期刊
出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.2112887119
关键词
HIV-1; antibody; neutralization; protein engineering
资金
- Natural Sciences and Engineering Research Council of Canada (NSERC) [6280100058]
- Canadian Institutes of Health Research (CIHR) [PJ4-169662]
- European Union [790012]
- Hospital for Sick Children Restracomp Postdoctoral Fellowship
- NSERC postgraduate doctoral scholarship
- Basque Government [PRE_2019_2_0046, IT1196-19]
- Canadian Institute for Advanced Research (CIFAR) Azrieli Global Scholar program
- Ontario Early Researcher Awards program
- Canada Research Chairs program
- NSERC [GPIN-2019-06442]
- CIHR Project Grant-Priority Announcement [PJH-175379]
- CIHR Canada Graduate Scholarship (CGS-M)
- Spanish Ministry of Sci-ence, Innovation and Universities (MCIU)
- Spanish Research Agency/The European Regional Development Fund (AEI/FEDER) [RTI2018-095624-B-C21]
- Ontario Research Fund
- Marie Curie Actions (MSCA) [790012] Funding Source: Marie Curie Actions (MSCA)
In this study, HIV-1 bNAbs were engineered by directly fusing their Fab fragments to the human apoferritin light chain, resulting in a multispecific and avid molecule. The molecule exhibited high neutralization potency against a broad panel of HIV-1 pseudoviruses and demonstrated IgG-like bioavailability in vivo through Fc receptor modulation.
Deep mining of B cell repertoires of HIV-1-infected individuals has resulted in the isolation of dozens of HIV-1 broadly neutralizing antibodies (bNAbs). Yet, it remains uncertain whether any such bNAbs alone are sufficiently broad and potent to deploy therapeutically. Here, we engineered HIV-1 bNAbs for their combination on a single multispecific and avid molecule via direct genetic fusion of their Fab fragments to the human apoferritin light chain. The resulting molecule demonstrated a remarkable median IC50 value of 0.0009 mu g/mL and 100% neutralization coverage of a broad HIV-1 pseudovirus panel (118 isolates) at a 4 mu g/mL cutoff-a 32-fold enhancement in viral neutralization potency compared to a mixture of the corresponding HIV-1 bNAbs. Importantly, Fc incorporation on the molecule and engineering to modulate Fc receptor binding resulted in IgG-like bioavailability in vivo. This robust plug-and-play antibody design is relevant against indications where multispecificity and avidity are leveraged simultaneously to mediate optimal biological activity.
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