Immunoglobulin single variable domain antibody against RSV prefusion F protein
Inventors
Saelens, Xavier • Schepens, Bert • ROSSEY, Iebe • Graham, Barney • McLellan, Jason • GILMAN, Morgan
Assignees
V18 Vzw • Universiteit Gent • Vlaams Instituut voor Biotechnologie VIB • Dartmouth College • US Department of Health and Human Services
Publication Number
US-10501528-B2
Publication Date
2019-12-10
Expiration Date
2036-06-20
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Abstract
The present invention relates to immunoglobulin single variable domains (ISVDs) that are directed against respiratory syncytial virus (RSV). More specifically, it relates to ISVDs that bind to the prefusion form of the fusion (F) protein of RSV. The invention relates further to the use of these ISVDs for prevention and/or treatment of RSV infections, and to pharmaceutical compositions comprising these ISVDs.
Core Innovation
The invention relates to immunoglobulin single variable domains (ISVDs) directed against the respiratory syncytial virus (RSV), specifically binding to the prefusion form of the fusion (F) protein of RSV. These ISVDs can be used for prevention and treatment of RSV infections, and pharmaceutical compositions comprising these ISVDs are also disclosed.
The problem addressed is the lack of effective prophylactic vaccines and RSV-specific therapeutic small molecules despite RSV being a leading cause of acute airway infections in infants and young children. Existing antibody treatment (palivizumab) is expensive, limited to prophylactic use, and binds both pre- and postfusion conformations but is not widely accessible. Conventional antibodies are cumbersome to produce, have limited stability, and can be sterically hindered in epitope recognition due to their large size. Additionally, prior ISVDs showed weak neutralization activity against RSV serotype B, often needing multivalent formats for potency.
Surprisingly, the invention demonstrates that monovalent ISVDs can show strong neutralization activity against both RSV serotypes A and B, overcoming previous limitations. These ISVDs bind specifically to epitopes unique to the prefusion conformation of the F protein, achieving potent neutralization in a monovalent format without the need for multivalent constructs. The ISVDs disclosed include specified CDR sequences and can be administered as proteins or via nucleic acids, host cells, and pharmaceutical compositions for therapeutic or prophylactic use against RSV.
Claims Coverage
The patent contains one independent claim covering an immunoglobulin single variable domain and related claims addressing compositions, nucleic acids, host cells, and methods for RSV inhibition.
Immunoglobulin single variable domain that binds RSV prefusion F protein with potent neutralization
An ISVD that binds specifically to the prefusion form of RSV fusion protein, exhibiting monovalent neutralization activity against RSV serotypes A and B with IC50 values differing by ten-fold or less, and binding a defined conformational epitope comprising specific amino acid residues of RSV prefusion F protein, and comprising specified CDR1, CDR2, and CDR3 sequences.
RSV binding construct comprising the ISVD
An RSV binding construct comprising the immunoglobulin single variable domain as described, enabling binding to the prefusion form of RSV F protein.
Nucleic acid encoding the ISVD
A purified nucleic acid encoding the defined ISVD.
Transformed host cell for production
A host cell transformed or transfected with the nucleic acid encoding the ISVD for expression and production purposes.
Method of producing the ISVD
A method comprising culturing the transformed host cell to produce the ISVD.
Methods of inhibiting RSV infection by ISVD administration
Methods of inhibiting RSV infection in a subject by administering the ISVD or RSV binding construct or pharmaceutical compositions comprising the ISVD, including prophylactic administration.
The claims collectively cover a monovalent ISVD targeting a specific prefusion conformation epitope of RSV F protein with potent neutralizing activity, related binding constructs, nucleic acids, host cells, pharmaceutical compositions, and methods of administration for RSV infection inhibition, emphasizing potency against both RSV serotypes A and B.
Stated Advantages
Monovalent ISVDs demonstrate strong neutralization activity against both RSV serotype A and B, overcoming prior limitations of weak neutralization for serotype B.
ISVDs specifically bind the prefusion conformation of RSV F protein, which is associated with higher neutralization potency compared to antibodies binding both pre- and postfusion forms.
Smaller size of ISVDs compared to conventional antibodies confers potential for better epitope recognition in complex samples due to reduced steric hindrance.
ISVDs may offer improved stability and ease of production compared to conventional full-length antibodies.
The invention enables production of ISVDs via nucleic acids and host cells, supporting scalable and flexible manufacturing.
Documented Applications
Use of ISVDs and RSV binding constructs for prevention and therapeutic treatment of RSV infections in subjects.
Administration routes include systemic, oral, intranasal, and potential gene therapy approaches using nucleic acid or vector delivery.
Formulation of pharmaceutical compositions comprising ISVDs directed against RSV prefusion F protein for medicament use.
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