Truncated HIV envelope proteins (ENV), methods and compositions related thereto
Inventors
Kalyanaraman, Vaniambadi • Whitney, Stephen • VanCott, Thomas C. • Polonis, Victoria • Alving, Carl • Matyas, Gary R. • Rao, Mangala • Marovich, Mary • McCutchan, Francine • Tovanabutra, Sodsai • Sanders-Buell, Eric
Assignees
Henry M Jackson Foundation for Advancedment of Military Medicine Inc • Advanced Bioscience Laboratories Inc • United States Department of the Army
Publication Number
US-10081658-B2
Publication Date
2018-09-25
Expiration Date
2032-04-25
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Abstract
The instant application provides methods and related compositions pertaining to novel HIV envelope proteins. In some embodiments, the invention relates to methods and compositions for the preparation, production, and administration of isolated novel HIV envelope nucleic acid and protein sequences suitable, for example, as vaccines against HIV.
Core Innovation
The invention relates to novel HIV envelope proteins (Env) that are truncated and mutated specifically in the native gp120/gp41 cleavage site to prevent protease cleavage, comprising the membrane proximal external region (MPER) of gp41, and truncated prior to the transmembrane domain. These isolated proteins and corresponding nucleic acids are designed for preparation, production, and administration, for example as vaccines against HIV.
HIV Env proteins produced by the invention include about 1-10 hydrophilic amino acids at the C-terminus, typically comprising residues such as three lysines. The HIV Env proteins can bind integrin α4β7 and comprise epitopes recognized by broadly neutralizing antibodies such as 2F5 and 4E10, including the 4E10 epitope sequence LWYIK.
The background addresses the problem of the extreme genetic diversity of HIV, difficulties in eliciting broad neutralizing antibodies due to immune evasion strategies and sequence variability of HIV-1 Env, and the challenges in developing effective vaccines. Existing HIV vaccines fail to generate broad and potent neutralizing antibodies necessary for protective immunity. The invention aims to overcome these challenges by providing modified HIV Env proteins that include the MPER region and are designed to optimally present neutralizing epitopes, thereby eliciting broad neutralizing antibodies and robust cell-mediated immunity against diverse HIV clades.
Claims Coverage
The patent includes one independent claim covering a peptide comprising a truncated HIV Env protein with specific mutations and modifications, and additional dependent claims covering compositions, methods of immunization, vaccines, kits, and nucleic acid sequences encoding such peptides.
Truncated HIV Env protein with gp120/gp41 cleavage site mutation
An isolated peptide comprising a truncated HIV Env protein that is mutated in the native gp120/gp41 cleavage site to prevent protease cleavage and is truncated prior to the transmembrane domain.
Inclusion of MPER and hydrophilic C-terminal amino acids
The peptide comprises the membrane proximal external region (MPER) of gp41, including the 4E10 epitope with amino acid sequence LWYIK, and includes about 1-10 hydrophilic amino acids at its C-terminus, such as three lysines, contiguous with the MPER sequence.
Amino acid sequence identity to SEQ ID NO: 1
The peptide comprises an amino acid sequence having 99% or greater identity to the amino acid sequence depicted in SEQ ID NO: 1, including embodiments fully matching this sequence.
Compositions and vaccines comprising the peptide
Compositions comprising the peptide and a pharmaceutically acceptable carrier, including subunit vaccines containing the peptide.
Methods of immunization and conferring immunity
Methods of generating antibodies against HIV and conferring immunity in a mammal by administering compositions containing the peptide, optionally including adjuvants such as liposome formulations containing dimyristoyl phosphatidylcholine, dimyristoyl phosphatidylglycerol, cholesterol, and phospholipid A, by injection.
Binding to integrin α4β7 and competition assays
Peptides that bind integrin α4β7 and methods of generating antibodies that compete with the peptide for integrin α4β7 binding.
Nucleic acids encoding the peptide and kits
Isolated nucleic acids encoding amino acid sequences with high identity to SEQ ID NOs: 1, 3, 4, 5, 7 or 9, vectors and host cells comprising them, as well as kits comprising compositions of isolated peptides and instructions for administration.
The independent claim covers a truncated HIV Env peptide mutated to prevent cleavage, containing the MPER including the 4E10 epitope and hydrophilic C-terminal residues, with high sequence identity to SEQ ID NO: 1. Dependent claims cover specific sequences, related compositions, vaccines, methods of immunization for generating neutralizing antibodies and conferring immunity, nucleic acids and expression vectors encoding the peptides, kits comprising these components, and interaction with integrin α4β7.
Stated Advantages
The HIV Env proteins comprise the entirety of the gp41 ectodomain including the MPER, improving exposure of neutralizing epitopes to elicit broad and potent neutralizing antibodies against diverse HIV strains.
The modification of the gp120/gp41 cleavage site to prevent protease cleavage results in stable Env proteins suitable for vaccine development.
Inclusion of hydrophilic amino acid tails, such as lysines, improves solubility and potentially enhances epitope presentation for immune recognition.
The Env proteins bind integrin α4β7, allowing generation of antibodies that interfere with HIV-1 interactions important for infection.
The designs support production in mammalian cells with codon optimization and improved expression.
The invention provides reagents for screening and mapping broadly neutralizing antibodies and small molecules, enhancing vaccine and anti-viral development.
Documented Applications
Use as immunogens in vaccines to elicit broad neutralizing antibodies and robust cell-mediated immunity against HIV.
Use in subunit vaccines and nucleic acid vaccines comprising isolated Env proteins or encoding nucleic acids.
Methods of immunization and conferring immunity against HIV in mammals including humans, non-human primates, dogs, rabbits, guinea pigs, and mice.
Reagents for screening and identification of broadly neutralizing antibodies and mapping serum neutralization activity.
Screening of small molecules that compete for binding of broadly neutralizing antibodies as potential immunogens or anti-viral compounds.
Production of recombinant HIV Env proteins in mammalian host cells, including CHO cells, for vaccine development and immunological studies.
Kits comprising the Env compositions along with instructions for administration for therapeutic or prophylactic use.
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