A humanized murine monoclonal antibody protects mice either before or after challenge with virulent Venezuelan equine encephalomyelitis virus
A humanized murine monoclonal antibody protects mice either before or after challenge with virulent Venezuelan equine encephalomyelitis virus
复制标题
DOI：
10.1099/vir.0.81925-0
复制
发表时间：
2006-09-01
影响因子：
3.8
通讯作者：
Roehrig, John T.
中科院分区：
文献类型：
--
作者：
Hunt, Ann R.;Frederickson, Shana;Roehrig, John T.
人源化单克隆抗体（mAb）已经开发出来，并评估其预防或治愈委内瑞拉马脑脊髓炎病毒（VEEV）感染的潜力。使用组合抗体文库和噬菌体展示技术将VEEV中和性保护性鼠mAb 3B 4C-4人源化。评价人源化VEEV结合Fab的病毒中和能力，然后将选择的Fab转化为全免疫球蛋白（IG）G1，并产生稳定的细胞系。命名为Hy 4 IgG的人源化mAb Hy 4 - 26 C具有与3B 4C-4类似的病毒中和能力。在成年Swiss韦伯斯特小鼠中进行纯化Hy 4 IgG的被动抗体保护研究。低至100 ng Hy 4 IgG保护了90%的用100 μ L腹腔内（i. p.）抗体转移后24小时，强毒VEEV（特立尼达驴）的平均发病率（MD50）剂量;同样，500 μ g Hy 4 IgG保护了80%接种100个鼻内MD50剂量VEEV的小鼠。此外，10 μ g被动Hy 4 IgG保护70%的小鼠免受高达10（7）i.p.MD50的VEEV攻击剂量。Hy 4 IgG还保护小鼠免受另一种流行性VEEV品种1C（P676）的攻击。重要的是，对已经感染VEEV的小鼠治疗性施用人源化mAb在VEEV接种后1小时内治愈了90%的Hy 4 IgG治疗的小鼠，并且在病毒感染后24小时治愈了75%的治疗的小鼠。
A humanized monoclonal antibody (mAb) has been developed and its potential to protect from or cure a Venezuelan equine encephalomyelitis virus (VEEV) infection was evaluated. The VEEV-neutralizing, protective murine mAb 3B4C-4 was humanized using combinatorial antibody libraries and phage-display technology. Humanized VEEV-binding Fabs were evaluated for virus-neutralizing capacity, then selected Fabs were converted to whole immunoglobulin (Ig) G1, and stable cell lines were generated. The humanized mAb Hy4-26C, designated Hy4 IgG, had virus-neutralizing capacity similar to that of 3B4C-4. Passive antibody protection studies with purified Hy4 IgG were performed in adult Swiss Webster mice. As little as 100 ng Hy4 IgG protected 90% of mice challenged with 100 intraperitoneal (i.p.) mean morbidity (MD50) doses of virulent VEEV (Trinidad donkey) 24 h after antibody transfer; also, 500 mu g Hy4 IgG protected 80% of mice inoculated with 100 intranasal MD50 doses of VEEV. Moreover, 10 mu g passive Hy4 IgG protected 70% of mice from a VEEV challenge dose as great as 10(7) i.p. MD50. Hy4 IgG also protected mice from challenge with another epizootic VEEV variety, 1C (P676). Importantly, therapeutic administration of the humanized mAb to mice already infected with VEEV cured 90% of mice treated with Hy4 IgG within 1h of VEEV inoculation and 75% of mice treated 24 h after virus infection.