A High-Affinity Native Human Antibody Neutralizes Human Cytomegalovirus Infection of Diverse Cell Types
A High-Affinity Native Human Antibody Neutralizes Human Cytomegalovirus Infection of Diverse Cell Types
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DOI：
10.1128/aac.04295-14
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发表时间：
2015-03-01
影响因子：
4.9
通讯作者：
Pereira, Lenore
中科院分区：
文献类型：
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作者：
Kauvar, Lawrence M.;Liu, Keyi;Pereira, Lenore
人巨细胞病毒（HCMV）是导致移植受者预后不良的最常见感染。母体感染和经胎盘传播是永久性出生缺陷的主要原因。虽然没有预防HCMV感染的主动疫苗已被批准，但用HCMV特异性免疫球蛋白进行被动免疫已显示出治疗移植和先天性适应症的前景。已知靶向病毒糖蛋白B（gB）表面蛋白的抗体可中和HCMV感染性，高亲和力结合是理想的特性，既可与促进病毒穿过胎盘传播的低亲和力抗体竞争，又可取代结合附近表位的非中和抗体。使用小型化筛选技术来表征从单个人B淋巴细胞分泌的IgG，先前克隆了30种针对gB的抗体。这里描述了最有效的克隆TRL 345。其测得的亲和力为1 pM的高度保守的位点I的AD-2表位的gB。证实了15株主要HCMV临床分离株的菌株非依赖性中和。TRL 345可防止HCMV感染胎盘成纤维细胞、平滑肌细胞、内皮细胞和上皮细胞，并抑制感染后HCMV在上皮细胞中的扩散。预防先天性传播的潜在效用得到了对病毒传播至胎儿至关重要的胎盘细胞类型（包括分化的细胞滋养层、滋养层祖细胞和胎盘成纤维细胞）的HCMV感染的阻断的支持。此外，TRL 345有效控制人胎盘锚定绒毛的离体感染。TRL 345已在商业规模上使用，是临床评价的候选药物。
Human cytomegalovirus (HCMV) is the most common infection causing poor outcomes among transplant recipients. Maternal infection and transplacental transmission are major causes of permanent birth defects. Although no active vaccines to prevent HCMV infection have been approved, passive immunization with HCMV-specific immunoglobulin has shown promise in the treatment of both transplant and congenital indications. Antibodies targeting the viral glycoprotein B (gB) surface protein are known to neutralize HCMV infectivity, with high-affinity binding being a desirable trait, both to compete with low-affinity antibodies that promote the transmission of virus across the placenta and to displace nonneutralizing antibodies binding nearby epitopes. Using a miniaturized screening technology to characterize secreted IgG from single human B lymphocytes, 30 antibodies directed against gB were previously cloned. The most potent clone, TRL345, is described here. Its measured affinity was 1 pM for the highly conserved site I of the AD-2 epitope of gB. Strain-independent neutralization was confirmed for 15 primary HCMV clinical isolates. TRL345 prevented HCMV infection of placental fibroblasts, smooth muscle cells, endothelial cells, and epithelial cells, and it inhibited postinfection HCMV spread in epithelial cells. The potential utility for preventing congenital transmission is supported by the blockage of HCMV infection of placental cell types central to virus transmission to the fetus, including differentiating cytotrophoblasts, trophoblast progenitor cells, and placental fibroblasts. Further, TRL345 was effective at controlling an ex vivo infection of human placental anchoring villi. TRL345 has been utilized on a commercial scale and is a candidate for clinical evaluation.