EP4580670A2 - Immunogènes de vaccin contre le vih pour l'induction d'anticorps ciblant le glycane v3 - Google Patents

Immunogènes de vaccin contre le vih pour l'induction d'anticorps ciblant le glycane v3

Info

Publication number
EP4580670A2
EP4580670A2 EP23861577.7A EP23861577A EP4580670A2 EP 4580670 A2 EP4580670 A2 EP 4580670A2 EP 23861577 A EP23861577 A EP 23861577A EP 4580670 A2 EP4580670 A2 EP 4580670A2
Authority
EP
European Patent Office
Prior art keywords
envelope
hiv
glycan
certain embodiments
boost
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP23861577.7A
Other languages
German (de)
English (en)
Inventor
Rory HENDERSON
Priyamvada Acharya
Victoria STALLS
Barton F. Haynes
Kshitij G. WAGH
Bette T. Korber
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Duke University
Triad National Security LLC
Original Assignee
Duke University
Triad National Security LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Duke University, Triad National Security LLC filed Critical Duke University
Publication of EP4580670A2 publication Critical patent/EP4580670A2/fr
Pending legal-status Critical Current

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K16/00—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies
    • C07K16/08—Immunoglobulins [IG], e.g. monoclonal or polyclonal antibodies against material from viruses
    • C07K16/10—RNA viruses
    • C07K16/112—Retroviridae (F), e.g. leukemia viruses
    • C07K16/114—Lentivirus (G), e.g. human immunodeficiency virus [HIV], feline immunodeficiency virus [FIV] or simian immunodeficiency virus [SIV]
    • C07K16/1145—Env proteins, e.g. gp41, gp110/120, gp160, V3, principal neutralising domain [PND] or CD4-binding site
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K39/12—Viral antigens
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/005—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from viruses
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/555—Medicinal preparations containing antigens or antibodies characterised by a specific combination antigen/adjuvant
    • A61K2039/55511—Organic adjuvants
    • A61K2039/55555—Liposomes; Vesicles, e.g. nanoparticles; Spheres, e.g. nanospheres; Polymers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/57—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2
    • A61K2039/575—Medicinal preparations containing antigens or antibodies characterised by the type of response, e.g. Th1, Th2 humoral response
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2299/00—Coordinates from 3D structures of peptides, e.g. proteins or enzymes
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/33—Crossreactivity, e.g. for species or epitope, or lack of said crossreactivity
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/30—Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34—Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/50—Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56—Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565—Complementarity determining region [CDR]
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/70—Immunoglobulins specific features characterized by effect upon binding to a cell or to an antigen
    • C07K2317/76—Antagonist effect on antigen, e.g. neutralization or inhibition of binding
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/90—Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92—Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16034—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16122—New viral proteins or individual genes, new structural or functional aspects of known viral proteins or genes
    • C—CHEMISTRY; METALLURGY
    • C12—BIOCHEMISTRY; BEER; SPIRITS; WINE; VINEGAR; MICROBIOLOGY; ENZYMOLOGY; MUTATION OR GENETIC ENGINEERING
    • C12N—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA
    • C12N2740/00—Reverse transcribing RNA viruses
    • C12N2740/00011—Details
    • C12N2740/10011—Retroviridae
    • C12N2740/16011—Human Immunodeficiency Virus, HIV
    • C12N2740/16111—Human Immunodeficiency Virus, HIV concerning HIV env
    • C12N2740/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • the present invention relates in general, to a composition suitable for use in inducing anti-HIV-1 antibodies, and, in particular, to immunogenic compositions comprising envelope proteins and nucleic acids to induce cross-reactive neutralizing antibodies and increase their breadth of coverage.
  • the invention also relates to methods of inducing such broadly neutralizing anti-HIV-1 antibodies using such compositions.
  • the invention provides compositions and methods for induction of an immune response, for example cross-reactive (broadly) neutralizing (bn) Ab induction.
  • one or more of the mutations as described in Table 1 can be incorporated into envelope CH848.3.D0949.10.17 (also referred to as CH848.d0949.10.17WT) and variants thereof, including, but not limited to, CH848.d0949.10.17 DT (also referred to as CH848.d0949.10.17.N133D.N138T).
  • one or more of the mutations as described in Table 1 can be incorporated into envelope >CH848.3.D0949.10.17chim.6R.DS.SOSIP.664 as provided in Figure 52.
  • one or more of the mutations as described in Table 1 can be incorporated into envelope CH848.d0808.15.15 and variants thereof. In some embodiments, one or more of the mutations as described in Table 1 can be incorporated into envelope CH848.d0358.80.06 and variants thereof. In some embodiments, one or more of the mutations as described in Table 1 can be incorporated into envelope CH848.d1432.5.41 and variants thereof. In some embodiments, one or more of the mutations as described in Table 1 can be incorporated into envelope CH848.d1621.4.44 and variants thereof. In some embodiments, one or more of the mutations as described in Table 1 can be incorporated into envelope CH848.d1305.10.35 and variants thereof.
  • the invention provides a selection of a series of immunogens and immunogen designs for induction of neutralizing HIV-1 antibodies, e.g. but not limited to V3 glycan epitope targeting antibodies, the selection comprising envelopes as follows: 1) 2 ActiveUS 200859022 Attorney Docket No.: 1234300-00423WO1 (DU7897PCT) Date of Electronic Filing: August 31, 2023 CH848.d0949.10.17 DT (also referred to as CH848.d0949.10.17.N133D.N138T), 2) CH848.d0949.10.17 (also referred to as CH848.d0949.10.17WT), 3) CH848.d0808.15.15, 4) CH848.d0358.80.06, 5) CH848.d1432.5.41, 6) CH848.d1621.4.44 and 7) CH848.d1305.10.35 (see Tables 3 and 4), wherein one or more of the mutations as described in
  • V3 glycan epitope targeting antibodies the selection comprising envelopes as follows: 1) CH848.d0949.10.17 DT (also referred to as CH848.d0949.10.17.N133D.N138T), 2) CH848.d0949.10.17 (also referred to as CH848.d0949.10.17WT), 3) CH848.d0808.15.15, 4) CH848.d0358.80.06, 5) CH848.d1432.5.41, 6) CH848.d1621.4.44, 7) CH848.d1305.10.35, (see Tables 3 and 4) and 8) any HIV-1 envelope sequence from the CH848 infected individual and variants thereof comprising one or more of the mutations as described in Table 1 or Table 2B.
  • the selection comprises additional HIV-1 Envs, P0402.c2.11 and ZM246F.
  • the methods use compositions comprising HIV-1 envelope immunogens designed to bind to precursors, and/or unmutated common ancestors (UCAs) of different HIV-1 bnAbs. In certain embodiments, these are UCAs of V1V2 glycan and V3 glycan binding antibodies.
  • UCAs common ancestors
  • the invention provides HIV-1 envelope immunogen designs with multimerization and variable region sequence optimization for enhanced UCA-targeting.
  • the invention provides HIV-1 envelope immunogen designs with multimerization and variable region sequence optimization for enhanced targeting and inductions of multiple antibody lineages, e.g.
  • the invention provides a recombinant HIV-1 envelope sequence or nucleic acid encoding a recombinant protein HIV-1 envelope sequence comprising a mutation of amino acid residue N300.
  • the mutation is N300G, N300A, N300R, N300K or N300D.
  • the envelope further comprises a mutation at position N302.
  • the mutation is N302D.
  • the envelope comprises mutations N300G and N302D.
  • the envelope comprises mutations N300A and N302D.
  • the envelope comprises mutations N300R and N302D.
  • the envelope comprises mutations N300K and N302D.
  • the invention provides compositions comprising recombinant HIV-1 envelopes and/or nucleic acids encoding these envelopes with modifications at position 415 (HXB2 numbering).
  • HIV-1 envelope position 415 can modulate glycan 332 interaction.
  • the invention provides a recombinant HIV-1 envelope sequence or nucleic acid encoding a recombinant protein HIV-1 envelope sequence comprising a mutation of amino acid residue T415.
  • the mutation is T415S, T415N or T415A.
  • the amino acid numbering position is with respect to HXB2 envelope sequence.
  • the invention provides compositions comprising recombinant HIV-1 envelopes and/or nucleic acids encoding these envelopes with modifications at position 323 (HXB2 numbering). [0026] To optimize around glycan 301, in certain embodiments position 323 of an HIV-1 envelope is modified. [0027] In certain embodiments, the invention provides a recombinant HIV-1 envelope sequence or nucleic acid encoding a recombinant protein HIV-1 envelope sequence comprising a mutation of amino acid residue I323. In certain embodiments, the mutation is I323N, I323Q, I323R or I323K. In certain embodiments, the envelope further comprises mutation at amino acid residue T303. In certain embodiment, the mutation is T303N.
  • the envelope comprises mutations I323N and T303N. In certain embodiment, the envelope comprises mutations I323Q and T303N. In certain embodiment, the envelope comprises mutations I323R and T303N. In certain embodiment, the envelope comprises mutations I323K and T303N.
  • the amino acid numbering position is with respect to HXB2 envelope sequence. [0028] In certain aspects the invention provides compositions comprising recombinant HIV-1 envelopes and/or nucleic acids encoding these envelopes with modifications at position 444 (HXB2 numbering).
  • the invention provides compositions comprising recombinant HIV-1 envelopes and/or nucleic acids encoding these envelopes with modifications at any one or more of position 300, position 302, position 417, position 330, position 415, position 323, position 303, position 444, position 439, position 443, position 137, and position 327.
  • the recombinant HIV-1 envelope comprises modifications to one or more of these positions.
  • the amino acid numbering position is with respect to HXB2 envelope sequence.
  • the recombinant HIV-1 envelope comprises modifications to all of these positions.
  • the recombinant HIV-1 envelope comprises modifications to a subset of these positions.
  • the d526 V1 loop as described in Table 2B can be incorporated into envelope CH848.d0808.15.15 and variants thereof. In some embodiments, the d526 V1 loop as described in Table 2B can be incorporated into envelope CH848.d0358.80.06 and variants thereof. In some embodiments, the d526 V1 loop as described in Table 2B can be incorporated into envelope CH848.d1432.5.41 and variants thereof. In some embodiments, the d526 V1 loop as described in Table 2B can be incorporated into envelope CH848.d1621.4.44 and variants thereof.
  • the d526 V1 loop as described in Table 2B can be incorporated into envelope CH848.d1305.10.35 and variants thereof.
  • the invention provides compositions comprising recombinant HIV-1 envelopes and/or nucleic acids encoding these envelopes with modifications at any one or more of position 300, position 302, position 417, position 330, position 415, position 323, position 303, position 444, position 439, position 443, position 137, and position 327 (see e.g., Table 1) and comprising the sequence of d526 V1 loop as described in Table 2B.
  • the recombinant HIV-1 envelope comprises modifications to one or more of these positions.
  • the envelope comprises additional mutations stabilizing the recombinant HIV-1 envelope trimer.
  • these include, but are not limited to, SOSIP mutations.
  • mutations are selected from sets F1- F14, VT1-VT8 mutations described herein, or any combination or subcombination within a set.
  • the selected mutations are F14.
  • the selected mutations are VT8.
  • the selected mutations are F14 and VT8 combined.
  • the invention provides a recombinant HIV-1 envelope of Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B).
  • CH848.d0949.10.17DT envelope comprises additional modifications D230N.H289N.P291S.E169K and is referred to as CH848.d0949.10.17 DTe.
  • CH848.d0949.10.17 envelope comprises additional modifications D230N.H289N.P291S.E169K and is referred to as CH848.d0949.10.17WTe.
  • CH848.d0949.10.17DT envelope comprises additional modifications referred to as CH848.0949.10.17DT.GS designs. See Table 2A.
  • CH848.d0949.10.17DT.GS envelopes comprise additional modifications D230N.H289N.P291S.E169K. See Table 2A.
  • the envelope in the selections for immunization are included as trimers, protein and/or mRNA.
  • the envelope in the selections for immunization are included as nanoparticles, protein and/or mRNA.
  • the designation scNP refers to a non-limiting embodiment of a protein nanoparticle formed by sortase conjugation reaction.
  • nanoparticles comprise fusion proteins, for example ferritin-envelope fusion proteins.
  • the inventive designs comprise modifications, including without limitation fusion of the HIV-1 envelope with ferritin using linkers between the HIV-1 envelope and ferritin designed to optimize ferritin nanoparticle assembly.
  • the nucleic acid is mRNA.
  • the mRNA is comprised in a lipid nano-particle (LNP).
  • LNP lipid nano-particle
  • the invention provides compositions comprising a nanoparticle which comprises any one of the recombinant HIV-1 envelopes of the invention, e.g., as disclosed in Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B) or Table 2B.
  • the invention provides compositions comprising a nanoparticle which comprises any one of the recombinant HIV-1 envelopes of the invention, e.g., as disclosed in Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B) or Table 2B, wherein the nanoparticle is a ferritin self-assembling nanoparticle.
  • the invention provides a composition comprising a nanoparticle and a carrier, wherein the nanoparticle comprises trimers of any of the recombinant HIV-1 envelopes, e.g. as disclosed in Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B) or Table 2B.
  • the nanoparticle is a ferritin self-assembling nanoparticle.
  • the nanoparticle comprises multimers of trimers. Provided also are method for using these compositions comprising nanoparticles.
  • the invention provides a method of inducing an immune response in a subject comprising administering an immunogenic composition comprising any one of the recombinant HIV-1 envelopes of the invention e.g., as disclosed in Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B) or Table 2B, or compositions comprising these recombinant HIV-1 envelopes, in an amount sufficient to induce an immune response.
  • the composition is administered as a prime and/or a boost.
  • the composition is administered as a prime.
  • the composition is administered as a boost.
  • the composition comprises nanoparticles.
  • methods of the invention further comprise administering an adjuvant.
  • the invention provides a composition comprising a plurality of nanoparticles comprising a plurality of the recombinant HIV-1 envelopes or trimers of recombinant HIV-1 envelopes of the invention, e.g., as disclosed in Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B) or Table 2B.
  • the envelopes/trimers of the invention are multimeric when comprised in a nanoparticle.
  • the nanoparticle size is suitable for delivery.
  • the nanoparticles are ferritin based nanoparticles.
  • the invention provides nucleic acids comprising sequences encoding HIV-1 envelopes of the invention, e.g., as disclosed in Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications 11 ActiveUS 200859022 Attorney Docket No.: 1234300-00423WO1 (DU7897PCT) Date of Electronic Filing: August 31, 2023 described in Tables 2A-B) or Table 2B.
  • the nucleic acids are DNAs.
  • the nucleic acids are mRNAs, modified or unmodified, suitable for use any use, e.g. but not limited to use as pharmaceutical compositions.
  • the invention provides expression vectors comprising the nucleic acids of the invention.
  • the invention provides a pharmaceutical composition comprising mRNAs encoding the inventive HIV-1 envelopes of the invention, e.g., as disclosed in Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B) or Table 2B. In certain embodiments, these are optionally formulated in lipid nanoparticles (LNPs). In certain embodiments, the mRNAs are modified. Modifications include without limitations modified ribonucleotides, poly-A tail, 5’cap. [0061] In certain embodiments, the nucleic acids are formulated in lipid, such as but not limited to LNPs. Non-limiting embodiments include LNPs without polyethylene glycol.
  • the invention provides a nucleic acid encoding any of the recombinant HIV-1 envelopes and methods for their use to induce immune response in a subject in need thereof.
  • the invention provides a method of inducing an immune response comprising administering an immunogenic composition comprising a prime immunogen followed by at least one boost immunogen from Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B) or Table 2B, wherein the boost immunogens are administered in an amount sufficient to induce an immune response.
  • the method further comprises administering an immunogenic composition comprising any HIV-1 envelope sequence from 12 ActiveUS 200859022 Attorney Docket No.: 1234300-00423WO1 (DU7897PCT) Date of Electronic Filing: August 31, 2023 the CH848 infected individual and variants thereof comprising one or more of the mutations as described in Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B) or Table 2B.
  • an immunogenic composition comprising any HIV-1 envelope sequence from 12 ActiveUS 200859022 Attorney Docket No.: 1234300-00423WO1 (DU7897PCT) Date of Electronic Filing: August 31, 2023 the CH848 infected individual and variants thereof comprising one or more of the mutations as described in Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B) or Table 2B.
  • the methods further comprise administering a boost from Table 4, wherein the boost is CH848.1432.5.41 in any suitable form.
  • the methods further comprise administering a boost from Table 4, wherein the boost is CH848.1621.4.44 in any suitable form.
  • the methods further comprise administering a boost from Table 4, wherein the boost is CH848.1305.10.35 in any suitable form.
  • the methods further comprise comprising administering a boost from Table 4, wherein the boost is P0402.c2.11 (G) in any suitable form.
  • the boost comprises envelope CH848.3.D0949.10.17chim.6R.DS.SOSIP.664_N300G.
  • the prime and/or boost immunogen are administered as a nanoparticle.
  • the nanoparticle is a ferritin nanoparticle.
  • the methods further comprise administering the prime and/or boost immunogen as a mRNA-LNP formulation. 13 ActiveUS 200859022 Attorney Docket No.: 1234300-00423WO1 (DU7897PCT) Date of Electronic Filing: August 31, 2023 [0073]
  • the methods further comprise administering any suitable adjuvant.
  • FIG. 1A-B The V3-glycan targeting DH270 broadly neutralizing antibody lineage.
  • A) (upper left) A DH270 antibody Fab bound HIV-1 Envelope ectodomain highlighting the gp120 (blue) and gp41 (orange) domains.
  • Antibody Fab heavy and light chains depicted with epitope glycans (dark blue).
  • FIGS 11A-H The I4 to mature DH270.2 and DH270.3 transition.
  • the I4 branch point structures Mature antibodies DH270.2 and DH270.3.
  • the I3 to I2 and DH270.1 branch point A) Lineage tree highlighting the I3 and I2 intermediate antibodies and the mature DH270.1 (M1) antibody. B) Top views of the I2 and DH270.1 contact sites. Heavy and light chain mutation alpha-carbons are presented as spheres. C) Alignment (gp120 only) of I3 and I2 bound state structures highlighting the shift in gp120 V1 loop arrangement and contact between the I2 R84 sidechain and the N137-glycan. D) Alignment (gp120 only) of UCA and I2 bound structures highlighting conformational similarity between the gp120 V1 loops.
  • FIG. 15A-H The I2 to I1, DH270.4, DH270.5, and DH270.6 transition.
  • Figures 44A-B show non-limited embodiments of designs of 19CV3 sequences.
  • Figure 44B underlined is the signal peptide and the preceding four amino acids indicate the cloning site/kozak sequence (VDTA (SEQ ID NO: 3)) neither of which that would not be part of the final recombinant protein.
  • Figure 44A discloses SEQ ID NOS 257-260, respectively, in order of appearance.
  • Figure 44B discloses SEQ ID NOS 261-264, respectively, in order of appearance.
  • Figures 45A-B show non-limited embodiments of designs of 19CV3 sequences.
  • Amino acids H66A_A582T_L587A are referred to JS2 or “joe2” mutations.
  • underlined is the signal peptide and the preceding four amino acids indicate the cloning site/kozak sequence (VDTA (SEQ ID NO: 3)) neither of which that would not be part of the final recombinant protein.
  • Figure 45A discloses SEQ ID NOS 265- 274, respectively, in order of appearance.
  • Figure 45B discloses SEQ ID NOS 275-284, respectively, in order of appearance.
  • Figure 46 shows non-limiting examples of envelopes designs and sequences of 10.17 DT.GS envelope designs.
  • Figure 46 discloses SEQ ID NOS 285-310, respectively, in order of appearance.
  • Figure 47 shows non-limiting examples of envelopes designs and sequences described in Table 3.
  • Figure 47 discloses SEQ ID NOS 311-318, respectively, in order of appearance.
  • Figure 48 shows non-limiting examples of envelope designs and sequences described in Table 4—envelopes CH848.0808.15.15, CH848.1621.4.44, CH848.1305.10.35, P0402.c2.11 (G), ZM246F (C).
  • Figure 48 discloses SEQ ID NOS 319-380, respectively, in order of appearance.
  • Figure 49 shows non-limiting examples of designs and sequences based on envelope CH848.0358.80.06 and CH848.1432.5.41.
  • Figure 49 discloses SEQ ID NOS 381-400, respectively, in order of appearance.
  • 21 ActiveUS 200859022 Attorney Docket No.: 1234300-00423WO1 (DU7897PCT) Date of Electronic Filing: August 31, 2023
  • Figures 50A-C show comparison of V1-V3 sites in d358 ( Figure 50A), d949 ( Figure 50B), d1432 ( Figure 50C) Envs.
  • V1 loop residues and GDIR/K motifs are colored light pink and orange, respectively.
  • the distance between d358 Arg and glycan is 2.9 ⁇ .
  • Figures 51A-B show interactions observed in the V1-V3 sites of d358 and d526 Envs.
  • the selection of HIV-1 envelopes may be grouped in various combinations of primes and boosts, either as nucleic acids, proteins, or combinations thereof.
  • the compositions are pharmaceutical compositions which are therapeutic and/or immunogenic.
  • the compositions comprise amounts of envelopes which are therapeutic and/or immunogenic.
  • the invention provides a composition for a prime boost immunization regimen comprising any one of the envelopes described herein, or any combination thereof wherein the envelope is a prime or boost immunogen.
  • the composition for a prime boost immunization regimen comprises one or more envelopes described herein.
  • nucleic acid encoding an envelope is operably linked to a promoter inserted an expression vector.
  • compositions comprise a suitable carrier.
  • compositions comprise a suitable adjuvant.
  • the induced immune response includes induction of antibodies, including but not limited to autologous and/or cross-reactive (broadly) neutralizing antibodies against HIV-1 envelope.
  • antibodies including but not limited to autologous and/or cross-reactive (broadly) neutralizing antibodies against HIV-1 envelope.
  • Various assays that analyze whether an immunogenic composition induces an immune response, and the type of antibodies induced are known in the art and are also described herein.
  • the invention provides an expression vector comprising any of the nucleic acid sequences of the invention, wherein the nucleic acid is operably linked to a promoter.
  • the invention provides an expression vector comprising a nucleic acid sequence encoding any of the polypeptides of the invention, wherein the nucleic acid is operably linked to a promoter.
  • the invention provides a 23 ActiveUS 200859022 Attorney Docket No.: 1234300-00423WO1 (DU7897PCT) Date of Electronic Filing: August 31, 2023 composition comprising any one of the nucleic acid sequences of invention.
  • the invention provides a composition comprising at least one nucleic acid sequence encoding any one of the polypeptides of the invention.
  • the envelope used in the compositions and methods of the invention is a gp160, gp150, gp145, gp140, gp120, gp41, N-terminal deletion variants as described herein, cleavage resistant variants as described herein, or codon optimized sequences thereof.
  • the composition comprises envelopes as trimers.
  • envelope proteins are multimerized, for example trimers are attached to a particle such that multiple copies of the trimer are attached and the multimerized envelope is prepared and formulated for immunization in a human.
  • the compositions comprise envelopes, including but not limited to trimers as a particulate, high-density array on liposomes or other particles, for example but not limited to nanoparticles.
  • the trimers are in a well ordered, near native like or closed conformation.
  • the trimer compositions comprise a homogenous mix of native like trimers.
  • the trimer compositions comprise at least 85%, 90%, 95% native like trimers.
  • the envelope is any of the forms of HIV-1 envelope.
  • the envelope is gp120, gp140, gp145 (i.e. with a transmembrane domain), or gp150.
  • gp140 is designed to form a stable trimer. See Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B) and Table 2B for non-limiting examples of sequence designs.
  • envelope protomers form a trimer which is not a SOSIP timer.
  • the trimer is a SOSIP based trimer wherein each protomer comprises additional modifications.
  • envelope trimers are recombinantly produced.
  • the nucleic acid comprises a nucleic acid sequence which encodes a gp120, gp140, gp145, gp150, or gp160.
  • 24 ActiveUS 200859022 Attorney Docket No.: 1234300-00423WO1 (DU7897PCT) Date of Electronic Filing: August 31, 2023 [0127]
  • the vector is any suitable vector. Non-limiting examples include, VSV, replicating rAdenovirus type 4, MVA, Chimp adenovirus vectors, pox vectors, and the like.
  • the nucleic acids are administered in NanoTaxi block polymer nanospheres.
  • a non-limiting embodiment of a combination of TLR7/8 and TLR9 agonist comprises R848 and oCpG in STS (see Moody et al. (2014) J. Virol. March 2014 vol. 88 no. 6 3329-3339).
  • the adjuvant is an LNP. See e.g., without limitation Shirai et al. “Lipid Nanoparticle Acts as a Potential Adjuvant for Influenza Split Vaccine without Inducing Inflammatory Responses” Vaccines 2020, 8, 433; doi:10.3390/vaccines8030433, published 3 August 2020.
  • the invention provides a recombinant HIV-1 envelope polypeptide as described here, wherein the polypeptide is a non-naturally occurring protomer designed to form an envelope trimer.
  • the invention also provides nucleic acids encoding these recombinant polypeptides. Non-limiting examples of amino acids and nucleic acid of such protomers are disclosed herein.
  • the invention provides a recombinant trimer comprising three identical protomers of an envelope.
  • the invention provides an immunogenic composition comprising the recombinant trimer and a carrier, wherein the 25 ActiveUS 200859022 Attorney Docket No.: 1234300-00423WO1 (DU7897PCT) Date of Electronic Filing: August 31, 2023 trimer comprises three identical protomers of an HIV-1 envelope as described herein.
  • the invention provides an immunogenic composition comprising nucleic acid encoding these recombinant HIV-1 envelope and a carrier.
  • Described herein are nucleic and amino acids sequences of HIV-1 envelopes.
  • the sequences for use as immunogens are in any suitable form.
  • the described HIV-1 envelope sequences are gp160s.
  • the described HIV-1 envelope sequences are gp120s.
  • Other sequences for example but not limited to stable SOSIP trimer designs, gp145s, gp140s, both cleaved and uncleaved, gp140 Envs with the deletion of the cleavage (C) site, fusion (F) and immunodominant (I) region in gp41-- QDPHG ⁇ DV ⁇ JS ⁇ &), ⁇ JS ⁇ &), ⁇ JS ⁇ (QYV ⁇ ZLWK ⁇ WKH ⁇ GHOHWLRQ ⁇ RI ⁇ RQO ⁇ WKH ⁇ FOHDYDJH ⁇ & ⁇ VLWH ⁇ and fusion (F) domain -- naPHG ⁇ DV ⁇ JS ⁇ &) ⁇ JS ⁇ &) ⁇ JS ⁇ (QYV ⁇ ZLWK ⁇ WKH ⁇ GHOHWLRQ ⁇ RI ⁇ only the cleavage (C)—QDPHG ⁇ JS ⁇ & ⁇ JS ⁇ & ⁇ 6HH ⁇ H ⁇ J ⁇ /LDR ⁇ HW ⁇ DO ⁇ Virology 2006
  • nucleic acid sequences are codon optimized for optimal expression in a host cell, for example a mammalian cell, a rBCG cell or any other suitable expression system.
  • An HIV-1 envelope has various structurally defined fragments/forms: gp160; gp140-- -including cleaved gp140 and uncleaved gp140 (gp140C), gp140CF, or gp140CFI; gp120 and gp41.
  • gp160 gp160
  • gp140 envelope forms are also well known in the art, along with the various specific changes which give rise to the gp140C (uncleaved envelope), gp140CF and gp140CFI forms. Envelope gp140 forms are designed by introducing a stop codon within the gp41 sequence. See Chakrabarti et al. at Figure 1.
  • Envelope gp140CF refers to a gp140 HIV-1 envelope design with a deletion of the cleavage (C) site and fusion (F) region.
  • Envelope gp140CFI refers to a gp140 HIV-1 envelope design with a deletion of the cleavage (C) site, fusion (F) and immunodominant (I) region in gp41.
  • C cleavage
  • F fusion
  • I immunodominant
  • the envelope design in accordance with the present invention involves deletion of residues (e.g., 5-11, 5, 6, 7, 8, 9, 10, or 11 amino acids) at the N- terminus.
  • residues e.g., 5-11, 5, 6, 7, 8, 9, 10, or 11 amino acids
  • amino acid residues ranging from 4 residues or even fewer to 14 residues or even more are deleted. These residues are between the maturation (signal peptide, usually ending with CXX, wherein X is any amino acid) and "VPVXXXX".
  • the invention provides composition and methods which use a selection of Envs, as gp120s, gp140s cleaved and uncleaved, gp145s, gp150s and gp160s, stabilized and/or multimerized trimers, as proteins, DNAs, RNAs, or any combination thereof, administered as primes and boosts to elicit an immune response.
  • Envs as proteins could be co-administered with nucleic acid vectors containing Envs to amplify antibody induction.
  • the compositions and methods include any immunogenic HIV-1 sequences to give the best coverage for T cell help and cytotoxic T cell induction.
  • the compositions and methods include mosaic and/or consensus HIV-1 genes to give the best coverage for T cell help and cytotoxic T cell induction.
  • the compositions and methods include mosaic group M and/or consensus genes to give the best coverage for T cell help and cytotoxic T cell induction.
  • the mosaic genes are any suitable gene from the HIV-1 genome.
  • the mosaic genes are Env genes, Gag genes, Pol genes, Nef genes, or any combination thereof. See e.g. US Patent No. 7951377.
  • the mosaic genes are bivalent mosaics. In some embodiments the mosaic genes are trivalent.
  • the mosaic genes are administered in a suitable vector with each immunization with Env gene inserts in a suitable vector and/or as a protein.
  • the mosaic genes for example as bivalent mosaic Gag group M consensus genes, are administered in a suitable vector, for example but not limited to HSV2, would be administered with each immunization with Env gene inserts in a suitable vector, for example but not limited to HSV-2.
  • the invention provides compositions and methods of Env genetic immunization either alone or with Env proteins to recreate the swarms of evolved viruses that have led to bnAb induction. Nucleotide-based vaccines offer a flexible vector format to immunize against virtually any protein antigen.
  • the invention contemplates using immunogenic compositions wherein immunogens are delivered as DNA. See Graham BS, Enama ME, Nason MC, Gordon IJ, Peel SA, et al. (2013) DNA Vaccine Delivered by a Needle-Free Injection Device Improves Potency of Priming for Antibody and CD8+ T-Cell Responses after rAd5 Boost in a Randomized Clinical Trial. PLoS ONE 8(4): e59340, page 9.
  • DNA is delivered as naked DNA.
  • DNA is formulated for delivery by a gene gun.
  • DNA is administered by electroporation, or by a needle-free injection technology, for example but not limited to Biojector device.
  • the DNA is inserted in vectors.
  • the DNA is delivered using a suitable vector for expression in mammalian cells.
  • the nucleic acids encoding the envelopes are optimized for expression.
  • DNA is optimized, e.g. codon optimized, for expression.
  • the invention provides nucleic acids comprising sequences encoding envelopes of the invention.
  • the nucleic acids are DNAs.
  • the nucleic acids are mRNAs.
  • the invention provides expression vectors comprising the nucleic acids of the invention.
  • the invention provides a pharmaceutical composition comprising mRNAs encoding the inventive antibodies. In certain embodiments, these are optionally formulated in lipid nanoparticles (LNPs). In certain embodiments, the mRNAs are modified. Modifications include without limitations modified ribonucleotides, poly-A tail, 5’cap. [0147] In certain aspects the invention provides nucleic acids encoding the inventive envelopes. In non-limiting embodiments, the nucleic acids are mRNA, modified or unmodified, suitable for use any use, e.g. but not limited to use as pharmaceutical compositions. In certain embodiments, the nucleic acids are formulated in lipid, such as but not limited to LNPs.
  • nucleic acid encoding an envelope is operably linked to a promoter inserted an expression vector.
  • compositions comprise a suitable carrier.
  • compositions comprise a suitable adjuvant.
  • invention provides an expression vector comprising any of the nucleic acid sequences of the invention, wherein the nucleic acid is operably linked to a promoter.
  • compositions can include an adjuvant, such as, for example but not limited to 3M052, alum, poly IC, MF-59 or other squalene-based adjuvant, ASOIB, or other liposomal based adjuvant suitable for protein or nucleic acid immunization.
  • the adjuvant is GSK AS01E adjuvant containing MPL and QS21. This adjuvant has been shown by GSK to be as potent as the similar adjuvant AS01B but to be less reactogenic using HBsAg as vaccine antigen (Leroux-Roels et al., IABS Conference, April 2013).
  • TLR agonists are used as adjuvants.
  • a plausible vaccine regimen to initiate and select for developing bnAbs would include a priming immunogen encoding, Lys327 and a boosting immunogen encoding Arg327.
  • the Arg327 boosting immunogen would optimally target the affinity maturing DH270 lineage members, while not optimally binding the DH270 antibodies that lack affinity maturation.
  • Non-limiting embodiments of vaccination regimens could include: priming with CH848.3.D0949.10.17 based envelope design also with Lys327, followed by administering of CH848.3.D0949.10.17 based envelope design with Arg327.
  • the target for HIV-1 bnAbs is the envelope (Env) spike fusion protein (Saunders et al., (2019) Science 366, eaay7199; Ward & Wilson (2015) Trends in biochemical sciences 40, 101-107; Steichen et al., (2019) Cell reports 20, 1805-1817; Torrents de la Pe ⁇ a (2017) Cell reports 20, 1805-1817).
  • the native Env is a trimer of gp120-gp41 heterodimers that are heavily shielded from the host immune systems by N-linked glycosylation and further protected from neutralization by conformational masking and considerable sequence variability.
  • V3 variable loop
  • a glycosylated region near the third variable loop (V3) of HIV-1 Env forms a supersite of vulnerability that is targeted by antibodies originating from diverse germline genes in multiple HIV-1 infected individuals (Moyo & 53 ActiveUS 200859022 Attorney Docket No.: 1234300-00423WO1 (DU7897PCT) Date of Electronic Filing: August 31, 2023 Moore (2020) Expert Opinion on Therapeutic Targets 24, 499-509).
  • the development of a broadly neutralizing V3-glycan antibody was studied in an HIV-infected African male from Malawi (CH848), who was followed from the time of infection up to 5 years after transmission (Bonsignori et al., (2017) Transl Med 9).
  • DH270 antibodies were detected in the CH848 individual at week 186 and coincided with the appearance of HIV-1 with shortened variable loop 1 (V1) (Bonsignori et al., (2017) Sci Transl Med 9).
  • the DH270 unmutated common ancestor does not neutralize heterologous HIV-1, although a single amino acid change at position 57 of the heavy chain that substituted a glycine for an arginine (G57R) resulted in heterologous HIV-1 neutralization, albeit with limited breadth.
  • G57R arginine
  • the early DH270 lineage members were able to neutralize heterologous viruses with short V1 loops.
  • HIV-1 bnAbs including those in the DH270 lineage, are enriched for key, low probability mutations (Wiehe et al., (2016) Cell host & microbe 23, 759-765.e756). Second, of the forty-two mutations in the most broad and potent member, only twelve are needed to reach ninety percent of its breadth allowing us to pinpoint the most critical regions of the antibody that need to be optimized (Swanson et al., (2021) Cell Reports 36, 109561).
  • DH270 lineage antibody Fabs [0200] The structures of several DH270 antigen binding fragments (Fabs) have been previously determined, including inferred DH270 UCAs, DH270.3, DH270.5, and DH270.6.
  • V3-glycan associated DH270.6 structure clarifies the role of individual residues critical for neutralization breadth, it does not reveal the structural pathway underlying the evolution of this breadth, nor how off-track mutations limit breadth and potency in different DH270 sub-lineages.
  • a soluble SOSIP trimer derived from a virus isolated from the CH848 individual at day 949 post infection was used for preparing complexes with DH270 lineage Fabs for structural studies.
  • Lower branch mature antibody DH270.3 (M3), and upper branch mature antibody DH270.1 (M1) and intermediate antibody I2 show several mutations clustered in or adjacent to the LCDR3 region, presumably improving interactions with the N301-glycan base (cluster (5)).
  • the lower branch mature antibody DH270.2 (M2) acquired mutations focused on cluster (1), improving interactions at the N332-glycan D1 arm in a manner similar to the I3 intermediate.
  • the I2 intermediate acquired additional mutations at clusters (3), (4), and (7).
  • DH270.5 (M5) and DH270.6 (M6) antibodies acquired several mutations near the LCDR1/V L N-terminus where interactions with the N301-glycan D arms may occur.
  • the cryo-EM reconstructions in this region were poorly resolved, precluding a precise definition of these interactions.
  • DH270 lineage maturation involved sequential affinity gain at distinct sites, and that specific structural solutions were necessary for affinity gain and development of neutralization breadth. This is exemplified in the dichotomy between neutralization gains facilitated by mutations in the lower branch and mutations gained in the upper branch.
  • the interaction of the antibody LCDR3 with the N301- glycan base was, for example, a clear target of maturation after the I3 and I4 intermediates.
  • the I5 intermediate showed further rotation about the phi dihedral in the direction of the S27Y mutation without additional changes in the theta rotation angle. Together, these results demonstrate that early mutations in the DH270 lineage facilitate improved contacts, shift the position of the antibody relative to the bound Env, and alter Env conformation particularly of the V1 loop and N301 glycan, with the angular and conformational changes further strengthening antibody-Env interactions.
  • the I5 branch point Mutations in I3 set the path toward broad neutralization.
  • Heavy chain mutations include V11M, R87T, and the improbable R98T mutation, while light chain mutations include L48Y and S54N.
  • the cryo-EM reconstruction of the I3 Fab bound Env was determined to a resolution of 4.5 ⁇ .
  • the V1 loop conformational change induced by the V H residue R57 was retained as was the interaction of V L residue Y27 with the N301-glycan ( Figures 9B, 10A and 10B). No major differences were observed in the Env structure (RMSDs ⁇ 0.9 ⁇ ; Figure 10C).
  • V L L48Y and V H R98T mutations introduce new hydrogen bonding contacts, with the Y48 hydroxyl interacting with the N332-glycan, and the release of D115 through the R98T mutation allowing closer interaction of D115 with the N332-glycan ( Figures 9C 10D).
  • the I3 V H R98T substitution introduced a hydrogen bond between the side chains of residues T98 and the V H Y27 ( Figure 10E), thus bolstering internal stability of the antibody structure by compensating for the loss of the cation-p interaction of R98 with Y27.
  • the V H R87T and V L S54N mutations are distant from the gp120-interactive region of the antibody.
  • the I4 intermediate acquired a larger number of V H mutations including two in the HCDR3, Y106V and S108Y. Consequently, Y106 is positioned closer to the Env surface relative to the Y108 in I4, resulting in N332 GlcNac-2 to I4 Y108 hydroxyl hydrogen bonding. (Figure 9F).
  • the overall fold of the HCDR3 region was not affected by these mutations ( Figure 9F).
  • the S84R mutation is in proximity to the distal sugar units of the N156-glycan. Densities for the sidechain and this portion of the N156-glycan were, however, not visible in the cryo-EM reconstruction ( Figures 10J and 10K).
  • the light chain contains two non-paratope mutations, R56W and V100I. No changes were observed at the V100I position relative to the I5 or I3.
  • Residue R59W of the I4 light chain that is adjacent to the LCDR2 region displayed a modest rearrangement that shifts the position of distal N332- glycan interactive residues (Figure 10L). This was not associated with apparent changes in antibody interactions with the glycan though it may confer stabilization of the LCDR2 loop and therefore the glycan interaction.
  • the resin was washed with 25 mL of phosphate-buffered saline (PBS) containing a total of 340 mM NaCl. Thirty mL of 10 mM glycine pH 2.4, 150 mM NaCl were used to elute the antibody off of the protein A resin.
  • the pH of the eluted antibody solution 66 ActiveUS 200859022 Attorney Docket No.: 1234300-00423WO1 (DU7897PCT) Date of Electronic Filing: August 31, 2023 was increased to approximately 7 by the addition of 1M Tris pH8.0.
  • the antibody solution was buffer exchanged into PBS with successive rounds of centrifugation, filtered, and stored at -80 °C.
  • the number and time interval between boost can be determined experimentally.
  • the envelopes in Table 1 (and optionally comprising any combinations of additional modifications, such as the modifications described in Tables 2A-B) or Table 2B will be produced under cGMP conditions as a recombinant protein and/or mRNA formulated in LNP for use in Phase I clinical trial.
  • Example 3 [0241] Despite the lengths of d0358.80.06 V1 loop (18aa) and d1432.5.41 V1 loop (24aa), their coverage of the V3-glycan site is similar to the shorter V1 loop (11aa) in d0949.10.17, leaving most of the site exposed.
  • d949 Env was shown as neutralizable by the early DH270 clones, while d358 was resistant and only neutralized by the matured bnAb.
  • a novel H-bond between R327 on V3 and the N332-GlcNAc-2 was observed in d358 where N332 acted as a protection layer.
  • the density of N332-glycan was less clear in d949 Env with a R327K mutation. This interaction was also not seen in d1432 R327 because of the I326P mutation that twisted the R327 sidechain away from the N332-glycan.
  • GDIR SEQ ID NO: 2
  • D0526.25.02 Env has an extremely long V1 loop (28aa) that binds the N332-glycan- D1-arm. Therefore, the V1 loop in d526 held the N332-glycan tighter than the V3 loop in d358 by a more optimal leverage.

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Abstract

L'invention concerne des enveloppes de VIH-1 modifiées, des compositions comprenant lesdites enveloppes modifiées, des acides nucléiques codant lesdites enveloppes modifiées, des compositions comprenant lesdits acides nucléiques, et des méthodes d'utilisation desdites enveloppes VIH-1 modifiées et/ou desdits acides nucléiques afin d'induire des réponses immunitaires.
EP23861577.7A 2022-08-31 2023-08-31 Immunogènes de vaccin contre le vih pour l'induction d'anticorps ciblant le glycane v3 Pending EP4580670A2 (fr)

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