WO2021062546A1 - Use of ibalizumab for the treatment of hiv-2 infection - Google Patents
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K16/00—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
- C07K16/18—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
- C07K16/28—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
- C07K16/2803—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily
- C07K16/2812—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against the immunoglobulin superfamily against CD4
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P31/00—Antiinfectives, i.e. antibiotics, antiseptics, chemotherapeutics
- A61P31/12—Antivirals
- A61P31/14—Antivirals for RNA viruses
- A61P31/18—Antivirals for RNA viruses for HIV
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- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K2317/00—Immunoglobulins specific features
- C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
- C07K2317/24—Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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- 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
Definitions
- the present disclosure generally relates to the management of infections by the human immunodeficiency virus (HIV), and more particularly HIV-2 infection and related diseases.
- HIV human immunodeficiency virus
- HIV infection is responsible for the most devastating global pandemic of the last century. More than 39 million people have died of HIV/AIDS since 1981.
- HIV-1 which was discovered first, is the most widespread type worldwide. HIV-2 is more than 55% genetically different from HIV-1. HIV-2 is most common in western Africa and is becoming more common in India, although numbers there are still relatively small. Small numbers of cases have also been seen in Portugal, France, other European countries including the UK and the Americas, largely in individuals of west African origin or their sexual partners.
- HIV-2 and HIV-1 infections lead to different immunological and clinical outcomes.
- the majority of HIV-2-infected subjects have reduced general immune activation, higher CD4 + T-cell counts, low plasma viremia, and longer disease-free survival (Berry et al., J Hum Virol 1998, 1 :457-68; Drylewicz et a!., AIDS 2008, 22:457-68; Marlink et a!., Science 1994, 265: 1587-90; Poulsen et a/., Lancet 1997, 349: 911-14). Nevertheless, the mortality risk is equivalent in HIV-1 and HIV-2 infections (de Sylva et al., Trends Microbiol.
- HIV infections are typically treated by highly active antiretroviral therapy (HAART), which employs a combination of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and/or protease inhibitors (Pis).
- HAART highly active antiretroviral therapy
- NRTIs nucleoside/nucleotide reverse transcriptase inhibitors
- NRTIs non-nucleoside reverse transcriptase inhibitors
- Pro protease inhibitors
- HIV-2 is naturally resistant to NNRTIs and is less sensitive to some Pis.
- most HAART regimens used in HIV-1 patients are unable to fully suppress HIV-2 replication, to increase CD4 + T-cell counts or prevent appearance of drug-resistant mutations (Borrego and Taveira, AIDS Rev. 2013, 15:49-61).
- Another class of HIV drugs are HIV entry inhibitors, which prevent the entry of the virus into cells. HIV entry into host cells is a complicated process that involves at least three steps: (1) an attachment step that requires CD4 receptor binding, (2) co-receptor binding, and (3) a fusion process.
- Env The envelope glycoprotein (Env) on the surface of virions mediates entry.
- Heterotrimeric Env spikes are composed of three surface glycoproteins (gp120) atop three transmembrane glycoproteins (gp41).
- the gp41 subunits which assemble into a trimer, comprise the “stalk” of Env that anchors the Env into the viral membrane.
- the gp120 subunits comprise the “head” of Env that is able to bind to cellular receptors.
- Virions can first attach to target cells in a relatively nonspecific manner, followed by specific binding of HIV gp120 to the CD4 receptor on the cellular membrane.
- This binding induces a conformational change in gp120 that opens up a high-affinity binding site located within the third variable loop (V3) and surrounding surfaces for the chemokine co-receptors (primarily CCR5 and CXCR4).
- V3 variable loop
- chemokine co-receptors primarily CCR5 and CXCR4
- Co receptor binding results in further conformational rearrangements of gp120 that expose the fusion-peptide domain of gp41. Insertion of this hydrophobic domain into the cell membrane leads to the formation of a hairpin-like fold in the gp41 subunits.
- HR heptad repeat
- HIV-2 isolates may infect peripheral blood mononuclear cells (PBMCs) independently of the CCR5 and CXCR4 co-receptors, while others enter into CD4-negative cells via CCR5 or CXCR4 (Reeves et a!., J Virol. 1999, 73:7795- 804).
- HIV-2 isolates are typically less sensitive to recombinant soluble CD4 (rsCD4) than HIV-1 isolates.
- rsCD4 recombinant soluble CD4
- the small molecule B S-378806 which binds gp120 with high affinity, has strong antiviral activity against HIV-1 but not against HIV-2.
- the present disclosure generally relates to the management of infections by the human immunodeficiency virus (HIV), and more particularly HIV-2 infection and related diseases.
- HIV human immunodeficiency virus
- the present disclosure provides the following items:
- a method for treating infection by human immunodeficiency virus type 2 comprising administering to a subject in need thereof an effective amount of ibalizumab or of an antibody or an antigen-binding fragment thereof that competes with ibalizumab for binding to human CD4, such as an antibody comprising the following complementary determining regions (CDRs): CDRL1 : QSLLYSTNQKNY (SEQ ID NO:3); CDRL2: WAS; CDRL3: QQYYS (SEQ ID NO:4); CDRH1 : GYTFTSYV (SEQ ID NO:5); CDRH2: INPYNDGT (SEQ ID NO:6) and CDRH3: AR, or an antibody comprising the variable region of the light chain of ibalizumab (residues 1-112 of SEQ ID NO:1) and/or the variable region of the heavy chain of ibalizumab (residues 1-122 of SEQ ID NO:2).
- CDRs complementary determining
- NRTIs Nucleoside reverse transcriptase inhibitors
- NRTIs Non-Nucleoside reverse transcriptase inhibitors
- Pis protease inhibitors
- CDRs complementary determining regions
- CDRs complementary determining
- any one of items 18 to 22, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration according to a dosage regimen comprising an initial administration at a first dose and one or more maintenance administrations at a second dose.
- NRTIs Nucleoside reverse transcriptase inhibitors
- NRTIs Non-Nucleoside reverse transcriptase inhibitors
- Pis protease inhibitors
- CDRs complementary determining regions
- the antibody or antigen-binding fragment thereof preferably ibalizumab, for use of item
- HIV-2 viral load is reduced by at least 0.5 logio.
- the antibody or antigen-binding fragment thereof preferably ibalizumab, for use of any one of items 36 to 38, wherein said use increases or maintains CD4 + cell counts in the subject.
- the antibody or antigen-binding fragment thereof for use of any one of items 36 to 39, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration according to a dosage regimen comprising an initial administration at a first dose and one or more maintenance administrations at a second dose.
- the antibody or antigen-binding fragment thereof preferably ibalizumab, for use of item
- the first dose is about 1000 to about 3000 mg.
- the antibody or antigen-binding fragment thereof preferably ibalizumab, for use of item
- the antibody or antigen-binding fragment thereof preferably ibalizumab, for use of any one of items 40 to 42, wherein the second dose is about 400 to about 1200 mg.
- the antibody or antigen-binding fragment thereof preferably ibalizumab, for use of item 43, wherein the second dose is about 800 mg.
- the antibody or antigen-binding fragment thereof for use of any one of items 36 to 44, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for intravenous administration.
- the antibody or antigen-binding fragment thereof for use of any one of items 36 to 45, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration as a monotherapy.
- the antibody or antigen-binding fragment thereof for use of any one of items 36 to 45, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration in combination with at least one additional antiretroviral agent.
- the antibody or antigen-binding fragment thereof for use of item 47, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration in combination with highly active antiretroviral therapy (HAART).
- HAART highly active antiretroviral therapy
- the antibody or antigen-binding fragment thereof preferably ibalizumab, for use of any one of items 36 to 48, wherein the subject is infected by an HIV-2 strain that is resistant to at least one antiretroviral agent.
- the antibody or antigen-binding fragment thereof preferably ibalizumab, for use of item 49, wherein the HIV-2 strain is resistant to at least one antiretroviral agent from each of three following three classes: Nucleoside reverse transcriptase inhibitors (NRTIs), Non-Nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pis).
- NRTIs Nucleoside reverse transcriptase inhibitors
- NRTIs Non-Nucleoside reverse transcriptase inhibitors
- Pis protease inhibitors
- the antibody or antigen-binding fragment thereof preferably ibalizumab, for use of any one of items 36 to 50, wherein the HIV-2 is of the A or B subtype.
- the antibody or antigen-binding fragment thereof for use of any one of items 36 to 51 , wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is in a saline solution.
- FIG. 1A depicts graphs showing the viral RNA levels (upper graph) and CD4 counts (lower graph) at various time points over the study period in patient No. 1.
- DO GIGHAART optimized gigatherapy
- DO Iba first dose ibalizumab
- Stop Iba end of ibalizumab treatment.
- FIG. 1B depicts graphs showing the viral RNA levels (upper graph) and CD4 counts (lower graph) at various time points over the study period in patient No. 2.
- FIG. 1C depicts graphs showing the viral RNA levels (upper graph) and CD4 counts (lower graph) at various time points over the study period in patient No. 3.
- FIG. 1D depicts graphs showing the viral RNA levels (upper graph) and CD4 counts (lower graph) at various time points over the study period in patient No. 4.
- FIG. 2A shows the amino acid sequence of the light chain of ibalizumab (SEQ ID NO:1), with the predicted complementary determining regions (CDRs) in bold and underlined.
- FIG. 2B shows the amino acid sequence of the heavy chain of ibalizumab (SEQ ID NO:2), with the predicted complementary determining regions (CDRs) in bold and underlined.
- FIG. 3A is a graph showing the effect of increasing concentrations of ibalizumab (0.001 to 10 pg/mL) on the replication of seven HIV-2 strains (ROD, AD, LE, DA, CL, SO and Dl).
- FIG. 3B is a table showing the half-maximal inhibitory concentration (IC 5 o) and maximum percent inhibition (MPI) for the effect of ibalizumab on the replication of the seven HIV-2 strains.
- the anti-CD4 monoclonal antibody ibalizumab reduces viral load and/or increases or maintains CD4 + T-cell counts in patients infected with HIV-2, and has the ability to inhibit the replication of several strains of HIV-2 in vitro.
- Ibalizumab commercialized under the tradename Trogarzo ® , is a human lgG4 anti- CD4 MAb derived from a murine MAb (mu5A8) that targets domain 2 of the CD4 receptor. It leads to conformational changes of the CD4 T cell receptor-gp120 complex thus preventing HIV fusion and entry. Whereas the antiviral activity of ibalizumab against HIV-1 is well documented and it has been approved by the FDA for the treatment of multidrug-resistant HIV-1 infection, its effects against HIV-2 infection have never been reported.
- the present disclosure provides a method for treating infection by human immunodeficiency virus type 2 (HIV-2) comprising administering to a subject in need thereof an effective amount of ibalizumab, or of an antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab.
- HBV-2 human immunodeficiency virus type 2
- the present disclosure provides the use of ibalizumab, or of an antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab, for treating HIV-2 infection in a subject.
- the present disclosure provides the use of ibalizumab, or of an antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab, for the manufacture of a medicament for treating HIV-2 infection in a subject.
- the present disclosure provides ibalizumab, or an antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab, for treating HIV-2 infection in a subject.
- Ibalizumab is a human lgG4 anti-CD4 Ab described in PCT publication No. WO 92/09305.
- the amino acid sequences of the light and heavy chains of ibalizumab are shown in FIG. 2A and FIG. 2B, respectively.
- Ibalizumab has been shown to bind a conformational epitope formed by amino acids L96, P121 , P122, and Q163 in domain 2 of human CD4, with residues E77 and S79 in domain 1 of CD4 also contributing. These residues cluster on the interface between domains 1 and 2 of human CD4 on a surface opposite the site where gp120 and the MHC-II molecule bind on domain 1 (Song et al., J Virol.
- amino acids 121 to 124 and 127 to 134, in domain 2 are important for binding of ibalizumab to CD4 (Burkly, L.C. et al., J. Immunol. 1992. 149:1779-1787). It may be predicted that other antibodies or antigen-binding fragments thereof that bind to the same epitope as ibalizumab, or to an epitope that at least partly overlaps with the epitope recognized by ibalizumab, would also be useful for blocking HIV-2 entry and treating HIV-2 infection in a subject.
- Such antibodies or antigen-binding fragments thereof may be identified, for example, by assessing whether they are able to compete with ibalizumab for binding to CD4, as shown for antibody M-T441 (Adipogen ® Life Sciences, Cat. No. ANC-148-020) that binds an epitope that overlap with the epitope recognized by ibalizumab and competes with ibalizumab for binding to CD4 (Song et al., J Virol. 2010 Jul;84(14):6935-42).
- the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab competes with ibalizumab for binding to human CD4.
- the antibody may be derived from ibalizumab, e.g. an antibody comprising an amino acid sequence having at least 50, 60, 70, 80, 90, 95, 96, 97, 98 or 99% sequence identity with the sequence of ibalizumab (or the sequences of the heavy and light chain variable regions, or an antigen-binding fragment thereof.
- the antibody or antigen-binding fragment thereof may comprise the same complementarity determining regions (CDRs) as ibalizumab, combined with one or more framework regions (FRs) that differ from ibalizumab.
- antibody or antigen-binding fragment thereof refers to any type of antibody/antibody fragment including monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies, humanized antibodies, CDR-grafted antibodies, chimeric antibodies and antibody fragments so long as they bind to the same epitope as ibalizumab, or to an epitope that at least partly overlaps with the epitope recognized by ibalizumab.
- Antibody fragments comprise a portion of a full-length antibody, generally an antigen binding or variable region thereof.
- antibody fragments include Fab, Fab', F(ab') , and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules (e.g., single-chain FV, scFV), single domain antibodies (e.g., from camelids), shark NAR single domain antibodies, and multispecific antibodies formed from antibody fragments.
- Antibody fragments can also refer to binding moieties comprising CDRs or antigen binding domains including, but not limited to, V H regions (V , V H -V H ), anticalins, PepBodies, antibody-T- cell epitope fusions (Troybodies) or Peptibodies.
- the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising the amino acid sequences QSLLYSTNQKNY (SEQ ID NO:3), WAS and QQYYS (SEQ ID NO:4) of the three light chain CDRs set forth in Fig. 2A; and a heavy chain variable region comprising the amino acid sequences GYTFTSYV (SEQ ID NO:5), INPYNDGT (SEQ ID NO:6) and AR of the three heavy chain CDRs set forth in Fig. 2B.
- the antibody or antigen-binding fragment thereof is an antibody comprising the variable region of the light chain defined the amino acid sequence of SEQ ID NO: 1 (residues 1-112) and the variable region of the heavy chain comprising the amino acid sequence of SEQ ID NO: 2 (residues 1-122).
- the antibody or antigen-binding fragment thereof is an antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2.
- the administration or use reduces HIV-2 viral load in the subject. In an embodiment, the administration or use increases or maintains CD4 + cell counts in the subject. In another embodiment, the administration or use (i) reduces HIV-2 viral load and (ii) increases or stabilizes CD4 + cell counts, in the subject. In another embodiment, the administration or use reduces and maintains HIV-2 viral load at an undetectable level over a treatment period. In another embodiment, the administration or use maintains CD4 + cell counts at levels of 100 CD4 + cells/mI of blood or more in the subject, in further embodiments at levels of 125, 150, 175 or 200 CD4 + cells/mI of blood or more in the subject.
- the baseline CD4 + cell count in the subject is 800 CD4 + cells/mI or less, 600 CD4 + cells/mI or less, 500 CD4 + cells/mI or less, 400 CD4 + cells/mI or less, 300 CD4 + cells/mI or less, 250 CD4 + cells/mI or less, or 200 CD4 + cells/mI or less.
- the baseline viral load in the subject is 200 copies of RNA/ml of blood or more, 400 copies of RNA/ml of blood or more, 600 copies of RNA/ml of blood or more, 800 copies of RNA/ml of blood or more, 1000 copies of RNA/ml of blood or more, 1500 copies of RNA ml of blood or more, or 2000 copies of RNA/ml of blood or more.
- CD4 + cell counts increases or maintains CD4 + cell counts as used herein means that the CD4 + cell count in the subject does not decrease by 10% or more relative to the baseline CD4 + cell count (prior to the initiation of ibalizumab treatment) over a defined treatment period, i.e. the CD4 + cell count decreases by less than 10%, remains the same or increases relative to the baseline CD4 + cell count over a defined treatment period.
- the term “reduces HIV-2 viral load” as used herein means that the viral load in the subject decreases by at least 10% relative to the baseline viral load (prior to the initiation of ibalizumab treatment) over a defined period. In an embodiment, the viral load in the subject decreases by at least 0.5 logi 0 relative to the baseline viral load.
- the subject is co-infected by HIV-1. In another embodiment, the subject is not co-infected by HIV-1.
- the subject is infected by an HIV-2 strain or isolate that is resistant to antiretroviral therapy (ART), for example a multi-drug resistant (MDR) HIV-2 strain.
- ART antiretroviral therapy
- MDR multi-drug resistant HIV-2 strain.
- the HIV-2 strain or isolate is resistant to at least one antiretroviral agent or class of antiretroviral agents (e.g., NRTIs, NNRTIs, Pis, or Integrase Inhibitors).
- the HIV-2 strain or isolate is resistant to at least two antiretroviral agents or classes of antiretroviral agents.
- the HIV-2 strain or isolate is resistant to at least three antiretroviral agents or classes of antiretroviral agents.
- the HIV-2 strain or isolate is resistant to at least one antiretroviral agent from each of three following three classes: NRTIs, NNRTIs and Pis.
- the HIV-2 strain or isolate is resistant to salvage gigatherapy, for example the salvage gigatherapy regimen described at Example 1.
- the term “resistant to ART” means that administration of the antiretroviral agent(s) does not result in a decrease of the viral load to undetectable levels in the subject.
- the viral load is stable or increases following administration of the antiretroviral agent(s).
- the subject is infected by an HIV-2 strain or isolate of the A, B, C, D or E subtype. In an embodiment, the subject is infected by an HIV-2 strain or isolate of the A subtype. In another embodiment, the subject is infected by an HIV-2 strain or isolate of the B subtype.
- the ibalizumab, or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab is present in a pharmaceutical composition with one or more pharmaceutically acceptable carriers or excipients.
- the carrier/excipient can be suitable, for example, for intravenous, parenteral, subcutaneous, or intramuscular administration.
- Therapeutic formulations are prepared using standard methods known in the art by mixing the active ingredient having the desired degree of purity with one or more optional pharmaceutically acceptable carriers, excipients and/or stabilizers (see Remington: The Science and Practice of Pharmacy, by Loyd V Allen, Jr, 2012, 22 nd edition, Pharmaceutical Press; Handbook of Pharmaceutical Excipients, by Rowe et al., 2012, 7 th edition, Pharmaceutical Press).
- the ibalizumab is present in a pharmaceutical composition with a saline solution, e.g., a 0.9% NaCI solution.
- any suitable amount of the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab), or the pharmaceutical composition may be administered to a subject.
- the dosages will depend on many factors including the mode of administration.
- the amount of ibalizumab (or of the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) contained within a single dose will be an amount that effectively delay the progression or treat HIV-2 infection without inducing significant toxicity.
- the appropriate dosage of the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) will depend on certain factors such as the severity and course of the disease or condition (e.g., AIDS), previous therapy, the patient's clinical history and response to the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab), and the discretion of the attending physician.
- the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) is suitably administered to the patient at one time or over a series of treatments.
- the present disclosure provides dosages for the compounds and compositions comprising same. For example, depending on the type and severity of the disease, about 1 pg/kg to to 1000 mg per kg (mg/kg) of body weight per day.
- the effective dose may be about 0.5 mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg to about 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg or 200 mg/kg, or may range between any two of the foregoing values.
- a typical daily dosage might range from about 1 mg/kg to 100 mg/kg, depending on the factors mentioned above.
- the treatment may be sustained until a desired suppression of disease symptoms occurs, or may be continued for the lifetime of the patient.
- the progress of this therapy is easily monitored by conventional techniques and assays, such as the assays for measuring viral load and CD4 counts described herein.
- the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) may be administered according to a defined dosage regimen.
- the treatment regimen comprises an initial administration/use at a first dose (single loading dose), and one or more maintenance administration(s)/use(s) at a second dose.
- the second dose is lower than the first dose.
- the first dose is about 1000 to about 3000 mg of ibalizumab (or of the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab), for example about 1200 to about 2800 mg, about 1500 to about 2500 mg, about 1800 mg to about 2200 mg, about 1900 mg to about 2100 mg, or about 2000 mg.
- the second dose is about 200 mg to about 1400 mg of ibalizumab, for example about 400 to about 1200 mg, about 600 to about 1000 mg, about 700 mg to about 900 mg, or about 800 mg.
- the time interval between the initial administration/use and the first maintenance administration/use is from 1 week to 4 weeks, or from 1 week to 3 weeks, or about 2 weeks. In an embodiment, the time interval between the maintenance administrations/uses is from 1 week to 4 weeks, or from 1 week to 3 weeks, or about 2 weeks.
- the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) is administered by intravenous, subcutaneous, or intramuscular administration.
- the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) is administered or used in combination with at least one additional therapeutic agent, e.g., an antiretroviral or HIV drug.
- at least one additional therapeutic agent e.g., an antiretroviral or HIV drug.
- the additional therapeutic agent may also be an antiretroviral therapy (ART), which may, e.g., be selected from any one or more of the following, or combinations thereof: efavirenz, emtricitabine, and tenofovir disoproxil fumarate (Atripla); emtricitabine, rilpivirine, and tenofovir disoproxil fumarate (Complera); elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (Stribild); lamivudine and zidovudine (Combivir); emtricitabine, FTC (Emtriva); lamivudine, 3TC (Epivir); abacavir and lamivudine (Ebzicom); zalcitabine, dideoxycytidine, ddC (Hivid); zidovudine, azidothymidine, AZT
- the additional therapeutic agent can also be an immunomodulator.
- the immunomodulator may be selected, e.g., from any one or more of the following, or combinations thereof: AS-101 , Bropirimine, Acemannan, CL246,738, EL10, FP-21399, Gamma Interferon, Granulocyte Macrophage Colony Stimulating Factor, HIV Core Particle Immunostimulant, IL-2, Immune Globulin Intravenous, IMREG-1 , IMREG-2, Imuthiol Diethyl Dithio Carbamate, Alpha-2 Interferon, Methionine-Enkephalin, MTP-PE, Muramyl-Tripeptide, Granulocyte Colony Stimulating Factor, Remune, CD4 (e.g., recombinant soluble CD4), rCD4-lgG hybrids, SK&F106528 Soluble T4, Thymopentin, Tumor Necrosis Factor, and Inflixima
- the additional therapeutic agent can also be a reservoir activator.
- the reservoir activator may be selected, e.g., from any one or more of the following, or combinations thereof: histone deacytelase (HDAC) inhibitors (e.g., romidepsin, vorinostat, and panobinostat), immunologic activators (e.g., cytokines and TLR agonists), and dedicated small molecule drugs.
- HDAC histone deacytelase
- romidepsin e.g., romidepsin, vorinostat, and panobinostat
- immunologic activators e.g., cytokines and TLR agonists
- dedicated small molecule drugs e.g., cytokines and TLR agonists
- Administration of an additional therapeutic agent may be prior to, concurrent with, or subsequent to the administration of ibalizumab (or of the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab).
- the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) is administered or used as a monotherapy, i.e. not in combination with an additional HIV drug.
- Example 1 Effect of ibalizumab in HAART-treated HIV-2-infected patients with multi-drug resistance (MDR) virus
- GIGHAART Optimized gigatherapy
- DBV/r darunavir/ritonavir 600/100 mg twice-a-day (b.i.d.) + atazanavir (ATV) 300 mg once-a- day (q.d.) + bictegravir/emtricitabine/Tenofovir (BIC/FTC/TAF) 50/200/25 mg q.d. + Dolutegravir (DTG) 50 mg q.d.
- GIGHAART darunavir/ritonavir (DRV/r) 600/100 mg twice-a-day (b.i.d.) + atazanavir (ATV) 300 mg once-a- day (q.d.) + bictegravir/emtricitabine/Tenofovir (BIC/FTC/TAF) 50/200/25 mg q.d.
- ZDV zidovudine 250 mg b.i.d.
- PFA phosphonoformate
- Ibalizumab Ibalizumab
- First dose single loading dose
- Plasma HIV-2 RNA pVL
- HIV-2 DNA were assessed by real time PCR.
- ARV trough plasma concentrations (Cmin) were determined using UPLC-MS/MS.
- Clinical data were collected every 2 weeks (W) as biological data on tolerance; HIV-2 RNA and CD4 count every 2W; plasma ARV concentrations every 4W; HIV-2 DNA every 12W.
- 11 HIV-2-infected patients with MDR virus could receive the above-noted regimen, four (4) of them during a > 12-week duration.
- the characteristics and results for these 4 patients are presented in Tables I to IV below, and the results for viral loads and CD4 cell counts are depicted in FIGs. 1A-D.
- Isolates from 6 HIV-2-infected persons, 1 from the ROD HIV-2 reference strain and the BRU HIV-1 reference strain were assessed for IBA inhibition and susceptibility.
- PHA-activated PBMC were incubated with increasing concentrations of ibalizumab for 1 hour, prior to infection with HIV-2.
- Two hours post-infection cells were washed then resuspended in complete RPMI media containing ibalizumab.
- HIV-2 replication was assessed on cell supernatant using a qRT-PCR-based assay (Generic HIV-2 Charge Virale, Biocentric, Cat. No. TR003-1101 C) .
- the phenotypic susceptibility to ibalizumab was assessed. All HIV-2 isolates were previously obtained by co-cultivation of PHA-activated PBMC pool obtained from healthy blood donors.
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Abstract
There are major differences in the susceptibility of human immunodeficiency virus type 1 (HIV-1) and human immunodeficiency virus type 2 (HIV-2) to currently available drugs, and novel approaches for the treatment of HIV-2 are needed. The present application relates to a method for treating infection by several HIV-2 strains/isolates, including multidrug resistant (MDR) HIV-2 strains, comprising administering to a subject in need thereof an effective amount of ibalizumab, or of an antibody or antigen-binding fragment thereof that binds the same antigenic epitope, or an overlapping epitope, as ibalizumab.
Description
TITLE OF INVENTION
USE OF IBALIZUMAB FOR THE TREATMENT OF HIV-2 INFECTION
CROSS REFERENCE TO RELATED APPLICATIONS
The present application claims the benefit of U.S. provisional application No. 62/909,087, filed on October 1, 2019, and of U.S. provisional application No. 62/960,966, filed on January 14, 2020, which are incorporated herein by reference in their entirety.
TECHNICAL FIELD
The present disclosure generally relates to the management of infections by the human immunodeficiency virus (HIV), and more particularly HIV-2 infection and related diseases.
BACKGROUND ART
HIV infection is responsible for the most devastating global pandemic of the last century. More than 39 million people have died of HIV/AIDS since 1981.
There are two major types of the human immunodeficiency virus. HIV-1 , which was discovered first, is the most widespread type worldwide. HIV-2 is more than 55% genetically different from HIV-1. HIV-2 is most common in western Africa and is becoming more common in India, although numbers there are still relatively small. Small numbers of cases have also been seen in Portugal, France, other European countries including the UK and the Americas, largely in individuals of west African origin or their sexual partners.
HIV-2 and HIV-1 infections lead to different immunological and clinical outcomes. Compared to HIV-1 patients, the majority of HIV-2-infected subjects have reduced general immune activation, higher CD4+ T-cell counts, low plasma viremia, and longer disease-free survival (Berry et al., J Hum Virol 1998, 1 :457-68; Drylewicz et a!., AIDS 2008, 22:457-68; Marlink et a!., Science 1994, 265: 1587-90; Poulsen et a/., Lancet 1997, 349: 911-14). Nevertheless, the mortality risk is equivalent in HIV-1 and HIV-2 infections (de Sylva et al., Trends Microbiol. 2008, 16:588-95; Drylewicz et al., 2008, supra ; Schim van der Loeff et al., AIDS 2002, 16: 1775-83; Rowland-Jones et al., Nat Immunol. 2007, 8: 329-31).
HIV infections are typically treated by highly active antiretroviral therapy (HAART), which employs a combination of nucleoside/nucleotide reverse transcriptase inhibitors (NRTIs), non-nucleoside reverse transcriptase inhibitors (NNRTIs), and/or protease inhibitors (Pis).
There are major differences in the susceptibility of HIV-1 and HIV-2 to currently available drugs, which is consistent with their high genetic variability. HIV-2 is naturally resistant to NNRTIs and is less sensitive to some Pis. Importantly, most HAART regimens used in HIV-1 patients are unable to fully suppress HIV-2 replication, to increase CD4+ T-cell counts or prevent appearance of drug-resistant mutations (Borrego and Taveira, AIDS Rev. 2013, 15:49-61).
Another class of HIV drugs are HIV entry inhibitors, which prevent the entry of the virus into cells. HIV entry into host cells is a complicated process that involves at least three steps: (1) an attachment step that requires CD4 receptor binding, (2) co-receptor binding, and (3) a fusion process. The envelope glycoprotein (Env) on the surface of virions mediates entry. Heterotrimeric Env spikes are composed of three surface glycoproteins (gp120) atop three transmembrane glycoproteins (gp41). The gp41 subunits, which assemble into a trimer, comprise the “stalk” of Env that anchors the Env into the viral membrane. The gp120 subunits comprise the “head” of Env that is able to bind to cellular receptors. Virions can first attach to target cells in a relatively nonspecific manner, followed by specific binding of HIV gp120 to the CD4 receptor on the cellular membrane. This binding induces a conformational change in gp120 that opens up a high-affinity binding site located within the third variable loop (V3) and surrounding surfaces for the chemokine co-receptors (primarily CCR5 and CXCR4). Co receptor binding results in further conformational rearrangements of gp120 that expose the fusion-peptide domain of gp41. Insertion of this hydrophobic domain into the cell membrane leads to the formation of a hairpin-like fold in the gp41 subunits. The heptad repeat (HR) regions, HR1 and HR2 of the three subunits of gp41 , fold and pack into a six-helix bundle, which brings the viral and cell membranes into juxtaposition and creates pores in the target cell membrane, enabling the release of viral capsid into the cytoplasm.
There are significant differences between the evolution of HIV-1 and HIV-2 Env glycoprotein during infection, and the mechanisms of viral entry, that lead to significant differences in the response to HIV entry inhibitors. For example, kinetic studies have shown that Env-mediated fusion is faster in HIV-2 than in HIV-1 , and the rate at which the coreceptor binding site in Env becomes exposed after CD4 binding is faster in HIV-2 than in HIV-1 (Gallo et ai. Retrovirology 2006, 3:90). Furthermore, some primary HIV-2 isolates may infect peripheral blood mononuclear cells (PBMCs) independently of the CCR5 and CXCR4 co-receptors, while others enter into CD4-negative cells via CCR5 or CXCR4 (Reeves et a!., J Virol. 1999, 73:7795- 804). HIV-2 isolates are typically less sensitive to recombinant soluble CD4 (rsCD4) than HIV-1 isolates. Also, the small molecule B S-378806, which binds gp120 with high affinity, has strong antiviral activity against HIV-1 but not against HIV-2.
There is thus a need for the development of novel approaches for the treatment of HIV- 2 infections.
The present description refers to a number of documents, the content of which is herein incorporated by reference in their entirety.
SUMMARY OF THE DISCLOSURE
The present disclosure generally relates to the management of infections by the human immunodeficiency virus (HIV), and more particularly HIV-2 infection and related diseases.
In various aspects and embodiments, the present disclosure provides the following items:
1. A method for treating infection by human immunodeficiency virus type 2 (HIV-2) comprising administering to a subject in need thereof an effective amount of ibalizumab or of an antibody or an antigen-binding fragment thereof that competes with ibalizumab for binding to human CD4, such as an antibody comprising the following complementary determining regions (CDRs): CDRL1 : QSLLYSTNQKNY (SEQ ID NO:3); CDRL2: WAS; CDRL3: QQYYS (SEQ ID NO:4); CDRH1 : GYTFTSYV (SEQ ID NO:5); CDRH2: INPYNDGT (SEQ ID NO:6) and CDRH3: AR, or an antibody comprising the variable region of the light chain of ibalizumab (residues 1-112 of SEQ ID NO:1) and/or the variable region of the heavy chain of ibalizumab (residues 1-122 of SEQ ID NO:2).
2. The method of item 1 , wherein said administering reduces HIV-2 viral load in the subject.
3. The method of item 2, wherein HIV-2 viral load is reduced by at least 0.5 logio.
4. The method of any one of items 1 to 3, wherein said administering increases or maintains CD4+ cell counts in the subject.
5. The method of any one of items 1 to 4, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is administered according to a dosage regimen comprising an initial administration at a first dose and one or more maintenance administrations at a second dose.
6. The method of item 5, wherein the first dose is about 1000 to about 3000 mg.
7. The method of item 6, wherein the first dose is about 2000 mg.
8. The method of any one of items 5 to 7, wherein the second dose is about 400 to about 1200 mg.
9. The method of item 8, wherein the second dose is about 800 mg.
10. The method of any one of items 1 to 9, wherein the ibalizumab is administered intravenously.
11. The method of any one of items 1 to 10, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is administered as a monotherapy.
12. The method of any one of items 1 to 10, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is administered in combination with at least one additional antiretroviral agent.
13. The method of item 12, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is administered in combination with highly active antiretroviral therapy (HAART).
14. The method of any one of items 1 to 13, wherein the subject is infected by an HIV-2 strain that is resistant to at least one antiretroviral agent.
15. The method of item 14, wherein the HIV-2 strain is resistant to at least one antiretroviral agent from each of three following three classes: Nucleoside reverse transcriptase inhibitors (NRTIs), Non-Nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pis).
16. The method of any one of items 1 to 15, wherein the HIV-2 is of the A or B subtype.
17. The method of any one of items 1 to 16, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is in a saline solution.
18. Use of ibalizumab or of an antibody or an antigen-binding fragment thereof that competes with ibalizumab for binding to human CD4, such as an antibody comprising the following complementary determining regions (CDRs): CDRL1 : QSLLYSTNQKNY (SEQ ID NO:3); CDRL2: WAS; CDRL3: QQYYS (SEQ ID NO:4); CDRH1 : GYTFTSYV (SEQ ID NO:5); CDRH2: INPYNDGT (SEQ ID NO:6) and CDRH3: AR, or an antibody comprising the variable region of the light chain of ibalizumab (residues 1-112 of SEQ ID NO:1) and/or the variable region of the heavy chain of ibalizumab (residues 1-122 of SEQ ID NO:2), for treating infection by human immunodeficiency virus type 2 (HIV-2) in a subject.
19. Use of ibalizumab or of an antibody or an antigen-binding fragment thereof that competes with ibalizumab for binding to human CD4, such as an antibody comprising the following complementary determining regions (CDRs): CDRL1 : QSLLYSTNQKNY (SEQ ID NO:3); CDRL2: WAS; CDRL3: QQYYS (SEQ ID NO:4); CDRH1 : GYTFTSYV (SEQ ID NO:5); CDRH2: INPYNDGT (SEQ ID NO:6) and CDRH3: AR, or an antibody comprising the variable region of the light chain of ibalizumab (residues 1-112 of SEQ ID NO:1) and/or the variable region of the heavy chain of ibalizumab (residues 1-122 of SEQ ID NO:2), for the preparation of a medicament for treating infection by human immunodeficiency virus type 2 (HIV-2) in a subject.
20. The use of item 18 or 19, wherein said use reduces HIV-2 viral load in the subject.
21 . The use of item 20, wherein HIV-2 viral load is reduced by at least 0.5 logio.
22. The use of any one of items 18 to 21 , wherein said use increases or maintains CD4+ cell counts in the subject.
23. The use of any one of items 18 to 22, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration according to a dosage regimen comprising an initial administration at a first dose and one or more maintenance administrations at a second dose.
24. The use of item 23, wherein the first dose is about 1000 to about 3000 mg.
25. The use of item 24, wherein the first dose is about 2000 mg.
26. The use of any one of items 23 to 25, wherein the second dose is about 400 to about 1200 mg.
27. The use of item 26, wherein the second dose is about 800 mg.
28. The use of any one of items 18 to 27, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for intravenous administration.
29. The use of any one of items 18 to 28, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration as a monotherapy.
30. The use of any one of items 18 to 28, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration in combination with at least one additional antiretroviral agent.
31 . The use of item 30, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration in combination with highly active antiretroviral therapy (HAART).
32. The use of any one of items 18 to 31 , wherein the subject is infected by an HIV-2 strain that is resistant to at least one antiretroviral agent.
33. The use of item 32, wherein the HIV-2 strain is resistant to at least one antiretroviral agent from each of three following three classes: Nucleoside reverse transcriptase inhibitors (NRTIs), Non-Nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pis).
34. The use of any one of items 18 to 33, wherein the HIV-2 is of the A or B subtype.
35. The use of any one of items 18 to 33, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is in a saline solution.
36. Ibalizumab or of an antibody or an antigen-binding fragment thereof that competes with ibalizumab for binding to human CD4, such as an antibody comprising the following complementary determining regions (CDRs): CDRL1 : QSLLYSTNQKNY (SEQ ID NO:3); CDRL2: WAS; CDRL3: QQYYS (SEQ ID NO:4); CDRH1 : GYTFTSYV (SEQ ID NO:5); CDRH2: INPYNDGT (SEQ ID NO:6) and CDRH3: AR, or an antibody comprising the variable region of the light chain of ibalizumab (residues 1-112 of SEQ ID NO:1) and/or the variable region of the heavy chain of ibalizumab (residues 1-122 of SEQ ID NO:2), for use in treating infection by human immunodeficiency virus type 2 (HIV-2) in a subject.
37. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of item
36, wherein said use reduces HIV-2 viral load in the subject.
38. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of item
37, wherein HIV-2 viral load is reduced by at least 0.5 logio.
39. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of any one of items 36 to 38, wherein said use increases or maintains CD4+ cell counts in the subject.
40. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of any one of items 36 to 39, wherein the antibody or antigen-binding fragment thereof, preferably
ibalizumab, is for administration according to a dosage regimen comprising an initial administration at a first dose and one or more maintenance administrations at a second dose.
41. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of item
40, wherein the first dose is about 1000 to about 3000 mg.
42. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of item
41 , wherein the first dose is about 2000 mg.
43. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of any one of items 40 to 42, wherein the second dose is about 400 to about 1200 mg.
44. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of item 43, wherein the second dose is about 800 mg.
45. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of any one of items 36 to 44, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for intravenous administration.
46. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of any one of items 36 to 45, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration as a monotherapy.
47. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of any one of items 36 to 45, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration in combination with at least one additional antiretroviral agent.
48. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of item 47, wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is for administration in combination with highly active antiretroviral therapy (HAART).
49. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of any one of items 36 to 48, wherein the subject is infected by an HIV-2 strain that is resistant to at least one antiretroviral agent.
50. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of item 49, wherein the HIV-2 strain is resistant to at least one antiretroviral agent from each of three following three classes: Nucleoside reverse transcriptase inhibitors (NRTIs), Non-Nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pis).
51. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of any one of items 36 to 50, wherein the HIV-2 is of the A or B subtype.
52. The antibody or antigen-binding fragment thereof, preferably ibalizumab, for use of any one of items 36 to 51 , wherein the antibody or antigen-binding fragment thereof, preferably ibalizumab, is in a saline solution.
Other objects, advantages and features of the present disclosure will become more apparent upon reading of the following non-restrictive description of specific embodiments thereof, given by way of example only with reference to the accompanying drawings.
BRIEF DESCRIPTION OF DRAWINGS
In the appended drawings:
FIG. 1A depicts graphs showing the viral RNA levels (upper graph) and CD4 counts (lower graph) at various time points over the study period in patient No. 1. DO GIGHAART, optimized gigatherapy; DO Iba, first dose ibalizumab; Stop Iba, end of ibalizumab treatment.
FIG. 1B depicts graphs showing the viral RNA levels (upper graph) and CD4 counts (lower graph) at various time points over the study period in patient No. 2.
FIG. 1C depicts graphs showing the viral RNA levels (upper graph) and CD4 counts (lower graph) at various time points over the study period in patient No. 3.
FIG. 1D depicts graphs showing the viral RNA levels (upper graph) and CD4 counts (lower graph) at various time points over the study period in patient No. 4.
FIG. 2A shows the amino acid sequence of the light chain of ibalizumab (SEQ ID NO:1), with the predicted complementary determining regions (CDRs) in bold and underlined.
FIG. 2B shows the amino acid sequence of the heavy chain of ibalizumab (SEQ ID NO:2), with the predicted complementary determining regions (CDRs) in bold and underlined.
FIG. 3A is a graph showing the effect of increasing concentrations of ibalizumab (0.001 to 10 pg/mL) on the replication of seven HIV-2 strains (ROD, AD, LE, DA, CL, SO and Dl).
FIG. 3B is a table showing the half-maximal inhibitory concentration (IC5o) and maximum percent inhibition (MPI) for the effect of ibalizumab on the replication of the seven HIV-2 strains.
DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS
In the studies described herein, it is shown that the anti-CD4 monoclonal antibody ibalizumab reduces viral load and/or increases or maintains CD4+ T-cell counts in patients infected with HIV-2, and has the ability to inhibit the replication of several strains of HIV-2 in vitro.
Ibalizumab, commercialized under the tradename Trogarzo®, is a human lgG4 anti- CD4 MAb derived from a murine MAb (mu5A8) that targets domain 2 of the CD4 receptor. It leads to conformational changes of the CD4 T cell receptor-gp120 complex thus preventing HIV fusion and entry. Whereas the antiviral activity of ibalizumab against HIV-1 is well documented and it has been approved by the FDA for the treatment of multidrug-resistant HIV-1 infection, its effects against HIV-2 infection have never been reported. As noted above, there are significant differences in the response to antiretroviral drugs such as HIV entry inhibitors between HIV-1 and HIV-2, and thus the effect of ibalizumab against HIV-2 cannot be predicted from its effect on HIV-1. Furthermore, experiments performed using the murine precursor of ibalizumab (MAb 5A8) have shown that it does not block rsCD4 enhancement of HIV-2 fusion in CD4+ T cells, thus strongly suggesting that ibalizumab would be ineffective against HIV-2 infection (Borrego
and Taveira, AIDS Reviews 2013; 15: 49-61). Thus, the beneficial effects of ibalizumab administration in HIV-2-infected patients reported herein could not be expected.
Accordingly, in an aspect, the present disclosure provides a method for treating infection by human immunodeficiency virus type 2 (HIV-2) comprising administering to a subject in need thereof an effective amount of ibalizumab, or of an antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab.
In another aspect, the present disclosure provides the use of ibalizumab, or of an antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab, for treating HIV-2 infection in a subject.
In another aspect, the present disclosure provides the use of ibalizumab, or of an antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab, for the manufacture of a medicament for treating HIV-2 infection in a subject.
In another aspect, the present disclosure provides ibalizumab, or an antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab, for treating HIV-2 infection in a subject.
Ibalizumab is a human lgG4 anti-CD4 Ab described in PCT publication No. WO 92/09305. The amino acid sequences of the light and heavy chains of ibalizumab are shown in FIG. 2A and FIG. 2B, respectively. Ibalizumab has been shown to bind a conformational epitope formed by amino acids L96, P121 , P122, and Q163 in domain 2 of human CD4, with residues E77 and S79 in domain 1 of CD4 also contributing. These residues cluster on the interface between domains 1 and 2 of human CD4 on a surface opposite the site where gp120 and the MHC-II molecule bind on domain 1 (Song et al., J Virol. 2010 Jul;84(14):6935-42). It has also been shown that amino acids 121 to 124 and 127 to 134, in domain 2 are important for binding of ibalizumab to CD4 (Burkly, L.C. et al., J. Immunol. 1992. 149:1779-1787). It may be predicted that other antibodies or antigen-binding fragments thereof that bind to the same epitope as ibalizumab, or to an epitope that at least partly overlaps with the epitope recognized by ibalizumab, would also be useful for blocking HIV-2 entry and treating HIV-2 infection in a subject. Such antibodies or antigen-binding fragments thereof may be identified, for example, by assessing whether they are able to compete with ibalizumab for binding to CD4, as shown for antibody M-T441 (Adipogen® Life Sciences, Cat. No. ANC-148-020) that binds an epitope that overlap with the epitope recognized by ibalizumab and competes with ibalizumab for binding to CD4 (Song et al., J Virol. 2010 Jul;84(14):6935-42). Thus, the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab competes with ibalizumab for binding to human CD4.
The antibody may be derived from ibalizumab, e.g. an antibody comprising an amino acid sequence having at least 50, 60, 70, 80, 90, 95, 96, 97, 98 or 99% sequence identity with
the sequence of ibalizumab (or the sequences of the heavy and light chain variable regions, or an antigen-binding fragment thereof. The antibody or antigen-binding fragment thereof may comprise the same complementarity determining regions (CDRs) as ibalizumab, combined with one or more framework regions (FRs) that differ from ibalizumab.
The term “antibody or antigen-binding fragment thereof as used herein refers to any type of antibody/antibody fragment including monoclonal antibodies (including full-length monoclonal antibodies), polyclonal antibodies, multispecific antibodies, humanized antibodies, CDR-grafted antibodies, chimeric antibodies and antibody fragments so long as they bind to the same epitope as ibalizumab, or to an epitope that at least partly overlaps with the epitope recognized by ibalizumab. Antibody fragments comprise a portion of a full-length antibody, generally an antigen binding or variable region thereof. Examples of antibody fragments include Fab, Fab', F(ab') , and Fv fragments, diabodies, linear antibodies, single-chain antibody molecules (e.g., single-chain FV, scFV), single domain antibodies (e.g., from camelids), shark NAR single domain antibodies, and multispecific antibodies formed from antibody fragments. Antibody fragments can also refer to binding moieties comprising CDRs or antigen binding domains including, but not limited to, VH regions (V , VH-VH), anticalins, PepBodies, antibody-T- cell epitope fusions (Troybodies) or Peptibodies.
In an embodiment, the antibody or antigen-binding fragment thereof comprises: a light chain variable region comprising the amino acid sequences QSLLYSTNQKNY (SEQ ID NO:3), WAS and QQYYS (SEQ ID NO:4) of the three light chain CDRs set forth in Fig. 2A; and a heavy chain variable region comprising the amino acid sequences GYTFTSYV (SEQ ID NO:5), INPYNDGT (SEQ ID NO:6) and AR of the three heavy chain CDRs set forth in Fig. 2B.
In an embodiment, the antibody or antigen-binding fragment thereof is an antibody comprising the variable region of the light chain defined the amino acid sequence of SEQ ID NO: 1 (residues 1-112) and the variable region of the heavy chain comprising the amino acid sequence of SEQ ID NO: 2 (residues 1-122).
In an embodiment, the antibody or antigen-binding fragment thereof is an antibody comprising a light chain comprising the amino acid sequence of SEQ ID NO: 1 and a heavy chain comprising the amino acid sequence of SEQ ID NO: 2.
In an embodiment, the administration or use reduces HIV-2 viral load in the subject. In an embodiment, the administration or use increases or maintains CD4+ cell counts in the subject. In another embodiment, the administration or use (i) reduces HIV-2 viral load and (ii) increases or stabilizes CD4+ cell counts, in the subject. In another embodiment, the administration or use reduces and maintains HIV-2 viral load at an undetectable level over a treatment period. In another embodiment, the administration or use maintains CD4+ cell counts at levels of 100 CD4+ cells/mI of blood or more in the subject, in further embodiments at levels of 125, 150, 175 or 200 CD4+ cells/mI of blood or more in the subject.
In embodiments, the baseline CD4+ cell count in the subject is 800 CD4+ cells/mI or less, 600 CD4+ cells/mI or less, 500 CD4+ cells/mI or less, 400 CD4+ cells/mI or less, 300 CD4+ cells/mI or less, 250 CD4+ cells/mI or less, or 200 CD4+ cells/mI or less.
In embodiments, the baseline viral load in the subject is 200 copies of RNA/ml of blood or more, 400 copies of RNA/ml of blood or more, 600 copies of RNA/ml of blood or more, 800 copies of RNA/ml of blood or more, 1000 copies of RNA/ml of blood or more, 1500 copies of RNA ml of blood or more, or 2000 copies of RNA/ml of blood or more.
The term “increases or maintains CD4+ cell counts” as used herein means that the CD4+ cell count in the subject does not decrease by 10% or more relative to the baseline CD4+ cell count (prior to the initiation of ibalizumab treatment) over a defined treatment period, i.e. the CD4+ cell count decreases by less than 10%, remains the same or increases relative to the baseline CD4+ cell count over a defined treatment period.
The term “reduces HIV-2 viral load” as used herein means that the viral load in the subject decreases by at least 10% relative to the baseline viral load (prior to the initiation of ibalizumab treatment) over a defined period. In an embodiment, the viral load in the subject decreases by at least 0.5 logi0 relative to the baseline viral load.
In an embodiment, the subject is co-infected by HIV-1. In another embodiment, the subject is not co-infected by HIV-1.
In an embodiment, the subject is infected by an HIV-2 strain or isolate that is resistant to antiretroviral therapy (ART), for example a multi-drug resistant (MDR) HIV-2 strain. In an embodiment, the HIV-2 strain or isolate is resistant to at least one antiretroviral agent or class of antiretroviral agents (e.g., NRTIs, NNRTIs, Pis, or Integrase Inhibitors). In an embodiment, the HIV-2 strain or isolate is resistant to at least two antiretroviral agents or classes of antiretroviral agents. In an embodiment, the HIV-2 strain or isolate is resistant to at least three antiretroviral agents or classes of antiretroviral agents. In an embodiment, the HIV-2 strain or isolate is resistant to at least one antiretroviral agent from each of three following three classes: NRTIs, NNRTIs and Pis. In an embodiment, the HIV-2 strain or isolate is resistant to salvage gigatherapy, for example the salvage gigatherapy regimen described at Example 1. The term “resistant to ART” means that administration of the antiretroviral agent(s) does not result in a decrease of the viral load to undetectable levels in the subject. In an embodiment, the viral load is stable or increases following administration of the antiretroviral agent(s).
In an embodiment, the subject is infected by an HIV-2 strain or isolate of the A, B, C, D or E subtype. In an embodiment, the subject is infected by an HIV-2 strain or isolate of the A subtype. In another embodiment, the subject is infected by an HIV-2 strain or isolate of the B subtype.
In an embodiment, the ibalizumab, or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab, is present in a
pharmaceutical composition with one or more pharmaceutically acceptable carriers or excipients. The carrier/excipient can be suitable, for example, for intravenous, parenteral, subcutaneous, or intramuscular administration. Therapeutic formulations are prepared using standard methods known in the art by mixing the active ingredient having the desired degree of purity with one or more optional pharmaceutically acceptable carriers, excipients and/or stabilizers (see Remington: The Science and Practice of Pharmacy, by Loyd V Allen, Jr, 2012, 22nd edition, Pharmaceutical Press; Handbook of Pharmaceutical Excipients, by Rowe et al., 2012, 7th edition, Pharmaceutical Press). In an embodiment, the ibalizumab is present in a pharmaceutical composition with a saline solution, e.g., a 0.9% NaCI solution.
Any suitable amount of the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab), or the pharmaceutical composition may be administered to a subject. The dosages will depend on many factors including the mode of administration. Typically, the amount of ibalizumab (or of the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) contained within a single dose will be an amount that effectively delay the progression or treat HIV-2 infection without inducing significant toxicity.
The appropriate dosage of the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) will depend on certain factors such as the severity and course of the disease or condition (e.g., AIDS), previous therapy, the patient's clinical history and response to the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab), and the discretion of the attending physician. The ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) is suitably administered to the patient at one time or over a series of treatments. The present disclosure provides dosages for the compounds and compositions comprising same. For example, depending on the type and severity of the disease, about 1 pg/kg to to 1000 mg per kg (mg/kg) of body weight per day. Further, the effective dose may be about 0.5 mg/kg, 1 mg/kg, 5 mg/kg, 10 mg/kg, 15 mg/kg, or 20 mg/kg to about 25 mg/kg, 30 mg/kg, 35 mg/kg, 40 mg/kg, 45 mg/kg, 50 mg/kg, 55 mg/kg, 60 mg/kg, 70 mg/kg, 75 mg/kg, 80 mg/kg, 90 mg/kg, 100 mg/kg, 125 mg/kg, 150 mg/kg, 175 mg/kg or 200 mg/kg, or may range between any two of the foregoing values. A typical daily dosage might range from about 1 mg/kg to 100 mg/kg, depending on the factors mentioned above. For repeated administrations over several days or longer, depending on the condition, the treatment may be sustained until a desired suppression of disease symptoms occurs, or may be continued for the lifetime of the patient. The progress of this therapy is easily monitored by conventional techniques and assays, such as the assays for measuring viral load and CD4 counts described herein.
The ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) may be administered according to a defined dosage regimen. In an embodiment, the treatment regimen comprises an initial administration/use at a first dose (single loading dose), and one or more maintenance administration(s)/use(s) at a second dose. In an embodiment, the second dose is lower than the first dose. In an embodiment, the first dose is about 1000 to about 3000 mg of ibalizumab (or of the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab), for example about 1200 to about 2800 mg, about 1500 to about 2500 mg, about 1800 mg to about 2200 mg, about 1900 mg to about 2100 mg, or about 2000 mg. In an embodiment, the second dose is about 200 mg to about 1400 mg of ibalizumab, for example about 400 to about 1200 mg, about 600 to about 1000 mg, about 700 mg to about 900 mg, or about 800 mg. In embodiments, the time interval between the initial administration/use and the first maintenance administration/use is from 1 week to 4 weeks, or from 1 week to 3 weeks, or about 2 weeks. In an embodiment, the time interval between the maintenance administrations/uses is from 1 week to 4 weeks, or from 1 week to 3 weeks, or about 2 weeks. In an embodiment, the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) is administered by intravenous, subcutaneous, or intramuscular administration.
In an embodiment, the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) is administered or used in combination with at least one additional therapeutic agent, e.g., an antiretroviral or HIV drug.
The additional therapeutic agent may also be an antiretroviral therapy (ART), which may, e.g., be selected from any one or more of the following, or combinations thereof: efavirenz, emtricitabine, and tenofovir disoproxil fumarate (Atripla); emtricitabine, rilpivirine, and tenofovir disoproxil fumarate (Complera); elvitegravir, cobicistat, emtricitabine, and tenofovir disoproxil fumarate (Stribild); lamivudine and zidovudine (Combivir); emtricitabine, FTC (Emtriva); lamivudine, 3TC (Epivir); abacavir and lamivudine (Ebzicom); zalcitabine, dideoxycytidine, ddC (Hivid); zidovudine, azidothymidine, AZT, ZDV (Retrovir); abacavir, zidovudine, and lamivudine (Trizivir); tenofovir disoproxil fumarate and emtricitabine (Truvada); enteric coated didanosine, ddl EC (Videx EC); didanosine, dideoxyinosine, ddl (Videx); tenofovir disoproxil fumarate, TDF (Viread); stavudine, d4T (Zerit); abacavir sulfate, ABC (Ziagen); Rilpivirine (Edurant); Etravirine (Intelence); delavirdine, DLV (Rescriptor); efavirenz, EFV (Sustiva) ; nevirapine, NVP (Viramune or Viramune XR); amprenavir, APV (Agenerase); tipranavir, TPV (Aptivus); indinavir, IDV (Crixivan); saquinavir (Fortovase); saquinavir mesylate, SQV (Invirase); lopinavir and ritonavir, LPV/RTV (Kaletra); Fosamprenavir Calcium, FOS-APV (Lexiva); ritonavir, RTV (Norvir); Darunavir (Prezista); atazanavir sulfate, ATV (Reyataz); nelfinavir mesylate, NFV (Viracept);
enfuvirtide, T-20 (Fuzeon); maraviroc (Selzentry); raltegravir, RAL (Isentress); and dolutegravir (Tivicay).
The additional therapeutic agent can also be an immunomodulator. The immunomodulator may be selected, e.g., from any one or more of the following, or combinations thereof: AS-101 , Bropirimine, Acemannan, CL246,738, EL10, FP-21399, Gamma Interferon, Granulocyte Macrophage Colony Stimulating Factor, HIV Core Particle Immunostimulant, IL-2, Immune Globulin Intravenous, IMREG-1 , IMREG-2, Imuthiol Diethyl Dithio Carbamate, Alpha-2 Interferon, Methionine-Enkephalin, MTP-PE, Muramyl-Tripeptide, Granulocyte Colony Stimulating Factor, Remune, CD4 (e.g., recombinant soluble CD4), rCD4-lgG hybrids, SK&F106528 Soluble T4, Thymopentin, Tumor Necrosis Factor, and Infliximab.
The additional therapeutic agent can also be a reservoir activator. The reservoir activator may be selected, e.g., from any one or more of the following, or combinations thereof: histone deacytelase (HDAC) inhibitors (e.g., romidepsin, vorinostat, and panobinostat), immunologic activators (e.g., cytokines and TLR agonists), and dedicated small molecule drugs.
Administration of an additional therapeutic agent may be prior to, concurrent with, or subsequent to the administration of ibalizumab (or of the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab).
In another embodiment, the ibalizumab (or the antibody or antigen-binding fragment thereof that binds the same antigenic epitope (or an overlapping epitope) as ibalizumab) is administered or used as a monotherapy, i.e. not in combination with an additional HIV drug.
MODE(S) FOR CARRYING OUT THE INVENTION
The present disclosure is illustrated in further detail by the following non-limiting examples.
Example 1 : Effect of ibalizumab in HAART-treated HIV-2-infected patients with multi-drug resistance (MDR) virus
Methods
The following salvage regimen was used: Optimized gigatherapy (GIGHAART) (darunavir/ritonavir (DRV/r) 600/100 mg twice-a-day (b.i.d.) + atazanavir (ATV) 300 mg once-a- day (q.d.) + bictegravir/emtricitabine/Tenofovir (BIC/FTC/TAF) 50/200/25 mg q.d. + Dolutegravir (DTG) 50 mg q.d. + zidovudine (ZDV) 250 mg b.i.d.) according to cumulative historical genotypic resistance results and to expected ARV interactions, associated first to phosphonoformate (PFA) (induction 90 mg/kg bid followed by maintenance 90 mg/kg/d or biweekly, depending on tolerance, then to Ibalizumab (Trogarzo®) using the following dosage regimen approved for HIV-1 infection: First dose (single loading dose) of 2000 mg IV infused over at least 30 min, followed 2 weeks later by maintenance doses of 800 mg IV every two weeks (q2weeks) infused over at least 15-30 min).
Plasma HIV-2 RNA (pVL) and HIV-2 DNA were assessed by real time PCR. ARV trough plasma concentrations (Cmin) were determined using UPLC-MS/MS.
Clinical data were collected every 2 weeks (W) as biological data on tolerance; HIV-2 RNA and CD4 count every 2W; plasma ARV concentrations every 4W; HIV-2 DNA every 12W.
Results
11 HIV-2-infected patients with MDR virus could receive the above-noted regimen, four (4) of them during a > 12-week duration. The characteristics and results for these 4 patients are presented in Tables I to IV below, and the results for viral loads and CD4 cell counts are depicted in FIGs. 1A-D.
No adverse events were observed. In 2 of 4 patients, HIV-2 RNA was undetectable at week 12 and 24, respectively, and CD4 counts rose above 200/mI_ in 3 patients. ARV Cmin was high, leading to maximal inhibitory quotient for MDR HIV-2, suggesting good adherence in patient 4. In patients 1 and 4, CD4 T cell counts started to decline shortly after the discontinuation of ibaluzimab administration, suggesting that ibaluzimab inhibits HIV-2-mediated CD4 T cell killing. Furthermore, patient 1 appears to be resistant to HAART as evidenced by the increase in viral RNA (with a decrease in CD4 counts) after HAART initiation, but a sharp decrease in viral RNA was measured following ibaluzimab administration (FIG. 1A). Administration of ibaluzimab was associated with an important increase, followed by the stabilization, of CD4 T cell counts in patient No. 3 (FIG. 1C).
Example 2: Effect of ibalizumab on the replication of several HIV-2 isolates
Methods
Isolates from 6 HIV-2-infected persons, 1 from the ROD HIV-2 reference strain and the BRU HIV-1 reference strain were assessed for IBA inhibition and susceptibility. PHA-activated PBMC were incubated with increasing concentrations of ibalizumab for 1 hour, prior to infection with HIV-2. Two hours post-infection, cells were washed then resuspended in complete RPMI media containing ibalizumab. At day 4 post-infection, HIV-2 replication was assessed on cell supernatant using a qRT-PCR-based assay (Generic HIV-2 Charge Virale, Biocentric, Cat. No. TR003-1101 C) . The phenotypic susceptibility to ibalizumab, as measured by Maximum Percent Inhibition (MPI), was assessed. All HIV-2 isolates were previously obtained by co-cultivation of PHA-activated PBMC pool obtained from healthy blood donors.
Results
The results depicted in FIGs. 3A and 3B show all seven HIV-2 isolates tested, including 3 subtype A and 4 subtype B isolates, are sensitive to ibalizumab, with IC5o ranging from 0.002 to 0.18 pg/mL, similar to that obtained with the HIV-1 reference strain (IC5o = 0.01 pg/mL). These results provide evidence that ibalizumab has broad anti-HIV-2 activity.
Although the present invention has been described hereinabove by way of specific embodiments thereof, it can be modified, without departing from the spirit and nature of the subject invention as defined in the appended claims. In the claims, the word "comprising" is used as an open-ended term, substantially equivalent to the phrase "including, but not limited to". The singular forms "a", "an" and "the" include corresponding plural references unless the context clearly dictates otherwise.
Claims
1. A method for treating infection by human immunodeficiency virus type 2 (HIV-2) comprising administering to a subject in need thereof an effective amount of ibalizumab.
2. The method of claim 1, wherein said administering reduces HIV-2 viral load in the subject.
3. The method of claim 2, wherein HIV-2 viral load is reduced by at least 0.5 logio.
4. The method of any one of claims 1 to 3, wherein said administering increases or maintains CD4+ cell counts in the subject.
5. The method of any one of claims 1 to 4, wherein the ibalizumab is administered according to a dosage regimen comprising an initial administration at a first dose and one or more maintenance administrations at a second dose.
6. The method of claim 5, wherein the first dose is about 1000 to about 3000 mg.
7. The method of claim 6, wherein the first dose is about 2000 mg.
8. The method of any one of claims 5 to 7, wherein the second dose is about 400 to about 1200 mg.
9. The method of claim 8, wherein the second dose is about 800 mg.
10. The method of any one of claims 1 to 9, wherein the ibalizumab is administered intravenously.
11. The method of any one of claims 1 to 10, wherein the ibalizumab is administered as a monotherapy.
12. The method of any one of claims 1 to 10, wherein the ibalizumab is administered in combination with at least one additional antiretroviral agent.
13. The method of claim 12, wherein the ibalizumab is administered in combination with highly active antiretroviral therapy (HAART).
14. The method of any one of claims 1 to 13, wherein the subject is infected by an HIV-2 strain that is resistant to at least one antiretroviral agent.
15. The method of claim 14, wherein the HIV-2 strain is resistant to at least one antiretroviral agent from each of three following three classes: Nucleoside reverse transcriptase inhibitors (NRTIs), Non-Nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pis).
16. The method of any one of claims 1 to 15, wherein the HIV-2 is of the A or B subtype.
17. The method of any one of claims 1 to 16, wherein the ibalizumab is in a saline solution.
18. Use of ibalizumab for treating infection by human immunodeficiency virus type 2 (HIV- 2) in a subject.
19. Use of ibalizumab for the preparation of a medicament for treating infection by human immunodeficiency virus type 2 (HIV-2) in a subject.
20. The use of claim 18 or 19, wherein said use reduces HIV-2 viral load in the subject.
21 . The use of claim 20, wherein HIV-2 viral load is reduced by at least 0.5 logi0.
22. The use of any one of claims 18 to 21 , wherein said use increases or maintains CD4+ cell counts in the subject.
23. The use of any one of claims 18 to 22, wherein the ibalizumab is for administration according to a dosage regimen comprising an initial administration at a first dose and one or more maintenance administrations at a second dose.
24. The use of claim 23, wherein the first dose is about 1000 to about 3000 mg.
25. The use of claim 24, wherein the first dose is about 2000 mg.
26. The use of any one of claims 23 to 25, wherein the second dose is about 400 to about
1200 mg.
27. The use of claim 26, wherein the second dose is about 800 mg.
28. The use of any one of claims 18 to 27, wherein the ibalizumab is for intravenous administration.
29. The use of any one of claims 18 to 28, wherein the ibalizumab is for administration as a monotherapy.
30. The use of any one of claims 18 to 28, wherein the ibalizumab is for administration in combination with at least one additional antiretroviral agent.
31. The use of claim 30, wherein the ibalizumab is for administration in combination with highly active antiretroviral therapy (HAART).
32. The use of any one of claims 18 to 31 , wherein the subject is infected by an HIV-2 strain that is resistant to at least one antiretroviral agent.
33. The use of claim 32, wherein the HIV-2 strain is resistant to at least one antiretroviral agent from each of three following three classes: Nucleoside reverse transcriptase inhibitors (NRTIs), Non-Nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pis).
34. The use of any one of claims 18 to 33, wherein the HIV-2 is of the A or B subtype.
35. The use of any one of claims 18 to 34, wherein the ibalizumab is in a saline solution.
36. Ibalizumab for use in treating infection by human immunodeficiency virus type 2 (HIV-2) in a subject.
37. The ibalizumab for use of claim 36, wherein said use reduces HIV-2 viral load in the subject.
38. The ibalizumab for use of claim 37, wherein HIV-2 viral load is reduced by at least 0.5 log-io.
39. The ibalizumab for use of any one of claims 36 to 38, wherein said use increases or maintains CD4+ cell counts in the subject.
40. The ibalizumab for use of any one of claims 36 to 39, wherein the ibalizumab is for administration according to a dosage regimen comprising an initial administration at a first dose and one or more maintenance administrations at a second dose.
41. The ibalizumab for use of claim 40, wherein the first dose is about 1000 to about 3000 mg.
42. The ibalizumab for use of claim 41 , wherein the first dose is about 2000 mg.
43. The ibalizumab for use of any one of claims 40 to 42, wherein the second dose is about 400 to about 1200 mg.
44. The ibalizumab for use of claim 43, wherein the second dose is about 800 mg.
45. The ibalizumab for use of any one of claims 36 to 44, wherein the ibalizumab is for intravenous administration.
46. The ibalizumab for use of any one of claims 36 to 45, wherein the ibalizumab is for administration as a monotherapy.
47. The ibalizumab for use of any one of claims 36 to 45, wherein the ibalizumab is for administration in combination with at least one additional antiretroviral agent.
48. The ibalizumab for use of claim 47, wherein the ibalizumab is for administration in combination with highly active antiretroviral therapy (HAART).
49. The ibalizumab for use of any one of claims 36 to 48, wherein the subject is infected by an HIV-2 strain that is resistant to at least one antiretroviral agent.
50. The ibalizumab for use of claim 49, wherein the HIV-2 strain is resistant to at least one antiretroviral agent from each of three following three classes: Nucleoside reverse transcriptase inhibitors (NRTIs), Non-Nucleoside reverse transcriptase inhibitors (NNRTIs) and protease inhibitors (Pis).
51 . The ibalizumab for use of any one of claims 36 to 50, wherein the HIV-2 is of the A or B subtype.
52. The ibalizumab for use of any one of claims 36 to 51 , wherein the ibalizumab is in a saline solution.
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