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Nat Med.:科学家研制治疗血友病新型抗体

来源:中国科学报 2012-10-20 13:20

科学家在近期发表的《自然—医学》杂志上撰文称,他们研制出一种抗体可以代替血友病中某一缺失蛋白发挥作用并逆转患有该病的非人灵长类的止血功能缺陷。

A型血友病患者体内缺乏凝血蛋白因子VIII,通常需要通过注射FVIII蛋白获得治疗。但由于患者体内容易产生针对FVIII的抗体来阻止该蛋白发挥作用,因而研究出一种新的治疗方法是必须的。即便FVIII可以产生疗效,仍需要通过对患者进行频繁的静脉注射才能维持这种疗效,由此会产生新问题,对儿童来说更是如此。

在一项新的治疗策略中,Takehisa Kitazawa等人研制出一种抗体,其具有VIII因子的特性。VIII因子的运作机制是:将IXa因子和X因子两种蛋白引入到血液级联中,让其产生相互接触。这种新抗体可以模拟VIII因子,将IXa和X两种因子结合并固定。该抗体能够修复血友病患病人类的血液凝固功能——即便这些患者体内存在着FVIII抗体,并可以让处在临床前的A型血友病患病猕猴产生止血功能。

与FVII注射相比,这种新抗体的优点在于其可以不受FVII抗体影响、可以进行皮下注射以及无需频繁注射。不过,目前该抗体还需要进一步优化才能用于临床试验。(生物谷Bioon.com)

A bispecific antibody to factors IXa and X restores factor VIII hemostatic activity in a hemophilia A model

Kitazawa T, Igawa T, Sampei Z, Muto A, Kojima T, Soeda T, Yoshihashi K, Okuyama-Nishida Y, Saito H, Tsunoda H, Suzuki T, Adachi H, Miyazaki T, Ishii S, Kamata-Sakurai M, Iida T, Harada A, Esaki K, Funaki M, Moriyama C, Tanaka E, Kikuchi Y, Wakabayashi T, Wada M, Goto M, Toyoda T, Ueyama A, Suzuki S, Haraya K, Tachibana T, Kawabe Y, Shima M, Yoshioka A, Hattori K.

Hemophilia A is a bleeding disorder resulting from coagulation factor VIII (FVIII) deficiency. Exogenously provided FVIII effectively reduces bleeding complications in patients with severe hemophilia A. In approximately 30% of such patients, however, the 'foreignness' of the FVIII molecule causes them to develop inhibitory antibodies against FVIII (inhibitors), precluding FVIII treatment in this set of patients. Moreover, the poor pharmacokinetics of FVIII, attributed to low subcutaneous bioavailability and a short half-life of 0.5 d, necessitates frequent intravenous injections. To overcome these drawbacks, we generated a humanized bispecific antibody to factor IXa (FIXa) and factor X (FX), termed hBS23, that places these two factors into spatially appropriate positions and mimics the cofactor function of FVIII. hBS23 exerted coagulation activity in FVIII-deficient plasma, even in the presence of inhibitors, and showed in vivo hemostatic activity in a nonhuman primate model of acquired hemophilia A. Notably, hBS23 had high subcutaneous bioavailability and a 2-week half-life and would not be expected to elicit the development of FVIII-specific inhibitory antibodies, as its molecular structure, and hence antigenicity, differs from that of FVIII. A long-acting, subcutaneously injectable agent that is unaffected by the presence of inhibitors could markedly reduce the burden of care for the treatment of hemophilia A.

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