WO2015081158A1 - Procédé de traitement du vih par perturbation de la signalisation pd-1/pd-l1 - Google Patents

Procédé de traitement du vih par perturbation de la signalisation pd-1/pd-l1 Download PDF

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WO2015081158A1
WO2015081158A1 PCT/US2014/067547 US2014067547W WO2015081158A1 WO 2015081158 A1 WO2015081158 A1 WO 2015081158A1 US 2014067547 W US2014067547 W US 2014067547W WO 2015081158 A1 WO2015081158 A1 WO 2015081158A1
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chain variable
variable region
seq
heavy chain
light chain
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PCT/US2014/067547
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English (en)
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Stephen W. MASON
Scott Joseph BALSITIS
James Burton WHITNEY
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Bristol-Myers Squibb Company
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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
    • C07K16/2827—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 B7 molecules, e.g. CD80, CD86
    • 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
    • A61K39/395—Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • 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
    • A61K2039/505—Medicinal preparations containing antigens or antibodies comprising antibodies

Definitions

  • This invention relates to methods for treating an HIV patient comprising administering to the patient antibodies that disrupt the PD-1/PD-L1 signaling pathway.
  • PD-1 is a member of the Ig superfamily that is up regulated on activated lymphocytes and monocytes.
  • PD-1 is expressed on activated CD4 and CD8 T cells, B cells and myeloid cells.
  • Two cell surface glycoprotein ligands for PD-1 have been identified, Programmed Death Ligand-1 (PD-L1) and Programmed Death Ligand-2 (PD-L2).
  • PD-L1 is expressed on T cells, B cells, monocytes, macrophages and dendritic cells (DCs) and its expression can be induced by activation of T lymphocytes, monocytes, mactophages and DCs.
  • PD-L2 is expressed on non- lymphoid tissues and is up-regulated on monocytes and DCs after activation. The engagement of PD-1/PD-L1/2 inhibits CD3 -mediated T cell proliferation and cytokine production.
  • PD-1/PD-L1 has been shown to function as a negative regulator of immune responses to viral infections. It is known that PD-1 expression is increased on CD8 T cells during acute viral infections. However, it remains up-regulated on virus-specific CD8 T cells during chronic viral infections rendering those CD8 T cells "exhausted” with limited functional capacity.
  • This invention describes methods to block the PD-1/PD-L1 signaling pathway by administering anti-PD- Ll antibodies to subjects infected with HIV.
  • the present disclosure provides a method for treating a subject infected with HIV, which method comprises administering to the subject a composition comprising a therapeutically effective amount of an agent that disrupts, reduces or suppresses signaling from an inhibitory immunoregulator.
  • the agent may be an antibody (Ab).
  • the inhibitory immunoregulator may be a component of the PD-1/PD-L1 signaling pathway.
  • the Ab may disrupt the interaction between PD-1 and PD-Ll .
  • the Ab may be an anti-PD-Ll Ab.
  • cART combination anti-retroviral therapy
  • cART combination anti-retroviral therapy
  • FIGURES Figures 1A-1F Cross-competition of FITC-conjugated human anti-hPD-Ll mAbs for binding to human PD-L1 (hPD-Ll) expressed on CHO cells as described in Example 1.
  • Binding of labeled 10H10 was partially blocked by 10A5, 11E6 and 13G4 and was significantly blocked by itself; B, Binding of labeled 3G10 was significantly blocked by each of the tested anti-PD-Ll Abs except 10H10; C, Binding of labeled 10A5 was significantly blocked by each of the tested anti-PD-Ll Abs except 10H10; D, Binding of labeled 11E6 was significantly blocked by each of the tested anti-PD-Ll Abs except 10H10; and E, Binding of labeled 12A4 was significantly blocked by each of the tested anti-PD-Ll Abs except 10H10; and F, Binding of labeled 13G4 was significantly blocked by each of the tested anti-PD-Ll Abs except 10H10.
  • FIG. 2A and 2B Geometric mean for viral load rebound post-ARV treatment interruption (post-TI) for BMS-936559- treated and isotype control antibody-treated SIV- infected Rhesus macaques as described in Example 2 (Fig. 2A). Geometric mean for viral load rebound post-TI of responders and non-responders within the BMS-936559- treatment group (Fig. 2B). BMS-936559-treatment responders are defined as having slower rebound and viral load ⁇ 1000 RNA cp/mL for >3 weeks.
  • FIG. 3 Kinetics of viral load rebound post-ARV treatment interruption for individual animals from the BMS-936559-treated and isotype control groups of SIV- infected Rhesus macaques as described in Example 2.
  • the asterisks in figure legend are indicating Mama A*01, which is a Rhesus monkey HLA haplotype that may lead to spontaneous suppression of SIV.
  • FIGS 6 A and 6B Comparison of post-rebound (post-TI) with pre-ARV viral loads as described in Example 2. 4 of 8 in BMS-936559 -treated group have >2 log change in VL from pre-ARV (only 1 of 5 in isotype control group) (6A). A significant difference (p-value ⁇ 0.05 in Mann- Whitney U-test) in post-rebound VL between BMS- 936559- and isotype control-treated groups was observed (6B).
  • FIG. 7 Body weight (A), lymphocyte (B) and serum alanine aminotransferase levels (C) in ARV-suppressed SIV -infected Rhesus macques before antibody treatment (pre-mAb), during antibody administration (dose 1, 2,3, 4, 5) and after termination of ARVT (Post-TI), as indicated in Example 2.
  • FIG. 8 SIV-peptide specific cytokine responses (Interferon-gamma [IFNy], Tumor Necrosis Factor-Alpha [TNFa] and Interleukin-2 [IL-2]) in CD8+ T cells from lymph nodes of SIV-infected Rhesus macaques pre- and post-treatment with BMS- 936559 or isotype control antibody as described in Example 2.
  • IFNy Interferon-gamma
  • TNFa Tumor Necrosis Factor-Alpha
  • IL-2 Interleukin-2
  • a subject infected with HIV comprises administering to the subject a therapeutically effective amount of an Ab or an antigen-binding portion thereof that disrupts the interaction between the PD-1 receptor and its ligand, PD-Ll .
  • the Ab or antigen-binding portion thereof may bind specifically to PD-Ll .
  • cART combination anti-retro viral therapy
  • administering refers to the physical introduction of a composition comprising a therapeutic agent to a subject, using any of the various methods and delivery systems known to those skilled in the art.
  • Preferred routes of administration for Abs described herein include intravenous, intramuscular, subcutaneous or other parenteral routes of administration, for example by injection or infusion.
  • an Ab described herein can be administered via a non-parenteral route, such as a topical, epidermal or mucosal route of administration, for example, intranasally, orally, vaginally, rectally, sublingually or topically.
  • Administering can also be performed, for example, once, a plurality of times, and/or over one or more extended periods, such as once a month, once per two weeks, once a week, twice a week, or once per day.
  • an “antibody” shall include, without limitation, a glycoprotein
  • immunoglobulin which binds specifically to an antigen and comprises at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds, or an antigen- binding portion thereof.
  • H chain comprises a heavy chain variable region
  • V # a heavy chain constant region
  • the heavy chain constant region comprises three constant domains, Cm, Cm and Cm-
  • Each light chain comprises a light chain variable region (abbreviated herein as Vi or V K ) and a light chain constant region.
  • the light chain constant region is comprises one constant domain, C L .
  • the V# and V £ regions can be further subdivided into regions of hypervariability, termed
  • CDRs complementarity determining regions
  • FR framework regions
  • Each Y H and Vi comprises three CDRs and four FRs, arranged from amino-terminus to carboxy-terminus in the following order: FR1 , CDR1 , FR2, CDR2, FR3, CDR3, FR4.
  • the variable regions of the heavy and light chains contain a binding domain that interacts with an antigen.
  • the constant regions of the Abs may mediate the binding of the immunoglobulin to host tissues or factors, including various cells of the immune system (e.g., effector cells) and the first component (Clq) of the classical complement system.
  • Antibodies typically bind specifically to their cognate antigen with high affinity, reflected by a dissociation constant (K D ) of 10 "5 to 10 "11 M or less. Any K D greater than about 10 "4 M is generally considered to indicate nonspecific binding.
  • K D dissociation constant
  • an Ab that "binds specifically" to an antigen refers to an Ab that binds to the antigen and substantially identical antigens with high affinity, which means having a K D of 10 "7 M or less, 10 "8 M or less, 5 x 10 ⁇ 9 M or less, 10 ⁇ 9 M or less, or 10 "10 M or less, but does not bind with high affinity to unrelated antigens.
  • An antigen is "substantially identical" to a given antigen if it exhibits a high degree of sequence identity to the given antigen, for example, if it exhibits at least 80%, at least 90%, at least 95%, at least 97%, or at least 99% sequence identity to the sequence of the given antigen.
  • an Ab that binds specifically to human PD-Ll may also have cross-reactivity with PD-Ll antigens from certain non-human primate species.
  • An immunoglobulin may derive from any of the commonly known isotypes, including but not limited to IgA, secretory IgA, IgG and IgM.
  • IgG subclasses are also well known to those in the art and include but are not limited to human IgGl, IgG2, IgG3 and IgG4.
  • “Isotype” refers to the Ab class or subclass (e.g., IgM or IgGl) that is encoded by the heavy chain constant region genes.
  • antibody includes, by way of example, both naturally occurring and non-naturally occurring Abs; monoclonal and polyclonal Abs; chimeric and humanized Abs; human or nonhuman Abs; wholly synthetic Abs; and single chain Abs.
  • a nonhuman Ab may be humanized by recombinant methods to reduce its immunogenicity in man.
  • the term "antibody” also includes an antigen-binding fragment or an antigen-binding portion of any of the aforementioned immunoglobulins, and includes a monovalent and a divalent fragment or portion, and a single chain Ab.
  • an "isolated antibody” refers to an Ab that is substantially free of other Abs having different antigenic specificities (e.g., an isolated Ab that binds specifically to PD- Ll is substantially free of Abs that bind specifically to antigens other than PD-Ll).
  • An isolated Ab that binds specifically to PD-Ll may, however, have cross-reactivity to other antigens, such as PD-Ll molecules from different species.
  • an isolated Ab may be substantially free of other cellular material and/or chemicals.
  • an "isolated" nucleic acid refers to a nucleic acid composition of matter that is markedly different, i.e., has a distinctive chemical identity, nature and utility, from nucleic acids as they exist in nature.
  • an isolated DNA unlike native DNA, is a free-standing portion of a native DNA and not an integral part of a larger structural complex, the chromosome, found in nature.
  • an isolated DNA unlike native genomic DNA, can typically be used in applications or methods for which native genomic DNA is unsuited, e.g., as a PCR primer or a hybridization probe for, among other things, measuring gene expression and detecting biomarker genes or mutations for diagnosing disease or assessing the efficacy of a therapeutic.
  • An isolated nucleic acid may be purified so as to be substantially free of other cellular components or other contaminants, e.g., other cellular nucleic acids or proteins, using standard techniques well known in the art. Examples of isolated nucleic acids include fragments of genomic DNA, PCR- amplified DNA, cDNA and RNA.
  • mAb monoclonal antibody
  • MAbs refers to a preparation of Ab molecules of single molecular composition, i.e., Ab molecules whose primary sequences are essentially identical, and which exhibits essentially a single binding specificity and affinity for a particular epitope.
  • a mAb is an example of an isolated Ab.
  • MAbs may be produced by hybridoma, recombinant, transgenic or other techniques known to those skilled in the art.
  • Human antibody refers to an Ab having variable regions in which both the framework and CDR regions are derived from human germline immunoglobulin sequences. Furthermore, if the Ab contains a constant region, the constant region also is derived from human germline immunoglobulin sequences.
  • the human Abs of the invention may include amino acid residues not encoded by human germline
  • immunoglobulin sequences e.g. , mutations introduced by random or site-specific mutagenesis in vitro or by somatic mutation in vivo.
  • human antibody as used herein, is not intended to include Abs in which CDR sequences derived from the germline of another mammalian species, such as a mouse, have been grafted onto human framework sequences.
  • a “humanized” antibody refers to an Ab in which some, most or all of the amino acids outside the CDR domains of a non-human Ab are replaced with corresponding amino acids derived from human immunoglobulins. In one embodiment of a humanized form of an Ab, some, most or all of the amino acids outside the CDR domains have been replaced with amino acids from human immunoglobulins, whereas some, most or all amino acids within one or more CDR regions are unchanged. Small additions, deletions, insertions, substitutions or modifications of amino acids are permissible as long as they do not abrogate the ability of the Ab to bind to a particular antigen.
  • a "humanized” Ab retains an antigenic specificity similar to that of the original Ab.
  • a “chimeric antibody” refers to an Ab in which the variable regions are derived from one species and the constant regions are derived from another species, such as an Ab in which the variable regions are derived from a mouse Ab and the constant regions are derived from a human Ab.
  • an “antigen-binding portion" of an Ab refers to one or more fragments of an Ab that retain the ability to bind specifically to the antigen bound by the whole Ab.
  • an “immune response” refers to the action of a cell of the immune system (for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils) and soluble macromolecules produced by any of these cells or the liver (including Abs, cytokines, and complement) that results in selective targeting, binding to, damage to, destruction of, and/or elimination from a vertebrate's body of invading pathogens, cells or tissues infected with pathogens, cancerous or other abnormal cells, or, in cases of autoimmunity or pathological inflammation, normal human cells or tissues.
  • a cell of the immune system for example, T lymphocytes, B lymphocytes, natural killer (NK) cells, macrophages, eosinophils, mast cells, dendritic cells and neutrophils
  • soluble macromolecules produced by any of these cells or the liver (including Abs, cytokines, and complement) that results
  • an “immunoregulator” refers to a substance, an agent, a signaling pathway or a component thereof that regulates an immune response. "Regulating,” “modifying” or
  • modulating an immune response refers to any alteration in a cell of the immune system or in the activity of such cell. Such regulation includes stimulation or suppression of the immune system which may be manifested by an increase or decrease in the number of various cell types, an increase or decrease in the activity of these cells, or any other changes which can occur within the immune system.
  • Treatment or “therapy” of a subject refers to any type of intervention or process performed on, or the administration of an active agent to, the subject with the objective of reversing, alleviating, ameliorating, inhibiting, slowing down or preventing the onset, progression, development, severity or recurrence of a symptom, complication, condition or biochemical indicia associated with a disease.
  • effectiveness or potency of an existing immune response in a subject may be achieved, for example, by overcoming mechanisms that suppress the endogenous host immune response or by stimulating mechanisms that enhance the endogenous host immune response.
  • the "Programmed Death- 1 (PD-1)" receptor refers to an immunoinhibitory receptor belonging to the CD28 family. PD-1 is expressed predominantly on previously activated T cells in vivo, and binds to two ligands, PD-L1 and PD-L2.
  • the term "PD-1” as used herein includes human PD-1 (hPD-1), variants, iso forms, and species homo logs of hPD-1, and analogs having at least one common epitope with hPD-1. The complete hPD-1 sequence can be found under GENBANK® Accession No. U64863.
  • P-L1 Programmed Death Ligand-1
  • PD-L1 is one of two cell surface glycoprotein ligands for PD-1 (the other being PD-L2) that downregulate T cell activation and cytokine secretion upon binding to PD-1.
  • the term "PD-L1” as used herein includes human PD-L1 (hPD-Ll), variants, iso forms, and species homo logs of hPD-Ll, and analogs having at least one common epitope with hPD-Ll .
  • the complete hPD-Ll sequence can be found under GENBANK® Accession No. Q9NZQ7.
  • a “signal transduction pathway” or “signaling pathway” refers to the biochemical relationship between a variety of signal transduction molecules that play a role in the transmission of a signal from one portion of a cell to another portion of the cell.
  • a “cell surface receptor” includes, for example, molecules and complexes of molecules that are located on the surface of a cell and are capable of receiving a signal and transmitting such a signal across the plasma membrane of a cell.
  • An “inhibitor” of signaling refers to a compound or agent that antagonizes or reduces the initiation, reception or transmission of a signal, be that signal stimulatory or inhibitory, by any component of a signaling pathway such as a receptor or its ligand.
  • Antiretroviral ARV
  • cART combination antiretroviral therapy
  • Entry Inhibitors interfere with the virus' ability to bind to receptors on the outer surface of the cell in which it is trying to enter. When receptor binding fails, HIV cannot infect the cell.
  • Fusion Inhibitors interfere with the virus's ability to fuse with a cellular membrane, preventing HIV from entering a cell.
  • Reverse Transcriptase Inhibitors prevent the HIV enzyme reverse transcriptase (RT) from converting single-stranded HIV RNA into double-stranded HIV DNA (a process called reverse transcription).
  • RT inhibitors There are two types of RT inhibitors, nucleoside/nucleotide RT inhibitors (NRTIs) and non-nucleoside RT inhibitors (NNRTIs).
  • NRTIs are faulty DNA building blocks. When one of these faulty building blocks is added to a growing HIV DNA chain, no further correct DNA building blocks can be added, thereby halting HIV DNA synthesis.
  • NNRTIs bind to RT, thereby interfering with its ability to convert HIV RNA into HIV DNA.
  • Integrase Inhibitors block the HIV enzyme integrase, which the virus uses to integrate its genetic material into the DNA of the cell it has infected.
  • protease Protease Inhibitors
  • ART anti-retroviral therapy
  • cART combination anti-retro viral therapy
  • HAART highly active anti-retroviral therapy
  • a “subject” includes any human or nonhuman animal.
  • the term “nonhuman animal” includes, but is not limited to, vertebrates such as nonhuman primates, sheep, dogs, cats, rabbits and ferrets, rodents such as mice, rats and guinea pigs, avian species such as chickens, amphibians, and reptiles.
  • the subject is a mammal such as a nonhuman primate, sheep, dog, cat, rabbit, ferret or rodent.
  • the subject is a primate.
  • the subject is a human such as a human patient.
  • the terms, "subject,” “patient” and “individual” are used interchangeably herein.
  • a subject who is currently on combination anti-retroviral therapy (cART) treatment means that the subject is currently being treated with a cART regimen.
  • the subject who is currently being treated with a cART regimen may have been treated with a different cART regimen before switching to the current cART regimen.
  • the subject who is currently on combination anti-retroviral therapy (cART) treatment may have been on cART treatment for a period of time but with different cART regimens.
  • a stable cART regimen means there are no changes in the components of the antiretroviral therapy for a period of time, for example, at least 30, 60, 90, 120, or 180 days, or 1, 2, or 3 years.
  • any concentration range, percentage range, ratio range or integer range is to be understood to include the value of any integer within the recited range and, when appropriate, fractions thereof (such as one tenth and one hundredth of an integer), unless otherwise indicated.
  • a subject infected with HIV comprising administering to the subject a therapeutically effective amount of an Ab or an antigen- binding that binds specifically to PD-L1.
  • the subject may be currently on combination anti-retro viral therapy (cART) treatment.
  • the cART treatment (or regimen) may comprise at least two drugs.
  • the cART treatment (or regimen) may comprise at least three drugs.
  • the cART treatment may comprise at least three anti-retroviral drugs selected from entry inhibitors, fusion inhibitors, reverse transcriptase (RT) inhibitors, nucleoside/nucleotide RT inhibitors, non- nucleoside RT inhibitors, integrase inhibitors, and protease inhibitors.
  • the cART treatment or regimen may comprise an integrase inhibitor, a non-nucleoside reverse transcriptase inhibitor (NNRTI), and a protease inhibitor (PI).
  • the cART treatment or regimen may comprise at least four drugs.
  • the patient may have been on cART treatment for at least 1, 2, 3, 4, 5, 6, 8, 9, 12, 18, 24, 36 or 48 months.
  • the patient may have been on cART treatment for at least 1 year.
  • the patient may have been on cART treatment for at least 2 years.
  • the patient may have been on a stable cART regimen with no changes in the components of the antiretroviral therapy for at least 30, 60, 90, 120, 180 days or 1 year. In some embodiments, the patient may have been on a stable cART regimen with no changes in the components of the
  • the subject may have a suppressed viral load (VL).
  • VL suppressed viral load
  • the term "suppressed VL” means a reduced VL as compared to the VL before the patient started any cART treatment (pre-cART treatment VL).
  • the subject may have a suppressed VL before the antibody or an antigen-binding portion thereof is administered.
  • the subject may have a suppressed VL of less than 2000, less than 1000, less than 500, less than 200, less than 100, less than 50, less than 40, less than 30, less than 20, or less than 10 RNA copies/mL.
  • the subject may have a suppressed VL of less than 1000 RNA copies/mL before the antibody or an antigen-binding portion thereof is administered.
  • the subject may have a suppressed VL of less than 100 RNA copies/mL before the antibody or an antigen- binding portion thereof is administered. In some embodiments, the subject may have a suppressed VL of less than 50 RNA copies/mL before the antibody or an antigen-binding portion thereof is administered. In some embodiments, the subject may have a fully suppressed VL.
  • "fully suppressed VL” means VL below the limit of detection for commonly used commercial and FDA approved methods. In some embodiments, a suppressed VL is less than 20 or 40 RNA copies/mL, which is the limit of detection for the tests typically used to quantify HIV VL in infected patients (e.g. ⁇ 40 copies/mL obtained by the Abbott m2000 assay or ⁇ 20 copies/mL by the Roche
  • the method may further comprise removing the cART treatment after the antibody or an antigen-binding portion thereof is administered.
  • Removing the cART treatment means stopping or suspending temporarily, or permanently, the cART treatment.
  • the viral load of the subject may be suppressed after the cART treatment is removed ("post-ARV interruption").
  • the term “suppressed VL” means a reduced VL as compared to the pre-cART treatment VL.
  • the viral load, after the cART treatment is removed may be less than 2000, less than 1000, less than 500, less than 200, less than 100, less than 50 RNA, or less than 20 copies/mL or below the limit of detection for commonly used commercial and FDA approved methods.
  • the viral load may be suppressed for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 36, or 48 weeks, or at least 1, 2, or 3 years after the cART treatment is removed. In some embodiments, the viral load may be suppressed for at least 3 weeks after the cART treatment is removed. In some embodiments, the viral load may be suppressed for at least 4 weeks after the cART treatment is removed. In some embodiments, the viral load may be suppressed for at least 6 weeks after the cART treatment is removed. In some embodiments, the viral load may be suppressed for at least 3 months after the cART treatment is removed. In some embodiments, the viral load may be suppressed for at least 6 months after the cART treatment is removed.
  • the viral load, after the cART treatment is removed may be less than 2000, less than 1000, less than 500, less than 200, less than 100, less than 50 RNA, or less than 20 copies/mL or below the limit of detection for commonly used commercial and FDA approved methods, for at least 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 36, or 48 weeks, or at least 1, 2, or 3 years.
  • the viral load, after the cART treatment is removed may be less than 1000 RNA copies/mL for at least 6 weeks, or 3, 6, 9, 12, 18, 24, or 36 months.
  • the viral load, after the cART treatment is removed may be less than 1000 RNA copies/mL for at least 6 weeks.
  • the viral load, after the cART treatment is removed may be less than 1000 RNA copies/mL for at least 3 months. In some embodiments, the viral load, after the cART treatment is removed, may be less than 1000 RNA copies/mL for 3-6 months. In some embodiments, the viral load, after the cART treatment is removed, may be less than 1000 RNA copies/mL for at least 6 months.
  • the viral load, after the cART treatment is removed may be less than 50 RNA copies/mL for at least 6 weeks, or 3, 6, 9, 12, 18, 24, or 36 months. In some embodiments, the viral load, after the cART treatment is removed, may be less than 50 RNA copies/mL for at least 6 weeks. In some embodiments, the viral load, after the cART treatment is removed, may be less than 50 RNA copies/mL for at least 3 months. In some embodiments, the viral load, after the cART treatment is removed, may be less than 50 RNA copies/mL for 3-6 months. In some embodiments, the viral load, after the cART treatment is removed, may be less than 50 RNA copies/mL for at least 6 months.
  • the viral load, after the cART treatment is removed may be less than 20 RNA copies/mL for at least 3 months. In some embodiments, the viral load, after the cART treatment is removed, may be less than 20 RNA copies/mL for at least 6 months. In some embodiments, the viral load, after the cART treatment is removed, may be below the limit of detection for a commonly used commercial and FDA approved method for at least 3 months. In some embodiments, the sustained viral load of the subject is below the limit of detection for a commonly used commercial and FDA approved method for at least 6 months.
  • the viral load may be suppressed following an initial viral load rebound after the cART treatment is removed.
  • initial viral load rebound means an increase in VL as compared to the VL before the cART treatment is removed.
  • Anti-PD-Ll Antibodies Each of the anti-PD-Ll HuMAbs disclosed in U.S. Patent No. 7,943,743, which is incorporated by reference herein in its entirety, has been demonstrated to exhibit one or more of the following characteristics (a) binds to human PD-Ll with a K D of 1 x 10 ⁇ 7 M or less; (b) inhibits the binding of PD-Ll to PD-1; (c) reverses exhaustion of virus- specific T cell observed during chronic infections and (d) reverses the suppressive effect of T regulatory cells on T cell effector cells and/or dendritic cells.
  • an anti-PD-Ll Ab or antigen-binding portion thereof may bind specifically to human PD-Ll wherein the antibody exhibits at least one of the following properties:
  • (d) increases interleukin-2 (IL-2) secretion in an MLR or similar assay.
  • IL-2 interleukin-2
  • Exemplary anti-PD-Ll Abs include the anti-PD-Ll HuMAbs 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 disclosed in U.S. Patent No. 7,943,743.
  • the antibody or an antigen-binding portion thereof may be an IgGl, IgG2 or IgG4 isotype.
  • the antibody or an antigen-binding portion thereof may be an antibody fragment or a single chain antibody.
  • the antibody or an antigen-binding portion thereof may bind to human PD- Ll with a K D of lx 10 "8 M or less, 5xlO ⁇ 9 M or less, 2xlO ⁇ 9 M or less, or lxlO ⁇ 9 M or less. In some embodiments, the antibody or an antigen-binding portion thereof may bind to human PD-Ll with a K D of 2xlO ⁇ 9 M or less.
  • an anti-PD-Ll Ab or antigen-binding portion thereof may bind specifically to human PD-Ll and comprise: (a) a human heavy chain variable region comprising the sequence set forth in SEQ ID NO: 1 and a human light chain variable region comprising the sequence set forth in SEQ ID NO: 11; (b) a human heavy chain variable region comprising the sequence set forth in SEQ ID NO: 2 and a human light chain variable region comprising the sequence set forth in SEQ ID NO: 12; (c) a human heavy chain variable region comprising the sequence set forth in SEQ ID NO: 3 and a human light chain variable region comprising the sequence set forth in SEQ ID NO: 13; (d) a human heavy chain variable region comprising the sequence set forth in SEQ ID NO: 4 and a human light chain variable region comprising the sequence set forth in SEQ ID NO: 14; (e) a human heavy chain variable region comprising the sequence set forth in SEQ ID NO: 5 and a human light chain variable region comprising the sequence set forth in SEQ
  • V# and Y L sequences can be "mixed and matched" to create other anti-PD-Ll Abs of the invention.
  • PD-L1 binding of such "mixed and matched" Abs can be tested using binding assays e.g., ELISAs, western blots, radioimmunoassays and BIACORE® analysis that are well known in the art ⁇ see, e.g., U.S. Patent No. 7,943,743).
  • binding assays e.g., ELISAs, western blots, radioimmunoassays and BIACORE® analysis that are well known in the art ⁇ see, e.g., U.S. Patent No. 7,943,743).
  • a Y H sequence from a particular V#/V L pairing may be replaced with a structurally similar Y H sequence.
  • an anti-PD-Ll Ab, or antigen binding portion thereof may bind specifically to human PD-L1 and comprise:
  • a heavy chain variable region comprising an amino acid sequence selected from SEQ ID NOs: l, 2, 3, 4, 5, 6, 7, 8, 9, and 10;
  • the anti-PD-Ll Abs or antigen-binding portions thereof may bind specifically to PD-L1 and comprise a heavy chain variable region derived from a particular germline heavy chain immunoglobulin and/or a light chain variable region derived from a particular germline light chain immunoglobulin.
  • the anti-PD-Ll Abs may comprise: (a) a heavy chain variable region comprising a sequence derived from a human Y H 1-18, 1-69, 1-3 or 3-9 germline sequence, and/or a light chain variable region comprising a sequence derived from a human V K L6, LI 5, A27 or LI 8 germline sequence.
  • a heavy chain variable region comprising a sequence derived from a human Y H 1-18, 1-69, 1-3 or 3-9 germline sequence
  • a light chain variable region comprising a sequence derived from a human V K L6, LI 5, A27 or LI 8 germline sequence.
  • Exemplary amino acid sequences of the and V K regions encoded by the Y H 1-18, Y H 1-3, V H 1-69, Y H 3-9, V K L6, V K L15 and V K A27 germline genes are provided in U.S. Patent No. 7,943,743.
  • the antibody or antigen-binding portions thereof may comprise: (a) a heavy chain variable region that comprises a sequence derived from a human Y 1-18 germline sequence, and a light chain variable region that comprises a sequence derived from a human V K L6 germline sequence; (b) a heavy chain variable region that comprises a sequence derived from a human Y H 1-69 germline sequence, and a light chain variable region that comprises a sequence derived from a human V K L6 germline sequence; (c) a heavy chain variable region that comprises a sequence derived from a human Y 1-3 germline sequence, and a light chain variable region that comprises a sequence derived from a human V K L15 germline sequence; (d) a heavy chain variable region that comprises a sequence derived from a human Y H 1-69 germline sequence, and a light chain variable region that comprises a sequence derived from a human V K A27 germline sequence; (e) a heavy chain variable region that comprises a sequence derived from a
  • An example of an Ab having a Y H and a V K derived from Y H 1-18 and V K L6 germline sequences, respectively, is 3G10.
  • Examples of Abs having and V K regions derived from Y H 1-69 and V K L6 germline sequences, respectively, include 12A4, 1B12, 7H1 and 12B7.
  • An example of an Ab having a Y H and a V K derived from Y H 1-3 and V K L15 germline sequences, respectively, is 10A5.
  • Examples of Abs having Y H and V K regions derived from V H 1-69 and V K A27 germline sequences, respectively, include 5F8, 11E6 and 1 lE6a.
  • An example of an Ab having a V # and a V K derived from V H 3-9 and V K L15 germline sequences, respectively, is 10H10.
  • An example of an Ab having a Y H and a V K derived from 1-3 and V K L15 germline sequences, respectively, is 10A5.
  • An example of an Ab having a V# and a V K derived from V# 3-9 and V K LI 8 germline sequences, respectively, is 13G4.
  • anti-PD-Ll Abs or antigen-binding portion thereof may comprise heavy and light chain variable regions having amino acid sequences that are highly similar, homologous or identical to the amino acid sequences of the exemplary anti-PD-Ll Abs described herein, wherein the Ab retains the functional properties of the exemplary anti-PD-Ll Abs.
  • the anti-PD-Ll Abs may include mAbs comprising a heavy chain variable region and a light chain variable region, wherein the heavy chain variable region comprises a sequence that is at least 80%, 85%, 90%, 95%, 96%), 97%), 98%o or 99% identical to an amino acid sequence selected from SEQ ID NOs.
  • the anti-PD-Ll Abs may comprise a heavy chain variable region comprising a sequence that is at least 95% identical to an amino acid sequence selected from SEQ ID NOs. 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, and a light chain variable region comprising a sequence that is at least 95% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs. 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
  • the anti-PD-Ll Abs may comprise a heavy chain variable region comprising a sequence that is at least 98% identical to an amino acid sequence selected from SEQ ID NOs. 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10, and a light chain variable region comprising a sequence that is at least 98% identical to an amino acid sequence selected from the group consisting of SEQ ID NOs. 11, 12, 13, 14, 15, 16, 17, 18, 19, and 20.
  • the anti-PD-Ll Abs may comprise (a) a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: l, and a light chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: l 1; (b) a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2, and a light chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 12; (c) a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:3, and a light chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 13; (d) a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:4, and a light chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 14; (e) a heavy chain variable region comprising an
  • the anti-PD-Ll Abs or antigen-binding portion thereof may comprise a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2, and a light chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 12.
  • the anti-PD-Ll Abs or antigen-binding portion thereof may comprise a heavy chain variable region comprising SEQ ID NO:2, and a light chain variable region comprising SEQ ID NO: 12.
  • the CDR domains of the above anti-PD-Ll HuMAbs have been delineated using the Kabat system, and these Abs may also be defined by combinations of their 3 heavy chain and 3 light chain CDRs (for example, see U.S. Patent No.
  • each of these Abs can bind to PD-Ll and antigen-binding specificity is provided primarily by the CDRl , CDR2, and CDR3 regions
  • the V H CDRl , CDR2, and CDR3 sequences and V K CDRl, CDR2, and CDR3 sequences can be "mixed and matched" (i.e., CDRs from different Abs can be mixed and match, although each Ab contains a V H CDRl, CDR2, and CDR3 and a V K CDRl, CDR2, and CDR3) to create other anti-PD-Ll Abs that also constitute Abs of the invention.
  • PD-Ll binding of such "mixed and matched" Abs can be tested using, for example, ELISAs, western blots, radioimmunoassays and BIACORE® analysis.
  • anti-PD-Ll Abs may comprise heavy and light chain variable regions each comprising CDRl, CDR2 and CDR3 domains, wherein one or more of these CDR domains comprise sequences that are the same as the CDR sequences of the anti-PD-Ll Abs described herein (e.g., 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 and 13G4), or conservative modifications thereof, and wherein the Abs retain the desired functional properties of the preferred anti-PD-Ll Abs of the invention.
  • CDR sequences of the anti-PD-Ll Abs described herein e.g., 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 and 13G4
  • anti- PD-Ll Abs of the invention include isolated Abs comprising 6 CDRs, wherein the Abs are defined by specifying the sequence of the heavy chain CDR3 domain.
  • the V H and/or V L amino acid sequences may exhibit at least 95%, 96%, 97%, 98% or 99% identity to the sequences described herein and have the same V H CDRl, CDR2, and CDR3 or V K CDRl, CDR2, and CDR3 as the sequences.
  • the anti-PD-Ll Abs or antigen-binding portion thereof may comprise a heavy chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO:2, and a light chain variable region comprising an amino acid sequence that is at least 95% identical to SEQ ID NO: 12; and (a) a heavy chain variable region CDRl comprising SEQ ID NO:22; (b) a heavy chain variable region CDR2 comprising SEQ ID NO:32; (c) a heavy chain variable region CDR3 comprising SEQ ID NO:42; (d) a light chain variable region CDR1 comprising SEQ ID NO:52; (e) a light chain variable region CDR2 comprising SEQ ID NO: 62; and (f) a light chain variable region CDR3 comprising SEQ ID NO: 72.
  • the anti-PD-Ll Abs or antigen-binding portion thereof may comprise (a) a heavy chain variable region CDR1 comprising SEQ ID NO:22; (b) a heavy chain variable region CDR2 comprising SEQ ID NO:32; (c) a heavy chain variable region CDR3 comprising SEQ ID NO:42; (d) a light chain variable region CDR1 comprising SEQ ID NO:52; (e) a light chain variable region CDR2 comprising SEQ ID NO:62; and (f) a light chain variable region CDR3 comprising SEQ ID NO:72.
  • the anti-PD-Ll Abs or antigen-binding portion thereof may comprise (a) a heavy chain variable region CDR1 comprising SEQ ID NO:21; (b) a heavy chain variable region CDR2 comprising SEQ ID NO:31; (c) a heavy chain variable region CDR3 comprising SEQ ID NO:41; (d) a light chain variable region CDR1 comprising SEQ ID NO:51; (e) a light chain variable region CDR2 comprising SEQ ID NO:61; and (f) a light chain variable region CDR3 comprising SEQ ID NO:71.
  • the anti-PD-Ll Abs or antigen-binding portion thereof may comprise (a) a heavy chain variable region CDR1 comprising SEQ ID NO:23; (b) a heavy chain variable region CDR2 comprising SEQ ID NO:33; (c) a heavy chain variable region CDR3 comprising SEQ ID NO:43; (d) a light chain variable region CDR1 comprising SEQ ID NO:53; (e) a light chain variable region CDR2 comprising SEQ ID NO: 63; and (f) a light chain variable region CDR3 comprising SEQ ID NO: 73.
  • the anti-PD-Ll Abs also include isolated Abs that bind specifically to human PD-Ll and cross-compete for binding to human PD-Ll with any of HuMAbs 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 and 13G4.
  • the anti-PD-Ll Abs include isolated Abs or antigen-binding portions thereof that cross- compete for binding to PD-Ll with a reference Ab or a reference antigen-binding portion thereof comprising: (a) a human heavy chain variable region comprising the sequence set forth in SEQ ID NO: 1 and a human light chain variable region comprising the sequence set forth in SEQ ID NO: 11; (b) a human heavy chain variable region comprising the sequence set forth in SEQ ID NO: 2 and a human light chain variable region comprising the sequence set forth in SEQ ID NO: 12; (c) a human heavy chain variable region comprising the sequence set forth in SEQ ID NO: 3 and a human light chain variable region comprising the sequence set forth in SEQ ID NO: 13; (d) a human heavy chain variable region comprising the sequence set forth in SEQ ID NO: 4 and a human light chain variable region comprising the sequence set forth in SEQ ID NO: 14; (e) a human heavy chain variable region comprising the sequence set forth in SEQ ID NO: 5
  • cross- competing Abs are expected to have very similar functional properties by virtue of their binding to the same epitope region of PD-Ll .
  • cross-competing anti-PD-Ll mAbs 3G10, 1B12, 13G4, 12A4 (BMS-936559), 10A5, 12B7, 11E6 and 5F8 have been shown to have similar functional properties (see U.S. Patent No. 7,943,743 at Examples 3-11), whereas mAb 10H10, which binds to a different epitope region, behaves differently (U.S. Patent No. 7,943,743 at Example 11).
  • cross-competing Abs can be identified in standard PD-Ll binding assays, e.g., BIACORE® analysis, ELISA assays or flow cytometry, that are well known to persons skilled in the art.
  • the Abs that cross-compete for binding to human PD-Ll with, or bind to the same epitope region of human PD-L1 as, 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7 or 13G4 may be mAbs, preferably chimeric Abs, or humanized or human Abs.
  • Such human mAbs can be prepared and isolated as described in U.S. Patent No. 7,943,743.
  • the antibody or an antigen-binding portion thereof may cross-compete for binding to PD-L1 with a reference antibody which comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12. In some embodiments, the antibody or an antigen-binding portion thereof may bind to the same epitope as a reference antibody which comprises a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2 and a light chain variable region comprising the amino acid sequence of SEQ ID NO: 12.
  • Anti-PD-Ll Abs provided herein also include antigen-binding portions of the above Abs, including Fab, F(ab') 2 Fd, Fv, and scFv, di-scFv or bi-scFv, and scFv-Fc fragments, diabodies, triabodies, tetrabodies, and isolated CDRs ⁇ see Hollinger and Hudson, 2005; Olafsen and Wu, 2010, for further details). Nucleic Acid Molecules Encoding Antibodies
  • nucleic acid molecules that encode any of the Abs described herein. These nucleic acids may be present in whole cells, in a cell lysate, or in a partially purified or substantially pure form.
  • a nucleic acid of the invention can be, for example, DNA or RNA, and may or may not contain intronic sequences.
  • the nucleic acid is a cDNA.
  • Nucleic acids provided herein can be obtained using standard molecular biology techniques.
  • Abs expressed by hybridomas e.g., hybridomas prepared from transgenic mice carrying human immunoglobulin genes as described further below
  • cDNAs encoding the light and heavy chains of the Ab made by the hybridoma can be obtained by standard PCR amplification or cDNA cloning techniques.
  • Nucleic acids encoding Abs obtained from an immunoglobulin gene library e.g., using phage display techniques
  • the nucleic acids molecules described herein include those encoding the and V K sequences of the anti-PD-Ll HuMAbs, 3G10, 12A4, 10A5, 5F8, 10H10, 1B12, 7H1, 11E6, 12B7, and 13G4 (disclosed in U.S. Patent No. 7,943,743).
  • An isolated DNA encoding the V H region can be converted to a full-length heavy chain gene by operatively linking the V ⁇ -encoding DNA to another DNA molecule encoding heavy chain constant regions (Cm, Cm and Cm), the sequences of which are known in the art and can be obtained by standard PCR amplification.
  • the heavy chain constant region can be an IgGl, IgG2, IgG3, IgG4, IgA, IgE, IgM or IgD constant region. In some embodiments, the heavy chain constant region may be an IgGl, IgG2 or IgG4 constant region.
  • an isolated DNA encoding the Vi region can be converted to a full- length light chain gene by operatively linking the Vi-encoding DNA to another DNA molecule encoding the light chain constant region (C L ), the sequence of which is known in the art and can be obtained by standard PCR amplification.
  • the light chain constant region can be a kappa or lambda constant region. In some embodiments, the light chain constant region may be a kappa constant region.
  • Antibodies of the present invention may be constituted in a composition, e.g. , a pharmaceutical composition, containing one Ab or a combination of Abs, or an antigen- binding portion(s) thereof, and a pharmaceutically acceptable carrier.
  • a pharmaceutically acceptable carrier includes any and all solvents, dispersion media, coatings, antibacterial and antifungal agents, isotonic and absorption delaying agents, and the like that are physiologically compatible.
  • the carrier is suitable for intravenous, intramuscular, subcutaneous, parenteral or epidermal administration (e.g., by injection or infusion).
  • a pharmaceutical composition of the invention may include one or more pharmaceutically acceptable salts, anti-oxidant, aqueous and nonaqueous carriers, and/or adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • the dosage may range from about 0.0001 to about 100 mg/kg, usually from about 0.001 to about 50 mg/kg, from about 0.01 to about 20 mg/kg, or from about 0.1 to about 10 mg/kg, of the subject's body weight. In some embodiments, the dosage is within the range of 0.1-10 mg/kg body weight. For example, dosages can be about 0.1, 0.3, 1, 3, 5 or 10 mg/kg body weight. In some embodiment, the dosage is about 0.1, 0.3, 3, or 10 mg/kg body weight.
  • the dosage may a fixed dose ranging from 0.001 to 2000 mg, from 0.01 to 1500 mg, from 0.1 to 1000 mg, from 1 to 1000 mg, from 1 to 500 mg, from 1 to 100 mg, from 100 to 200 mg, from 200 to 300 mg, from 300 to 400 mg, from 400 to 500 mg, from 500 to 600 mg, from 600 to 700 mg, from 700 to 800 mg, from 800 to 900 mg, or from 900 to 1000 mg.
  • the dosing schedule is typically designed to achieve exposures that result in sustained receptor occupancy (RO) based on typical pharmacokinetic properties of an Ab.
  • An exemplary treatment regime may entail administration once per week, once every two weeks, once every three weeks, once every four weeks, once a month, once every 3 months or once every three to 6 months.
  • compositions described herein may be varied so as to obtain an amount of the active ingredient which is effective to achieve the desired therapeutic response for a particular patient, composition, and mode of administration, without being unduly toxic to the patient.
  • the selected dosage level will depend upon a variety of pharmacokinetic factors including the activity of the particular compositions of the present invention employed, the route of
  • a composition of the present invention can be administered via one or more routes of administration using one or more of a variety of methods well known in the art. As will be appreciated by the skilled artisan, the route and/or mode of administration will vary depending upon the desired results.
  • HIV-1 persists in latently-infected resting CD4+T-cells and possibly other tissues or cellular reservoirs. Elimination of replication competent pro-virus (i.e., HIV viral DNA that has been integrated into the human genome, typically within active human genes) within latently infected cells is necessary to cure HIV-1 infection. Consequently, reduction or elimination of HIV-1 reservoirs that persist on suppressive cART may require the combination of multiple therapeutic modalities. Hence, the testing of interventions that have the potential both to impact persistent HIV-1 and be combined with other interventions that may be additive or synergistic is a necessary step in a comprehensive strategy for cure research.
  • replication competent pro-virus i.e., HIV viral DNA that has been integrated into the human genome, typically within active human genes
  • HIV-1 specific immune response An important factor in the ineffective HIV-1 specific immune response is that chronic HIV-1 infection leads to up-regulation of inhibitory co-receptors on T-cells (e.g. PD-1 and CTLA4), which are cellular makers of immune exhaustion.
  • T-cells e.g. PD-1 and CTLA4
  • PD-1 expression on HIV-1 specific CD 8+ and CD4+ T- cells is reduced by antiretroviral therapy, but its expression remains elevated compared to uninfected participants, especially in patients with less robust CD4+ T-cell responses (Day 2006, Trautman 2006, Petrova 2006).
  • PD-L1 a ligand for PD-1, in addition to being inducibly expressed on antigen-presenting cells, is also up-regulated on both CD4+ and CD8+ HIV-1 specific T cells in response to HIV-1 infection, and levels of PD-L1 on T-cells in this context remain elevated despite suppression of HIV-1 by cART (Sachdeva et al, J. Acquir. Immune. Defic. Syndr., 54(5):447-454 (2010);
  • Blocking the PD-1 pathway using an antibody to PD-1 in a macaque model of SIV infection resulted in rapid expansion of virus-specific CD8+ T-cells with improved functional quality of antiviral CD8+ T- cells in the blood and gut as demonstrated by the generation of poly- functional cells capable of co-producing cytokines IFN- ⁇ , TNF-a and IL-2.
  • These immune responses were associated with significant changes in plasma SIV RNA and prolonged survival in the absence of antiretroviral therapy.
  • anti-PD-Ll BMS-936559 also known as MDX-1105
  • MDX-1105 anti-PD-Ll
  • Example 2 Data provided in Example 2 show that virally suppressed monkeys while on ARV treated with an anti-PD-Ll Ab (BMS-936559) achieve durable suppression ( Figure 2). Further, upon removal of ARV, there is a 7-10 day delay in the rebound of viral load in anti-PD-Ll treated group compared to the iso-type control group. Additionally, the anti- PD-Ll treated group had about 2-4 logio lower viral load at 6 weeks post- ARV interruption compared to the corresponding pre -ARV viral load ( Figure 3, Figure 6).
  • CHO cells transfected to express hPD-Ll (CHO/PD-L1 cells) were incubated with 10 ⁇ g/ml of each of ten unconjugated human anti-PD-Ll mAbs (5F8, 7H1, 10H10, 1B12, 3G10, 10A5, 11E6, 12A4, 12B7, and 13G4) or human IgGl (hlgGl) isotype control Ab for 20 min at 4°C.
  • FITC- conjugated HuMAbs Different quantities of the various FITC- conjugated HuMAbs were used due to differences in binding efficiency following labeling, and the optimal amounts of these FITC-conjugated HuMAbs were previously determined by dose-titration analysis of binding to CHO/PD-L1 cells. Binding of FITC- conjugated 10H10, 3G10, 10A5, 11E6, 12A4 or 13G4 to the CHO/PD-L1 cells was measured by flow cytometry.
  • Each of anti-PD-Ll HuMAbs 5F8, 7H1, 1B12, 3G10, 10A5, 11E6, 12A4, 12B7 and 13G4 substantially blocked binding of labeled mAbs 3G10 ( Figure IB), 10A5 ( Figure 1C), 11E6 ( Figure ID), 12A4 ( Figure IE) and 13G4 ( Figure IF) to CHO/PD-L1 cells as measured by MFI, though mAbs 5F8 and 13G4 generally blocked binding of the labeled mAbs to a slightly lesser extent.
  • Tissue biopsies (lymph node, rectal) were collected before administration of the antibody, before termination of ARV and post termination of ARV.
  • Dose cohort 1 0.3 mg/kg BMS- 936559
  • Dose cohort 2 0.3 mg/kg BMS- 936559
  • Anti-PD-Ll antibody /placebo infusion will occur over 60 minutes via IV infusion.
  • the study will enroll sequential dose-rising cohorts. Participants will be followed for 48 weeks with frequent safety evaluations in the first 4 weeks.
  • the subject should have been receiving a stable cART regimen containing at least three agents (not including ritonavir if less than a 200mg total daily dose) with no changes in the components of their antiretroviral therapy for at least 90 days prior to study entry.
  • One of the agents includes an integrase inhibitor, NNRTI (Non-Nucleoside Reverse Transcriptase Inhibitors), or a boosted-PI (protease inhibitor).
  • Plasma HIV-1 RNA level of the subject should be below detected limit obtained by FDA- approved assays (limit of detection: 75, 50, 40 or 20) for >2 years on cART.
  • Plasma HIV-1 RNA level of the subject should be ⁇ 40 copies/mL obtained by the Abbott m2000 assay or ⁇ 20 copies/mL by the Roche TAQMAN® v2.0 assay within 90 days prior to entry.
  • AUC, C max BMS-936559 exposure
  • biomarkers including, but not limited to, HIV-1 RNA by SCA, HIV-1 DNA, 2LTR circle DNA, cell-associated HIV-1 RNA and RNA/DNA ratios in total CD4+ cells, receptor occupancy, and markers of immune response.
  • Cohort 1 Participants will receive 0.3 mg/kg of BMS-936559 or placebo, administered as a single 60 minute infusion one time.
  • Cohort 2 Participants will receive 1 mg/kg of BMS-936559 or placebo, administered as a single 60 minute infusion one time.
  • Cohort 3 Participants will receive 3 mg/kg of BMS-936559 or placebo, administered as a single 60 minute infusion one time.
  • Cohort 3 Participants will receive 10 mg/kg of BMS-936559 or placebo, administered as a single 60 minute infusion one time.
  • BMS-936559 will be supplied as an injection, 100 mg/vial (10 mg/mL). It is a colorless, clear to slightly opalescent, essentially free of particles, sterile, non-pyrogenic solution contained in 10-mL Type I glass vials, stoppered with 20-mm stoppers, and sealed with 20-mm aluminum seals.
  • Each vial of drug product contains the labeled amount of BMS-936559 drug substance and sodium citrate, sodium chloride, mannitol, diethylenetriamine pentaacetic acid (pentetic acid), and polysorbate 80. The concentration of each vial is 10 mg/mL at a pH of 6.5. A 5% overfill is included in each vial. Placebo for BMS-936559 will be sodium chloride for injection 0.9%, USP. EXAMPLE 4
  • IL-2, IFNy, and TNFa production by CD4+ and CD8+ T cells were conducted using freshly isolated lymphocytes derived from the blood and lymph nodes of SIV-infected Rhesus macaques pre- and post-treatment with BMS-936559 or isotype control antibody as described in Example 2. Lymphocytes were counted using a Guava EasyCyte automatic cytometer (Millipore) and approximately 2 x 10 6 lymphocytes were used per sample in a 96-well V-bottom plate.
  • Cells were stimulated with 2 ⁇ g/mL of SIVmac239 Gag peptide pool (NIH AIDS reagent Program, cat# 6204) and 1 ⁇ g/mL each of anti-CD28 and anti-CD49d antibodies (BD Biosciences). Cells were incubated at 37°C for 6 hours, with the addition GOLGISTOP® and GOLGIPLUG® (BD Biosciences) at a final dilution of 1 : 1 ,500 and 1 : 1 ,000, respectively, after the first hour.
  • SIVmac239 Gag peptide pool NIH AIDS reagent Program, cat# 6204
  • anti-CD28 and anti-CD49d antibodies BD Biosciences
  • the following conjugated antibodies and staining reagents were used: CD3- Horizon V450, CD4-PerCP-Cy5.5, CD8-APC-Cy7, CD69-ECD (Beckman Coulter), IL- 2-APC, IFNy-PE-Cy, and TNFa-FITC and Yellow LIVE/DEAD Fixable Dead Cell Stain (Invitrogen). All antibodies were from BD Biosciences unless otherwise indicated. The value of percentage cytokine positive cells, in un-stimulated samples, was subtracted from corresponding value in stimulated samples.
  • the percent of cytokine -producing T cells was higher in cells from lymph node samples than cytokine responses measured from peripheral blood. Within a compartment, the percent of cytokine -producing cells was similar between CD4 + and CD8 T cells. There was a limited change in cytokine production by CD4 T cells between pre- and post- BMS-936559 treatment in either lymph node or peripheral blood samples. Limited changes were also noted in cytokine production by CD8 + T cells between pre- and post-treatment in peripheral blood samples. There was however, an increase in cytokine production by CD8 + T cells in lymph node samples. All BMS- 936559-treated animals showed increases in IFN- ⁇ and/or TNFa production post- treatment in comparison to control animals ( Figure 8).

Abstract

La présente invention concerne des procédés de traitement d'un sujet infecté par le VIH qui est à ce moment-là sous traitement par thérapie antirétrovirale combinée (TARc), comprenant l'administration au sujet d'une quantité thérapeutiquement efficace d'un anticorps ou d'une portion liant l'antigène de celui-ci qui perturbe l'interaction entre la protéine de mort cellulaire programmée 1 (PD-1) et le ligand de protéine de mort cellulaire programmée 1 (PD-L1), l'anticorps ou sa portion liant l'antigène se liant spécifiquement à PD-L1.
PCT/US2014/067547 2013-11-26 2014-11-26 Procédé de traitement du vih par perturbation de la signalisation pd-1/pd-l1 WO2015081158A1 (fr)

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