WO2016184962A1 - Traitement de patients souffrant d'une infection par le vih - Google Patents

Traitement de patients souffrant d'une infection par le vih Download PDF

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WO2016184962A1
WO2016184962A1 PCT/EP2016/061265 EP2016061265W WO2016184962A1 WO 2016184962 A1 WO2016184962 A1 WO 2016184962A1 EP 2016061265 W EP2016061265 W EP 2016061265W WO 2016184962 A1 WO2016184962 A1 WO 2016184962A1
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hiv
immunogenic compound
peptide
group
cooh
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PCT/EP2016/061265
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Joël Crouzet
Raphaël Ho Tsong Fang
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Innavirvax
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    • 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
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • 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
    • A61K2039/55505—Inorganic adjuvants
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6037—Bacterial toxins, e.g. diphteria toxoid [DT], tetanus toxoid [TT]
    • 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
    • A61K2039/60—Medicinal preparations containing antigens or antibodies characteristics by the carrier linked to the antigen
    • A61K2039/6031—Proteins
    • A61K2039/6081—Albumin; Keyhole limpet haemocyanin [KLH]
    • 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
    • A61K2039/62—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier
    • A61K2039/627—Medicinal preparations containing antigens or antibodies characterised by the link between antigen and carrier characterised by the linker
    • 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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16122—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
    • C12N2760/00—MICROORGANISMS OR ENZYMES; COMPOSITIONS THEREOF; PROPAGATING, PRESERVING, OR MAINTAINING MICROORGANISMS; MUTATION OR GENETIC ENGINEERING; CULTURE MEDIA ssRNA viruses negative-sense
    • C12N2760/00011—Details
    • C12N2760/16011—Orthomyxoviridae
    • C12N2760/16111—Influenzavirus A, i.e. influenza A virus
    • C12N2760/16134—Use of virus or viral component as vaccine, e.g. live-attenuated or inactivated virus, VLP, viral protein

Definitions

  • This invention relates to the treatment and prevention of HIV or HIV-related conditions in individuals.
  • HIV Human Immunodeficiency Virus
  • Current therapies have succeeded in controlling the disease but long-term use of Anti-Retroviral Therapy (ART) is limited due to the nature of the viral replication cycle of those viruses, but also by issues of side effects and the availability of antivirals in developing countries.
  • ART Anti-Retroviral Therapy
  • the reservoir in HIV-infected individuals, relates to the proviral latency, which is the ability of a virus to lie dormant within a cell. Latency is the phase of the viral replication cycle in which, after initial infection, proliferation of virus particles ceases without full eradication.
  • the phenomenon of proviral latency is associated to the appearance of so-called "reservoirs" within the host, which are generally difficult to reach, and which are also one of the main reasons of the difficulty to provide with a sterilizing cure and / or a functional cure for HIV. Methods and uses for specifically targeting such "latent" reservoirs are thus actively pursued, in order to allow the patients to control their infection without antiretrovirals.
  • WO2013/179262 teaches immunogenic compounds derived from a HIV gp41 peptide, for treating a condition caused by the infection of an individual with a HIV virus. This document showed that such immunogenic compounds were able to raise antibodies having the ability to reduce the NK-induced CD4 T cell lysis in individuals infected with an HIV virus.
  • Vieillard et al. JAIDS; 61(3):403-5; 2012
  • JAIDS Vieillard et al.
  • the invention relates to an immunogenic compound comprising an antigenic peptide derived from the HIV gp41 protein, for use for treating an HIV-infected individual that is not under anti-retro viral treatment.
  • the invention further relates to vaccine compositions comprising said immunogenic compound for the uses described herein.
  • the invention relates to a vaccine composition comprising said immunogenic compound, for use for treating an HIV-infected individual that is not under anti-retroviral treatment.
  • Figure 1 Immunization Schedule.
  • A. Schedule for three injections (DO, week 4 and week 8) at 0.1 ⁇ g and 20 ⁇ g of antigenic peptide equivalent.
  • B. Schedule for three injections (DO, week 4 and week 8) at 1 ⁇ g and 10 ⁇ g of antigenic peptide equivalent, and an additional booster injection at week 24.
  • follow-up visits are scheduled at week 48, week 60, week 72 and week 84.
  • Figure 2 Dose-dependent Immunogenicity at week 12.
  • Dose- dependent evolution over time P 0.003.
  • Figure 3 Variation of the HIV DNA from baseline over time at week 60 and 84, in placebo vs non responder vs responder patients.
  • the y-axis represents the HIV DNA change from baseline in log copies per 10 6 Peripheral Blood Mononuclear Cells (PBMC). From left to right: placebo group, non-responder patients, responder patients.
  • Figure 4 Evolution of HIV DNA per million of PBMCs over time, in Responders vs Non Responders + placebo.
  • the y-axis represents the HIV DNA change from baseline in log copies per 10 6 Peripheral Blood Mononuclear Cells (PBMC).
  • PBMC Peripheral Blood Mononuclear Cells
  • the x- axis represents time, at 12, 36, 60 and 84 weeks after the first administration of the immunogenic compound.
  • Non Responders + placebos are represented by "o”.
  • Responders are represented by "+”.p values of ANOVA test for differences between the groups are shown, p corresponds to the significance of the changes from baseline
  • Figure 5 Anti-3S Dose-Dependent Change of Total HIV DNA over time at week 12, 36, 60 and 84.
  • the y-axis represents the HIV DNA change from baseline in log copies per 10 6 Peripheral Blood Mononuclear Cells (PBMC).
  • PBMC Peripheral Blood Mononuclear Cells
  • the x-axis represents the anti-3S total antibodies at the corresponding time, expressed in log A.U. A. At week 12. B. At week 36. C. At week 60. D. At week 84.
  • Figure 6 Variation of the CD4/CD8 ratio over time, in placebo vs non responder vs responder patients.
  • the y-axis represents the CD4/CD8 ratio.
  • the x-axis represents for each patient the measurements corresponding, from left to right, to the baseline (week 0) and at week 24.
  • Figure 7 Variation of the CD4 and CD8% at week 24 after injection of the immunogenic compound.
  • the present invention has for purpose to meet the aforementioned needs.
  • the present invention provides anti-HIV immunogenic compounds, and compositions thereof, comprising antigenic peptides derived from the gp41 protein of HIV, for treating an HIV-infected individual that is not under anti-retroviral treatment.
  • the invention relates to such immunogenic compounds, and/or compositions thereof, for use as a medicament; which includes compositions in the form of pharmaceutical compositions and/or vaccine compositions.
  • the invention also relates to such immunogenic compounds, and/or compositions thereof, for use as a medicament, or for the preparation of a medicament, for treating an HIV-infected individual that is not under anti-retroviral treatment.
  • HIV-1 gp41 is composed of three domains, an extracellular domain (ectodomain), a transmembrane domain and an intracellular domain (endodomain).
  • the gp41 ectodomain contains three major functional regions, i.e., the fusion peptide located at the N-terminus of gp41, followed by two 4-3 heptad repeats adjacent to the N- and C- terminal portions of the gp41 ectodomain, designated NHR (N-terminal heptad repeat) and CHR (C-terminal heptad repeat), respectively.
  • N- and C-terminal repeats are also named as "HR1" and "HR2". Both NHR and CHR regions function as essential structures required for conformational changes during the process of membrane fusion between HIV-1 and CD4+ T cells.
  • immunogenic compounds comprising an antigenic peptide derived from the gp41 protein of a HIV virus can both (i) reduce Peripheral Blood Mononuclear Cells (PBMC)-associated HIV DNA levels in HIV-infected individuals, and/or (ii) maintain or restore T cell homeostasis and thus high level of CD4 + T cell count.
  • PBMC Peripheral Blood Mononuclear Cells
  • PBMCs Peripheral Blood Mononuclear Cells
  • the total cell-associated HIV DNA has been recently proposed as a standardized clinical marker for measuring HIV reservoirs in HIV-infected individuals. Most notably, it has been recently determined that this value represents the global capacity of the reservoirs to produce virus over time.
  • HIV DNA is a distinct marker from HIV RNA. HIV DNA is expressed as a number of copies per 10 6 PBMCs, and is indicative of the integration of the HIV genome in cellular "reservoirs", which includes CD4 + T cells. Although distinct, HIV-DNA levels are positively correlated to HIV-RNA and negatively to CD4 + T cell count. Thus, high HIV DNA is also indicative of the progression to low CD4 counts, to AIDS, and ultimately to death. It is also predictive of progression to immunodeficiency when measured at the time of primary infection. Thus, HIV-DNA is also a marker that may contribute to decide early treatment initiation and is predictive of the status of the infection, in particular in the absence of anti-retroviral treatment.
  • the inventors have further shown in the examples that the administration of an immunogenic compound comprising an antigenic peptide derived from gp41 in HIV- infected individuals, lead to an increase of the CD4/CD8 ratio in the responder group, 24 weeks after the first injection.
  • the CD4/CD8 is established as an indicator of immune system health, and thus its restoration and/or increase is indicative of immune restoration (Serrano- Villar et al, PLOS Pathogens, vol 10, 2014).
  • the term “comprising” encompasses “consisting of.
  • the terms “patient” and “individual” encompass humans and non-human animals, which includes non-human mammals, and/or any organism that is prone to HIV infection.
  • « preventing » also encompasses « reducing the likelihood of occurrence » or « reducing the likelihood of reoccurrence »
  • an "anti-retroviral agent” or “anti-retroviral treatment” or more specifically an “anti-HIV agent” or “anti-HIV treatment” relates to the administration of a compound, or combination of compounds, for fighting HIV infection.
  • the expressions "increased” and “decreased” are understood as relative values, determined based on a reference value established before in a same or similar individual, for instance at a previous stage of the disease. They may be determined over a variable length of time, as long as such length is clinically significant for assessing a variation in said individual.
  • the invention relates to an immunogenic compound comprising an antigenic peptide derived from the gp41 protein of an HIV virus, for use for treating an HIV-infected individual that is not under anti-retroviral treatment.
  • the immunogenic compound is being administered for a time suitable for establishing and also sustaining an antibody response in said individual.
  • the determination of an antibody response can be established by determining the presence in said individual of antibodies directed against said antigenic peptide.
  • the detection of an antibody response directed against the said antigenic peptide derived from the HIV gp41 protein may be conventionally performed, for example by using an ELISA assay.
  • the results of the ELISA assay are analyzed against a control curve generated by using a serial of anti- antigenic peptide antibodies at known dilutions or at known concentrations.
  • HIV viral load or “HIV viral titer” generally refers to:
  • the immunogenic compounds of the invention can be administered to HIV-infected individuals not under anti-retroviral treatment; wherein said individuals are characterized by:
  • PBMC Peripheral Blood Mononuclear Cells
  • the immunogenic compounds of the invention can be administered to HIV-infected individuals for reducing the PBMC-associated HIV DNA level.
  • the invention relates to an immunogenic compound comprising an antigenic peptide derived from the gp41 protein of an HIV virus for its use as defined above, for reducing HIV reservoirs.
  • the invention relates to an immunogenic compound comprising an antigenic peptide derived from the gp41 protein of an HIV virus for its use as defined above, for reducing or controlling the PBMC- associated HIV DNA level before initiation of an anti-retroviral treatment in said individual.
  • the invention relates to an immunogenic compound comprising an antigenic peptide derived from the gp41 protein of an HIV virus for its use as defined above, for treating or preventing or delaying a rebound of HIV viral loads in said individual, for instance after termination of an anti-retroviral treatment.
  • the invention relates to an immunogenic compound comprising an antigenic peptide derived from the gp41 protein of an HIV virus for its use as defined above, for reducing the likelihood of rebound of HIV viral loads in said individual.
  • the invention relates to a vaccine composition, comprising at least one immunogenic compound comprising an antigenic peptide derived from the gp41 protein of an HIV virus for a use as defined above.
  • the invention relates to a vaccine composition comprising said immunogenic compound, for use for treating an HIV-infected individual that is not under anti-retroviral treatment.
  • An immunogenic compound comprising an antigenic peptide derived from the gp41 protein of a HIV virus can also be used for the preparation of any composition, in particular any pharmaceutical composition and/or vaccine composition for a use as defined above.
  • HIV infection encompasses the infection of a host animal, particularly a human host, by the HIV virus, including type 1 human immunodeficiency virus (HIV-1).
  • HIV may include HIV-I, HIV-2 and all forms, subtypes, clades and variations thereof, which includes HIV-I strains belonging to the HIV-I B subtype, HIV-I C subtype, and HIV-I recombinants.
  • the HIV virus is HIV-I.
  • HIV-1 can be used herein to refer to any strains, forms, subtypes, clades and variations in the HIV- 1 family.
  • HIV-related condition encompasses any symptom or set of symptoms commonly found in HIV-infected patients, including symptoms belonging to conditions associated with AIDS (Acquired Immune Deficiency Syndrome).
  • a carrier of HIV-1 may be identified by any methods known in the art. For example, a person can be identified as an HIV- 1 carrier on the basis that the person is anti- HIV-1 antibody positive, or is HIV-1 -positive, or has symptoms of AIDS. That is, "treating HIV-1 infection” should be understood as treating a patient who is at any one of the several stages of HIV infection progression, in particular HIV-1, infection progression.
  • an "HIV-infected individual not under anti-retroviral treatment” encompasses any HIV-infected individual that is not under anti-retroviral treatment at the time of the administration of said immunogenic compound, which includes any HIV-infected individual that has never been under anti-retroviral treatment for treating said HIV infection.
  • the HIV-infected individuals which are specifically considered by the invention are HIV-infected individuals who are not under anti-retroviral treatment at the time of the administration of said immunogenic compound, which includes HIV-infected individuals who have never been under anti-retroviral treatment for the purpose of treating said HIV infection.
  • HIV-infected individuals not under anti-retroviral treatment differ from the broader category of HIV-infected individuals under retroviral treatment, because of the fact that the viral replication is active and that they exhibit distinct biological markers of HIV infection.
  • An anti-retroviral treatment may also comprise the administration of at least one drug selected from: ART (Antiretroviral Therapy), HAART (Highly Active Antiretro viral Therapy).
  • ART Antiretroviral Therapy
  • HAART Highly Active Antiretro viral Therapy
  • ART and HAART are known in the Art and generally relate to combinations of two, three or more antiretroviral medicines.
  • antiretroviral medicines encompass:
  • nucleoside/nucleotide reverse transcriptase inhibitors also called nucleoside analogs, such as abacavir, emtricitabine, and tenofovir;
  • NRTIs n- nucleoside reverse transcriptase inhibitors
  • protease inhibitors such as atazanavir, darunavir, and ritonavir
  • entry inhibitors such as enfuvirtide and maraviroc
  • integrase inhibitors such as dolutegravir and raltegravir.
  • anti-retroviral treatments include, in a non-limitative manner, the administration of at least one drug selected from: Zidovudine, Lamivudine, Emtricitabine, Didanosine, Stavudine, Abacavir, Zalcitabine, Tenofivir, Racivir, Amdoxovir, Apricitabine, Elvucitabine, Efavirenz, Nevirapine, Etravirine, Delavirdine, Rilpvirine, Tenofovir, Fosalvudine, Amprenavir, Tipranavir, Indinavir, Saquinavir, Fosamprenavir, Ritonavir, Darunavir, Atazanavir, Nelfinavir, Lopinavir, Raltegravir, Elvitegravir, Dolutegravir, Enfuvirtide, Maraviroc, Vicriviroc, and combinations thereof.
  • at least one drug selected from: Zidovudine, Lamivudine, Emtricitabine,
  • it may be an HIV-infected individual not under an anti-retroviral treatment comprising the administration of at least one drug selected from: ART (Antiretro viral Therapy) and HAART (Highly Active Antiretro viral Therapy), and combinations thereof.
  • ART Antiretro viral Therapy
  • HAART Highly Active Antiretro viral Therapy
  • it may be an HIV-infected individual who has never been under an anti-retroviral treatment comprising the administration of at least one drug selected from: ART (Antiretro viral Therapy) or HAART (Highly Active Antiretroviral Therapy), and combinations thereof
  • the first stage is referred herein as the "acute infection stage, or the "acute primary infection syndrome” (which can be asymptomatic or associated with an influenza- like illness with fevers, malaise, diarrhoea and neurologic symptoms such as headache).
  • This stage generally corresponds to the period which extends from day 1 to about 1 to 3 months after HIV infection.
  • large amounts of virus are produced, thereby increasing the viral load (or HIV RNA level) in the HIV-infected individual.
  • the CD4 cell count may also decrease rapidly to low levels.
  • the viral load or HIV RNA
  • the median of HIV-DNA levels in individuals with a primary infection is generally higher than at a chronic state.
  • a "primo-infected" individual refers in particular to an HIV- infected individual in the early stages of the infection, who has generally been contaminated within a period of less than one year, which includes less than 6 months or even less than 3 months.
  • the HIV-infected individual not under anti- retroviral treatment is a primo- infected individual.
  • the second stage is referred herein as the "clinical latency stage” or "asymptomatic infection”.
  • This stage generally corresponds to the stage where the HIV- infected individual is asymptomatic, and where the disease enters into its chronic state.
  • the viral load or HIV RNA
  • This stage is highly variable in length, and depends on multiple factors, such as the nature of the HIV strain, the efficacy of a treatment, host factors and so on. It may last for years, in particular if the individual previously had been under anti-retroviral treatment.
  • the HIV-infected individual not under anti- retroviral treatment is an individual at the asymptomatic infection stage.
  • the third stage is referred herein as the "AIDS phase". It corresponds to the symptomatic stage, wherein the HIV-infected individual exhibits an HIV-related condition, including symptoms belonging to the condition that is generally known as AIDS. It also corresponds to the stage, where the viral load increases up to high levels, while the CD4 + T cell count drops well below a physiological level, in particular below 200 cells/mm 3 . This stage also corresponds to a life-threatening stage, in the absence of treatment. All the HIV-infected individuals belonging to the above-mentioned stages are considered by the invention.
  • the HIV-infected individuals not under anti-retroviral treatment can be further characterized based on distinct biological markers at the time of the administration of said immunogenic compound.
  • HIV-infected individuals according to the invention may be further characterized by a high or increased CD4+ cell count, optionally above 350 per mm 3 of blood plasma at the time of the administration of said immunogenic compound, which includes above 350, 400, 450, 500, 550, 600, 650, and 700 per mm 3 of blood plasma at the time of the administration of said immunogenic compound.
  • HIV-infected individuals according to the invention may be further characterized by a high or increased viral load, optionally, above 1000 HIV RNA copies / mL of blood plasma, at the time of the administration of said immunogenic compound; which includes above 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000 and 10000 HIV RNA copies / mL of blood plasma, at the time of the administration of said immunogenic compound.
  • HIV-infected individuals may be further characterized by a high or increased Peripheral Blood Mononuclear Cells (PBMC)- associated HIV DNA level, optionally above 1000 copies per 10 6 PBMCs, at the time of the administration of said immunogenic compound; which includes above 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 20000, 30000, 40000 and 50000 copies per 10 6 PBMCs, at the time of the administration of said immunogenic compound.
  • PBMC Peripheral Blood Mononuclear Cells
  • PBMC Peripheral Blood Mononuclear Cells
  • the HIV-infected individuals not under anti-retroviral treatment are characterized by a high or increased CD4+ cell count, optionally above 350 per mm 3 of blood plasma at the time of the administration of said immunogenic compound; which includes above 500 per mm 3 of blood plasma at the time of the administration of said immunogenic compound.
  • HIV-infected individuals not under anti- retro viral treatment are characterized by:
  • HIV-infected individuals not under anti- retro viral treatment are characterized by:
  • PBMC Peripheral Blood Mononuclear Cells
  • HIV DNA level optionally above 10000 copies per 10 6 PBMCs, at the time of the administration of said immunogenic compound
  • HIV-infected individuals not under anti- retro viral treatment are characterized by:
  • PBMC Peripheral Blood Mononuclear Cells
  • the "HIV viral load” relates to the number of copies of HIV RNA per mL of blood plasma and is expressed in HIV RNA copies per mL of blood plasma, according to known methods, which includes nucleic acid-based tests such as reverse- transcriptase polymerase chain reaction (RT-PCR), branched DNA (bDNA), or nucleic acid sequence-based amplification (NASBA) analysis.
  • RT-PCR reverse- transcriptase polymerase chain reaction
  • bDNA branched DNA
  • NASBA nucleic acid sequence-based amplification
  • HIV viral load test is ordered when a person is first diagnosed.
  • the test results function as a baseline measurement that shows how actively the virus is reproducing.
  • the HIV viral load test is then performed over time and compared to said baseline measurement or to a reference value, in order to assess a relative variation of the HIV viral load.
  • conventional methods for determining HIV viral load include:
  • RNA iii determining the number of copies of HIV RNA per milliliter of plasma, for example, by reverse-transcriptase polymerase chain reaction (RT-PCR), branched DNA (bDNA), or nucleic acid sequence-based amplification (NASBA) analysis.
  • RT-PCR reverse-transcriptase polymerase chain reaction
  • bDNA branched DNA
  • NASBA nucleic acid sequence-based amplification
  • step (iv) optionally comparing the result obtained at step (iii) with a reference value and/or a baseline measurement.
  • HIV RNA level is low (for example, below 500 HIV RNA copies/mL of plasma), this is indicative that the virus may not be actively replicating and the disease may progress more slowly.
  • a low viral load is usually below 1000 HIV RNA copies/mL of plasma; which includes between 20 and 500 copies/mL of plasma, or 40 to 500 copies/mL of plasma, depending on the type and sensitivity of the test that is used. This result indicates that HIV is not actively reproducing and that the risk of disease progression is low.
  • a low viral load may consist of a viral load below 500 HIV RNA copies/mL of plasma; which includes below 450, 400, 350, 300, 250, 200, 150, 100, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, and 1 HIV RNA copies/mL.
  • a high viral load may consist of a viral load above 1000 HIV RNA copies/mL of plasma; which includes above 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 20000, 30000, 40000, 50000, 60000, 70000, 80000, 90000 and 100000 HIV RNA copies/mL of plasma.
  • An undetectable viral load for routine methods is generally below 40 copies/mL of plasma, which includes 20 copies/mL of plasma, in particular when measured with a method and/or kits selected from: COBAS® AmpliPrep/COBAS® TaqMan® HIV-1 Test and COBAS® AMPLICOR HIV-1 MONITOR Test sold by Roche Molecular Diagnostic or NucliSENS EasyQ®HIV-l sold by Biomerieux Diagnostics.
  • an undetectable viral load in a patient with diagnosed HIV infection does not mean that the patient is cured; it means only that the level of HIV RNA is currently below the limit of detection of the technique. What is more, an undetectable viral load does not necessarily rule out the presence of HIV in latent reservoirs.
  • Changes in viral load are generally more important during HIV monitoring than obtaining a single test result.
  • An increasing viral load indicates either that the infection is getting worse or that the virus has developed resistance to the drugs that are being used for therapy and are no longer effective.
  • a decreasing viral load indicates improvement, treatment effectiveness, and a decrease in HIV replication.
  • a high CD4+ T cell count may correspond to a physiological (or
  • CD4+ T cell count which includes equal or superior to 350 CD4+ cells/mm 3 of plasma, which generally varies between 500 and 1500 CD4+ T cells/mm 3 of plasma, though it may be lower for some individuals.
  • an increased, or restored, CD4+ T cell count may correspond to an increase in the CD4+ T cell count, compared to the CD4+ T cell count before the administration of said immunogenic compound.
  • a low CD4+ T cell count includes a CD4+ T cell count inferior to 350 / mm 3 in blood plasma, which includes inferior to 350, 300, 250, 200, 150, 100 and 50 / mm 3 in blood plasma.
  • a high CD4+ T cell count includes a CD4+ T cell count superior to 350 / mm 3 in blood plasma, which includes superior to 350, 400, 450, 500, 550, 600, 650, 700, 750, 800, 850, 900, 950, 1000, 1100, 1200, 1300, 1400 and 1500 CD4+ T cells/mm 3 of plasma.
  • a low PBMC-associated HIV DNA level may consist of an HIV DNA level below 1000 HIV DNA copies per million of PBMCs; which includes below 500, 450, 400, 350, 300, 250, 200, 150, 100, 50, 40, 30, 20, 10, 9, 8, 7, 6, 5, 4, 3, 2, and 1 copie(s) per million of PBMCs.
  • a high PBMC-associated HIV DNA level includes above 1000 HIV DNA copies per million of Peripheral Blood Mononuclear Cells (PBMCs); which includes above 1000, 2000, 3000, 4000, 5000, 6000, 7000, 8000, 9000, 10000, 50000 and 100000 HIV DNA copies per million of PBMCs.
  • PBMCs Peripheral Blood Mononuclear Cells
  • PBMCs are known in the Art and refer to blood cells having a round nucleus, which includes lymphocytes (including T cells), monocytes and macrophages.
  • Protocols for isolating PBMCs are known in the Art.
  • PBMCs are separated from whole blood on FicoU-Hypaque so as to obtain a PBMC extract; the amount of total DNA is then quantified by real-time PCR from said PBMC extract.
  • the PBMC-associated HIV DNA level is preferably determined according to the protocols disclosed in Rouzioux et al. ("Quantification of total HIV1- DNA in peripheral blood mononuclear cells"; Methods Mol. Biol; 1087:261-70; 2014), and as further detailed in the Material & Methods section.
  • HIV-DNA levels are then reported in copies per million of PBMCs for total DNA extracted from PBMCs isolated by FicoU-Hypaque.
  • Each one of the above-mentioned parameters defines a sub-group of HIV- infected individuals not under anti-retroviral treatment. However, those groups are not mutually exclusive, and can be further combined.
  • Immunogenic compounds of the invention consist of compounds comprising an antigenic peptide derived from the gp41 protein of a HIV virus.
  • the antigenic peptide is a peptide derived from the gp41 protein and located between the N-terminal heptad repeat 1 (HR1) and the HR2 regions.
  • the peptide sequence SEQ ID N°l is provided, which corresponds to an antigenic peptide fragment of gp41 located between the N-terminal heptad repeat 1 (HR1) and the HR2 regions.
  • the antigenic peptide is a peptide derived from the gp41 protein, and comprising at least one fragment of gp41 derived from the amino acid sequence SEQ ID N°l or 2; or of a functionally equivalent sequence thereof.
  • the immunogenic compound comprises an antigenic peptide derived from the gp41 protein of a HIV virus; said antigenic peptide comprising 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, or 50 (preferably consecutive) amino acids from the amino acid sequence SEQ ID N°l, or of a functionally equivalent sequence thereof.
  • the antigenic peptide is a peptide derived from the gp41 protein and located between the HRl and HR2 regions, and comprising at least 1, 2, 3, 4, 5 or 6 amino acids of the well-conserved 3S motif, also referred herein as the "SWSNKS" motif (SEQ ID N°2) when considering a reference gp41 protein isolated from HIV strains, including naturally-occuring and no n- naturally occuring HIV strains, such as R5 and X4 HIV-1 strains.
  • SWSNKS well-conserved 3S motif
  • antigenic peptides derived from the gp41 protein of strains obtained from HIV-infected patients are considered as functionally equivalent sequences in the sense of the invention, such as the ones disclosed in Curriu et al. ( « Viremic HIV infected individuals with high CD4 T cells and functional envelope proteins show anti-gp41 antibodies with unique specificity and function ; PLoS one ;7(2) ; 2012).
  • the antigenic peptide derived from the gp41 protein of a HIV virus comprises the amino acid sequence:
  • - X 2 is selected from the group consisting of W (Tryptophane) and A (Alanine),
  • - X3 is selected from the group consisting of K (Lysine) and R (Arginine),
  • the antigenic peptide derived from the gp41 protein of a HIV virus comprises at least 6 consecutive amino acids derived from the said gp41 protein, which includes at least 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50 consecutive amino acids derived from the said gp41 protein, or of a functionally equivalent sequence thereof.
  • the antigenic peptide derived from the gp41 protein of a HIV virus comprises from 5 to 100 amino acids of the said gp41 protein; which includes 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67?
  • the antigenic peptide derived from the gp41 protein of a HIV virus as defined above is preferably at least 6 amino acids long.
  • Immunogenic compounds suitable for the invention are notably disclosed in WO2004/070385, WO2005/076001, WO 2012140620 and WO2013/179262.
  • the immunogenic compound is a compound as defined above, wherein the said antigenic peptide derived from gp41 is of the formula (I) :
  • PepNt consists of a polypeptide having an amino acid length varying from 0 to 20 amino acid residues and located at the N-terminal end of the polypeptide of formula (I);
  • - CORE consists of a polypeptide comprising the amino acid sequence:
  • - X 2 is selected from the group consisting of W (Tryptophane) and A (Alanine)
  • - X3 is selected from the group consisting of K (Lysine) and R (Arginine)
  • - X 4 is selected from the group consisting of S (Serine) and T (Threonine), and - "PepCt” consists of a polypeptide having an amino acid length varying from 0 to 20 amino acid residues and located at the C-terminal end of the polypeptide of formula (I).
  • the antigenic peptide derived from the gp41 protein of a HIV virus, as defined above, or alternatively the CORE of said antigenic peptide of formula (I), comprises the amino acid sequence selected from:
  • « PepNt » consists of a peptide having from 1 to 10 amino acid residues in length, which includes from 1 to 5 amino acid residues in length.
  • Nt is a peptide having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues in length.
  • « PepNt » comprises or consists of the amino acid sequence NH2-PWNA-COOH (SEQ ID N°7).
  • « PepCt » consists of a peptide having from 1 to 10 amino acid residues in length, which includes from 1 to 5 amino acid residues in length.
  • Ct is a peptide having 1, 2, 3, 4, 5, 6, 7, 8, 9 or 10 amino acid residues in length. In some embodiments, Ct has 5 or 6 amino acid residues in length.
  • « PepCt » comprises or consists of the amino acid sequence NH2-LDDIW-COOH (SEQ ID N° 8).
  • the said antigenic peptide is of the following formula (II) : NH 2 - [Nt] y -P-W-N-Xi-S-X 2 -S-N-X3 -X4-X5-X6-X7-I-W-[Ct] z-COOH (II), wherein :
  • - y is an integer meaning 0 or 1
  • - Nt consists of a peptide having from 1 to 16 amino acids in length
  • - Ct consists of a peptide having from 1 to 15 amino acids in length
  • - Xi is an amino acid selected from the group consisting of A (Alanine), T (threonine), S (Serine) and N (Asparagine),
  • - X 2 is an amino acid selected from the group consisting of W (Tryptophane) and A (Alanine),
  • - X 3 is selected from the group consisting of K (Lysine) and R (Arginine),
  • - X 4 is selected from the group consisting of S (Serine) and T (Threonine),
  • - X 5 is selected from the group consisting of L (Leucine), Y (Tyrosine) and Q (Glutamine),
  • - X 6 is selected from the group consisting of D (Aspartic acid), N (Asparagine), E (Glutamic acid), S (Serine), G (Glycine) and K (Lysine),
  • the antigenic peptide derived from gp41 may comprise at least one fragment of any one of any one of 3S regions of gp41 disclosed in Curriu et al. ("Viremic HIV infected individuals with high CD4 T cells and functional envelope proteins show anti-gp41 antibodies with unique specificity and function" ; PLoS one ;7(2) ; 2012), especially in Table 1 and Figure 3A of Curriu.
  • the antigenic peptide may be selected from the group consisting of:
  • - m is an integer meaning 0 or 1
  • - n is an integer meaning 0 or 1
  • - Al is an amino acid residue
  • - A2 is an amino acid residue.
  • the antigenic peptide is selected from the group consisting of the following formulae (Ilia) and (Illb) :
  • - m is an integer meaning 0 or 1
  • - n is an integer meaning 0 or 1
  • - Al is an amino acid residue
  • - A2 is an amino acid residue.
  • the immunogenic compound further includes amino acids which are not derived from gp41.
  • the C- and/or N-terminal ends of a peptide of formula (I) could deviate from the natural sequences expressly specified herein by modification of the terminal NH 2 - group and/or COOH-group and/or by modification of a NH 2 group and/or a COOH group of a lateral chain of an amino acid residue contained therein.
  • These groups may for instance be acylated, acetylated, amidated or modified to provide a binding site for a carrier molecule.
  • amino acids may be added to the N-terminal end of the antigenic peptide such as cysteines.
  • the immunogenic compound comprises an antigenic peptide selected from the group consisting of
  • the 3S peptide of SEQ ID N°9 was previously identified as a candidate anti- HIV antigen by Vieillard et al. (Vieillard et al., 2008, PNAS, Vol. 105 (6) : 2100-2104).
  • any one of the above-mentioned antigenic peptides is linked to a carrier molecule.
  • carrier molecules used for generating an immunogenic product comprising a polypeptide of formula (I) linked to a carrier molecule are well in the general knowledge of the one skilled in the art.
  • the function of the carrier molecule is to provide cytokine help (or T-cell help) in order to enhance the immune response against HIV- 1.
  • the carrier molecule to which the peptide is optionally bound can be selected from a wide variety of known carriers.
  • carrier molecules for vaccine purposes encompass proteins such as human or bovine serum albumin and keyhole limpet haemocyanin (KLH) and fatty acids.
  • KLH keyhole limpet haemocyanin
  • Other embodiments of carrier molecules to which an antigenic peptide of formula (I) may be covalently linked include bacterial toxins or toxoids, such as diphtheria, cholera, E. coli heat labile or tetanus toxoids, the N.
  • the carrier molecule is an amine- containing carrier protein.
  • the antigenic peptide is covalently bound to the carrier molecule by its N-terminal end amino acid residue.
  • the carrier molecule is a CRM197 protein, of sequence SEQ ID N°ll, as described for instance in WO2013/179262.
  • the CRM 197 protein consists of a non- toxic mutant of the well- known diphtheria toxin, which mutant was initially described by Uchida et al. (1973, J. Biol. Chem., Vol. 248 : 3838-3844).
  • the CRM197 mutant protein was initially described as the translation product of the mutant tox97 gene where a G— »A transition led to the substitution of the glycine (G) residue at position 52 of the wild-type diphtheria toxin with a glutamic acid residue (E).
  • the amount of antigenic peptide linked to one carrier molecule is measured preferably by Amino Acid Analysis.
  • This method is the methodology conventionally used to determine the amino acid composition of proteins. Proteins are macromolecules consisting of covalently bonded amino acid residues organized as a linear polymer. The peptide bonds are broken upon incubation under acid condition leading to the release of amino acids. An amino acid analysis is then performed on the product of the hydrolysis.
  • Amino Acid Analysis is preferably used to determine the rate of coupling of the antigenic peptide on a carrier molecule such as CRM197. This was possible since some amino acids may be both present on the carrier molecule and the grafted peptides and others may be only present on the carrier molecule. Based on the results of the amino acids present, a calculation allowed to determine the coupling ratio of the peptide of formula (I) onto CRM 197.
  • RP-HPLC reverse phase high pressure liquid chromatography
  • this instrument has a pre- or post-column derivatization capability and the detector is an ultraviolet-visible or fluorescence detector depending on the derivatization method used.
  • An integrator is used for the transforming the analog signal from the detector and for quantitation of each amino acid.
  • the quantification method of reference herein of the peptide-protein conjugates is performed by integration of the monomer peak at 215 nm obtained by isocratic SE-HPLC in 50 mM phosphate buffer pH6.8 using a Phenomenex column (BioSep SEC S2000) at a defined flow.
  • the determination of the protein content can also be made by other methods such as BCA assay using the BCA Protein Assay Kit (Thermo Scientific), which is not a reference method herein.
  • This kit is a detergent-compatible bicinchoninic acid formulation for the colorimetric detection and quantification of total protein.
  • BSA is used as the reference material in the protein determination.
  • Absorbance at 562nm is linear with increasing protein concentrations. The inventors have shown that quantifying the peptide- protein conjugates by this method lead to a reduced quantification value in respect to the reference method described above, i.e. a value of around 0.8 times the quantification value found with the reference method described above.
  • the said antigenic peptide is covalently bound to the carrier molecule through a linker moiety.
  • the said restricted family of linker agents encompasses, or even consists of, the linker agents named GMBS, sulfo-GMBS, SMPB and sulfo-SMPB.
  • the said linker agent is selected form the group consisting of GMBS ( ⁇ -[ ⁇ - maleimidobutyryl-oxy]succinimide ester), Sulfo-GMBS (N-[Y-maleimidobutyryl- oxy]sulfosuccinimide ester), SMPB (succinimidyl 4-[/?-maleimidophenyi]butyrate) and Sulfo-SMPB (sulfo succinimidyl 4-[/?-maleimidophenyl]butyrate).
  • GMBS ⁇ -[ ⁇ - maleimidobutyryl-oxy]succinimide ester
  • Sulfo-GMBS N-[Y-maleimidobutyryl- oxy]sulfosuccinimide ester
  • SMPB succinimidyl 4-[/?-maleimidophenyi]butyrate
  • Sulfo-SMPB sulfo succinimidyl 4-[/?-maleimidoph
  • GMBS N- hydroxysuccinimide
  • Sulfo-GMBS Sulfo-GMBS
  • SMPB Sulfo-SMPB
  • GMBS, Sulfo-GMBS, SMPB and Sulfo-SMPB consist of heterobifunctional linker agents that contain both a N- hydroxysuccinimide (NHS) ester group and a maleimide group.
  • NHS N- hydroxysuccinimide
  • Conjugation using GMBS, Sulfo-GMBS, SMPB or Sulfo-SMPB is usually performed by a two-step procedure.
  • the amine-containing protein e.g. CRM197
  • the linker agent e.g. a several-fold molar excess of the linker agent at pH 7-9 to form amide bonds, followed by removal of excess non-reacted linker agent, usually by desalting or dialysis.
  • the sulfhydryl-containing molecule e.g. peptide of formula (I)
  • the maleimide groups already attached to the first protein e.g. free maleimide groups of the linker chain that is already covalently linked to CRM197
  • SMPB or Sulfo-SMPB as linker agents for covalently linking peptides of formula (I) to the amine-containing carrier protein, in particular the CRM 197 carrier protein, leads to a conjugate of formula (VII) below:
  • - Rl consists of one reactive group of the amine-containing carrier protein, and wherein the NH group attached thereto derives from (i) the alpha amino group located at the N-terminal end of the amine-containing carrier protein or (ii) a lateral chain amino group from a Lysine (K) amino acid residue of the amine-containing carrier protein.
  • - R2 consists of a peptide of formula (I), and wherein the sulphur (S) atom attached thereto derives from a sulfhydryl (SH) group of a cysteine residue located at the N-terminal end or at the C-terminal end of a peptide of formula (I).
  • S sulphur
  • SH sulfhydryl
  • the sulfhydryl moiety could be part of an unnatural amino acid, or any other molecule present at the end of the peptide of formula (I).
  • GMBS or Sulfo-GMBS as linker agents for covalently linking peptides of formula (I) to the amine-containing carrier protein, in particular the CRM 197 carrier, protein leads to a conjugate of formula (VIII) below:
  • - Rl consists of one reactive group of the amine-containing carrier protein, and wherein the NH group attached thereto derives from (i) the alpha amino group located at the N-terminal end of the amine-containing carrier proteinor (ii) a lateral chain amino group from a Lysine (K) amino acid residue of the amine-containing carrier protein.
  • R2 consists of a peptide of formula (I), and wherein the sulphur (S) atom attached thereto derives from a sulfhydryl (SH) group of a cysteine residue located at the
  • a peptide of formula (I) N-terminal end or at the C-terminal end of a peptide of formula (I).
  • the sulfhydryl moiety could be part of an unnatural amino acid, or any other molecule present at the end of the peptide of formula (I).
  • an amine-containing carrier protein such as the
  • CRM197 protein comprises a plurality of reactive groups Rl, so that a plurality of peptides of formula (I) may be linked to CRM 197 in a conjugate of formula (VII) or (VIII).
  • an immunogenic compound as defined above are those wherein a plurality of reactive groups of the amine-containing carrier protein, in particular CRM 197, are covalently linked to an antigenic peptide, which peptide generally possesses a cysteine residue at its N-terminal end, according to the covalent linkage represented by formula (VII) or (VIII) above.
  • a mean number of antigenic peptides ranging from 2 to 20 are covalently linked to one molecule of CRM 197.
  • a mean number of from 5 to 10 antigenic peptides which includes a mean number of from 7-8 peptides of formula (I), are covalently linked to one molecule of CRM 197.
  • This invention also relates to compositions comprising an immunogenic compound as defined above, in combination with one or more immuno adjuvant substances.
  • composition as defined herein which comprises an immunogenic compound as defined above, and which further comprises one or more immuno -adjuvant substances may also be termed an "immunogenic composition” or alternatively a “vaccine composition” in the present specification.
  • an immunogenic composition according to the invention there is no substantial distinction to be made between an immunogenic composition according to the invention and a vaccine composition according to the invention, beyond the terms employed to designate such compositions, excepted that the features of the vaccine composition shall comply with the technical requirements of the various drug agencies for the grant of marketing authorizations for human or veterinary use.
  • an immunogenic composition according to the invention may not comply to the requirements of drug agencies while being usable for administration to animals, e.g. for producing antibodies in a given individual, wherein the generated antibodies are expected to exert a preventive or a therapeutic effect in the HIV-infected individual.
  • compositions according to the invention encompass both (i) immunogenic compositions and (ii) vaccine compositions.
  • an immuno adjuvant may be selected form the group consisting of (i) mineral salts, (ii) emulsions, (iii) microbial natural or synthetic derivatives, (iv) combination adjuvants, (v) cytokine-derived or accessory molecules- derived adjuvants, and (vi) particulate formulations. Accordingly, lists of suitable immunoadjuvants have been described in the Art, and especially in WO2013/179262 which provides a complete list of immunoadjuvants suitable for preparing compositions of the invention.
  • emulsion-based immunoadjuvants are also selected from the group consisting of MontanideTM (SEPPIC) adjuvants, including Montanide ISA 51 which is a water- in-oil stabilized emulsion, and (4) ISA-720 which is a stabilized composition comprising water and squalene.
  • SEPPIC MontanideTM
  • ISA 51 which is a water- in-oil stabilized emulsion
  • ISA-720 which is a stabilized composition comprising water and squalene.
  • Immunogenic compositions of the invention preferably include a pharmaceutically acceptable carrier.
  • Suitable pharmaceutically acceptable carriers and/or diluents include any and all conventional solvents, dispersion media, fillers, solid carriers, aqueous solutions, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like.
  • Suitable pharmaceutically acceptable carriers include, for example, one or more of water, saline, phosphate buffered saline, dextrose, glycerol, ethanol and the like, as well as combinations thereof.
  • Pharmaceutically acceptable carriers may further comprise minor amounts of auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody.
  • auxiliary substances such as wetting or emulsifying agents, preservatives or buffers, which enhance the shelf life or effectiveness of the antibody.
  • the preparation and use of pharmaceutically acceptable carriers is well known in the art. Except insofar as any conventional media or agent is incompatible with the active ingredient, use thereof in the immunogenic compositions of the present invention is contemplated.
  • Such immunogenic compounds, and compostions thereof can be administered parenterally, e.g., by injection, either by subcutaneous, intradermal or intramuscular route, as well as orally or intranasally.
  • Other modes of administration employ oral formulations, pulmonary formulations, suppositories, and transdermal applications, for example, without limitation.
  • Oral formulations include such normally employed excipients as, for example, pharmaceutical grades of mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, and the like, without limitation.
  • the immunogenic compounds, and compositions thereof are administered parenterally, and most preferably intramuscularly.
  • an amount of antigenic peptide is expressed as "antigenic peptide equivalent" , which consists of the amount of antigenic peptide that is contained in the considered immunogenic compound material.
  • the antigenic peptide equivalent when the antigenic peptide is coupled to a carrier molecule, the antigenic peptide equivalent only corresponds to the amount of antigenic peptide present and does not include the amount of other ingredients that are effectively administered.
  • an immunogenic compound, or composition thereof, used according to the invention comprises an antigenic peptide of the invention in an amount which is adapted to the administration of from 10 ng to 10 mg of the said antigenic peptide to an individual in need thereof, when expressed as an antigenic peptide equivalent.
  • an equivalent amount of an antigenic peptide of from 10 ng to 10 mg encompasses an amount of peptide of about 20 ng, 30 ng, 40 ng, 50 ng, 60 ng, 70 ng, 80 ng, 90 ng, 100 ng, 150 ng, 200 ng, 250 ng, 300 ng, 350 ng, 400 ng, 450 ng, 500 ng, 550 ng, 600 ng, 700 ng, 800 ng, 900 ng, 1 ⁇ g, 2 ⁇ g, 3 ⁇ g, 4 ⁇ g, 5 ⁇ g, 6 ⁇ g, 7 ⁇ g, 8 ⁇ g, 9 ⁇ g, 10 ⁇ g, 20 ⁇ g, 30 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, 80 ⁇ g, 90 ⁇ g, 100 ⁇ g, 110 ⁇ g, 120 ⁇ g, 130 ⁇ g, 140 ⁇ g, 150 ⁇ g, 160 ⁇ g, 170 ⁇ g, 180 ⁇
  • the antigenic peptide is administered in an equivalent amount ranging from 1 ⁇ g to 80 ⁇ g.
  • the equivalent amount of antigenic peptide may be of about 10, 5 ⁇ g, 10 ⁇ g, 20 ⁇ g, 30 ⁇ g, 40 ⁇ g, 50 ⁇ g, 60 ⁇ g, 70 ⁇ g, or 80 ⁇ g.
  • an immunogenic compound, or composition thereof, used according to the invention comprises an antigenic peptide of the invention in an equivalent amount which is adapted to multiple parenteral administrations, which includes 1, 2, 3, 4, 5 and 6 administrations, and preferably 6 doses per year.
  • the first cycle is composed of three administrations every 4 weeks.
  • the immunogenic compound, or composition thereof is administered, as a booster injection, about every 12 weeks after the first cycle, which includes being administered, as a booster injection, in a period ranging from 8 to 48 weeks after the latest administration, which includes 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 and 48 weeks after.
  • the immunogenic compound is administered parenterally, for example intramuscularly, in 3 to 6 administrations, and preferably 6 doses within a year, wherein the fourth, fifth and sixth administration is administered, as a booster injection, in a period ranging from 8 to 48 weeks after the latest administration.
  • the administration of the said immunogenic compound raises, in said HIV-infected individuals, an antibody response directed against the antigenic peptide derived from the gp41 protein, which antibody response has been shown by the inventors to cause a reduction in the PBMC-associated DNA, and thus a reduction of the HIV reservoir in the said HIV-infected individuals.
  • the detection of an antibody response directed against the said antigenic peptide derived from the HIV gp41 protein may be conventionally performed, for example by using an ELISA assay.
  • the results of the ELISA assay are analyzed against a control curve generated by using a serial of anti- antigenic peptide antibodies at known dilutions or at known concentrations.
  • the said immunogenic compound is administered only once.
  • the said immunogenic compound is administered a plurality of times.
  • the said immunogenic compound is administered a number of times ranging from 2 to 6.
  • the said immunogenic compound may be administered twice, with the second administration being performed about four weeks subsequent to the first administration.
  • the said immunogenic compound may be administered three times, with the second administration being performed about four weeks subsequent to the first administration and the third administration being performed about four weeks subsequent to the second administration
  • the said immunogenic compound may be administered according to the following treatment schedule :
  • - T2 Tl + about four weeks :3 rd administration of the immunogenic compound
  • - T3 T2 + about twelve weeks : 4 th administration of the immunogenic compound
  • T4 T3 + about twelve weeks :5 th administration of the immunogenic compound
  • T5 T4 + about twelve weeks: 6 th administration of the immunogenic compound.
  • maintaining an immune response against an antigen, and herein against an antigenic peptide derived from the HIV gp41 protein, may require timely booster administration of an immunogenic compound comprising the said antigen.
  • the immunogenic compound comprising the antigenic peptide derived from the gp41 protein may be administered at appropriate time intervals.
  • one or more subsequent administrations of the immunogenic compound comprising the antigenic peptide derived from the gp41 protein may be performed at time intervals ranging from 3 months to 24 months, which includes at time intervals ranging from 6 months to 12 months.
  • the HIV-infected individual is subject to a regular monitoring of one or more of the following physiological parameters including (i) the level of PBMC-associated HIV DNA, (ii) the level of the HIV RNA and (iii) the level of CD4+ T cells.
  • a further administration of an immunogenic compound comprising an antigenic peptide derived from the HIV gp41 protein may be decided in the HIV-infected individuals when one or more of the following physiological changes is detected or determined: - an increase of the level of PBMC-associated HIV DNA as compared to a previous measurement of this parameter in the said HIV-infected individual,
  • the said further administration of the immunogenic compound that is decided is aimed at maintaining or increasing the immune response against the antigenic peptide derived from the HIV gp41 protein and thus maintaining or increasing the viral control by the HIV-infected individual.
  • an immunogenic compound comprising an antigenic peptide derived from the HIV gp41 protein drastically reduce the PBMC-associated HIV DNA level
  • the inventors believe that the administration of the said compound may lead, at least for some of the HIV-infected individuals treated therewith, to a total eradication of the HIV virus and thus to a complete cure to the said individuals.
  • the immunogenic compound may be administered alone or in combination with other compounds, including Latency Reversing Agents (LRA) or compounds that have either a shock, or a kill effect, and compounds behaving as immune boost.
  • LRA Latency Reversing Agents
  • the immunogenic compound may also be administered in combination with Latency Reversing Agents (LRA), such as agents can be selected in a group consisting of histone deacetylase inhibitors (HDACi), including romidepsin, panobinostat, vorinostat, givnostat, belinostat, sirtuin inhibitors, NF-KB-inducing agents, protein kinase C agonists, T cell activators and TLR agonists, immune checkpoint inhibitors selected in a group comprising PD-1 inhibitors and PDL-1 inhibitors (including Pembrolizumab, Nivolumab, Pidilizumab, BMS 936559, MPDL3280A), LAG-3 inhibitors, TIGIT inhibitors, and CTLA-4 inhibitors, pro-apoptotic and cell differentiating molecules including JQ1, Nutlin3, Disulfiram, aphidicolin, Wnt small molecules inhibitors and Notch inhibitors.
  • HDACi histone deacet
  • the immunogenic compound may also be administered in combination with at least one drug selected from one or more immunotherapy inducing an HIV-antigen specific immune response with either a Thl and or a Th2 type immune response, and other immunotherapies acting more as immune boost and including IL-15, IL-7 or revlimid could be also used in synergy.
  • Example 1 Preparation of an immunogenic compound derived from gp41, and compositions thereof.
  • the following immunogenic compounds or conjugates were synthesized. There were derived from KLH and CRM197 using either MBS or SMPB as crosslinker molecules.
  • the used peptide was the 3S peptide consisting of SEQ ID N°2 with either an additional cysteine residue at its amino-terminus end or at its carboxy-terminus end.
  • the peptide which is termed "Nter(Cys)-3S" above comprises the 3S reference peptide of SEQ ID N°2 herein.
  • sulfo-SMPB Sulfo- (Succinimidyl-4-(p-maleimidophenyl) Butyrate)
  • sulfo-MBS Sulfo-(m- Maleimidobenzoyl-N-hydroxysuccinimide) ester
  • These molecules consist of a maleimide moiety linked by a polyethylene chain to an ester of N-hydroxysuccinimide (Cross-linking of protein by w-maleimido alkanoyl N-hydroxysuccinimido esters. Partis M.D and al. Journal of Protein Chemistry, vol.2, No 3, 1983).
  • the succinimide moiety can react with amino groups of the protein. Once this reaction has occurred, the maleimide moiety reacts with sulfhydryl groups of the 3S peptides. They are different in length, 7,3 A for sulfo-
  • the coupling reaction was a two-step reaction.
  • the first step was the activation of the CRM 197 with the cross-linker. 15 milligrams of linker, diluted in dimethyl sulfoxide were added to 20 milligrams of CRM 197 in a volume of 5-20 mL of conjugation buffer (PBS 10 mM pH 7-pH 7.4) and mixed gently for 30-90 min at room temperature (Protective immunogenicity of two synthetic peptides selected from the amino acid sequence of Bordetella pertussis toxin subunit SI. Askelof P. and al. PNAS, vol.87, pp 1347-1351, February 1990).
  • conjugation buffer PBS 10 mM pH 7-pH 7.4
  • the immuno-conjugates were then purified by size exclusion chromatography.
  • the immuno-conjugates were analyzed using an amino acid analysis (AAA) to determine the peptide/CRM197 ratio.
  • AAA amino acid analysis
  • the CRM197-3S peptide was lyophilized with a lyoprotector (Lyophilisation and development of solid protein pharmaceuticals. Wang W. International Journal of Pharmaceutics 203 (2000) 1- 60; Fundamentals of freeze-drying. Nail S.L and al. Pharm Biotechnol. 2002; 14:281-360).
  • AAA amino acid analysis
  • VAC-3S is a sterile suspension for intramuscular injection containing the 3S drug substance adsorbed on aluminium hydroxide in buffered isotonic saline. The manufacturing of VAC-3S was performed in compliance with the GMP.
  • the 3S drug substance is formulated at concentrations ranging from 1 to 40 ⁇ g/mL of 3S16Nter peptide equivalent with aluminium hydroxide (1 mg/mL of Al 3+ ions) provided by Brenntag (Alhydrogel 85 2 -Ph Eur), 150 mM sodium chloride (European pharmacopoeia) and 1 mM sodium phosphate (European pharmacopoeia). Products for injection are used for the formulation of the vaccine. The final pH is at 6.8. VAC-3S contains no preservative.
  • the vaccine After shaking, the vaccine is a homogeneous white suspension ready to use. If needed to achieve the needed concentration of 3S16Nter the vaccine is diluted in aluminium hydroxide (1 mg/mL of Al 3+ ions) provided by Brenntag (Alhydrogel 85 2%- Ph Eur), 150 mM sodium chloride (European pharmacopoeia) and 1 mM sodium phosphate (European pharmacopoeia), equilibrated at pH 6.8. The vaccine could be injected intramuscularly in the deltoid. A sterile syringe with sterile needle is used for injection. Patients should receive at least 6 doses of 0.5 mL each, with a minimum interval of 2 to 4 weeks between vaccinations.
  • Example 2 Preparation of an immunogenic compound derived from gp41, and compositions thereof, for clinical use.
  • the following immunogenic compound or conjugate was synthesized. It was derived from CRM197 using SMPB as crosslinker molecule (as shown in example 1).
  • the used peptide was a mutated 3S (m3S) peptide consisting of SEQ ID N°13 (NH 2 - PWNASASNKSLDDIW-COOH) with an additional cysteine residue at its amino- terminus end to allow the chemical coupling the cross linker leading to CRM197-SMPB- Nter(Cys)-m3S
  • the peptide which is termed "Nter(Cys)-m3S" above consists of the 3S peptide of SEQ ID N°14 herein.
  • the heterobifunctional cross-linker sulfo-SMPB (Sulfo-(Succinimidyl-4-(p- maleimidophenyl) Butyrate) was used. These molecules consist of a maleimide moiety linked by a polyethylene chain to an ester of N-hydroxysuccinimide (Cross-linking of protein by w-maleimido alkanoyl N-hydroxysuccinimido esters. Partis M.D and al. Journal of Protein Chemistry, vol.2, No 3, 1983).
  • the succinimide moiety can react with amino groups of the protein. Once this reaction has occurred, the maleimide moiety reacts with sulfhydryl groups of the 3S peptides. They are different in length, 7,3 A for sulfo- MBS and 11.6 A for sulfo-SMPB.
  • the linker elimination and buffer exchange were made by size exclusion chromatography (SEC).
  • the coupling reaction was a two-step reaction.
  • the first step was the activation of the CRM 197 with the cross-linker. 15 milligrams of linker, diluted in dimethyl sulfoxide were added to 20 milligrams of CRM 197 in a volume of 5-20 ml of conjugation buffer (PBS 10 mM pH7-pH7.4) and mixed gently for 30-90 min at room temperature (Protective immunogenicity of two synthetic peptides selected from the amino acid sequence of Bordetella pertussis toxin subunit SI. Askelof P. and al. PNAS, vol.87, pp 1347-1351, February 1990).
  • the immuno-conjugate obtained and corresponding to the m3S peptide of SEQ ID N° 9 which comprises a Cys residue at the N-terminal end, the CRM 197 carrier and SMPB as a linker was found spontaneously soluble in water or in 0.9% NaCl solution.
  • VAC-3S is a sterile suspension for intramuscular injection containing the 3S drug substance adsorbed on aluminium hydroxide in buffered isotonic saline.
  • the manufacturing of VAC-3S was performed in compliance with the GMP.
  • the 3S drug substance is formulated at the concentration of 0.02 mg/mL of 3S16Nter peptide comprising the antigenic peptide of sequence SEQ ID N°9, equivalent in 0.5 mL with aluminium hydroxide (1 mg/mL of Al ions) provided by Brenntag (Alhydrogel 85 2 -Ph Eur), 150 mM sodium chloride (European pharmacopoeia) and 1 mM sodium phosphate (European pharmacopoeia). Products for injection are used for the formulation of the vaccine. The final pH is at 6.8. VAC-3S contains no preservative.
  • the vaccine After shaking, the vaccine is a homogeneous white suspension ready to use.
  • the vaccine could be injected intramuscularly in the deltoid.
  • a sterile syringe with sterile needle is used for injection.
  • Patients should receive at least 6 doses of 0.5 mL each, with a minimum interval of 2 to 4 weeks between vaccinations.
  • the four patient populations are further detailed in Table 1 here below.
  • the administration protocol is also detailed in figures 1A and IB.
  • N 8; 7 M / 1 F for modified As Treated (mAI population ( patient replaced after 1 st vaccination).
  • Example 3 Assessment of the dose-dependent immunogenicity at week 12 based on the amount of immunogenic compound that is administered.
  • the ELISA assay was designed to perform the measurement of total Ig antibodies that would recognize the peptides of SEQ ID N°9, also called anti-3S peptide antibodies.
  • the anti-3S IgG antibody titers were determined by an Enzyme-Linked Immunosorbent Assay (ELISA).
  • the antigen coated to the Nunc Maxisorp micro plates is a 3S peptide conjugated to bovine serum albumin (BSA) with a different linker than the one used for the synthesis of the immuno-conjugates: SMCC (succinimidyl-4-(N- maleimidomethyl)cyclohexane- l-carboxylate) (produced from Imject® Maleimide Activated BSA Protein Kits purchased from Thermo Fisher Scientific, Waltham, USA) .
  • BSA bovine serum albumin
  • the anti-m3S IgG antibodies are revealed by a colorimetric reaction using a goat anti- mouse IgG (Fc), conjugated to the HorseRadish Peroxydase (HRP) (Jackson Immunoresearch, West Grove, USA), and the HRP substrate: the tetramethylbenzidine (TMB) (Sigma, Missouri, USA).
  • Fc goat anti- mouse IgG
  • HRP substrate the tetramethylbenzidine
  • Results are provided in figure 2, which show that the percentage of responsive patients increases with a higher amounts of immunogenic compounds, at week 12.
  • the HIV DNA level is measured using the protocols described in Rouzioux et al. ("Quantification of total HIV 1 -DNA in peripheral blood mononuclear cells"; Methods Mol. Biol; 1087:261-70; 2014).
  • the HIV DNA level can be expressed either in log copies per 10 6 PBMC cells or in log copies per mL of whole blood.
  • PBMC pellets are stored at -80°C until use.
  • the total DNA is isolated from PBMC (Peripheral Blood Mononuclear Cells).
  • PBMC pellets are prepared by Ficoll-Hypaque gradient, while cell pellets are obtained from whole blood after centrifugation (2,500 rpm, 10 min) and plasma decantation. Purified CD4+ T cells, cell pellet, or even whole blood can be used.
  • Total DNA is extracted from PBMCs using a QIAamp DNA mini kit (QIAGEN, Courtaboeuf, France) according to the manufacturer's instructions, to obtain 100 ⁇ _, of eluate.
  • the kit NucleoSpin® Blood (Macherey-Nagel) is preferred for DNA extraction from cell pellets and whole blood samples. The procedure is standardized in order to obtain an absolute quantification of HIV-DNA as described in Rouzioux et al. ("Quantification of total HIV 1 -DNA in peripheral blood mononuclear cells"; Methods Mol. Biol; 1087:261-70; 2014).
  • Figures 3 to 5 report HIV-DNA levels corresponding to HIV-DNA in copies per million of PBMCs for total DNA extracted from PBMCs isolated by Ficoll-Hypaque.
  • Figure 6 reports the corresponding value but expressed in copies per mL of whole blood.
  • the protocol is set up as described previously.
  • Figure 3 provides evidence of a decrease in the HIV-DNA levels in the responder group at weeks 60 and 84, which thus provides evidence of a decrease in the HIV latent reservoirs.
  • This link is confirmed by Figures 5A, 5B, 5C and 5D showing at the 12, 36, 60 and 84 weeks an inverse correlation between the level of anti-3S antibodies in patients participating to the trial and level of HIV DNA change from baseline (in Log of copies per million of PBMC).
  • FIG. 5A, 5B, 5C and 5D shows at the 12, 36, 60 and 84 weeks an inverse correlation between the level of anti-3S antibodies in patients participating to the trial and level of HIV DNA change from baseline (in Log of copies per million of PBMC).
  • Figures 6 and 7 also reports a significant increase of the CD4/CD8 ratio in Responders and not the non-Responders and Placebo groups, at week 24 and thus immune restoration since an increase of the CD4/CD8 ratio corresponds to improved immune functions (Serrano-Villar et ah, PLOS Pathogens, vol. 10, 2014). These results in HIV-infected patients vaccinated with VAC-3Sclearly show the dual capacity of VAC-3S to improve immune functions of patients, but also and unexpectedly to decrease the HIV reservoir through the decrease of the HIV DNA.

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Abstract

L'invention concerne un composé immunogène comprenant un peptide antigénique dérivé de la protéine gp41 du VIH, et destiné à être utilisé dans le traitement d'un patient souffrant d'une infection par le VIH mais non sous traitement anti-rétroviral.
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* Cited by examiner, † Cited by third party
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US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
WO2023280833A1 (fr) * 2021-07-05 2023-01-12 Diaccurate Nouveaux antigènes et vaccins
WO2023034932A1 (fr) * 2021-09-02 2023-03-09 Vaxcyte, Inc. Stabilisation de compositions de vaccin à adjuvant et leur utilisation

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Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10287353B2 (en) 2016-05-11 2019-05-14 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US10385131B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
US10385130B2 (en) 2016-05-11 2019-08-20 Huya Bioscience International, Llc Combination therapies of HDAC inhibitors and PD-1 inhibitors
US11535670B2 (en) 2016-05-11 2022-12-27 Huyabio International, Llc Combination therapies of HDAC inhibitors and PD-L1 inhibitors
WO2023280833A1 (fr) * 2021-07-05 2023-01-12 Diaccurate Nouveaux antigènes et vaccins
WO2023034932A1 (fr) * 2021-09-02 2023-03-09 Vaxcyte, Inc. Stabilisation de compositions de vaccin à adjuvant et leur utilisation

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