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Prefusion RSV F proteins and their use

A pre-fusion, protein technology, applied in the pre-fusion RSV F protein and its application field, can solve problems such as unsuccessful

Active Publication Date: 2016-04-06
UNITED STATES OF AMERICA
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Due to its mandatory role in RSV invasion, the RSV F protein is the target of neutralizing antibodies and the subject of vaccine development; however, like other RSV antigens, previous efforts to develop RSV F protein-based vaccines have proven unsuccessful

Method used

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  • Prefusion RSV F proteins and their use
  • Prefusion RSV F proteins and their use
  • Prefusion RSV F proteins and their use

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0858] Structure of the prefusion F trimer of respiratory syncytial virus bound to a human antibody

[0859] The prefusion conformation of the respiratory syncytial virus (RSV) fusion (F) glycoprotein is the target of the majority of RSV neutralizing antibodies in human sera, but its metastability hampers characterization. To overcome this obstacle, a postfusion conformation that does not bind F and is more effective than the prophylactic antibody palivizumab was identified. 10 times larger antibody. The co-crystal structure of one of these antibodies, D25, in complex with the F glycoprotein revealed that D25 locks F in its prefusion state. Comparison of prefusion and postfusion F conformations defines rearrangements required to mediate RSV invasion. The D25-F glycoprotein structure reveals a new vulnerable site, the antigenic site, at the top of the F glycoprotein with prefusion specificity and quaternary properties Structure and antigenic site of RSV F trimer before fus...

Embodiment 2

[0892] Stabilization of RSV F protein

[0893] This example illustrates the design of an exemplary RSV F protein stabilized in a prefusion conformation. Crystal structure of RSV F protein in complex with D25Fab ​​(i.e. in pre-fusion conformation) and post-fusion RSV F protein (for example disclosed in McLellan et al., J. Virol., 85, 7788, 2011, where coordinates are deposited under PDB accession number 3RRR) A comparison of the structures of the membrane revealed a drastic structural rearrangement between the prefusion and postfusion conformations in the membrane-proximal and membrane-distal lobes, providing guidance for the stabilization of the prefusion conformation of RSV F. Based on a comparison of the pre-fusion and post-fusion RSV F structures, there are two regions undergoing large conformational changes, located in the F 1 The N- and C-termini of the subunits. For example, as shown in Figure 2, F 1 Positions 137-216 and 461-513 of the polypeptide undergo structural ...

Embodiment 3

[0933] Membrane-proximal lobe that stabilizes PreF antigen

[0934] As discussed above, the crystal structure of the RSV F protein in complex with D25Fab ​​(i.e., in a prefusion conformation) and the postfusion RSV F protein (for example, are disclosed in McLellan et al., J. Virol., 85, 7788, 2011, where coordinates are in PDB A comparison of the structure of accession number 3RRR) reveals a drastic structural rearrangement between the prefusion and postfusion conformations in the distal lobe of the membrane. Based on a comparison of the pre-fusion and post-fusion RSV F structures, there are two regions undergoing large conformational changes, located in the F 1 The N- and C-termini of the subunits. For example, as shown in Figure 2, F 1 Positions 137-216 and 461-513 of the polypeptide undergo structural rearrangements between the prefusion and postfusion F protein conformations, while the F 1 Positions 271-460 of the polypeptide remained relatively unchanged. This example...

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Abstract

Disclosed are Respiratory Syncytial Virus (RSV) antigens including a recombinant RSV F protein stabilized in a prefusion conformation. Also disclosed are nucleic acids encoding the antigens and methods of producing the antigens. Methods for generating an immune response in a subject are also disclosed. In some embodiments, the method is a method for treating or preventing a RSV infection in a subject by administering a therapeutically effective amount of the antigen to the subject.

Description

[0001] related application [0002] This application claims U.S. Provisional Application No. 61 / 780,910 filed March 13, 2013, U.S. Provisional Application No. 61 / 798,389 filed March 15, 2013, U.S. Provisional Application No. 61 / 798,389 filed July 23, 2013 61 / 857,613 and the priority of US Provisional Application No. 61 / 863,909 filed August 9, 2013, each of which is incorporated by reference in its entirety. technical field [0003] The present disclosure relates to polypeptides, polynucleotides, compositions, and methods of use thereof for inducing and detecting an immune response against respiratory syncytial virus (RSV). Background of the invention [0004] Respiratory syncytial virus (RSV) is an enveloped, non-segmented, negative-sense RNA virus in the genus Pneumovirus of the family Paramyxoviridae. It is the most common cause of bronchiolitis and pneumonia in children during their first year of life. RSV also causes recurrent infections, including severe lower respira...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/135A61K39/00A61K39/155A61K38/10A61P43/00C12N15/45C12N15/62
CPCA61K39/155A61K2039/53A61K2039/55561A61K2039/55566C12N2760/18534A61K2039/5252A61K2039/5254A61K2039/543A61K2039/55505C12N2710/10343A61K39/12C07K2319/21C07K2319/22C07K2319/50C07K2319/70C07K2319/735C12N2760/18522C07K14/005A61P31/14A61P43/00C12N2760/18523C07K2319/00C07K14/135G01N33/564C12N7/00
Inventor 邝达平B·S·格雷厄姆J·S·麦克莱伦M·G·乔伊斯M·兼清张宝山J·博因顿I·S·乔治夫M·潘切拉C·索托S·斯来瓦特森G·斯图尔特-琼斯陈磊陈曼莊國瑜J·戈尔曼G·奥菲克M·萨斯特里杨永平周同庆
Owner UNITED STATES OF AMERICA
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