EP3472202A1 - Methods and compositions for the treatment of celiac disease, non-celiac gluten sensitivity, and refractory celiac disease - Google Patents

Methods and compositions for the treatment of celiac disease, non-celiac gluten sensitivity, and refractory celiac disease

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Publication number
EP3472202A1
EP3472202A1 EP16733804.5A EP16733804A EP3472202A1 EP 3472202 A1 EP3472202 A1 EP 3472202A1 EP 16733804 A EP16733804 A EP 16733804A EP 3472202 A1 EP3472202 A1 EP 3472202A1
Authority
EP
European Patent Office
Prior art keywords
antibody
sequence
administered
seq
pharmaceutical composition
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP16733804.5A
Other languages
German (de)
English (en)
French (fr)
Inventor
Francisco Leon
Wayne H. TSUJI
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Amgen Inc
Celimmune LLC
Original Assignee
Amgen Inc
Celimmune LLC
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Amgen Inc, Celimmune LLC filed Critical Amgen Inc
Publication of EP3472202A1 publication Critical patent/EP3472202A1/en
Pending legal-status Critical Current

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Classifications

    • 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
    • C07K16/24—Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against cytokines, lymphokines or interferons
    • C07K16/244—Interleukins [IL]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/12—Antidiarrhoeals
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P37/00—Drugs for immunological or allergic disorders
    • A61P37/02—Immunomodulators
    • 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
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00—Medicinal preparations containing antigens or antibodies
    • A61K2039/545—Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K2317/00—Immunoglobulins specific features
    • C07K2317/20—Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/21—Immunoglobulins specific features characterized by taxonomic origin from primates, e.g. man
    • 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

  • compositions and methods disclosed herein relate to the treatment of inflammatory disorders, in particular Celiac Disease, Refractory Celiac Disease and Non- celiac gluten sensitivity.
  • CD Celiac disease
  • CD was the first autoimmune disease with an identified antigen, gluten, the main protein present in some of the most common cereals (e.g., wheat, barley, rye). Humans lack enzymes to fully digest gluten, which, in the right genetic context, triggers inflammation and autoimmunity in the gut and other organs following deamination by the enzyme transglutaminase (tTG). CD presents in a several forms, presenting challenges for treatment.
  • CD is the only common autoimmune disorder with no approved medication.
  • the only available strategy for the management of CD is a lifelong total avoidance of gluten.
  • the ubiquitous presence of gluten makes total avoidance very difficult, if not impossible.
  • As little as 50 mg/day (a normal diet contains greater than 10 g/day) triggers activation of T cells in the small bowel and causes intestinal mucosal damage (Catassi et al, 2007).
  • GFD gluten free diet
  • Approximately 20% of individuals diagnosed with celiac disease have persistent symptoms or anemia with or without a positive tissue transglutaminase antibody (a molecular marker indicating celiac).
  • Non-Responsive Celiac Disease is defined by the persistent signs, symptoms or laboratory abnormalities typical of CD, despite abstaining from dietary gluten for six to twelve months (Rubio-Tapia et al, 2013). Currently there are no effective treatments for NRCD.
  • Refractory Celiac Disease is characterized by a rare but specific complication of persistent exposure to gluten in CD, which affects approximately 1% of celiac patients (Lebwohl et al, 2013).
  • RCD is characterized by severe intestinal mucosal atrophy and gastrointestinal symptoms in the absence of gluten consumption and in the presence of small bowel aberrant intestinal intra-epithelial lymphocytes (IELs) (Verbeek et al., 2008, vanWanrooij et al., 2014). The cut-off of 20% aberrant IELs in the small bowel separates RCD Type I ( ⁇ 20%) vs. RCD Type II (RCD-II, 20% or greater).
  • IELs intestinal intra-epithelial lymphocytes
  • RCD-I can be treated symptomatically with steroids
  • RCD-II can be treated symptomatically with steroids
  • Enteropathy -Associated T Cell Lymphoma is a high-grade, systemic, T cell lymphoma almost exclusively seen as a complication of RCD-II (Nijeboer et al, 2015). Diagnosis includes imaging and histology to demonstrate the presence of malignant T cells in extra-epithelial locations such as lymph nodes or other organs. The treatment of EATL relies on surgical resection and chemotherapy, but the prognosis is very poor, with a 5-year survival of less than 20% (Nijeboer et al, 2015).
  • Non-celiac gluten sensitivity has been proposed to refer to the spectrum of conditions reported by these patients (Lundin and Alaedini, 2012).
  • Non-celiac gluten sensitivity is currently understood as a condition associated with the experiencing of various symptoms in response to ingestion of foods containing wheat, rye, and barley, and the resolution of symptoms on removal of those foods from diet in individuals in whom CD and wheat allergy have been ruled out (Lundin and Alaedini, 2012).
  • the invention relates to a method of treating celiac disease or non- celiac gluten sensitivity in a subject in need thereof, comprising administering a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof to the subject, wherein the therapeutically effective amount comprises 1 -20 unit doses each administered at about 1-12 week intervals, each unit dose independently comprising about 50-1000 mg, preferably 75-600 mg, more preferably about 75 mg, about 150 mg, about 300 mg or about 600 mg of the anti-IL-15 antibody or antigen-binding fragment thereof.
  • the therapeutically effective amount comprises 6 unit doses administered at about 2 week intervals.
  • Each unit dose may be administered by subcutaneous inj ection or intravenous injection.
  • the invention relates to a pharmaceutical composition for the treatment of, or a pharmaceutical composition for use in a method of treating, celiac disease or non-celiac gluten sensitivity, comprising a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof, wherein the therapeutically effective amount comprises 1-20 unit doses each to be administered at about 1 -12 week intervals, each unit dose independently comprising about 50-1000 mg, preferably 75-600 mg, more preferably about 75 mg, about 150 mg, about 300 mg or about 600 mg of the anti- IL-15 antibody or antigen-binding fragment thereof.
  • the therapeutically effective amount comprises 6 unit doses to be administered at 2 week intervals. Each unit dose can be administered by subcutaneous injection or intravenous injection.
  • Another aspect of the invention relates to a method of treating refractory celiac disease in a subject in need thereof, comprising administering a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof to the subject, wherein the therapeutically effective amount comprises 1 -20 unit doses each administered at about 1-12 week intervals, each unit dose independently comprising about 1 -50 mg/kg, preferably about 4-16 mg/kg, more preferably about 4 mg/kg, about 8 mg/kg, about 12 mg/kg or about 16 mg/kg of the anti-IL-15 antibody or antigen-binding fragment thereof.
  • the therapeutically effective amount comprises 6 unit doses administered at 2 week intervals, and an optional additional loading dose at week 1.
  • Each unit dose is administered by subcutaneous injection or intravenous injection.
  • the refractory celiac disease is type I or type II refractory celiac disease.
  • a pharmaceutical composition for the treatment of, or a pharmaceutical composition for use in a method of treating, refractory celiac disease comprising a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof, wherein the therapeutically effective amount comprises 1 -20 unit doses each administered at about 1-12 week intervals, each unit dose independently comprising about 1-50 mg/kg, preferably about 4-16 mg/kg, more preferably about 4 mg/kg, about 8 mg/kg, about 12 mg/kg or about 16 mg/kg of the anti-IL-15 antibody or antigen-binding fragment thereof.
  • the therapeutically effective amount in some embodiments comprises 6 unit doses to be administered at 2 week intervals, and an optional additional loading dose to be administered at week 1.
  • Each unit dose can be administered by subcutaneous injection or intravenous injection.
  • the refractory celiac disease can be type I or type II.
  • the antibody may have a heavy chain variable region comprising one or more complementarity determining regions of SEQ ID NOs:5-7, or a sequence having at least 80% sequence identity thereto.
  • the antibody may, in certain embodiments, have a light chain variable region comprising one or more complementarity determining regions of SEQ ID NOs:8-10, or a sequence having at least 80% sequence identity thereto.
  • the antibody in some embodiments has a heavy chain variable region comprising the amino acid sequence of SEQ ID NO:2, or a sequence having at least 80% sequence identity thereto.
  • the antibody may have a light chain variable region comprising the amino acid sequence of SEQ ID NO:4, or a sequence having at least 80% sequence identity thereto.
  • FIG. 1 illustrates a schematic structure of AMG 714.
  • FIG. 2 illustrates villi present in the gut of healthy subject and subjects with active celiac disease.
  • FIG. 3 illustrates a simplified schematic of celiac and refractory celiac disease pathophysiology.
  • FIG. 4 illustrates a simplified schematic of IL-15 signaling in RCD-II.
  • FIG. 5 illustrates a simplified schematic of the multiple roles of IL-15 in celiac and refractory celiac disease.
  • compositions and methods disclosed herein relate to the treatment of gastrointestinal disorders such as CD, NRCD, RCD, EATL and NCGS by modulating an activity of IL-15 using, e.g., a therapeutically effective amount of an IL-15 antagonist.
  • the IL-15 antagonist is an antibody.
  • IL-15 can be blocked by AMG 714, a monoclonal antibody which can bind to, and inhibit the function of IL-15.
  • compositions provided herein can include a therapeutically effective amount of a recombinant monoclonal antibody or antigen-binding fragments against IL-15, in particular human IL-15.
  • Suitable antibodies can include, for example, murine, chimeric, humanized and fully human antibodies, as well as other antibody forms known in the art.
  • the antibody can include but is not limited to those disclosed in U. S. Patent Nos. 7,247,304, 7,329,405, 7, 153,507, 7,597,892, 7,585,961 and 8,345, 105, all of which are incorporated herein by reference in their entirety.
  • the antibody can be provided in the form of a recombinantly expressed glycoprotein, using methods disclosed in, e.g., International Patent Application No. WO2007/07087384, which is incorporated herein by reference in its entirety.
  • the antibody is a fully human monoclonal antibody that binds IL-15.
  • the antibody is AMG 714 which has a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO:2 and/or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO:4.
  • the antibody can also have amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to SEQ ID NO: 2 and/or SEQ ID NO: 4.
  • the antibody can include a light chain variable region comprising one or more complementarity determining regions (CDRs) set forth in SEQ ID NOs: 8-10, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ ID NOs: 8-10).
  • the antibody can alternatively or additionally include a heavy chain variable region comprising one or more CDRs set forth in SEQ ID NOs:5-7, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ ID NOs: 5- 7).
  • a human monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof includes a light chain variable region comprising all three CDRs set forth in SEQ ID NOs: 8-10, or conservative amino acid substitutions thereof, and a heavy chain variable region comprising all three CDRs set forth in SEQ ID NOs: 5-7, or conservative amino acid substitutions thereof.
  • the pharmaceutical compositions disclosed herein can include a therapeutically effective amount of an isolated monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof and a pharmaceutically acceptable carrier.
  • the pharmaceutical compositions can be used to treat or prevent a disorder associated with an overexpression of human IL-15 and/or in which a down regulation or inhibition of human IL-15 induced effects is beneficial.
  • Also provided herein is a method of treating or preventing a disorder associated with an overexpression of human IL-15 and/or in which a down regulation or inhibition of human IL-15 induced effects is beneficial, by administering to a subject a therapeutically effective amount of an isolated anti-IL-15 antibody, or an antigen-binding fragment thereof.
  • Exemplary disorders that can be treated or prevented using the presently disclosed methods or compositions include, but are not limited to, Celiac Disease, Non-Responsive Celiac Disease, Refractory Celiac Disease, Enteropathy-Associated T Cell Lymphoma, and Gluten-Sensitive Enteropathy.
  • Other disorders that can be treated include vasculitis, psoriasis, multiple sclerosis, rheumatoid arthritis (RA), inflammatory disorders (e.g., inflammatory bowel disease), allograft rejection, graft versus host disease, T-cell lymphoma, and T-cell leukemia.
  • the term “about” means within 20%, more preferably within 10% and most preferably within 5%.
  • the term “substantially” means more than 50%, preferably more than 80%, and most preferably more than 90% or 95%.
  • Interleukin 15 is a pro-inflammatory cytokine that serves as a potent growth, survival, and activation factor for T cells, particularly intestinal intraepithelial lymphocytes (IELs), and for natural killer (NK) cells. Increased expression of IL-15 has been demonstrated in a variety of inflammatory conditions, including CD, rheumatoid arthritis (RA), and psoriasis (Malamut et al, 2010).
  • IL-15 is considered a central regulator of CD immunopathology and a non-redundant driver of lymphomagenesis in RCD. Inhibition of IL-15 by an antagonist is an attractive therapeutic target for the treatment of CD. Targeting of IL-15 by a fully human monoclonal antibody to bind IL-15 has served to elucidate the signaling mechanism facilitated by IL-15 in CD and has established experimental proof principle for the advantages of modulating downstream effectors of IL-15 (Malamut et al, 2010).
  • antibody as referred to herein includes whole antibodies and any antigen (e.g., IL-15) binding fragment (i.e., "antigen-binding portion") or single chain thereof.
  • An “antibody” refers to a protein comprising at least two heavy (H) chains and two light (L) chains inter-connected by disulfide bonds, or an antigen binding portion thereof.
  • Each heavy chain is comprised of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region.
  • the heavy chain constant region is comprised of three domains, CHI, CH2 and CH3.
  • Each light chain is comprised of a light chain variable region (abbreviated herein as VL) and a light chain constant region.
  • the light chain constant region is comprised of one domain, CL.
  • the VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity determining regions (CDR), interspersed with regions that are more conserved, termed framework regions (FR).
  • CDR complementarity determining regions
  • FR framework regions
  • Each VH and VL is composed of 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 antibodies 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.
  • antibody also includes various antibody modification and/or derivative forms, including without limitation, an anti-IL-15 antibody, or antigen-binding fragment thereof, coupled with or linked to an additional molecular entity, such as one or more different antibodies or antigen-binding fragments thereof (e.g., a bi-specific, tri-specific, or multi-specific), pharmaceutical agents, peptides or proteins, and detection agent or labels.
  • additional molecular entity such as one or more different antibodies or antigen-binding fragments thereof (e.g., a bi-specific, tri-specific, or multi-specific), pharmaceutical agents, peptides or proteins, and detection agent or labels.
  • antibody also includes single chain antibodies, diabodi.es, domain antibodies, nanobodies, and unibodies.
  • antigen-binding portion and "antigen-binding fragment” of an antibody (or simply “antibody portion”), as used herein, refer to one or more fragments of an antibody that selectively bind to an antigen (e.g., IL-15). It has been shown that the antigen-binding function of an antibody can be performed by fragments of a full-length antibody.
  • an antigen e.g., IL-15
  • antigen-binding fragments encompassed within the term "antigen- binding portion" of an antibody include (i) a Fab fragment, a monovalent fragment consisting of the VL, VH, CL and CHI domains; (ii) a F(ab')2 fragment, a bivalent fragment comprising two Fab fragments linked by a disulfide bridge at the hinge region; (iii) a Fd fragment consisting of the VH and CHI domains; (iv) a Fv fragment consisting of the VL and VH domains of a single arm of an antibody, (v) a dAb fragment (Ward et al, Nature 341 :544-546 (1989)), which consists of a VH domain; and (vi) an isolated complementarity determining region (CDR) or (vii) a combination of two or more isolated CDRs which may optionally be joined by a synthetic linker.
  • CDR complementarity determining region
  • the two domains of the Fv fragment, VL and VH are coded for by separate genes, they can be joined, using recombinant methods, by a synthetic linker that enables them to be made as a single protein chain in which the VL and VH regions pair to form monovalent molecules (known as single chain Fv (scFv); see e.g., Bird et al., Science 242:423-426 (1988); and Huston et al, Proc. Natl. Acad. Sci. USA 85:5879-5883 (1988)).
  • single chain Fv single chain Fv
  • Such single chain antibodies are also intended to be encompassed within the terms "antigen-binding portion" and "antigen-binding fragment” of an antibody.
  • human monoclonal antibody refers to an antibody which displays a single binding specificity and affinity for a particular epitope. Accordingly, the term “human monoclonal antibody” refers to an antibody which displays a single binding specificity and which has variable and constant regions derived from human germline immunoglobulin sequences.
  • human monoclonal antibodies are produced by a hybridoma which includes a B cell obtained from a transgenic non-human animal, e.g., a transgenic mouse, having a genome comprising a human heavy chain transgene and a light chain transgene fused to an immortalized cell.
  • human monoclonal antibodies can be produced by Chinese hamster ovary (CHO) cells.
  • recombinant human antibody includes all human antibodies that are prepared, expressed, created or isolated by recombinant means, such as (a) antibodies isolated from an animal (e.g., a mouse) that is transgenic or transchromosomal for human immunoglobulin genes or a hybridoma prepared therefrom,
  • antibodies isolated from a host cell e.g., CHO cell transformed to express the antibody, e.g., from a transfectoma
  • antibodies isolated from a recombinant, combinatorial human antibody library e.g., antibodies prepared, expressed, created or isolated by any other means that involve splicing of human immunoglobulin gene sequences to other DNA sequences.
  • recombinant human antibodies have variable and constant regions derived from human germline immunoglobulin sequences.
  • such recombinant human antibodies can be subjected to in vitro mutagenesis (or, when an animal transgenic for human Ig sequences is used, in vivo somatic mutagenesis) and thus the amino acid sequences of the VH and VL regions of the recombinant antibodies are sequences that, while derived from and related to human germline VH and VL sequences, may not naturally exist within the human antibody germline repertoire in vivo.
  • a heterologous antibody is defined in relation to the transgenic non-human organism producing such an antibody. This term refers to an antibody having an amino acid sequence or an encoding nucleic acid sequence corresponding to that found in an organism not consisting of the transgenic non-human animal, and generally from a species other than that of the transgenic non-human animal.
  • an "isolated antibody,” as used herein, refers to an antibody which is substantially free of other antibodies having different antigenic specificities (e.g., an isolated antibody that specifically binds to IL-15 is substantially free of antibodies that specifically bind antigens other than IL-15).
  • An isolated antibody that specifically binds to an epitope of IL- 15 may, however, have cross-reactivity to other related cytokines or to other IL-15 proteins from different species. However, the antibody preferably always binds to human IL-15.
  • an isolated antibody is typically substantially free of other cellular material and/or chemicals.
  • a combination of "isolated" monoclonal antibodies having different IL-15 specificities are combined in a well-defined composition.
  • binding refers to an antibody or a fragment thereof, binding to a predetermined antigen.
  • the antibody binds with an affinity (K D ) of approximately less than 10 "7 M, such as approximately less than 10 "8 M, 10 "9 M or 10 "10 M or even lower when determined by surface plasmon resonance (SPR) technology in a BIACORE 3000 instrument using recombinant human IL-15 as the analyte and the antibody as the ligand, and binds to the predetermined antigen with an affinity that is at least two-fold greater than its affinity for binding to a non-specific antigen (e.g., BSA, casein) other than the predetermined antigen or a closely-related antigen.
  • a non-specific antigen e.g., BSA, casein
  • K D is intended to refer to the dissociation equilibrium constant of a particular antibody-antigen interaction.
  • nucleic acid molecule refers to DNA and RNA molecules.
  • a nucleic acid molecule may be single-stranded or double-stranded, but preferably is double-stranded DNA.
  • isolated nucleic acid molecule refers to a nucleic acid molecule in which the nucleotide sequences encoding the antibody or antibody portion are free of other nucleotide sequences encoding antibodies or antibody portions that bind antigens other than IL-15, which other sequences may naturally flank the nucleic acid in human genomic DNA.
  • the human anti-IL-15 antibody can have a heavy chain variable region (VH) encoded by the nucleotide sequence set forth in SEQ ID NO: 1 , or conservative nucleic acid substitutions (e.g., silent mutation) thereof, and/or a light chain variable region (VL) encoded by the nucleotide sequence set forth in SEQ ID NO: 3, or conservative nucleic acid substitutions thereof.
  • VH heavy chain variable region
  • VL light chain variable region
  • the antibody can also have VH and VL's encoded by nucleotide sequences having about 80%, 85%, 90%, 95% or greater identity to SEQ ID NO: 1 and/or SEQ ID NO: 3, respectively.
  • the antibody can have a heavy chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 2, or conservative amino acid substitutions thereof, and/or a light chain variable region comprising the amino acid sequence set forth in SEQ ID NO: 4, or conservative amino acid substitutions thereof.
  • the antibody can also have amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to SEQ ID NO: 2 and/or SEQ ID NO: 4.
  • the antibody can include a light chain variable region comprising one or more complementarity determining regions (CDRs) set forth in SEQ ID NOs: 8-10, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ ID NOs: 8-10, or having 1 or 2 or 3 or 4 amino acid substitutions or changes thereto).
  • CDRs complementarity determining regions
  • the antibody can alternatively or additionally include a heavy chain variable region comprising one or more CDRs set forth in SEQ ID NOs: 5-7, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ ID NOs: 5-7, or having 1 or 2 or 3 or 4 amino acid substitutions or changes thereto).
  • a heavy chain variable region comprising one or more CDRs set forth in SEQ ID NOs: 5-7, or homologous sequences thereof (e.g., having amino acid sequences of about 80%, 85%, 90%, 95% or greater identity to any of SEQ ID NOs: 5-7, or having 1 or 2 or 3 or 4 amino acid substitutions or changes thereto).
  • a human monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof includes a light chain variable region comprising all three CDRs set forth in SEQ ID NOs: 8-10, or conservative amino acid substitutions thereof, and a heavy chain variable region comprising all three CDRs set forth in SEQ ID NOs: 5-7, or conservative amino acid substitutions thereof.
  • One embodiment of the present invention also encompasses "conservative sequence modifications" or “conservative sequence substitutions” of the sequences set forth in SEQ ID NOs: 1-10, i.e., nucleotide and amino acid sequence modifications which do not significantly affect or alter the binding characteristics of the antibody encoded by the nucleotide sequence or containing the amino acid sequence.
  • conservative sequence modifications include nucleotide and amino acid substitutions, additions and deletions.
  • Modifications can be introduced into SEQ ID NOs: 1-10 by standard techniques known in the art, such as site-directed mutagenesis and PCR-mediated mutagenesis.
  • Conservative amino acid substitutions include ones in which the amino acid residue is replaced with an amino acid residue having a similar side chain.
  • Families of amino acid residues having similar side chains have been defined in the art. These families include amino acids with basic side chains (e.g., lysine, arginine, histidine), acidic side chains (e.g., aspartic acid, glutamic acid), uncharged polar side chains (e.g., glycine, asparagine, glutamine, serine, threonine, tyrosine, cysteine, tryptophan), nonpolar side chains (e.g., alanine, valine, leucine, isoleucine, proline, phenylalanine, methionine), beta-branched side chains (e.g., threonine, valine, isoleucine) and aromatic side chains (e.g., tyrosine, phenylalanine, tryptophan, histidine).
  • a predicted nonessential amino acid residue in a human anti- IL-15 antibody is preferably replaced with another amino acid residue from the same side chain
  • antibodies encoded by the (heavy and light chain variable region) nucleotide sequences disclosed herein and/or containing the (heavy and light chain variable region) amino acid sequences disclosed herein include substantially similar antibodies encoded by or containing similar sequences, which have been conservatively modified. Further, discussion as to how such substantially similar antibodies can be generated based on the partial (i.e., heavy and light chain variable regions) sequences disclosed herein as SEQ ID Nos: l-4 is provided below.
  • nucleic acids For nucleic acids, the term "substantial homology" indicates that two nucleic acids, or designated sequences thereof, when optimally aligned and compared, are identical, with appropriate nucleotide insertions or deletions, in at least about 80% of the nucleotides, usually at least about 90% to 95%, and more preferably at least about 98% to 99.5% of the nucleotides. Alternatively, substantial homology exists when the segments will hybridize under selective hybridization conditions, to the complement of the strand.
  • the term "homology” indicates the degree of identity between two amino acid sequences when optimally aligned and compared with appropriate insertions or deletions.
  • the comparison of sequences and determination of percent identity between two sequences can be accomplished using a mathematical algorithm.
  • the percent identity between two nucleotide sequences can be determined using the GAP program in the GCG software package (available at www.gcg.com), using a NWSgapdna. CMP matrix and a gap weight of 40, 50, 60, 70, or 80 and a length weight of 1, 2, 3, 4, 5, or 6.
  • the percent identity between two nucleotide or amino acid sequences can also be determined using the algorithm of E. Meyers and W. Miller (CABIOS, 4: 11-17 (1989)) which has been incorporated into the ALIGN program (version 2.0), using a PAM120 weight residue table, a gap length penalty of 12 and a gap penalty of 4.
  • the percent identity between two amino acid sequences can be determined using the Needleman and Wunsch (J. Mol. Biol. (48):444-453 (1970)) algorithm which has been incorporated into the GAP program in the GCG software package (available at www.gcg.com), using either a Blossum 62 matrix or a PAM250 matrix, and a gap weight of 16, 14, 12, 10, 8, 6, or 4 and a length weight of 1, 2, 3, 4, 5, or 6.
  • the nucleic acid and protein sequences of the present invention can further be used as a "query sequence" to perform a search against public databases to, for example, identify related sequences.
  • Such searches can be performed using the NBLAST and XBLAST programs (version 2.0) of Altschul, et al, J. Mol. Biol. 215:403-10 (1990).
  • Gapped BLAST can be utilized as described in Altschul et al, Nucleic Acids Res. 25(17):3389-3402 (1997).
  • the default parameters of the respective programs e.g., XBLAST and NBLAST
  • XBLAST and NBLAST See www.ncbi.nlm.nih.gov.
  • the term "subject” includes any human or non-human animal.
  • the methods and compositions of the present invention can be used to treat a subject having an inflammatory disease, such as celiac disease, Refractory Celiac Disease, Enteropathy-Associated T Cell Lymphoma and Non-celiac gluten sensitivity.
  • non-human animal includes all vertebrates, e.g., mammals and non-mammals, such as non-human primates, sheep, dog, cow, chickens, amphibians, reptiles, etc.
  • a "therapeutically effective dosage” or “therapeutically effective amount” for inflammatory disorders such as Celiac Disease, Refractory Celiac Disease, Gluten- Sensitive Enteropathy and/or Enteropathy-Associated T Cell Lymphoma, or the like, will preferably result in an improvement of patient's clinical outcome or otherwise ameliorate signs and/or symptoms in a subject.
  • a therapeutically effective dosage of AMG-714 can result in improved clinical outcomes and/or improve laboratory test results of patients receiving treatment, for example the parameters to be monitored in clinical trials and/or physician assessments, as set forth herein.
  • a “unit dose” refers to an amount of pharmaceutical composition, in particular the active ingredient therein (e.g., an anti-IL-15 antibody such as AMG 714) that is administered to a subject in one treatment session.
  • a treatment session may be continuous, e.g., uninterrupted parenteral administration (e.g., subcutaneous or intravenous) of a single bolus for a duration of time (e.g., 1 hour, 2 hours).
  • a treatment session can also be divided into two or more subsessions, such that one unit dose is administered over time (e.g., 12 hours, 24 hours) with each bolus followed by a break or recovery time.
  • 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, spinal or epidermal administration (e.g., by injection or infusion).
  • the antibody may be coated in a material to protect the compound from the action of acids and other natural conditions that may inactivate the compound.
  • a "pharmaceutically acceptable salt” refers to a salt that retains the desired biological activity of the parent compound and does not impart any undesired toxicological effects (see e.g., Berge, S.M., et al, J. Pharm. Sci. 66: 1 -19 (1977)). Examples of such salts include acid addition salts and base addition salts.
  • Acid addition salts include those derived from nontoxic inorganic acids, such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like, as well as from nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • nontoxic inorganic acids such as hydrochloric, nitric, phosphoric, sulfuric, hydrobromic, hydroiodic, phosphorous and the like
  • nontoxic organic acids such as aliphatic mono- and dicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoic acids, aromatic acids, aliphatic and aromatic sulfonic acids and the like.
  • Base addition salts include those derived from alkaline earth metals, such as sodium, potassium, magnesium, calcium and the like, as well as from nontoxic organic amines, such as ⁇ , ⁇ '- dibenzylethylenediamine, N-methylglucamine, chloroprocaine, choline, diethanolamine, ethylenediamine, procaine and the like.
  • the present invention includes, in one aspect, a pharmaceutical composition having a therapeutically effective amount of a therapeutic antibody or an antigen-binding fragment thereof (e.g., a human monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof), which can be formulated together with a pharmaceutically acceptable carrier.
  • a therapeutic antibody or an antigen-binding fragment thereof e.g., a human monoclonal antibody that binds IL-15 or an antigen-binding fragment thereof
  • AMG 714 a fully human immunoglobulin (IgGlK) monoclonal antibody (mAb) that binds to interleukin 15 (IL-15), is useful as a treatment for, e.g., celiac disease, gluten-free diet (GFD) non-responsive celiac disease (NRCD), non- celiac gluten sensitivity and Type II refractory celiac disease (RCD-II).
  • IgGlK immunoglobulin monoclonal antibody
  • IL-15 interleukin 15
  • GFD gluten-free diet
  • NRCD non-responsive celiac disease
  • RCD-II Type II refractory celiac disease
  • Interleukin 15 IL-15
  • IL-15 a glycoprotein of approximately 14-15 kDa
  • IL-15 exerts biological effects on many immunologically relevant cells (Fehniger and Caligiuri, 2001). While important differences are present across species, IL-15 generally acts as a development, homeostasis, and activation factor for NK cells and memory phenotype CD8+ T cells, including IELs. It also induces the production of chemokines and cytokines by these cell types. IL-15 potently stimulates the production of pro-inflammatory cytokines such as IL-1, IL-6, and TNF-a by monocytes/macrophages.
  • pro-inflammatory cytokines such as IL-1, IL-6, and TNF-a by monocytes/macrophages.
  • IL-15 produced by follicular dendritic cells is known to support germinal center B cell proliferation and immunoglobulin class switching (Park et al, 2004; Litinskiy et al, 2002).
  • Targeted disruption of either the IL-15 or IL-15Ra genes in mice has been shown to result in the loss of NK, NK-T, T cell receptor gamma delta (TCRy5+) IELs, and memory CD8+ T cells (Lodolce et al, 1998).
  • TCRy5+ T cell receptor gamma delta
  • memory CD8+ T cells Lodolce et al, 1998.
  • IL-15 knockout mice these defects are reversible by the administration of exogenous IL-15 (Kennedy et al, 2000).
  • human NK cells are not entirely dependent on IL-15 (Lebrec et al, 2013).
  • IL-15 messenger RNA is expressed in a wide variety of tissues and cell types. However, expression of IL-15 protein is much more restricted and is subject to multiple post-transcriptional control mechanisms. Sources of IL-15 protein include monocytes, macrophages, epithelial and fibroblastic cells, and bone marrow stromal cells (Fehniger and Caligiuri, 2001). IL-15 and its receptor are also expressed in some organs outside the immune system; the role of IL-15 in these systems is less well understood. The absence of any overt defects outside the immune system in IL-15 and IL-15Ra knockout mice suggests that IL-15 may not be essential in any other system.
  • IL-15 binds to a heterotrimeric receptor that consists of a ⁇ chain that is shared with the IL-2 receptor (CD122 or IL-2/IL-15RP), the common ⁇ chain (yC) shared with IL-2, -4,
  • IL-15 binds with high affinity to the IL-
  • IL-15/IL-15Ra complex with the other two components of the complete receptor complex can occur in a cis configuration, in which all three receptor components are present on the same cell, or in a trans configuration, in which the IL-15/IL-15Ra pair is on one cell and the receptor ⁇ and yC chains are on another (Schluns et al., 2005).
  • IL-15 can also associate with IL-15Ra on the cell surface and then be cleaved into soluble cytokine/receptor complexes that have the potential to stimulate CD8+ T cells and NK cells (Anthony et al, 2015).
  • Increased expression of IL-15 has been demonstrated in a variety of inflammatory conditions, including RA, psoriasis, inflammatory bowel disease, graft-versus-host disease, solid organ transplant rejection (Blaser et al., 2005; Conti et al, 2003; Gianfrani et al, 2005; Mclnnes and Gracie, 2004), and celiac disease (Gianfrani et al., 2005; Meresse et al, 2012).
  • AMG 714 a fully human immunoglobulin (IgGlK) monoclonal antibody, binds to and inhibits the function of IL-15 in all its known forms (cis, trans, soluble IL-15 bound to IL-15 receptor alpha (IL-15Ra)).
  • AMG 714 inhibits IL-15-induced T cell proliferation and shows a dose-dependent inhibition of IL-15-induced tumor necrosis factor alpha (TNF-a) production.
  • TNF-a tumor necrosis factor alpha
  • AMG 714 can be produced by any antibody production methods generally known in the art.
  • AMG 714 may be produced from a B cell hybridoma cell line.
  • AMG 714 can also be produced by a mammalian cell line such as Chinese hamster ovary (CHO) cell line.
  • CHO Chinese hamster ovary
  • the heavy chain C-terminal lysine can be absent from the version produced by CHO cells (Dick Jr. et al, Biotechnol. Bioeng. 2008;100: 1132-1143).
  • AMG 714 was found to recognize an epitope that is essential for the interaction between human IL-15 (hIL-15) and its receptor complex.
  • AMG 714 showed a dose-dependent inhibition of IL-15-induced proliferation of peripheral blood T cells and cell lines expressing IL-15 receptors, as well as a dose-dependent inhibition of hIL- 15 -induced TNF-a production.
  • AMG 714 was found to be efficacious in a mouse model of celiac disease triggered by the transgenic expression of human IL-15 in the gut epithelium. In this model, AMG 714 prevented IEL activation and proliferation, as well as histological abnormalities.
  • AMG 714 was able to induce apoptosis of human IELs in ex vivo culture of small intestinal explants from patients with active celiac disease and RCD-II.
  • AMG 714 Due to low binding potency of AMG 714 for macaque IL-15, the safety profile of AMG 714 has been evaluated in nonclinical studies in non-human primates (NHPs), specifically cynomolgus monkeys, using the surrogate molecule Hu714MuXHu.
  • NHPs non-human primates
  • Hu714MuXHu the inhibition of IL-15 by Hu714MuXHu resulted in reversible NK cell reduction and associated gastrointestinal infections in some animals; however, NK cell depletion has not been observed in humans (Lebrec et al, 2013) and no corresponding gastroenteritis or enteric infections have been reported as a frequent adverse event (AE) in human studies. No other toxicology signals have been observed.
  • NK cell depletion seen in NHPs appears to be related to a difference between human and cynomolgus monkey in the sensitivity of NK cells to IL-15 blockade.
  • Human NK cells are not dependent on IL-15 for their survival, possibly due to the redundant role of IL-2 on human NK cells.
  • AMG 714 has been studied in four clinical trials, including one Phase 1 study in NHV (30 subjects on AMG 714, 10 on placebo, intravenous [IV] and subcutaneous [SC]), one Phase 1 study in RA (29 subjects on AMG 714, no placebo, IV), a Phase lb/2a in psoriasis (14 patients on AMG 714, 6 on placebo, SC), and a Phase 2b study in RA (121 subjects on AMG 714, 58 on placebo, SC). To date, AMG 714 has been well tolerated and its safety profile has been generally comparable to placebo with the exception of injection site reactions, which were more commonly reported in subjects exposed to AMG 714.
  • AMG 714 demonstrated a response in approximately 60% of patients in both Phase 1 and Phase 2 studies versus a response of approximately 30% in the placebo group. AMG 714 also led to decreases in inflammatory biomarkers such as C- reactive protein (CRP) and erythrocyte sedimentation rate (ESR). AMG 714 did not demonstrate a response in clinical trials with psoriasis patients, suggesting AMG 714's action is selective, unlike that of broad systemic immune suppressants.
  • CRP C- reactive protein
  • ESR erythrocyte sedimentation rate
  • AMG 714 has a PK profile consistent with a typical human immunoglobulin Gl antibody with no apparent target-mediated disposition and a half-life of 20 to 22 days. Immunogenicity of AMG 714 has been reported in only one blood sample from one subject in the entire clinical program to date.
  • compositions of the present invention also can be administered in combination therapy, i.e., combined with other agents.
  • the combination therapy can include a composition of the present invention with at least one or more additional therapeutic agents, such as anti-inflammatory agents, DMARDs (disease- modifying anti-rheumatic drugs), immunosuppressive agents, chemotherapeutics, and psoriasis agents.
  • additional therapeutic agents such as anti-inflammatory agents, DMARDs (disease- modifying anti-rheumatic drugs), immunosuppressive agents, chemotherapeutics, and psoriasis agents.
  • the pharmaceutical compositions of the invention can also be administered in conjunction with radiation therapy.
  • Co-administration with other antibodies, such as CD4 specific antibodies and IL-2 specific antibodies are also encompassed by the invention. Such combinations with CD4 specific antibodies or IL-2 specific antibodies are considered particularly useful for treating autoimmune diseases and transplant rejections.
  • a composition of the present invention can be administered by a variety of methods 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.
  • the active compounds can be prepared with carriers that will protect the compound against rapid release, such as a controlled release formulation, including implants, transdermal patches, and microencapsulated delivery systems.
  • Biodegradable, biocompatible polymers can be used, such as ethylene vinyl acetate, polyanhydrides, polygly colic acid, collagen, polyorthoesters, and polylactic acid. Many methods for the preparation of such formulations are generally known to those skilled in the art. See, e.g., Sustained and Controlled Release Drug Delivery Systems, J.R. Robinson, ed., Marcel Dekker, Inc., New York, 1978.
  • the compound may be administered to a subject in an appropriate carrier, for example, liposomes, or a diluent.
  • suitable diluents include saline and aqueous buffer solutions.
  • Liposomes include water- in-oil-in- water CGF emulsions as well as conventional liposomes (Strejan et al, J. Neuroimmunol. 7:27 (1984)).
  • Pharmaceutically acceptable carriers include sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • sterile aqueous solutions or dispersions and sterile powders for the extemporaneous preparation of sterile injectable solutions or dispersion.
  • the use of such media and agents for pharmaceutically active substances is known in the art. Except insofar as any conventional media or agent is incompatible with the active compound, use thereof in the pharmaceutical compositions of the invention is contemplated. Supplementary active compounds can also be incorporated into the compositions.
  • compositions typically must be sterile and stable under the conditions of manufacture and storage.
  • the composition can be formulated as a solution, microemulsion, liposome, or other ordered structure suitable to high drug concentration.
  • the carrier can be a solvent or dispersion medium containing, for example, water, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyethylene glycol, and the like), and suitable mixtures thereof.
  • the proper fluidity can be maintained, for example, by the use of a coating such as lecithin, by the maintenance of the required particle size in the case of dispersion and by the use of surfactants.
  • isotonic agents for example, sugars, polyalcohols such as mannitol, sorbitol, or sodium chloride in the composition.
  • Prolonged absorption of the injectable compositions can be brought about by including in the composition an agent that delays absorption, for example, monostearate salts and gelatin.
  • Sterile injectable solutions can be prepared by incorporating the active compound in the required amount in an appropriate solvent with one or a combination of ingredients enumerated above, as required, followed by sterilization microfiltration.
  • dispersions are prepared by incorporating the active compound into a sterile vehicle that contains a basic dispersion medium and the required other ingredients from those enumerated above.
  • the preferred methods of preparation are vacuum drying and freeze-drying (lyophilization) that yield a powder of the active ingredient plus any additional desired ingredient from a previously sterile-filtered solution thereof.
  • Dosage regimens can be adjusted to provide the optimum desired response (e.g., a therapeutic response). For example, a single bolus may be administered, several divided doses may be administered over time or the dose may be proportionally reduced or increased as indicated by the exigencies of the therapeutic situation.
  • the human antibodies of the invention may be administered once or twice weekly by subcutaneous injection or once or twice monthly by subcutaneous injection.
  • Dosage unit form refers to physically discrete units suited as unitary dosages for the subjects to be treated; each unit contains a predetermined quantity of active compound calculated to produce the desired therapeutic effect in association with the required pharmaceutical carrier.
  • the specification for the dosage unit forms of the invention are dictated by and directly dependent on (a) the unique characteristics of the active compound and the particular therapeutic effect to be achieved, and (b) the limitations inherent in the art of compounding such an active compound for the treatment of sensitivity in individuals.
  • antioxidants examples include: (1) water soluble antioxidants, such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like; (2) oil-soluble antioxidants, such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), lecithin, propyl gallate, alpha-tocopherol, and the like; and (3) metal chelating agents, such as citric acid, ethylenediamine tetraacetic acid (EDTA), sorbitol, tartaric acid, phosphoric acid, and the like.
  • water soluble antioxidants such as ascorbic acid, cysteine hydrochloride, sodium bisulfate, sodium metabisulfite, sodium sulfite and the like
  • oil-soluble antioxidants such as ascorbyl palmitate, butylated hydroxyanisole (BHA), butylated hydroxytoluene (BHT), le
  • formulations of the present invention include those suitable for oral, nasal, topical (including buccal and sublingual), rectal, vaginal and/or parenteral administration.
  • the formulations may conveniently be presented in unit dose form and may be prepared by any methods known in the art of pharmacy.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will vary depending upon the subject being treated, and the particular mode of administration.
  • the amount of active ingredient which can be combined with a carrier material to produce a single dosage form will generally be that amount of the composition which produces a therapeutic effect. Generally, out of one hundred per cent, this amount will range from about 0.001 per cent to about ninety percent of active ingredient, preferably from about 0.005 per cent to about 70 per cent, most preferably from about 0.01 per cent to about 30 per cent.
  • compositions of this invention include powders, sprays, ointments, pastes, creams, lotions, gels, solutions, patches and inhalants.
  • the active compound may be mixed under sterile conditions with a pharmaceutically acceptable carrier, and with any preservatives, buffers, or propellants which may be required.
  • aqueous and nonaqueous carriers examples include water, ethanol, polyols (such as glycerol, propylene glycol, polyethylene glycol, and the like), and suitable mixtures thereof, vegetable oils, such as olive oil, and injectable organic esters, such as ethyl oleate.
  • polyols such as glycerol, propylene glycol, polyethylene glycol, and the like
  • vegetable oils such as olive oil
  • injectable organic esters such as ethyl oleate.
  • Proper fluidity can be maintained, for example, by the use of coating materials, such as lecithin, by the maintenance of the required particle size in the case of dispersions, and by the use of surfactants.
  • These compositions may also contain adjuvants such as preservatives, wetting agents, emulsifying agents and dispersing agents.
  • Prevention of presence of microorganisms may be ensured both by sterilization procedures, supra, and by the inclusion of various antibacterial and antifungal agents, for example, paraben, chlorobutanol, phenol sorbic acid, and the like. It may also be desirable to include isotonic agents, such as sugars, sodium chloride, and the like into the compositions. In addition, prolonged absorption of the injectable pharmaceutical form may be brought about by the inclusion of agents which delay absorption such as aluminum monostearate and gelatin.
  • the compounds of the present invention are administered as pharmaceuticals, to humans and animals, they can be given alone or as a pharmaceutical composition containing, for example, 0.001 to 90% (more preferably, 0.005 to 70%, such as 0.01 to 30%) of active ingredient in combination with a pharmaceutically acceptable carrier.
  • parenteral administration and “administered parenterally” as used herein means modes of administration other than enteral and topical administration, usually by injection, and includes, without limitation, intravenous, intramuscular, intraarterial, intrathecal, intracapsular, intraorbital, intracardiac, intradermal, intraperitoneal, transtracheal, subcutaneous, subcuticular, intraarticular, subcapsular, subarachnoid, intraspinal, epidural and intrastemal injection and infusion.
  • subcutaneous and/or intravenous administration can be used, certain advantages and disadvantages of which are summarized below.
  • the compounds of the present invention which may be used in a suitable hydrated form, and/or the pharmaceutical compositions of the present invention, are formulated into pharmaceutically acceptable dosage forms by conventional methods known to those of skill in the art.
  • compositions of the present invention 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 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, or the ester, salt or amide thereof, the route of administration, the time of administration, the rate of excretion of the particular compound being employed, the duration of the treatment, other drugs, compounds and/or materials used in combination with the particular compositions employed, the age, sex, weight, condition, general health and prior medical history of the patient being treated, and like factors well known in the medical arts.
  • a physician or veterinarian having ordinary skill in the art can readily determine and prescribe the effective amount of the pharmaceutical composition required.
  • the physician or veterinarian could start doses of the compounds of the invention employed in the pharmaceutical composition at levels lower than that required in order to achieve the desired therapeutic effect and gradually increase the dosage until the desired effect is achieved.
  • a suitable daily dose of a composition of the invention will be that amount of the compound which is the lowest dose effective to produce a therapeutic effect.
  • Such an effective dose will generally depend upon the factors described above. It is preferred that administration be intravenous, intramuscular, intraperitoneal, or subcutaneous, preferably administered proximal to the site of the target.
  • the effective daily dose of a therapeutic composition may be administered as two, three, four, five, six or more sub-doses administered separately at appropriate intervals throughout the day, optionally, in unit dose forms. While it is possible for a compound of the present invention to be administered alone, it is preferable to administer the compound as a pharmaceutical formulation (composition).
  • Therapeutic compositions can be administered with medical devices known in the art.
  • a therapeutic composition of the invention can be administered with a needleless hypodermic injection device, such as the devices disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556.
  • a needleless hypodermic injection device such as the devices disclosed in U.S. Patent Nos. 5,399,163, 5,383,851, 5,312,335, 5,064,413, 4,941,880, 4,790,824, or 4,596,556.
  • Examples of well-known implants and modules useful in the present invention include: U.S. Patent No. 4,487,603, which discloses an implantable micro-infusion pump for dispensing medication at a controlled rate; U.S. Patent No. 4., 486, 194, which discloses a therapeutic device for administering medicants through the skin; U.S. Patent No.
  • the therapeutic antibodies of the present invention can be formulated to aid in proper distribution in vivo.
  • the blood-brain barrier (BBB) excludes many highly hydrophilic compounds.
  • BBB blood-brain barrier
  • therapeutic compounds of the invention in crossing the BBB if desired, they can be formulated, for example, in liposomes.
  • liposomes For methods of manufacturing liposomes, see, e.g., U.S. Patents 4,522,811; 5,374,548; and 5,399,331.
  • the liposomes may comprise one or more moieties which are selectively transported into specific cells or organs, thus enhance targeted drug delivery (see, e.g., V.V. Ranade J. Clin. Pharmacol. 29:685 (1989).
  • Exemplary targeting moieties include folate or biotin (see, e.g., U.S. Patent 5,416,016 to Low et al); mannosides (Umezawa et al., Biochem. Biophys. Res. Commun. 153: 1038 (1988)); antibodies (P.G. Bloeman et al., FEBS Lett. 357: 140 (1995); M. Owais et al, Antimicrob. Agents Chemother. 39: 180 (1995)); surfactant protein A receptor (Briscoe et al, Am. J. Physiol.
  • the therapeutic compounds of the present invention can be formulated in liposomes; and the liposomes can include a targeting moiety.
  • the therapeutic compounds formulated in liposomes can be delivered by bolus injection to a site proximal to a tumor or infection.
  • the composition must be fluid to the extent that the composition can be easily drawn into a syringe.
  • the liposome composition can be stable under the conditions of manufacture and storage.
  • the liposome composition can be preserved against the contaminating action of microorganisms such as bacteria and fungi.
  • composition of the present invention can be formulated to prevent or reduce the transport across the placenta. This can be done by methods known in the art, e.g., by PEGylation of the antibody or by use of F(ab)2' fragments. Further references can be made to "Cunningham-Rundles C, Zhuo Z, Griffith B, Keenan J. (1992) Biological activities of polyethylene-glycol immunoglobulin conjugates.” Resistance to enzymatic degradation. J Immunol Methods. 152: 177-190; and to Landor M. (1995) Maternal-fetal transfer of immunoglobulins, Ann Allergy Asthma Immunol 74:279-283.
  • the composition must be sterile and fluid to the extent that the composition is deliverable by syringe.
  • the carrier can be an isotonic buffered saline solution, ethanol, polyol (for example, glycerol, propylene glycol, and liquid polyetheylene glycol, and the like), and suitable mixtures thereof.
  • Proper fluidity can be maintained, for example, by use of coating such as lecithin, by maintenance of required particle size in the case of dispersion and by use of surfactants.
  • the active compound when suitably protected, as described above, the compound may be orally administered, for example, with an inert diluent or an assimilable edible carrier.
  • Celiac disease is a systemic autoimmune disease triggered by gluten consumption in genetically susceptible individuals (Green and Cellier, 2007).
  • US United States
  • EU European Union
  • Celiac was the first autoimmune disease with an identified antigen: gluten, the main protein present in some of the most common cereals (e.g., wheat, barley, rye).
  • Modern diets are increasingly enriched with gluten and it is also used as an additive in processed foods, cosmetics, and oral medications.
  • Gluten is the second most common food ingredient after sugar and, in some countries, is present in up to 80% of foodstuff.
  • Humans lack enzymes to fully digest gluten, which, in the right genetic context (i.e., the presence of HLA-DQ2/8, Thl -prone immune system), triggers inflammation and autoimmunity in the gut and other organs following deamidation by the enzyme transglutaminase (tTG), which itself becomes a target for auto-antibodies.
  • tTG transglutaminase
  • IL-15 is believed to be a key mediator in both the adaptive immune response, leading to extra-intestinal manifestations, and the innate immune response, leading to intestinal mucosal atrophy and gastrointestinal symptoms.
  • Celiac disease causes debilitating symptoms and potentially serious medical complications.
  • gastrointestinal symptoms derived from gut mucosal damage dominate the patient-reported symptoms at diagnosis.
  • the normal villi aborptive finger-like prolongations
  • the intestinal crypt depth CD
  • VH:CD ratio is one of the main descriptors of the severity of celiac disease (Taavela et al, 2013).
  • celiac disease is the only common autoimmune disorder with no approved medication.
  • the only available strategy for the management of celiac disease is a lifelong total avoidance of gluten. While simple in theory, in practice, the ubiquity of gluten in foodstuffs, medications, household substances, cosmetics, and even gluten-free items makes total avoidance of gluten difficult, if not impossible.
  • the main challenge to the successful maintenance of a gluten free diet is that cereal flours are widely used in the food industry and are present in most food products either naturally or as additives.
  • gluten-free products can be purchased, commercially manufactured gluten-free products may be difficult to find, tend to be less flavorful, and are more expensive than regular gluten-containing foods, which can sometimes deter patients from adhering to a GFD.
  • many countries are deficient in the appropriate labeling of food products. Even in countries with superior labeling guidelines, foods labeled "gluten-free" may nevertheless contain gluten. For example, in northern European countries, gluten amounts of up to 100 parts per million (ppm) are permitted in gluten-free products designated for celiac sufferers (Gibert et al, 2006).
  • NRCD has been defined as "persistent symptoms, signs or laboratory abnormalities typical of celiac disease, despite 6-12 months of dietary gluten avoidance" (Rubio-Tapia et al, 2013).
  • Substantial experimental data support multiple actions of IL-15 in the pathophysiology of CD and RCD (Abadie and Jabri et al, 2014) as illustrated in FIG. 5.
  • IL-15 is an essential, non-redundant growth and activation factor for the IELs which destroy the intestinal mucosa.
  • the expression of IL-15 in the intestinal epithelium is necessary for villous atrophy.
  • IL-15 drives progression towards lymphomagenesis and potentially fatal RCD-II (Malamut et al, 2010).
  • IL-15 mediates the adaptive immune response as well.
  • IL-15 enhances the presentation of deami dated gluten peptides (DGP) by antigen-presenting cells (APCs).
  • APCs antigen-presenting cells
  • IL-15 renders the activated CD4+ T cells resistant to inhibition by regulatory T cell.
  • IL-15 is believed to be the main mediator in the mucosal damage that ensues in response to gluten exposure in celiac disease (Korneychuk et al., 2014).
  • the expression of IL-15 in the intestinal epithelium is necessary for villous atrophy in animal models of celiac disease and circumstantial evidence suggests this to be the case in humans as well.
  • IL-15 renders effector T cells resistant to inhibition by regulatory T cells (T reg ) (Abadie and Jabri 2014), promoting the loss of tolerance to food antigens (DePaolo et al, 2011; Korneychuk et al, 2014).
  • One of the mouse models of celiac disease is an IL-15-transgenic mouse, in which IL-15 overexpression by gut epithelial cells leads to celiac-like presentations, including T and B cell-mediated pathology (Yokoyama et al., 2009 and 2011). IEL apoptosis has been observed in this animal model after treatment with the anti-IL-15 mAb AMG 714 (Malamut et al, 2010) or anti-IL-15R mAbs (Yokoyama et al, 2009). IL-15 has been proven to be a key factor in the loss of tolerance to food antigens (DePaolo et al, 2011 ; Korneychuk, et al, 2014).
  • Non-celiac gluten sensitivity or non-celiac gluten sensitivity has been proposed to refer to the spectrum of conditions reported by these patients (Lundin and Alaedini, 2012).
  • Non-celiac gluten sensitivity is currently understood as a condition associated with the experiencing of various symptoms in response to ingestion of foods containing wheat, rye, and barley, and the resolution of symptoms on removal of those foods from diet in individuals in whom CD and wheat allergy have been ruled out (Lundin and Alaedini, 2012).
  • the symptoms may be accompanied with an increase in levels of antibody to gluten.
  • the majority of symptoms associated with NCGS are subjective, including abdominal pain, headache, "brain fog,” tingling and/or numbness in hands and feet, fatigue, and musculoskeletal pain.
  • other symptoms such as rash and diarrhea, as well as more severe neurologic and psychiatric conditions including schizophrenia and cerebellar ataxia, have also been reported to be associated with NCGS.
  • the present invention provides methods and compositions for treating celiac disease or non-celiac gluten sensitivity by administering a therapeutically effective amount of an anti-IL-15 antibody or antigen-binding fragment thereof disclosed herein.
  • a therapeutically effective amount of the anti-IL-15 antibody or antigen- binding fragment thereof can achieve, e.g., for the treatment of CD or NCGS one or more of, (1) attenuation of gluten-induced small intestinal mucosal morphological injury, (2) reduction of villous height to crypt depth (VH:CD) ratio, (3) attenuation of gluten-induced small intestinal mucosal inflammation measured as intraepithelial lymphocyte (IELs) density, (4) attenuation of gluten-induced small intestinal mucosal morphological injury using a grouped classification of Marsh score, (5) attenuation of gluten-induced serum antibodies by measuring of anti-tissue transglutaminase antibodies (anti-tTG IgA) and anti- deamidated gliadin peptide (anti
  • NCGS NCGS Additional endpoints for NCGS include an ad-hoc list of symptoms (Di Sabatino et al, Clinical Gastroenterology and Hepatology 2015;13: 1604-1612) or a severity patient- reported outcome like a visual analogue scale (VAS) (Elli et al, Nutrients 2016, 8, 84; doi: 10.3390/nu8020084).
  • VAS visual analogue scale
  • the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 50-1000 mg of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof.
  • the unit dose can be: about 50- 100 mg, about 100-150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg, about 500- 550 mg, about 550-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg or about 900-1000 mg, or higher or lower, or any numerical value therebetween, of the anti- IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
  • the amount or unit dose can be: about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-110 mg, about 110-120 mg, about 120-130 mg, about 130-140 mg, about 140-150 mg, about 150-160 mg, about 160-170 mg, about 170-180 mg, about 180-190 mg, about 190-200 mg, about 200-210 mg, about 210-220 mg, about 220-230 mg, about 230-240 mg, about 240-250 mg, about 250- 260 mg, about 260-270 mg, about 270-280 mg, about 280-290 mg, about 290-300 mg, about 300-310 mg, about 310-320 mg, about 320-330 mg, about 330-340 mg, about 340- 350 mg, about 350-360 mg, about 360-370 mg, about 370-380 mg, about 380-390 mg, about 390-400 mg, about 400-410 mg, about 410-420 mg, about
  • the amount or unit dose can be: about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385
  • the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 1 -50 mg/kg (patient weight) of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof.
  • the unit dose can be: about 1 -10 mg/kg, about 10-20 mg/kg, about 20-30 mg/kg, about 30-40 mg/kg, or about 40-50 mg/kg, or higher or lower, or any numerical value therebetween, of the anti-IL- 15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
  • the amount or unit dose can be: about 1-5 mg/kg, about 5-10 mg/kg, about 10-15 mg/kg, about 15-20 mg/kg, about 20-25 mg/kg, about 25-30 mg/kg, about 30-35 mg/kg, about 35-40 mg/kg, about 40-45 mg/kg, or about 45-50 mg/kg.
  • a preferred dosage can include: about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 1 1, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, or about 50 mg/kg, of the anti- IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
  • the anti- IL-15 antibody e.g., AMG 714
  • each subject can receive at least one (e.g., 1 -100) unit dose disclosed herein, depending on the severity of the disease and/or effectiveness of the treatment.
  • the subj ect may receive 2-20 unit doses which can be the same or different (e.g., one or more initial unit doses can be smaller or larger than later unit dose(s)) from one another.
  • the pharmaceutical compositions disclosed herein can be administered, in unit doses disclosed herein, by subcutaneous or intravenous injection every 1-20 weeks.
  • the pharmaceutical composition is administered subcutaneously.
  • the pharmaceutical composition is administered intravenously.
  • administration can occur every 1 -5, 5-10, 10-15, or 15-20 weeks.
  • administration can occur every 1 -2, 2-4, 4-6, 6-8, 8- 10, 10-12, 12-14, 14-16, 16-18, or 18-20 weeks.
  • administration can occur every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks.
  • the unit doses can be given at the same intervals (e.g., every 1 -20 weeks). Alternatively, at least a portion of the unit doses are given at different (e.g., shortened or prolonged) intervals than the other unit doses.
  • the present invention relates to a pharmaceutical composition, as described herein, for use in treating celiac or non-celiac gluten sensitivity, wherein the pharmaceutical composition comprises an anti-IL-15 antibody (e.g., AMG 714).
  • the pharmaceutical composition comprises 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714).
  • the pharmaceutical composition comprises 150 mg or 300 mg of an anti-IL- 15 antibody (e.g., AMG 714).
  • the pharmaceutical composition is administered subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms.
  • the pharmaceutical composition is administered subcutaneously every 2 weeks. In another particular embodiment, the pharmaceutical composition is administered intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the pharmaceutical composition is administered intravenously every 2 weeks.
  • the present invention relates to a pharmaceutical composition, as described herein, for use in a method of treating celiac or non-celiac gluten sensitivity, wherein the method comprises administering (e.g., subcutaneously) an anti-IL-15 antibody (e.g., AMG 714).
  • the method comprises administering (e.g., subcutaneously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714).
  • the method comprises administering (e.g., subcutaneously) 150 mg or 300 mg of an anti-IL-15 antibody (e.g., AMG 714).
  • the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the method comprises administering subcutaneously every 2 weeks. In another particular embodiment, the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the method comprises administering intravenously every 2 weeks.
  • the present invention relates to a method of treating celiac or non- celiac gluten sensitivity, wherein the method comprises administering (e.g., subcutaneously) an anti-IL-15 antibody (e.g., AMG 714).
  • the method comprises administering (e.g., subcutaneously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714).
  • the method comprises administering (e.g., subcutaneously) 150 mg or 300 mg of an anti-IL-15 antibody (e.g., AMG 714).
  • the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the method comprises administering subcutaneously every 2 weeks. In another particular embodiment, the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the method comprises administering intravenously every 2 weeks.
  • 150 or 300 mg of an anti-IL 15 antibody (e.g., AMG 714) is administered once every 2 weeks (q2w) via subcutaneous injection.
  • RCD refractory celiac disease
  • RCD patients can be further classified according to the proportion and characteristics of aberrant IELs. Patients with a low proportion of aberrant IELs, defined as less than 20% of total IELs (less than 20 IELs per 100 epithelial cells), as determined by flow cytometry, are referred to as Type I RCD (RCD-I). These aberrant IELs are generally polyclonal, and RCD-I patients are not at increased risk of developing overt extra epithelial lymphoma (i.e., enteropathy-associated T cell lymphoma [EATL]) and have a typical 5-year survival (vanWanrooij et al, 2014).
  • TTL enteropathy-associated T cell lymphoma
  • FIG. 3 illustrates the pathophysiology of celiac and refractory celiac disease, as described by Schuppan et al.
  • RCD-II Type II RCD
  • the IELs are typically monoclonal and the risk of developing EATL is dramatically increased to greater than 50% (Nijeboer et al., 2015).
  • the aberrant IELs proliferate in the absence of gluten due to accumulation of anti- apoptotic mechanisms, hence the term "refractory" indicating that the disease, a non- Hodgkin slow-growing intraepithelial lymphoma, appears not to be dependent on gluten since it is not responsive to the strictest GFD. As illustrated in FIG.
  • IL-15 is believed to be the main driver of transformation and maintenance of the aberrant IELs (Meresse et al, 2012).
  • Experimental proof of principle has been established for IL-15 inhibition in RCD-II by the finding that blocking IL-15 with the anti-IL-15 mAb AMG 714 induces IEL apoptosis in human small bowel biopsies from active celiac and RCD-II patients (Malamut et al, 2010).
  • IEL apoptosis has been observed in animal models of celiac disease treated with anti-IL-15 AMG 714 (Malamut et al, 2010) or anti-IL-15-receptor mAbs (Yokoyama et al., 2009).
  • the aberrant monoclonal IELs have been demonstrated to be precursors of EATL based on the observation that the T cell receptor (TCR) re-arrangement repertoire is similar in sequential biopsies from RCD-II patients who develop EATL.
  • RCD-II is considered to be an in situ low-grade T cell lymphoma of the small bowel.
  • a thorough study of the low grade IEL proliferation in RCD-II has revealed a characteristic phenotype with the presence of intracellular CD3 without surface CD3 or TCR and generally no CD8 expression with expression of CD103, which is shared by high grade EATL proliferations.
  • This phenotype is distinct from the normal phenotype of IELs in uncomplicated celiac disease and, together with the common presence of a clonal TCR re-arrangement in the intestinal biopsy, confirms the diagnosis of RCD and allows follow-up of the expansion.
  • RCD-II The treatment of RCD-II is difficult as aberrant lymphocytes are scattered throughout the whole small intestinal epithelium and, usually, in the stomach and colon, thereby precluding surgery. In addition, there is no standard of care for RCD-II. Attempts of chemotherapies have been mostly ineffective and/or dangerous for patients. Cladribine (Tack et al, 2011a; Tack et al, 2011b) and autologous bone marrow transplantation have been used and shown to transiently improve the digestive symptoms and histology but not monoclonal proliferation. The prognosis of RCD-II is poor, with death occurring within 3- 10 years mainly due to intractable diarrhea, EATL, or the rare dissemination of low grade lymphocyte proliferation to other tissues (e.g., skin, lungs).
  • EATL is a high-grade, systemic, T cell lymphoma almost exclusively seen as a complication of RCD-II (Nijeboer et al, 2015). Diagnosis includes imaging and histology to demonstrate the presence of malignant T cells in extra-epithelial locations such as lymph nodes or other organs. The treatment of EATL relies on surgical resection and chemotherapy, but the prognosis is very poor, with a 5-year survival of less than 20% (Nijeboer et al, 2015).
  • the present invention provides methods and compositions for treating Type I or
  • Type II Refractory Celiac Disease by administering a therapeutically effective amount of an anti-IL-15 antibody (e.g., AMG 714) or antigen-binding fragment thereof disclosed herein.
  • an anti-IL-15 antibody e.g., AMG 714
  • AMG 714 antigen-binding fragment thereof disclosed herein.
  • a therapeutically effective amount of the anti-IL-15 antibody e.g., a therapeutically effective amount of the anti-IL-15 antibody (e.g., a therapeutically effective amount of the anti-IL-15 antibody (e.g., a therapeutically effective amount of the anti-IL-15 antibody (e.g., a therapeutically effective amount of the anti-IL-15 antibody (e.g., a therapeutically effective amount of the anti-IL-15 antibody (e.g.,
  • AMG 7114 or antigen-binding fragment thereof can achieve, e.g., for the treatment of RCD-
  • I or RCD-II one or more of, (1) a measure of the immunological response by quantification of the reduction from baseline in the % of aberrant intestinal intraepithelial lymphocytes
  • IELs vs. total IELs as assessed by flow-cytometry
  • the measure of the immunological response by quantification of the reduction from baseline in the % of aberrant IELs vs. intestinal epithelial cells
  • histological response Improvement from baseline in small intestinal villous height to crypt depth (VH:CD) ratio, Marsh score or total IEL counts
  • clinical response Change from baseline in clinical symptoms by the Bristol Stool Form Scale (BSFS) and Gastrointestinal Symptom Rating Scale (GSRS), including the celiac disease GSRS (CeD-GSRS).
  • BSFS Bristol Stool Form Scale
  • GSRS Gastrointestinal Symptom Rating Scale
  • the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 1-50 mg/kg (patient weight) of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof.
  • the unit dose can be: about 1-10 mg/kg, about 10-20 mg/kg, about 20-30 mg/kg, about 30-40 mg/kg, or about 40-50 mg/kg, or higher or lower, or any numerical value therebetween, of the anti-IL- 15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
  • the amount or unit dose can be: about 1-5 mg/kg, about 5-10 mg/kg, about 10-15 mg/kg, about 15-20 mg/kg, about 20-25 mg/kg, about 25-30 mg/kg, about 30-35 mg/kg, about 35-40 mg/kg, about 40-45 mg/kg, or about 45-50 mg/kg.
  • a preferred dosage can include: about 2, about 3, about 4, about 5, about 6, about 7, about 8, about 9, about 10, about 11, about 12, about 13, about 14, about 15, about 16, about 17, about 18, about 19, about 20, about 21, about 22, about 23, about 24, about 25, about 26, about 27, about 28, about 29, about 30, about 31, about 32, about 33, about 34, about 35, about 36, about 37, about 38, about 39, about 40, about 41, about 42, about 43, about 44, about 45, about 46, about 47, about 48, about 49, or about 50 mg/kg, of the anti- IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
  • the anti- IL-15 antibody e.g., AMG 714
  • the amount or unit dose of the pharmaceutical compositions disclosed herein can include about 50-1000 mg of the anti-IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof.
  • the unit dose can be: about 50- 100 mg, about 100-150 mg, about 150-200 mg, about 200-250 mg, about 250-300 mg, about 300-350 mg, about 350-400 mg, about 400-450 mg, about 450-500 mg, about 500- 550 mg, about 550-600 mg, about 600-700 mg, about 700-800 mg, about 800-900 mg or about 900-1000 mg, or higher or lower, or any numerical value therebetween, of the anti- IL-15 antibody (e.g., AMG 714) or antigen-biding fragment thereof disclosed herein.
  • the amount or unit dose can be: about 50-60 mg, about 60-70 mg, about 70-80 mg, about 80-90 mg, about 90-100 mg, about 100-110 mg, about 110-120 mg, about 120-130 mg, about 130-140 mg, about 140-150 mg, about 150-160 mg, about 160-170 mg, about 170-180 mg, about 180-190 mg, about 190-200 mg, about 200-210 mg, about 210-220 mg, about 220-230 mg, about 230-240 mg, about 240-250 mg, about 250- 260 mg, about 260-270 mg, about 270-280 mg, about 280-290 mg, about 290-300 mg, about 300-310 mg, about 310-320 mg, about 320-330 mg, about 330-340 mg, about 340- 350 mg, about 350-360 mg, about 360-370 mg, about 370-380 mg, about 380-390 mg, about 390-400 mg, about 400-410 mg, about 410-420 mg, about
  • the amount or unit dose can be: about 50, about 55, about 60, about 65, about 70, about 75, about 80, about 85, about 90, about 95, about 100, about 105, about 110, about 115, about 120, about 125, about 130, about 135, about 140, about 145, about 150, about 155, about 160, about 165, about 170, about 175, about 180, about 185, about 190, about 195, about 200, about 205, about 210, about 220, about 225, about 230, about 235, about 240, about 245, about 250, about 255, about 260, about 265, about 270, about 275, about 280, about 285, about 290, about 295, about 300, about 305, about 310, about 315, about 320, about 325, about 330, about 335, about 340, about 345, about 350, about 355, about 360, about 365, about 370, about 375, about 380, about 385
  • each subject can receive at least one (e.g., 1-100) unit dose disclosed herein, depending on the severity of the disease and/or effectiveness of the treatment.
  • the subj ect may receive 2-20 unit doses which can be the same or different (e.g., one or more initial unit doses can be smaller or larger than later unit dose(s)) from one another.
  • the pharmaceutical compositions disclosed herein can be administered, in unit doses disclosed herein, by subcutaneous or intravenous injection every 1-20 weeks.
  • the pharmaceutical composition is administered subcutaneously.
  • the pharmaceutical composition is administered intravenously.
  • administration can occur every 1 -5, 5-10, 10-15, or 15-20 weeks.
  • administration can occur every 1 -2, 2-4, 4-6, 6-8, 8- 10, 10-12, 12-14, 14-16, 16-18, or 18-20 weeks.
  • administration can occur every 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11 , 12, 13, 14, 15, 16, 17, 18, 19, or 20 weeks.
  • the unit doses can be given at the same intervals (e.g., every 1 -20 weeks).
  • At least a portion of the unit doses are given at different (e.g., shortened or prolonged) intervals than the other unit doses.
  • one or more additional loading doses can be given at, e.g., week 1 or any other time to boost the dosage.
  • the present invention relates to a pharmaceutical composition, as described herein, for use in treating Type II refractory celiac disease patients, e.g., patients with in situ small bowel T Cell lymphoma, wherein the pharmaceutical composition comprises an anti-IL-15 antibody (e.g., AMG 714).
  • the pharmaceutical composition comprises 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714).
  • the pharmaceutical composition comprises 8 mg/kg of AMG 714.
  • the pharmaceutical composition is administered (e.g., intravenously) every 1 , 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms.
  • pharmaceutical composition is administered (e.g., intravenously) every 2 weeks.
  • pharmaceutical composition is administered subcutaneously every 1 , 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms.
  • the pharmaceutical composition is administered subcutaneously every 2 weeks.
  • the present invention relates to a pharmaceutical composition, as described herein, for use in a method of treating Type II refractory celiac disease patients e.g., patients with in situ small bowel T Cell lymphoma, wherein the method comprises administering (e.g., intravenously) an anti-IL-15 antibody (e.g., AMG 714). In some embodiments, the method comprises administering (e.g., intravenously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti-IL-15 antibody (e.g., AMG 714).
  • an anti-IL-15 antibody e.g., AMG 714
  • the method comprises administering (e.g., intravenously) 8 mg/kg of an anti-IL-15 antibody (e.g., AMG 714).
  • the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms.
  • the method comprises administering subcutaneously every 2 weeks.
  • the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms.
  • the method comprises administering intravenously every 2 weeks.
  • the present invention relates to a method of treating Type II refractory celiac disease patients or patients with in situ small bowel T Cell lymphoma, wherein the method comprises administering (e.g., intravenously) an anti-IL-15 antibody (e.g., AMG 714).
  • the method comprises administering (e.g., intravenously) 75 mg, 150 mg, 300 mg, 600 mg, 4 mg/kg, 8 mg/kg or 12 mg/kg of an anti- IL-15 antibody (e.g., AMG 714).
  • the method comprises administering (e.g., intravenously) 8 mg/kg of an anti-IL-15 antibody (e.g., AMG 714).
  • the method comprises administering the pharmaceutical composition subcutaneously every 1, 2 or 4 weeks, until, e.g., alleviation or elimination of signs and/or symptoms. In one embodiment, the method comprises administering subcutaneously every 2 weeks. In another particular embodiment, the method comprises administering intravenously every 1, 2 or 4 weeks until, e.g., alleviation or elimination of signs and/or symptoms. In another particular embodiment, the method comprises administering intravenously every 2 weeks.
  • 8 mg/kg of an anti-IL-15 antibody e.g., AMG 714
  • 8 mg/kg of an anti-IL 15 antibody is administered intravenously at week 0, week 1, and once every 2 weeks (q2w) thereafter.
  • Example 1 Phase 2a, Randomized, Double-Blind, Placebo-Controlled, Parallel-Group Study to Evaluate Efficacy and Safety of AMG714 in Adult Patients with Celiac Disease
  • AMG 714 can be administered to adult patients with CD.
  • the primary objective of this study is to assess the efficacy of AMG 714 in attenuating the effects of gluten exposure in adults with CD.
  • the secondary objective is to assess the safety and tolerability of AMG 714 when administered to adult patients with celiac disease exposed to a gluten challenge.
  • the exploratory objectives are to assess the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD correlations of AMG 714.
  • VH:CD is the morphometric measure of the length of the small intestinal villi with respect to the depth of the crypts.
  • GSRS Gastrointestinal Symptom Rating Scale
  • the protocol is designed to be a Phase 2a, randomized, double-blind, placebo- controlled, parallel -group study to evaluate the efficacy and safety of AMG 714 for the attenuation of the effects of gluten exposure in adult patients with celiac disease during a gluten challenge.
  • All study subjects can undergo upper gastrointestinal endoscopy and biopsy prior to baseline (Visit 1, Week 0/Day 0) and at the end of the 12-week study period while still on the gluten challenge and within 5 days before Visit 7 (Week 12/Day 84) in order to assess changes from baseline in VH:CD ratio, IELs, and Marsh score.
  • Safety will be monitored on an ongoing basis and subjects may undergo unscheduled visits if needed for safety reasons. Safety will be assessed throughout the study by clinical laboratory tests, physical examination, vital signs, and AE monitoring.
  • the selection of dosing levels for the celiac disease study is 150 and 300 mg once every 2 weeks (q2w) via subcutaneous injection (SC). While there is no prior experience with AMG 714 in celiac disease nor any understanding of the potential PK/PD relationship in this disease, toxicology and human studies to date support the dosing regimen selected for this study. The highest doses of AMG 714 studied in previous clinical trials were a single SC dose of 700 mg and SC doses of 300 mg every two weeks for 12 weeks, with no safety signals identified to date.
  • the dosing regimen is expected to provide trough levels above the concentration of AMG 714 used in vitro (10 ⁇ g/mL) to induce apoptosis of activated IELs in biopsies of patients with active celiac disease (Malamut et al, 2010).
  • Serum exposure can be monitored with frequent PK sampling. Tissue effects can be monitored with experimental biomarkers to be measured in the biopsies to be obtained throughout the study.
  • Example 2 Phase 2a Study to Evaluate Efficacy and Safety of AMG 714 in Adult Patients with Type II Refractory Celiac Disease
  • AMG 714 can be studied in adult patients with Type II Refractory Celiac Disease.
  • the primary objective of this study will be to assess the efficacy of AMG 714 in treating RCD-II in adult patients.
  • the secondary object of this study will be to assess the safety and tolerability of AMG 714 when administered to adult patients with RCD-II.
  • the exploratory objectives of this study will be to assess the pharmacokinetics (PK), pharmacodynamics (PD), and PK/PD correlations of AMG 714.
  • Primary outcome/endpoint measures include immunological response, e.g., reduction from baseline in the % of aberrant small bowel intestinal intraepithelial lymphocytes (surface CD3- intracellular CD3+).
  • Time Frame Baseline and 12 weeks. Reduction from baseline in the % of aberrant intestinal intraepithelial lymphocytes can be measured by, e.g., flow cytometry after small intestinal biopsy collection.
  • Histological response Improvement from baseline in small intestinal morphology as measured by the Villous Height to Crypt Depth (VH:CD) ratio in intestinal biopsy material.
  • Time Frame Baseline and 12 weeks.
  • Clinical response Change from baseline in clinical symptoms as measured by the Gastrointestinal Symptom Rating Scale (GSRS).
  • GSRS Gastrointestinal Symptom Rating Scale
  • outcome/endpoint measures include safety and tolerability: Number of participants with treatment-related adverse events as assessed by Common Terminology Criteria for Adverse Events (CTCAE). Time Frame: 12 weeks. The frequency and nature of adverse events can be collected and analyzed.
  • the protocol is designed to be a Phase 2a randomized, double-blind, placebo- controlled, parallel group study to evaluate the efficacy and safety of AMG 714 for the treatment of adult patients with RCD-II.
  • All subjects who meet the study entry criteria can be randomized at a 2: 1 ratio to receive either 8 mg/kg AMG 714 or placebo every 2 weeks for a total of 7 times over 10 weeks, with evaluation of the primary endpoint at Week 12.
  • AMG 714 or placebo can be administered at the clinical site in a double-blind fashion via intravenous (IV) infusion over 120 minutes.
  • the final study dose will be administered at Visit 7 (Week 10/Day 70).
  • An end-of- study efficacy visit will be conducted at Visit 8 (Week 12/Day 84).
  • the final study visit will be conducted 6 weeks after the last dose of study drug at Visit 9 (Week 16/Day 112).
  • All study subjects can undergo upper gastrointestinal endoscopy with mucosal biopsy prior to baseline (i.e., prior to Visit 1, Week 0/Day 0) and within 7 days of Visit 8 (Week 12/Day 84) in order to assess changes from baseline in aberrant and abnormal IELs, VH:CD ratio, TCR clonality, Marsh score and total IEL counts.
  • Safety can be monitored on an ongoing basis and subjects may undergo unscheduled visits for safety reasons, if needed. Safety will be assessed throughout the study by clinical laboratory tests, physical examination, vital sign and AE monitoring.
  • the proposed dose of 8 mg/kg IV for 10 weeks, once every 2 weeks (q2w) with an extra dose at week 1, can account for the presumed protein-losing enteropathy typical of RCD-II (up to 40% protein loss can be expected based on albumin levels in RCD-II patients) and for the larger target organ area (small bowel as compared to more localized joints).

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AU2016411388A1 (en) 2018-11-08
BR112018076287A2 (pt) 2019-03-26
TW202327653A (zh) 2023-07-16
JP2022001577A (ja) 2022-01-06
MX2024001374A (es) 2024-02-27
MX2018015363A (es) 2019-04-15
WO2017217985A1 (en) 2017-12-21
AU2024205264A1 (en) 2024-08-22
EA201892707A1 (ru) 2019-05-31
CA3020894A1 (en) 2017-12-21
JP2019521981A (ja) 2019-08-08
TW201803591A (zh) 2018-02-01
AR108790A1 (es) 2018-09-26

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