Improvement of antibody functionality by structure-guided paratope engraftment

被引：35

作者：

Liu, Qingbo ^{[1
]}

Lai, Yen-Ting ^{[2
]}

Zhang, Peng ^{[1
]}

Louder, Mark K. ^{[2
]}

Pegu, Amarendra ^{[2
]}

Rawi, Reda ^{[2
]}

Asokan, Mangaiarkarasi ^{[2
]}

Chen, Xuejun ^{[2
]}

Shen, Chen-Hsiang ^{[2
]}

Chuang, Gwo-Yu ^{[2
]}

Yang, Eun Sung ^{[2
]}

Miao, Huiyi ^{[1
]}

Wang, Yuge ^{[1
]}

Fauci, Anthony S. ^{[1
]}

Kwong, Peter D. ^{[2
]}

Mascola, John R. ^{[2
]}

Lusso, Paolo ^{[1
]}

机构：

[1] NIAID, Immunoregulat Lab, NIH, Bldg 10, Bethesda, MD 20892 USA

[2] NIAID, Vaccine Res Ctr, NIH, 9000 Rockville Pike, Bethesda, MD 20892 USA

来源：

NATURE COMMUNICATIONS | 2019年 / 10卷 / 1期

关键词：

BISPECIFIC ANTIBODIES; HIV-ANTIBODIES; BROAD; MATURATION; CD4; IDENTIFICATION; NEUTRALIZATION; PROTECTION; FRAMEWORK; SEQUENCE;

D O I：

10.1038/s41467-019-08658-4

中图分类号：

O [数理科学和化学]; P [天文学、地球科学]; Q [生物科学]; N [自然科学总论];

学科分类号：

07 ; 0710 ; 09 ;

摘要：

Broadly neutralizing antibodies (bNAbs) represent a promising alternative to antiretroviral drugs for HIV-1 prevention and treatment. Selected antibodies to the CD4-binding site bolster envelope trimer binding via quaternary contacts. Here, we rationally engraft a new paratope, i.e., the extended heavy-chain framework region 3 (FR3) loop of VRC03, which mediates quaternary interaction, onto several potent bNAbs, enabling them to reach an adjacent gp120 protomer. The interactive quaternary surface is delineated by solving the crystal structure of two FR3 loop-chimeric antibodies. Chimerization enhances the neutralizing activity of several potent bNAbs against a majority of global HIV-1 strains. Compared to unmodified antibodies, chimeric antibodies display lower autoreactivity and prolonged in vivo half-life in huFcRn mice and rhesus macaques. Thus, paratope engraftment may be used to expand the epitope repertory of natural antibodies, improving their functionality for disease prevention and treatment.

引用

页数：13

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