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Title: Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8

Authors:
; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ;
Publication Date:
Research Org.:
Argonne National Lab. (ANL), Argonne, IL (United States). Advanced Photon Source (APS)
Sponsoring Org.:
NIAID
OSTI Identifier:
1258692
Resource Type:
Journal Article
Resource Relation:
Journal Name: PLoS ONE; Journal Volume: 11; Journal Issue: 6
Country of Publication:
United States
Language:
ENGLISH

Citation Formats

Soto, Cinque, Ofek, Gilad, Joyce, M. Gordon, Zhang, Baoshan, McKee, Krisha, Longo, Nancy S., Yang, Yongping, Huang, Jinghe, Parks, Robert, Eudailey, Joshua, Lloyd, Krissey E., Alam, S. Munir, Haynes, Barton F., Mullikin, James C., Connors, Mark, Mascola, John R., Shapiro, Lawrence, Kwong, Peter D., and Jiang, Shibo. Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8. United States: N. p., 2016. Web. doi:10.1371/journal.pone.0157409.
Soto, Cinque, Ofek, Gilad, Joyce, M. Gordon, Zhang, Baoshan, McKee, Krisha, Longo, Nancy S., Yang, Yongping, Huang, Jinghe, Parks, Robert, Eudailey, Joshua, Lloyd, Krissey E., Alam, S. Munir, Haynes, Barton F., Mullikin, James C., Connors, Mark, Mascola, John R., Shapiro, Lawrence, Kwong, Peter D., & Jiang, Shibo. Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8. United States. doi:10.1371/journal.pone.0157409.
Soto, Cinque, Ofek, Gilad, Joyce, M. Gordon, Zhang, Baoshan, McKee, Krisha, Longo, Nancy S., Yang, Yongping, Huang, Jinghe, Parks, Robert, Eudailey, Joshua, Lloyd, Krissey E., Alam, S. Munir, Haynes, Barton F., Mullikin, James C., Connors, Mark, Mascola, John R., Shapiro, Lawrence, Kwong, Peter D., and Jiang, Shibo. 2016. "Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8". United States. doi:10.1371/journal.pone.0157409.
@article{osti_1258692,
title = {Developmental Pathway of the MPER-Directed HIV-1-Neutralizing Antibody 10E8},
author = {Soto, Cinque and Ofek, Gilad and Joyce, M. Gordon and Zhang, Baoshan and McKee, Krisha and Longo, Nancy S. and Yang, Yongping and Huang, Jinghe and Parks, Robert and Eudailey, Joshua and Lloyd, Krissey E. and Alam, S. Munir and Haynes, Barton F. and Mullikin, James C. and Connors, Mark and Mascola, John R. and Shapiro, Lawrence and Kwong, Peter D. and Jiang, Shibo},
abstractNote = {},
doi = {10.1371/journal.pone.0157409},
journal = {PLoS ONE},
number = 6,
volume = 11,
place = {United States},
year = 2016,
month = 6
}
  • ABSTRACT Extraordinary antibodies capable of near pan-neutralization of HIV-1 have been identified. One of the broadest is antibody 10E8, which recognizes the membrane-proximal external region (MPER) of the HIV-1 envelope and neutralizes >95% of circulating HIV-1 strains. If delivered passively, 10E8 might serve to prevent or treat HIV-1 infection. Antibody 10E8, however, is markedly less soluble than other antibodies. Here, we describe the use of both structural biology and somatic variation to develop optimized versions of 10E8 with increased solubility. From the structure of 10E8, we identified a prominent hydrophobic patch; reversion of four hydrophobic residues in this patch tomore » their hydrophilic germ line counterparts resulted in an ~10-fold decrease in turbidity. We also used somatic variants of 10E8, identified previously by next-generation sequencing, to optimize heavy and light chains; this process yielded several improved variants. Of these, variant 10E8v4 with 26 changes versus the parent 10E8 was the most soluble, with a paratope we showed crystallographically to be virtually identical to that of 10E8, a potency on a panel of 200 HIV-1 isolates also similar to that of 10E8, and a half-life in rhesus macaques of ~10 days. An anomaly in 10E8v4 size exclusion chromatography that appeared to be related to conformational isomerization was resolved by engineering an interchain disulfide. Thus, by combining a structure-based approach with natural variation in potency and solubility from the 10E8 lineage, we successfully created variants of 10E8 which retained the potency and extraordinary neutralization breadth of the parent 10E8 but with substantially increased solubility. IMPORTANCE Antibody 10E8 could be used to prevent HIV-1 infection, if manufactured and delivered economically. It suffers, however, from issues of solubility, which impede manufacturing. We hypothesized that the physical characteristic of 10E8 could be improved through rational design, without compromising breadth and potency. We used structural biology to identify hydrophobic patches on 10E8, which did not appear to be involved in 10E8 function. Reversion of hydrophobic residues in these patches to their hydrophilic germ line counterparts increased solubility. Next, clues from somatic variants of 10E8, identified by next-generation sequencing, were incorporated. A combination of structure-based design and somatic variant optimization led to 10E8v4, with substantially improved solubility and similar potency compared to the parent 10E8. The cocrystal structure of antibody 10E8v4 with its HIV-1 epitope was highly similar to that with the parent 10E8, despite 26 alterations in sequence and substantially improved solubility. Antibody 10E8v4 may be suitable for manufacturing.« less
  • HIV-1 uses a diverse N-linked-glycan shield to evade recognition by antibody. Select human antibodies, such as the clonally related PG9 and PG16, recognize glycopeptide epitopes in the HIV-1 V1–V2 region and penetrate this shield, but their ability to accommodate diverse glycans is unclear. Here we report the structure of antibody PG16 bound to a scaffolded V1–V2, showing an epitope comprising both high mannose–type and complex-type N-linked glycans. We combined structure, NMR and mutagenesis analyses to characterize glycan recognition by PG9 and PG16. Three PG16-specific residues, arginine, serine and histidine (RSH), were critical for binding sialic acid on complex-type glycans, andmore » introduction of these residues into PG9 produced a chimeric antibody with enhanced HIV-1 neutralization. Although HIV-1–glycan diversity facilitates evasion, antibody somatic diversity can overcome this and can provide clues to guide the design of modified antibodies with enhanced neutralization.« less