. Altering the IgG backbone of anti-mCD20 from IgG2a to IgG1 reduced overall depletion of B cells (including memory B cells), and marginal zone, B-10, and B-1b cells were specifically unaffected. While neither antibody was effective alone, in combination with rapamycin, anti-mCD20 IgG2a but not IgG1 was able to reverse inhibitors in HA mice. This regimen was particularly effective for starting titres of ~10 BU. Although IgG1 anti-mCD20 spared potentially tolerogenic B cell subsets, IgG2a directed sustained hyporesponsiveness when administered in conjunction with rapamycin. This regimen represents a promising treatment for inhibitor reversal in HA, as both of these compounds have been extensively used in human patients.