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三特异性广泛中和HIV抗体在猕猴中介导对猿猴免疫缺陷病毒的有效保护。

Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques.

作者信息

Xu Ling, Pegu Amarendra, Rao Ercole, Doria-Rose Nicole, Beninga Jochen, McKee Krisha, Lord Dana M, Wei Ronnie R, Deng Gejing, Louder Mark, Schmidt Stephen D, Mankoff Zachary, Wu Lan, Asokan Mangaiarkarasi, Beil Christian, Lange Christian, Leuschner Wulf Dirk, Kruip Jochen, Sendak Rebecca, Kwon Young Do, Zhou Tongqing, Chen Xuejun, Bailer Robert T, Wang Keyun, Choe Misook, Tartaglia Lawrence J, Barouch Dan H, O'Dell Sijy, Todd John-Paul, Burton Dennis R, Roederer Mario, Connors Mark, Koup Richard A, Kwong Peter D, Yang Zhi-Yong, Mascola John R, Nabel Gary J

机构信息

Sanofi, 640 Memorial Drive, Cambridge, MA 02139, USA.

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20892, USA.

出版信息

Science. 2017 Oct 6;358(6359):85-90. doi: 10.1126/science.aan8630. Epub 2017 Sep 20.

DOI:10.1126/science.aan8630
PMID:28931639
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC5978417/
Abstract

The development of an effective AIDS vaccine has been challenging because of viral genetic diversity and the difficulty of generating broadly neutralizing antibodies (bnAbs). We engineered trispecific antibodies (Abs) that allow a single molecule to interact with three independent HIV-1 envelope determinants: the CD4 binding site, the membrane-proximal external region (MPER), and the V1V2 glycan site. Trispecific Abs exhibited higher potency and breadth than any previously described single bnAb, showed pharmacokinetics similar to those of human bnAbs, and conferred complete immunity against a mixture of simian-human immunodeficiency viruses (SHIVs) in nonhuman primates, in contrast to single bnAbs. Trispecific Abs thus constitute a platform to engage multiple therapeutic targets through a single protein, and they may be applicable for treatment of diverse diseases, including infections, cancer, and autoimmunity.

摘要

由于病毒的基因多样性以及产生广泛中和抗体（bnAbs）的困难，开发一种有效的艾滋病疫苗一直具有挑战性。我们设计了三特异性抗体（Abs），使单个分子能够与三个独立的HIV-1包膜决定簇相互作用：CD4结合位点、膜近端外部区域（MPER）和V1V2聚糖位点。与任何先前描述的单一bnAb相比，三特异性抗体表现出更高的效力和广度，其药代动力学与人bnAbs相似，并且与单一bnAb不同，它能使非人灵长类动物对猿猴-人类免疫缺陷病毒（SHIVs）混合物产生完全免疫。因此，三特异性抗体构成了一个通过单一蛋白质作用于多个治疗靶点的平台，它们可能适用于治疗多种疾病，包括感染、癌症和自身免疫性疾病。

相似文献

[1]
Trispecific broadly neutralizing HIV antibodies mediate potent SHIV protection in macaques.

Science. 2017-10-6

[2]
Development of Broadly Neutralizing Antibodies and Their Mapping by Monomeric gp120 in Human Immunodeficiency Virus Type 1-Infected Humans and Simian-Human Immunodeficiency Virus SHIVSF162P3N-Infected Macaques.

J Virol. 2016-3-28

[3]
Protective Efficacy of Broadly Neutralizing Antibodies with Incomplete Neutralization Activity against Simian-Human Immunodeficiency Virus in Rhesus Monkeys.

J Virol. 2017-9-27

[4]
A single injection of anti-HIV-1 antibodies protects against repeated SHIV challenges.

Nature. 2016-5-5

[5]
Enhanced potency of a broadly neutralizing HIV-1 antibody in vitro improves protection against lentiviral infection in vivo.

J Virol. 2014-11

[6]
AAV-expressed eCD4-Ig provides durable protection from multiple SHIV challenges.

Nature. 2015-2-18

[7]
Engineering HIV envelope protein to activate germline B cell receptors of broadly neutralizing anti-CD4 binding site antibodies.

J Exp Med. 2013-3-25

[8]
Anti-V3/Glycan and Anti-MPER Neutralizing Antibodies, but Not Anti-V2/Glycan Site Antibodies, Are Strongly Associated with Greater Anti-HIV-1 Neutralization Breadth and Potency.

J Virol. 2015-5

[9]
Systematic Assessment of Antiviral Potency, Breadth, and Synergy of Triple Broadly Neutralizing Antibody Combinations against Simian-Human Immunodeficiency Viruses.

J Virol. 2021-1-13

[10]
Targeting the HIV-1 Spike and Coreceptor with Bi- and Trispecific Antibodies for Single-Component Broad Inhibition of Entry.

J Virol. 2018-8-29

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[2]
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J Nanobiotechnology. 2025-7-4

[3]
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[4]
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[5]
Breaking Barriers to an HIV-1 Cure: Innovations in Gene Editing, Immune Modulation, and Reservoir Eradication.

Life (Basel). 2025-2-11

[6]
Engineering of CD8 T cells with an HIV-specific synthetic notch receptor to secrete broadly therapeutic antibodies for combining antiviral humoral and cellular immune responses.

mBio. 2025-4-9

[7]
Immune Alterations and Viral Reservoir Atlas in SIV-Infected Chinese Rhesus Macaques.

Infect Dis Rep. 2025-2-6

[8]
HIV diagnosis during acute infection: implications of long-acting preexposure prophylaxis and other evolving challenges.

Curr Opin HIV AIDS. 2025-5-1

[9]
Neutralizing antibody landscape of the non-polio Enteroviruses and future strategy.

Front Immunol. 2025-1-14

[10]
HIV Vaccine Development at a Crossroads: New B and T Cell Approaches.

Vaccines (Basel). 2024-9-12

本文引用的文献

[1]
Early antibody therapy can induce long-lasting immunity to SHIV.

Nature. 2017-3-23

[2]
Identification and specificity of broadly neutralizing antibodies against HIV.

Immunol Rev. 2017-1

[3]
The HIV-1 envelope glycoprotein structure: nailing down a moving target.

Immunol Rev. 2017-1

[4]
Antibody gene transfer with adeno-associated viral vectors as a method for HIV prevention.

Immunol Rev. 2017-1

[5]
Use of broadly neutralizing antibodies for HIV-1 prevention.

Immunol Rev. 2017-1

[6]
The quest for an antibody-based HIV vaccine.

Immunol Rev. 2017-1

[7]
HIV antibodies for treatment of HIV infection.

Immunol Rev. 2017-1

[8]
Antibody 10-1074 suppresses viremia in HIV-1-infected individuals.

Nat Med. 2017-2

[9]
Broadly Neutralizing Antibodies for HIV-1 Prevention or Immunotherapy.

N Engl J Med. 2016-11-24

[10]
Effect of HIV Antibody VRC01 on Viral Rebound after Treatment Interruption.

N Engl J Med. 2016-11-24

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