HIV-1 Env fusion peptide immunogens and their use
Inventors
Kwong, Peter • Kong, Rui • Zhou, Tongqing • Mascola, John • Xu, Kai • Cheng, Cheng • Chuang, Gwo-Yu • liu, Kevin • Zhang, Baoshan • Ou, Li • Kong, Wing-pui
Assignees
US Department of Health and Human Services
Publication Number
US-11602559-B2
Publication Date
2023-03-14
Expiration Date
2037-10-03
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Abstract
Embodiments of immunogens based on the HIV-1 Env fusion peptide and methods of their use and production are disclosed. Nucleic acid molecules encoding the immunogens are also provided. In several embodiments, the immunogens can be used to generate an immune response to HIV-1 Env in a subject, for example, to treat or prevent an HIV-1 infection in the subject.
Core Innovation
Embodiments of immunogens based on the HIV-1 Env fusion peptide and methods of their use and production are disclosed. The immunogens include HIV-1 Env fusion peptide or a portion thereof, and can be used to generate a neutralizing immune response to HIV-1 in a subject. Immunogenic conjugates consist of a polypeptide corresponding to residues 512 to one of residues 517-521 of HIV-1 Env protein, optionally linked to a heterologous carrier such as tetanus toxin C fragment or diphtheria toxin variant CRM197. Epitope scaffold proteins comprise the HIV-1 Env fusion peptide linked to a scaffold protein to preserve the native fusion peptide conformation and elicit a neutralizing immune response. In addition, recombinant protein nanoparticles containing the HIV-1 Env fusion peptide linked to subunits of ferritin or lumazine synthase protein nanoparticles are described. Recombinant HIV-1 Env ectodomain trimers with selective removal of N-linked glycosylation sites near the fusion peptide are also disclosed to expose the fusion peptide and facilitate immune recognition.
The major problem being solved is the lack of agents capable of eliciting a neutralizing humoral immune response protective against HIV-1 infection. Despite extensive efforts, an effective immunogen based on the HIV-1 Env glycoprotein capable of eliciting broadly neutralizing antibodies has been elusive. The HIV-1 virus employs various mechanisms to evade humoral recognition, including a glycan shield that masks important epitopes such as the fusion peptide. The present invention addresses these challenges by focusing the immune response on the conserved N-terminal region of the HIV-1 Env fusion peptide, which can be presented in various immunogenic formats to elicit a neutralizing immune response that neutralizes diverse tier 2 strains of HIV-1.
Claims Coverage
The claims include one independent claim directed to an immunogen and several dependent claims covering compositions and methods of use, collectively defining the main inventive features related to the fusion peptide immunogen, its specific chemical linkage, and its immunological activity.
Immunogen comprising HIV-1 Env fusion peptide conjugated to tetanus toxoid heavy chain C fragment
The immunogen comprises an HIV-1 Env fusion peptide of the sequence AVGIGAVF (residues 1-8 of SEQ ID NO: 1) conjugated to a tetanus toxoid heavy chain C fragment carrier protein by a heterologous linker; the immunogen elicits a neutralizing immune response to HIV-1 in a subject.
Linkage of fusion peptide to carrier via specific linker chemistry
The fusion peptide is conjugated to the carrier by a linker between a lysine residue on the tetanus toxoid heavy chain C fragment and a heterologous cysteine residue fused to the C-terminal residue of the fusion peptide; a Sulfo-SIAB linker is an example of such a linker.
Control of fusion peptide to carrier molar ratio
The average molar ratio of the fusion peptide to the carrier protein in the immunogenic conjugate is between about 1:1 and 1000:1.
Specific binding to VRC34 antibody
The immunogen specifically binds to a VRC34 antibody, indicating preservation of the fusion peptide epitope.
Immunogenic compositions and adjuvants
Immunogenic compositions comprising the immunogen and a pharmaceutically acceptable carrier are claimed, optionally further comprising an adjuvant such as a saponin adjuvant or a carbomer-lecithin adjuvant.
Methods of generating immune responses and treatment
Methods comprising administration of an effective amount of the immunogen to generate an immune response to HIV-1 in a subject are claimed, including prime-boost immunization protocols with administration of the immunogen followed by a soluble HIV-1 envelope trimer stabilized in a prefusion conformation and optionally deglycosylated at positions N88, N230, N241, and N611; the immune response can treat, inhibit, or prevent HIV-1 infection and replication.
The claims collectively cover an immunogen comprising the HIV-1 Env fusion peptide conjugated to tetanus toxoid heavy chain C fragment via a specific linker chemistry, pharmaceutical compositions including the immunogen, and methods of eliciting immune responses and treating HIV-1 infection using the immunogen and related prime-boost regimens with stabilized HIV-1 Env trimers.
Stated Advantages
The disclosed immunogens elicit a surprisingly effective immune response that neutralizes diverse tier 2-strains of HIV-1, a result previously sought but not achieved.
Immunization protocols with the fusion peptide conjugated to carrier followed by immunization with stabilized HIV-1 Env trimers elicit antibodies neutralizing over 30% of HIV-1 strains in a standardized 208 pseudovirus panel, demonstrating breadth.
The elicited neutralizing response exhibits high breadth despite relatively low overall neutralization titers, an uncommon but desirable characteristic similar to broadly neutralizing antibodies.
Documented Applications
Use of the disclosed immunogens to generate an immune response to HIV-1 Env in a subject for the treatment or prevention of HIV-1 infection.
Use of nucleic acid molecules encoding the immunogens and expression vectors including such nucleic acids for expression in cells and vaccination.
Use of prime-boost immunization methods administering the fusion peptide immunogen and a stabilized, optionally deglycosylated, soluble HIV-1 Env trimer to elicit improved neutralizing antibody responses.
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