IgG3 enhances neutralization potency and Fc effector function of an HIV V2-specific broadly neutralizing antibody.,PLoS Pathogens

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IgG3 enhances neutralization potency and Fc effector function of an HIV V2-specific broadly neutralizing antibody.
PLoS Pathogens ( IF 5.5 ) Pub Date : 2019-12-16 , DOI: 10.1371/journal.ppat.1008064
Simone I Richardson _{1,

2} , Bronwen E Lambson _{1,

2} , Andrew R Crowley ₃ , Arman Bashirova _{4,

5} , Cathrine Scheepers _{1,

2} , Nigel Garrett _{6,

7} , Salim Abdool Karim _{6,

7,

8} , Nonhlanhla N Mkhize _{1,

2} , Mary Carrington _{4,

5} , Margaret E Ackerman ₃ , Penny L Moore _{1,

2,

6} , Lynn Morris _{1,

2,

6}

Affiliation

Broadly neutralizing antibodies (bNAbs) protect against HIV infection in non-human primates and their efficacy may be enhanced through interaction with Fc receptors on immune cells. Antibody isotype is a modulator of this binding with the IgG3 subclass mediating potent Fc effector function and is associated with HIV vaccine efficacy and HIV control. BNAb functions are typically assessed independently of the constant region with which they are naturally expressed. To examine the role of natural isotype in the context of a bNAb lineage we studied CAP256, an HIV-infected individual that mounted a potent V2-specific bNAb response. CAP256 expressed persistently high levels of plasma IgG3 which we found mediated both broad neutralizing activity and potent Fc function. Sequencing of germline DNA and the constant regions of V2-directed bNAbs from this donor revealed the expression of a novel IGHG3 allele as well as IGHG3*17, an allele that produces IgG3 antibodies with increased plasma half-life. Both allelic variants were used to generate CAP256-VRC26.25 and CAP256-VRC26.29 IgG3 bNAbs and these were compared to IgG1 versions. IgG3 variants were shown to have significantly higher phagocytosis and trogocytosis compared to IgG1 versions, which corresponded to increased affinity for FcγRIIa. Neutralization potency was also significantly higher for IgG3 bNAbs, particularly against viruses lacking the N160 glycan. By exchanging hinge regions between subclass variants, we showed that hinge length modulated both neutralization potency and Fc function. This study showed that co-operation between the variable and natural IgG3 constant regions enhanced the polyfunctionality of antibodies, indicating the value of leveraging genetic variation which could be exploited for passive immunity.

中文翻译：

IgG3 增强 HIV V2 特异性广泛中和抗体的中和效力和 Fc 效应器功能。

广泛中和抗体 (bNAb) 可以保护非人类灵长类动物免受 HIV 感染，并且通过与免疫细胞上的 Fc 受体相互作用可以增强其功效。抗体同种型是与 IgG3 亚类结合的调节剂，介导有效的 Fc 效应器功能，并与 HIV 疫苗功效和 HIV 控制相关。 BNAb 功能的评估通常独立于其天然表达的恒定区。为了研究天然同种型在 bNAb 谱系中的作用，我们研究了 CAP256，这是一种 HIV 感染者，它产生了有效的 V2 特异性 bNAb 反应。 CAP256 持续表达高水平的血浆 IgG3，我们发现它介导广泛的中和活性和有效的 Fc 功能。对来自该供体的种系 DNA 和 V2 定向 bNAb 恒定区的测序揭示了一种新型 IGHG3 等位基因以及 IGHG3*17 的表达，IGHG3*17 是一种产生血浆半衰期延长的 IgG3 抗体的等位基因。两种等位基因变体均用于生成 CAP256-VRC26.25 和 CAP256-VRC26.29 IgG3 bNAb，并将其与 IgG1 版本进行比较。与 IgG1 版本相比，IgG3 变体具有显着更高的吞噬作用和吞噬作用，这对应于对 FcγRIIa 的亲和力增加。 IgG3 bNAb 的中和效力也明显更高，特别是针对缺乏 N160 聚糖的病毒。通过在亚类变体之间交换铰链区，我们发现铰链长度可调节中和效力和 Fc 功能。这项研究表明，可变区和天然 IgG3 恒定区之间的合作增强了抗体的多功能性，表明利用可用于被动免疫的遗传变异的价值。

更新日期：2019-12-17

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