Redesigned HIV antibodies exhibit enhanced neutralizing potency and breadth

Willis, Jordan R.; Sapparapu, Gopal; Murrell, Sasha; Julien, Jean-Philippe; Singh, Vidisha; King, Hannah A. D.; Yan, Xin; Pickens, Jennifer A.; LaBranche, Celia C.; Slaughter, James C.; Montefiori, David C.; Wilson, Ian A.; Meiler, Jens; Crowe, James E.

doi:10.1172/jci80693

Cited by 30 publications

(39 citation statements)

References 49 publications

(52 reference statements)

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“…However, discussants pointed to deeper potential benefit of these data if the structure and function of these immune receptors could be cataloged or predicted. Structural classification and prediction of protein loops or larger structures is difficult, but the structures of antibodies and TCRs conform to a number of structural constraints, and increasingly it is feasible to predict and design or re-design the structure of antigen combining sites, using computational tools such as ROSETTA [16,17]. We envision a point in time during development of the Human Immunome Program, in which we are able to assign structure, specificity and function to the immune receptors that were acquired originally as sequences.…”

Section: Biological Analysismentioning

confidence: 99%

Deciphering the human immunome

Crowe

Koff

2015

Expert Review of Vaccines

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Section: Biological Analysismentioning

confidence: 99%

Deciphering the human immunome

Crowe

Koff

2015

Expert Review of Vaccines

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“…Willis and colleagues turned to the Rosetta Design software suite (reviewed in ref. 30) to solve this problem (8). The PG9 CDHR3 sequence was redesigned computationally to optimize its thermodynamic stability with a predicted increase in binding energy (based on the starting structure in ref.…”

Section: Conflict Of Interestmentioning

confidence: 99%

“…13). Willis et al used these computations, coupled with visual inspection of energetically favored residues that might alter function, to whittle down the possible designs down to three single-point mutations, N100 F Y, N100 F L, and D100 L N, as well as two other variants with either two or four mutations (8). This is an example of the power of Rosetta Design to rationally reduce the number of candidate structures for in-depth analysis of structure and function.…”

Section: Conflict Of Interestmentioning

confidence: 99%

“…If an immunogen can be found that stimulates primary B cells that are specific for the PG9 bnmAb series, it is likely that a protracted immunization schedule will not be necessary to achieve neutralization fitness. Willis and collaborators shed new light on how the PG9 series of bnmAbs reach neutralization fitness without extensive somatic hypermutation; the authors demonstrated that a point mutation in HCDR3 can markedly increase the neutralization potency and breadth of PG9 (8). While it may not be surprising that a single mutation can improve the neutralization fitness of PG9, the way in which Willis et al identified this mutation and how it increases neutralization fitness provides important insight into improving bnmAb function.…”

Section: Conflict Of Interestmentioning

confidence: 99%

“…6,7). In this issue, Willis and collaborators further extend this knowledge through their employment of a computer model to predict mutations that markedly improved the neutralization potency and breadth of PG9 (8).…”

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confidence: 96%

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Honing a harder-hitting hammerhead improves broadly neutralizing antibody breadth and potency

Lewis¹

2015

J. Clin. Invest.

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C o m m e n t a r yBroadly neutralizing antibodies: good or bad news for HIV-1 vaccination?PG9 was one of the first broadly neutralizing monoclonal antibodies (bnmAbs) isolated from an HIV-1-infected individual and was shown to potently neutralize more than 85% of HIV-1 isolates that it was tested against (1). Isolation of PG9 and the related bnmAb PG16 (1, 2) presaged an ongoing explosion in the knowledge of the HIV-1 epitopes recognized by bnmAbs (reviewed in refs. 3, 4; see ref. 5) and how bnmAbs evolve over the course of infection (reviewed in refs. 6, 7). In this issue, Willis and collaborators further extend this knowledge through their employment of a computer model to predict mutations that markedly improved the neutralization potency and breadth of PG9 (8). bnmAbs can be characterized in terms of their neutralization fitness, which herein refers to the combination of neutralization potency (half the maximal neutralization titer) and neutralization breadth (the percentage of representative viral panels neutralized) for a given bnmAB. Previous reports have shown that mixtures of bnmAbs with known specificity are able to potently neutralize essentially all variants in panels that represent circulating HIV-1 strains (9). Such results are promising because they suggest that a universal AIDS vaccine is possible, provided a suitable immunogen and immunization schedule can be found. Moreover, the goal of a universal vaccine has been made more likely, as the result of an increasingly clear picture of the epitopes recognized by neutralization-fit bnmAbs and recent studies that have also provided important insight into the HIV-1 envelope (Env) glycoprotein trimer structure (10-12), which is targeted by many bnmAbs, including PG9. The Env trimer consists of three copies of gp160, which comprises a receptor-binding domain (gp120) and a membrane-anchored domain (gp41) Unfortunately, neutralization-fit bnmAbs have only been observed in HIV-1-infected people (3) and SIV-infected rhesus macaques (23); these bnmAbs are not detectable until approximately 2 1/2 years (24) and two-thirds of a year (23) after infection, respectively. The convergence of several lineage studies indicates that neutralization-fit bnmAbs arise only in response to exposure to different viral variants over these time periods (6, 7). Thus, the emergence of bnmAbs is the result of a predator-prey interaction in which the bnmAbs become increasingly "fit" in response to the increased viral variation that emerges in response to antibody pressure. Many of the identified pathways to neutralization fitness differ among studies, and it is not yet clear whether these pathways can be recapitulated by vaccination. Currently, it appears that lengthy (and clinically cumbersome) immunizaRelated Article: p. 2523 Conflict of interest:The author owns shares in Profectus BioSciences, which is developing vaccines against HIV-1 and is a sub-contractor on NIH Small Business Innovative Research grants awarded to Profectus BioSciences; otherwise, there are no consulting ...

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Structural prediction of antibody‐APRIL complexes by computational docking constrained by antigen saturation mutagenesis library data

Wollacott

Robinson

Ramakrishnan

et al. 2019

J of Molecular Recognition

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IgA nephropathy (IgAN) is the most prevalent cause of primary glomerular disease worldwide, and the cytokine A PRoliferation‐Inducing Ligand (APRIL) is emerging as a key player in IgAN pathogenesis and disease progression. For a panel of anti‐human APRIL antibodies with known antagonistic activity, we sought to define their structural mode of engagement to understand molecular mechanisms of action and aid rational antibody engineering. Reliable computational prediction of antibody‐antigen complexes remains challenging, and experimental methods such as X‐ray co‐crystallography and cryoEM have considerable technical, resource, and throughput barriers. To overcome these limitations, we implemented an integrated and accessible experimental‐computational workflow to more accurately predict structures of antibody‐APRIL complexes. Specifically, a yeast surface display library encoding site‐saturation mutagenized surface positions of APRIL was screened against a panel of anti‐APRIL antibodies to rapidly obtain a comprehensive biochemical profile of mutational impact on binding for each antibody. The experimentally derived mutational profile data were used as quantitative constraints in a computational docking workflow optimized for antibodies, resulting in robust structural models of antibody‐antigen complexes. The model results were confirmed by solving the cocrystal structure of one antibody‐APRIL complex, which revealed strong agreement with our model. The models were used to rationally select and engineer one antibody for cross‐species APRIL binding, which quite often aids further testing in relevant animal models. Collectively, we demonstrate a rapid, integrated computational‐experimental approach to robustly predict antibody‐antigen structures information, which can aid rational antibody engineering and provide insights into molecular mechanisms of action.

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Redesigned HIV antibodies exhibit enhanced neutralizing potency and breadth

Cited by 30 publications

References 49 publications

Deciphering the human immunome

Deciphering the human immunome

Honing a harder-hitting hammerhead improves broadly neutralizing antibody breadth and potency

Structural prediction of antibody‐APRIL complexes by computational docking constrained by antigen saturation mutagenesis library data

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