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Genevieve Losonsky - One of the best experts on this subject based on the ideXlab platform.
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a randomized controlled trial of Motavizumab versus palivizumab for the prophylaxis of serious respiratory syncytial virus disease in children with hemodynamically significant congenital heart disease
Pediatric Research, 2011Co-Authors: Timothy F Feltes, Brian Harris, Genevieve Losonsky, Henry M Sondheimer, Robert M R Tulloh, Kathryn M Jensen, Pamela M GriffinAbstract:Children with hemodynamically significant congenital heart disease (CHD) are at risk for serious respiratory syncytial virus (RSV) disease. This study was designed to assess the safety and tolerability of Motavizumab versus palivizumab in children with CHD and was not powered for efficacy. Patients (n = 1236) aged ≤24 mo were randomized to receive five monthly doses (15 mg/kg) of Motavizumab or palivizumab during the RSV season. Adverse events (AEs) and serious AEs (SAEs) were recorded through 30 d after the last dose. RSV hospitalizations and RSV outpatient medically attended lower respiratory tract infections (MALRI; season 2) were summarized. Approximately 93 and 50% of patients reported an AE or SAE, respectively. Skin events occurred in 19.3% of Motavizumab recipients and 16.2% of palivizumab recipients. Rates of hospitalizations and RSV MALRI were similar between treatment groups [relative risk (RR): 0.75; 95% CI, 0.34-1.59 and RR: 0.49; 95% CI, 0.10-1.99, respectively; both p > 0.05]. Motavizumab and palivizumab had similar safety profiles in children with hemodynamically significantly CHD; with the exception of skin events which were increased in Motavizumab recipients. Safety and efficacy were consistent with another study comparing Motavizumab with palivizumab in premature infants without CHD.
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Motavizumab for prophylaxis of respiratory syncytial virus in high risk children a noninferiority trial
Pediatrics, 2010Co-Authors: Xavier Carbonellestrany, Brian Harris, Edward M Connor, Micki Hultquist, Eric A. F. Simões, Ron Dagan, Caroline B Hall, Genevieve LosonskyAbstract:OBJECTIVE: Palivizumab reduces respiratory syncytial virus (RSV) hospitalization in children at high risk by ∼50% compared with placebo. We compared the efficacy and safety of Motavizumab, an investigational monoclonal antibody with enhanced anti-RSV activity in preclinical studies, with palivizumab. METHODS: This randomized, double-blind, multinational, phase 3, noninferiority trial assessed safety and RSV hospitalization in 6635 preterm infants aged ≤6 months at enrollment or children aged ≤24 months with chronic lung disease of prematurity who received 15 mg/kg palivizumab or Motavizumab monthly. Secondary end points included outpatient medically attended lower respiratory tract infections (MALRIs), RSV-specific LRIs, otitis media, antibiotic use, development of antiMotavizumab antibodies, and Motavizumab serum concentrations. RESULTS: Motavizumab recipients had a 26% relative reduction in RSV hospitalization compared with palivizumab recipients, achieving noninferiority. Motavizumab was superior to palivizumab for reduction of RSV-specific outpatient MALRIs (50% relative reduction). Overall, adverse events (AEs) were not significantly different between groups. Cutaneous events were reported in 2 percentage points more Motavizumab recipients (7.2% vs 5.1%); most were mild, but 0.3% resulted in dosing discontinuation. Antidrug antibodies (ADA) were detected in 1.8% of Motavizumab recipients. Patients with anti-drug antibody reported 6 RSV events and 17 cutaneous events. CONCLUSIONS: Children receiving prophylaxis with Motavizumab or palivizumab had low rates of RSV hospitalization; Motavizumab recipients experienced 50% fewer RSV MALRIs than palivizumab recipients. AEs were similar in both groups, although cutaneous AEs were higher for Motavizumab recipients. Motavizumab may offer an improved alternative in prophylaxis for serious RSV disease in infants and children at high risk.
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Motavizumab for prophylaxis of respiratory syncytial virus in high risk children a noninferiority trial
Pediatrics, 2010Co-Authors: Xavier Carbonellestrany, Brian Harris, Edward M Connor, Micki Hultquist, Eric A. F. Simões, Ron Dagan, Caroline B Hall, Genevieve LosonskyAbstract:OBJECTIVE: Palivizumab reduces respiratory syncytial virus (RSV) hospitalization in children at high risk by ∼50% compared with placebo. We compared the efficacy and safety of Motavizumab, an investigational monoclonal antibody with enhanced anti-RSV activity in preclinical studies, with palivizumab. METHODS: This randomized, double-blind, multinational, phase 3, noninferiority trial assessed safety and RSV hospitalization in 6635 preterm infants aged ≤6 months at enrollment or children aged ≤24 months with chronic lung disease of prematurity who received 15 mg/kg palivizumab or Motavizumab monthly. Secondary end points included outpatient medically attended lower respiratory tract infections (MALRIs), RSV-specific LRIs, otitis media, antibiotic use, development of antiMotavizumab antibodies, and Motavizumab serum concentrations. RESULTS: Motavizumab recipients had a 26% relative reduction in RSV hospitalization compared with palivizumab recipients, achieving noninferiority. Motavizumab was superior to palivizumab for reduction of RSV-specific outpatient MALRIs (50% relative reduction). Overall, adverse events (AEs) were not significantly different between groups. Cutaneous events were reported in 2 percentage points more Motavizumab recipients (7.2% vs 5.1%); most were mild, but 0.3% resulted in dosing discontinuation. Antidrug antibodies (ADA) were detected in 1.8% of Motavizumab recipients. Patients with anti-drug antibody reported 6 RSV events and 17 cutaneous events. CONCLUSIONS: Children receiving prophylaxis with Motavizumab or palivizumab had low rates of RSV hospitalization; Motavizumab recipients experienced 50% fewer RSV MALRIs than palivizumab recipients. AEs were similar in both groups, although cutaneous AEs were higher for Motavizumab recipients. Motavizumab may offer an improved alternative in prophylaxis for serious RSV disease in infants and children at high risk.
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safety and antiviral activity of Motavizumab a respiratory syncytial virus rsv specific humanized monoclonal antibody when administered to rsv infected children
Pediatric Infectious Disease Journal, 2009Co-Authors: Rosanna Lagos, Edward M Connor, Micki Hultquist, John P Devincenzo, Alma Munoz, Joann Suzich, Genevieve LosonskyAbstract:Previously healthy children hospitalized with respiratory syncytial virus (RSV) received Motavizumab (3, 15, or 30 mg/kg intravenously), an RSV-specific monoclonal antibody, or placebo. Safety, tolerability, Motavizumab concentrations, and immunogenicity were assessed. Cultivatable RSV in the upper respiratory tract was significantly reduced with Motavizumab compared with placebo day 1 post-treatment. No adverse events were considered Motavizumab-related by site investigators.
Peter D Kwong - One of the best experts on this subject based on the ideXlab platform.
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structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes
Journal of Virology, 2011Co-Authors: Jason S Mclellan, Yongping Yang, Barney S. Graham, Peter D KwongAbstract:Respiratory syncytial virus (RSV) invades host cells via a type I fusion (F) glycoprotein that undergoes dramatic structural rearrangements during the fusion process. Neutralizing monoclonal antibodies, such as 101F, palivizumab, and Motavizumab, target two major antigenic sites on the RSV F glycoprotein. The structures of these sites as peptide complexes with Motavizumab and 101F have been previously determined, but a structure for the trimeric RSV F glycoprotein ectodomain has remained elusive. To address this issue, we undertook structural and biophysical studies on stable ectodomain constructs. Here, we present the 2.8-A crystal structure of the trimeric RSV F ectodomain in its postfusion conformation. The structure revealed that the 101F and Motavizumab epitopes are present in the postfusion state and that their conformations are similar to those observed in the antibody-bound peptide structures. Both antibodies bound the postfusion F glycoprotein with high affinity in surface plasmon resonance experiments. Modeling of the antibodies bound to the F glycoprotein predicts that the 101F epitope is larger than the linear peptide and restricted to a single protomer in the trimer, whereas Motavizumab likely contacts residues on two protomers, indicating a quaternary epitope. Mechanistically, these results suggest that 101F and Motavizumab can bind to multiple conformations of the fusion glycoprotein and can neutralize late in the entry process. The structural preservation of neutralizing epitopes in the postfusion state suggests that this conformation can elicit neutralizing antibodies and serve as a useful vaccine antigen.
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design and characterization of epitope scaffold immunogens that present the Motavizumab epitope from respiratory syncytial virus
Journal of Molecular Biology, 2011Co-Authors: Jason S Mclellan, Barney S. Graham, Yongping Yang, Man Chen, Bruno E Correia, William R Schief, Peter D KwongAbstract:Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, but an effective vaccine has not yet been developed. An ideal vaccine would elicit protective antibodies while avoiding virus-specific T-cell responses, which have been implicated in vaccine-enhanced disease with previous RSV vaccines. We propose that heterologous proteins designed to present RSV-neutralizing antibody epitopes and to elicit cognate antibodies have the potential to fulfill these vaccine requirements, as they can be fashioned to be free of viral T-cell epitopes. Here we present the design and characterization of three epitope-scaffolds that present the epitope of Motavizumab, a potent neutralizing antibody that binds to a helix–loop–helix motif in the RSV fusion glycoprotein. Two of the epitope-scaffolds could be purified, and one epitope-scaffold based on a Staphylococcus aureus protein A domain bound Motavizumab with kinetic and thermodynamic properties consistent with the free epitope-scaffold being stabilized in a conformation that closely resembled the Motavizumab-bound state. This epitope-scaffold was well folded as assessed by circular dichroism and isothermal titration calorimetry, and its crystal structure (determined in complex with Motavizumab to 1.9 A resolution) was similar to the computationally designed model, with all hydrogen-bond interactions critical for binding to Motavizumab preserved. Immunization of mice with this epitope-scaffold failed to elicit neutralizing antibodies but did elicit sera with F binding activity. The elicitation of F binding antibodies suggests that some of the design criteria for eliciting protective antibodies without virus-specific T-cell responses are being met, but additional optimization of these novel immunogens is required.
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structural basis of respiratory syncytial virus neutralization by Motavizumab
Nature Structural & Molecular Biology, 2010Co-Authors: Jason S Mclellan, Albert Kim, Barney S. Graham, Yongping Yang, Man Chen, Peter D KwongAbstract:Respiratory syncytial virus (RSV) is a highly contagious illness in young children. The structure of antibody drug Motavizumab in complex with a 24-residue peptide corresponding to its epitope on RSV-fusion glycoprotein suggests why it is more potent than its predecessor, palivizumab (Synagis).
Barney S. Graham - One of the best experts on this subject based on the ideXlab platform.
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future opportunities for passive immunity against viral diseases
The Journal of Infectious Diseases, 2011Co-Authors: Barney S. GrahamAbstract:(See the article by Schepens et al, on pages 1692–701.) Antibodies are key effector molecules for protection against viral infections. The protection afforded by immunization with licensed antiviral vaccines is mediated by vaccine-induced antibody in most cases. Passively administered antibodies have been shown to be effective against diseases caused by a wide variety of RNA and DNA viruses, and polyclonal immunoglobulin products have been licensed for clinical use for cytomegalovirus, hepatitis A and B viruses, measles virus, poliovirus, rabies virus, respiratory syncytial virus, and varicella zoster virus. Thus, it is surprising that of the 29 licensed monoclonal antibody (mAb) products developed over the last 25 years, only 1 is for use against a microbial pathogen, respiratory syncytial virus (RSV). The rest are for autoimmune diseases, malignancy, asthma, or angioedema. Palivizumab is a humanized immunoglobin G1 (IgG1) mAb derived from the original murine mAb 1129 [1], and is licensed for the prophylactic treatment of premature infants to prevent severe disease from RSV [2]. Palivizumab and its higher-affinity derivative, Motavizumab, recognize an epitope in the RSV fusion (F) glycoprotein (antigenic site II) and the atomic structure of the interaction has been characterized [3]. In this issue of the Journal of Infectious Diseases, Schepens et al. have reported the development of Nanobodies (Ablynx) specific for the palivizumab epitope and have evaluated their potency in vivo in a murine model [4]. Nanobodies are proteins representing the variable domain of the heavy chain from antibodies produced by members of the family Camelidae (camels, llamas, and alpacas). Cartilaginous fish (eg, sharks, skates, and rays) and camelids have uniquely developed heavy-chain-only immunoglobulin molecules that recognize and bind antigenic sites with just the single variable domain at the tip of the heavy chain. The basis for this adaptation is unknown, but there is evidence of convergent evolution [5]. The variable domains tend to have relatively long antigen-binding loops and because the light chain present in human antibodies is not in the way, they are ideally suited for reaching epitopes residing in clefts or pockets. For example, llama-derived heavy-chain variable domains (VHH) have been discovered that can reach into the CD4 binding pocket of human immunodeficiency virus (HIV) gp120, resulting in broad neutralizing activity [6]. Heavy-chain-only antibodies tend to have more charged and polar residues in the framework 2 region of the variable domain, which in classic human immunoglobulins, has highly conserved hydrophobic sequences that are adjacent to the light chain. The VHH also has a relatively high frequency of cysteine residues that allow intradomain disulfide bonds, and together with the polar interactions between loops help to stabilize the antigen-binding sites, perhaps to compensate for the lost stabilizing effect of a light chain [5, 6]. The investigators immunized llamas with a trimeric transmembrane-deleted form of the F glycoprotein, and then cloned VHH sequences into a phagemid vector. The resulting phage library was screened for binding to F, and sequences were identified that competed for binding with palivizumab. Microneutralization assays against the RSV Long strain (a prototypic subtype A laboratory-adapted isolate) showed that the monovalent VHH-designated RSV-D3 is about 3-fold more potent than the palivizumab antigen-binding fragment (Fab). Interestingly, a bivalent version of RSV-D3 made with Gly-Ser linkers is about 40-fold more potent than the bivalent palivizumab mAb. One of the important characteristics of palivizumab is that it is equally potent against subtype B RSV strains. Surprisingly, the bivalent RSV-D3 was about 600-fold less potent against the RSV B1 strain than it was against the subtype A virus [7]. The reason for the difference in cross-reactivity is intriguing because neutralization escape mutations for palivizumab also escape RSV-D3, suggesting similar contact residues. It may be related to the size of the interaction area, or it is possible that the VHH is a relatively rigid, preorganized structure that gives it higher affinity, but makes it less flexible for adjusting to minor variations in epitope structure. Defining the crystal structure of the interaction may be informative for understanding cross-neutralization and other fundamental aspects of viral neutralization. It may also provide insight as to why the structurally conserved, scaffolded palivizumab epitope can elicit antibodies that bind F, but do not neutralize RSV [8]. The RSV-D3 bivalent Nanobody neutralizes by inhibiting fusion and not by blocking attachment. This is also true for palivizumab and Motavizumab, so it is not surprising. The epitope appears to be present throughout the fusion process, based on modeling of the prefusion F trimer and structure of the postfusion trimer [9]. The assumption based on structural analysis is that palivizumab and Motavizumab inhibit fusion by binding a prehairpin fusion intermediate structure, thereby interfering with formation of the final 6-helix bundle that pulls the virus and target cell membranes together [9]. While the Motavizumab Fab appears to clash with the adjacent oligomer in the prefusion trimer model [3], the small size of the VHH may provide an advantage of Nanobodies over mAb because of the potential for binding F in the prefusion state. This would be another reason to evaluate the crystal structure of the RSV-D3 bound to F or to the palivizumab epitope. Size matters, not just for accessing cryptic epitopes but also for biodistribution and pharmacokinetics. Schepens and colleagues treated mice with RSV-D3 Nanobodies both before and after RSV challenge. Nasal administration was chosen because there is relatively rapid renal clearance of the monovalent (15 kilodaltons [Kda]) and bivalent (30 Kda) VHHs when given parenterally. They showed there is bioactive VHH in lung homogenates up to 72 hours after intranasal delivery. When anesthetized mice received 100 μg in 50 μL intranasally 4 or 24 hours prior to RSV challenge, bivalent VHH-treated mice had a similar outcome as palivizumab-treated mice, with no detectable virus in lung at 3 and 5 days postchallenge and no weight loss. Delivered at 4 hours prechallenge, a dose of 12 μg partially suppressed virus titer. As in vitro, bivalent VHHs were more potent in vivo than monovalent VHHs. Therefore, size matters, but so does avidity, dose, delivery route, and timing. For passively administered antibodies or Nanobodies, it is important to determine the tissue-specific half-life and what factors may affect the persistence of active product when given by a particular route. For example, if given topically, what is the susceptibility of Nanobodies to proteases found in mucosal secretions? Using antibodies to treat viral infections has historically been less successful than using antibodies prophylactically. For example, treatment of RSV-infected patients with RSV immune globulin or palivizumab has not shown clinical benefit. Nevertheless, there are examples of success, including the finding that treatment of patients infected with the Junin arenavirus (Argentine hemorrhagic fever) with immune serum reduces mortality when given up to 8 days after the onset of symptoms [10]. Also, patients with antibody deficiencies who are infected with enteroviruses have been shown to benefit from immunoglobulin treatment [11]. In the current study, Schepens et al. treated mice 4 hours, 24 hours, or 48 hours postchallenge and then evaluated RSV titers and RNA in lung homogenates at day 5. While inflammatory cell counts in BAL and RSV titers appear to be partially reduced, there was little reduction in viral RNA, and some of the plaque reduction may be confounded by in vitro neutralization from residual RSV-D3 in lung. The requirements for antibody-mediated functions to effectively treat a virus infection may extend beyond those needed to prevent infection. Activities such as antibody-dependent cellular cytotoxicity, antibody-dependent cell-mediated virus inhibition, or antibody-mediated complement-dependent cytolysis may be useful for clearing virus-infected cells, but require fragment crystallizable region (Fc region)–mediated interactions with cellular effectors. Nanobodies do not support these functions, and appear to neutralize primarily by having strong binding affinity to antigenic sites that can interfere with viral entry. Another challenge for treatment of self-limited virus infections in general is that it is difficult to recognize clinical manifestations and diagnose infection soon enough for antiviral therapy to make a difference.
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structure of respiratory syncytial virus fusion glycoprotein in the postfusion conformation reveals preservation of neutralizing epitopes
Journal of Virology, 2011Co-Authors: Jason S Mclellan, Yongping Yang, Barney S. Graham, Peter D KwongAbstract:Respiratory syncytial virus (RSV) invades host cells via a type I fusion (F) glycoprotein that undergoes dramatic structural rearrangements during the fusion process. Neutralizing monoclonal antibodies, such as 101F, palivizumab, and Motavizumab, target two major antigenic sites on the RSV F glycoprotein. The structures of these sites as peptide complexes with Motavizumab and 101F have been previously determined, but a structure for the trimeric RSV F glycoprotein ectodomain has remained elusive. To address this issue, we undertook structural and biophysical studies on stable ectodomain constructs. Here, we present the 2.8-A crystal structure of the trimeric RSV F ectodomain in its postfusion conformation. The structure revealed that the 101F and Motavizumab epitopes are present in the postfusion state and that their conformations are similar to those observed in the antibody-bound peptide structures. Both antibodies bound the postfusion F glycoprotein with high affinity in surface plasmon resonance experiments. Modeling of the antibodies bound to the F glycoprotein predicts that the 101F epitope is larger than the linear peptide and restricted to a single protomer in the trimer, whereas Motavizumab likely contacts residues on two protomers, indicating a quaternary epitope. Mechanistically, these results suggest that 101F and Motavizumab can bind to multiple conformations of the fusion glycoprotein and can neutralize late in the entry process. The structural preservation of neutralizing epitopes in the postfusion state suggests that this conformation can elicit neutralizing antibodies and serve as a useful vaccine antigen.
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design and characterization of epitope scaffold immunogens that present the Motavizumab epitope from respiratory syncytial virus
Journal of Molecular Biology, 2011Co-Authors: Jason S Mclellan, Barney S. Graham, Yongping Yang, Man Chen, Bruno E Correia, William R Schief, Peter D KwongAbstract:Respiratory syncytial virus (RSV) is a major cause of respiratory tract infections in infants, but an effective vaccine has not yet been developed. An ideal vaccine would elicit protective antibodies while avoiding virus-specific T-cell responses, which have been implicated in vaccine-enhanced disease with previous RSV vaccines. We propose that heterologous proteins designed to present RSV-neutralizing antibody epitopes and to elicit cognate antibodies have the potential to fulfill these vaccine requirements, as they can be fashioned to be free of viral T-cell epitopes. Here we present the design and characterization of three epitope-scaffolds that present the epitope of Motavizumab, a potent neutralizing antibody that binds to a helix–loop–helix motif in the RSV fusion glycoprotein. Two of the epitope-scaffolds could be purified, and one epitope-scaffold based on a Staphylococcus aureus protein A domain bound Motavizumab with kinetic and thermodynamic properties consistent with the free epitope-scaffold being stabilized in a conformation that closely resembled the Motavizumab-bound state. This epitope-scaffold was well folded as assessed by circular dichroism and isothermal titration calorimetry, and its crystal structure (determined in complex with Motavizumab to 1.9 A resolution) was similar to the computationally designed model, with all hydrogen-bond interactions critical for binding to Motavizumab preserved. Immunization of mice with this epitope-scaffold failed to elicit neutralizing antibodies but did elicit sera with F binding activity. The elicitation of F binding antibodies suggests that some of the design criteria for eliciting protective antibodies without virus-specific T-cell responses are being met, but additional optimization of these novel immunogens is required.
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structural basis of respiratory syncytial virus neutralization by Motavizumab
Nature Structural & Molecular Biology, 2010Co-Authors: Jason S Mclellan, Albert Kim, Barney S. Graham, Yongping Yang, Man Chen, Peter D KwongAbstract:Respiratory syncytial virus (RSV) is a highly contagious illness in young children. The structure of antibody drug Motavizumab in complex with a 24-residue peptide corresponding to its epitope on RSV-fusion glycoprotein suggests why it is more potent than its predecessor, palivizumab (Synagis).
Nita K Patel - One of the best experts on this subject based on the ideXlab platform.
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Analysis of Respiratory Syncytial Virus Preclinical and Clinical Variants Resistant to Neutralization by Monoclonal Antibodies
2016Co-Authors: Palivizumab And/or Motavizumab, Qing Zhu, Josie M Mcauliffe, Nita K Patel, Chinfen Yang, Wei Zhu, Frances J. Palmer-hill, On Liang, Leslie WachterAbstract:Background. Palivizumab is a US Food and Drug Administration–approved monoclonal antibody for the prevention of respiratory syncytial virus (RSV) lower respiratory disease in high-risk infants. Motavizumab, derived from palivizumab with enhanced antiviral activity, has recently been tested in humans. Although palivizumab escape mutants have been generated in the laboratory, the development of resistant RSV in patients receiving palivizumab has not been reported previously. Methods. We generated palivizumab and Motavizumab escape mutants in vitro and examined the development of resistant mutants in RSV-breakthrough patients receiving immunoprophylaxis. The effect of these mutations on neutralization by palivizumab and Motavizumab and in vitro fitness was studied. Results. Antibody-resistant RSV variants selected in vitro had mutations at position 272 of the fusion protein, from lysine to asparagine, methionine, threonine, glutamine, or glutamate. Variants containing mutations at positions 272 and 275 were detected in breakthrough patients. All these variants were resistant to palivizumab, but only the glutamate variant at position 272 demonstrated resistance to Motavizumab. Mixtures of wild-type and variant RSV soon lost the resistant phenotype in the absence of selection. Conclusions. Resistant RSV variants were detected in a small subset (5%) of RSV breakthrough cases. The fitness of these variants was impaired, compared to wild-type RSV
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AM14 is a prefusion-specific neutralizing antibody.
2015Co-Authors: Morgan S. A. Gilman, Man Chen, Qing Zhu, Nita K Patel, Syed M. Moin, Vicente Mas, Kari Kramer, Stephanie C. Kabeche, Azad Kumar, Concepción PalomoAbstract:(A) Neutralization of laboratory strains and clinical isolates of RSV. Red bars are geometric means. (B) Binding of AM14 and Motavizumab IgGs to immobilized RSV F proteins was measured using a Luminex system. (C) Binding of AM14 Fab to immobilized prefusion RSV F was measured by surface plasmon resonance. Best fit of the data to a 1:1 binding model is shown in red.
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analysis of respiratory syncytial virus preclinical and clinical variants resistant to neutralization by monoclonal antibodies palivizumab and or Motavizumab
The Journal of Infectious Diseases, 2011Co-Authors: Qing Zhu, Josie M Mcauliffe, Nita K Patel, Frances Palmerhill, Chinfen Yang, Brandon Liang, Wei Zhu, Leslie Wachter, Susan Wilson, Randall S MacgillAbstract:Respiratory syncytial virus (RSV) is a member of the Pneumovirus genus in the Paramyxoviridae family. The RSV genome consists of a negative-sense, nonsegmented, single strand of RNA encoding 10 proteins [1]. RSV is an enveloped virus, and its antigenicity is determined by 2 transmembrane glycoproteins, the attachment glycoprotein (G) and the fusion (F) protein. RSV is classified into A and B subgroups, originally based on antigenic differences in the G protein [2]. RSV is the most serious respiratory pathogen in infants and young children, causing annual epidemics of bronchiolitis and pneumonia worldwide [1, 3, 4]. Overall, RSV infection is responsible for ∼2% of the hospitalization rate among infants <1 year of age [5]. This rate increases at least 4–5-fold among children at high risk of severe RSV disease, including premature infants and those with chronic lung disease of prematurity, immunodeficiency, or complicated congenital heart disease [6–12]. RSV infection in infants and children can cause lung function deterioration that may be sustained for months after the acute illness, and in some circumstances, years of recurrent wheezing or asthma may ensue [13, 14]. To date, prevention of RSV disease has only been achieved by the passive administration of RSV-specific immunoglobulin. Prophylaxis with palivizumab (MedImmune), a humanized monoclonal antibody (mAb) that is directed against the RSV F protein, can significantly reduce the rate of RSV-related hospitalizations in high-risk infants [15, 16]. Motavizumab (MEDI-524; MedImmune), an enhanced mAb developed by affinity maturation of palivizumab [17–19], is in clinical development. Nonclinical studies demonstrated that Motavizumab was more effective than palivizumab at neutralizing RSV in vitro. In addition, at equivalent serum and lung levels, Motavizumab was shown to be superior to palivizumab at reducing RSV infection in both the upper and lower airways of cotton rats [18]. Motavizumab and palivizumab bind antigenic site A, a highly conserved region on the RSV F protein between amino acids 258 and 275 [20]. Similar to other RNA viruses, replication of RSV depends on an RNA polymerase that lacks proofreading and repair capability, resulting in a relatively high mutation rate. This mutability could increase the potential for the generation of resistant mutants under selective drug pressure, such as antibody prophylaxis. In vitro development of RSV A mutants resistant to palivizumab has been reported previously. Beeler and Coelingh [20] isolated RSV monoclonal antibody resistant mutants (MARMs) containing phenotypic amino acid variations at positions 262, 275, and 276 of the F protein with use of the murine precursor to palivizumab, mAb1129. Sullender et al [21–23] also isolated palivizumab MARMs containing mutations at positions 268 and 272. The potential for resistance to occur was also explored during the clinical development of palivizumab. In a prospective study using a binding assay that was predictive of palivizumab neutralization, the investigators showed that palivizumab bound to all 25 RSV isolates collected from patients actively receiving palivizumab [24]. However, the number of samples was small in this study, and the assay was suboptimal for detecting minor drug-resistant viral populations. Recently, nucleotide sequence analysis of RSV isolates collected directly from nasal wash specimens from infants who received palivizumab and still developed acute lower tract respiratory infection revealed an F protein mutation at position 272 from lysine (K) to glutamate (E). Although the susceptibility of this variant to neutralization by palivizumab could not be determined because it did not propagate in cell culture [25], it was suggested that this K272E variant would most likely be less susceptible to neutralization by palivizumab, because multiple in vitro-selected palivizumab MARMs contain mutations at this position. To date, the data available on the rate of emergence of clinical resistant variants during treatment are limited. In the present study, we describe the in vitro selection and characterization of additional palivizumab MARMs and a novel Motavizumab MARM. We also examined amino acid changes in the F protein of RSV isolates collected from RSV-breakthrough patients receiving palivizumab or Motavizumab in a large phase 3 clinical study comparing Motavizumab with palivizumab (MI-CP110: Study of MEDI-524; for the prophylaxis of RSV disease in high risk children) [26]. The sensitivity of these immunoprophylaxis breakthrough isolates to Motavizumab and palivizumab was determined using recombinant RSV (rRSV). Moreover, the effect of these neutralization-resistant mutations on in vitro fitness was assessed.
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analysis of respiratory syncytial virus preclinical and clinical variants resistant to neutralization by monoclonal antibodies palivizumab and or Motavizumab
The Journal of Infectious Diseases, 2011Co-Authors: Josie M Mcauliffe, Nita K Patel, Frances Palmerhill, Chinfen Yang, Brandon Liang, Leslie Wachter, Susan Wilson, Randall S Macgill, Lan Su, Subramaniam KrishnanAbstract:BACKGROUND: Palivizumab is a US Food and Drug Administration-approved monoclonal antibody for the prevention of respiratory syncytial virus (RSV) lower respiratory disease in high-risk infants. Motavizumab, derived from palivizumab with enhanced antiviral activity, has recently been tested in humans. Although palivizumab escape mutants have been generated in the laboratory, the development of resistant RSV in patients receiving palivizumab has not been reported previously. METHODS: We generated palivizumab and Motavizumab escape mutants in vitro and examined the development of resistant mutants in RSV-breakthrough patients receiving immunoprophylaxis. The effect of these mutations on neutralization by palivizumab and Motavizumab and in vitro fitness was studied. RESULTS: Antibody-resistant RSV variants selected in vitro had mutations at position 272 of the fusion protein, from lysine to asparagine, methionine, threonine, glutamine, or glutamate. Variants containing mutations at positions 272 and 275 were detected in breakthrough patients. All these variants were resistant to palivizumab, but only the glutamate variant at position 272 demonstrated resistance to Motavizumab. Mixtures of wild-type and variant RSV soon lost the resistant phenotype in the absence of selection. CONCLUSIONS: Resistant RSV variants were detected in a small subset (∼ 5%) of RSV breakthrough cases. The fitness of these variants was impaired, compared to wild-type RSV.
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development of Motavizumab an ultra potent antibody for the prevention of respiratory syncytial virus infection in the upper and lower respiratory tract
Journal of Molecular Biology, 2007Co-Authors: Herren Wu, Nita K Patel, David Pfarr, Syd Johnson, Yambasu A Brewah, Robert M Woods, Wendy I White, James F Young, Peter A KienerAbstract:Respiratory syncytial virus (RSV) is the leading cause of viral bronchiolitis and pneumonia in infants and children. Currently, palivizumab is the only approved monoclonal antibody (mAb) for prophylaxis of RSV. However, a small percentage of patients are not protected by palivizumab; in addition, palivizumab does not inhibit RSV replication effectively in the upper respiratory tract. We report here the development and characterization of Motavizumab, an ultra-potent, affinity-matured, humanized mAb derived from palivizumab. Several palivizumab variants that enhanced the neutralization of RSV in vitro by up to 44-fold were generated; however, in vivo prophylaxis of cotton rats with these antibodies conferred only about a twofold improvement in potency over palivizumab. This unexpected small increase of in vivo potency was caused by poor serum pharmacokinetics and lung bio-availability that resulted from unexpectedly broad tissue binding. Subsequent analyses revealed that changes at three amino acids arising from the affinity maturation markedly increased the non-specific binding to various tissues. Our results suggested that kon-driven mutations are more likely to initiate non-specific binding events than koff-driven mutations. Reversion of these three residues to the original sequences greatly diminished the tissue binding. The resulting mAb, Motavizumab, binds to RSV F protein 70-fold better than palivizumab, and exhibits about a 20-fold improvement in neutralization of RSV in vitro. In cotton rats, at equivalent concentrations, Motavizumab reduced pulmonary RSV titers to up to 100-fold lower levels than did palivizumab and, unlike palivizumab, Motavizumab very potently inhibited viral replication in the upper respiratory tract. This affinity-enhanced mAb is being investigated in pivotal clinical trials. Importantly, our engineering process offers precious insights into the improvement of other therapeutic mAbs.
Brian Harris - One of the best experts on this subject based on the ideXlab platform.
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efficacy of Motavizumab for the prevention of respiratory syncytial virus disease in healthy native american infants a phase 3 randomised double blind placebo controlled trial
Lancet Infectious Diseases, 2015Co-Authors: Katherine L Obrien, Brian Harris, Pamela M Griffin, Aruna Chandran, Robert C Weatherholtz, Hasan S Jafri, Terramika Bellamy, Eugene Millar, Kathryn Jensen, Raymond ReidAbstract:Summary Background Respiratory syncytial virus (RSV) is a leading cause of acute lower respiratory tract infections in children. We aimed to assess the safety and efficacy of an anti-RSV monoclonal antibody (Motavizumab) in healthy term (≥36 weeks' gestational age) infants for the prevention of medically attended RSV acute lower respiratory tract infections. Methods This phase 3, double-blind, placebo-controlled, randomised trial enrolled healthy Native American infants aged 6 months or younger who were born at 36 weeks' gestational age in southwestern USA, on the Navajo Nation, the White Mountain Apache reservation, and the San Carlos Apache Indian reservation. Participants were randomly assigned (2:1) to receive either five monthly intramuscular doses of Motavizumab (15 mg/kg) or placebo. They were followed up for 150 days after the first dose, and the primary endpoints were respiratory admission to hospital with a positive result for RSV by RT-PCR and death caused by RSV. Participants were followed up for medically attended wheezing until they reached age 3 years. Analysis was by intention to treat (ITT). This trial is registered with ClinicalTrials.gov, number NCT00121108. Findings During the autumn seasons (October to December) between 2004 and 2007, 2127 infants of the 2596 infants enrolled were randomly assigned to receive either Motavizumab (1417) or placebo (710). After ITT analysis, Motavizumab resulted in an 87% relative reduction (relative risk [RR] 0·13, 95% CI 0·08–0·21) in the proportion of infants admitted to hospital with RSV (21 [2%] of 1417 participants who received Motavizumab; 80 [11%] of 710 participants who received placebo, p vs 90 [14·0%] participants randomly assigned to receive placebo). Interpretation To our knowledge, this is the only trial of an anti-RSV antibody to prevent serious RSV disease in healthy term infants. Motavizumab significantly reduced the RSV-associated inpatient and outpatient burden and set a benchmark for the efficacy of RSV prevention strategies. The findings do not support a direct, generalisable, causal association between RSV lower respiratory tract infection and subsequent long-term wheezing in term infants. Funding MedImmune.
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a randomized controlled trial of Motavizumab versus palivizumab for the prophylaxis of serious respiratory syncytial virus disease in children with hemodynamically significant congenital heart disease
Pediatric Research, 2011Co-Authors: Timothy F Feltes, Brian Harris, Genevieve Losonsky, Henry M Sondheimer, Robert M R Tulloh, Kathryn M Jensen, Pamela M GriffinAbstract:Children with hemodynamically significant congenital heart disease (CHD) are at risk for serious respiratory syncytial virus (RSV) disease. This study was designed to assess the safety and tolerability of Motavizumab versus palivizumab in children with CHD and was not powered for efficacy. Patients (n = 1236) aged ≤24 mo were randomized to receive five monthly doses (15 mg/kg) of Motavizumab or palivizumab during the RSV season. Adverse events (AEs) and serious AEs (SAEs) were recorded through 30 d after the last dose. RSV hospitalizations and RSV outpatient medically attended lower respiratory tract infections (MALRI; season 2) were summarized. Approximately 93 and 50% of patients reported an AE or SAE, respectively. Skin events occurred in 19.3% of Motavizumab recipients and 16.2% of palivizumab recipients. Rates of hospitalizations and RSV MALRI were similar between treatment groups [relative risk (RR): 0.75; 95% CI, 0.34-1.59 and RR: 0.49; 95% CI, 0.10-1.99, respectively; both p > 0.05]. Motavizumab and palivizumab had similar safety profiles in children with hemodynamically significantly CHD; with the exception of skin events which were increased in Motavizumab recipients. Safety and efficacy were consistent with another study comparing Motavizumab with palivizumab in premature infants without CHD.
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Motavizumab for prophylaxis of respiratory syncytial virus in high risk children a noninferiority trial
Pediatrics, 2010Co-Authors: Xavier Carbonellestrany, Brian Harris, Edward M Connor, Micki Hultquist, Eric A. F. Simões, Ron Dagan, Caroline B Hall, Genevieve LosonskyAbstract:OBJECTIVE: Palivizumab reduces respiratory syncytial virus (RSV) hospitalization in children at high risk by ∼50% compared with placebo. We compared the efficacy and safety of Motavizumab, an investigational monoclonal antibody with enhanced anti-RSV activity in preclinical studies, with palivizumab. METHODS: This randomized, double-blind, multinational, phase 3, noninferiority trial assessed safety and RSV hospitalization in 6635 preterm infants aged ≤6 months at enrollment or children aged ≤24 months with chronic lung disease of prematurity who received 15 mg/kg palivizumab or Motavizumab monthly. Secondary end points included outpatient medically attended lower respiratory tract infections (MALRIs), RSV-specific LRIs, otitis media, antibiotic use, development of antiMotavizumab antibodies, and Motavizumab serum concentrations. RESULTS: Motavizumab recipients had a 26% relative reduction in RSV hospitalization compared with palivizumab recipients, achieving noninferiority. Motavizumab was superior to palivizumab for reduction of RSV-specific outpatient MALRIs (50% relative reduction). Overall, adverse events (AEs) were not significantly different between groups. Cutaneous events were reported in 2 percentage points more Motavizumab recipients (7.2% vs 5.1%); most were mild, but 0.3% resulted in dosing discontinuation. Antidrug antibodies (ADA) were detected in 1.8% of Motavizumab recipients. Patients with anti-drug antibody reported 6 RSV events and 17 cutaneous events. CONCLUSIONS: Children receiving prophylaxis with Motavizumab or palivizumab had low rates of RSV hospitalization; Motavizumab recipients experienced 50% fewer RSV MALRIs than palivizumab recipients. AEs were similar in both groups, although cutaneous AEs were higher for Motavizumab recipients. Motavizumab may offer an improved alternative in prophylaxis for serious RSV disease in infants and children at high risk.
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Motavizumab for prophylaxis of respiratory syncytial virus in high risk children a noninferiority trial
Pediatrics, 2010Co-Authors: Xavier Carbonellestrany, Brian Harris, Edward M Connor, Micki Hultquist, Eric A. F. Simões, Ron Dagan, Caroline B Hall, Genevieve LosonskyAbstract:OBJECTIVE: Palivizumab reduces respiratory syncytial virus (RSV) hospitalization in children at high risk by ∼50% compared with placebo. We compared the efficacy and safety of Motavizumab, an investigational monoclonal antibody with enhanced anti-RSV activity in preclinical studies, with palivizumab. METHODS: This randomized, double-blind, multinational, phase 3, noninferiority trial assessed safety and RSV hospitalization in 6635 preterm infants aged ≤6 months at enrollment or children aged ≤24 months with chronic lung disease of prematurity who received 15 mg/kg palivizumab or Motavizumab monthly. Secondary end points included outpatient medically attended lower respiratory tract infections (MALRIs), RSV-specific LRIs, otitis media, antibiotic use, development of antiMotavizumab antibodies, and Motavizumab serum concentrations. RESULTS: Motavizumab recipients had a 26% relative reduction in RSV hospitalization compared with palivizumab recipients, achieving noninferiority. Motavizumab was superior to palivizumab for reduction of RSV-specific outpatient MALRIs (50% relative reduction). Overall, adverse events (AEs) were not significantly different between groups. Cutaneous events were reported in 2 percentage points more Motavizumab recipients (7.2% vs 5.1%); most were mild, but 0.3% resulted in dosing discontinuation. Antidrug antibodies (ADA) were detected in 1.8% of Motavizumab recipients. Patients with anti-drug antibody reported 6 RSV events and 17 cutaneous events. CONCLUSIONS: Children receiving prophylaxis with Motavizumab or palivizumab had low rates of RSV hospitalization; Motavizumab recipients experienced 50% fewer RSV MALRIs than palivizumab recipients. AEs were similar in both groups, although cutaneous AEs were higher for Motavizumab recipients. Motavizumab may offer an improved alternative in prophylaxis for serious RSV disease in infants and children at high risk.