Palivizumab in the prophylaxis of respiratory syncytial virus infection

Cardenas, Silvia; Auais, Alexander; Piedimonte, Giovanni

doi:10.1586/14787210.3.5.719

Cited by 40 publications

(29 citation statements)

References 32 publications

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“…Monoclonal antibodies such as palivizumab (Synagis) that interfere with fusion activity of RSV F are already in clinical use for the prophylactic treatment of children at high risk for RSV disease (10). The present study shows that Synagis can significantly reduce F-triggered apoptosis and shedding of polarized epithelial cells.…”

Section: Discussionmentioning

confidence: 54%

The Fusion Protein of Respiratory Syncytial Virus Triggers p53-Dependent Apoptosis

Eckardt-Michel

Lorek

Baxmann

et al. 2008

J Virol

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Section: Discussionmentioning

confidence: 54%

The Fusion Protein of Respiratory Syncytial Virus Triggers p53-Dependent Apoptosis

Eckardt-Michel

Lorek

Baxmann

et al. 2008

J Virol

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“…Second, the optimization of the tissue distribution of a given therapeutic antibody would also potentially enhance its efficacy. Indeed, the latter is directly linked to the efficiency with which the molecule reaches its site of action, such as the respiratory tract (38) and rheumatoid joints (39). Third, the ability to up-regulate effector functions could be an important tool in increasing the potency of various therapeutic antibodies, to the Human and cynomolgus monkey sera were injected at a 1:2500 dilution on a surface onto which 2103 RU of MEDI-524 and 2124 RU of MEDI-524-YTE had been coupled.…”

Section: Discussionmentioning

confidence: 99%

Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)

Dall’Acqua¹,

Kiener²,

Wu³

2006

Journal of Biological Chemistry

550

490

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We describe here the functional implications of an increase in IgG binding to the neonatal Fc receptor. We have defined in a systematic fashion the relationship between enhanced FcRn binding of a humanized anti-respiratory sincytial virus (RSV) monoclonal antibody (MEDI-524) and the corresponding biological consequences in cynomolgus monkeys. The triple mutation M252Y/S254T/T256E (YTE) was introduced into the Fc portion of MEDI-524. Whereas these substitutions did not affect the ability of MEDI-524 to bind to its cognate antigen and inhibit RSV replication, they resulted in a 10-fold increase in its binding to both cynomolgus monkey and human FcRn at pH 6.0. MEDI-524-YTE was efficiently released from FcRn at pH 7.4 in both cases. We show that MEDI-524-YTE consistently exhibited a nearly 4-fold increase in serum half-life in cynomolgus monkeys when compared with MEDI-524. This constituted the largest half-life improvement described to date for an IgG in a primate. For the first time, we demonstrate that these sustained serum levels resulted in an up to 4-fold increase in lung bioavailability. Importantly, we also establish that our non-human primate model is relevant to human. Finally, we report that the YTE triple substitution provided a means to modulate the antibodydependent cell-mediated cytotoxicity (ADCC) activity of a humanized IgG1 directed against the human integrin ␣ v ␤ 3 . Therefore, the YTE substitutions allow the simultaneous modulation of serum half-life, tissue distribution and activity of a given human IgG1.

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“…This form of the RSV F protein will also induce antibodies specific for sites present on the postfusion form of the protein. A humanized monoclonal antibody, palivizumab, which is specific for site II (45,46) has proven to be a useful prophylactic for RSV in infants. Thus, inclusion of the prefusion form of the F protein in virus-like particle RSV vaccine candidates should stimulate antibodies to all sites associated with protective responses and enhance protective responses without the necessity of added adjuvants.…”

Section: Figmentioning

confidence: 99%

Murine Immune Responses to Virus-Like Particle-Associated Pre- and Postfusion Forms of the Respiratory Syncytial Virus F Protein

Cullen

Schmidt

Kenward

et al. 2015

J Virol

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Virus IMPORTANCEThe development of vaccines for respiratory syncytial virus has been hampered by a lack of understanding of the requirements for eliciting high titers of neutralizing antibodies. The results of this study suggest that particle-associated RSV F protein containing mutations that stabilize the structure in a prefusion conformation may stimulate higher titers of protective antibodies than particles containing F protein in a wild-type or postfusion conformation. These findings indicate that the prefusion F protein assembled into VLPs has the potential to produce a successful RSV vaccine candidate.H uman respiratory syncytial virus (RSV) is the most significant cause of acute viral respiratory disease in infants and young children (1). There are from 34 to 65 million RSV infections resulting in acute lower respiratory disease requiring hospitalization and 160,000 to 199,000 deaths per year worldwide (2). Elderly populations are also at significant risk for serious RSV disease. In the United States, the virus accounts for 10,000 deaths and 14,000 to 60,000 hospitalizations per year among individuals more than 64 years of age (3-5). Indeed, RSV infection of this population is at least as significant as influenza virus infections. RSV infections result in high mortality rates in immunocompromised populations, particularly stem cell transplant recipients (6) and individuals with cardiopulmonary diseases (7). Despite the significance of RSV disease in different populations, there are no vaccines available.Failure to develop a licensed RSV vaccine is not due to lack of effort as numerous vaccine candidates have been characterized in preclinical and clinical studies spanning 5 decades (summarized in references 8 to 9). While many problems have uniquely hindered RSV vaccine development, a major hurdle has been a lack of understanding of requirements for generation of protective immunity to RSV infection. Many vaccine candidates are protective in animal models and, while stimulating antibody responses in humans, have failed to induce high levels of neutralizing antibodies and protection from virus challenge in human trials (reviewed in references 10 and 11). Although there are likely many reasons for these observations, one important issue has been a lack of clear understanding of the most effective form of the RSV antigens, particularly the F protein, for stimulating potent neutralizing antibodies.The paramyxovirus F protein is folded into a metastable conformation and upon fusion activation refolds, through a series of conformational intermediates, into the postfusion conformation, which is structurally very different from the prefusion form (12)(13)(14)(15)(16)(17)(18)(19). While it is logical to assume that the prefusion form of F protein should be more effective in stimulating optimally neutralizing antibodies, recent structural studies have shown that the postfusion form of the F protein contains at least some epitopes recognized by neutralizing monoclonal antibodies (17, 18). Thus, it has been a...

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Palivizumab in the prophylaxis of respiratory syncytial virus infection

Cited by 40 publications

References 32 publications

The Fusion Protein of Respiratory Syncytial Virus Triggers p53-Dependent Apoptosis

The Fusion Protein of Respiratory Syncytial Virus Triggers p53-Dependent Apoptosis

Properties of Human IgG1s Engineered for Enhanced Binding to the Neonatal Fc Receptor (FcRn)

Murine Immune Responses to Virus-Like Particle-Associated Pre- and Postfusion Forms of the Respiratory Syncytial Virus F Protein

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