Human cytomegalovirus gB polypeptide
Inventors
Liu, Yuhang • CHE, Ye • Chi, Xiaoyuan Sherry • Dormitzer, Philip Ralph • Nicki, Jennifer Anne • Yao, Xiaojie
Assignees
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Publication Number
US-12447207-B2
Publication Date
2025-10-21
Expiration Date
Abstract
Polypeptides and cytomegalovirus (CMV) antigens that include at least two introduced amino acid mutations relative to the amino acid sequence of the wild-type HCMV glycoprotein B (gB). For example, polypeptides stabilized in a conformation alternative to the gB postfusion conformation. Compositions including the polypeptides and uses thereof.
Core Innovation
The disclosure relates to human cytomegalovirus (HCMV) glycoprotein B (gB) immunogenic compositions that include RNA formulated in a lipid nanoparticle. The RNA encodes an HCMV gB protein in prefusion conformation and/or non-postfusion conformation, where the gB protein comprises engineered disulfide mutations and, in some embodiments, additional amino acid mutations.
A central aspect is engineering the gB amino acid sequence by introducing engineered disulfide/cysteine mutations selected from D217C, Y589C, M371C, W506C, N524C, and M684C, with positions numbered according to SEQ ID NO:1. The disclosure also describes combinations of at least one engineered disulfide mutation with additional substitutions at positions defined relative to SEQ ID NO:1, including YIH155-157→GHR, W240→A, C246→S, and further specified substitutions.
The compositions include RNA in a lipid nanoparticle, with embodiments describing a cationic lipid, a PEG-modified lipid, a sterol, and a non-cationic lipid, with refinements to component options and molar ratio ranges. The engineered gB polypeptides are described in connection with prefusion-specific antibody binding and binding to bis(aryl)thiourea compounds.
The disclosure states that the engineered gB polypeptides form a prefusion conformation and can induce immune responses and reduce CMV infection and shedding. The compositions are described in immunogenic, pharmaceutical, and vaccine contexts for use of the engineered gB immunogens and RNA formulations.
Claims Coverage
The independent claims cover HCMV immunogenic compositions where RNA is formulated in a lipid nanoparticle and encodes engineered gB polypeptides. Across the independent claims, the inventive features are the engineered disulfide mutations within gB and, in some claims, those mutations combined with additional specified amino acid substitutions.
RNA encoding gB with engineered disulfide cysteine mutations
An HCMV immunogenic composition comprising RNA formulated in a lipid nanoparticle, wherein the RNA encodes an amino acid sequence for a glycoprotein B (gB) protein comprising at least one engineered disulfide mutation, where the gB protein comprises a cysteine mutation selected from D217C, Y589C, M371C, W506C, N524C, and M684C numbered according to SEQ ID NO:1.
RNA encoding gB with engineered disulfide mutations plus additional specified substitutions
An HCMV immunogenic composition comprising RNA formulated in a lipid nanoparticle, wherein the RNA encodes an amino acid sequence for a gB protein comprising at least two amino acid mutations, where the at least two amino acid mutations comprise at least one engineered disulfide mutation selected from D217C and Y589C, and M371C and W506C, and at least one additional mutation selected from substitutions at positions defined relative to SEQ ID NO:1, including YIH155-157→GHR, W240→A, C246→S, P655→S, F678→S, L680→T, R685→A, MIALDI648-653→GSGKDG, R693→V, I767 and I768→C, D703 and P704→C, and Y696 and V697→C.
Overall, the independent claims cover HCMV immunogenic compositions where RNA in a lipid nanoparticle encodes gB proteins containing engineered disulfide mutations, optionally combined with additional defined amino acid substitutions at positions numbered according to SEQ ID NO:1.
Stated Advantages
The engineered gB polypeptides form a prefusion conformation not present in postfusion.
The engineered immunogens can bind prefusion-specific antibodies.
The engineered immunogens can bind bis(aryl)thiourea compounds.
The engineered gB polypeptides can induce immune responses.
The engineered gB immunogenic approach reduces CMV infection and shedding.
The disclosure broadly outlines compositions and methods to reduce or prevent CMV infection.
The disclosure broadly outlines compositions and methods to elicit immune responses.
Documented Applications
HCMV immunogenic composition use as a vaccine/immunogenic formulation comprising RNA formulated in a lipid nanoparticle encoding engineered gB protein variants.
Inducing immune responses with engineered gB prefusion conformation to reduce CMV infection and shedding.
A pharmaceutical/vaccine context is described for immunogenic compositions using the engineered gB immunogens and/or RNA formulations, including an intended use to reduce or prevent CMV infection and/or elicit immune responses.
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