Recombinant HIV-1 envelope proteins and their use
Inventors
Kwong, Peter • Pancera, Marie • Zhou, Tongqing • Georgiev, Ivelin • Joyce, Michael Gordon • Acharya, Priyamvada • Gorman, Jason • Yang, YongPing • Stewart-Jones, Guillaume • Chen, Rita • Chuang, Gwo-Yu • Mascola, John • Zhang, Baoshan • Cheng, Cheng • Sastry, Mallika • Druz, Aliaksandr
Assignees
US Department of Health and Human Services
Publication Number
US-12145968-B2
Publication Date
2024-11-19
Expiration Date
2035-09-04
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Abstract
HIV-1 Env ectodomain trimers stabilized in a prefusion mature closed conformation and methods of their use and production are disclosed. In several embodiments, the HIV-1 Env ectodomain trimers and/or nucleic acid molecules can be used to generate an immune response to HIV-1 in a subject. In additional embodiments, the therapeutically effective amount of the HIV-1 Env ectodomain trimers can be administered to a subject in a method of treating or preventing HIV-1 infection.
Core Innovation
HIV-1 Env ectodomain trimers stabilized in a prefusion mature closed conformation are disclosed, including the atomic-level three dimensional structure of such trimers bound by neutralizing antibodies. These recombinant trimers resist transition to the CD4-bound open conformation when incubated with a molar excess of soluble CD4, retaining the prefusion mature closed conformation when used as immunogens. This retention avoids exposure of highly antigenic sites on the open conformation targeted by poorly neutralizing antibodies and maximizes exposure of sites on the V1V2 cap targeted by broadly neutralizing antibodies.
The problem solved by this invention is the difficulty in developing an effective HIV-1 vaccine due to the immunoevasion of the HIV-1 Env ectodomain trimer. The HIV-1 Env trimer undergoes structural rearrangements from a prefusion mature closed conformation that evades antibody recognition, through intermediate receptor-bound conformations, to a postfusion conformation. Lack of atomic-level structure of the prefusion mature closed conformation stymied efforts to design stable immunogens that maintain this desired conformation in vivo.
By providing the atomic-level structure of the HIV-1 Env ectodomain trimer in the prefusion mature closed conformation and describing recombinant trimers stabilized in this conformation through one or more amino acid substitutions, the invention enables the design of immunogens that generate a neutralizing immune response protective against HIV-1 infection. The stabilized trimers can specifically bind to broadly neutralizing antibodies but not to antibodies specific for CD4-induced open conformations, enhancing vaccine specificity and effectiveness.
Claims Coverage
The patent includes 12 claims covering mRNA molecules encoding recombinant HIV-1 Env proteins with specific cysteine substitutions, vectors, host cells, compositions, and methods of generating immune responses and treating HIV-1 infection.
Encoding HIV-1 Env proteins with stabilizing cysteine substitutions
mRNA molecules encoding recombinant HIV-1 Env proteins comprising cysteine substitutions at positions 201 and 433 corresponding to HXB2 reference, optionally with specific substitutions I201C and A433C.
Additional stabilizing amino acid substitutions
mRNA further comprising methionine substitution at position 302 (N302M) and leucine substitution at position 320 (T320L), cysteine substitutions at positions 501 and 605 (A501C, T605C), and proline substitution at position 559 (I559P).
Modification of cleavage site to enhance stability
mRNA where native furin cleavage site separating gp120 and gp41 is substituted with six arginine residues.
Recombinant expression systems
Vectors comprising the mRNA molecule, isolated host cells comprising such vectors, and immunogenic compositions including the mRNA and a pharmaceutically acceptable carrier.
Methods of immune response induction and HIV-1 treatment
Methods for generating an immune response to HIV-1 Env in a subject by administering effective amounts of the mRNA, including prime-boost regimens, especially where the subject is at risk of or has HIV-1 infection.
The claims cover recombinant mRNA molecules encoding HIV-1 Env proteins stabilized by specific cysteine and amino acid substitutions, vectors and host cells utilizing these sequences, pharmaceutical compositions including the mRNA, and methods for inducing an immune response and treating or preventing HIV-1 infection by administering these mRNA molecules.
Stated Advantages
Recombinant HIV-1 Env ectodomain trimers stabilized in the prefusion mature closed conformation resist CD4-induced conformational changes, thereby avoiding induction of ineffective antibodies and improving vaccine specificity.
Stabilized trimers maintain exposure of broadly neutralizing antibody epitopes, enhancing the potential to generate a protective neutralizing immune response against HIV-1.
Molecular modifications increase physical and antigenic stability of the HIV-1 Env trimer in conditions relevant for vaccine manufacturing and administration.
Documented Applications
Generating an immune response to HIV-1 Env in a subject by administering recombinant mRNA encoding stabilized HIV-1 Env proteins.
Treating or preventing HIV-1 infection in a subject by administering a therapeutically effective amount of recombinant mRNA encoding stabilized HIV-1 Env proteins.
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