Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity.
Identification and multidimensional optimization of an asymmetric bispecific IgG antibody mimicking the function of factor VIII cofactor activity.
复制标题
DOI：
10.1371/journal.pone.0057479
复制
发表时间：
2013
期刊：
影响因子：
3.7
通讯作者：
Hattori K
中科院分区：
文献类型：
--
作者：
Sampei Z;Igawa T;Soeda T;Okuyama-Nishida Y;Moriyama C;Wakabayashi T;Tanaka E;Muto A;Kojima T;Kitazawa T;Yoshihashi K;Harada A;Funaki M;Haraya K;Tachibana T;Suzuki S;Esaki K;Nabuchi Y;Hattori K
在血友病A中，使用外源性因子VIII（FVIII）进行常规预防需要频繁静脉注射，并可能导致抗凝血因子VIII同种抗体（凝血因子VIII抑制剂）的产生。为了克服这些缺点，我们筛选了针对因子IXa（FIXa）和因子X（FX）的不对称双特异性IgG抗体，模拟FVIII辅因子功能。由于先导双特异性抗体的治疗潜力是边际的，因此通过修饰其与FIXa和FX的结合特性来改善FVIII模拟活性，并且通过工程化可变区的电荷特性来改善药代动力学。通过框架/互补决定区改组鉴定抗FIXa和抗FX重链的共同轻链，并通过两条重链的pI工程化以促进从副产物混合物中离子交换色谱纯化双特异性抗体，克服了制造双特异性抗体的困难。还进行了工程改造以克服低溶解度和脱酰胺。多维优化的双特异性抗体hBS 910在人FVIII缺陷型血浆中表现出有效的FVIII模拟活性，并且在食蟹猴中具有3周的半衰期和高皮下生物利用度。重要的是，hBS 910的活性不受FVIII抑制剂的影响，而抗hBS 910抗体不抑制FVIII活性，允许使用hBS 910而不考虑FVIII抑制剂的产生或存在。此外，hBS 910可以在大生产规模上纯化并配制成用于临床使用的皮下注射液体制剂。hBS 910的这些特征使得能够以长给药间隔通过皮下递送进行常规预防，而不考虑FVIII抑制剂的产生或存在。我们预期hBS 910（研究药物名称：ACE 910）将为重度血友病A患者提供显著获益。
In hemophilia A, routine prophylaxis with exogenous factor VIII (FVIII) requires frequent intravenous injections and can lead to the development of anti-FVIII alloantibodies (FVIII inhibitors). To overcome these drawbacks, we screened asymmetric bispecific IgG antibodies to factor IXa (FIXa) and factor X (FX), mimicking the FVIII cofactor function. Since the therapeutic potential of the lead bispecific antibody was marginal, FVIII-mimetic activity was improved by modifying its binding properties to FIXa and FX, and the pharmacokinetics was improved by engineering the charge properties of the variable region. Difficulties in manufacturing the bispecific antibody were overcome by identifying a common light chain for the anti-FIXa and anti-FX heavy chains through framework/complementarity determining region shuffling, and by pI engineering of the two heavy chains to facilitate ion exchange chromatographic purification of the bispecific antibody from the mixture of byproducts. Engineering to overcome low solubility and deamidation was also performed. The multidimensionally optimized bispecific antibody hBS910 exhibited potent FVIII-mimetic activity in human FVIII-deficient plasma, and had a half-life of 3 weeks and high subcutaneous bioavailability in cynomolgus monkeys. Importantly, the activity of hBS910 was not affected by FVIII inhibitors, while anti-hBS910 antibodies did not inhibit FVIII activity, allowing the use of hBS910 without considering the development or presence of FVIII inhibitors. Furthermore, hBS910 could be purified on a large manufacturing scale and formulated into a subcutaneously injectable liquid formulation for clinical use. These features of hBS910 enable routine prophylaxis by subcutaneous delivery at a long dosing interval without considering the development or presence of FVIII inhibitors. We expect that hBS910 (investigational drug name: ACE910) will provide significant benefit for severe hemophilia A patients.
登录
查看更多内容
影响因子：
2.4
作者：
Igawa, T.;Tsunoda, H.;Hattori, K.
通讯作者：
Hattori, K.
影响因子：
100.3
作者：
Beck, Alain;Wurch, Thierry;Corvaia, Nathalie
通讯作者：
Corvaia, Nathalie
DOI：
10.1074/jbc.m110.113910
发表时间：
2010-07-02
期刊：
The Journal of biological chemistry
影响因子：
--
作者：
Jackman J;Chen Y;Huang A;Moffat B;Scheer JM;Leong SR;Lee WP;Zhang J;Sharma N;Lu Y;Iyer S;Shields RL;Chiang N;Bauer MC;Wadley D;Roose-Girma M;Vandlen R;Yansura DG;Wu Y;Wu LC
通讯作者：
Wu LC
影响因子：
158.5
作者：
Leissinger, Cindy;Gringeri, Alessandro;Mantovani, Lorenzo
通讯作者：
Mantovani, Lorenzo
影响因子：
20.3
作者：
Bjorkman, Sven;Oh, MyungShin;Collins, Peter W.
通讯作者：
Collins, Peter W.