Clinical Potential of Prefusion RSV F-specific Antibodies

Rossey, Iebe; McLellan, Jason S.; Saelens, Xavier; Schepens, Bert

doi:10.1016/j.tim.2017.09.009

Cited by 55 publications

(53 citation statements)

References 65 publications

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“…Structures of F proteins complexed with neutralizing antibodies have been solved for a number of pneumo-and paramyxovirus family members including RSV (Figure 3), HPIV3, and NiV. Distinct antigenic sites were identified on RSV F (Figure 4): conformation-dependent site Ø that is located at the apex of prefusion F and a dominant target for nAbs [36,[76][77][78]; sites II and IV that are present in both the pre-and postfusion F conformations [67,79]; site III that likewise exists in both F conformations, but undergoes rearrangement of secondary structure elements forming the epitope [80,81]; site V located between sites Ø and III on prefusion F [82,83]; and post-fusion F site I [84,85]. A cryo-EM structure of HPIV3 F complexed with nAb PIA174 likewise locates the binding site to the apex of the prefusion F trimer, establishing contact with residues of all three F protomers [37].…”

Section: Druggable Sites and Neutralizing Epitopesmentioning

confidence: 99%

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Aggarwal

Plemper

2020

Viruses

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Paramyxoviruses and pneumoviruses infect cells through fusion (F) protein-mediated merger of the viral envelope with target membranes. Members of these families include a range of major human and animal pathogens, such as respiratory syncytial virus (RSV), measles virus (MeV), human parainfluenza viruses (HPIVs), and highly pathogenic Nipah virus (NiV). High-resolution F protein structures in both the metastable pre-and the postfusion conformation have been solved for several members of the families and a number of F-targeting entry inhibitors have progressed to advanced development or clinical testing. However, small-molecule RSV entry inhibitors have overall disappointed in clinical trials and viral resistance developed rapidly in experimental settings and patients, raising the question of whether the available structural information may provide a path to counteract viral escape through proactive inhibitor engineering. This article will summarize current mechanistic insight into F-mediated membrane fusion and examine the contribution of structural information to the development of small-molecule F inhibitors. Implications are outlined for future drug target selection and rational drug engineering strategies.Viruses 2020, 12, 342 2 of 16 from its natural bat host to domestic animals, resulting in case/fatality rates reaching from 40% to over 90% [9]. Continued spillover into the human population must be expected, and human-to-human transmission through respiratory secretions, urine, and saliva has been documented [10].Of the pneumoviruses, RSV infects almost all children before two years of age and is responsible for over 100,000 hospitalizations yearly in the United States alone. The monoclonal antibody palivizumab has been approved for immunoprophylaxis against RSV infection [11], however, use is restricted to high-risk patients due to the high-cost and need for prophylactic administration.Given the health, medical and economic burden associated with paramyxo-and pneumovirus infections, a major and currently unmet clinical need exists to expedite the development of novel safe and effective therapeutics for improved disease management and outbreak control. Current direct-acting therapeutics predominantly focus on preventing viral entry through neutralizing antibodies (nAbs) and on small-molecules targeting the envelope glycoproteins or inhibiting the viral RNA-dependent RNA polymerase (RdRP) complex. Reflecting major efforts to identify a cost-effective alternative to high-price passive immunization with anti-RSV nAbs, a number of compounds have entered advanced preclinical development and clinical testing in recent years (Table 1). Breakthroughs in the structural and functional characterization of the viral entry machinery and polymerase complexes in the past decade [12][13][14][15][16][17][18][19][20][21] have furthermore created a novel opportunity for structure-informed mechanistic characterization and ligand optimization.

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Section: Druggable Sites and Neutralizing Epitopesmentioning

confidence: 99%

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Aggarwal

Plemper

2020

Viruses

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“…* inhibit RSV fusion through a similar mechanism, and RSV variants exhibiting drug resistance have displayed cross-resistance to these inhibitors. Adapted from (Douglas et al (2005); Triana-Baltzer et al (2009b); Boeckh and Englund (2010); Kiso et al (2010); Sleeman et al (2010); Watanabe et al (2010); Guzmán-Suarez et al (2012); Moss et al (2012); Adedeji et al (2013); Matz (2013); Clark et al (2014); DeVincenzo et al (2014, 2015); Rossignol (2014); Byrn et al (2015); Battles et al (2016); Waghmare et al (2016); Coates et al (2017); Heylen et al (2017); Jorquera and Tripp (2017); Kim et al (2017); Koszalka et al (2017); Mejias et al (2017); Roymans et al (2017); Shahani et al (2017); Heo (2018); Omoto et al (2018); Rossey et al (2018), and Stevens et al (2018) .…”

Section: Treatmentmentioning

confidence: 99%

Respiratory Viral Infections in Patients With Cancer or Undergoing Hematopoietic Cell Transplant

2018

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Survival rates for pediatric cancer have steadily improved over time but it remains a significant cause of morbidity and mortality among children. Infections are a major complication of cancer and its treatment. Community acquired respiratory viral infections (CRV) in these patients increase morbidity, mortality and can lead to delay in chemotherapy. These are the result of infections with a heterogeneous group of viruses including RNA viruses, such as respiratory syncytial virus (RSV), influenza virus (IV), parainfluenza virus (PIV), metapneumovirus (HMPV), rhinovirus (RhV), and coronavirus (CoV). These infections maintain a similar seasonal pattern to those of immunocompetent patients. Clinical manifestations vary significantly depending on the type of virus and the type and degree of immunosuppression, ranging from asymptomatic or mild disease to rapidly progressive fatal pneumonia Infections in this population are characterized by a high rate of progression from upper to lower respiratory tract infection and prolonged viral shedding. Use of corticosteroids and immunosuppressive therapy are risk factors for severe disease. The clinical course is often difficult to predict, and clinical signs are unreliable. Accurate prognostic viral and immune markers, which have become part of the standard of care for systemic viral infections, are currently lacking; and management of CRV infections remains controversial. Defining effective prophylactic and therapeutic strategies is challenging, especially considering, the spectrum of immunocompromised patients, the variety of respiratory viruses, and the presence of other opportunistic infections and medical problems. Prevention remains one of the most important strategies against these viruses. Early diagnosis, supportive care and antivirals at an early stage, when available and indicated, have proven beneficial. However, with the exception of neuraminidase inhibitors for influenza infection, there are no accepted treatments. In high-risk patients, pre-emptive treatment with antivirals for upper respiratory tract infection (URTI) to decrease progression to LRTI is a common strategy. In the future, viral load and immune markers may prove beneficial in predicting severe disease, supporting decision making and monitor treatment in this population.

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“…[17][18][19][20][21][22][23] There are at least six major antigenic sites on RSV F reported in the literature (Ø, I, II, III, IV, V). 24 PreF-specific antibodies targeting the apex sites, including site Ø, are immunodominant and account for a large proportion of neutralizing activity in human sera. 25,26 A recent study has reported that the PreF-specific site V is targeted by nearly half of the most potent nAbs isolated from healthy adults.…”

Section: Introductionmentioning

confidence: 99%

“…30 MAbs targeting various antigenic sites of RSV and hMPV have previously been isolated via different methods. 24,27,[31][32][33][34][35][36][37][38][39][40][41][42][43][44][45] Furthermore, the crystal structures of RSV and hMPV F proteins in both PreF and PostF conformations, as well as complex structures with mAbs targeting various antigenic sites, have been reported. 20,21,[28][29][30][31][32][33][34][35]37,[45][46][47][48][49] The structures of PreF and PostF antigens between RSV and hMPV are remarkably conserved, albeit only sharing about 35% sequence identity.…”

Section: Introductionmentioning

confidence: 99%

Characterization of potent RSV neutralizing antibodies isolated from human memory B cells and identification of diverse RSV/hMPV cross-neutralizing epitopes

Xiao

Tang

Cox

et al. 2019

mAbs

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Respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection in young children and older adults. Currently, no licensed vaccine is available, and therapeutic options are limited. The primary target of neutralizing antibodies to RSV is the surface fusion (F) glycoprotein. Understanding the recognition of antibodies with high neutralization potencies to RSV F antigen will provide critical insights in developing efficacious RSV antibodies and vaccines. In this study, we isolated and characterized a panel of monoclonal antibodies (mAbs) with high binding affinity to RSV prefusion F trimer and neutralization potency to RSV viruses. The mAbs were mapped to previously defined antigenic sites, and some that mapped to the same antigenic sites showed remarkable diversity in specificity, binding, and neutralization potencies. We found that the isolated site III mAbs shared highly conserved germline V-gene usage, but had different cross-reactivities to human metapneumovirus (hMPV), possibly due to the distinct modes/angles of interaction with RSV and hMPV F proteins. Furthermore, we identified a subset of potent RSV/hMPV cross-neutralizing mAbs that target antigenic site IV and the recently defined antigenic site V, while the majority of the mAbs targeting these two sites only neutralize RSV. Additionally, the isolated mAbs targeting site Ø were mono-specific for RSV and showed a wide range of neutralizing potencies on different RSV subtypes. Our data exemplify the diversity of anti-RSV mAbs and provide new insights into the immune recognition of respiratory viruses in the Pneumoviridae family.

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Clinical Potential of Prefusion RSV F-specific Antibodies

Cited by 55 publications

References 65 publications

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Structural Insight into Paramyxovirus and Pneumovirus Entry Inhibition

Respiratory Viral Infections in Patients With Cancer or Undergoing Hematopoietic Cell Transplant

Characterization of potent RSV neutralizing antibodies isolated from human memory B cells and identification of diverse RSV/hMPV cross-neutralizing epitopes

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