Conformationally specific viral immunogens
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Publication Number
US-10155023-B2
Publication Date
2018-12-18
Expiration Date
Abstract
The present invention provides methods of making engineered viral proteins and protein complexes that are useful as vaccine immunogens, engineered viral proteins and protein complexes made using such methods, and pharmaceutical compositions comprising such engineered viral proteins and protein complexes. Such engineered viral proteins and protein complexes may comprise one or more cross-links that stabilize the conformation of an antibody epitope, such as a quaternary neutralizing antibody, and may exhibit an enhanced ability to elicit a protective immune response when administered to a subject as a component of a vaccine.
Core Innovation
The invention relates to conformationally-specific viral vaccine immunogens engineered by introducing targeted cross-links into viral proteins or protein complexes to stabilize tertiary and quaternary epitope conformations. The stabilization reduces conformational masking while enhancing binding to neutralizing or broadly neutralizing antibodies and activation of B cell receptors. The engineered immunogens are capable of eliciting neutralizing or broadly neutralizing humoral responses and protective immune responses.
A key implementation is an HIV trimeric spike protein complex in which at least two dityrosine cross-links are introduced into the V1/V2 loop distal to the stem. The cross-links are between amino acid positions 143 and 150 and between amino acid positions 160 and 180. This cross-linking preserves quaternary neutralizing epitopes and maintains relevant conformations of the viral spike complex.
Conformationally targeted dityrosine cross-links can be combined with tyrosine substitutions using targeted staples to generate intermolecular trimerizing cross-links that preserve neutralizing epitope display. The resulting immunogens are assessed for improved binding to antibodies and enhanced antibody responses, with confirmation by dityrosine cross-link detection approaches and binding or immunoassay measurements.
Claims Coverage
The claims include two independent claims covering a method for producing an HIV immunogen and an HIV trimeric spike protein complex. The core inventive features are stabilization of an HIV trimeric spike protein complex, at least two dityrosine cross-links, specific V1/V2 loop placement distal to the stem, defined cross-link pairings between amino-acid positions 143–150 and 160–180, and capacity to elicit a neutralizing or broadly neutralizing humoral response.
Stabilized HIV trimeric spike immunogen with V1/V2 distal dityrosine cross-links
A method for producing an HIV immunogen comprising obtaining a stabilized HIV trimeric spike protein complex which has the capacity to elicit a neutralizing or a broadly neutralizing humoral response, wherein the stabilized HIV trimeric spike protein complex is produced by introducing at least two dityrosine cross-links between amino acids at positions 143 and 150 and amino acids at positions 160 and 180 in the V1/V2 loop distal to the stem.
HIV trimeric spike protein complex with defined V1/V2 distal dityrosine cross-links
An HIV trimeric spike protein complex comprising at least two dityrosine cross-links, wherein the dityrosine cross-links are between positions 143 and 150, and between positions 160 and 180 in the V1/V2 loop distal to the stem.
The claims coverage centers on stabilizing an HIV trimeric spike protein complex by introducing at least two dityrosine cross-links in the V1/V2 loop distal to the stem, with cross-links specified between amino-acid positions 143–150 and 160–180, for producing immunogens capable of eliciting neutralizing or broadly neutralizing humoral responses.
Stated Advantages
Stabilizes tertiary and quaternary epitope conformations to preserve quaternary neutralizing epitopes.
Reduces conformational masking.
Enhances binding to neutralizing or broadly neutralizing antibodies.
Activates B cell receptors.
Elicits neutralizing or broadly neutralizing humoral responses.
Induces protective immune response.
Provides improved antibody responses in animals as described in the partial content.
May support stabilization properties such as thermostability and reduced aggregation as described in the partial content.
Documented Applications
Use as a method for producing an HIV immunogen capable of eliciting neutralizing or broadly neutralizing humoral responses.
Use as an HIV vaccine immunogen based on an HIV trimeric spike protein complex comprising specified V1/V2 distal dityrosine cross-links.
Use in a pharmaceutical composition comprising a pharmaceutically effective amount of the HIV trimeric spike protein complex and a pharmaceutically acceptable carrier.
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