Antibody Conjugation Approach Enhances Breadth and Potency of Neutralization of Anti-HIV-1 Antibodies and CD4-IgG
Antibody Conjugation Approach Enhances Breadth and Potency of Neutralization of Anti-HIV-1 Antibodies and CD4-IgG
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DOI：
10.1128/jvi.03146-12
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发表时间：
2013-05-01
影响因子：
5.4
通讯作者：
Barbas, Carlos F., III
中科院分区：
文献类型：
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作者：
Gavrilyuk, Julia;Ban, Hitoshi;Barbas, Carlos F., III
广泛中和抗体PG 9和PG 16可有效中和70 - 80%的循环HIV-1分离株。在这项研究中，PG 9和PG 16的中和能力进一步增强了生物共轭与aplaviroc，病毒进入宿主细胞的小分子抑制剂。一种新的空气稳定的重氮六氟磷酸盐试剂，允许在温和条件下快速，酪氨酸选择性功能化的蛋白质和抗体，用于制备一系列aplaviroc-conjugated抗体，包括b12，2G 12，PG 9，PG 16，和CD 4-IgG。结合抗体通过两种机制阻断HIV-1进入：通过与病毒本身结合和通过阻断宿主细胞上的CCR 5受体。化学修饰没有显著改变亲本抗体对非耐药HIV-1菌株的效力。缀合不改变血液中模型IgG的药代动力学。针对一组117种HIV-1菌株测试了PG 9-aplaviroc缀合物，发现其100%中和病毒。在117株HIV-1毒株中的36株的中和研究中，PG 9-aplaviroc偶联物IC 50低于PG 9。这些结果支持了这种新的双特异性抗体方法，并为联合HIV-1治疗提供了一种潜在的新策略。
Broadly neutralizing antibodies PG9 and PG16 effectively neutralize 70 to 80% of circulating HIV-1 isolates. In this study, the neutralization abilities of PG9 and PG16 were further enhanced by bioconjugation with aplaviroc, a small-molecule inhibitor of virus entry into host cells. A novel air-stable diazonium hexafluorophosphate reagent that allows for rapid, tyrosine-selective functionalization of proteins and antibodies under mild conditions was used to prepare a series of aplaviroc-conjugated antibodies, including b12, 2G12, PG9, PG16, and CD4-IgG. The conjugated antibodies blocked HIV-1 entry through two mechanisms: by binding to the virus itself and by blocking the CCR5 receptor on host cells. Chemical modification did not significantly alter the potency of the parent antibodies against nonresistant HIV-1 strains. Conjugation did not alter the pharmacokinetics of a model IgG in blood. The PG9-aplaviroc conjugate was tested against a panel of 117 HIV-1 strains and was found to neutralize 100% of the viruses. PG9-aplaviroc conjugate IC50s were lower than those of PG9 in neutralization studies of 36 of the 117 HIV-1 strains. These results support this new approach to bispecific antibodies and offer a potential new strategy for combining HIV-1 therapies.