Russell Karen E, Olsen Eva H N, Raymer Robin A, Merricks Elizabeth P, Bellinger Dwight A, Read Marjorie S, Rup Bonita J, Keith James C, McCarthy Kyle P, Schaub Robert G, Nichols Timothy C
Francis Owen Blood Research Laboratory, Department of Pathology and Laboratory Medicine, UNC School of Medicine, CB# 3114, 350 S Old Fayetteville Rd, Chapel Hill, NC 27516.
Blood. 2003 Dec 15;102(13):4393-8. doi: 10.1182/blood-2003-05-1498. Epub 2003 Aug 21.
Intravenous administration of recombinant human factor IX (rhFIX) acutely corrects the coagulopathy in hemophilia B dogs. To date, 20 of 20 dogs developed inhibitory antibodies to the xenoprotein, making it impossible to determine if new human FIX products, formulations, or methods of chronic administration can reduce bleeding frequency. Our goal was to determine whether hemophilia B dogs rendered tolerant to rhFIX would have reduced bleeding episodes while on sustained prophylactic rhFIX administered subcutaneously. Reproducible methods were developed for inducing tolerance to rhFIX in this strain of hemophilia B dogs, resulting in a significant reduction in the development of inhibitors relative to historical controls (5 of 12 versus 20 or 20, P <.001). The 7 of 12 tolerized hemophilia B dogs exhibited shortened whole blood clotting times (WBCTs), sustained detectable FIX antigen, undetectable Bethesda inhibitors, transient or no detectable antihuman FIX antibody titers by enzyme-linked immunosorbent assay (ELISA), and normal clearance of infused rhFIX. Tolerized hemophilia B dogs had 69% reduction in bleeding frequency in year 1 compared with nontolerized hemophilia B dogs (P =.0007). If proven safe in human clinical trials, subcutaneous rhFIX may provide an alternate approach to prophylactic therapy in selected patients with hemophilia B.
静脉注射重组人凝血因子IX（rhFIX）可迅速纠正B型血友病犬的凝血病。迄今为止，20只犬中有20只产生了针对该异种蛋白的抑制性抗体，这使得无法确定新型人FIX产品、制剂或长期给药方法是否能降低出血频率。我们的目标是确定对rhFIX产生耐受性的B型血友病犬在皮下持续预防性给予rhFIX时出血发作次数是否会减少。我们开发了可重复的方法来诱导这种B型血友病犬对rhFIX产生耐受性，与历史对照相比，抑制剂的产生显著减少（12只中有5只，而历史对照为20只或20只，P <.001）。12只产生耐受性的B型血友病犬中有7只表现出全血凝固时间（WBCT）缩短、FIX抗原持续可检测、贝塞斯达抑制剂不可检测、通过酶联免疫吸附测定（ELISA）检测到的抗人FIX抗体滴度短暂或无、以及注入的rhFIX清除正常。与未产生耐受性的B型血友病犬相比，产生耐受性的B型血友病犬在第1年的出血频率降低了69%（P =.0007）。如果在人体临床试验中被证明是安全的，皮下注射rhFIX可能为部分B型血友病患者的预防性治疗提供一种替代方法。
